JP2007517543A - Polymer compounds and their use - Google Patents

Abstract

Compositions comprising fibrosis inhibitors and / or polymeric compounds prevent the formation of surgical adhesions, treat inflammatory arthritis, treat scars and keloids, treat vascular diseases, and prevent cartilage loss It can be applied to various medical treatments including In one embodiment, the present invention provides a composition comprising both a fiber formation inhibitor and a polymer or prepolymer (ie, a compound that forms a polymer). In one embodiment, these compositions are formed in situ when the precursor is delivered to a site in the body or site of the implant.

Description

(Background of the Invention)
The present invention generally relates to polymeric compounds, including therapeutic agents (eg, fibrogenesis inhibitors or anti-infective agents) and methods of making and using such compounds.

(Description of related technology)
Polymer compounds, particularly polymer compounds comprising synthetic polymers or combinations of synthetic and naturally occurring polymers, have been used in a variety of medical applications, such as as surgical adhesives, human tissue engineering, and bioadhesive material prevention . Patent Document 1 describes the use of collagen and synthetic polymer conjugates prepared by covalently binding collagen to synthetic hydrophilic polymers such as various polyethylene glycol derivatives. Related Patent Document 2 describes various active polyethylene glycols and various linkages that can be used for the production of collagen and synthetic polymer conjugates having various physical and chemical properties. Related Patent Document 3 also describes a synthetic hydrophilic polyethylene glycol conjugate, and the conjugate includes a naturally occurring polymer such as a polysaccharide. Patent Document 4 discloses a crosslinkable biological composition prepared using a hydrophobic crosslinker or a mixture of a hydrophilic and a hydrophobic crosslinker. In Patent Document 5, there is a description of a bioadhesive made of collagen and crosslinked using a multifunctional activated synthetic hydrophilic polymer. A composition useful for the prevention of surgical adhesives consisting of a matrix material and an adhesive bond inhibitor is disclosed in US Pat. No. 6,037,086 (U.S. Patent Application No. 08 / 403,360, filed March 14, 1995). Here, the substrate material is made of collagen, and the binding material is made of at least one tissue reaction functional group and at least one substrate reaction functional group. A bioadhesive composition consisting of crosslinkable collagen using a multifunctionally activated synthetic hydrophilic polymer and a method for achieving adhesion of the first and second surfaces using such a composition is patented Document 5 (US Patent Application No. 08 / 476,825 (filing date: June 7, 1995)). Here, the first surface and the second at least one may be a natural tissue surface. Patent Document 7 describes a crosslinkable polymer composition comprising one composition having a plurality of nucleophilic groups and another composition having a plurality of electrophilic groups. Covalent bonding of nucleophilic and electrophilic groups forms a three-dimensional substrate with a variety of medical applications, including tissue adhesion, synthetic graft surface coating, and drug delivery. Recent developments include the addition of a third composition having a nucleophilic group or an electrophilic group, as described in US Pat. U.S. Patent Nos. 6,099,028 and 5,099,9 disclose in situ crosslinked or crosslinked polymers, particularly poly (ethylene glycol) based polymers, to produce crosslinked compositions. Reference Non-Patent Document 1, Poloxamer discloses prevention of post-surgical adhesion using photopolymerized polyethylene glycol-co-lactic acid diacrylate hydrogel and physically cross-linked polyethylene glycol-co-polypropylene glycol hydrogel 407 (BASF Corporation, Mount Olive, NJ). The polymerizable cyanoacrylate has also been described for use as a tissue adhesive (Non-Patent Document 2). Two-part synthetic polymer compositions have been described that, when mixed, not only bind covalent bonds to each other, but also form exposed tissue surfaces (US Pat. Application No. 08 / 769,806 corresponds to Patent Document 7).
U.S. Pat.No. 5,162,430 U.S. Pat.No. 5,328,955 U.S. Pat.No. 5,324,775 European Patent No. 732109 U.S. Pat.No. 5,614,587 U.S. Pat.No. 5,580,923 U.S. Patent No. 5,874,500 U.S. Patent 6,458,889 US Patent No. 6,051,648 U.S. Patent No. 6,312,725 International Application Publication No. 97/22371 Pamphlet Westand Hubbell, Biomaterials (1995) 16: 1153-1156 Ellis et al., J. Otolaryngol. (1990) 19: 68-72

(Summary of Invention)
Briefly, in one embodiment, the present invention provides a composition comprising both a fiber formation inhibitor and a polymer or prepolymer (ie, a compound that forms a polymer). In one embodiment, these compositions are formed in situ when the precursor is delivered to a site in the body or site of the implant. For example, the composition of the present invention includes a cross-linking reaction product, and two compounds (a multifunctional polynucleophilic compound and a multifunctional polyelectrophilic compound) are host (in other words, a patient) in which a fibrous inhibitor exists. It is formed when it reaches the site. However, the compositions of the present invention also include a mixture of a fiber formation inhibitor and a polymer that can be used in a patient's body to achieve beneficial effects (e.g., beneficial effects described herein). Can be delivered to any site.

  In some embodiments, the polymer itself is useful in a variety of ways, including prevention of surgical adhesions.

  In another aspect, the present invention also provides a method for treating and / or preventing surgical adhesions. Surgical bonding is, for example, gynecological surgery, abdominal surgery, heart surgery, orthopedic surgery, reconstruction surgery. It can also be the result of spinal or neurosurgery such as cosmetic surgery.

  In another aspect, the present invention provides a method for the treatment or prevention of inflammatory arthritis, such as osteoarthritis and indirect rheumatism. The method also includes delivering a fibrosis inhibitor (optionally with the polymer) to a patient in need.

  In another aspect, the present invention provides for prevention of cartilage loss that may occur after, for example, indirect injury. The method also includes delivering the fibrosis inhibitor indirectly to the patient in need (optionally with the polymer).

  In another aspect, the present invention also provides a method for treating hypertrophic scars and keloids. The method also includes delivering a fibrosis inhibitor (optionally with a polymer) to a patient's scar or keloid in need.

  In another aspect, the present invention also provides a method of treating a vascular disease such as, for example, stenosis, restenosis or atherosclerosis. The method includes delivery of a fibrosis inhibitor around the blood vessel.

  In another aspect, the present invention also provides a method of implanting a medical device comprising: (a) a medical procedure i) a fibrosis inhibitor, ii) an anti-infective agent, iii) a polymer, iv) a fibrosis inhibitor. V) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer, or transplanted into a host tissue. Immersion, and (b) implantation of the medical device into the host.

  Depending on the situation, in another aspect, the invention provides the following: a method of implanting a medical device comprising: (a) the medical device is implanted with a fibrosis inhibitor or of a transplanted host Immersion in the tissue, and (b) implantation of the medical device into the host. The method of implanting a medical device consists of: (a) the medical device is implanted with an anti-infective or immersed in the transplanted host tissue, and (b) the medical device is implanted into the host. The method of implanting a medical device comprises: (a) the medical device is implanted with a polymer, or immersed in the implanted host tissue, and (b) the medical device is implanted into the host. A method for implanting a medical device comprises: (a) the medical device is implanted with a composition comprising a fibrosis inhibitor and a polymer, or is immersed in the tissue of the implanted host, and (b) is implanted into the host. Implanting medical devices. A method for implanting a medical device comprises: (a) the medical device is implanted with a composition comprising an anti-infective and a polymer, or is immersed in the tissue of the implanted host; and (b) medical treatment to the host. Implanting the device. A method of implanting a medical device comprises: (a) the medical device is implanted with a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer, or is immersed in the tissue of the implanted host; and (b) ) Implanting medical devices into the host.

  These and other aspects of the invention will be apparent upon reference to the following detailed description and attached drawings. Furthermore, this document contains a variety of reference materials that describe in more detail certain treatments and / or compositions, and are thus incorporated by reference in their entirety.

(Detailed description of the invention)
(Definition)
Before describing the invention, it is considered helpful to first understand certain terms used in this document.

   “Fibrosis”, “scarring or scarring” or “fibrotic response” means the formation of fibrous (scar) tissue that occurs in response to injury or medical practice. Therapeutic agents that inhibit fibrosis or scarring or scarring refer herein to "fibrosis inhibitors", "fibrosis inhibitors", "scarring inhibitors", and the like, where the agents are Inhibits fiber formation by one or more of the following actions. Inhibition of inflammation or acute inflammatory response, inhibition of migration or proliferation of connective tissue cells (fibroblasts, smooth muscle cells, vascular smooth muscle cells, etc.), inhibition of angiogenesis, reduction of ECM production or extracellular matrix (ECM) ) Reduction of production or promotion of ECM dissociation and / or inhibition of tissue remodeling. After the use of surgery or instruments (including medical devices and transplantation of grafts), passages in the body (blood vessels, gastrointestinal tract, airways, urinary tract, male / female genital tract, ear canal, etc.) or When scarring occurs in a confined space (such as a lumen) so that it is completely blocked by scar tissue, it means “stenosis” (narrowing). This means "restenosis" when scarring occurs after a surgical procedure (such as the placement of a medical device or implant) initially and then scarring occurs and again blocks the body passage.

  “Host”, “person”, “subject”, “patient” and the like are used interchangeably and refer to an organism to which a device or graft of the present invention is to be transplanted.

  “Transplanted” means that the device or implant is fully or partially placed in the host. A device is partially implanted when a portion of the device reaches the host or reaches the outside of the host.

  The terms “inhibit fibrosis”, “reduce fibrosis”, “inhibit scarring” and the like are used interchangeably and may occur in the absence of a drug or composition By the action of an agent or composition that reduces the formation of fibrous tissue by a statistically significant amount.

   "Anti-infective" means an agent or composition that inhibits the growth of microorganisms and / or slows the growth rate of microorganisms and / or causes direct poisoning of microorganisms at or near the site of the drug . These processes are expected to occur at a statistically significant level at or near the site of the drug or composition compared to the effect in the absence of the drug or composition.

  “Inhibition of infection” means the ability of a drug or composition to prevent microorganisms from accumulating and / or growing at or near the site of the drug. These processes are expected to occur at a statistically significant level at or near the site of the drug or composition compared to the effect in the absence of the drug or composition.

  By “inhibitor” is meant an agent that prevents a biological process from occurring or slows the rate or degree of occurrence of a biological process. This process may refer to general processes such as scarring or scarring and is also associated with specific biological actions such as, for example, molecular processes that lead to the release of cytokines.

  “Antagonist” means an agent that prevents a biological process from occurring or slows the rate or degree of occurrence of a biological process. This process may be a general process, but in general this means that the drug competes with the molecule for the active site of the molecule or the molecule interacts with the molecular site. It refers to the drug action that is not allowed to occur. In this situation, efficacy means that the molecular process has been inhibited.

  “Agonist” means an agent that stimulates a biological process or stimulates the speed or degree of occurrence of a biological process. This process may refer to general processes such as scarring or scarring and is also associated with specific biological actions such as, for example, molecular processes that lead to the release of cytokines.

  An “anti-microtubule drug” is understood to include any protein, peptide, chemical, or other molecule that acts to impair microtubule function, for example, by preventing polymerization stabilization. Should be. Compounds that stabilize microtubule polymerization are referred to herein as “microtubule stabilizers”. For determination of the microtubule inhibitory activity of specific compounds, for example, Smith et al. (Cancer Lett 79 (2): 213-219, 1994) and Mooberry et al. (CancerLett. 96 (2): 261-266, 1995) A wide variety of methods can be used, including the assessment methods (assays) described by.

  “Medical device”, “graft”, “device”, “medical device”, “medical implant”, “graft / device” and the like are used interchangeably and relate to restoration of physiological function, disease Partial or complete placement in the patient's body for one or more therapeutic or prophylactic purposes, such as symptom relief, therapeutic delivery, repair, replacement or augmentation of damaged or diseased organs or tissues Means any object designed to be. Usually composed of exogenous biocompatible synthetic materials (medical stainless steel, titanium and other metals, as well as polymers such as polyurethane, silicon, PLA, PLGA and other materials), but some medical Devices and implants include animal-derived materials (such as whole animal organs, animal tissues such as heart valves, as well as collagen, hyaluronic acid, proteins, carbohydrates, and other naturally occurring or chemically modified molecules. Xenografts ”), materials from organ donors (whole organs, tissues such as bone grafts, skin transplants, etc.“ homografts ”), or patient's own materials (saphenous vein grafts, skin grafts, tendons) / "Autografts" such as ligaments / muscle grafts). Representative examples of particularly useful medical devices in the present invention include vascular stents, gastrointestinal stents, tracheal / bronchial stents, urogenital stents, ENT stents, intra-articular grafts, intraocular lenses, hypertrophic scars. And keloid grafts, vascular grafts, anastomotic coupling devices, implantable sensors, implantable pumps, soft tissue grafts (such as cosmetic implants and implants for reconstruction surgery), implantable electrical devices Implantable neurostimulators and implantable leads, surgical adhesive barriers, glaucoma drainage devices, surgical films and meshes, prosthetic heart valves, middle ear cavity ventilation tubes, penile grafts, endotracheal tubes and Tracheal cannula, peritoneal dialysis catheter, intracranial pressure monitor, vena cava filter, central venous catheter (CVC), auxiliary artificial heart (LVAD, etc.) , Artificial spine, urinary catheter (Folley) catheter, prosthetic bladder sphincter, orthopedic graft, gastrointestinal drainage tube, and the like.

  “Cartilage protection” means prevention of cartilage loss. Cartilage is formed from chondrocytes, and cartilage protection is to protect chondrocytes from death.

  “Drug release” means the presence of a statistically significant drug or a small component thereof, which is separated from the implant / device and / or active on (or within) the implant / device. Keep.

  “Biodegradable” refers to a material in which at least part of the degradation process takes place in (or any of) a biological system as a medium. “Degradation” means a chain scission process whereby the polymer chains are cleaved into oligomers and monomers. Chain breakage may occur by various mechanisms, for example, by chemical reactions (hydrolysis, etc.) or by thermal decomposition or photolysis processes. Polymer degradation can be characterized, for example, using gel permeation chromatography (GPC), which monitors changes in polymer molecular weight during erosion and drug release. Biodegradability also means that a material can be degraded by an erosion process that takes place in and / or within a biological system. “Erosion” means a process in which most of the material is lost. In the case of a polymer system, the material may be a monomer, oligomer, part of the polymer backbone, part of the polymer bulk, etc. Erosion includes (i) surface erosion that affects only the surface and not the interior of the substrate, and (ii) most erosion where the entire system hydrates rapidly and the polymer chains are cleaved throughout the substrate. and so on. Depending on the type of polymer, erosion typically occurs by one of three basic mechanisms (Heller, J., CRC Critical Review in Therapeutic Drug Carrier Systems (1984), 1 (1), 39-90), Siepmann et al., Adv. DrugDel. Rev. (2001), 48, 229-247, etc.). Drug Del. Rev. (2001), 48, 229-247): (1) Water-soluble polymers that are insolubilized by covalent cross-linking and solubilized as cross-links or backbones undergo hydrolysis. (2) Polymers that were initially water-insoluble are solubilized by hydrolysis, ionization, or the circulation of pendant groups. (3) Hydrophobic polymers are converted into small water-soluble molecules by backbone cleavage. Techniques that characterize erosion include thermal analysis (such as DSC), X-ray diffraction, scanning electron microscopy (SEM), electron paramagnetic resonance spectroscopy (EPR), NMR imaging, and mass loss during erosion experiments. There are records. For fines, photon correlation spectroscopy (PCS) and other particle size measurement techniques can also be used to monitor changes in the particle size of the device that can be eroded over time.

  As used herein, an “analog” is structurally similar to the parent compound but slightly different in composition (eg, having one atom or functional group different or added, or Means the compound being removed). Analogs may or may not have chemical or physical properties different from the prototype compound, and may or may not have improved biological and / or chemical activity. For example, an analog may have a higher hydrophilicity or a change in reactivity compared to the parent compound. Analogs may mimic the chemical and / or biological activity of the parent compound (ie, have similar or identical activities) or in some cases have increased or decreased activity Sometimes. Analogs include natural variants of the original compound and non-naturally occurring (eg, recombinant) variants. An example of an analog is a mutein (a mutein) (ie, a protein analog in which at least one amino acid has been removed, added, or replaced with another amino acid). Other types of analogs include isomers (enantiomers, diasteromers, etc.), chiral variants of other types of compounds, and structural isomers. Analogs also include branched and cyclic variants of linear compounds. For example, linear compounds include analogs that have been branched or otherwise substituted to share certain desirable properties, such as improved hydrophilicity or bioavailability.

  As used herein, “derivative” means a variant of a chemically or biologically modified compound, structurally similar to the parent compound, and (virtually or theoretically) the parent compound. Means something that can be derived from “Derivatives” differ from “analogues” in that the parent compound can be a starting material for producing “derivatives”, while the parent compound is not necessarily used as a starting material for the production of “analogues”. You don't have to. A derivative may or may not have chemical or physical properties different from the parent compound. For example, a derivative may have high hydrophilicity or may have changed reactivity compared to the parent compound. Derivatization (ie, modification) may involve substitution of one or more moieties in the molecule (such as functional group changes). For example, hydrogen can be replaced with a halogen such as fluorine or chlorine, and the hydroxyl group (—OH) can be replaced with a carboxylic acid moiety (—COOH). The term “derivative” also includes conjugates as well as prodrugs of the parent compound (ie, chemically modified derivatives that can be converted to the original compound under physiological conditions). For example, a prodrug may be an inactive state of an active drug. Under physiological conditions, the prodrug can be converted to the activated state of the compound. Prodrugs can be formed, for example, by substituting one or two hydrogen atoms in the nitrogen atom with an acyl group (acyl prodrug) or a carbamic acid group (carbamate prodrug). Detailed information on prodrugs can be found, for example, in Fleisher et al., Advanced Drug Delivery Reviews 19 (1996) 115. Design of Prodrugs, H. Bundgaard (editor), Elsevier, 1985. Or H. Bundgaard, Drugs of the Future 16 (1991) 443. The term “analog” is used to describe all solvates, such as hydrates or adducts (eg, alcohol adducts), active metabolites, and salts of the parent compound. The type of salt that can be prepared depends on the nature of the moieties within the compound. For example, an acidic group such as a carboxylic acid group can be an alkali metal salt or alkaline earth metal salt (eg, sodium salt, potassium salt, magnesium salt and calcium salt, as well as salts with physiologically acceptable quaternary ammonium ions, Can form acid addition salts with ammonia, physiologically acceptable organic amines (triethylamine, ethanolamine or tris- (2-hydroxyethyl) amine), etc. Basic groups can be, for example, inorganic acids (hydrochloric acid, sulfuric acid or Acid addition salts using organic carboxylic acids or sulfonic acids (acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid, etc.) Compounds that contain both basic and acidic groups (basic nitrogen atoms are carboxylated The group can be present as a zwitterion, for example by mixing the compound with an inorganic or organic acid or base in a solvent or diluent, or by cation exchange from other salts. Or obtained by conventional and well-known methods such as by anion exchange.

  As used herein, the term “hyaluronic acid” or “HA” means all forms of hyaluronic acid described or referenced herein, treated or chemically or physically modified forms, and Includes cross-linked hyaluronic acid (eg, covalently, ionic, compounded or physically). HA is a glycosaminoglycan consisting of a linear chain of approximately 2500 repeating disaccharide units. Each disaccharide unit is an N acetylglucosamine residue attached to glucuronic acid. Hyaluronic acid is a natural substance found in the extracellular matrix of many tissues, including synovial joint fluid, ocular vitreous humor, cartilage, blood vessels, skin and umbilical cord. Commercial forms of hyaluronic acid with a molecular weight of about 1.2 million to 1.5 million daltons (Da) have been extracted from chicken crowns and other animal sources. Another source of HA is HA isolated from the cell culture / fermentation process. Low molecular weight HA formulations are also available from various commercial sources. The molecule can consist of variable lengths (i.e., different numbers of repeating disaccharide units and different branching patterns) at several sites without departing from the scope of the present invention (through addition or subtraction of different functional groups). Can denature.

  The term “interaction” means a form of covalent bonding, non-covalent bonding, or both. Thus, this term includes cross-linking, which includes intramolecular cross-linking and optional intermolecular cross-linking when generated by covalent bond formation. The covalent bond between the two reactive groups may be direct, in which case the atoms of the reactive group are directly bonded to the atoms of other reactive groups or indirectly bonded through a linking group. Non-covalent bonds include ionic (electrostatic) bonds, hydrogen bonds, or associations of hydrogen molecular segments, which may be the same or different. In addition to covalent bonds, cross-linked substrates include such intramolecular and / or intermolecular non-covalent bonds.

  When referring to polymers, the terms “hydrophilic” and “hydrophobic” are generally defined in terms of HLB values, ie, hydrophilic lipophilic balance. A high HLB value indicates a hydrophilic compound, and a low HLB value characterizes a hydrophobic compound. HLB values are well known in the art and generally range from 1-18. Desirable multifunctional compound nuclei are hydrophilic, but as long as the multifunctional compound as a whole contains at least one hydrophilic component, there are also crosslinkable hydrophilic components.

  The term “synthetic” refers to polymers, synthetics and other materials such as “chemical synthesis”. For example, the synthetic material of the present composition may have the same molecular structure as the naturally occurring material, but the material itself incorporated into the inventive composition has been chemically synthesized laboratory or industrially. “Synthetic” materials also include semi-synthetic materials, ie naturally occurring materials that are chemically modified in some way obtained from natural sources. However, in general, this synthetic material is a pure synthetic material. In other words, it is not a semi-synthetic material and does not have the same structure as a naturally occurring material.

  The term “effective amount” means the amount of the composition necessary to obtain the desired effect. For example, “an amount that promotes tissue growth” in the composition means an amount necessary to stimulate tissue growth to a detectable extent. In this context, tissues include connective tissue, bone, cartilage, epidermis and dermis, blood, and other tissues. The actual amount determined as an effective amount varies depending on factors such as the patient's size, medical condition, sex and age, but can be easily determined by a caregiver.

  The term “in situ” as used herein refers to the site of administration. Accordingly, the composition of the present invention can be injected or applied to a specific site within a patient, such as a site that needs to be augmented, and can be crosslinked at the site of injection. A suitable site is an intradermal or subcutaneous site to enhance skin support for bone repair at the fracture site, typically within the sphincter tissue for sphincter reinforcement (e.g., recovery of incontinence), tissue regrowth. Within wounds or sutures to promote, or within or adjacent to blood vessel anastomoses to promote blood vessel regrowth.

  The term “aqueous medium” includes solutions, suspensions, colloids, and similar media containing water. The term “aqueous environment” means an environment containing an aqueous medium. Similarly, “dry environment” means an environment that does not contain a water-soluble medium.

A related nomenclature is molecular structure and the following definitions apply:
As used herein, the term “alkyl” means a branched or unbranched saturated hydrocarbon group, usually methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl. , And the like, and need not contain from 1 to about 24 carbon atoms, such as cyclopentyl, cyclohexyl, and the like. Generally, although not necessarily, alkyl groups contain 1 to about 12 carbon atoms. The term “lower alkyl” means 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. “Substituted alkyl” means alkyl substituted with one or more substituents. “Alkylene”, “lower alkylene” and “substituted alkylene” refer to divalent alkyl, lower alkyl, and substituted alkyl groups, respectively.

  The term “aryl” as used herein, unless otherwise specified, is a single aromatic ring (monocyclic) or multiple aromatic rings fused together, covalently linked, or a methylene or ethylene moiety, etc. Linked to a common group. The common linking group may be a carbonyl found in benzophenone, an oxygen atom found in diphenyl ether, or a nitrogen atom found in diphenylamine. Desirable aryl groups include one aromatic ring or two fused or linked aromatic rings such as phenyl, naphthyl, biphenyl, diphenyl ether, diphenylamine, benzophenone, and the like. “Substituted aryl” means an aryl moiety that is substituted with one or more substituents, and as used herein, the terms “heteroatom-containing aryl” and “heteroaryl” refer to at least one carbon atom being a heteroatom. Means aryl substituted with The terms “arylene” and “substituted arylene” refer to divalent aryl and substituted aryl groups as defined above.

  The term “heteroatom-containing” in the “heteroatom-containing hydrocarbyl group” refers to a molecule or molecular fragment in which one or more carbon atoms are replaced with atoms other than carbon, such as nitrogen, oxygen, sulfur, phosphorus or silicon. means.

  `` Hydrocarbyl '' means a monovalent hydrocarbyl radical containing 1 to about 30 carbon atoms, preferably 1 to about 24 carbon atoms, most preferably 1 to about 12 carbon atoms, and can be an alkyl group, an aryl group, etc. Branched or non-molecular, saturated or unsaturated species, and the like are included. The term “lower hydrocarbylene” means a hydrocarbyl group of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. The term `` hydrocarbylene '' means a divalent hydrocarbyl moiety containing 1 to about 30 carbon atoms, preferably 1 to about 24 carbon atoms, most preferably 1 to about 12 carbon atoms, Or includes unbranched, saturated or unsaturated species, and the like. The term “lower hydrocarbylene” means a hydrocarbylene group of 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. “Substituted hydrocarbyl” means a hydrocarbyl substituted with one or more substituents, and the terms “heteroatom-containing hydrocarbyl” and “heterohydrocarbyl” refer to a hydrocarbyl in which at least one carbon atom is replaced with a heteroatom. Means. Similarly, “substituted hydrocarbylene” refers to a hydrocarbylene substituted with one or more substituents, and the terms “heteroatom-containing hydrocarbylene” and “heterohydrocarbylene” include at least one Means hydrocarbylene in which one carbon atom is replaced by a heteroatom. Unless otherwise specified, “hydrocarbyl” means both unsubstituted / substituted hydrocarbyl and “heteroatom-containing hydrocarbyl” means both unsubstituted / substituted heteroatom-containing hydrocarbyl.

  “Substituted”, such as “substituted hydrocarbyl”, “substituted alkyl”, etc., as pointed out in the above definition, includes at least one hydrogen atom bonded to a carbon atom in a hydrocarbyl, alkyl, or other moiety. , Alkoxy, hydroxy, halo, nitro, and the like, which are substituted with one or more substituents. Unless otherwise indicated, it is to be understood that a specified molecular segment can be substituted with one or more substituents that do not compromise the usefulness of the compound. For example, “succinimidyl” is intended to include sulfosuccinimidyl and other succinimidyl groups substituted with ring carbon atoms, such as unsubstituted succinimidyl and alkoxy substituents, polyether substituents, or the like. .

  Concentration ranges, percentage ranges, or ratio ranges detailed herein are also integers and fractions (1 / 10th of an integer) of any concentration, percentage, or ratio within that range, unless otherwise specified. And 1/100). In addition, the ranges of numbers related to physical features such as polymer subunits, sizes, and thicknesses detailed herein are intended to include any integer within the stated ranges unless otherwise specified. Should be understood. As used herein, the term “about” means ± 15% of the specified structure, value, or range.

  “A” and “an” mean one or more specified items. For example, the term “apolymer” means both a single polymer and a mixture of a plurality of polymers. By “a multifunctional compound” is meant not only a single multifunctional mixture but also a mixture of a plurality of the same or different multifunctional compounds. Reference to “a reactive group” means not only a mixture of a plurality of reactive groups but also a mixture of a single reactive group.

  As mentioned above, the present invention provides a polymer composition that significantly improves the ability to inhibit the formation of reactive scar tissue on or around the surface of the device or implant or at the treatment site. A number of polymer compositions and therapeutic agents are described herein.

  The present invention provides for combinations of compositions (such as polymers) comprising one or more therapeutic agents, as described below. Methods for making and using such compositions are also described in further detail below.

A. Therapeutic Agents In one embodiment, the present invention discloses a pharmaceutical agent that inhibits one or more aspects in the generation of excessive fibrous (scar) tissue. Suitable fiber formation inhibitors or stenosis inhibitors can be readily determined based on in vitro and in vivo (animal) models, such as those shown in Examples 20-33. Agents that inhibit fibrosis can also be identified by in vivo models including inhibition of intimal hyperplasia in the rat balloon carotid artery model (Examples 25 and 33). The test methods described in Examples 24 and 32 can be used to determine whether an agent can inhibit cell proliferation in fibroblasts and smooth muscle cells. In one embodiment of the invention, the agent has an IC ₅₀ in the range of about 10 ⁻⁶ to about 10 ⁻¹⁰ M for inhibition of cell proliferation. The test method described in Example 28 can be used to determine whether a drug can inhibit the migration of fibroblasts and smooth muscle cells. In one aspect of the invention, the agent has an IC ₅₀ for inhibition of cell migration within the range of about 10 ⁻⁶ to about 10 ⁻⁹ M. The test methods described herein show that the drug is produced by the production of nitric oxide in macrophages (Example 20) and / or TNF-α production by macrophages (Example 21) and / or IL-1β by macrophages Example 29), and / or can be used to determine whether macrophage can inhibit IL-8 production (Example 30) and / or inhibition of MCP-1 by macrophages (Example 31) . In one aspect of the invention, the agent has an IC ₅₀ for inhibition of any one of these inflammatory processes within the range of about 10 ⁻⁶ to about 10 ^{−10 m} . The test method described in Example 26 can be used to determine whether an agent can inhibit MMP production. In one aspect of the invention, the agent has an IC ₅₀ for inhibition of MMP production within the range of about 10 ⁻⁴ to about 10 ⁻⁸ M. The test method described in Example 27 (also known as the CAM assay) can be used to determine whether an agent can inhibit angiogenesis. In one aspect of the invention, the agent has an IC ₅₀ for inhibition of angiogenesis inhibition in the range of about 10 ⁻⁶ to about 10 ⁻¹⁰ M. Agents that reduce the formation of surgical adhesions can be identified by in vivo models, including the rabbit surgical adhesion model (Examples 23, 42 and 43) and the rat cecal sidewall model (Example 22). A pharmacologically active agent (described below) can be administered appropriately, alone or through a carrier (described below), to cure the clinical problems described above (described below). The amount can be delivered to the tissue.

  In this invention, a number of useful therapeutic compounds that can inhibit fiber formation have been identified, including:

1) Angiogenesis inhibitors In one embodiment, the pharmacologically active fibrosis inhibitor compound is an angiogenesis inhibitor (eg, 2-ME (NSC-659853), PI-88 (D-mannose, O- 6-O-phosphono-α-D-mannopyranosyl- (1-3) -O-α-D-mannopyranosyl- (1-3) -O-α-D-mannopyranosyl- (1-3) -O-α- D-mannopyranosyl- (1-2) -hydrogen sulfate), thalidomide (1H-isoindole-1,3 (2H) -dione, 2- (2,6-dioxo-3-piperidinyl)-), CDC-394 , CC-5079, ENMD-0995 (S-3-amino-phthalidoglutarimide), AVE-8062A, Batalanib, SH-268, Halofuginone hydrobromide, Atipurimod dimaleate (2-azaspivo (4.5) Decan-2-propanamine, N, N-diethyl-8,8-dipropyl, dimaleate), ATN-224, CHIR-258, combretastatin A-4 (phenol, 2-methoxy-5- (2- (3 , 4,5-trimethoxyphenyl) ethenyl)-, (Z)-), GCS-100LE, or Analogues or derivatives of, or the like).

2) 5-lipoxygenase inhibitors and antagonists In another embodiment, the pharmacologically active fibrosis inhibitor compound is a 5-lipoxygenase inhibitor or antagonist (eg, Wy-50295 (2-naphthalene acetic acid, α- Methyl-6- (2-quinolinylmethoxy)-, (S)-), ONO-LP-269 (2,11,14-eicosatrienamide, N- (4-hydroxy-2- (1H-tetrazole) -5-yl) -8-quinolinyl)-, (E, Z, Z)-), lycoferon (1H-pyrrolidine-5-acetic acid, 6- (4-chlorophenyl) -2,3-dihydro-2,2- Dimethyl-7-phenyl-), CMI-568 (urea, N-butyl-N-hydroxy-N '-(4- (3- (methylsulfonyl) -2-propoxy-5- (tetrahydro-5- (3, 4,5-trimethoxyphenyl) -2-furanyl) phenoxy) butyl)-, trans-), IP-751 ((3R, 4R)-(δ6) -THC-DMH-11-acid), PF-5901 ( Benzenemethanol, α-pentyl-3- (2-quinolinylmethoxy)-), LY-293111 (benzoic acid, 2- (3- (3-((5- Til-4'-fluoro-2-hydroxy (1,1'-biphenyl) -4-yl) oxy) propoxy) -2-propylphenoxy)-), RG-5901-A (benzenemethanol, α-pentyl-3 -(2-quinolinylmethoxy)-, hydrochloride), rilopirox (2 (1H) -pyridinone, 6-((4- (4-chlorophenoxy) phenoxy) methyl) -1-hydroxy-4-methyl-) , L-674636 (acetic acid, ((4- (4-chlorophenyl) -1- (4- (2-quinolinylmethoxy) phenyl) butyl) thio) -AS)), 7-((3- (4- Methoxy-tetrahydro-2H-pyran-4-yl) phenyl) methoxy) -4-phenylnaphtho (2,3-c) furan-1 (3H) -one, MK-886 (1H-indole-2-propanoic acid, 1-((4-chlorophenyl) methyl) -3-((1,1-dimethylethyl) thio) -α, α-dimethyl-5- (1-methylethyl)-), kifrapon (1H-indole-2- Propanoic acid, 1-((4-chlorophenyl) methyl) -3-((1,1-dimethylethyl) thio) -α, α-dimethyl-5- (2-alkyl Linylmethoxy)-), kifrapon (1H-indole-2-propanoic acid, 1-((4-chlorophenyl) methyl) -3-((1,1-dimethylethyl) thio) -α, α-dimethyl-5- ( 2-quinolinylmethoxy)-), docebenone (2,5-cyclohexadiene-1,4-dione, 2- (12-hydroxy-5,10-dodecadiynyl) -3,5,6-trimethyl-), zileuton (Urea, N- (1-benzo (b) thien-2-ylethyl) -N-hydroxy-), or analogs and derivatives thereof).

3) Chemokine receptor antagonist CCR (1, 3, and 5)
In another example, a pharmacologically active fibrosis-inhibiting compound is a chemokine receptor antagonist that inhibits one or more subtypes of CCR (1, 3, and 5) (eg, ONO-4128 ( 1,4,9-triazaspiro (5.5) undecane-2,5-dione, 1-butyl-3- (cyclohexylmethyl) -9-((2,3-dihydro-1,4-benzodioxin-6-yl) Methyl-), L-381, CT-112 (L-arginine, L-threonyl-L-threonyl-L-seryl-L-glutaminyl-L-valyl-L-arginyl-L-prolyl-), AS-900004, SCH-C, ZK-811752, PD-172084, UK-427857, SB-380732, vMIPII, SB-265610, DPC-168, TAK-779 (N, N-dimethyl-N- (4- (2- (4 -Methylphenyl) -6,7-dihydro-5H-benzocyclohepten-8-ylcarboxamide) benyl) tetrahydro-2H-pyran-4-aminium chloride), TAK-220, KRH-1120), GSK766994, SSR- 150106, or analogs and derivatives thereof). Other examples of chemokine receptor antagonists include a-immunokine-NNS03, BX-471, CCX-282, Sch-350634, Sch-351125, Sch-417690, SCH-C, and analogs and derivatives thereof. is there.

4) Cell cycle inhibitor In another embodiment, the pharmacologically active fiber formation inhibitor compound is a cell cycle inhibitor. Representative examples of such agents include taxanes such as paclitaxel (detailed below) and docetaxel (Schiff et al., Nature 277: 665-667, 1979. Long and Fairchild, Cancer Research 54: 4355-4361, 1994. Ringel and Horwitz , J. Nat'l Cancer Inst. 83 (4): 288-291, 1991. Pazdur et al., Cancer Treat. Rev. 19 (40): 351-386, 1993) Etanidazole, Nimorazole (BAChabner and DL Longo. Cancer Chemotherapy). and Biotherapy-Principles and Practice. Lippincott-Raven Publishers, New York, 1996, p.554), perfluorinated compounds (with hyperbaric oxygen), infusion, erythropoietin, BW12C, nicotinamide, hydralazine, BSO, WR-2721, IudR , DudR, etanidazole, WR-2721, BSO, monosubstituted ketoaldehyde compounds (LGEgyud. Keto-aldehyde-amine addition products and method of making same. US Pat. No. 4,066,650, Jan. 3, 1978), nitroimidazole (KCAgrawa Nitroimidazole radiosensitizers for Hypoxic tumor cells and compositions thereof. US Pat. No. 4,462,992, July 31, 1984) 5-substituted-4-nitroimidazole (Adams et al., Int. J. Radiat. Biol. Relat. Stud. Phys., Chem. Med. 40 (2): 153-161, 1981), SR-2508 (Brown et al., Int. J. Radiat. Oncol., Biol. Phys. 7 (6): 695-703. 1981), 2H-isoindoledione (JA Myers, 2H-Isoindolediones, the synthesis and use as radiosensitizers. Patent 4,494,547, January 22, 1985), Chiral (((2-bromoethyl) -amino) methyl) -nitro -1H-imidazole-1-ethanol (VGBeylin et al., Process for preparing chiral (((2-bromoethyl) -amino) methyl) -nitro-1H-imidazole-1-ethanol and relatedcompounds. US Pat. No. 5,543,527, 1996 8 6th of month. US Pat. No. 4,797,397, January 10, 1989. US Pat. No. 5,342,959, August 30, 1994), nitroaniline derivatives (WADenny, et al., Nitroaniline derivatives and the use as anti-tumor agents. US Pat. No. 5,571,845, November 5, 1996), DNA affinity Hypoxia-selective cytotoxins (MVPapadopoulou-Rosenzweig. DNA-affinic hypoxia selective cytotoxins. US Pat. No. 5,602,142, February 11, 1997), Halogenated DNA ligand (RFMartin. Halogenated DNA ligand radiosensitizers for cancer therapy. US patent) 5,641,764, June 24, 1997), 1,2,4 benzotriazine oxides (WW Lee et al., 1,2,4-benzotriazine oxides as radiosensitizers and selective cytotoxic agents. US Pat. No. 5,616,584, April 1997) 1st US Patent 5,624,925, April 29, 1997. Processfor Preparing 1,2,4 Benzotriazine oxides. US Patent 5,175,287, December 29, 1992), Nitric Oxide (JBMitchell et al., Use of Nitric oxide) releasing compounds as hypoxic cell radiationsensitizers. US Pat. No. 5,650,442 July 22, 1997), 2-nitroimidazole derivatives (MJ Suto et al., 2-Nitroimidazolederivatives useful as radiosensitizers for hypoxic tumor cells. US Patent No. 4,797,397, January 10, 1989. T. Suzuki. 2-Nitroimidazole derivative US Patent No. 5,270,330, December 14, 1993. T. Suzuki et al., 2-Nitroimidazole derivative, production thereof, and radiosensitizer containing the same as active ingredient. No. 5,270,330, December 14, 1993. T. Suzuki. 2-Nitroimidazole derivative, production thereof and radiosensitizer containing the same asactive ingredient, patent EP 0 513 351 B1, January 24, 1991), fluorinated nitroazole derivative (T. Kagiya.Fluorine-containing nitroazole derivatives and radiosensitizer comprising thesame. US Pat. No. 4,927,941, May 22, 1990), Copper (MJ Abrams. Copper Radiosensitizers. US Pat. No. 5,100,885, March 31, 1992), Multimodal Cancer Therapy (DHPicker et al., Combination modality cancer therapy. US Pat. No. 4,681,091, Jul. 21, 1987), 5-CldC or (d) H ₄ U or 5-halo-2′-halo-2′-deoxy-cytidine or -uridine derivatives ( SBGreer. Method and Materials for sensitizing neoplastic tissue to radiation. US Pat. No. 4,894,364, January 16, 1990, KASkov. Platinum Complexes with one radiosensitizing ligand. US Pat. No. 4,921,963, May 1, 1990 KASkov. Platinum Complexes with one radiosensitizing li Patent EP 0 287 317A3), fluorinated nitroazole derivatives (T. Kagiya. Fluorine-containing nitroazole derivatives and radiosensitizer comprising the same. US Pat. No. 4,927,941, May 22, 1990), Benzamide (WWLee. Substituted Benzamide) Radiosensitizers. US Pat. No. 5,032,617, July 16, 1991), self-generated substances (LGEgyud. Autobiotics and the use in nonself cells in vivo. US Pat. No. 5,147,652, September 15, 1992), benzamide and nicotinic acid Amide (WWLee et al., Benzamide and Nictoinamide Radiosensitizers. US Patent 5,215,738, June 1, 1993), Acridine Intercalator (M.Papadopoulou-Rosenzweig. Acridine Intercalator based hypoxia selective cytotoxins. US Patent 5,294,715, 1994 3) 15), fluorinated nitroimidazoles (T. Kagiya et al., Fluorine containing nitroimidazole compounds. US Pat. No. 5,304,654, April 19, 1994), hydroxylation Texafurin (JLSessler et al., Hydroxylated texaphrins. US Pat. No. 5,457,183, October 10, 1995), hydroxylated compound derivative (T. Suzuki et al., Heterocyclic compound derivative, production antagonist andradiosensitizer and antiviral agent containing said derivative as activeingredient. Publication number 011106775 A (Japan), October 22, 1987. T. Suzuki et al., Heterocyclic compound compound, production thereof and radiosensitizer, antiviral agent and anti cancer agent containing said derivative as active ingredient. Publication number 01139596A (Japan), November 25, 1987. S. Sakaguchi et al., Heterocyclic compound derivative, itsproduction and radiosensitizer containing said derivative as active ingredient, publication number 63170375A (Japan), January 7, 1987), fluorine-containing 3-nitro-1,2,4-triazole (T. Kagitani et al., Novel fluorine-containing 3-nitro-1,2,4-triazole and radiosensitizer containing same compound. Publication number 02076861A (Japan), March 31, 1988), 5-thiotretrazole derivative or its salt ( E. Kano et al., Radiosensitizer for Hypoxiccell. Publication No. 61010511 A (Japan), June 26, 1984), Nitrothiazole (T. Kagitani et al., Radiation-sensitizingagent. Publication No. 61167616 A (Japan) January 22, 1985 ), Imidazole derivatives (S. Inayma et al., Imidazolederivative. Publication number 6203767 A (Japan) August 1, 1985. Publication number 62030768 A (Japan) August 1, 1985. Publication number 62030777A (Japan) August 1985 1 day), 4-nitro-1,2,3-triazole (T. Kagitani et al., Radiosensitizer. Publication number 620 39525A (Japan), August 15, 1985), 3-nitro-1,2,4-triazole (T. Kagitani et al., Radiosensitizer. Publication No. 62138427A (Japan), December 12, 1985), anticancer effect Regulator (H. Amagase. Carcinostatic action regulator. Publication number 63099017A (Japan), November 21, 1986), 4,5-dinitroimidazole derivative (S. Inayama. 4,5-Dinitroimidazolederivative. Publication number 63310873 A (Japan) ) June 9, 1987), nitrotriazole compound (T. Kagitanil Nitrotriazole Compound. Publication number 07149737 A (Japan) June 22, 1993), cisplatin, doxorbin, misonidazole, mitomycin, tilipazamine, nitrosourea, mercaptopurine, methotrexate , Flurouracil, bleomycin, vincristine, carboplatin, epirubicin, doxorubicin, cyclophosphamide, vindesine, etoposide (IFTannock. Review Article: Treatment o Journal of Clinical Oncology 14 (12): 3156-3174, 1996), Camptothecin (Ewend MG et al., Local delivery of chemotherapy and concurrent external beam radiotherapy prolongs survival in metastatic brain tumor models. Cancer Research 56 (22) : 5217-5223, 1996) and paclitaxel (Tishler RB et al., Taxol: a novel radiation sensitizer. International Journal of Radiation Oncology and Biological Physics 22 (3): 613-617, 1992).

In addition, many of the cell cycle inhibitors described above include a variety of analogs and derivatives, including but not limited to cisplatin, cyclophosphamide, misonidazole, tilipazamine, nitrosourea, mercaptopurine, methotrexate, There are flurouracil, epirubicin, doxorubicin, vindesine and etoposide. Analogs and derivatives include (CPA) ₂ Pt (DOLYM) and (DACH) Pt (DOLYM) cisplatin (Choi et al., Arch. Pharmacal Res. 22 (2): 151-156, 1999), cis- (PtCl ₂ ( 4,7-H-5-methyl-7-oxo) 1,2,4 (triazolo (1,5-a) pyrimidine) ₂ ) (Navarro et al., J. Med. Chem. 41 (3): 332-338 1998), (Pt (cis-1,4-DACH) (trans-Cl ₂ ) (CBDCA)) 1/2 MeOH cisplatin (Shamsuddin et al., Inorg. Chem. 36 (25): 5969-5971, 1997), 4-pyridoxate diammine hydroxyplatinum (Tokunaga et al., Pharm. Sci. 3 (7): 353-356, 1997), Pt (II) ・ ・ ・ Pt (II) (Pt ₂ (NHCHN (C (CH ₂ ) (CH ₃ ))) ₄ ) (Navarro et al., Inorg. Chem. 35 (26): 7829-7835, 1996), 254-S cisplatin analogues (Koga et al., Neurol. Res. 18 (3): 244-247. 1996), cisplatin analogues with o-phenylenediamine ligand (Koeckerbauer and Bednarski, J. Inorg. Biochem. 62 (4): 281-298, 1996), trans, cis- (Pt (OAc) ₂ I ₂ ( En)) (Kratochwil et al., JM ed. Chem. 39 (13): 2499-2507, 1996), 1,2-diarylethylenediamine ligand of estrogen (with sulfur-containing amino acids and glutathione) (Bednarski, J. Inorg. Biochem. 62 ( 1): 75, 1996), cis-1,4-diaminocyclohexane cisplatin analog (Shamsuddin et al., J. Inorg. Biochem. 61 (4): 291-301, 1996), cis- (Pt (NH ₃ ) ( 4-amino TEMP-O) {d (GpG)}) 5'-oriented isomers (Dunham and Lippard, J. Am. Chem. Soc. 117 (43): 10702-12, 1995), including chelating diamines Cisplatin analogs (Koeckerbauer and Bednarski, J. Pharm. Sci. 84 (7): 819-23, 1995), cisplatin analogs containing 1,2-diarylethyleneamine ligands (Otto et al., J. Cancer Res. Clin. Oncol. 121 (1): 31-8, 1995), (ethylenediamine) platinum (II) complex (Pasini et al., J. Chem. Soc., Dalton Trans. 4: 579-85, 1995), CI-973 cisplatin-like Body (Ya ng et al., Int. J. Oncol. 5 (3): 597-602, 1994), cis-diamminedichloroplatinum (II) and its analogs cis-1,1-cyclobutanedicarbosilate (2R) -2-methyl 1,4-butanedium-min platinum (II) and cis-diammine (glycolato) platinum (Claycamp and Zimbrick, J. Inorg. Biochem., 26 (4): 257-67, 1986. Fan et al., Cancer Res. 48 (11): 3135-9, 1988. Heiger-Bernays et al., Biochemistry 29 (36): 8461-6, 1990. Kikkawa et al., J. Exp. Clin. Cancer Res. 12 (4): 233-40, 1993. Murray et al., Biochemistry 31 (47): 11812-17, 1992. Takahashi et al., Cancer Chemother. Pharmacol. 33 (1): 31-5, 1993), cis-amine-cyclohexylamine-dichloroplatinum (II) (Yoshida et al., Biochem. Pharmacol. 48 (4): 793-9, 1994). ), Gem-diphosphonate cisplatin analog (FR 2683529), (meso-1,2-bis (2,6-dichloro-4-hydroxyprenyl) ethylenediamine) dichloroplatinum (II) (Bednarski et al., J. Med. Chem. 35 (23): 4479-85, 1992), cisplatin analogs containing a chain dansyl group (Hartwig et al., J. Am. Chem. Soc. 114 (21): 8292-3, 1992), platinum ( II) Polyamines (Siegmann et al., Inorg. Met.-ContainingPolym. Mater., (Proc. Am. Chem. Soc. Int. Symp.), 335-61, 1990), cis- (3H) dichloro (ethylenediamine) platinum ( II) (Eastman, Anal. Biochem. 197 (2): 311-15, 1991), trans-diamminedichloroplatinum (II) and cis- (Pt (NH ₃ ) ₂ (N ₃ -cytosine) Cl) (Bellon and Lippard, Biophys. Chem. 35 (2-3): 179-88, 1990), 3H-cis-1,2-di Aminocyclohexanedichloroplatinum (II) and 3H-cis-1,2-diaminocyclohexanemalonatoplatinum (II) (Oswald et al., Res. Commun. Chem. Pathol. Pharmacol. 64 (1): 41-58, 1989), Platinum amino acid containing diaminocarboxylatoplatinum (EPA 296321), trans- (D, 1) -1,2-diaminocyclohexane carrier ligand (Wyrick and Chaney, J. Labelled Compd. Radiopharm. 25 (4): 349-57 , 1988), cisplatin analogues derived from aminoalkylaminoanthraquinone (Kitov et al., Eur. J. Med. Chem. 23 (4): 381-3, 1988), spiroplatin, carboplatin, iproplatin and JM40 platinum analogues (Schroyen) Eur. J. Cancer Clin. Oncol. 24 (8): 1309-12, 1988), cis platinum derivatives containing bidentate tertiarydiamine (Orbell et al., Inorg. Chim. Acta 152 (2): 125-34. 1988), platinum (II), platinum (IV) (Liu and Wang, Shandong Yike Daxue Xuebao 24 (1): 35-41, 1986), cis -Diammine (1,1-cyclobutanedicarboxylato-) platinum (II) (carboplatin, JM8) and ethylenediammine-malonatoplatinum (II) (JM40) (Begg et al., Radiother. Oncol. 9 (2): 157-65 1987), JM8 and JM9 cisplatin analogues (Harstrick et al., Int. J. Androl. 10 (1), 139-45, 1987), (NPr4) 2 ((PtCL4) .cis- (PtCl2- (NH2Me) 2 )) (Brammer et al., J. Chem. Soc., Chem. Commun. 6: 443-5, 1987), aliphatic tricarboxylic acid platinum complex (EPA 185225), cis-dichloro (amino acid) (tert-butylamine) platinum ( II) Complexes (Pasini and Bersanetti, Inorg. Chim. Acta 107 (4): 259-67, 1985), 4-hydroperoxysilcophosphamide (Ballard et al., Cancer Chemother. Pharmacol. 26 (6): 397-402, 1990 ), Acyclouridine cyclophosphamide derivatives (Zakerinia et al., Helv. Chim. Acta 73 (4): 912-15, 1990), 1,3,2-dioxa- and -oxazaphosphorinane cyclophosphamide analogues Body (Yang and others Tetrahedron44 (20): 6305-14, 1988), C5-substituted cyclophosphamide analogues (Spada, University of Rhode Island Dissertation, 1987), tetrahydrooxazine cyclophosphamide analogues (Valente, University of Rochester Dissertation, 1988), Phenyl ketone cyclophosphamide analogues (Hales et al., Teratology 39 (1): 31-7, 1989), phenylketophosphamide cyclophosphamide analogues (Ludeman et al., J. Med. Chem. 29 (5): 716-27, 1986), ASTA Z-7557 cyclophosphamide analogue (Evans et al., Int. J. Cancer 34 (6): 883-90, 1984), 3- (1-oxy-2,2,6 , 6-Tetramethyl-4-piperidinyl) cyclophosphamide (Tsui et al., J. Med. Chem. 25 (9): 1106-10, 1982), 2-oxobis (2-β-chloroethylamino) -4 -, 6-Dimethyl-1,3,2-oxazaphosphorinane cyclophosphamide (Carpenter et al., Phosphorus Sulfur 12 (3): 287-93, 1982), 5-fluoro- and 5-chlorocycl Lofosphamide (Foster et al., J. Med. Chem. 24 (12): 1399-403, 1981), cis- and trans-4-phenylcyclophosphamide (Boyd et al., J. Med. Chem. 23 (4): 372 -5, 1980), 5-bromocyclophosphamide, 3,5-dehydrocyclophosphamide (Ludeman et al., J. Med. Chem. 22 (2): 151-8, 1979), 4-ethoxycarbonylcyclophosphamide Analog (Foster, J. Pharm. Sci. 67 (5): 709-10, 1978), arylaminotetrahydro-2H-1,3,2-oxazaphospholine 2-oxide cyclophosphamide analog ( Hamacher, Arch. Pharm. (Weinheim, Ger.) 310 (5): J, 428-34, 1977), NSC-26271 cyclophosphamide analogues (Montgomery and Struck, CancerTreat. Rep. 60 (4): J381 -93, 1976), cyclophosphamide analogues with a benzo ring structure (Ludeman and Zon, J. Med. Chem. 18 (12): J1251-3, 1975), 6-trifluoromethylcyclophosphamide (Farmer And Cox, J. Med. Chem 18 (11): J1106-10, 1975), 4-methylcyclophosphamide and 6-methycyclophosphamide analogues (Cox et al., Biochem. Pharmacol. 24 (5): J599-606, 1975), FCE 23762 Doxorubicin derivatives (Quaglia et al., J. Liq. Chromatogr. 17 (18): 3911-3923, 1994), annamycin (Zou et al., J. Pharm. Sci. 82 (11): 1151-1154, 1993), ruboxil ( Rapoport et al., J. Controlled Release 58 (2): 153-162, 1999), anthracycline disaccharide doxorubicin analogues (Pratesi et al., Clin. Cancer Res. 4 (11): 2833-2839, 1998), N- (tri Fluoroacetyl) doxorubicin and 4′-O-acetyl-N- (trifluoroacetyl) doxorubicin (Berube and Lepage, Synth. Commun. 28 (6): 1109-1116, 1998), 2-pyrrolinodoxorubicin (Nagy et al., Proc. Nat'l Acad. Sci. USA 95 (4): 1794-1799, 1998), disaccharide doxorubicin analogues (Arcamone et al., J. Nat'l Cancer Inst. 89 (16): 1217-1223, 1997), 4-deme Xyl-7-O- (2,6-dideoxy-4-O- (2,3,6-trideoxy-3-amino-α-L-lyxo-hexopyranosyl) -α-L-lyxo-hexopyranosyl) -adriami Sinon doxorubicin disaccharide analog (Monteagudo et al., Carbohydr. Res. 300 (1): 11-16, 1997), 2-pyrrolinodoxorubicin (Nagy et al., Proc. Nat'l Acad. Sci. USA 94 (2): 652-656, 1997), morpholinyl doxorubicin analogues (Duran et al., Cancer Chemother. Pharmacol. 38 (3): 210-216, 1996), enaminomalonyl-β-alanine doxorubicin derivatives (Seitz et al., Tetrahedron Lett. 36 (9): 1413-16, 1995), cephalosporin doxorubicin derivatives (Vrudhula et al., J. Med. Chem. 38 (8): 1380-5, 1995), hydroxyl bicine (Solary et al., Int. J. Cancer 58 (1): 85-94, 1994), methoxymorpholinodoxorubicin derivatives (Kuhl et al., Cancer Chemother. Pharmacol. 33 (1): 10-16, 1993), (6-maleimidocaproyl) hydrazone doxol Bicine derivatives (Willner et al., Bioconjugate Chem. 4 (6): 521-7, 1993), N- (5,5-diacetoxypent-1-yl) doxorubicin (Cherif and Farquhar, J. Med. Chem. 35 (17 ): 3208-14, 1992), FCE 23762 methoxymorpholinyl doxorubicin derivative (Ripamonti et al., Br. J. Cancer 65 (5): 703-7, 1992), N-hydroxysuccinimide ester doxorubicin derivative (Demant et al., Biochim Biophys. Acta 1118 (1): 83-90, 1991), polydeoxynucleotide doxorubicin derivatives (Ruggiero et al., Biochim. Biophys. Acta 1129 (3): 294-302, 1991), morpholinyl doxorubicin derivatives (EPA 434960) ), Mitoxantrone doxorubicin analogue (Krapcho et al., J. Med. Chem. 34 (8): 2373-80. 1991), AD198 doxorubicin analogue (Traganos et al., CancerRes. 51 (14): 3682-9, 1991) ), 4-demethoxy-3'-N-trifluoroacetyl doxorubicin (Horton et al., DrugDes. Delivery 6 (2) 123-9,1990), 4'-epi-doxorubicin (Drzewoski other, Pol J.Pharmacol Pharm 40 (2...): 159-65,1988. Weenen et al., Eur. J. Cancer Clin. Oncol. 20 (7): 919-26, 1984), alkylated cyanomorpholinodoxorubicin derivatives (Scudder et al., J. Nat'l Cancer Inst. 80 (16): 1294-8, 1988), deoxydihydroiodooxorubicin (EPA 275966), adriblastin (Kalishevskaya et al., Vestn. Mosk. Univ., 16 (Biol. 1): 21-7, 1988), 4'-deoxyxorubicin (Schoelzel et al. Leuk. Res. 10 (12): 1455-9, 1986), 4-demethyoxy-4'-o-methyldoxorubicin (Giuliani et al., Proc. Int. Congr. Chemother. 16: 285-70-285-77, 1983), 3'-deamino-3'-hydroxydoxorubicin (Horton et al., J. Antibiot. 37 (8): 853-8, 1984), 4-demethyoxide xorubicin analogue (Barbieri et al., Drugs Exp. Clin. Res. 10 (2): 85-90, 1984), NL-leucyl doxorubicin derivatives (Trouet et al., Anthracyclines (Proc. Int. Symp. Tumor Pharmacother.), 179-81, 1983), 3′-deamino-3 '-(4-Methoxy-1-piperidi D) doxorubicin derivative (4,314,054), 3'-deamino-3 '-(4-morpholinyl) doxorubicin derivative (4,301,277), 4'-deoxyxorubicin and 4'-o-methyldoxorubicin (Giuliani et al., Int. J. Cancer 27 (1): 5-13, 1981), aglyconxorubicin derivatives (Chan and Watson, J. Pharm. Sci. 67 (12): 1748-52, 1978), SM 5887 (Pharma Japan 1468: 20, 1995), MX -2 (Pharma Japan 1420: 19, 1994), 4'-deoxy-13 (S) -dihydro-4'-iododoxorubicin (EP 275966),
Morpholinyl doxorubicin derivative (EPA434960), 3'-deamino-3 '-(4-methoxy-1-piperidinyl) doxorubicin derivative (4,314,054), doxorubicin-14-valerate, morpholinodoxorubicin (5,004,606), 3'-deamino -3 '-(3''-cyano-4''-morpholinyl doxorubicin, 3'-deamino-3'-(3 ''-cyano-4 ''-morpholinyl) -13-dihydroxorubicin, (3 ' -Deamino-3 '-(3''-cyano-4''-morpholinyl) daunorubicin, 3'-deamino-3'-(3 ''-cyano-4 ''-morpholinyl) -3-dihydrodaunorubicin, and 3 '-Deamino-3'-(4 ''-morpholinyl-5-iminodoxorubicin and derivatives (4,585,859), 3'-deamino-3 '-(4-methoxy-1-piperidinyl) doxorubicin derivatives (4,314,054) and 3-deamino -3- (4-morpholinyl) doxorubicin derivative (4,301,277), 4,5-dimethylmysonidazole (Born et al., Biochem. Pharmacol. 43 (6): 1337-44, 1992), azo and azoxymisonidazole derivatives (Gattavecchia and Tonelli, Int. J. Radiat. Biol. Relat. Stud. Phys., Chem. Med. 45 (5): 469- 77, 1984), RB90740 (Wardman et al., Br. J. Cancer, 74 Suppl. (27): S70-S74, 1996), 6-bromo and 6-chloro-2,3-dihydro-1,4-benzothiazine nitroso Urea derivatives (Rai et al., Heterocycl. Commun. 2 (6): 587-592, 1996), diamino acid nitrosourea derivatives (Dulude et al., Bioorg. Med. Chem. Lett. 4 (22): 2697-700, 1994). Dulude et al., Bioorg. Med. Chem. 3 (2): 151-60, 1995), amino acid nitrosourea derivatives (Zheleva et al., Pharmazie 50 (1): 25-6, 1995), 3 ', 4'-didemethoxy-3 ', 4'-Dioxo-4-deoxypodophyllotoxin nitrosourea derivatives (Miyahara et al., Heterocycles 39 (1): 361-9, 1994), ACNU (Matsunaga et al., Immunopharmacology 23 (3): 199-204, 1992) , Tertiary phosphine oxide nitrosourea derivatives (Gu guva et al., Pharmazie 46 (8): 603, 1991), sulfameridine and sulfamethizole nitrosourea derivatives (Chiang et al., Zhonghua Yaozue Zazhi 43 (5): 401-6, 1991), thymidine nitrosourea analogues (Zhang et al., Cancer) Commun. 3 (4): 119-26, 1991), 1,3-bis (2-chloroethyl) -1-nitrosourea (August et al., CancerRes. 51 (6): 1586-90, 1991), 2,2 , 6,6-tetramethyl-1-oxopiperidinium nitrosourea derivatives (USSR 1261253), 2- and 4-deoxy sugar nitrosourea derivatives (4,902,791), nitrotriazole compounds (USSR 1336489), hotemstin (Boutin et al., Eur. J. Cancer Clin. Oncol. 25 (9): 1311-16, 1989), pyrimidine (II) nitrosourea derivatives (Wei et al., Chung-huaYao Hsueh Tsa Chih 41 (1): 19-26, 1989), CGP 6809 (Schieweck et al., Cancer Chemother. Pharmacol. 23 (6): 341-7, 1989), B-3839 (Prajda et al., In Vivo 2 (2): 151-4, 1988), 5-halogen Nocytosine nitrosourea derivatives (Chiang and Tseng, T'ai-wan Yao Hsueh Tsa Chih 38 (1): 37-43, 1986), 1- (2-chloroethyl) -3-isobutyl-3- (β-maltosyl)- 1-nitrosourea (Fujimoto and Ogawa, J. Pharmacobio-Dyn. 10 (7): 341-5, 1987), sulfur-containing nitrosourea (Tang et al., Yaoxue Xuebao21 (7): 502-9, 1986), Sho Sugars, 6-(((((2-chloroethyl) nitrosoamino-) carbonyl) amino) -6-deoxysucrose (NS-1C), and 6 '-(((((2-chloroethyl) nitrosoamino) carbonyl) amino) -6'-deoxysucrose (NS-1D) nitrosourea derivatives (Tanoh et al., Chemotherapy (Tokyo) 33 (11): 969-77, 1985), CNCC, RFCNU and chlorozotocin (Mena et al., Chemotherapy (Basel) 32 (2 ): 131-7, 1986), CNUA (Edanami et al., Chemotherapy (Tokyo) 33 (5): 455-61, 1985), 1- (2-chloroethyl) -3-isobutyl-3- (β-maltosyl)- 1-nitrosourea (Fujimoto and Ogawa, Jpn. J. Cancer Res. 76 (7): 651-6, 1985), choline-like nitrosoalkylureas (Belyaev et al., Izv. Akad. NAUK SSSR, Ser. Khim. 3: 553-7 1985), sucrose nitrosourea derivative (JP 84219300), sulfa drug nitrosourea analogue (Chiang et al., Proc. Nat'lSci. Counc., Repub. China, Part A 8 (1): 18-22, 1984) , DONU (Asanuma et al., J. Jpn. Soc. Cancer Ther. 17 (8): 2035-43, 1982), N, N'-bis (N- (2-chloroethyl) -N-nitrosocarbamoyl) cystamine (CNCC) ) (Blazsek et al., Toxicol. Appl. Pharmacol. 74 (2): 250-7, 1984), Dimethylnitrosourea (Krutova et al., Izv. Akad. NAUKSSSR, Ser. Biol. 3: 439-45, 1984), GANU (Sava and Giraldi, Cancer Chemother. Pharmacol. 10 (3): 167-9, 1983), CCNU (Capelli et al., Med., Biol., Environ. 11 (1): 111-16, 1983), 5-amino Methyl-2'-deoxyuridine nitrosourea analogue (Shiau, ShihTa Hsueh Pao (Taipei) 27: 681-9, 1982) TA-077 (Fujimoto and Ogawa, Cancer Chemother. Pharmacol. 9 (3): 134-9, 1982), gentianose nitrosourea derivatives (JP 82 80396), CNCC, RFCNU, RPCNU and chlorozotocin (CZT) (Marzin et al., INSERMSymp., 19 (Nitrosoureas Cancer Treat.): 165-74, 1981), thiocolchicine nitrosourea analog (George, ShihTa Hsueh Pao (Taipei) 25: 355-62, 1980), 2-chloroethyl-nitrosourea (Zeller) And Eisenbrand, Oncology 38 (1): 39-42, 1981), ACNU, (1- (4-amino-2-methyl-5-pyrimidinyl) methyl-3- (2-chloroethyl) -3-nitrosourea hydrochloride) (Shibuya et al., GanTo Kagaku Ryoho 7 (8): 1393-401, 1980), N-deacetylmethylthiocolchicine nitrosourea analogue (Lin et al., J. Med. Chem. 23 (12): 1440-2, 1980) , Pyridine and piperidine nitrosourea derivatives (Crider et al., J. Med. Chem. 23 (8): 848-51, 1980), methyl-CCNU (Zimber and Perk, Refu Vet. 35 (1): 28, 1978), fencesimidonitrosourea derivatives (Crider et al., J. Med. Chem. 23 (3): 324-6, 1980), ergoline nitrosourea derivatives (Crider et al., J. Med. Chem. 22 (1): 32-5, 1979), glucopyranose nitrosourea derivative (JP 78 95917), 1- (2-chloroethyl) -3-cyclohexyl-1-nitrosourea (Farmer et al., J Med. Chem. 21 (6): 514-20, 1978), 4- (3- (2-chloroethyl) -3-nitrosoleido-o) -cis-cyclohexanecarboxylic acid (Drewinko et al., CancerTreat. Rep. 61 (8): J1513-18, 1977), RPCNU (ICIG 1163) (Larnicol et al., Biomedicine 26 (3): J176-81, 1977), IOB-252 (Sorodoc et al., Rev. Roum. Med., Virol. 28 ( 1): J55-61, 1977), 1,3-bis (2-chloroethyl) -1-nitrosourea (BCNU) (Siebert and Eisenbrand, Mutat. Res. 42 (1): J45-50, 1977), 1 -Tetrahydroxycyclopentyl-3-nitroso-3- (2-chloroethyl) -urea (4,039,578), d-1- 1- (β-Chloroethyl) -3- (2-oxo-3-hexahydroazepinyl) -1-nitrosourea (3,859,277) and gentianose nitrosourea derivatives (JP57080396), 6-S-aminoacyloxymethyl mercapto Purine derivatives (Harada et al., Chem. Pharm. Bull. 43 (10): 793-6, 1995), 6-mercaptopurine (6-MP) (Kashida et al., Biol. Pharm. Bull. 18 (11): 1492 7, 1995), 7,8-polymethyleneimidazo-1,3,2-diazaphosphorine (Nilov et al., Mendeleev Commun. 2:67, 1995), azathioprine (Chifotides et al., J. Inorg. Biochem. 56 (4): 249 -64, 1994), methyl-D-glucopyranoside mercaptopurine derivatives (DaSilva et al., Eur. J. Med. Chem. 29 (2): 149-52, 1994) and s-alkynyl mercaptopurine derivatives (Ratsino et al., Khim. -Farm.Zh. 15 (8): 65-7, 1981), methotrexate derivatives containing indoline ring and modified ornithine or glutamic acid (Matsuoka Bull. 45 (7): 1146-1150, 1997), methotrexate derivatives containing alkyl-substituted benzene rings C (Matsuoka et al., Chem. Pharm. Bull. 44 (12): 2287-2293, 1996) , A methotrexate derivative containing a benzoxazine or benzothiazine moiety (Matsuoka et al., J. Med. Chem. 40 (1): 105-111, 1997), 10-deazaaminopterin analog (DeGraw et al., J. Med. Chem. 40 (3): 370-376, 1997), 5-deazaaminopterin and 5,10-dideazaaminopterin methotrexate analogues (Piper et al., J. Med. Chem. 40 (3): 377-384, 1997 ), Methotrexate derivatives containing an indoline moiety (Matsuoka et al., Chem. Pharm. Bull. 44 (7): 1332-1337, 1996), lipophilic amide methotrexate derivatives (Pignatello et al., WorldMeet. Pharm., Biopharm. Pharm. Technol. , 563-4, 1995), including L-threo- (2S, 4S) -4-fluoroglutamic acid and DL-3,3-difluoroglutamic acid Totrexate analog (Hart et al., J. Med. Chem. 39 (1): 56-65, 1996), methotrexate tetrahydroquinazoline analog (Gangjee et al., J. Heterocycl. Chem. 32 (1): 243-8, 1995) ), N- (α-aminoacyl) methotrexate derivatives (Cheung et al., Pteridines 3 (1-2): 101-2, 1992), biotin methotrexate derivatives (Fan et al., Pteridines 3 (1-2): 131-2, 1992) , D-glutamic acid or D-erythro, threo-4-fluoroglutamate methotrexate analogue (McGuire et al., Biochem. Pharmacol. 42 (12): 2400-3, 1991), β, γ-methanomethotrexate analogue (Rosowsky et al., Pteridines 2 (3): 133-9, 1991), 10-deazaaminopterin (10-EDAM) analog (Braakhuis et al., Chem. Biol. Pteridines, Proc. Int. Symp. Pteridines Folic Acid Deriv., 1027- 30, 1989), γ-tetrazole methotrexate analogue (Kalman et al., Chem. Biol. Pteridines, Proc. Int. Symp. Pteridines Folic Ac id Deriv., 1154-7, 1989), N- (L-α-aminoacyl) methotrexate derivatives (Cheung et al., Heterocycles 28 (2): 751-8, 1989), meta and ortho isomers of aminopterin (Rosowsky et al. , J. Med. Chem. 32 (12): 2582, 1989), hydroxymethylmethotrexate (DE 267495), γ-fluoromethotrexate (McGuire et al., CancerRes. 49 (16): 4517-25, 1989), polyglutamyl methotrexate Derivatives (Kumar et al., Cancer Res. 46 (10): 5020-3, 1986), gem-diphosphonate methotrexate analogues (WO 88/06158), α- and γ-substituted methotrexate analogues (Tsushima et al., Tetrahedron44 (17 ): 5375-87, 1988), 5-methyl-5-deazamethotrexate analog (4,725,687), Nδ-acyl-Nα- (4-amino-4-deoxypteroyl) -L-ornithine derivative (Rosowsky et al., J. Med. Chem. 31 (7): 1332-7, 1988), 8-deazamethotrexate analogues (Kuehl et al., CancerRe s. 48 (6): 1481-8, 1988), acivicin methotrexate analogues (Rosowsky et al., J. Med. Chem. 30 (8): 1463-9, 1987), polymeric platinol methotrexate derivatives (Carraher Polym. Sci. Technol. (Plenum), 35 (Adv. Biomed. Polym.): 311-24, 1987), methotrexate-γ-dimyristoyl phosphatidylethanolamine (Kinsky et al., Biochim. Biophys. Acta 917) (2): 211-18, 1987), methotrexate polyglutamate analogues (Rosowsky et al., Chem. Biol. Pteridines, Pteridines Folic Acid Deriv., Proc. Int. Symp. Pteridines Folic Acid Deriv .: Chem., Biol. Clin Aspects, 985-8, 1986), poly-γ-glutamyl methotrexate derivatives (Kisliuk et al., Chem. Biol. Pteridines, Pteridines Folic Acid Deriv., Proc. Int. Symp. Pteridines Folic Acid Deriv .: Chem., Biol. Clin Aspects: 989-92, 1986), methotrexate deoxyuridylate derivatives (Webber et al., Chem. Biol. Pteridines, Pter Ind. Symp. Pteridines Folic Acid Deriv .: Chem., Biol. Clin. Aspects: 659-62, 1986), iodoacetyl lysine methotrexate analogues (Delcamp et al., Chem. Biol. Pteridines, Pteridines Folic Acid Deriv., Proc. Int. Symp. Pteridines Folic Acid Deriv .: Chem., Biol. Clin. Aspects: 807-9, 1986), 2, .Ω.-methotrexate analogs containing diaminoalkanoic acids (McGuire et al., Biochem. Pharmacol. 35 (15): 2607-13, 1986), polyglutamate methotrexate derivatives (Kamen and Winick, Methods Enzymol. 122 (Vitam. Coenzymes, Pt. G): 339-46, 1986), 5-methyl- 5-deaza analogues (Piper et al., J. Med. Chem. 29 (6): 1080-7, 1986), quinazoline methotrexate analogues (Mastropaolo et al., J. Med. Chem. 29 (1): 155-8, 1986), pyrazine methotrexate analogues (Lever and Vestal,
J. Heterocycl. Chem. 22 (1): 5-6, 1985), cysteic acid and homocysteic acid methotrexate analogues (4,490,529), γ-tert-butyl methotrexate ester (Rosowsky et al., J. Med. Chem. 28 ( 5): 660-7, 1985), fluorinate domethotrexate analogue (Tsushima et al., Heterocycles 23 (1): 45-9, 1985), folate methotrexate analogue (Trombe, J. Bacteriol. 160 (3): 849- 53, 1984), phosphonoglutamate analogues (Sturtz and Guillamot, Eur. J. Med. Chem .-- Chim. Ther. 19 (3): 267-73, 1984), poly (L-lysine) methotrexate conjugates (Rosowsky et al., J. Med. Chem. 27 (7): 888-93, 1984), dilysine and trilysine methotrexate derivatives (Forsch and Rosawsky, J. Org. Chem. 49 (7): 1305-9, 1984). 7-hydroxymethotrexate (Fabre et al., Cancer Res. 43 (10): 4648-52, 1983), poly-γ-glutamyl methotrexate analogues (Piper and Montgomery, Adv. Exp. Med. Biol., 163 (Folyl Antifolyl Polyglutamates): 95-100, 1983), 3 ′, 5′-dichloromethotrexate (Rosowsky and Yu, J. Med. Chem. 26 (10): 1448-52, 1983), diazo ketone and chloromethyl ketone methotrexate analogues (Gangjee et al., J. Pharm. Sci. 71 (6): 717-19, 1982), 10-propargylaminopterin and alkyl methotrexate analogues (Piper et al. J. Med. Chem. 25 (7): 877-80, 1982), lectin derivatives of methotrexate (Lin et al., JNCI 66 (3): 523-8, 1981), polyglutamate methotrexate derivatives (Galivan, Mol. Pharmacol. 17 (1): 105-10, 1980), halogenated methotrexate derivatives (Fox, JNCI 58 (4): J955-8, 1977), 8-alkyl-7,8-dihydro analogs (Chaykovsky et al., J Med. Chem. 20 (10): J1323-7, 1977), 7-methylmethotrexate derivatives and dichloromethotrexate (Rosowsky and Chen, J. Med. Chem. 17 (12): J1308-11, 1974), lipophilic methotrexate derivatives and 3 ′, 5′-dichloromethotrexate (Rosowsky, J. Med. Chem. 16 (10): J1190-3 1973), deazaamethopterin analogues (Montgomery et al., Ann. NYAcad. Sci. 186: J227-34, 1971), MX068 (Pharma Japan, 1658: 18, 1999) and cysteic acid and homocysteic acid methotrexate analogues (EPA0142220), N3-alkylated analogues of 5-fluorouracil (Kozai et al., J. Chem. Soc., Perkin Trans. 1 (19): 3145-3146, 1998), 1,4-oxaheteroe 5-Fluorouracil derivatives with pan moieties (Gomez et al., Tetrahedron54 (43): 13295-13312, 1998), 5-fluorouracil and nucleoside analogues (Li, AnticancerRes. 17 (1A): 21-27, 1997), Cis- and trans-5-fluoro-5,6-dihydro-6-alkoxyuracil (Van derWilt et al., Br. J. Cancer 68 (4): 702-7, 1993), Clopentane 5-fluorouracil analogue (Hronowski and Szarek, Can. J. Chem. 70 (4): 1162-9, 1992), A-OT-fluorouracil (Zhang et al., Zongguo Yiyao GongyeZazhi 20 (11): 513- 15, 1989), N4-trimethoxybenzoyl-5'-deoxy-5-fluorocytidine and 5'-deoxy-5-fluorouridine (Miwa et al., Chem. Pharm. Bull. 38 (4): 998-1003, 1990 ), 1-hexylcarbamoyl-5-fluorouracil (Hoshi et al., J. Pharmacobio-Dun. 3 (9): 478-81, 1980. Maehara et al., Chemotherapy (Basel) 34 (6): 484-9, 1988), B-3839 (Prajda et al., In Vivo 2 (2): 151-4, 1988), uracil-1- (2-tetrahydrofuryl) -5-Fluorouracil (Anai et al., Oncology 45 (3): 144-7, 1988), 1- (2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) -5-fluorouracil (Suzuko et al., Mol. Pharmacol. 31 (3): 301-6, 1987), doxyfluridine (Matuura et al., Oyo Yakuri 29 (5): 803-31, 1985), 5'-deoxy-5-fluorouridine (Bollag And Hartmann, Eur. J. Cancer 16 (4): 427-32, 1980), 1-acetyl-3-O-toluyl-5-fluorouracil (Okada, Hiroshima J. Med. Sci. 28 (1): 49. -66, 1979), 5-fluorouracil-m-formylbenzene-sulfonate (JP 55059173), N '-(2-furanidyl) -5-fluorouracil (JP53149985) and 1- (2-tetrahydrofuryl)- 5-Fluorouracil (JP 52089680), 4'-epidoxorubicin (Lanius, A dv. Chemother. Gastrointest. Cancer, (Int. Symp.), 159-67, 1984), N-substituted deacetylvinblastine amide (vindesine) sulfate (Conrad et al., J. Med. Chem. 22 (4): 391- 400, 1979), and etoposide analogues including Cu (II) -VP-16 (etoposide) complex (Tawa et al., Bioorg. Med. Chem. 6 (7): 1003-1008, 1998), pyrrole carboxamidino ( Ji et al., Bioorg. Med. Chem. Lett. 7 (5): 607-612, 1997), 4β-amino etoposide analogue (Hu, University of North Carolina Dissertation, 1992), γ-lactone ring-modified arylamino etoposide analogue (Zhou et al., J. Med. Chem. 37 (2): 287-92, 1994), N-glucosyl etoposide analogues (Allevi et al., Tetrahedron Lett. 34 (45): 7313-16, 1993), etoposide A- Ring analogs (Kadow et al., Bioorg. Med. Chem. Lett. 2 (1): 17-22, 1992), 4′-deshydroxy-4′-methyl etoposide (Saulnier et al., Bioorg. Med. Chem. Lett. 2 (10): 1213-18, 1992), Penz Rum ring etoposide analogues (Sinha et al., Eur. J. Cancer 26 (5): 590-3, 1990) and E-ring desoxyetoposide analogues (Saulnier et al., J. Med. Chem. 32 (7): 1418 -20, 1989).

  In one embodiment of the invention, the cell cycle inhibitor is paclitaxel, a compound that disrupts mitosis (M phase) by binding to tubulin and forming an abnormal mitotic spindle, or an analog thereof Or a derivative. In brief, paclitaxel is a highly derivatized diterpenoid (Wani et al., J. Am. Chem. Soc. 93: 2325, 1971), also known as the yew (scientific name Taxus brevifolia, or Pacific Yew) ) And Taxomyces Andreanae epidermis and harvested and dried, as well as from endophytic fungi of Pacific yew (Stierle et al., Science 60: 214-216, 1993). “Paclitaxel” (in this document, for example, TAXOL (Bristol MyersSquibb, New York, NY), TAXOTERE (Aventis Pharmaceuticals, France), docetaxel, 10-desacetyl analog of paclitaxel, and 3′N of paclitaxel -Debenzoyl-3'Nt-butoxycarbonyl analogs, etc., including pharmaceutical forms, prodrugs, analogs and derivatives) are readily prepared using techniques well known to those skilled in the art (Schiff et al., Nature 277: 665-667, 1979, Long and Fairchild, Cancer Research 54: 4355-4361, 1994. Ringeland Horwitz, J. Nat'l Cancer Inst. 83 (4): 288-291, 1991. Pazdur. Others, CancerTreat. Rev. 19 (4): 351-386, 1993. WO 94/07882, WO 94/07881, WO 94/07880, WO94 / 07876, WO 93/23555, WO 93/10076, WO94 / 00156, WO 93/24476, EP 590267, WO94 / 20089, US Patent No. 5,294,63 7,5,283,253,5,279,949,5,274,137,5,202,448,5,200,534,5,229,529,5,254,580,5,412,092,5,395,850,5,380,751,5,350,866,4,857,653,5,272,171,5,411,984,5,248,796,5,248,796,5,422,364,5,300,638,5,294,637,5,362,831,5,440,056,4,814,470,5,278,324,5,352,805, 5,411,984, 5,059,699, 4,942,184, Tetrahedron Letters 35 (52): 9709-9712, 1994. J. Med. Chem. 35: 4230-4237, 1992. J. Med. Chem. 34: 992-998, 1991. J. Natural Prod 57 (10): 1404-1410, 1994, J. Natural Prod. 57 (11): 1580-1583, 1994. J. Am. Chem. Soc. 110: 6558-6560, 1988, etc.) or a variety of commercial sources including, for example, Sigma Chemical Co. (from T7402-Taxus brevifolia) in St. Louis, Missouri Available from

  Representative examples of paclitaxel derivatives and analogs include 7-deoxy-docetaxol, 7,8-cyclopropataxane, N-substituted 2-azetidones, 6,7-epoxy paclitaxel, 6,7-modified Paclitaxel, 10-desacetoxytaxol, 10-deacetyltaxol (derived from 10-deacetylbaccatin III), carbon salt derivatives of phosphonooxy and taxol, taxol 2 ', 7-di (sodium 1,2-benzenedicarboxylate, 10-desacetoxy-11,12-dihydrotaxol-10,12 (18) -diene derivative, 10-desacetoxytaxol, protaxol (a derivative of 2'-O-ester and / or 7-O-ester), ( 2′-O-carbon salts and / or 7-O-carbon salt derivatives), asymmetric synthesis of taxol side chains, fluorotaxol, 9-deoxotaxane, (13-acetyl-9-deoxobaccatin III, 9-de Oxotaxol, 7-deoxy-9-deoxotaxol, 10-desacetoxy-7-deoxy-9-deoxotaxol, derivatives containing hydrogen and acetyl groups as well as hydroxy and tert-butoxycarbonylamino, sulfonated 2'- Acryloyl taxol and sulfonated 2′-O-acyl acid taxol derivatives, succinyl taxol, 2′-γ-aminobutyryl taxol formate, 2′-acetyl taxol, 7-acetyl taxol, 7-glycine carbamate taxol, 2 '-OH-7-PEG (5000) carbamate taxol, 2'-benzoyl and 2', 7-dibenzoyl taxol derivatives, other prodrugs (2'-acetyltaxol, 2 ', 7-diacetyltaxol, 2 'Succinyl taxol, 2'-(beta-alanyl) -taxol), 2'γ-aminobutyryl taxol formate, 2'-succinyl Ethylene glycol derivatives of xol, 2'-glutaryltaxol, 2 '-(N, N-dimethylglycyl) taxol, 2'-(2- (N, N-diethylamino) propionyl) taxol, 2'orthocarboxybenzoyltaxol 2 'aliphatic carboxylic acid derivatives of taxol, prodrug {2' (N, N-diethylaminopropionyl) taxol, 2 '(N, N-dimethylglycyl) taxol, 7 (N, N-dimethylglycyl) taxol 2 ', 7-di- (N, N-dimethylglycyl) taxol, 7 (N, N-diethylaminopropionyl) taxol, 2', 7-di (N, N-diethylaminopropionyl) taxol, 2 '-( L-glycyl) taxol, 7- (L-glycyl) taxol, 2 ', 7-di (L-glycyl) taxol, 2'-(L-alanyl) taxol, 7- (L-alanyl) taxol, 2 ', 7-di (L-alanyl) taxol, 2 '-(L-leucyl) taxol, 7- (L-leucyl) taxo , 2 ', 7-di (L-Leucyl) taxol, 2'-(L-Isoleucil) taxol, 7- (L-Isoleucil) taxol, 2 ', 7-Di (L-Isoleucil) taxol, 2'-( L-valyl) taxol, 7- (L-valyl) taxol, 2'7-di (L-valyl) taxol, 2 '-(L-phenylalanyl) taxol, 7- (L-phenylalanyl) taxol, 2 ', 7-di (L-phenylalanyl) taxol, 2'-(L-prolyl) taxol, 7- (L-prolyl) taxol, 2 ', 7-di (L-prolyl) taxol, 2'- (L-lysyl) taxol, 7- (L-lysyl) taxol, 2 ', 7-di (L-lysyl) taxol, 2'-(L-glutamyl) taxol, 7- (L-glutamyl) taxol, 2 ' , 7-di (L-glutamyl) taxol, 2 '-(L-arginyl) taxol, 7- (L-arginyl) taxol, 2', 7-di (L-arginyl) taxol}, modified phenylisoserine side chain Taxol analog, TAXOTERE, (N-de Nzoyl-N-tert- (butoxycaronyl) -10-deacetyltaxol, and taxanes (such as baccatin III, cephalomannin, 10-deacetylbaccatin III, brevifoliol, yunantaxusin and taxin) And other taxane analogs and derivatives, including 14-β-hydroxy-10 deacetylbaccatin III, debenzoyl-2-acyl paclitaxel derivatives, benzoate paclitaxel derivatives, phosphonooxy and carbon salt paclitaxel derivatives, sulfones 2'-acryloyl taxol, sulfonated 2'-O-acyl acid paclitaxel derivative, 18-site-substituted paclitaxel derivative, chlorinated paclitaxel analog, C4 methoxy ether paclitaxel derivative, sulfonamide taxane derivative, brominated paclitaxel Analogues, girald taxane derivatives, nitrophenyl paclitaxel, 10-deacetylated substituted paclitaxel derivatives, 14-beta-hydroxy-10 deacetylbaccatin III taxane derivatives, C7 taxane derivatives, C10 taxane derivatives, 2-debenzoyl-2 -Acyl taxane derivatives, 2-debenzoyl and -2-acyl paclitaxel derivatives, taxanes and baccatin III analogues containing new C2 and C4 functional groups, n-acyl paclitaxel analogues, 10-deacetylbaccatin III and 10-de 7-protected-10-deacetylbaccatin III derivative from acetyltaxol A, 10-deacetyltaxol B, and 10-deacetyltaxol, benzoate derivative of taxol, 2-aroyl-4-acylpaclitaxel analog, ortho -Ester paclitaxel analog, 2-aroyl-4-acyl paclitaxe And 1-deoxypaclitaxel and 1-deoxypaclitaxel analogs.

  In one embodiment, the cell cycle inhibitor is a taxane having the formula (C1):

The part highlighted in gray can be replaced, and the part not highlighted is the taxane core. The side chain (labeled “A” in the chart) is preferably present because the compound has good quality activity as a cell cycle inhibitor. Examples of compounds having this structure include paclitaxel (MerckIndex entry 7117), docetaxel (Taxotere, MerckIndex entry 3458) and 3'-desphenyl-3 '-(4-nitrophenyl) -N-debenzoyl-N- (t -Butoxycarbonyl) -10-deacetyltaxol.

  In one embodiment, suitable taxanes such as paclitaxel and analogs and derivatives thereof are disclosed as having structure (C2) in US Pat. No. 5,440,056:

X is oxygen (paclitaxel), hydrogen (9-deoxy derivative), thioacyl, or dihydroxyl precursor, and R ₁ is selected from paclitaxel or taxotere side chain of formula (C3) or alkanoyl.

R ₇ is selected from hydrogen, alkyl, phenyl, alkoxy, amino, phenoxy (substituted or unsubstituted), and R ₈ is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, phenyl (substituted or unsubstituted), α or selected from β-naphthyl, and R ₉ is selected from hydrogen, alkanoyl, substituted alkanoyl, and aminoalkanoyl, where substituted is hydroxy, sulfhydryl, total alkoxy, carboxyl, halogen, thioalkoxy, N, N-diethylamino , Alkylamino, dialkylamino, nitro, and -OSO ₃ H, and / or may include groups containing such substitutions, where R ₂ is hydrogen, hydroxy, alkyl, alkanoyloxy, aminoalkanoyloxy, and Peptidylalkanoyloxy Is selected from hydrogen or oxygen-containing group, R ₃ is hydrogen, hydroxy, alkyl, alkanoyloxy, amino alkanoyloxy, and Bae selected from hydrogen or oxygen-containing groups such as peptidyl alkanoyloxy, or even a silyl containing group or a sulfur-containing R ₄ is selected from acyl, alkyl, alkanoyl, aminoalkanoyl, peptidylalkanoyl and aroyl, R ₅ is selected from acyl, alkyl, alkanoyl, aminoalkanoyl, peptidylalkanoyl and aroyl, and R ₆ is hydrogen, hydroxy Selected from hydrogen or oxygen containing groups such as alkyl, alkanoyloxy, aminoalkanoyloxy, and peptidylalkanoyloxy.

In one embodiment, paclitaxel analogs and derivatives useful as cell cycle inhibitors are disclosed in PCT International Patent Application WO 93/10076. As disclosed in this publication, analogs or derivatives have side chains attached to the taxane nucleus at C ₁₃ as shown in the following structure (formula C4) to confer antitumor activity to the taxane. There is a case.

WO 93/10076 discloses that a taxane nucleus can be substituted at any position except an existing methyl group. Such substitutions include, for example, hydrogen, alkanoyloxy, alkenoyloxy, allyl oiloxy. In addition, oxo groups can be attached to carbons labeled 2, 4, 9 and / or 10. Similarly, an oxetane ring can be attached to carbons 4 and 5. Similarly, the oxirane ring can be attached to the carbon labeled 4.

In one embodiment, a taxane-based cell cycle inhibitor useful in the present invention is disclosed in US Pat. No. 5,440,056, which discloses 9-deoxotaxane. There is a compound in which the label 9 of the taxane structure shown in the above formula (formula C4) is deficient in oxo group. The taxane ring can be substituted with H, OH, OR, or O—CO—R, where R is alkyl or aminoalkyl (respectively) at the carbon positions of the 1, 7, and 10 labels. Similarly, at the carbon positions of the 2 and 4 labels (respectively), it can be substituted with an allyol, alkanoyl, aminoalkanoyl or alkyl group. The side chain of formula (C3) can be substituted at the positions of R ₇ and R ₈ (respectively) with a phenyl ring, a substituted phenyl ring, a linear alkane, and a group containing any of hydrogen, oxygen, nitrogen.

  In general, taxanes, particularly paclitaxel, are thought to function as cell cycle inhibitors by acting as microtubule inhibitors, more specifically as stabilizers. These compounds have been shown to be useful in the treatment of cell proliferative diseases including: non-small cell (NSC) lung cancer, breast cancer, prostate cancer, cervical cancer, endometrial cancer, Head and neck cancer.

  In another embodiment, the microtubule inhibitor is an albendazole (carbamic acid, (5- (propylthio) -1H-benzimidazol-2-yl]-, methyl ester), LY-355703 (1,4-dioxa- 8,11-diazacyclohexadec-13-ene-2,5,9,12-tetraone, 10-((3-chloro-4-methoxyphenyl) methyl) -6,6-dimethyl-3- (2 -Methylpropyl) -16-((1S) -1-((2S, 3R) -3-phenyloxiranyl) ethyl)-, (3S, 10R, 13E, 16S)-), vindesine (vincaleucoblastine , 3- (aminocarbonyl) -O4-deacetyl-3-de (methoxycarbonyl)-), or WAY-174286.

  In another aspect, the cell cycle inhibitor is a vinca alkaloid. Vinca alkaloids have the following general structure. These are indole-dihydroindole dimers.

As disclosed in US Pat. Nos. 4,841,045 and 5,030,620, R ₁ can be a formyl or methyl group, and can alternatively be hydrogen. R ₁ can also be an alkyl group or an aldehyde-substituted alkyl (eg, CH ₂ CHO). In general, R ₂ is a CH ₃ group or an NH ₂ group. However, instead of substituting with a lower alkyl ester, an ester bound to the dihydroindole core, where R is NH ₂ , an amino acid ester, or a peptide ester, can be substituted with C (O) —R. R ₃ is usually C (O) CH ₃ , CH ₃ or hydrogen. As an alternative, the bifunctional group can be linked by a protein fragment such as maleoyl amino acid. R ₃ can also be substituted to form an alkyl ester, which can be further substituted. R ₄ can be —CH ₂ — or a single bond. R ₅ and R ₆ can be hydrogen, OH or lower alkyl (generally —CH ₂ CH ₃ ). Alternatively, R ₆ and R ₇ can be combined to form an oxetane ring. R ₇ may alternatively be hydrogen. For further substitutions, the methyl group can then be replaced with other alkyl groups, thereby derivatizing the unsaturated ring by adding side chains such as alkanes, alkenes, alkynes, halogens, esters, amides, or amino groups. Also includes molecules.

  Typical vinca alkaloids are vinblastine, vincristine, vincristine sulfate, vindesine, and vinorelbine having the following structure:

Analogs usually require side chains (shaded parts) to have activity. These compounds are thought to act as cell cycle inhibitors due to their function as microtubule inhibitors, more specifically, their ability to inhibit polymerization. These compounds treat proliferative disorders such as NSC lung cancer, small cell lung cancer, breast cancer, prostate cancer, brain cancer, head and neck cancer, retinoblastoma, bladder cancer, penile cancer, and soft tissue sarcoma. Have been shown to be useful.

  In another embodiment, the cell cycle inhibitor is camptothecin, or an analog or derivative thereof. Camptothecin has the following general structure:

In this structure, X is generally oxygen, but in the case of 21-lactam derivatives, it can be other groups such as NH. R ₁ is usually hydrogen or OH, but may be other groups such as a terminally hydroxylated C _1-3 alkane. R ₂ is usually hydrogen or a group containing amino such as (CH ₃ ) ₂ NHCH ₂ , but other groups such as NO ₂ , NH ₂ , halogen, etc. (disclosed in US Pat. No. 5,552,156), or these It may be a single chain alkane containing a group. R ₃ is usually hydrogen or a short chain alkyl such as C ₂ H ₅ . R ₄ is usually hydrogen but may be other groups such as a methylenedioxy group with R ₁ .

  Typical camptothecin compounds include topotecan, irinotecan (CPT-11), 9-aminocamptothecin, 21-lactam-20 (S) -camptothecin, 10,11-methylenedioxycamptothecin, SN-38, 9-nitrocamptothecin And 10-hydroxycamptothecin. A typical compound has the following structure:

Camptothecin has five rings as shown here. In order to maximize activity and minimize toxicity, the ring with label E must remain intact (a lactone rather than a carboxylate form). These compounds are useful as cell cycle inhibitors and may function as topoisomerase I inhibitors and / or DNA cleaving agents. These have been shown to be useful in the treatment of proliferative disorders such as NSC lung cancer, small cell lung cancer, cervical cancer, and the like.

  In another embodiment, the cell cycle inhibitor is podophyllotoxin, or a derivative or analog thereof. Typical compounds of this type include etoposide and teniposide, which have the following structure:

These compounds are believed to function as cell cycle inhibitors, as topoisomerase II inhibitors and / or DNA cleaving agents. They have been shown to be useful as antiproliferative agents in small cell lung cancer, prostate cancer, brain cancer, and retinoblastoma.

  Another example of a DNA topoisomerase inhibitor is luruthecan dihydrochloride (11H-1,4-dioxyno (2,3-g) pyrano (3 ', 4': 6,7) indolizino (1,2-b) Kirin-9,12 (8H, 14H) -dione, 8-ethyl-2,3-dihydro-8-hydroxy-15-((4-methyl-1-piperazinyl) methyl)-, dihydrochloride, (S) -) There is.

  In another aspect, the cell cycle inhibitor is an anthracycline. Anthracyclines have the following general structure, where the R group may be a variant of an organic acid group.

According to US Pat. No. 5,594,158, suitable R groups are as follows: R ₁ is CH ₃ or CH ₂ OH, R ₂ is daunosamine or hydrogen, R ₃ and R ₄ are OH, NO ₂ , NH ₂ , F, Cl, Br, I, CN, H or those, respectively R _5-7 are all H or R ₅ , R ₆ is H, R ₇ and R ₈ are alkyl or halogen, or vice versa. R ₇ and R ₈ are H and R ₅ and R ₆ are alkyl or halogen.

According to US Pat. No. 5,843,903, R2 may be a glycoconjugate peptide. According to US Pat. Nos. 4,215,062 and 4,296,105, R ₅ may be OH or an ether-linked alkyl group. R ₁ also can be linked to the anthracycline ring by alkyl or a group other than C (O), such as branched alkyl groups having C (O) linking moiety at its end portion, as this example, -CH ₂ CH (CH ₂ —X) C (O) —R _{1 and the} like, where X is H or an alkyl group (see US Pat. No. 4,215,062). Alternatively, R ₂ may be a group to which a functional group = N—NHC (O) —Y is bonded, where Y is a group such as phenyl or a substituted phenyl ring. Alternatively, R ₃ can have the following structure:

Here, R ₉ is OH in the plane or out of plane of the ring, or a second sugar moiety such as R ₃ . R ₁₀ is H, or forms a secondary amine with a group such as a saturated or partially saturated 5- or 6-membered heterocyclic aromatic group having at least one ring nitrogen (US Pat. (See 5,843,903). Alternatively, R ₁₀ can be derived from an amino acid having the structure —C (O) CH (NHR ₁₁ ) (R ₁₂ ), where R ₁₁ is H or together with R _{12 is} C ₃₋ Forms a _4- part alkylene. R ₁₂ includes H, alkyl, aminoalkyl, amino, hydroxy, mercapto, phenyl, benzyl or methylthio (see US Pat. No. 4,296,105).

  Typical anthracyclines are doxorubicin, daunorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, and carubicin. Suitable compounds have the following structure:

Other suitable anthracyclines include anthramycin, mitoxantrone, menogalyl, nogaramycin, aclacinomycin A, olivomycin A, chromomycin A ₃ and pricamycin having the following structure:

These compounds are believed to function as cell cycle inhibitors, as topoisomerase inhibitors and / or DNA cleaving agents. These are proliferative, such as small cell lung cancer, breast cancer, endometrial cancer, head and neck cancer, retinoblastoma, liver cancer, bile duct cancer, islet cell cancer, bladder cancer, and soft tissue sarcoma It has been shown to be useful in the treatment of disorders.

  In another aspect, the cell cycle inhibitor is a platinum compound. In general, suitable platinum complexes are Pt (II) or Pt (IV) complexes having the following basic structure:

Here, X and Y are anionic leaving groups such as sulfate, phosphate, carboxylate, and halogen. R ₁ and R ₂ can be further substituted with alkyl, amine, aminoalkyl and are essentially inert or bridging groups. In the Pt (II) complex, Z ₁ and Z ₂ are not present. In Pt (IV), Z ₁ and Z ₂ can be negative groups such as halogen, hydroxy, carboxylate, ester, sulfate or phosphate. See the following US patent number. 4,588,831 and 4,250,189.

  Suitable platinum complexes can contain multiple platinum atoms. See US Pat. Nos. 5,409,915 and 5,380,897. For example, platinum bis complex or triplatinum complex type:

Exemplary platinum compounds include cisplatin, carboplatin, oxaliplatin and miboplatin having the following structure:

These compounds are considered to function as cell cycle inhibitors by binding to DNA, that is, acting as DNA alkylating agents. These compounds are NSC lung cancer, small cell lung cancer, breast cancer, cervical cancer, brain cancer, head and neck cancer, esophageal cancer, retinoblastoma, liver cancer, bile duct cancer, bladder cancer, penis It has been shown to be useful in the treatment of cell proliferative diseases such as cancer, vulvar cancer and soft tissue sarcoma.

  In another embodiment, the cell cycle inhibitor is nitrosourea. Has the following general structure (C5), where the general R groups are:

Other suitable R groups include cyclic alkanes, alkanes, halogen substituents, saccharides, aryl groups and heteroaryl groups, phosphonyl groups, sulfonyl groups, and the like. As disclosed in U.S. Patent No. 4,367,239, R is _{CH 2 -C (X) (Y} ) is it is appropriate (Z), where X and Y are, or the same of the following groups Different constituents: phenyl, cyclyl, or phenyl groups substituted with halogen, lower alkyl (C _1-4 ), trifluoromethyl, cyano, phenyl, cyclohexyl, lower alkyloxy (C _1-4 ), etc. Or a cyclohexyl group. Z has a structure of -alkylene-NR ₁ R ₂ , wherein R ₁ and R ₂ have the same or different constituents as the lower alkyl group (C _1-4 ) or benzyl group, or R ₁ and R ₂ can be combined to form a saturated 5- or 6-membered heterocycle such as pyrrolidine, piperidine, morpholine, thiomorpholine, N-lower alkylpiperazine, where the heterocycle can be any lower alkyl group. Can be substituted.

As disclosed in US Pat. No. 6,096,923, R and R ′ in (C5) are the same or different, each having 1-10 carbons, substituted or unsubstituted carbonization Hydrogen. Substitutions include hydrocarbyl groups, halo groups, ester groups, amide groups, carboxylic acids, ether groups, thioether groups and alcohol groups. As disclosed in US Pat. No. 4,472,379, R of formula (C5) is an amide bond and a pyranose structure (eg, methyl 2 ′-(N- (N- (2-chloroethyl) -N-nitroso-carbamoyl)) -Glycyl) amino-2'-deoxy-α-D-glucopyranoside). As disclosed in US Pat. No. 4,150,146, R in formula (C5) can be an alkyl group of 2 to 6 carbons, and can be substituted with an ester group, a sulfonyl group, or a hydroxyl group. It can also be substituted with a carboxylic acid or CONH ₂ group.

  Exemplary nitrosoureas include BCNU (carmustine), methyl-CCNU (semmustine), CCNU (lomustine), ranimustine, nimustine, chlorozotocin, hotemustine, and streptozocin having the following structure:

These nitrosourea compounds are considered to function as cell cycle inhibitors by binding to DNA, that is, functioning as DNA alkylating agents. These cell cycle inhibitors have been shown to be useful in the treatment of cell proliferative diseases such as islet cell cancer, small cell lung cancer, melanoma, brain cancer and the like.

  In another embodiment, the cell cycle inhibitor is nitroimidazole, where exemplary nitroimidazoles include metronidazole, benznidazole, etanidazole, and misonidazole having the structure:

Suitable nitroimidazole compounds are described in US Pat. Nos. 4,371,540 and 4,462,992.

  In another aspect, the cell cycle inhibitor is a folate antagonist such as methotrexate or a derivative or analog thereof, such as edatrexate, trimetrexate, raltitrexed, pyritrexim, denopterin, tomdex, and pteropterin . Methotrexate analogs have the following general structure:

The R group can be selected from organic acid groups, particularly those described in US Pat. Nos. 5,166,149 and 5,382,582. R ₁ is N, R ₂ is N or C (CH ₃ ), R ₃ and R ₃ 'are H or alkyl (such as CH ₃ ), R ₄ is a single bond or NR (where R is H or an alkyl group) can do. R _5,6,8 can be H, OCH ₃ or can alternatively be a halogen or hydro group. R ₇ is a side chain with the following general structure.

Here, n = 1 for methotrexate and n = 3 for pteropterin. The carboxyl group in the side chain can be esterified or can form salts such as Zn ²⁺ salts. R ₉ and R ₁₀ can be NH ₂ and can also be alkyl substituted.

  A typical folic acid antagonist compound has the following structure:

These compounds are thought to function as cell cycle inhibitors by acting as antimetabolites of folic acid. They have been shown to be useful in the treatment of cell proliferative diseases such as soft tissue sarcoma, small cell lung cancer, breast cancer, brain cancer, head and neck cancer, bladder cancer, and penile cancer.

  In another embodiment, the cell cycle inhibitor is a cytidine analog, such as cytarabine or a derivative or analog thereof, enocitabine, FMdC ((E (-2'-deoxy-2 '-(fluoromethylene) cytidine), gemcitabine , 5-azacytidine, ancitabine, and 6-azauridine, etc. Typical compounds have the following structure:

These compounds are thought to function as cell cycle inhibitors by acting as antimetabolites of pyrimidine. These compounds have been shown to be useful in the treatment of cell proliferative diseases such as, for example, pancreatic cancer, breast cancer, cervical cancer, NSC lung cancer, and bile duct cancer.

  In another aspect, the cell cycle inhibitor is a pyrimidine analog. In one embodiment, the pyrimidine analog has the following general structure:

Here, positions 2 ′, 3 ′ and 5 ′ of the sugar ring (R ₂ , R ₃ and R ₄ , respectively) are hydrogen, hydroxyl, phosphoryl (see US Pat. No. 4,086,417, etc.) or esters (US Pat. No. 3,894,000). No.). Esters can be of the alkyl, cycloalkyl, aryl or heterocyclo / aryl type. The 2 ′ carbon can be hydroxylated with either R ₂ or R ₂ ′ and the other group is H. Alternatively, the 2 ′ carbon can be substituted with a fluoro or difluoro cytidine such as gemcitabine. Alternatively, the sugar can be substituted to another heterocyclic group such as a furyl group, or an amide-linked alkane such as an alkane, alkyl ether, or C (O) NH (CH ₂ ) ₅ CH ₃ . The 2 ° amine can be substituted with an aliphatic acyl (R ₁ ) linked by an amide (see, eg, US Pat. No. 3,991,045) or urethane (see, eg, US Pat. No. 3,894,000) linkage. It can also be further substituted to form a quaternary ammonium salt. R _{5 on the} pyrimidine ring is either N or CR, where R is hydrogen, a group containing halogen, or alkyl (see, eg, US Pat. No. 4,086,417). R ₆ and R ₇ together form an oxo group or R ₆ = -NH-R ₁ and R ₇ = H. Or R ₈ is hydrogen, R ₇ and R ₈ can together form a double bond, Although R ₈ may be the X, wherein X is as follows.

Specific pyrimidine analogs are described in US Pat. No. 3,894,000 (see 2′-O-palmityl-ara-cytidine, 3′-O-benzoyl-ara-cytidine and over 10 examples), US Pat. No. 3,991,045. (See N4-acyl-1-bD-arabinofuranosylcytosine and numerous acyl group derivatives listed therein (such as palmitoyl)).

  In another embodiment, the cell cycle inhibitor is a fluoropyrimidine analog such as 5-fluorouracil, or an analog or derivative thereof, such as carmofur, doxyfluridine, emiteflu, tegafur, and floxuridine. A typical compound has the following structure:

Other suitable fluoropyrimidine analogs include 5-FudR (5-fluoro-deoxyuridine), or analogs or derivatives thereof, including 5-iododeoxyuridine (5-IudR), 5-bromo Deoxyuridine (5-BudR), fluorouridine triphosphate (5-FUTP) and fluorodeoxyuridine monophosphate (5-dFUMP). A typical compound has the following structure:

These compounds are thought to function as cell cycle inhibitors by acting as antimetabolites of pyrimidine. These compounds are found in cells such as breast cancer, cervical cancer, non-melanoma skin, head and neck cancer, esophageal cancer, bile duct cancer, pancreatic cancer, islet cell cancer, penile cancer, and vulvar cancer. It has been shown to be useful in the treatment of proliferative diseases.

  In another aspect, the cell cycle inhibitor is a purine analog. Purine analogs have the following general structure:

Where X is generally carbon, R ₁ is hydrogen, halogen, amine or substituted phenyl, R ₂ is hydrogen, primary amine, secondary amine, tertiary amine, sulfur-containing group (generally -SH), alkane, Cyclic alkanes, heterocyclic rings or sugars, R ₃ is hydrogen, sugar (generally furanose or pyranose structure), substituted sugars or cyclic or heterocyclic alkanes or aryl groups. See US Pat. No. 5,602,140 for compounds of this type.

In the case of pentostatin, X-R2 is, -CH ₂ CH (OH) - is. In this case, a second carbon atom is inserted into the ring between X and the adjacent nitrogen atom. XN double bond becomes a single bond.

  U.S. Pat. No. 5,446,139 describes a suitable purine analog of this type shown in the following formula:

Here, N represents nitrogen, and V, W, X, and Z are either carbon or nitrogen under the following conditions. Ring A can have 0 to 3 nitrogen atoms in its structure. If there are two nitrogens in ring A, one must be in the W position. If there is only one, it must be outside the Q position. V and Q must not be nitrogen at the same time. Z and Q must not be nitrogen at the same time. When Z is nitrogen, R ₃ is not present. Further, R _1-3 is independently hydrogen, halogen, C _1-7 alkyl, C _1-7 alkenyl, hydroxyl, mercapto, C _1-7 alkylthio, C _1-7 alkoxy, C _2-7 alkenyloxy, Any of the groups containing aryloxy, nitro, primary amine, secondary amine or tertiary amine. R _5-8 is hydrogen, or at most two positions each contain one of OH, halogen, cyano, azide, substituted amino, and R ₅ and R ₇ together form a double bond it can. Y is hydrogen, C _1-7 alkylcarbonyl, or monophosphate, diphosphate or triphosphate.

  Exemplary suitable purine analogs include 6-mercaptopurine, tiguanosine, thiaminpurine, cladribine, fludaribine, tubercidin, puromycin, pentoxyphylline, where these compounds can optionally be phosphorylated. A typical compound has the following structure:

These compounds are thought to function as cell cycle inhibitors by acting as purine antimetabolites.

  In another embodiment, the cell cycle inhibitor is a nitrogen mustard. A number of suitable nitrogen mustards are known and are suitable for use as the cell cycle inhibitors of the present invention. A suitable nitrogen mustard is also known as cyclophosphamide.

  A desirable nitrogen mustard has the following general structure:

Where Ag is

Or —CH ₃ or other alkanes, or chlorinated alkanes (generally CH ₂ CH (CH ₃ ) Cl), or a polycyclic acid group such as B, or a substituted phenyl such as C or a heterocyclic group such as D .

Examples of suitable nitrogen mustards are disclosed in US Pat. No. 3,808,297, where A is:

R _1-2 is hydrogen or CH ₂ CH ₂ Cl, R ₃ is a group containing hydrogen or oxygen such as hydroperoxy, and R ₄ can be an alkyl, aryl, or heterocyclic ring.

  The annular portion need not be kept intact. See US Pat. Nos. 5,472,956, 4,908,356, and 4,841,085 which describe the following types of structures:

Here, R ₁ is hydrogen or CH ₂ CH ₂ Cl, and R _2-6 is various substituents.

  Typical nitrogen mustards include methyl chloro etamine and analogs or derivatives thereof, such as methyl chloro etamine oxide hydrochloride, nobenbiquin, mannomustine (a type of halogenated sugar) and the like. A typical compound has the following structure:

The nitrogen mustard may be cyclophosphamide, ifosfamide, perphosphamide, or trophosphamide, where these compounds have the following structure:

Nitrogen mustard, estramustine or may be an analog thereof or derivatives, including phenesterine, prednimustine, and the like estramustine PO _4. Thus, a suitable nitrogen mustard type cell cycle inhibitor of the present invention has the following structure:

The nitrogen mustard may be chlorambucil, or an analogue or derivative thereof, such as melphalan or chlormaphazine. Thus, a suitable nitrogen mustard type cell cycle inhibitor of the present invention has the following structural structure:

The nitrogen mustard may be uracil mustard and has the following structure.

Nitrogen mustard is thought to function as a cell cycle inhibitor by acting as a DNA alkylating agent. Nitrogen mustard has been shown to be useful in the treatment of cell proliferative diseases such as small cell lung cancer, breast cancer, cervical cancer, head and neck cancer, prostate cancer, retinoblastoma, and soft tissue sarcoma. Has been.

  The cell cycle inhibitor of the present invention may be hydroxyurea. Hydroxyurea has the following general structure.

Suitable hydroxyureas are disclosed, for example, in US Pat. No. 6,080,874, where R ₁ is:

R ₂ is an alkyl group having 1 to 4 carbons, R ₃ is H, acyl, methyl, either ethyl and mixtures thereof, and the like Mechirueteru to it.

Other suitable hydroxyureas are disclosed, for example, in U.S. Pat.No. 5,665,768 where R ₁ is, for example, N- (3- (5- (4-fluorophenylthio) -furyl) -2-cyclopentene- 1-yl) cycloalkenyl groups such as N-hydroxyurea, wherein R ₂ is hydrogen or an alkyl group having 1 to 4 carbons, R ₃ is hydrogen and X is hydrogen or a cation.

Other suitable hydroxyureas are disclosed, for example, in U.S. Pat.No. 4,299,778, where R ₁ is a phenyl group substituted with one or more fluorine atoms, R ₂ is a cyclopropyl group, and R ₃ And X is hydrogen.

Other suitable hydroxyureas are disclosed in US Pat. No. 5,066,658, where R ₂ and R ₃ together with the adjacent nitrogen form the following formula:

Here, m is 1 or 2, n is 0 to 2, and Y is an alkyl group.

  In one embodiment, the hydroxyurea has the following structure:

Hydroxyurea is thought to function as a cell cycle inhibitor by acting to inhibit DNA synthesis.

  In another embodiment, the cell cycle inhibitor is a mitomycin, such as mitomycin C, or an analog or derivative thereof, such as porphyromycin. A typical compound has the following structure:

These compounds are thought to function as cell cycle inhibitors by acting as DNA alkylating agents. Mitomycin has been shown to be useful in the treatment of cell proliferative diseases such as esophageal cancer, liver cancer, bladder cancer, breast cancer and the like.

  In another embodiment, the cell cycle inhibitor is an alkyl sulfonate salt, such as busulfan, or an analog or derivative thereof, such as treosulfan, improsulfan, pipersulfan, and piperbroman. A typical compound has the following structure:

These compounds are thought to function as cell cycle inhibitors by acting as DNA alkylating agents.

  In another aspect, the cell cycle inhibitor is benzamide. In another aspect, the cell cycle inhibitor is nicotinamide. These compounds have the following basic structure:

Where X is either oxygen or sulfur, A may generally be NH ₂ or OH or an alkoxy group, B is nitrogen or CR ₄ , where R ₄ is a hydroxylated alkane with an H or ether linkage ( OCH ₂ CH ₂ OH, etc.), the alkane can be either linear or branched and can also contain one or more hydroxyl groups. Instead, B is NR ₅ , in which case the double bond in the ring concerned with B is a single bond. R ₅ is hydrogen and an alkyl or aryl group (see US Pat. No. 4,258,052), R ₂ is hydrogen, OR ₆ , SR ₆ or NHR ₆ where R ₆ is an alkyl group and R ₃ Is hydrogen, lower alkyl, ether-linked lower alkyl (—O-Meor-O-ethyl), etc. (see US Pat. No. 5,215,738).

  Suitable benzamide compounds have the following structure:

Here, additional compounds are disclosed in US Pat. No. 5,215,738 (32 compounds listed).

   Suitable nicotinamide compounds have the following structure:

Here, additional compounds are disclosed in US Pat. No. 5,215,738.

In another embodiment, the cell cycle inhibitor is a halogenated sugar, such as mitractol, or an analog or derivative thereof, such as mitoblonitol and mannomustine. A typical compound has the following structure:

In another embodiment, the cell cycle inhibitor is a diazo compound, such as azaserine, or an analog or derivative thereof, including 6-diazo-5-oxo-L-norleucine and 5-diazouracil (of pyrimidine analogs). One). A typical compound has the following structure:

Other compounds that can serve as cell cycle inhibitors according to the present invention include pazelliptin, wortmannin, metoclopuramide, RSU, butionine sulfoxime, turmeric, curcumin, AG337 (thymidylate synthase inhibitor), levamisole, lentinan (Polysaccharides), razoxan (EDTA analog), indomethacin, chlorpromazine, α and β interferons, MnBOPP, gadolinium texaphyrin, 4-amino-1,8-naphthalimide, CGP staurosporine derivatives, SR-2508, etc. There is.

  Thus, in one embodiment, the cell cycle inhibitor is a DNA alylating agent. In another aspect, the cell cycle inhibitor is a microtubule inhibitor. In another aspect, the cell cycle inhibitor is a topoisomerase inhibitor. In another embodiment, the cell cycle inhibitor is a DNA cleaving agent. In another aspect, the cell cycle inhibitor is an antimetabolite. In another embodiment, the cell cycle inhibitor functions by inhibiting adenosine deaminase (such as as a purine analog). In another embodiment, the cell cycle inhibitor functions by inhibiting purine ring synthesis and / or as a nucleotide exchange inhibitor (such as as a purine analog such as mercaptopurine). In another aspect, the cell cycle inhibitor functions by inhibiting dihydrofolate reduction and / or as a thymidine monophosphate block (such as methotrexate). In another embodiment, the cell cycle inhibitor functions by causing DNA damage (such as bleomycin). In another embodiment, the cell cycle inhibitor functions as a DNA intercalator and / or RNA synthesis inhibitor (or doxorubicin, aclarubicin, or detorubicin (acetic acid, diethoxy-, 2- (4-((3- Amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl) oxy) -1,2,3,4,6,11-hexahydro-2,5,12-trihydroxy-7-methoxy-6, 11-dioxo-2-naphthacenyl) -2-oxoethyl ester, (2S-cis)-) and the like). In another embodiment, the cell cycle inhibitor functions by inhibiting pyrimidine synthesis (such as N-phosphonoacetyl-L-aspartate). In another embodiment, the cell cycle inhibitor functions by inhibiting ribonucleotides (such as hydroxyurea). In another embodiment, the cell cycle inhibitor functions by inhibiting thymidine monophosphate (such as 5-fluorouracil). In another embodiment, the cell cycle inhibitor functions by inhibiting DNA synthesis (such as cytarabine). In another embodiment, the cell cycle inhibitor functions by generating DNA adduct formation (such as a platinum compound). In another embodiment, the cell cycle inhibitor functions by inhibiting protein synthesis (L-asparginase). In another aspect, the cell cycle inhibitor functions by inhibiting microtubule function (such as a taxane). In another aspect, the cell cycle inhibitor plays its role in one or more procedures of the biological pathway shown in FIG.

  Other cell cycle inhibitors useful in the invention, as well as a discussion of the mechanism of action, see Hardman JG, Limbird LE Molinoff RB, Ruddon R W., Gilman AGeditors, Chemotherapy of Neoplastic Diseases in Goodman and Gilman's ThePharmacological Basis of Therapeutics Ninth Edition, McGraw-Hill Health Professionals Division, New York, 1996, pages 1225-1287. Also, U.S. Patent Nos. 3,387,001, 3,808,297, 3,894,000, 3,991,045, 4,012,390, 4,057,548, 4,086,417, 4,144,237, 4,150,146, 4,210,584, 4,215,062, 4,250,189, 4,258,052,4,259,242,4,374,4,4 , 4,828,831,4,841,045,4,841,085,4,908,356,4,923,876,5,030,620,5,034,320,5,047,528,5,066,658,5,166,149,5,190,929,5,215,738,5,292,731,5,380,897,5,382,582,5,409,915,5,440,056,5,446,139,5,472,956,5,527,905,5,552,156,5,594,158,5,602,140,5,665,768,5,843,903 See also, 6,080,874, 6,096,923 and RE030561.

  In other examples, cell cycle inhibitors include camptothecin, mitoxantrone, etoposide, 5-fluorouracil, doxorubicin, methotrexate, perolside A, mitomycin C, or CDK-2 inhibitors, as well as the listed compounds. Analogs and derivatives of any compound belonging to the class are included.

  In other embodiments, the cell cycle inhibitor is HTI-286, pricamycin, or mitramycin, or analogs and derivatives thereof.

  Other examples of cell cycle inhibitors include 7-hexanoyltaxol (QP-2), cytochalasin A, lantorunculin D, actinomycin-D, Ro-31-7453 (3- (6-nitro -1-methyl-3-indolyl) -4- (1-methyl-3-indolyl) pyrrole-2,5-dione), PNU-151807, brostalysin, C2-ceramide, cytarabine ocphosphate (2 (1H)- Pyrimidinone, 4-amino-1- (5-O- (hydroxy (octadecyloxy) phosphinyl) -β-D-arabinofuranosyl)-, monosodium salt), paclitaxel (5β, 20-epoxy-1,2α, 4,7β, 10β, 13 α-Hexahydroxytakis-11-en-9-one-4,10-diacetate-2-benzoate-13- (α-phenyl hiplate)), doxorubicin (5,12-naphtha) Sendione, 10-((3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl) oxy) -7,8,9,10-tetrahydro-6,8,11-trihydroxy-8 -(Hydroxyacetyl) -1-methoxy-, (8S) -cis-), daunorubicin (5,12-naphthacenedione, 8-acetyl-10-((3-amino-2,3,6-trideoxy-α -L-lyxo-hexopyranosyl) oxy) -7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-, (8S-cis)-), gemcitabine hydrochloride (cytidine, 2'- Deoxy-2 ', 2'-difluoro-, monohydrochloride), nitacrine (1,3-propanediamine, N, N-dimethyl-N'-(1-nitro-9-acridinyl)-), carboplatin (platinum, Diammine (1,1-cyclobutanedicarboxylato (2-))-, (SP-4-2)-), altretoamine (1,3,5-triazine-2,4,6-triamine, N, N , N ′, N ′, N ″, N ″ -hexamethyl-), teniposide (Furo (3 ′, 4 ′: 6,7) naphtho (2,3-d) -1,3-dioxole-6 ( 5aH) -one, 5,8,8a, 9-tetrahydro-5- (4-hydroxy-3,5-dimethoxyphenyl) -9-((4,6-O- (2-thienylmethylene) -β-D - (Lucopyranosyl) oxy)-, (5R- (5alpha, 5aβ, 8aAlpha, 9β (R *)))-), eptaplatin (platinum, ((4R, 5R) -2- (1-methylethyl) -1,3 -Dioxolane-4,5-dimethanamine-κN4, κ N5) (propanedioato (2-)-κ O1, κ O3)-, (SP-4-2)-), amrubicin hydrochloride (5,12-naphthacene) Dione, 9-acetyl-9-amino-7-((2-deoxy-β-D-erythro-pentopyranosyl) oxy) -7,8,9,10-tetrahydro-6,11-dihydroxy-, hydrochloride, ( 7S-cis)-), ifosfamide (2H-1,3,2-oxazaphosphorin-2-amine, N, 3-bis (2-chloroethyl) tetrahydro-, 2-oxide), cladribine (adenosine, 2 -Chloro-2'-deoxy-), mitobronitol (D-mannitol, 1,6-dibromo-1,6-dideoxy-), fludaribine phosphate (9H-purine-6-amine, 2-fluoro-9- ( 5-O-phosphono-β-D-arabinofuranosyl)-), Enocitabine (docosana Mido, N- (1-β-D-arabinofuranosyl-1,2-dihydro-2-oxo-4-pyrimidinyl)-), vindesine (vincaleucoblastine, 3- (aminocarbonyl) -O4-deacetyl -3-de (methoxycarbonyl)-), idarubicin (5,12-naphthacenedione, 9-acetyl-7-((3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl) oxy ) -7,8,9,10-Tetrahydro-6,9,11-trihydroxy-, (7S-cis)-), dinostatin (neocardinostatin), vincristine (vincaleucoblastine, 22-oxo-) , Tegafur (2,4 (1H, 3H) -pyrimidinedione, 5-fluoro-1- (tetrahydro-2-furanyl)-), razoxane (2,6-piperazinedione, 4,4 '-(1-methyl- 1,2-ethanediyl) bis-), methotrexate (L-glutamic acid, N- (4-(((2,4-diamino-6-pteridinyl) methyl) methylamino) benzoyl)-), raltitrex (L-glutamic acid, N-((5-(((1,4-dihydro-2-methyl-4-oxo-6-quinazolinyl) methyl) methylamino) -2-thienyl) carbonyl)-), oxaliplatin (Platinum, (1,2-cyclohexanediamine-N, N ′) (ethanedioato (2-)-O, O ′)-, (SP-4-2- (1R-trans))-), doxyfluridine (uridine, 5'-deoxy-5-fluoro-), mitracitol (galactitol, 1,6-dibromo-1,6-dideoxy-), piraubicin (5,12-naphthacenedione, 10-((3-amino-2, 3,6-trideoxy-4-O- (tetrahydro-2H-pyran-2-yl) -α-L-lyxo-hexopyranosyl) oxy) -7,8,9,10-tetrahydro-6,8,11-tri Hydroxy-8- (hydroxyacetyl) -1-methoxy-, (8S- (8α, 10 α (S *)))-), docetaxel ((2R, 3S) -N-carboxy-3-phenylisoserine, N -tert-butyl ester, 5β, 20-epoxy-1,2α, 4,7β, 10β, 13α-hexahydroxytaxis-1 1-en-9-one 4-acetate 2-benzoate with 13-ester), capecitabine (cytidine, 5-deoxy-5-fluoro-N-((pentyloxy) carbonyl)-), cytarabine (2 ( 1H) -pyrimidone, 4-amino-1-β-D-arabinofuranosyl-), valrubicin (pentanoic acid, 2- (1,2,3,4,6,11-hexahydro-2,5,12- Trihydroxy-7-methoxy-6,11-dioxo-4-((2,3,6-trideoxy-3-((trifluoroacetyl) amino) -α-L-lyxo-hexopyranosyl) oxy) -2-naphthacenyl ) -2-oxoethyl ester (2S-cis)-), trophosphamide (3-2- (chloroethyl) -2- (bis (2-chloroethyl) amino) tetrahydro-2H-1,3,2-oxazaphospholine 2-oxide), prednimustine (pregna-1,4-diene-3,20-dione, 21- (4- (4- (bis (2-chloroethyl) amino) phenyl) -1-oxobutoxy) -11, 17-dihydroxy-, (11β)-), Romusti (Urea, N- (2-chloroethyl) -N'-cyclohexyl-N-nitroso-), epirubicin (5,12-naphthacenedione, 10-((3-amino-2,3,6-trideoxy-α -L-arabino-hexopyranosyl) oxy) -7,8,9,10-tetrahydro-6,8,11-trihydroxy-8- (hydroxyacetyl) -1-methoxy-, (8S-cis)-), or Analogs and derivatives thereof).

5) Cyclin-dependent protein kinase inhibitor In another embodiment, the pharmacologically active fibrogenesis inhibitor compound is a cyclin-dependent protein kinase inhibitor (R-roscovitine, CYC-101, CYC-103, CYC-400). , MX-7065, albocidib (4H-1-benzopyran-4-one, 2- (2-chlorophenyl) -5,7-dihydroxy-8- (3-hydroxy-1-methyl-4-piperidinyl)-, cis- (-)-), SU-9516, AG-12275, PD-0166285, CGP-79807, Fascapricin, GW-8510 (benzenesulfonamide, 4-(((Z)-(6,7-dihydro-7 -Oxo-8H-pyrrolo (2,3-g) benzothiazole-8-ylidene) methyl) amino) -N- (3-hydroxy-2,2-dimethylpropyl)-), GW-491619, indirubin 3 'monoxime GW8510, AZD-5438, ZK-CDK or analogs and derivatives thereof).

6) EGF (epidermal growth factor) receptor kinase inhibitor In another embodiment, the pharmacologically active fibrosis inhibitor compound is an EGF (epidermal growth factor) kinase inhibitor (erlotinib (4-quinazolinamine, N- (3-ethynylphenyl) -6,7-bis (2-methoxyethoxy)-, monohydrochloride), elvstatin, BIBX-1382, gefitinib (4-quinazolinamine, N- (3-chloro-4-) Fluorophenyl) -7-methoxy-6- (3- (4-morpholinyl) propoxy)), or analogs and derivatives thereof.

7) Elastase inhibitor In another embodiment, the pharmacologically active fibrosis inhibitor compound is an elastase inhibitor (ONO-6818, sivelestat sodium hydrate (glycine, N- (2-(((4- (2,2-dimethyl-1-oxopropoxy) phenyl) sulfonyl) amino) benzoyl)-), eldstein (acetic acid, ((2-oxo-2-((tetrahydro-2-oxo-3-thienyl) amino) Ethyl) thio)-), MDL-100948A, MDL-104238 (N- (4- (4-morpholinylcarbonyl) benzoyl) -L-valyl-N '-(3,3,4,4,4-penta Fluoro-1- (1-methylethyl) -2-oxobutyl) -L-2-azetoamide), MDL-27324 (L-prolinamide, N-((5- (diethylamino) -1-naphthalenyl) sulfonyl) -L -Alanyl-L-alanyl-N- (3,3,3-trifluoro-1- (1-methylethyl) -2-oxopropyl)-, (S)-), SR-26831 (thieno (3,2 -c) pyridinium, 5-((2-chlorophenyl) methyl) -2- (2,2-di Til-1-oxopropoxy) -4,5,6,7-tetrahydro-5-hydroxy-), Win-68794, Win-63110, SSR-69071 (2- (9 (2-piperidinoethoxy) -4 -Oxo-4H-pyrido (1,2-a) pyrimidin-2-yloxymethyl) -4- (1-methylethyl) -6-methoxy-1,2-benzisothiazol-3 (2H) -one ( one) -1,1-dioxide), (N (α)-(1-adamantylsulfonyl) N (epsilon) -succinyl-L-lysyl-L-prolyl-L-valinal), Ro-31-3537 (Nα -(1-adamantanesulfonyl) -N- (4-carboxybenzoyl) -L-lysyl-alanyl-L-valinal), R-665, FCE-28204, ((6R, 7R) -2- (benzoyloxy)- 7-methoxy-3-methyl-4-pivaloyl-3-cephem 1,1-dioxide), 1,2-benzisothiazol-3 (2H) -one, 2- (2,4-dinitrophenyl)-, 1,1-dioxide, L-658758 (L-proline, 1-((3-((acetyloxy) methyl) -7-methoxy-8-oxo-5-thia-1-azabicyclo (4.2. 0) Oct-2-en-2-yl) carbonyl)-, S, S-dioxide, (6R-cis)-), L-659286 (pyrrolidine, 1-((7-methoxy-8-oxo-3) -(((1,2,5,6-tetrahydro-2-methyl-5,6-dioxo-1,2,4-triazin-3-yl) thio) methyl) -5-thia-1-azabicyclo (4.2 .0) Oct-2-en-2-yl) carbonyl)-, S, S-dioxide, (6R-cis)-), L-680833 (benzeneacetic acid, 4-((3,3-diethyl-1 -(((1- (4-methylphenyl) butyl) amino) carbonyl) -4-oxo-2-azetidinyl) oxy)-, (S- (R *, S *))-), FK-706 (L -Prolinamide, N- (4-(((carboxymethyl) amino) carbonyl) benzoyl) -L-valyl-N- (3,3,3-trifluoro-1- (1-methylethyl) -2-oxo Propyl)-, monosodium salt), RocheR-665, or analogs and derivatives thereof.

8) Factor Xa inhibitor In another embodiment, the pharmacologically active fibrosis inhibitor compound is a factor Xa inhibitor (CY-222, Honda Parinukis sodium (α-D-glucopyranoside, methyl O- 2-Deoxy-6-O-sulfo-2- (sulfoamino) -α-D-glucopyranosyl- (1-4) -O-β-D-glucopyranuronosyl- (1-4) -O-2- Deoxy-3,6-di-O-sulfo-2- (sulfoamino) -α-D-glucopyranosyl- (1-4) -O-2-O-sulfo-α-L-idopyranuronosyl- (1 -4) -2-deoxy-2- (sulfoamino)-, 6- (hydrogen sulfate)), danaparoid sodium, or analogs and derivatives thereof.

9) Farnesyltransferase inhibitors In another embodiment, the pharmacologically active fibrosis inhibitor compound is a farnesyltransferase inhibitor (dichlorobenzoprim (2,4-diamino-5- (4- (3,4-dichloro) Benzylamino) -3-nitrophenyl) -6-ethylpyrimidine), B-581, B-956 (N- (8 (R) -amino-2 (S) -benzyl-5 (S) -isopropyl-9- Sulfanyl-3 (Z), 6 (E) -nonadienoyl) -L-methionine), OSI-754, perillyl alcohol (1-cyclohexene-1-methanol, 4- (1-methylethenyl)-, RPR-114334, lonafarnib (1-piperidinecarboxamide, 4- (2- (4-((11R) -3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo (5,6) cyclohepta (1,2-b ) Pyridin-11-yl) -1-piperidinyl) -2-oxoethyl)-), Sch-48755, Sch-226374, (7,8-dichloro-5H-dibenzo (b, e) (1,4) diazepine- 11-y1) -Pyridin-3-ylmethyl Min, J-104126, L-639749, L-731734 (pentanamide, 2-((2-((2-amino-3-mercaptopropyl) amino) -3-methylpentyl) amino) -3-methyl-N -(Tetrahydro-2-oxo-3-furanyl)-, (3S- (3R * (2R * (2R * (S *), 3S *), 3R *)))-), L-744832 (butanoic acid, 2-((2-((2-((2-amino-3-mercaptopropyl) amino) -3-methylpentyl) oxy) -1-oxo-3-phenylpropyl) amino) -4- (methylsulfonyl) -, 1-methylethyl ester, (2S- (1 (R * (R *)), 2R * (S *), 3R *))-), L-745631 (1-piperazinepropanethiol, β-amino- 2- (2-methoxyethyl) -4- (1-naphthalenylcarbonyl)-, (βR, 2S)-), N-acetyl-N-naphthylmethyl-2 (S)-((1- (4- Cyanobenzyl) -1H-imidazol-5-yl) acetyl) amino-3 (S) -methylpentamine, (2α) -2-hydroxy-24,25-dihydroxylanosto-8-en-3-one ), BMS-316810, UCF-1-C (2,4-Decadiena N- (5-hydroxy-5- (7-((2-hydroxy-5-oxo-1-cyclopenten-1-yl) amino-oxo-1,3,5-heptatrienyl) -2-oxo-7 -Oxabicyclo (4.1.0) hept-3-en-3-yl) -2,4,6-trimethyl-, (1S- (1α, 3 (2E, 4E, 6S *), 5α, 5 (1E, 3E, 5E), 6 α))-), UCF-116-B, ARGLABIN (3H-oxyleno (8,8a) azuleno (4,5-b) furan-8 (4aH) -one, 5,6,6a , 7,9a, 9b-Hexahydro-1,4a-dimethyl-7-methylene-, (3aR, 4aS, 6aS, 9aS, 9bR)-) (ARGLABIN- Paracure, Inc. (Virginia Beach, Virginia)), or Analogs and derivatives thereof).

10) Fibrinogen antagonist In another embodiment, the pharmacologically active fibrogenesis inhibitor compound is a fibrinogen antagonist (2 (S)-((p-toluenesulfonyl) amino) -3-((((5,6 , 7,8, -Tetrahydro-4-oxo-5- (2- (piperidin-4-yl) ethyl) -4H-pyrazolo- (1,5-a) (1,4) diazepin-2-yl) carbonyl ) -Amino) propionic acid, streptokinase (kinase (enzyme activity), strept-), urokinase (kinase (enzyme activity), uro-), plasminogen activator, pamiteplase, monteplase, hebelkinase, anistreplase, alteplase, pro -Urokinase, picotoamide (1,3-benzenedicarboxamide, 4-methoxy-N, N'-bis (3-pyridinylmethyl)-), or analogs and derivatives thereof).

11) Guanyl cyclase stimulant In another embodiment, the pharmacologically active fibrosis inhibitor compound is a guanylate cyclase stimulant (isosorbide-5-mononitrate (D-glucitol, 1,4: 3,6- Dianhydro-, 5-nitrate), or analogs and derivatives thereof.

12) Heat shock protein 90 antagonist In another embodiment, the pharmacologically active fibrosis inhibiting compound is a heat shock protein 90 antagonist (geldanamycin, NSC-33050 (17-allylaminogeldanamycin), With rifabutin (rifamycin XIV, 1 ', 4-didehydro-1-deoxy-1,4-dihydro-5'-(2-methylpropyl) -1-oxo-), 17AAG, or analogs and derivatives thereof is there.

13) HMGCoA reductase inhibitor In another example, the pharmacologically active fibrosis inhibitor compound is an HMGCoA reductase inhibitor (BCP-671, BB-476, fluvastatin (6-heptenoic acid, 7- (3- (4-Fluorophenyl) -1- (1-methylethyl) -1H-indol-2-yl) -3,5-dihydroxy-, monosodium salt, (R *, S *-(E))-(± )-), Dalvastatin (2H-pyran-2-one, 6- (2- (2- (2- (4-fluoro-3-methylphenyl) -4,4,6,6-tetramethyl-1-) Cyclohexen-1-yl) ethenyl) tetrahydro) -4-hydroxy-, (4α, 6β (E))-(+/-)-), gremvastatin (2H-pyran-2-one, 6- (2- (4- (4-Fluorophenyl) -2- (1-methylethyl) -6-phenyl-3-pyridinyl) ethenyl) tetrahydro-4-hydroxy-, (4R- (4α, 6β (E)))-) , S-2468, N- (1-oxododecyl) -4α, 10-dimethyl-8-aza-trans-decal-3β-ol, atorvastatin calcium (1H- Roll-1-heptanoic acid, 2- (4-fluorophenyl) -β, δ-dihydroxy-5- (1-methylethyl) -3-phenyl-4-((phenylamino) carbonyl)-, calcium salt (R -(R *, R *))-), CP-83101 (6,8-nonadienoic acid, 3,5-dihydroxy-9,9-diphenyl-, methyl ester, (R *, S *-(E)) -(+/-)-), pravastatin (1-naphthaleneheptanoic acid, 1,2,6,7,8,8a-hexahydro-β, δ, 6-trihydroxy-2-methyl-8- (2-methyl -1-oxobutoxy)-, monosodium salt, (1S- (1α (βS *, deltaS *), 2 α, 6 α, 8β (R *), 8a α))-), U-20685, pitavastatin ( 6-heptenoic acid, 7- (2-cyclopropyl-4- (4-fluorophenyl) -3-quinolinyl) -3,5-dihydroxy-, calcium salt (2: 1), (S- (R *, S *-(E)))-), N-((1-methylpropyl) carbonyl) -8- (2- (tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl) ethyl) -perhydro -Isoquinoline, dihydromebino (Butanoic acid, 2-methyl-, 1,2,3,4,4a, 7,8,8a-octahydro-3,7-dimethyl-8- (2- (tetrahydro-4-hydroxy-6-oxo- 2H-pyran-2-yl) ethyl) -1-naphthalenyl ester (1α (R *), 3α, 4a α, 7β, 8β (2S *, 4S *), 8aβ))-), HBS-107, Dihydromevinolin (butanoic acid, 2-methyl-, 1,2,3,4,4a, 7,8,8a-octahydro-3,7-dimethyl-8- (2- (tetrahydro-4-hydroxy-6- Oxo-2H-pyran-2-yl) ethyl) -1-naphthalenyl ester (1α (R *), 3 α, 4a α, 7β, 8β (2S *, 4S *), 8aβ))-), L- 669262 (butanoic acid, 2,2-dimethyl-, 1,2,6,7,8,8a-hexahydro-3,7-dimethyl-6-oxo-8- (2- (tetrahydro-4-hydroxy-6- Oxo-2H-pyran-2-yl) ethyl) -1-naphthalenyl (1S- (1α, 7β, 8β (2S *, 4S *), 8aβ))-), simvastatin (butanoic acid, 2,2-dimethyl- 1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8- (2- (tetrahydro-4-hydroxy-6-oxo-2H-pyran-2- L) ethyl) -1-naphthalenyl ester, (1S- (1α, 3α, 7β, 8β (2S *, 4S *), 8aβ))-), rosuvastatin calcium (6-heptenoic acid, 7- (4- ( 4-fluorophenyl) -6- (1-methylethyl) -2- (methyl (methylsulfonyl) amino) -5-pyrimdinyl) -3,5-dihydroxy-calcium salt (2: 1) (S- (R * , S *-(E)))), megglutol (2-hydroxy-2-methyl-1,3-propanedicarboxylic acid), lovastatin (butanoic acid, 2-methyl-, 1,2,3,7,8, 8a-Hexahydro-3,7-dimethyl-8- (2- (tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl) ethyl) -1-naphthalenyl ester, (1S- (1α. R *), 3 α, 7β, 8β (2S *, 4S *), 8aβ))-), or analogs and derivatives thereof.

14) Hydrorotate dehydrogenase inhibitor In another embodiment, the pharmacologically active fibrosis inhibitor compound is a hydroorotate dehydrogenase inhibitor (leflunomide (4-isoxazolecarboxamide, 5-methyl-N- (4- (Trifluoromethyl) phenyl)-), raflunimus (2-propenamide, 2-cyano-3-cyclopropyl-3-hydroxy-N- (3-methyl-4 (trifluoromethyl) phenyl)-, (Z) -), Or atovaquone (1,4-naphthalenedione, 2- (4- (4-chlorophenyl) cyclohexyl) -3-hydroxy-, trans-, or analogs and derivatives thereof).

15) IKK2 inhibitor The pharmacologically active fiber formation inhibiting compound is an IKK2 inhibitor (MLN-120B, SPC-839, or an analog or derivative thereof).

16) IL-1, ICE and IRAK antagonists In another embodiment, the pharmacologically active fibrosis inhibiting compound is an IL-1, ICE or IRAK antagonist (E-5090 (2-propenoic acid, 3- (5-ethyl-4-hydroxy-3-methoxy-1-naphthalenyl) -2-methyl-, (Z)-), CH-164, CH-172, CH-490, AMG-719, iguratimod (N- ( 3- (formylamino) -4-oxo-6-phenoxy-4H-chromen-7-yl) methanesulfonamide), AV94-88, prarnacasan (6H-pyridazino (1,2-a) (1,2) diazepine) -1-carboxamide, N-((2R, 3S) -2-ethoxytetrahydro-5-oxo-3-furanyl) octahydro-9-((1-isoquinolinylcarbonyl) amino) -6,10-dioxo- , (1S, 9S)-), (2S-cis) -5- (benzyloxycarbonylamino-1,2,4,5,6,7-hexahydro-4- (oxoazepino (3,2,1-hi) Indole-2-carbonyl) -amino) -4-oxobutanoic acid, AVE-9488, esonalimodo (benzenebutanoic acid) , Α-((acetylthio) methyl) -4-methyl-γ-oxo-), prarnacasan (6H-pyridazino (1,2-a) (1,2) diazepine-1-carboxamide, N-((2R, 3S ) -2-ethoxytetrahydro-5-oxo-3-furanyl) octahydro-9-((1-isoquinolinylcarbonyl) amino) -6,10-dioxo-, (1S, 9S)-), tranexamic acid ( Cyclohexanecarboxylic acid, 4- (aminomethyl)-, trans-), Win-72052, romazalit (Ro-31-3948) (propanoic acid, 2-((2- (4-chlorophenyl) -4-methyl-5- Oxazolyl) methoxy) -2-methyl-), PD-163594, SDZ-224-015 (L-alaninamide N-((phenylmethoxy) carbonyl) -L-valyl-N-((1S) -3-(( 2,6-dichlorobenzoyl) oxy) -1- (2-ethoxy-2-oxoethyl) -2-oxopropyl)-), L-709049 (L-alaninamide, N-acetyl-L-tyrosyl-L-valyl) -N- (2-carboxy-1-formylethyl)-, (S)-), TA-383 (1H-I Midazole, 2- (4-chlorophenyl) -4,5-dihydro-4,5-diphenyl-, monohydrochloride, cis-), EI-1507-1 (6a, 12a-epoxybenzo (a) anthracene-1, 12 (2H, 7H) -dione, 3,4-dihydro-3,7-dihydroxy-8-methoxy-3-methyl-), ethyl 4- (3,4-dimethoxyphenyl) -6,7-dimethoxy-2 -(1,2,4-triazol-1-ylmethyl) quinoline-3-carboxylate, EI-1941-1, TJ-114, Anakinra (interleukin 1 receptor antagonist (human isoform X reduction), N2 -L-methionyl-), IX-207-887 (acetic acid, (10-methoxy-4H-benzo (4,5) cyclohepta (1,2-b) thien-4-ylidene)-), K-832, or Analogs and derivatives thereof).

17) In another example of an IL-4 agonist, the pharmacologically active fibrosis-inhibiting compound is an IL-4 agonist (Gratyramil acetate (L-glutamic acid, polymer (L-alanine, L-lysine and L-tyrosine), acetate (salt)), or analogs and derivatives thereof.

18) In another embodiment of the immunomodulator, the pharmacologically active fibrogenesis inhibitory compound is an immunomodulator (biolimus, ABT-578, methylsulfamic acid 3- (2-methoxyphenoxy) -2-(((( Methylamino) sulfonyl) oxy) propyl ester, sirolimus (also called rapamycin or rapamune (American Home Products, Inc., Madison, NJ)), CCI-779 (rapamycin 42- (3-hydroxy-2- (Hydroxymethyl) -2-methylpropanoate)), LF-15-0195, NPC15669 (L-leucine, N-(((2,7-dimethyl-9H-fluoren-9-yl) methoxy) carbonyl)- ), NPC-15670 (L-leucine, N-(((4,5-dimethyl-9H-fluoren-9-yl) methoxy) carbonyl)-), NPC-16570 (4- (2- (fluorene-9- Yl) ethyloxy-carbonyl) aminobenzoic acid), sulfosamide (ethanol, 2-((3- (2-chloro Ethyl) tetrahydro-2H-1,3,2-oxazaphospholin-2-yl) amino)-, methanesulfonate (ester), P-oxide), tresperimus (2- (N- (4- ( 3-aminopropylamino) butyl) carbamoyloxy) -N- (6-guanidinohexyl) acetamide), 4- (2- (fluoren-9-yl) ethoxycarbonylamino) -benzo-hydroxamic acid, iaquinimod, PBI-1411 , Azathioprine (6-((1-methyl-4-nitro-1H-imidazol-5-yl) thio) -1H-purine), PBI0032, beclomethasone, MDL-28842 (9H-purin-6-amine, 9- ( 5-deoxy-5-fluoro-β-D-threo-pent-4-enofuranosyl)-, (Z)-), FK-788, AVE-1726, ZK-90695, ZK-90695, Ro-54864, didemnin- B, Illinois (Didemnin A, N- (1- (2-hydroxy-1-oxopropyl) -L-prolyl)-, (S)-), SDZ-62-826 (ethanaminium, 2-((hydroxy ((1-((octadecyl Xyl) carbonyl) -3-piperidinyl) methoxy) phosphinyl) oxy) -N, N, N-trimethyl-, inner salt), Argyrin B ((4S, 7S, 13R, 22R) -13-ethyl-4- (1H -Indol-3-ylmethyl) -7- (4-methoxy-1H-indol-3-ylmethyl) 18,22-dimethyl-16-methyl-en-24-thia-3,6,9,12,15,18 , 21,26-octazabicyclo (21.2.1) -hexacosa-1 (25), 23 (26) -diene-2,5,8,11,14,17,20-heptaone), everolimus (rapamycin, 42 -O- (2-hydroxyethyl)-), SAR-943, L-687795, 6-((4-chlorophenyl) sulfinyl) -2,3-dihydro-2- (4-methoxy-phenyl) -5-methyl -3-oxo-4-pyridazinecarbonitrile, 91Y78 (1H-imidazo (4,5-c) pyridin-4-amine, 1-β-D-ribofuranosyl-), auranofin (gold, (1-thio- β-D-glucopyranose 2,3,4,6-tetraacetato-S) (triethylphosphine)-), 27-0-demethylrapamycin, tipre (Androsta-1,4-dien-3-one, 17- (ethylthio) -9-fluoro-11-hydroxy-17- (methylthio)-, (11β, 17α)-), AI-402, LY- 178002 (4-thiazolidinone, 5-((3,5-bis (1,1-dimethylethyl) -4-hydroxyphenyl) methylene)-), SM-8849 (2-thiazolamine, 4- (1- (2 -Fluoro (1,1'-biphenyl) -4-yl) ethyl) -N-methyl-), piceatannol, resveratrol, triamcinolone acetonide (pregna-1,4-diene-3,20-dione, 9-Fluoro-11,21-dihydroxy-16,17-((1-methylethylidene) bis (oxy))-, (11β, 16α)-), cyclosporin (cyclosporin A), tacrolimus (15,19-epoxy- 3H-pyrido (2,1-c) (1,4) oxaazacyclotricosin-1,7,20,21 (4H, 23H) -tetraone, 5,6,8,11,12,13,14, 15,16,17,18,19,24,25,26,26a-Hexadecahydro-5,19-dihydroxy-3- (2- (4-hydroxy-3-methoxycyclo (Xyl) -1-methylethenyl) -14,16-dimethoxy-4,10,12,18-tetramethyl-8- (2-propenyl)-, (3S- (3R * (E (1S *, 3S *, 4S *)), 4S *, 5R *, 8S *, 9E, 12R *, 14R *, 15S *, 16R *, 18S *, 19S *, 26aR *))-), Gusperimus (heptanamide, 7-((amino Iminomethyl) amino) -N- (2-((4-((3-aminopropyl) amino) butyl) amino) -1-hydroxy-2-oxoethyl)-, (+/-)-), thixocortol Valato (pregn-4-ene-3,20-dione, 21-((2,2-dimethyl-1-oxopropyl) thio) -11,17-dihydroxy-, (11β)-), alefacept (immunoglobulin G1 1-92 LFA-3 (antigen) (human) fusion protein (dimer) with (human hinge-CH2-CH3 γ1-chain), halobetasol propionate (pregna-1,4-diene-3,20 -Dione, 21-chloro-6,9-difluoro-11-hydroxy-16-methyl-17- (1-oxopropoxy)-, (6α, 11β, 16β)-), iloprosttrometamol Pentanoic acid, 5- (hexahydro-5-hydroxy-4- (3-hydroxy-4-methyl-1-octen-6-ynyl) -2 (1H) -pentalenylidene)-), beraprost (1H-cyclopenta (b) Benzofuran-5-butanoic acid, 2,3,3a, 8b-tetrahydro-2-hydroxy-1- (3-hydroxy-4-methyl-1-octen-6-ynyl)-), rimexolone (androsta-1, 4-dien-3-one, 11-hydroxy-16,17-dimethyl-17- (1-oxopropyl)-, (11β, 16α, 17β)-), dexamethasone (pregna-1,4-diene-3, 20-dione, 9-fluoro-11,17,21-trihydroxy-16-methyl-, (11β, 16α)-), sulindac (cis-5-fluoro-2-methyl-1-((p-methylsulfinyl) ) Benzylidene) indene-3-acetic acid), progouritacin (1H-indole-3-acetic acid, 1- (4-chlorobenzoyl) -5-methoxy-2-methyl-, 2- (4- (3-(( 4- (Benzoylamino) -5- (dipropylamino) -1,5-dioxopen L) oxy) propyl) -1-piperazinyl) ethyl ester, (+/-)-), alcromethasone dipropionate (pregna-1,4-diene-3,20-dione, 7-chloro-11-hydroxy- 16-methyl-17,21-bis (1-oxopropoxy)-, (7α, 11β, 16α)-), pimecrolimus (15,19-epoxy-3H-pyrido (2,1-c) (1,4) Oxazacyclotricosin-1,7,20,21 (4H, 23H) -tetraone, 3- (2- (4-chloro-3-methoxycyclohexyl) -1-methyletheni) -8-ethyl-5,6, 8,11,12,13,14,15,16,17,18,19,24,25,26,26a-hexadecahydro-5,19-dihydroxy-14,16-dimethoxy-4,10,12, 18-tetramethyl-, (3S- (3R * (E (1S *, 3S *, 4R *)), 4S *, 5R *, 8S *, 9E, 12R *, 14R *, 15S *, 16R *, 18S *, 19S *, 26aR *))-), hydrocortisone-17-butyrate (pregn-4-ene-3,20-dione, 11,21-dihydroxy-17- (1-oxobutoxy)-, (11β) -), Mitoxantrone (9,10-anthracenedione, 1,4-dihydroxy-5,8-bi ((2-((2-hydroxyethyl) amino) ethyl) amino)-), mizoribine (1H-imidazole-4-carboxamide, 5-hydroxy-1-β-D-ribofuranosyl-), prednicarb (pregna- 1,4-diene-3,20-dione, 17-((ethoxycarbonyl) oxy) -11-hydroxy-21- (1-oxopropoxy)-, (11β)-), iobenzalit (benzoic acid, 2 -((2-Carboxyphenyl) amino) -4-chloro-), glucametacin (D-glucose, 2-(((1- (4-chlorobenzoyl) -5-methoxy-2-methyl-1H-indole-3 -Yl) acetyl) amino) -2-deoxy-), fluocortron monohydrate ((6α) -fluoro-16α-methylpregna-1,4-diene-11β, 21-diol-3,20-dione) , Fluocortin butyl (pregna-1,4-diene-21-oic acid, 6-fluoro-11-hydroxy-16-methyl-3,20-dioxo-, butyl ester, (6α, 11β, 16α) -), Gif Prednate (pregna-1,4-diene-3,20-dione, 21- (acetyloxy) -6,9-difluoro-11-hydroxy-17- (1-oxobutoxy)-, (6α, 11β)-) , Diflorazone diacetate (pregna-1,4-diene-3,20-dione, 17,21-bis (acetyloxy) -6,9-difluoro-11-hydroxy-16-methyl-, (6α, 11β , 16β)-), dexamethasone valerate (pregna-1,4-diene-3,20-dione, 9-fluoro-11,21-dihydroxy-16-methyl-17-((1-oxopentyl) oxy) -, (11β, 16α)-), methylprednisolone, deprodon propionate (pregna-1,4-diene-3,20-dione, 11-hydroxy-17- (1-oxopropoxy)-, (11. Beta.)-), Bucillamine (L-cysteine, N- (2-mercapto-2-methyl-1-oxopropyl)-), amsinonide (benzeneacetic acid, 2-amino-3-benzoyl-, monosodium salt, mono Hydrate), Acemetashi (1H-indole-3-acetic acid, 1- (4-chlorobenzoyl) -5-methoxy-2-methyl -, carboxymethyl ester), or a like analogs and derivatives).

  In addition, analogs of rapamycin include tacrolimus and its derivatives (such as EP0184162B1 and US Pat. No. 6,258,823), everolimus and its derivatives (such as US Pat. No. 5,665,772). For other representative examples of analogs and derivatives of sirolimus, see PCT Publication Nos. WO97 / 10502, WO 96/41807, WO 96/35423, WO 96/03430, WO 96/00282, WO 95/16691, WO95. / 15328, WO 95/07468, WO 95/04738, WO 95/04060, WO 94/25022, WO 94/21644, WO94 / 18207, WO 94/10843, WO 94/09010, WO 94/04540, WO 94 / 02485, WO 94/02137, WO94 / 02136, WO 93/25533, WO 93/18043, WO 93/13663, WO 93/11130, WO 93/10122, WO93 / 04680, WO 92/14737, and WO 92/05179 There is a description. Representative U.S. Patents are U.S. Pat.Nos. 5,258,389, 5,252,732, 5,247,076, 5,225,403, 5,221,625, 5,210,030, 5,208,241, 5,200,411, 5,198,421, 5,147,877, 5,140,018, 5,116,756, 5,109,112, 5,093,338, and 5,091,389.

  The structures of sirolimus, everolimus, and tacrolimus are as described below.

Furthermore, analogs and derivatives of sirolimus include tacrolimus and its derivatives (such as EP0184162B1 and US Pat. No. 6,258,823), everolimus and its derivatives (such as US Pat. No. 5,665,772). Other representative examples of analogs and derivatives of sirolimus include ABT-578 and others, including PCT publication numbers WO 97/10502, WO 96/41807, WO 96/35423, WO 96 / 03430, WO 9600282, WO 95/16691, WO9515328, WO 95/07468, WO 95/04738, WO 95/04060, WO 94/25022, WO 94/21644, WO 94/18207, WO94 / 10843, WO 94/09010 , WO 94/04540, WO 94/02485, WO 94/02137, WO 94/02136, WO93 / 25533, WO 93/18043, WO 93/13663, WO 93/11130, WO 93/10122, WO 93/04680, There are descriptions in WO92 / 14737 and WO92 / 05179. Representative U.S. Patents are U.S. Pat.Nos. 5,258,389, 5,252,732, 5,247,076, 5,225,403, 5,221,625, 5,210,030, 5,208,241, 5,200,411, 5,198,421, 5,147,877, 5,140,018, 5,116,756, 5,109,112, 5,093,338, and 5,091,389.

  In one embodiment, the fiber formation inhibitor may be rapamycin (sirolimus), everolimus, biolimus, tresperimus, auranofin, 27-0-demethylrapamycin, tacrolimus, gusperimus, pimecrolimus, or ABT-578.

19) Inosine monophosphate dehydrogenase inhibitor In another embodiment, the pharmacologically active compound is an inosine monophosphate dehydrogenase (IMPDH) inhibitor (mycophenolic acid, mycophenolate mofetil (4-hexene) Acid, 6- (1,3-dihydro-4-hydroxy-6-methoxy-7-methyl-3-oxo-5-isobenzofuranyl) -4-methyl-, 2- (4-morpholinyl) ethyl ester, (E)-), ribavirin (1H-1,2,4-triazole-3-carboxamide, 1-β-D-ribofuranosyl-), thiazofurin (4-thiazolecarboxamide, 2-β-D-ribofuranosyl-), vilamidine , Aminothiadiazole, thiophene furin, thiazofurin) or analogs and derivatives thereof. Other representative examples are U.S. Pat. 2002 / 0040022A1, 2002 / 0052513A1, 2002 / 0055483A1, 2002 / 0068346A1, 2002 / 0111378A1, 2002 / 0111495A1, 2002 / 0123520A1, 2002 / 0143176A1, 2002 / 0147160A1, 2002 / 0161038A1, 2002 / 0173491A1, 2002 / 0183315A1, 2002 / 0193612A1, 2003 / 0027845A1, 2003 / 0068302A1, 2003 / 0105073A1, 2003 / 0130254A1, 2003 / 0143197A1, 2003 / 0144300A1, 2003 / 0166201A1, 2003 / 0181497A1, 2003 / 0186974A1, 2003 / 0186989A1, 2003 / 0195202A1, and PCT publication numbers WO0024725A1, WO 00 / 25780A1, WO 00 / 26197A1, WO 00 / 51615A1, WO 00 / 56331A1, WO 00 / 73288A1, WO01 / 00622A1, WO 01 / 66706A1, WO 01 / 79246A2, WO 01 / 81340A2, WO 01 / 85952A2 , WO02 / 16382A1, WO 02 / 18369A2, WO 2051814A1, WO 2057287A2, WO2057425A2, WO 2060875A1, WO2060896A1, WO 2060898A1, WO 2068058A2, WO 3020298A1, WO 3037349A1, WO 3039548A1, WO3045901A2, WO 3047512A2, WO 3053958A1, WO 3055447A2, WO 3059269A2, WO 3063573A2, WO3087071A1, WO 90 / 01545A1, WO 97 / 40028A1, WO 97 / 40028A1, WO 97 / 40028A1 / 40381A1, and WO99 / 55663A1.

20) Leukotriene inhibitor
In another embodiment, the pharmacologically active compound is a leucotrain inhibitor (ONO-4057 (benzenepropanoic acid, 2- (4-carboxybutoxy) -6-((6- (4-methoxyphenyl)- 5-Hexenyl) oxy)-, (E)-), ONO-LB-448, pyromast 1,8-naphthyridin-2 (1H) -one, 4-hydroxy-1-phenyl-3- (1-pyrrolidinyl)- , Sch-40120 (benzo (b) (1,8) naphthyridine-5 (7H) -one, 10- (3-chlorophenyl) -6,8,9,10-tetrahydro-), L-656224 (4-benzo Furanol, 7-chloro-2-((4-methoxyphenyl) methyl) -3-methyl-5-propyl-), MAFP (methyl arachidonyl fluorophosphonate), ontazolast (2-benzoxazolamine, N- (2 -Cyclohexyl-1- (2-pyridinyl) ethyl) -5-methyl-, (S)-), amervant (carbamic acid, ((4-((3-((4- (1- (4-hydroxyphenyl) -1-methylethyl) phenoxy) methyl) pheny ) Methoxy) phenyl) iminomethyl) -ethyl ester), SB-201993 (benzoic acid, 3-(((((6-((1E) -2-carboxyethenyl) -5-((8- (4-methoxyphenyl) ) Octyl) oxy) -2-pyridinyl) methyl) thio) methyl)-), LY-203647 (ethanone, 1- (2-hydroxy-3-propyl-4- (4- (2- (4- (1H- Tetrazol-5-yl) butyl) -2H-tetrazol-5-yl) butoxy) phenyl)-), LY-210073, LY-223982 (benzenepropanoic acid, 5- (3-carboxybenzoyl) -2-((6 -(4-methoxyphenyl) -5-hexenyl) oxy)-, (E)-), LY-293111 (benzoic acid, 2- (3- (3-((5-ethyl-4'-fluoro-2- Hydroxy (1,1'-biphenyl) -4-yl) oxy) propoxy) -2-propylphenoxy)-), SM-9064 (pyrrolidine, 1- (4,11-dihydroxy-13- (4-methoxyphenyl) -1-oxo-5,7,9-tridecatrienyl)-, (E, E, E)-), T-0757 (2,6-octadienamide, N- (4-hydroxy- 3,5-dimethylphenyl) -3,7-dimethyl-, (2E)-), or analogs and derivatives thereof.

21) In another embodiment of the MCP-1 antagonist, the pharmacologically active compound is an MCP-1 antagonist (nitronaproxen (2-naphthaleneacetic acid, 6-methoxy-α-methyl 4- (nitrooxy) butyl ester) (Α S)-), vindarite (2- (1-benzylindazol-3-ylmethoxy) -2-methylpropanoic acid), 1-α-25 dihydroxyvitamin D ₃ or analogs and derivatives thereof).

22) MMP inhibitors In another embodiment, the pharmacologically active compound is a matrix metalloproteinase (MMP) inhibitor (D-9120, doxycycline (2-naphthacenecarboxamide, 4- (diethylamino) -1,4 , 4a, 5,5a, 6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy-6-methyl-1,11-dioxo- (4S- (4 α, 4a α, 5 α (lpha), 5a α, 6 α, 12a α))-), BB-2827, BB-1101 (2S-allyl-N1-hydroxy-3R-isobutyl-N4- (1S-methylcarbamoyl-2) -Phenylethyl) -succinamide), BB-2983, sorimastate (N '-(2,2-dimethyl-1 (S)-(N- (2-pyridyl) carbamoyl) propyl) -N4-hydroxy-2 (R) -Isobutyl-3 (S) -methoxysuccinamide), batimastat (butanediamide, N4-hydroxy-N1- (2- (methylamino) -2-oxo-1- (phenylmethyl) ethyl) -2- (2- Methylpropyl) -3-((2-thienylthio) methyl)-, ( 2R- (1 (S *), 2R *, 3S *))-), CH-138, CH-5902, D-1927, D-5410, EF-13 (γ-linolenic acid lithium salt), CMT-3 (2-naphthacenecarboxamide, 1,4,4a, 5,5a, 6,11,12a-octahydro-3,10,12,12a-tetrahydroxy-1,11-dioxo-, (4aS, 5aR, 12aS) -), Marimastat (N- (2,2-dimethyl-1 (S)-(N-methylcarbamoyl) propyl) -N, 3 (S) -dihydroxy-2 (R) -isobutylsuccinamide), TIMP'S, ONO-4817, levimastat (L-valineamide, N-((2S) -2-mercapto-1-oxo-4- (3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) butyl) -L -Leucyl-N, 3-dimethyl-), PS-508, CH-715, nimesulide (methanesulfonamide, N- (4-nitro-2-phenoxyphenyl)-), hexahydro-2- (2 (R)- (1 (RS)-(Hydroxycarbamoyl) -4-phenylbutyl) nonanoyl) -N- (2,2,6,6-etramethyl-4-piperidinyl) -3 (S) -pyridazinecarboxamide, Rs-113-080 Ro-1130830, Cipemasterat (1-piperidinebutanamide, β- (cyclopentylmethyl) -N-hydroxy-γ-oxo-α-((3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl) methyl )-, (αR, βR)-), 5- (4'-biphenyl) -5- (N- (4-nitrophenyl) piperazinyl) barbituric acid, 6-methoxy-1,2,3,4-tetrahydro -Noralman-1-carboxylic acid, Ro-31-4724 (L-alanine, N- (2- (2- (hydroxyamino) -2-oxoethyl) -4-methyl-1-oxopentyl) -L-leucyl- , Ethyl ester), purinomasterate (3-thiomorpholinecarboxamide, N-hydroxy-2,2-dimethyl-4-((4- (4-pyridinyloxy) phenyl) sulfonyl)-, (3R)-), AG-3433 ( 1H-pyrrole-3-propanoic acid, 1- (4'-cyano (1,1'-biphenyl) -4-yl) -b-((((3S) -tetrahydro-4,4-dimethyl-2-oxo -3-furanyl) amino) carbonyl)-, phenylmethyl ester (bS)-), PNU-142769 (2H-isoindole-2-butanamide, 1,3-dihydro-N-hydroxy-α-((3S) -3- (2-methylpropyl) -2-oxo-1 -(2-phenylethyl) -3-pyrrolidinyl) -1,3-dioxo-, (αR)-), (S) -1- (2-((((4,5-dihydro-5-thioxo-1 , 3,4-thiadiazol-2-yl) amino) -carbonyl) amino) -1-oxo-3- (pentafluorophenyl) propyl) -4- (2-pyridinyl) piperazine, SU-5402 (1H-pyrrole- 3-propanoic acid, 2-((1,2-dihydro-2-oxo-3H-indole-3-ylidene) methyl) -4-methyl-), SC-77964, PNU-171829, CGS-27023A, N- Hydroxy-2 (R)-((4-methoxybenzene-sulfonyl) (4-picolyl) amino) -2- (2-tetrahydrofuranyl) -acetamide, L-758354 ((1,1'-biphenyl) -4- Hexanoic acid, α-butyl-γ-(((2,2-dimethyl-1-((methylamino) carbonyl) propyl) amino) carbonyl) -4'-fluoro-, (αS- (α R *, γS * (R *)))-, GI-155704A, CPA-926, TMI-005, XL-784, or analogs and derivatives thereof. Other representative examples are U.S. Pat.Nos. 5,977,408,5,929,097,6,498,167,6,534,491,6,548,524,5,962,481,6,197,795,6,162,814,6,441,023,6,444,704,6,462,073,6,162,821,6,444,639,6,262,080,6,486,193,6,329,550,6,544,980,6,352,976,5,968,795,5,789,434,5,932,763,6,500,847,5,925,637,6,225,314,5,804,581, 5,863,915,5,859,047,5,861,428,5,886,043,6,288,063,5,939,583,6,166,082,5,874,473,5,886,022,5,932,577,5,854,277,5,886,024,6,495,565,6,642,255,6,495,548,6,479,502,5,696,082,5,700,838,6,444,639,6,262,080,6,486,193,6,329,550,6,544,980,6,352,976,5,968,795, 5,789,434, 5,932,763, 6,500,847, 5,925,637, 6,225,314, 5,804,581, 5,863,915, 5,859,047, 5,861,428, 5,88 6,043,6,288,063,5,939,583,6,166,082,5,874,473,5,886,022,5,932,577,5,854,277,5,886,024,6,495,565,6,642,255,6,495,548,6,479,502,5,696,082,5,700,838,5,861,436,5,691,382,5,763,621,5,866,717,5,902,791,5,962,529,6,017,889,6,022,873,6,022,898,6,103,739, 6,127,427,6,258,851,6,310,084,6,358,987,5,872,152,5,917,090,6,124,329,6,329,373,6,344,457,5,698,706,5,872,146,5,853,623,6,624,144,6,462,042,5,981,491,5,955,435,6,090,840,6,114,372,6,566,384,5,994,293,6,063,786,6,469,020,6,118,001,6,187,924,6,310,088, 5,994,312,6,180,611,6,110,896,6,380,253,5,455,262,5,470,834,6,147,114,6,333,324,6,489,324,6,362,183,6,372,758,6,448,250,6,492,367,6,380,258,6,583,299,5,239,078,5,892,112,5,773,438,5,696,147,6,066,662,6,600,057,5,990,158,5,731,293,6,277,876,6,521,606, 6,168,807, 6,506,414, 6,620,813, 5,684,152, 6,451,791, 6,476,027, 6,013,649, 6,503,892, 6,420,42 7,6,300,514,6,403,644,6,177,466,6,569,899,5,594,006,6,417,229,5,861,510,6,156,798,6,387,931,6,350,907,6,090,852,6,458,822,6,509,337,6,147,061,6,114,568,6,118,016,5,804,593,5,847,153,5,859,061,6,194,451,6,482,827,6,638,952,5,677,282,6,365,630, 6,130,254,6,455,569,6,057,369,6,576,628,6,110,924,6,472,396,6,548,667,5,618,844,6,495,578,6,627,411,5,514,716,5,256,657,5,773,428,6,037,472,6,579,890,5,932,595,6,013,792,6,420,415,5,532,265,5,691,381,5,639,746,5,672,598,5,830,915,6,630,516,5,324,634, 6,277,061,6,140,099,6,455,570,5,595,885,6,093,398,6,379,667,5,641,636,5,698,404,6,448,058,6,008,220,6,265,432,6,169,103,6,133,304,6,541,521,6,624,196,6,307,089,6,239,288,5,756,545,6,020,366,6,117,869,6,294,674,6,037,361,6,399,612,6,495,568,6,624,177, 5,948,780, 6,620,835, 6,284,513, 5,977,141, 6,153,612, 6,297,247, 6,559,142, 6,555,535, 6,350,885, 5,627,206, 5,665,764, 5,958,972, 6,420,408, 6,492,422, 6,340,709, 6,022,948, 6,274,703, 6,294,694, 6,531,499, 6,465,508,6,437,177,6,376,665,5,268,6,617,5 .

23) NFκB inhibitor In another embodiment, the pharmacologically active compound is an NFκB (NFKB) inhibitor (AVE-0545, Oxi-104 (benzamide, 4-amino-3-chloro-N- (2- (Diethylamino) ethyl)-), dexliptam, R-flurbiprofen ((1,1′-biphenyl) -4-acetic acid, 2-fluoro-α-methyl), SP100030 (2-chloro-N- (3, 5-di (trifluoromethyl) phenyl) -4- (trifluoromethyl) pyrimidine-5-carboxamide), AVE-0545, Viatris, AVE-0547, Bay11-7082, Bay 11-7085, 15 Deoxy-Prostyle Anjin J2, Bortezomib (boronic acid, ((1R) -3-methyl-1-(((2S) -1-oxo-3-phenyl-2-((pyrazinylcarbonyl) amino) propyl) amino) butyl)- , Benzamide derivatives and nicotinamide derivatives that inhibit NF-κB (such as those described in US Pat. Nos. 5,561,161 and 5,340,565 (OxiGene)), PG490-88Na, or analogs thereof Derivatives, etc.).

24) Nitric oxide agonists In another embodiment, the pharmacologically active compound is a nitric oxide antagonist (NCX-4016 (benzoic acid, 2- (acetyloxy)-, 3-((nitrooxy) methyl ) Phenyl ester, NCX-2216, L-arginine or analogs and derivatives thereof.

25) P38 MAP kinase inhibitor In another embodiment, the pharmacologically active compound is a p38 MAP kinase inhibitor (GW-2286, CGP-52411, BIRB-798, SB220025, RO-320-1195, RWJ- 67657, RWJ-68354, SCIO-469, SCIO-323, AMG-548, CMC-146, SD-31145, CC-8866, Ro-320-1195, PD-98059 (4H-1-benzopyran-4-one ( one), 2- (2-amino-3-methoxyphenyl)-), CGH-2466, dramapimod, SB-203580 (pyridine, 4- (5- (4-fluorophenyl) -2- (4- (methylsulfinyl) ) Phenyl) -1H-imidazol-4-yl)-), SB-220025 ((5- (2-amino-4-pyrimidinyl) -4- (4-fluorophenyl) -1- (4-piperidinyl) imidazole) , SB-281832, PD169316, SB202190, GSK-681323, EO-1606, GSK-681323, or analogs and derivatives thereof. 6,376,527, 6,444,696, 6,479,507, 6,509,361, 6,579,874, 6,630,485, National Patent Application Publication Nos. 2001 / 0044538A1, 2002 / 0013354A1, 2002 / 0049220A1, 2002 / 0103245A1, 2002 / 0151491A1, 2002 / 0156114A1, 2003 / 0018051A1, 2003 / 0073832A1, 2003 / 0130257A1, 2003 / 0130273A1, 2003 / 0130319A1, 2003 / 0139388A1, 20030139462A1, 2003 / 0149031A1, 2003 / 0166647A1, 2003 / 0181411A1, and PCT publication numbers WO00 / 63204A2, WO 01 / 21591A1, WO 01 / 35959A1, WO 01 / 74811A2, WO 02 / 18379A2, WO 2064594A2, WO2083622A2, WO 2094842A2, WO 2096426A1, WO 2101015A2, WO 2103000A2, WO 3008413A1, WO3016248A2, WO 3020715A1, WO 3024899A2, WO 3031431A1, WO3040103A1, WO 3053940A1, WO3053941A2, WO 3063799A2, WO 3079986A2, WO 30799860024A1, WO There are descriptions in WO99 / 01449A1, WO 99 / 58523A1, and the like.

26) Phosphodiesterase inhibitors In another embodiment, the pharmacologically active compound is a phosphodiesterase inhibitor (CDP-840 (pyridine, 4-((2R) -2- (3- (cyclopentyloxy) -4-methoxy). Phenyl) -2-phenylethyl)-), CH-3697, CT-2820, D-22888 (imidazo (1,5-a) pyrido (3,2-e) pyrazin-6 (5H) -one, 9- Ethyl-2-methoxy-7-methyl-5-propyl-), D-4418 (8-methoxyquinolin-5- (N- (2,5-dichloropyridin-3-yl)) carboxamide), 1- (3 -Cyclopentyloxy-4-methoxyphenyl) -2- (2,6-dichloro-4-pyridyl) ethanone oxime, D-4396, ONO-6126, CDC-998, CDC-801, V-11294A (3- ( 3- (cyclopentyloxy) -4-methoxybenzyl) -6- (ethylamino) -8-isopropyl-3H-purine hydrochloride), S, S'-methylene-bis (2- (8-cyclopropyl-3- Propyl-6- (4-pyridylmethylamino) -2-thio-3H-purine)) tetrahy Chloride, rolipram (2-pyrrolidinone, 4- (3- (cyclopentyloxy) -4-methoxyphenyl)-), CP-293121, CP-353164 (5- (3-cyclopentyloxy-4-methoxyphenyl) pyridine- 2-carboxamide), oxagrelate (6-phthalazinecarboxylic acid, 3,4-dihydro-1- (hydroxymethyl) -5,7-dimethyl-4-oxo-, ethyl ester), PD-168787, ibudilast ( 1-propanone, 2-methyl-1- (2- (1-methylethyl) pyrazolo (1,5-a) pyridin-3-yl)-), oxagrelate (6-phthalazinecarboxylic acid, 3,4 -Dihydro-1- (hydroxymethyl) -5,7-dimethyl-4-oxo-, ethyl ester), glyceolic acid (α-L-talo-oct-4-enofuranuronic acid, 1- (6-amino-9H- Purin-9-yl) -3,6-anhydro-6-C-carboxy-1,5-dideoxy-), KW-4490, KS-506, T-440, roflumilast (benzamide, 3- (cyclopropylmethyl) Xy) -N- (3,5-dichloro-4-pyridinyl) -4- (difluoromethoxy)-), rolipram, milrinone, triflucinal (benzoic acid, 2- (acetyloxy) -4- (trifluoromethyl) -), Anagrelide hydrochloride (imidazo (2,1-b) quinazolin-2 (3H) -one, 6,7-dichloro-1,5-dihydro-, monohydrochloride), cilostazol (2 (1H) -quinolinone, 6- (4- (1-cyclohexyl-1H-tetrazol-5-yl) butoxy) -3,4-dihydro-), propentophilin (1H-purine-2,6-dione, 3,7-dihydro-3 -Methyl-1- (5-oxohexyl) -7-propyl-), sildenafil citrate (piperazine, 1-((3- (4,7-dihydro-1-methyl-7-oxo-3-propyl- 1H-pyrazolo (4,3-d) pyrimidin-5-yl) -4-ethoxyphenyl) sulfonyl) -4-methyl, 2-hydroxy-1,2,3-propanetricarboxylate- (1: 1)) , Tadalafil (pyrazino (1 ', 2': 1,6) pyrido (3,4-b) indole 1,4-dione, 6- (1,3-benzodioxol-5-yl) -2,3,6,7 , 12,12a-Hexahydro-2-methyl-, (6R-trans)), vardenafil (piperazine, 1- (3- (1,4-dihydro-5-methyl (-4-oxo-7-propylimidazo (5 , 1-f) (1,2,4) -triazin-2-yl) -4-ethoxyphenyl) sulfonyl) -4-ethyl-), milrinone ((3,4′-bipyridine) -5-carbonitrile, 1,6-dihydro-2-methyl-6-oxo-), enoximone (2H-imidazol-2-one, 1,3-dihydro-4-methyl-5- (4- (methylthio) benzoyl)-), theophylline (1H-purine-2,6-dione, 3,7-dihydro-1,3-dimethyl-), ibudilast (1-propanone, 2-methyl-1- (2- (1-methylethyl) pyrazolo (1, 5-a) pyridin-3-yl)-), aminophylline (1H-purine-2,6-dione, 3,7-dihydro-1,3-dimethyl-, 1,2-ethanediamine (2: 1)- Compounds with Acebrophyrin (7H-purine-7-acetic acid, 1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-, trans-4-(((2-amino-3,5 -Dibromophenyl) methyl) amino) cyclohexanol (1: 1) compound), plafibride (propanamide, 2- (4-chlorophenoxy) -2-methyl-N-(((4-morpholinylmethyl) Amino) carbonyl)-), ioprinone hydrochloride (3-pyridinecarbonitrile, 1,2-dihydro-5-imidazo (1,2-a) pyridin-6-yl-6-methyl-2-oxo-, monohydro Chloride-), phosphosar (benzoic acid, 2- (phosphonooxy)-), amrinone ((3,4'-bipyridine) -6 (1H) -one, 5-amino-, or analogs and derivatives thereof) .

  Other examples of phosphodiesterase inhibitors include denbufilin (1H-purine-2,6-dione, 1,3-dibutyl-3,7-dihydro-7- (2-oxopropyl)-), propentophilin (1H -Purine-2,6-dione, 3,7-dihydro-3-methyl-1- (5-oxohexyl) -7-propyl-) and perlinone (5-pyrimidinecarbonitrile, 1,4-dihydro-2- Methyl-4-oxo-6-((3-pyridinylmethyl) amino)-) and the like.

  Other examples of phosphodiesterase III inhibitors include enoximone (2H-imidazol-2-one, 1,3-dihydro-4-methyl-5- (4- (methylthio) benzoyl)-), and saterinone (3-pyridine Carbonitrile, 1,2-dihydro-5- (4- (2-hydroxy-3- (4- (2-methoxyphenyl) -1-piperazinyl) propoxy) phenyl) -6-methyl-2-oxo-), etc. There is.

  Other examples of phosphodiesterase IV inhibitors include AWD-12-281, 3-Auinolinecarboxylic acid, 1-ethyl-6-fluoro-1,4-dihydro-7- (4-methyl-1-piperazinyl)- 4-oxo-), tadalafil (pyrazino (1 ', 2': 1,6) pyrido (3,4-b) indole 1,4-dione, 6- (1,3-benzodioxol-5-yl ) -2,3,6,7,12,12a-hexahydro-2-methyl-, (6R-trans)), and filaminast (ethanone, 1- (3- (cyclopentyloxy) -4-methoxyphenyl)-, O- (aminocarbonyl) oxime, (1E)-) and the like.

  Other examples of phosphodiesterase V inhibitors include vardenafil (piperazine, 1- (3- (1,4-dihydro-5-methyl (-4-oxo-7-propylimidazo (5,1-f) (1, 2,4) -triazin-2-yl) -4-ethoxyphenyl) sulfonyl) -4-ethyl-) and the like.

27) TGF beta inhibitor In another embodiment, the pharmacologically active compound is a TGF beta inhibitor (mannose-6-phosphate, LF-984, tamoxifen (ethanamine, 2- (4- (1, 2-diphenyl-1-butenyl) phenoxy) -N, N-dimethyl-, (Z)-), tranilast, or analogs and derivatives thereof.

28) Thromboxane A2 antagonist In another embodiment, the pharmacologically active compound is a thromboxane A2 antagonist (CGS-22652 (3-pyridineheptanoic acid, γ- (4-(((4-chlorophenyl)) (Sulfonyl) amino) butyl)-, (. +-.)-), Ozagrel (2-propenoic acid, 3- (4- (1H-imidazol-1-ylmethyl) phenyl)-, (E)-), argatroban ( 2-piperidinecarboxylic acid, 1- (5-((aminoiminomethyl) amino) -1-oxo-2-(((1,2,3,4-tetrahydro-3-methyl-8-quinolinyl) sulfonyl) amino ) Pentyl) -4-methyl-), ramatroban (9H-carbazole-9-propanoic acid, 3-(((4-fluorophenyl) sulfonyl) amino) -1,2,3,4-tetrahydro-, (R) -), Torasemide (3-pyridinesulfonamide, N-(((1-methylethyl) amino) carbonyl) -4-((3-methylphenyl) amino)-), gamma linoleic acid ((Z, Z, Z ) -6,9,12-Octadecatrienoic acid , Seratrodast (benzeneheptanoic acid, ξ- (2,4,5-trimethyl-3,6-dioxo-1,4-cyclohexadien-1-yl)-, (+/-)-, or analogues and derivatives thereof Etc.).

29) TNFa antagonist and TACE inhibitor In another embodiment, the pharmacologically active compound is a TNFa antagonist or TACE inhibitor (E-5531 (2-deoxy-6-0- (2-deoxy-3 -0- (3 (R)-(5 (Z) -dodecenoyloxy) -decyl) -6-0-methyl-2- (3-oxotetradecanamido) -4-O-phosphono-β-D -Glucopyranosyl) -3-0- (3 (R) -hydroxydecyl) -2- (3-oxotetradecanamido) -α-D-glucopyranose-1-O-phosphate), AZD-4717, glycophospho Peptical, UR-12715 (B = benzoic acid, 2-hydroxy-5-((4- (3- (4- (2-methyl-1H-imidazole (4,5-c) pyridin-1-yl) methyl ) -1-piperidinyl) -3-oxo-1-phenyl-1-propenyl) phenyl) azo) (Z)), PMS-601, AM-87, xyloadenosine (9H-purine-6-amine, 9-β -D-xylofuranosyl-), RDP-58, RDP-59, BB2275, benzydamine, E-3330 (undecanoic acid, 2-((4,5-dimethoxy-2-methyl-3,6-dioxy) -1,4-cyclohexadien-1-yl) methylene)-, (E)-), N- (D, L-2- (hydroxyaminocarbonyl) methyl-4-methylpentanoyl) -L-3- ( 2'-naphthyl) alanyl-L-alanine, 2-aminoethylamide, CP-564959, MLN-608, SPC-839, ENMD-0997, Sch-23863 ((2- (10,11-dihydro-5-ethoxy -5H-dibenzo (a, d) cyclohepten-S-yl) -N, N-dimethyl-ethanamine), SH-636, PKF-241-466, PKF-242-484, TNF-484A, siromilast (cis-4 -Cyano-4- (3- (cyclopentyloxy) -4-methoxyphenyl) cyclohexane-1-carboxylic acid), GW-3333, GW-4459, BMS-561392, AM-87, chlorochromene (acetic acid, ((8- Chloro-3- (2- (diethylamino) ethyl) -4-methyl-2-oxo-2H-1-benzopyran-7-yl) oxy)-, ethyl ester), thalidomide (1H-isoindole-1,3 ( 2H) -dione, 2- (2,6-dioxo-3-piperidinyl)-), vesnarinone (pipe Gin, 1- (3,4-dimethoxybenzoyl) -4- (1,2,3,4-tetrahydro-2-oxo-6-quinolinyl)-), infliximab, lentinan, etanercept (236-467-immunoglobulin G1 1-235-tumor necrosis factor receptor (human) fusion protein (human γ1-chain Fc fragment), diacerein (2-anthracenecarboxylic acid, 4,5-bis (acetyloxy) -9,10-dihydro- 9,10-dioxo-, or analogs and derivatives thereof).

30) Tyrosine kinase inhibitors In another embodiment, the pharmacologically active compound is a tyrosine kinase inhibitor (SKI-606, ER-068224, SD-208, N- (6-benzothiazolyl) -4- (2 -(1-Piperazinyl) pyrid-5-yl) -2-pyrimidineamine, celastrol (24,25,26-trinoroleana-1 (10), 3,5,7-tetraene-29-acid, 3-hydroxy -9,13-dimethyl-2-oxo-, (9beta., 13α, 14β, 20α)-), CP-127374 (geldanamycin, 17-demethoxy-17- (2-propenylamino)-), CP-564959, PD-171026, CGP-52411 (1H-isoindole-1,3 (2H) -dione, 4,5-bis (phenylamino)-), CGP-53716 (benzamide, N- (4-methyl) -3-((4- (3-pyridinyl) -2-pyrimidinyl) amino) phenyl)-), imatinib (4-((methyl-1-piperazinyl) methyl) -N- (4-methyl-3-(( 4- (3-pyridinyl) -2-pyrimidinyl) amino) -phenyl) benzamide methanesulfonate , NVP-AAK980-NX, KF-250706 (13-chloro, 5 (R), 6 (S) -epoxy-14,16-dihydroxy-11- (hydroimino) -3 (R) -methyl-3,4, 5,6,11,12-Hexahydro-1H-2-benzooxacyclotetradecin-1-one), 5- (3- (3-methoxy-4- (2-((E) -2-phenylethenyl) ) -4-Oxazolylmethoxy) phenyl) propyl) -3- (2-((E) -2-phenylethenyl) -4-oxazolylmethyl) -2,4-oxazolidinedione, genistein, NV- 06, or analogs and derivatives thereof.

31) Vitronectin inhibitors In another embodiment, the pharmacologically active compound is a vitronectin inhibitor (O- (9,10-dimethoxy-1,2,3,4,5,6-hexahydro-4- ( (1,4,5,6-tetrahydro-2-pyrimidinyl) hydrazono) -8-benz (e) azulenyl) -N-((phenylmethoxy) carbonyl) -DL-homoserine 2,3-dihydroxypropyl ester, (2S ) -Benzoylcarbonylamino-3- (2-((4S)-(3- (4,5-dihydro-1H-imidazol-2-ylamino) -propyl) -2,5-dioxo-imidazolidin-1-yl ) -Acetylamino) -propionate, Sch-221153, S-836, SC-68448 (β-((2-2-(((3-((aminoiminomethyl) amino) -phenyl) carbonyl) amino) acetyl) Amino) -3,5-dichlorobenzenepropanoic acid), SD-7784, S-247, or analogs and derivatives thereof.

32) Fibroblast growth factor inhibitor In another embodiment, the pharmacologically active compound is a fibroblast growth factor inhibitor (CT-052923 (((2H-benzo (d) 1,3-dioxalane- 5-methyl) amino) (4- (6,7-dimethoxyquinazolin-4-yl) piperazinyl) methane-1-thione), or analogs and derivatives thereof.

33) Protein kinase inhibitors In another embodiment, the pharmacologically active compound is a protein kinase inhibitor (KP-0201448, NPC15437 (hexaneamide, 2,6-diamino-N-((1- (1- Oxotridecyl) -2-piperidinyl) methyl)-), fasudil (1H-1,4-diazepine, hexahydro-1- (5-isoquinolinylsulfonyl)-), midostaurin (benzamide, N- (2,3 , 10,11,12,13-Hexahydro-10-methoxy-9-methyl-1-oxo-9,13-epoxy-1H, 9H-diindolo (1,2,3-gh: 3 ', 2', 1 '-lm) pyrrolo (3,4-j) (1,7) benzodiazonin-11-yl) -N-methyl-, (9α, 10β, 11β, 13α)-), fasudil (1H-1,4 -Diazepine, hexahydro-1- (5-isoquinolinylsulfonyl)-, dexnigurdipine (3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl-4- (3-nitrophenyl) -, 3- (4,4-diphenyl-1-piperidinyl) propyl methyl ester, Nohydrochloride, (R)-), LY-317615 (1H-pyrrole-2,5-dione, 3- (1-methyl-1H-indol-3-yl) -4- (1- (1- (2 -Pyridinylmethyl) -4-piperidinyl) -1H-indol-3-yl)-, monohydrochloride), perifosine (piperidinium, 4-((hydroxy (octadecyloxy) phosphinyl) oxy) -1,1-dimethyl-, internal Salt), LY-333531 (9H, 18H-5,21: 12,17-Dimethenodibenzo (e, k) pyrrolo (3,4-h) (1,4,13) oxadiazacyclohexadecin-18,20 (19H) -dione, 9-((diethylamino) methyl) -6,7,10,11-tetrahydro-, (S)-), Kynac, SPC-100270 (1,3-octadecanediol, 2-amino-, (S- (R *, R *))-), Kynacyte, or analogs and derivatives thereof).

34) PDGF receptor kinase inhibitor In another embodiment, the pharmacologically active compound is a PDGF receptor kinase inhibitor (such as RPR-127963E, or an analog or derivative thereof).

35) Endothelial growth factor receptor kinase inhibitor In another embodiment, the pharmacologically active compound is an endothelial growth factor receptor kinase inhibitor (CEP-7055, SU-0879 ((E) -3- (3 , 5-di-tert-butyl-4-hydroxyphenyl) -2- (aminothiocarbonyl) acrylonitrile), BIBF-1000, AG-013736 (CP-868596), AMG-706, AVE-0005, NM-3 ( 3- (2-methylcarboxymethyl) -6-methoxy-8-hydroxy-isocoumarin), Bay-43-9006, SU-011248, or analogs and derivatives thereof.

36) Retinoic acid receptor antagonists In another embodiment, the pharmacologically active compound is a retinoic acid receptor antagonist (etarotene (Ro-15-1570) (naphthalene, 6- (2- (4- ( Ethylsulfonyl) phenyl) -1-methylethenyl) -1,2,3,4-tetrahydro-1,1,4,4-tetramethyl-, (E)-), (2E, 4E) -3-methyl-5 -(2-((E) -2- (2,6,6-trimethyl-1-cyclohexen-1-yl) ethenyl) -1-cyclohexen-1-yl) -2,4-pentadienoic acid, tocoletinate (retinoin Acid, 3,4-dihydro-2,5,7,8-tetramethyl-2- (4,8,12-trimethyltridecyl) -2H-1-benzopyran-6-yl ester, (2R * (4R * , 8R *))-(±)-), arretinoin (retinoic acid, cis-9, trans-13-), bexarotene (benzoic acid, 4- (1- (5,6,7,8-tetrahydro-3) , 5,5,8,8-pentamethyl-2-naphthalenyl) ethenyl)-), tocoletinate (retinoic acid, 3,4-dihydro-2,5,7,8-te Lamethyl-2- (4,8,12-trimethyltridecyl) -2H-1-benzopyran-6-yl ester, (2R * (4R *, 8R *))-(±)-, or analogs and derivatives thereof Etc.).

37) Platelet-derived growth factor receptor kinase inhibitor In another embodiment, the pharmacologically active compound is a platelet-derived growth factor receptor kinase inhibitor (leflunomide (4-isoxazolecarboxamide, 5-methyl-N- (4- (trifluoromethyl) phenyl)-, or analogs and derivatives thereof).

38) In another embodiment of the fibrinogen antagonist, the pharmacologically active compound is a fibrinogin antagonist (picotamide (1,3-benzenedicarboxamide, 4-methoxy-N, N'-bis (3-pyridinylmethyl)- Or analogs and derivatives thereof.

39) In another embodiment of the antifungal agent, the pharmacologically active compound is an antifungal agent (miconazole, sulconizole, parthenolide, rosconitine, nystatin, isoconazole, fluconazole, ketoconazole, imidazole, itraconazole, terpinafine, eronazole, bifonazole, Clotrimazole, conazole, terconazole (piperazine, 1- (4-((2- (2,4-dichlorophenyl) -2- (1H-1,2,4-triazol-1-ylmethyl) -1,3-dioxolane -4-yl) methoxy) phenyl) -4- (1-methylethyl)-, cis-), isoconazole (1- (2- (2-6-dichlorobenzyloxy) -2- (2-, 4-dichlorophenyl) ) Ethyl)), griseofulvin (spiro (benzofuran-2 (3H), 1 '-(2) cyclohexane) -3,4'-dione, 7-chloro-2', 4,6-trimeth-oxy-6'methyl -, (1'S-trans)-), bifonazole (1H- Imidazole, 1-((1,1'-biphenyl) -4-ylphenylmethyl)-), econazole nitrate (1- (2-((4-chlorophenyl) methoxy) -2- (2,4-dichlorophenyl) ethyl ) -1H-imidazole nitrate), Croconazole (1H-imidazole, 1- (1- (2-((3-chlorophenyl) methoxy) phenyl) ethenyl)-), Sertaconazole (1H-imidazole, 1- (2 -((7-chlorobenzo (b) thien-3-yl) methoxy) -2- (2,4-dichlorophenyl) ethyl)-), omoconazole (1H-imidazole, 1- (2- (2- (4-chloro Phenoxy) ethoxy) -2- (2,4-dichlorophenyl) -1-methylethenyl)-, (Z)-), flutrimazole (1H-imidazole, 1-((2-fluorophenyl) (4-fluorophenyl) Phenylmethyl)-), fluconazole (1H-1,2,4-triazol-1-ethanol, α- (2,4-difluorophenyl) -α- (1H-1,2,4-triazol-1-ylmethyl) -) , Neticonazole (1H-imidazole, 1- (2- (methylthio) -1- (2- (pentyloxy) phenyl) ethenyl)-, monohydrochloride, (E)-), butconazole (1H-imidazole, 1- ( 4- (4-chlorophenyl) -2-((2,6-dichlorophenyl) thio) butyl)-, (+/-)-), clotrimazole (1-((2-chlorophenyl) diphenylmethyl) -1H- Imidazole, or analogs and derivatives thereof).

40) Bisphosphonates In another embodiment, the pharmacologically active compound is a bisphosphonate (such as clodronate, alendronate, puamidronate, zoledronic acid, or analogs and derivatives thereof).

41) Phospholipase A1 inhibitor In another embodiment, the pharmacologically active compound is a phospholipase A1 inhibitor (ioteprednol etabonate (androst-1,4-diene-17-carboxylic acid, 17- ((Ethoxycarbonyl) oxy) -11-hydroxy-3-oxo-, chloromethyl ester, (11β, 17α)-, or analogs and derivatives thereof).

42) Histamine H1 / H2 / H3 receptor antagonists In another embodiment, the pharmacologically active compound is a histamine H1, H2, or H3 receptor antagonist (ranitidine (1,1-ethenediamine, N- (2-(((5-((diethylamino) methyl) -2-furanyl) methyl) thio) ethyl) -N'-methyl-2-nitro-), niperotidine (N- (2-((5-(( Diethylamino) methyl) furfuryl) thio) ethyl) -2-nitro-N'-piperonyl-1,1-ethenediamine), famotidine (propanimidamide, 3-(((2-((aminoiminomethyl) amino)- 4-thiazolyl) methyl) thio) -N- (aminosulfonyl)-), roxitadine acetate HCl (acetamide, 2- (acetyloxy) -N- (3- (3- (1-piperidinylmethyl) phenoxy) Propyl)-, monohydrochloride), lafutidine (acetamide, 2-((2-furanylmethyl) sulfinyl) -N- (4-((4- (1-piperidinylmethyl) -2-pyridy Nyl) oxy) -2-butenyl)-, (Z)-), nizatazine (1,1-ethenediamine, N- (2-(((2-((diethylamino) methyl) -4-thiazolyl) methyl) thio) ) Ethyl) -N'-methyl-2-nitro-), ebrotidine (benzenesulfonamide, N-(((2-(((2-((aminoiminomethyl) amino) -4-thiazoly) methyl) thio) Ethyl) amino) methylene) -4-bromo-), lupatadine (5H-benzo (5,6) cyclohepta (1,2-b) pyridine, 8-chloro-6,11-dihydro-11- (1-(( 5-methyl-3-pyridinyl) methyl) -4-piperidinylidene)-, trihydrochloride-), fexofenadine HCl (benzeneacetic acid, 4- (1-hydroxy-4- (4 (hydroxydiphenylmethyl) -1- Piperidinyl) butyl) -α, α-dimethyl-, hydrochloride, or analogs and derivatives thereof.

43) In another embodiment of macrolide antibiotics, the pharmacologically active compound is a macrolide antibiotic (zilythromycin (erythromycin, 9-deoxo-11-deoxy-9,11- (imino (2 -(2-methoxyethoxy) ethylidene) oxy)-, (9S (R))-), flurithromycin ethyl succinate (erythromycin, 8-fluoro-mono (ethylbutanedioate) (ester)-), erythromycin Stinoplatate (erythromycin, 2'-propanoate, compound with N-acetyl-L-cysteine (1: 1)), clarithromycin (erythromycin, 6-O-methyl-), azithromycin (9-deoxo- 9a-aza-9a-methyl-9a-homoerythromycin-A), terithromycin (3-de ((2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl ) Oxy) -11,12-dideoxy-6-O-methyl-3- Xoxo-12,11- (oxycarbonyl ((4- (4- (3-pyridinyl) -1H-imidazol-1-yl) butyl) imino))-), roxithromycin (erythromycin, 9- (O- ( (2-methoxyethoxy) methyl) oxime)), roquitamycin (leucomycin V, 4B-butanoate 3B-propanoate), RV-11 (erythromycin monopropionate mercaptosuccinate), midecamycin acetate (leucomycin V, 3B, 9-diacetate 3,4B-dipropanoate), midecamycin (leucomycin V, 3,4B-dipropanoate), josamycin (leucomycin V, 3-acetate 4B- (3-methylbutanoate), or Analogs and derivatives thereof).

44) GPIIb / IIIa receptor antagonist In another embodiment, the pharmacologically active compound is a GPIIb / IIIa receptor antagonist (tirofiban hydrochloride (L-tyrosine, N- (butylsulfonyl) -O- ( 4- (4-piperidinyl) butyl)-, monohydrochloride-), eptifibatide (L-cysteine amide, N6- (aminoiminomethyl) -N2- (3-mercapto-1-oxopropyl) -L-lysylglycyl-L -α-aspartyl-L-tryptophyll-L-prolyl-, periodic (sex) (1-> 6) -disulfide), xemirofiban hydrochloride, or analogs and derivatives thereof.

45) Endothelin receptor antagonists In another embodiment, the pharmacologically active compound is an endothelin receptor antagonist (bosentan (benzenesulfonamide, 4- (1,1-dimethylethyl) -N- (6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) (2,2′-bipyrimidin) -4-yl)-, or analogs and derivatives thereof.

46) Peroxisome proliferator-responsive receptor agonist In another embodiment, the pharmacologically active compound is a peroxisome proliferator-responsive receptor agonist (gemfibrozil (pentanoic acid, 5- (2,5-dimethylphenoxy)). ) -2,2-dimethyl-), fenofibrate (propanoic acid, 2- (4- (4-chlorobenzoyl) phenoxy) -2-methyl-, 1-methylethyl ester), ciprofibrate (propanoic acid, 2- (4- (2,2-dichlorocyclopropyl) phenoxy) -2-methyl-), rosiglitazone maleate (2,4-thiazolidinedione, 5-((4- (2- (methyl-2-pyridinylamino) ethoxy) ) Phenyl) methyl)-, (Z) -2-butenedioate (1: 1)), pioglitazone hydrochloride (2,4-thiazolidinedione, 5-((4- (2- (5-ethyl-2- Pyridinyl) ethoxy) phenyl) methyl)-, monohydrochloride (+/-)-), etophylline lov Ibrate (propanoic acid, 2- (4-chlorophenoxy) -2-methyl-, 2- (1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7H-purine-7- Yl) ethyl ester), etofibrate (3-pyridinecarboxylic acid, 2- (2- (4-chlorophenoxy) -2-methyl-1-oxopropoxy) ethyl ester), clinofibrate (butanoic acid, 2,2 ' -(Cyclohexylidenebis (4,1-phenyleneoxy)) bis (2-methyl-)), bezafibrate (propanoic acid, 2- (4- (2-((4-chlorobenzoyl) amino) ethyl) phenoxy) -2-methyl-), vinylibrate (3-pyridinecarboxylic acid, 2- (2- (4-chlorophenoxy) -2-methyl-1-oxopropoxy) -1,3-propanediyl ester), or similar Body and derivatives).

  In one embodiment, the pharmacologically active compound is a peroxisome proliferator-activated receptor alpha agonist (GW-590735, GSK-677954, GSK501516, pioglitazone hydrochloride (2,4-thiazolidinedione, 5-(( 4- (2- (5-ethyl-2-pyridinyl) ethoxy) phenyl) methyl)-, monohydrochloride (+/-)-, or analogs and derivatives thereof).

47) In another embodiment of the estrogen receptor agent, the pharmacologically active compound is an estrogen receptor agent (such as estradiol, 17-β-estradiol, or analogs and derivatives thereof).

48) Somatostatin analogs In another embodiment, the pharmacologically active compound is a somatostatin analog (such as angiopeptin, or an analog or derivative thereof).

49) In another example of a neurokinin 1 antagonist, the pharmacologically active compound is a neurokinin 1 antagonist (GW-597599, ranepitant ((1,4'-bipiperidine) -1'-acetamide, N- (2- (acetyl ((2-methoxyphenyl) methyl) amino) -1- (1H-indol-3-ylmethyl) ethyl)-(R)-), norpitantium chloride (1-azoniabicyclo (2.2.2 ) Octane, 1- (2- (3- (3,4-dichlorophenyl) -1-((3- (1-methylethoxy) phenyl) acetyl) -3-piperidinyl) ethyl) -4-phenyl-, chloride , (S)-), or salezant (benzamide, N- (4- (4- (acetylamino) -4-phenyl-1-piperidinyl) -2- (3,4-dichlorophenyl) butyl) -N-methyl- , (S)-), or bohopitant (3-piperidineamine, N-((2-methoxy-5- (5- (trifluoromethyl) -1H-tetrazol-1-yl) phenyl) methyl) -2-phenyl -, (2S, 3S)-, or Analogues or derivatives of, or the like).

50) Neurokinin 3 antagonist In another embodiment, the pharmacologically active compound is a neurokinin 3 antagonist (tarnetant (4-quinolinecarboxamide, 3-hydroxy-2-phenyl-N-((1S)- 1-phenylpropyl)-, or analogs and derivatives thereof.

51) Neurokinin antagonist In another embodiment, the pharmacologically active compound is a neurokinin antagonist (GSK-679769, GSK-823296, SR-489686 (benzamide, N- (4- (4- (acetyl) Amino) -4-phenyl-1-piperidinyl) -2- (3,4-dichlorophenyl) butyl) -N-methyl-, (S)-), SB-223412, SB-235375 (4-quinolinecarboxamide, 3- Hydroxy-2-phenyl-N-((1S) -1-phenylpropyl)-), UK-226471, or analogs and derivatives thereof.

52) VLA-4 antagonists In another embodiment, the pharmacologically active compound is a VLA-4 antagonist (such as GSK683699, or an analogue or derivative thereof).

53) Osteoclast inhibitor In another embodiment, the pharmacologically active compound is an osteoclast inhibitor (ibandronic acid (phosphonic acid, (1-hydroxy-3- (methylpentylamino) propylidene) bis- ), Alendronate sodium, or analogs and derivatives thereof.

54) DNA Topoisomerase ATP Hydrolysis Inhibitor In another embodiment, the pharmacologically active compound is a DNA topoisomerase ATP hydrolysis inhibitor (enoxacin (1,8-naphthyridine-3-carboxylic acid, 1-ethyl-6 -Fluoro-1,4-dihydro-4-oxo-7- (1-piperazinyl)-), levofloxacin (7H-pyrido (1,2,3-de) -1,4-benzoxazine-6-carboxylic acid, 9-fluoro-2,3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-, (S)-), ofloxacin (7H-pyrido (1,2,3-de ) -1,4-benzoxazine-6-carboxylic acid, 9-fluoro-2,3-dihydro-3-methyl-10- (4-methyl-1-piperazinyl) -7-oxo-, (+/-) -), Pefloxacin (3-quinolinecarboxylic acid, 1-ethyl-6-fluoro-1,4-dihydro-7- (4-methyl-1-piperazinyl) -4-oxo-), pipemidic acid (pyrido (2, 3-d) Pyrimidine-6-carboxylic acid, 8-ethyl-5,8-dihydro-5-o So-2- (1-piperazinyl)-), pirarubicin (5,12-naphthacenedione, 10-((3-amino-2,3,6-trideoxy-4-O- (tetrahydro-2H-pyran-2 -Yl) -α-L-lyxo-hexopyranosyl) oxy) -7,8,9,10-tetrahydro-6,8,11-trihydroxy-8- (hydroxyacetyl) -1-methoxy-, (8S- ( 8α, 10 α (S *)))-), Sparfloxacin (3-quinolinecarboxylic acid, 5-amino-1-cyclopropyl-7- (3,5-dimethyl-1-piperazinyl) -6,8 -Difluoro-1,4-dihydro-4-oxo-, cis-), AVE-6971, sinoxacin ((1,3) dioxolo (4,5-g) cinnoline-3-carboxylic acid, 1-ethyl-1, 4-dihydro-4-oxo-), or analogs and derivatives thereof.

55) Angiotensin I converting enzyme inhibitor In another embodiment, the pharmacologically active compound is an angiotensin I converting enzyme inhibitor (ramipril (cyclopenta (b) pyrrole-2-carboxylic acid, 1- (2-(( 1- (ethoxycarbonyl) -3-phenylpropyl) amino) -1-oxopropyl) octahydro-, (2S- (1 (R * (R *)), 2α, 3aβ, 6aβ))-), trandolapril (1H-indole-2-carboxylic acid, 1- (2-((1-carboxy-3-phenylpropyl) amino) -1-oxopropyl) octahydro-, (2S- (1 (R * (R *)) , 2α, 3a α, 7aβ))-), fasidotolyl (L-alanine, N-((2S) -3- (acetylthio) -2- (1,3-benzodioxol-5-ylmethyl) -1- Oxopropyl)-, phenylmethyl ester), cilazapril (6H-pyridazino (1,2-a) (1,2) diazepine-1-carboxylic acid, 9-((1- (ethoxycarbonyl) -3-phenylpropyl)) Amino) octahydro-10-oki -, (1S- (1α, 9α (R *)))-), ramipril (cyclopenta (b) pyrrole-2-carboxylic acid, 1- (2-((1- (ethoxycarbonyl) -3-phenylpropyl) ) Amino) -1-oxopropyl) octahydro-, (2S- (1 (R * (R *)), 2α, 3aβ, 6aβ))-, or analogs and derivatives thereof).

56) Angiotensin II antagonist In another embodiment, the pharmacologically active compound is an angiotensin II antagonist (HR-720 (1H-imidazole-5-carboxylic acid, 2-butyl-4- (methylthio) -1 -((2 '-((((propylamino) carbonyl) amino) sulfonyl) (1,1'-biphenyl) -4-yl) methyl)-, dipotassium salts, or analogs and derivatives thereof).

57) Enkephalinase inhibitors In another embodiment, the pharmacologically active compound is an enkephalinase inhibitor (Aventis 100240 (pyrido (2,1-a) (2) benzoazepine-4-carboxylic acid, 7-((2- (acetylthio) -1-oxo-3-phenylpropyl) amino) -1,2,3,4,6,7,8,12b-octahydro-6-oxo-, (4S- (4α 7 α (R *), 12bβ))-), AVE-7688, or analogs and derivatives thereof.

58) Peroxisome proliferator-activated receptor gamma agonist insulin sensitizer In another embodiment, the pharmacologically active compound is a peroxisome proliferator activated receptor gamma agonist insulin sensitizer (my arabino). Rosiglitazone furanosyllenate (2,4-thiazolidinedione, 5-((4- (2- (methyl-2-pyridinylamino) ethoxy) phenyl) methyl)-, (Z) -2-butenedioate (1: 1 ), Farglitazar (GI-262570, GW-2570, GW-3995, GW-5393, GW-9765), LY-929, LY-519818, LY-674, or LSN-862), or analogs and derivatives thereof ).

59) Protein Kinase C Inhibitors In another embodiment, the pharmacologically active compound is a protein kinase C inhibitor (ruboxystaurine mesylate (9H, 18H-5,21: 12,17-dimethenodibenzo (e , k) pyrrolo (3,4-h) (1,4,13) oxadiazacyclohexadecin-18,20 (19H) -dione, 9-((diethylamino) methyl) -6,7,10,11 -Tetrahydro-, (S)-), saphingol (1,3-octadecanediol, 2-amino-, (S- (R *, R *))-), or enzastaurine hydrochloride (1H-pyrrole- 2,5-dione, 3- (1-methyl-1H-indol-3-yl) -4- (1- (1- (2-pyridinylmethyl) -4-piperidinyl) -1H-indol-3-yl)- , Monohydrochloride), or analogs and derivatives thereof.

60) ROCK (Rho kinase) inhibitor In another embodiment, the pharmacologically active compound is a ROCK (Rho kinase) inhibitor (Y-27632, HA-1077, H-1152 and 4- (amino) Alkyl) -N- (4-pyridyl) cyclohexanecarboxamide, or analogs and derivatives thereof.

61) CXCR3 inhibitor In another embodiment, the pharmacologically active compound is a CXCR3 inhibitor (such as T-487, T0906487, or analogs and derivatives thereof).

62) Itk inhibitors In another embodiment, the pharmacologically active compound is an Itk inhibitor (such as BMS-509744 or an analogue or derivative thereof).

63) Cytoplasmic phospholipase A ₂ -α inhibitor In another embodiment, the pharmacologically active compound is a cytoplasmic phospholipase A ₂ -α inhibitor (such as efipradib (PLA-902) or an analogue or derivative thereof) It is.

64) PPAR agonist
In another embodiment, the pharmacologically active compound is a PPAR agonist (metabolex ((-)-benzeneacetic acid, 4-chloro-α- (3- (trifluoromethyl) -phenoxy)-, 2- (Acetylamino) ethyl ester), baraglitazone (5- (4- (3-methyl-4-oxo-3,4-dihydro-quinazolin-2-yl-methoxy) -benzyl) -thiazolidine-2,4-dione ), Ciglitazone (2,4-thiazolidinedione, 5-((4-((1-methylcyclohexyl) methoxy) phenyl) methyl)-), DRF-10945, farglitazar, GSK-677954, GW-409544, GW-501516 , GW-590735, GW-590735, K-111, KRP-101, LSN-862, LY-519818, LY-674, LY-929, Muragurizar, BMS-298585 (Glycine, N-((4-methoxyphenoxy) Carbonyl) -N-((4- (2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy) phenyl) methyl)-), netoglitazone; isaglitazone (2,4-thiazolidinedione, 5- ( (6-((2-fluorophenyl) methoxy) -2-naphthalenyl) methyl)-), Actos AD-4833; U-72107A (2,4-thiazolidinedione, 5-((4- (2- (5- Ethyl-2-pyridinyl) ethoxy) phenyl) methyl)-, monohydrochloride (+/-)-), JTT-501; PNU-182716 (3,5-isoxazolidinedione, 4-((4- (2- (2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy) phenyl) methyl)-), AVANDIA (SBPharmco Puerto Rico, Inc. (Puerto Rico), BRL-48482, BRL-49653, BRL-49653c, Nyracta and Venvia (Both made by SmithKline Beecham (UK)), tesaglitazar ((2S) -2-ethoxy-3- (4- (2- (4-((methylsulfonyl) oxy) phenyl) ethoxy) phenyl) propanoic acid), troglitazone (2,4-thiazolidinedione, 5-((4-((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy) phenyl ) Methyl)-), and analogs thereof Derivatives, etc.).

65) In another embodiment of the immunosuppressive drug, the pharmacologically active compound is an immunosuppressant (bateblast (cyclohexanecarboxylic acid, 4-(((aminoiminomethyl) amino) methyl)-, 4- (1, 1-dimethylethyl) phenyl ester, trans-), cyclomunin, exalamide (benzamide, 2- (hexyloxy)-), LYN-001, CCI-779 (rapamycin 42- (3-hydroxy-2- (hydroxymethyl)- 2-methylpropanoate)), 1726, 1726-D, AVE-1726, or analogs and derivatives thereof.

66) Elb inhibitor In another embodiment, the pharmacologically active compound is an elb inhibitor (eg, caneltinib dihydrochloride (N- (4- (3- (chloro-4-fluoro-phenylamino)- 7- (3-morpholin-4-yl-propoxy) -quinazolin-6-yl) -acrylamide dihydrochloride), CP-724714, or analogs and derivatives thereof.

67) In another example of an apoptosis agonist, the pharmacologically active compound is an apoptosis agonist (CEFLATONIN (CGX-635) (Chemgenex Therapeutics, Inc., Menlo Park, Calif.), CHML, LBH-589, Metoclopuramide (benzamide, 4-amino-5-chloro-N- (2- (diethylamino) ethyl) -2-methoxy-), patpyrone (4,17-dioxabicyclo (14.1.0) heptadecane-5, 9-dione, 7,11-dihydroxy-8,8,10,12,16-pentamethyl-3- (1-methyl-2- (2-methyl-4-thiazolyl) ethenyl, (1R, 3S, 7S, 10R , 11S, 12S, 16R)), AN-9, Pibanex (butanoic acid, (2,2-dimethyl-1-oxopropoxy) methyl ester), SL-100, SL-102, SL-11093, SL-11098, SL-11099, SL-93, SL-98, SL-99, or analogs and derivatives thereof.

68) Lipocortin agonist In another embodiment, the pharmacologically active compound is a lipocortin agonist (CGP-13774 (9α-chloro-6α-fluoro-11β, 17α-dihydroxy-16α-methyl-3-oxo- 1,4-androstadiene-17β-carboxylic acid-methyl ester-17-propionate), or analogs and derivatives thereof.

69) VCAM-1 antagonist In another embodiment, the pharmacologically active compound is a VCAM-1 antagonist (such as DW-908e, or an analogue or derivative thereof).

70) In another embodiment of the collagen antagonist, the pharmacologically active compound is a collagen antagonist (E-5050 (benzenepropanamide, 4- (2,6-dimethylheptyl) -N- (2-hydroxyethyl)). ) -β-methyl-), rufilonyl (2,4-pyridinedicarboxamide, N, N′-bis (2-methoxyethyl)-), or analogs and derivatives thereof).

71) α2 Integrin Antagonist In another embodiment, the pharmacologically active compound is an α2 integrin antagonist (such as E-7820, or an analog or derivative thereof).

72) In another example of a TNFα inhibitor, the pharmacologically active compound is a TNFα inhibitor (ethyl pyruvate, Genz-29155, lentinan (Ajinomoto Co., Inc., Japan)), linamide (3-quinolinecarboxamide, 1,2-dihydro-4-hydroxy-N, 1-dimethyl-2-oxo-N-phenyl-), UR-1505, or analogs and derivatives thereof.

73) Nitric oxide inhibitors In another embodiment, the pharmacologically active compound is a nitric oxide inhibitor (such as guanidioethyl disulfide, or an analogue or derivative thereof).

74) Cathepsin inhibitors In another embodiment, the pharmacologically active compound is a cathepsin inhibitor (SB-462795, or an analog or derivative thereof).

Anti-Infectious Agents The present invention also provides a polymer composition and drug combination that reduces the likelihood of infection associated with implantation of the composition or medical implant.

  Infection is a common complication of transplanting foreign objects such as medical devices and grafts. Foreign substances are an ideal place for microorganisms to attach and colonize. There is also a hypothesis that biological defense against infection in the microenvironment around the foreign body is impaired. These factors make medical grafts particularly susceptible to infection, and eradication of such infections is often difficult if not impossible. In many cases, the infected graft or device must be surgically removed from the body to eradicate the infection.

  The present invention provides agents (such as chemotherapeutic agents) that can be released from the composition and have potent antimicrobial activity in very small doses. A variety of anti-infective agents can be used in combination with the present composition. A suitable anti-infective role can be easily determined based on the test method provided in Example 34). Described in more detail below are some representative examples of agents that can be used as anti-infective agents, as described below. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin) are discussed in further detail below.

A. Anthracyclines In one embodiment, the therapeutic anti-infective agent is an anthracycline. Anthracyclines have the following general structure, where the R group may be a variant of an organic acid group.

According to US Pat. No. 5,594,158, suitable R groups are as follows: R ₁ is CH ₃ or CH ₂ OH, R ₂ is daunosamine or H, and R ₃ and R ₄ are OH, NO ₂ , NH ₂ , F, Cl, Br, I, CN, H or In any of the groups derived from them, R ₅ is hydrogen, hydroxyl or methoxy and R _6-8 is all hydrogen. Alternatively, R ₅ and R ₆ are hydrogen and R ₇ and R ₈ are alkyl or halogen, or vice versa.

According to US Pat. No. 5,843,903, R ₁ may be a complex carbohydrate peptide. According to US Pat. No. 4,296,105, R ₅ may be an ether-linked alkyl group. According to US Pat. No. 4,215,062, R ₅ may be OH or an ether-linked alkyl group. R ₁ also can be linked to the anthracycline ring by alkyl or a group other than C (O), such as branched alkyl groups having C (O) linking moiety at its end portion, as this example, -CH ₂ CH (CH ₂ —X) C (O) —R _{1 and the} like, where X is hydrogen or an alkyl group (see US Pat. No. 4,215,062). Alternatively, R ₂ may be a group to which a functional group = N—NHC (O) —Y is bonded, where Y is a group such as phenyl or a substituted phenyl ring. Alternatively, R ₃ can have the following structure:

Here, R ₉ is OH in the plane or out of plane of the ring, or a second sugar moiety such as R ₃ . R ₁₀ is hydrogen or forms a secondary amine with a group such as a saturated or partially saturated 5- or 6-membered heterocyclic aromatic group having at least one ring nitrogen (US Patent No. (See 5,843,903). Alternatively, R ₁₀ can be derived from an amino acid having the structure —C (O) CH (NHR ₁₁ ) (R ₁₂ ), where R ₁₁ is H or together with R _{12 is} C ₃₋ Forms a _4- part alkylene. R ₁₂ includes hydrogen, alkyl, aminoalkyl, amino, hydroxyl, mercapto, phenyl, benzyl or methylthio (see US Pat. No. 4,296,105).

  Typical anthracyclines are doxorubicin, daunorubicin, idarubicin, epirubicin, pirarubicin, zorubicin, and carubicin. Suitable compounds have the following structure:

Other suitable anthracyclines include anthramycin, mitoxantrone, menogalyl, nogaramycin, aclacinomycin A, olivomycin A, chromomycin A ₃ and pricamycin having the following structure:

Other typical anthracyclines include doxorubicin derivative FCE 23762 (Quaglia et al., J. Liq. Chromatogr. 17 (18): 3911-3923, 1994), annamycin (Zou et al., J. Pharm. Sci. 82 (11): 1151-1154, 1993), ruboxil (Rapoport et al., J. Controlled Release 58 (2): 153-162, 1999), anthracycline disaccharide doxorubicin analog (Pratesi et al., Clin. Cancer Res. 4 (11): 2833-2839, 1998), N- (trifluoroacetyl) doxorubicin and 4′-O-acetyl-N- (trifluoroacetyl) doxorubicin (Berube & Lepage, Synth. Commun. 28 (6): 1109- 1116, 1998), 2-pyrrolinodoxorubicin (Nagy et al., Proc. Nat'l Acad. Sci. USA 95 (4): 1794-1799, 1998), disaccharide doxorubicin analogue (Arcamone et al., J. Nat'l CancerInst. 89 (16): 1217-1223, 1997), 4-demethoxy-7-O- (2,6-dideoxy-4-O- (2,3,6-trideoxy-3-amino-α-L-) lyxo-hexopyranosyl) -α-L-lyxo-hexopyranosyl) -adriamycinone doxorubicin disaccharide analogue (Monteagudo et al., Carbohydr. Res. 300 (1): 11-16, 1997), 2-pyrrolinodoxorubicin (Nagy et al., Proc. Nat 'lAcad. Sci. USA 94 (2): 652-656, 1997), morpholinyl doxorubicin analogues (Duran et al., Cancer Chemother. Pharmacol. 38 (3): 210-216, 1996), enaminomalonyl-β -Alanine doxorubicin derivatives (Seitz et al., Tetrahedron Lett. 36 (9): 1413-16, 1995), cephalosporin doxorubicin derivatives (Vrudhula et al., J. Med. Chem. 38 (8): 1380-5, 1995), Hydroxyrubicin (Solary et al., Int. J. Cancer 58 (1): 85-94, 1994), methoxymorpholinodoxorubicin derivatives (Kuhl et al., Cancer Chemother. Pharmacol. 33 (1): 10-16, 1993), (6 -Maleimidocaproyl) hydrazone doxorubicin derivative (Willner et al., Bioconjugate Chem. 4 (6): 521-7, 1993), N- (5,5-diacetoxypen To-1-yl) doxorubicin (Cherif & Farquhar, J. Med. Chem. 35 (17): 3208-14, 1992), FCE 23762 methoxymorpholinyl doxorubicin derivative (Ripamonti et al., Br. J. Cancer 65 (5 ): 703-7, 1992), N-hydroxysuccinimide ester doxorubicin derivatives (Demant et al., Biochim. Biophys. Acta 1118 (1): 83-90, 1991), polydeoxynucleotide doxorubicin derivatives (Ruggiero et al., Biochim. Biophys. Acta 1129 (3): 294-302, 1991), morpholinyl doxorubicin derivative (EPA 434960), mitoxantrone doxorubicin analog (Krapcho et al., J. Med. Chem. 34 (8): 2373-80. 1991) AD198 doxorubicin analog (Traganos et al., Cancer Res. 51 (14): 3682-9, 1991), 4-demethoxy-3'-N-trifluoroacetyl doxorubicin (Horton et al., Drug Des. Delivery 6 (2): 123-9, 1990), 4'-epidoxorubicin (Drzewoski et al., Pol. J. Pharmacol. Pharm. 40 (2): 159-65 1988. Weenen et al., Eur. J. Cancer Clin. Oncol. 20 (7): 919-26, 1984), alkylated cyanomorpholinodoxorubicin derivatives (Scudder et al., J. Nat'l Cancer Inst. 80 (16): 1294-8, 1988), deoxydihydroiodooxorubicin (EPA 275966), adriblastin (Kalishevskaya et al., Vestn. Mosk. Univ., 16 (Biol. 1): 21-7, 1988), 4'-deoxyxorubicin (Schoelzel et al. Leuk. Res. 10 (12): 1455-9, 1986), 4-demethyoxy-4'-o-methyldoxorubicin (Giuliani et al., Proc. Int. Congr. Chemother. 16: 285-70-285-77, 1983), 3'-deamino-3'-hydroxydoxorubicin (Horton et al., J. Antibiot. 37 (8): 853-8, 1984), 4-demethoxide xorubicin analog (Barbieri et al., Drugs Exp. Clin. Res. 10 (2): 85-90, 1984), NL-leucyl doxorubicin derivatives (Trouet et al., Anthracyclines (Proc. Int. Symp. TumorPharmacother.), 179-81, 1983), 3'-deamino-3 ' -(4-Methoxy-1-pipe Dinyl) doxorubicin derivatives (4,314,054), 3'-deamino-3 '-(4-morpholinyl) doxorubicin derivatives (4,301,277), 4'-deoxyxorubicin and 4'-o-methyl doxorubicin (Giuliani et al., Int. J. Cancer 27 (1): 5-13, 1981), aglycondoxorubicin derivatives (Chan & Watson, J. Pharm. Sci. 67 (12): 1748-52, 1978), SM 5887 (Pharma Japan 1468: 20, 1995), MX -2 (Pharma Japan 1420: 19, 1994), 4'-deoxy-13 (S) -dihydro-4'-iododoxorubicin (EP 275966), morpholinyl doxorubicin derivative (EPA 434960), 3'-deamino-3 '-(4-Methoxy-1-piperidinyl) doxorubicin derivative (US 4,314,054), doxorubicin-14-valerate, morpholino doxorubicin (US 5,004,606), 3'-deamino-3'-(3 ''- Cyano-4 ''-morpholinyl doxorubicin, 3'-deamino-3 '-(3''-cyano-4''-morpholinyl) -13-di Doxorubicin, (3'-deamino-3 '-(3''-cyano-4''-morpholinyl) daunorubicin, 3'-deamino-3'-(3 ''-cyano-4 ''-morpholinyl) -3- Dihydrodaunorubicin, and 3′-deamino-3 ′-(4 ″ -morpholinyl-5-iminodoxorubicin and derivatives (US Pat. No. 4,585,859), 3′-deamino-3 ′-(4-methoxy-1-piperidinyl) doxorubicin Derivatives (US 4,314,054), 3'-deamino-3 '-(4-morpholinyl) doxorubicin derivatives (US 4,301,277) and the like.

B. Fluoropyrimidine analogs In another embodiment, the fibrogenesis inhibitor therapeutic agent is a fluoropyrimidine analog, such as 5-fluorouracil, or an analog or derivative thereof, such as carmofur, doxyfluridine, emiteflu, tegafur, and furofur. There are coxuridine. A typical compound has the following structure:

Other suitable fluoropyrimidine analogs include 5-FudR (5-fluoro-deoxyuridine), or analogs or derivatives thereof, including 5-iododeoxyuridine (5-IudR), 5-bromo Deoxyuridine (5-BudR), fluorouridine triphosphate (5-FUTP) and fluorodeoxyuridine monophosphate (5-dFUMP). A typical compound has the following structure:

Other representative examples of fluoropyrimidine analogs include N3-alkylated analogs of 5-fluorouracil (Kozai et al., J. Chem. Soc., PerkinTrans. 1 (19): 3145-3146, 1998), 5-fluorouracil derivatives with a 1,4-oxaheteroepan moiety (Gomez et al., Tetrahedron 54 (43): 13295-13312, 1998), 5-fluorouracil and nucleoside analogues (Li, AnticancerRes. 17 ( 1A): 21-27, 1997), cis- and trans-5-fluoro-5,6-dihydro-6-alkoxyuracil (Van derWilt et al., Br. J. Cancer 68 (4): 702-7, 1993) , Cyclopentane 5-fluorouracil analogues (Hronowski and Szarek, Can. J. Chem. 70 (4): 1162-9, 1992), A-OT-fluorouracil (Zhang et al., Zongguo Yiyao Gongye Zazhi 20 (11) : 513-15, 1989), N4-trimethoxybenzoyl-5'-deoxy-5-fluorocytidine and 5'-deoxy-5-fluorouridine (Miwa et al., Chem. P) harm. Bull. 38 (4): 998-1003, 1990), 1-hexylcarbamoyl-5-fluorouracil (Hoshi et al., J. Pharmacobio-Dun. 3 (9): 478-81, 1980, Maehara et al., Chemotherapy (Basel) 34 (6): 484-9, 1988), B-3839 (Prajda et al., InVivo 2 (2): 151-4, 1988), uracil-1- (2-tetrahydrofuryl) -5-fluoro Uuracil (Anai et al., Oncology 45 (3): 144-7, 1988), 1- (2'-deoxy-2'-fluoro-β-D-arabinofuranosyl) -5-fluorouracil (Suzuko et al. Mol. Pharmacol. 31 (3): 301-6, 1987), doxyfluridine (Matuura et al., Oyo Yakuri 29 (5): 803-31, 1985), 5′-deoxy-5-fluorouridine (Bollag and Hartmann, Eur. J. Cancer 16 (4): 427-32, 1980), 1-acetyl-3-O-toluyl-5-fluorouracil (Okada, Hiroshima J. Med. Sci. 28 (1): 49-66, 1979), 5-fluorouracil-m-formylbenzene-sulfonate (JP 55059173), N '-(2-furanidyl) -5-fluoroura And the like Sil (JP53149985) and 1- (2-tetrahydrofuryl) -5-fluoro-U uracil (JP 52089680).

  These compounds are thought to function as therapeutic agents by acting as antimetabolites of pyrimidine.

C. Folate AntagonistsIn another embodiment, the anti-fibrosis therapeutic agent is a folate antagonist such as methotrexate or a derivative or analog thereof, including edatrexate, trimetrexate, raltitrexed, pyritrexim, denopterin, tomdex , And pteropterin. Methotrexate analogs have the following general structure:

The R group can be selected from organic acid groups, particularly those described in US Pat. Nos. 5,166,149 and 5,382,582. R ₁ is nitrogen, R ₂ is nitrogen or C (CH ₃ ), R ₃ and R ₃ 'are hydrogen or alkyl (such as CH ₃ ), R ₄ is a single bond or NR (where R is H or an alkyl group) can do. R _5,6,8 can be H, OCH ₃ or can alternatively be a halogen or hydro group. R ₇ is a side chain with the following general structure.

Here, n = 1 for methotrexate and n = 3 for pteropterin. The carboxyl group in the side chain can be esterified or can form salts such as Zn ²⁺ salts. R ₉ and R ₁₀ can be NH ₂ and can also be alkyl substituted.

  A typical folic acid antagonist compound has the following structure:

Other representative examples include 6-S-aminoacyloxymethyl mercaptopurine derivatives (Harada et al., Chem. Pharm. Bull. 43 (10): 793-6, 1995), 6-mercaptopurine (6-MP) (Kashida et al., Biol. Pharm. Bull. 18 (11): 1492-7, 1995), 7,8-polymethyleneimidazo-1,3,2-diazaphosphorine (Nilov et al., Mendeleev Commun. 2:67, 1995) Azathioprine (Chifotides et al., J. Inorg. Biochem. 56 (4): 249-64, 1994), methyl-D-glucopyranoside mercaptopurine derivatives (DaSilva et al., Eur. J. Med. Chem. 29 (2): 149 -52, 1994) and s-alkynyl mercaptopurine derivatives (Ratsino et al., Khim.-Farm. Zh. 15 (8): 65-7, 1981), as well as methotrexate derivatives containing indoline ring and modified ornithic acid or glutamic acid (Matsuoka et al., Chem. Pharm. Bull. 45 (7): 1146-1150, 1997), methotrexate derivatives containing alkyl-substituted benzene rings C (M atsuoka et al., Chem. Pharm. Bull. 44 (12): 2287-2293, 1996), methotrexate derivatives containing a benzoxazine or benzothiazine moiety (Matsuoka et al., J. Med. Chem. 40 (1): 105-111, 1997). ), 10-deazaaminopterin analogues (DeGraw et al., J. Med. Chem. 40 (3): 370-376, 1997), 5-deazaaminopterin and 5,10-dideazaaminopterin methotrexate analogues (Piper et al., J. Med. Chem. 40 (3): 377-384, 1997), methotrexate derivatives containing an indoline moiety (Matsuoka et al., Chem. Pharm. Bull. 44 (7): 1332-1337, 1996), Lipophilic amidomethotrexate derivatives (Pignatello et al., WorldMeet. Pharm., Biopharm. Pharm. Technol., 563-4, 1995), L-threo- (2S, 4S) -4-fluoroglutamic acid and DL-3,3-difluoro Methotrexate analogs containing glutamic acid (Hart et al., J. Med. Chem. 39 (1): 56-65, 1996), methotrexate tetrahydroquinazo Analogues (Gangjee et al., J. Heterocycl. Chem. 32 (1): 243-8, 1995), N- (L-aminoacyl) methotrexate derivatives (Cheung et al., Pteridines 3 (1-2): 101-2, 1992 ), Biotin methotrexate derivatives (Fan et al., Pteridines 3 (1-2): 131-2, 1992), D-glutamic acid or D-erythro, threo-4-fluoroglutamic acid methotrexate analogues (McGuire et al., Biochem. Pharmacol. 42 (12): 2400-3, 1991), β, γ-methanomethotrexate analog (Rosowsky et al., Pteridines2 (3): 133-9, 1991), 10-deazaaminopterin (10-EDAM) analog (Braakhuis) Chem. Biol. Pteridines, Proc. Int. Symp. Pteridines Folic Acid Deriv., 1027-30, 1989), γ-tetrazole methotrexate analogue (Kalman et al., Chem. Biol. Pteridines, Proc. Int. Symp. Pteridines Folic Acid Deriv., 1154-7, 1989), N- (L-α-aminoacyl) methotrexate derivatives (Cheung et al., Heterocycles 28 (2): 751-8, 1989 , Meta and ortho isomers of aminopterin (Rosowsky et al., J. Med. Chem. 32 (12): 2582, 1989), hydroxymethylmethotrexate (DE267495), γ-fluoromethotrexate (McGuire et al., Cancer Res. 49 (16 ): 4517-25, 1989), polyglutamyl methotrexate derivatives (Kumar et al., Cancer Res. 46 (10): 5020-3, 1986), gem-diphosphonate methotrexate analogues (WO 88/06158), α-and γ-substituted methotrexate analogues (Tsushima et al., Tetrahedron44 (17): 5375-87, 1988), 5-methyl-5-deazamethotrexate analogues (4,725,687), Nδ-acyl-Nα- (4-amino-4-) Deoxypteroyl) -L-ornithine derivative (Rosowsky et al., J. Med. Chem. 31 (7): 1332-7, 1988), 8-deazamethotrexate analogue (Kuehl et al., Cancer Res. 48 (6): 1481-8, 1988), acivicin methotrexate analogues (Rosowsky et al., J. Med. Chem. 30 (8): 1463-9, 1987) Polymeric Platinol Methotrexate Derivatives (Carraher et al., Polym. Sci. Technol. (Plenum), 35 (Adv. Biomed. Polym.): 311-24, 1987), methotrexate-γ-dimyristoyl phosphatidylethanolamine ( Kinsky et al., Biochim. Biophys. Acta 917 (2): 211-18, 1987), methotrexate polyglutamate analogues (Rosowsky et al., Chem. Biol. Pteridines, Pteridines Folic Acid Deriv., Proc. Int. Symp. Pteridines Folic Acid Deriv .: Chem., Biol. Clin. Aspects: 985-8, 1986), poly-γ-glutamyl methotrexate derivatives (Kisliuk et al., Chem. Biol. Pteridines, Pteridines Folic Acid Deriv., Proc. Int. Symp. Pteridines Folic Acid Deriv .: Chem., Biol. Clin. Aspects: 989-92, 1986), deoxyuridylic acid methotrexate derivatives (Webber et al., Chem. Biol. Pteridines, Pteridines Folic Acid Deriv., Proc. Int. Symp. Pteridines Folic Acid Deriv .: Chem., Biol. Clin. Aspects: 659-62, 1986), iodoacetyl Dimmetrexate analog (Delcamp et al., Chem. Biol. Pteridines, Pteridines Folic Acid Deriv., Proc. Int. Symp. Pteridines Folic Acid Deriv .: Chem., Biol. Clin. Aspects: 807-9, 1986), 2, .meth.trexate analogues containing .omega.-diaminoalkanoic acids (McGuire et al., Biochem. Pharmacol. 35 (15): 2607-13, 1986), polyglutamate methotrexate derivatives (Kamen and Winick, Methods Enzymol. 122 (Vitam. Coenzymes , Pt. G): 339-46, 1986), 5-methyl-5-deaza analogue (Piper et al., J. Med. Chem. 29 (6): 1080-7, 1986), quinazoline methotrexate analogue (Mastropaolo) Et al., J. Med. Chem. 29 (1): 155-8, 1986), pyrazine methotrexate analogues (Lever and Vestal, J. Heterocycl. Chem. 22 (1): 5-6, 1985), cysteic acid and Homocysteic acid methotrexate analogue (4,490,529), γ-tert-butyl methotrexate ester (Rosowsky et al., J. Med. Chem. 28 (5 ): 660-7, 1985), fluorinate domethotrexate analogue (Tsushima et al., Heterocycles 23 (1): 45-9, 1985), folate methotrexate analogue (Trombe, J. Bacteriol. 160 (3): 849-53 , 1984), phosphonoglutamate analogues (Sturtz and Guillamot, Eur. J. Med. Chem .-- Chim. Ther. 19 (3): 267-73, 1984), poly (L-lysine) methotrexate conjugates ( Rosowsky et al., J. Med. Chem. 27 (7): 888-93, 1984), dilysine and trilysine methotrexate derivatives (Forsch and Rosowsky, J. Org. Chem. 49 (7): 1305-9, 1984), 7-hydroxymethotrexate (Fabre et al., Cancer Res. 43 (10): 4648-52, 1983), poly-γ-glutamyl methotrexate analogues (Piper and Montgomery, Adv. Exp. Med. Biol., 163 (Folyl Antifolyl Polyglutamates ): 95-100, 1983), 3 ', 5'-dichloromethotrexate (Rosowsky and Yu, J. Med. Chem. 26 (10): 1448-52, 1983), diazoketone and Loromethyl ketone methotrexate analogue (Gangjee et al., J. Pharm. Sci. 71 (6): 717-19, 1982), 10-propargylaminopterin and alkyl methotrexate analogues (Piper et al., J. Med. Chem. 25 ( 7): 877-80, 1982), lectin derivatives of methotrexate (Lin et al., JNCI 66 (3): 523-8, 1981), polyglutamate methotrexate derivatives (Galivan, Mol. Pharmacol. 17 (1): 105- 10, 1980), halogenated methotrexate derivatives (Fox, JNCI 58 (4): J955-8, 1977), 8-alkyl-7,8-dihydro analogs (Chaykovsky et al., J. Med. Chem. 20 (10) : J1323-7, 1977), 7-methylmethotrexate derivatives and dichloromethotrexate (Rosowsky and Chen, J. Med. Chem. 17 (12): J1308-11, 1974), lipophilic methotrexate derivatives and 3 ', 5'- Dichloromethotrexate (Rosowsky, J. Med. Chem. 16 (10): J1190-3, 1973), deaza amethopterins Body (Montgomery other, Ann NYAcad Sci 186:... J227-34,1971), MX068 (Pharma Japan, 1658: 18,1999) and cysteic acid and homocysteic acid methotrexate analogues (EPA0142220) and the like.

  These compounds are thought to function as antimetabolites of folic acid.

D. Podophyllotoxin In another aspect, the anti-infective therapeutic is podophyllotoxin, or a derivative or analog thereof. Typical compounds of this type include etoposide and teniposide, which have the following structure:

Other representative examples of podophyllotoxins include Cu (II) -VP-16 (etoposide) complex (Tawa et al., Bioorg. Med. Chem. 6 (7): 1003-1008, 1998), pyrrole Etoposide analogues containing carboxamidino (Ji et al., Bioorg. Med. Chem. Lett. 7 (5): 607-612, 1997), 4β-amino etoposide analogues (Hu, University of North Carolina Dissertation, 1992), γ -Lactone ring-modified arylamino etoposide analog (Zhou et al., J. Med. Chem. 37 (2): 287-92, 1994), N-glucosyl etoposide analog (Allevi et al., Tetrahedron Lett. 34 (45): 7313 -16, 1993), etoposide A-ring analogs (Kadow et al., Bioorg. Med. Chem. Lett. 2 (1): 17-22, 1992), 4'-deshydroxy-4'-methyl etoposide (Saulnier et al. , Bioorg. Med. Chem. Lett. 2 (10): 1213-18, 1992), penzurum ring etoposide analogues (Sinha et al., Eur. J. Cancer 26 (5): 590-3, 1990) and the E-ring Desoxyetoposide analogue (Saulnier et al. J. Med. Chem. 32 (7): 1418-20, 1989).

  These compounds are believed to function as topoisomerase II inhibitors and / or DNA cleaving agents.

E. Camptothecin In another embodiment, the anti-infective therapeutic is camptothecin, or an analog or derivative thereof. Camptothecin has the following general structure:

In this structure, X is generally oxygen, but in the case of 21-lactam derivatives, it can be other groups such as NH. R ₁ is usually hydrogen or OH, but may be other groups such as a terminally hydroxylated C _1-3 alkane. R ₂ is usually hydrogen or a group containing amino such as (CH ₃ ) ₂ NHCH ₂ , but other groups such as NO ₂ , NH ₂ , halogen, etc. (disclosed in US Pat. No. 5,552,156), or these It may be a single chain alkane containing a group. R ₃ is usually hydrogen or a short chain alkyl such as C ₂ H ₅ . R ₄ is usually hydrogen but may be other groups such as a methylenedioxy group with R ₁ .

  Typical camptothecin compounds include topotecan, irinotecan (CPT-11), 9-aminocamptothecin, 21-lactam-20 (S) -camptothecin, 10,11-methylenedioxycamptothecin, SN-38, 9-nitrocamptothecin And 10-hydroxycamptothecin. A typical compound has the following structure:

Camptothecin has five rings as shown here. In order to maximize activity and minimize toxicity, the ring with label E must remain intact (a lactone rather than a carboxylate form).

  Camptothecin is believed to function as a topoisomerase inhibitor and / or a DNA cleaving agent.

F. Hydroxyurea The anti-infective therapeutic of the present invention may be hydroxyurea. Hydroxyurea has the following general structure.

Suitable hydroxyureas are disclosed, for example, in US Pat. No. 6,080,874, where R ₁ is:

R ₂ is an alkyl group having 1 to 4 carbons, R ₃ is any of hydrogen, acyl, methyl, ethyl, and mixtures thereof, such as methyl ether.

Other suitable hydroxyureas are disclosed, for example, in U.S. Pat.No. 5,665,768 where R ₁ is, for example, N- (3- (5- (4-fluorophenylthio) -furyl) -2-cyclopentene- 1-yl) cycloalkenyl groups such as N-hydroxyurea, wherein R ₂ is hydrogen or an alkyl group having 1 to 4 carbons, R ₃ is hydrogen and X is hydrogen or a cation.

Other suitable hydroxyureas are disclosed, for example, in U.S. Pat.No. 4,299,778, where R ₁ is a phenyl group substituted with one or more fluorine atoms, R ₂ is a cyclopropyl group, and R ₃ And X is hydrogen.

Other suitable hydroxyureas are disclosed in US Pat. No. 5,066,658, where R ₂ and R ₃ together with the adjacent nitrogen form the following formula:

Here, m is 1 or 2, n is 0 to 2, and Y is an alkyl group.

  In one embodiment, the hydroxyurea has the following structure:

These compounds are thought to function by inhibiting DNA synthesis.

G. Platinum Complexes In another embodiment, the anti-infective therapeutic is a platinum compound. In general, suitable platinum complexes are Pt (II) or Pt (IV) complexes having the following basic structure:

Here, X and Y are anionic leaving groups such as sulfate, phosphate, carboxylate, and halogen. R ₁ and R ₂ can be further substituted with alkyl, amine, aminoalkyl and are essentially inert or bridging groups. In the Pt (II) complex, Z ₁ and Z ₂ are not present. In Pt (IV), Z ₁ and Z ₂ can be negative groups such as halogen, hydroxy, carboxylate, ester, sulfate or phosphate. See also U.S. Pat. Nos. 4,588,831 and 4,250,189.

  Suitable platinum complexes can contain multiple platinum atoms. See US Pat. Nos. 5,409,915 and 5,380,897. For example, platinum bis complex or triplatinum complex type:

Exemplary platinum compounds include cisplatin, carboplatin, oxaliplatin and miboplatin having the following structure:

Other representative platinum compounds include (CPA) ₂ Pt (DOLYM) and (DACH) Pt (DOLYM) cisplatin (Choi et al., Arch. Pharmacal Res. 22 (2): 151-156, 1999), cis- ( PtCl ₂ (4,7-H-5-methyl-7-oxo) 1,2,4 (triazolo (1,5-a) pyrimidine) ₂ ) (Navarro et al., J. Med. Chem. 41 (3): 332-338, 1998), (Pt (cis-1,4-DACH) (trans-Cl ₂ ) (CBDCA)) 1/2 MeOH cisplatin (Shamsuddin et al., Inorg. Chem. 36 (25): 5969-5971, 1997), 4-pyridoxate diammine hydroxyplatinum (Tokunaga et al., Pharm. Sci. 3 (7): 353-356, 1997), Pt (II) ・ ・ ・ Pt (II) (Pt ₂ (NHCHN (C ( CH ₂ ) (CH ₃ ))) ₄ ) (Navarro et al., Inorg. Chem. 35 (26): 7829-7835, 1996), 254-S cisplatin analogues (Koga et al., Neurol. Res. 18 (3): 244-247, 1996), cisplatin analogues with o-phenylenediamine ligand (Koeckerbauer and Bednarski, J. Inorg. Biochem. 62 (4): 281-298, 1996), trans, cis- (Pt (OAc) ₂ I ₂ (En)) (Kratochwil et al., J Med. Chem. 39 (13): 2499-2507, 1996), cisplatin analogs containing 1,2-diarylethylenediamine ligands of estrogen (along with sulfur-containing amino acids and glutathione) (Bednarski, J. Inorg. Biochem. 62 (1): 75, 1996), cis-1,4-diaminocyclohexane cisplatin analog (Shamsuddin et al., J. Inorg. Biochem. 61 (4): 291-301, 1996), cis- (Pt (NH ₃ ) 5'-oriented isomer of (4-amino TEMP-O) {d (GpG)}) (Dunham and Lippard, J. Am. Chem. Soc. 117 (43): 10702-12, 1995), chelating diamine Containing cisplatin analogs (Koeckerbauer and Bednarski, J. Pharm. Sci. 84 (7): 819-23, 1995), cisplatin analogs containing 1,2-diarylethyleneamine ligands (Otto et al., J. Cancer Res. Clin Oncol. 121 (1): 31-8, 1995), (ethylenediamine) platinum (II) complex (Pasini et al., J. Chem. Soc., Dalton Trans. 4: 579-85, 1995), CI-973 cisplatin Analogs ( Yang et al., Int. J. Oncol. 5 (3): 597-602, 1994), cis-diamminedichloroplatinum (II) and its analogs cis-1,1-cyclobutanedicarbosilate (2R) -2-methyl 1,4-butanedium-min platinum (II) and cis-diammine (glycolato) platinum (Claycamp and Zimbrick, J. Inorg. Biochem., 26 (4): 257-67, 1986. Fan et al., Cancer Res. 48 (11): 3135-9, 1988. Heiger-Bernays et al., Biochemistry 29 (36): 8461-6, 1990. Kikkawa et al., J. Exp. Clin. Cancer Res. 12 (4): 233-40, 1993. Murray et al., Biochemistry 31 (47): 11812-17, 1992. Takahashi et al., Cancer Chemother. Pharmacol. 33 (1): 31-5, 1993), cis-amine-cyclohexylamine-dichloroplatinum (II) (Yoshida et al., Biochem. Pharmacol. 48 (4): 793-9, 1994). ), Gem-diphosphonate cisplatin analog (FR 2683529), (meso-1,2-bis (2,6-dichloro-4-hydroxyprenyl) ethylenediamine) dichloroplatinum (II) (Bednarski et al., J. Med. Chem. 35 (23): 4479-85, 1992), cisplatin analogs containing a chain dansyl group (Hartwig et al., J. Am. Chem. Soc. 114 (21): 8292-3, 1992), platinum ( II) Polyamine (Siegmann et al., Inorg. Met.-ContainingPolym. Mater., (Proc. Am. Chem. Soc. Int. Symp.), 335-61, 1990), cis- (3H) dichloro (ethylenediamine) platinum ( II) (Eastman, Anal. Biochem. 197 (2): 311-15, 1991), trans-diamminedichloroplatinum (II) and cis- (Pt (NH ₃ ) ₂ (N ₃ -cytosine) Cl) (Bellon and Lippard, Biophys. Chem. 35 (2-3): 179-88, 1990), 3H-cis-1,2- Aminocyclohexanedichloroplatinum (II) and 3H-cis-1,2-diaminocyclohexanemalonatoplatinum (II) (Oswald et al., Res. Commun. Chem. Pathol. Pharmacol. 64 (1): 41-58, 1989), Platinum amino acid containing diaminocarboxylatoplatinum (EPA 296321), trans- (D, 1) -1,2-diaminocyclohexane carrier ligand (Wyrick and Chaney, J. Labelled Compd. Radiopharm. 25 (4): 349-57 , 1988), cisplatin analogues derived from aminoalkylaminoanthraquinone (Kitov et al., Eur. J. Med. Chem. 23 (4): 381-3, 1988), spiroplatin, carboplatin, iproplatin and JM40 platinum analogues (Schroyen) Eur. J. Cancer Clin. Oncol. 24 (8): 1309-12, 1988), cis platinum derivatives containing bidentate tertiarydiamine (Orbell et al., Inorg. Chim. Acta 152 (2): 125-34. 1988), platinum (II), platinum (IV) (Liu and Wang, Shandong Yike Daxue Xuebao 24 (1): 35-41, 1986), Shi -Diammine (1,1-cyclobutanedicarboxylato-) platinum (II) (carboplatin, JM8) and ethylenediammine-malonatoplatinum (II) (JM40) (Begg et al., Radiother. Oncol. 9 (2): 157-65 1987), JM8 and JM9 cisplatin analogues (Harstrick et al., Int. J. Androl. 10 (1), 139-45, 1987), (NPr4) 2 ((PtCL4) .cis- (PtCl2- (NH2Me) 2 )) (Brammer et al., J. Chem. Soc., Chem. Commun. 6: 443-5, 1987), aliphatic tricarboxylic acid platinum complex (EPA 185225), cis-dichloro (amino acid) (tert-butylamine) platinum ( II) complexes (Pasini and Bersanetti, Inorg. Chim. Acta 107 (4): 259-67, 1985). These compounds are considered to function by binding to DNA, that is, by acting as a DNA alkylating agent.

Dosage of anti-infective drug The dose of drug administered from this composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the site of healing, and the type of condition being treated. . However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), and the total drug dose administered can be measured and the appropriate surface concentration of the active agent can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective agent is released from the polymeric compound at an effective concentration in the range of less than about 1 day to about 180 days over a period measured from the time of immersion in the tissue adjacent to the device. Generally, the release period is less than 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, about 90 days ~ About 180 days range.

A typical anti-infective agent used alone or in combination should be administered according to the following dosage guidelines. The total amount (dose) of the anti-infective agent in the composition is about 0.01 μg-1 μg, about 1 μg-10 μg, about 10 μg-1 mg, about 1 mg-10 mg, about 10 mg-100 mg , About 100 mg to 250 mg, about 250 mg to 1000 mg. The dosage (dose) of the drug per unit area of the device or tissue surface to which the anti-infective agent is applied is about 0.01 μg / mm ² to 1 μg / mm ² , about 1 μg / mm ² to 10 μg / mm ² , about 10 μg / mm ^{2 to} 100 μg / mm ² , about 100 μg / mm ² to 250 μg / mm ² , about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compounds which release an anti-infective agents in different proportions, administration parameters described above, a minimum concentration of about 10 ^-8 M to ^-7 M of the drug tissue surface, about 10 ^-7 M to ^-6 M, about 10 ^-6 M to ^-5 M, to be maintained at either about 10 ^-5 M to ^-4 M, it should be used in combination with the drug release rate from the composition.

(a) Anthracycline Anthracycline xorubicin is used as an example, but regardless of whether it is applied as a polymer coating, incorporated into the constituent polymer of the implant, or applied without a carrier polymer, the device or implant The total dose of doxorubicin to be applied should not exceed 25 mg (range 0.1 μg to 25 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 1 μg to 5 mg. The dose per unit area (eg, the amount of drug as a function of the surface area of the graft portion to which the drug is applied and / or mixed) should be in the range of 0.01 μg to 100 μg / mm ² of the surface area. In a particularly preferred embodiment, doxorubicin should be applied to the graft surface at a dose of 0.1 μg / mm ² to 10 μg / mm ² . Since doxorubicin is released at different rates from different polymer and non-polymer coatings, the above dose parameters can be used in combination with the drug release rate from the graft surface to achieve a minimum concentration of 10 ⁻ doxorubicin ⁷ to 10 ^-4 M should be to be maintained at the surface. Doxorubicin concentrations that are known to be lethal for multiple types of bacteria and fungi (eg, concentrations above 10 ^-4 M, although lower concentrations may be sufficient in some examples) Must be guaranteed to exceed In one preferred embodiment, doxorubicin is released from the surface of the implant such that anti-infective activity is maintained over a period of hours to months. In a particularly preferred embodiment, the drug is released at an effective concentration over a period of 1 week to 6 months. Based on the discussion provided herein, it is quite clear that analogs and derivatives of doxorubicin (described above) with similar functional activity can be used for the purposes of the present invention, and the above dosing parameters are , Adjusted according to the relative force of the analogue or derivative compared to the parent compound (e.g., compounds with twice the potency of doxorubicin are half the above parameters, compounds with potency half that of doxorubicin are Etc.).

Mitoxantrone is used as an example, but the entire mitoxantrone applied to the implant, whether applied as a polymer coating, incorporated into the polymer that makes up the device or implant, or applied without a carrier polymer. Dosage should not exceed 5 mg (range 0.01 μg to 5 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 0.1 μg to 1 mg. The dose per unit area (eg, the amount of drug as a function of the surface area of the graft portion to which the drug is applied and / or mixed) should fall within the range of 0.01 μg to 20 μg / mm ² of the surface area. In a particularly preferred embodiment, mitoxantrone should be applied to the graft surface at a dose of 0.05 μg / mm ^{2 to} 3 μg / mm ² . Because different polymers and non-polymeric coatings may release mitoxantrone at different rates, the above dosing parameters are implanted so that a minimum concentration of mitoxantrone of ^10-5 to ^10-6M is maintained on the surface. Should be used in combination with drug release rate from the strip. The drug concentration on the surface of the graft is known to be lethal to multiple species of bacteria and fungi (eg, concentrations above 10 ^-5 M, although lower drug levels may be sufficient in some examples) It is necessary to ensure that the mitoxantrone concentration is exceeded. In one preferred embodiment, mitoxantrone is released from the surface of the implant such that anti-infective activity is maintained over a period of hours to months. In a particularly preferred embodiment, the drug is released at an effective concentration over a period of 1 week to 6 months. Based on the discussion provided herein, it is very clear that analogs and derivatives of mitoxantrone (described above) with similar functional activity can be used for the purposes of the present invention, and the dosing parameters described above Is then adjusted according to the relative force of the analogue or derivative compared to the parent compound (eg, a compound with twice the potency of mitoxantrone is half the above parameters and the potency is half that of mitoxantrone. Some compounds are administered at twice the above parameters, etc.).

(b) Fluoropyrimidine When fluoropyrimidine 5-fluorouracil is used as an example, it can be applied to the graft whether it is applied as a polymer coating, mixed into the polymer that constitutes the device or graft component, or coated in the absence of a carrier polymer. The total dose of 5-fluorouracil applied should not exceed 250 mg (range 1.0 μg to 250 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 10 μg to 25 mg. The dose per unit area (eg, the amount of drug as a function of the surface area of the graft portion to which the drug is applied and / or mixed) should be in the range of 0.1 μg to 1 mg / mm ² of surface area. In a particularly preferred embodiment, 5-fluorouracil should be applied to the graft surface at a dosage of 1.0 μg / mm ² to 50 μg / mm ² . Since the coatings with different polymers and non-polymers may release 5-fluorouracil in different proportions, the above dosing parameters are such that a minimum concentration of 5-fluorouracil of 10 ⁻⁴ to 10 ⁻⁷ M is maintained on the surface. Should be used in combination with drug drug release rate from the graft. Surface drug concentrations are known to be lethal to a wide variety of bacteria and fungi (eg, concentrations above 10 ^-4 M, although lower drug levels are sufficient in some examples) It is necessary to ensure that the fluorouracil concentration is exceeded. In one preferred embodiment, 5-fluorouracil is released from the surface of the implant such that anti-infective activity is maintained over a period of hours to months. In a particularly preferred embodiment, the drug is released at an effective concentration over a period of 1 week to 6 months. Based on the discussion provided herein, it is very clear that analogs and derivatives of 5-fluorouracil having similar functional activity (as described above) can be used for the purposes of the present invention, and the dosing parameters described above Is then adjusted according to the relative force of the analog or derivative compared to the parent compound (eg, a compound with twice the potency of 5-fluorouracil is half the above parameters and has half the potency of doxorubicin) Are administered in twice the above parameters, etc.).

When used as an example (c) podophyllotoxin podophyllotoxin etoposide, applied as a polymer coating, it is applied in the state mixed, or carrier polymer is not to the polymer constituting the device or implant components, transplantation The total dose of etoposide applied to the strip should not exceed 25 mg (range 0.1 μg to 25 mg). In a particularly preferred embodiment, the total amount of drug applied should be in the range of 1 μg to 5 mg. The dose per unit area (eg, the amount of drug as a function of the surface area of the graft portion to which the drug is applied and / or mixed) should be in the range of 0.01 μg to 100 μg / mm ² of the surface area. In a particularly preferred embodiment, etoposide should be applied to the graft surface at a dose of 0.1 μg / mm ² to 10 μg / mm ² . Since different polymers and non-polymeric coatings may release etoposide in different proportions, the above dosing parameters are for drug drugs from the implant so that a concentration of etoposide of 10 ⁻⁵ to 10 ⁻⁶ M is maintained on the surface. Should be used in combination with the release rate. Etoposide concentrations that are known to be lethal for various types of bacteria and fungi (eg, concentrations above 10 ^-5 M, although lower drug levels may be sufficient in some examples) Must be guaranteed to exceed In one preferred embodiment, etoposide is released from the surface of the graft so that anti-infective activity is maintained over a period of hours to months. In a particularly preferred embodiment, the drug is released at an effective concentration over a period of 1 week to 6 months. Based on the discussion provided herein, it is quite clear that analogs and derivatives of etoposide with similar functional activity (as described above) can be used for the purposes of the present invention, and the above dosing parameters are , Adjusted according to the relative force of the analogue or derivative compared to the parent compound (e.g., compounds with twice the potency of etoposide are half the above parameters, compounds with potency half that of doxorubicin are Etc.).

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate) and / or podophyllotoxins (etoposide) are It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

Combinations of therapies In addition to the incorporation of the above therapeutic agents (ie, anti-infectives or fibrosis inhibitors), one or more other pharmacologically active agents may be incorporated into the composition to improve or enhance efficacy. it can. In one embodiment, the composition can further include a compound that has an inhibitory effect on pathological processes within or around the healing site. Further representative examples of pharmacologically active agents are, but not limited to, antithrombotic agents, antiproliferative agents, anti-inflammatory agents, antitumor agents, enzymes, receptor antagonists or agonists, hormones, antibiotics, antibacterial agents, antibodies , Cytokine inhibitors, IMPDH (inosine monophosphate dehydrogenase) inhibitors, tyrosine kinase inhibitors, MMP inhibitors, p38 MAP kinase inhibitors, immunosuppressants, apoptosis antagonists, caspase inhibitors and JNK inhibitors However, the present invention is not limited to this.

  The polymer composition can further include an antithrombotic agent, an antiplatelet agent, or a thrombolytic agent, thereby reducing the likelihood of a thrombotic phenomenon occurring during the implantation of a medical implant. Representative examples of antithrombotic, antiplatelet and thrombolytic agents include heparin, heparin fragments, organic salts of heparin, heparin complexes (eg benzalkonium heparinate, tridodecyl ammonium heparate), dextran, sulfonate Carbohydrate (dextran sulfate, etc.), coumadin, marine, heparinoid, danaparoid, argatroban chitosan sulfate, chondroitin sulfate, danaparoid, lepirudin, hirudin, AMP, adenosine, 2-chloroadenosine, acetylsalicylic acid, phenylbutazone, indomethacin, mecro These include phenamate, hydrochloroquine, dipyridamole, iloprost, streptokinase, factor Xa inhibitors (such as DX9065a), magnesium, and tissue plasminogen activator. Further examples include plasminogen, lys-plasminogen, α-2-antiplasmin, urokinase, aminocaproic acid, ticlopidine, clopidogrel, trapidyl (triazolopyrimidine), naphthidrofuryl, auritricarboxylic acid and glycoprotein IIb / IIIa inhibitor (absixamab , Eptifibatide, and tirogiban). Other drugs that have the ability to affect the rate of clotting include glycosaminoglycan, danaparoid, 4-hydroxycoumarin, warfarin sodium, dicoumarol, fenprocumone, indan-1,3-dione, acenocoumarol, There are anisindiones, and rodenticides (such as bromadiolone, brodifacoum, diphenadione, chlorofacinone and pidone).

  The component of the polymer may be or may include a hydrophilic polymer gel that itself has antithrombogenic properties. For example, the composition may be in the form of a coating comprising a hydrophilic biodegradable polymer that is physically removed from the surface of the device over time, thereby reducing platelet adhesion to the device surface. The gel composition can include a polymer or a mixture of polymers. Representative examples include alginate, chitosan and chitosan sulfate, hyaluronic acid, dextran sulfate, PLURONIC polymers (such as F-127 and F87), long chain PLURONIC polymers, various polyester-polyethers of various configurations. Block copolymers (AB, ABA, or BAB, etc., where A is a polyester such as PLA, PGA, PLGA, PCL or similar, such as MePEG-PLA, PLA-PEG-PLA, Similar to this). In one embodiment, the antithrombogenic composition includes a crosslinkable gel formed by a combination of molecules having two or more electrophilic end groups and two or more nucleophilic groups (such as PEG). be able to.

Polymeric ingredients from one of the following compound groups can further be included in the drug: anti-inflammatory drugs (eg, dexamethasone, cortisone, fludrocortisone, prednisone, prednisolone, 6α-methylprednisolone, triamcinolone, betamethasone, and aspirin ), MMP inhibitors (e.g., batimistat, marimistat, U.S. Pat. , 6,228,869,5,977,408,5,929,097,6,498,167,6,534,491,6,548,524,5,962,481,6,197,795,6,162,814,6,441,023,6,444,704,6,462,073,6,162,821,6,444,639,6,262,080,6,486,193,6,329,550,6,544,980,6,352,976,5,968,795,5,789,434,5,932,763,6,500,847,5,925,637,6,225,314 , 5,804,581, 5,863,915, 5,859,047, 5,861,428, 5,886,043, 6,288,0 63,5,939,583,6,166,082,5,874,473,5,886,022,5,932,577,5,854,277,5,886,024,6,495,565,6,642,255,6,495,548,6,479,502,5,696,082,5,700,838,6,444,639,6,262,080,6,486,193,6,329,550,6,544,980,6,352,976,5,968,795,5,789,434,5,932,763,6,500,847,5,925,637, 6,225,314,5,804,581,5,863,915,5,859,047,5,861,428,5,886,043,6,288,063,5,939,583,6,166,082,5,874,473,5,886,022,5,932,577,5,854,277,5,886,024,6,495,565,6,642,255,6,495,548,6,479,502,5,696,082,5,700,838,5,861,436,5,691,382,5,763,621,5,866,717,5,902,791, 5,962,529,6,017,889,6,022,873,6,022,898,6,103,739,6,127,427,6,258,851,6,310,084,6,358,987,5,872,152,5,917,090,6,124,329,6,329,373,6,344,457,5,698,706,5,872,146,5,853,623,6,624,144,6,462,042,5,981,491,5,955,435,6,090,840,6,114,372,6,566,384,5,994,293, 6,063,786, 6,469,020, 6,118,001, 6,187,924, 6,310,088, 5,994,312, 6,180,611, 6,110,896, 6,380,253 5,455,262,5,470,834,6,147,114,6,333,324,6,489,324,6,362,183,6,372,758,6,448,250,6,492,367,6,380,258,6,583,299,5,239,078,5,892,112,5,773,438,5,696,147,6,066,662,6,600,057,5,990,158,5,731,293,6,277,876,6,521,606,6,168,807,6,506,414,6,620,813,5,684,152, 6,451,791,6,476,027,6,013,649,6,503,892,6,420,427,6,300,514,6,403,644,6,177,466,6,569,899,5,594,006,6,417,229,5,861,510,6,156,798,6,387,931,6,350,907,6,090,852,6,458,822,6,509,337,6,147,061,6,114,568,6,118,016,5,804,593,5,847,153,5,859,061,6,194,451, 6,482,827,6,638,952,5,677,282,6,365,630,6,130,254,6,455,569,6,057,369,6,576,628,6,110,924,6,472,396,6,548,667,5,618,844,6,495,578,6,627,411,5,514,716,5,256,657,5,773,428,6,037,472,6,579,890,5,932,595,6,013,792,6,420,415,5,532,265,5,639,746,5,672,598, 5,830,915, 6,630,516, 5,324,634, 6,277,061, 6,140,099, 6,455,570, 5,595,885, 6,093,398, 6,3 79,667,5,641,636,5,698,404,6,448,058,6,008,220,6,265,432,6,169,103,6,133,304,6,541,521,6,624,196,6,307,089,6,239,288,5,756,545,6,020,366,6,117,869,6,294,674,6,037,361,6,399,612,6,495,568,6,624,177,5,948,780,6,620,835,6,284,513,5,977,141,6,153,612, 6,297,247,6,559,142,6,555,535,6,350,885,5,627,206,5,665,764,5,958,972,6,420,408,6,492,422,6,340,709,6,022,948,6,274,703,6,294,694,6,531,499,6,465,508,6,437,177,6,376,665,5,268,384,5,183,900,5,189,178,6,511,993,6,617,354,6,331,563,5,962,466,5,861,427, Representative examples of TIMPs included in 5,830,869 and 6,087,359), cytokine inhibitors (chlorpromazine, mycophenolic acid, rapamycin, 1α-hydroxyvitamin D ₃ ), IMPDH (inosine monophosphate dehydrogenase) inhibitors (eg, mycophenolic acid, Ribavirin, aminothiadiazole, thiophenfurin, (Azofurin, viramidine) (typical examples are U.S. Pat. Application No. 2002 / 0040022A1, 2002 / 0052513A1, 2002 / 0055483A1, 2002 / 0068346A1, 2002 / 0111378A1, 2002 / 0111495A1, 2002 / 0123520A1, 2002 / 0143176A1, 2002 / 0147160A1, 2002 / 0161038A1, 2002 / 0173491A1, 2002 / 0183315A1, 2002 / 0193612A1, 2003 / 0027845A1, 2003 / 0068302A1, 2003 / 0105073A1, 2003 / 0130254A1, 2003 / 0143197A1, 2003 / 0144300A1, 2003 / 0166201A1, 2003 / 0181497A1, 2003 / 0186974A1, 2003 / 0186989A1, and 2003 / 0195202A1, and PCT Publication Number WO 00 / 24725A1, WO 00 / 25780A1, WO 00 / 26197A1, WO 00 / 51615A1, WO 00 / 56331A1, WO00 / 73288A1, WO 01 / 00622A1, WO 01 / 66706A1, WO 01 / 79246A2, WO 01 / 81340A2, WO01 / 85952A2, WO 02 / 16382A1, WO 02 / 18369A2, WO 02 / 051814A1, WO 02 / 057287A2, WO02 / 05742 5A2, WO 02 / 060875A1, WO 02 / 060896A1, WO 02 / 060898A1, WO 02 / 068058A2, WO03 / 020298A1, WO 03 / 037349A1, WO 03 / 039548A1, WO 03 / 045901A2, WO 03 / 047512A2, WO03 / 053958A1, WO 03 / 055447A2, WO 03 / 059269A2, WO 03 / 063573A2, WO 03 / 087071A1, WO99 / 001545A1, WO 97 / 40028A1, WO 97 / 41211A1, WO 98 / 40381A1, and WO 99 / 55663A1), p38 MAP kinase inhibition Agent (MAPK) (Example: GW-2286, CGP-52411, BIRB-798, SB220025, RO-320-1195, RWJ-67657, RWJ-68354, SCIO-469) (representative examples are US Pat. Nos. 6,300,347, 6,316,464) 6,316,466; 6,376,527, 6,444,696, 6,479,507, 6,509,361, 6,579,874, and 6,630,485, and US Patent Application Publication Nos. 2001 / 0044538A1, 2002 / 0013354A1, 2002 / 0049220A1, 2002 / 0103245A1, 2002 / 0151491A1, 2002 / 0156114A1, 2003/0018051 2003 / 0073832A1, 2003 / 0130257A1, 2003 / 0130273A1, 2003 / 0130319A1, 2003 / 0139388A1, 2003 / 0139462A1, 2003 / 0149031A1, 2003 / 0166647A1, and 2003 / 0181411A1, and PCT publication numbers WO 00 / 63204A2, WO 01 / 21591A1 , WO 01 / 35959A 1, WO 01 / 74811A2, WO 02 / 18379A2, WO02 / 064594A2, WO 02 / 083622A2, WO 02 / 094842A2, WO 02 / 096426A1, WO 02 / 101015A2, WO02 / 103000A2, WO 03 / 008413A1, WO 03 / 016248A2, WO 03 / 020715A1, WO 03 / 024899A2, WO03 / 031431A1, WO 03 / 040103A1, WO 03 / 053940A1, WO 03 / 053941A2, WO 03 / 063799A2, WO03 / 079986A2, WO 03 / 080024A2, WO 03 / 082287A1, WO 97 / 44467A1, WO 99 / 01449A1, and WO99 / 58523A1) and immunomodulators (rapamycin, everolimus, ABT-578, rapamycin analogs including azathioprine azithromycin, tacrolimus and derivatives thereof (eg, described in EP0184162B1 and US Pat. No. 6,258,823) And everolimus and its derivatives (eg, US Pat. No. 5,665,772). Other representative examples of analogs and derivatives of sirolimus include ABT-578; for other examples, PCT publication numbers WO 97/10502, WO 96/41807, WO 96/35423, WO 96/03430 , WO 96/00282, WO 95/16691, WO95 / 15328, WO 95/07468, WO 95/04738, WO 95/04060, WO 94/25022, WO 94/21644, WO94 / 18207, WO 94/10843, WO 94/09010, WO 94/04540, WO 94/02485, WO 94/02137, WO94 / 02136, WO 93/25533, WO 93/18043, WO 93/13663, WO 93/11130, WO 93/10122, WO93 / 04680, WO 92/14737, and WO 92/05179 and U.S. Patent Nos. 6,342,507, 5,985,890, 5,604,234, 5,597,715, 5,583,139, 5,563,172, 5,561,228, 5,561,137, 5,541,193, 5,541,189, 5,534,632,5 5,318,895, 5,310,903, 5,310,901, 5,258,389, 5,252,732, 5,247,076, 5,225,403, 5,221,625, 5,210,030, 5,208,241, 5,200,411, 5,198,421, 5,147,877, 5,140,018, 5,116,756, 5,109,3138,09 89 describes it.

  Other examples of biologically active agents included in the compositions of the present invention include tyrosine kinase inhibitors (such as imatinib), ZK-222584, CGP-52411, CGP-53716, NVP-AAK980-NX, CP-127374 , CP-564959, PD-171026, PD-173956, PD-180970, SU-0879, and SKI-606, MMP inhibitors (such as Nimesulide), PKF-241-466, PKF-242-484, CGS-27023A, SAR-943, primostat, SC-77964, PNU-171829, AG-3433, PNU-142769, SU-5402 and dexipliptam, including p38MAP kinase inhibitors CGH-2466 and PD-98-59), immunosuppressants (including Argyrin B, Macrocyclic Lactone, ADZ-62-826, CCI-779, Tyromisole, Amsinonide, FK-778, AVE-1726, and MDL-28842), cytokine inhibitors (TNF-484A, PD-172084, CP- 293121, CP-353164, and PD-168787), NFKB inhibitors (such as AVE-0547, AVE-0545, and IPL-576092), HMGCoA reductase inhibitors (such as pravastatin, atorva Tachin, fluvastatin, dalvastatin, glenvastatin, pitavastatin, CP-83101, U-20685; anti-apoptotic drugs (eg, troloxamine, TCH-346 (N-methyl-N-propargyl-10-aminomethyl-dibenzo (b , f) oxepin) and caspase inhibitors (eg PF-5901 (benzenemethanol, α-pentyl-3- (2-quinolinylmethoxy)-), and JNK inhibitors (eg AS-602801)) .

  In another embodiment, the composition further comprises an antibiotic (eg, amoxicillin, trimethoprim-sulfamethoxazole, azithromycin, clarithromycin, amoxicillin-clavulanic acid, cefprozil, cefuroxime, cefpodoxime, or cefdinir) be able to.

  In certain embodiments, a polymer composition comprising a fibrosis inhibitor is combined with an agent that can alter the metabolism of the agent in vivo to enhance the efficacy of the fibrosis inhibitor. One type of therapeutic that can be used to alter drug metabolism includes agents capable of inhibiting the oxidation of anti-scarring agents by cytochrome P450 (CYP). In one embodiment, a composition comprising a fiber formation inhibitor (paclitaxel, rapamycin, everolimus, etc.) and a CYP inhibitor is provided and combined (such as applying a coating) with any of the devices described herein. This includes, but is not limited to, stents, implants, patches, valves, wraps, films, and the like. Representative examples of CYP inhibitors include flavones, azole antifungals, macrolide antibiotics, HIV protease inhibitors and antisense oligomers. Devices with a combination of fibrosis inhibitors and CYP inhibitors should be used to treat various proliferative conditions such as intimal proliferation, surgical adhesions, tumor growth that can lead to undesirable scarring or scarring of tissue Can do.

  In another embodiment, a polymer composition comprising an anti-infective agent (eg, anthracycline (eg, doxorubicin or mitoxantrone), fluoropyrimidine (eg, 5-fluorouracil), folic acid antagonist (eg, methotrexate and / Or podophyllotoxins (eg etoposide, etc.) can be combined with conventional antibiotics and / or antifungals to increase efficacy, and anti-infectives can also be antithrombotic and antiplatelet ( For example, heparin, dextran sulfate, danaparoid, lepirudin, hirudin, AMP, adenosine, 2-chloroadenosine, aspirin, phenylbutazone, indomethacin, meclofenamate, hydrochloroquine, dipyridamole, iloprost, ticlopidine, clopidogrel, abcixamab, eptifibati In combination with T. tirofiban, streptokinase, tissue plasminogen activator, etc.).

  Although the above therapeutic agents have been provided for illustrative purposes, it should be understood that the present invention is not so limited. For example, although drugs are specifically mentioned above, it should be understood that the invention also includes analogs, derivatives and conjugates of such drugs. As an example, paclitaxel is not only available for chemically available common forms of paclitaxel, but also for analogs (such as TAXOTERE as described above) and paclitaxel conjugates (such as paclitaxel-PEG, paclitaxel-dextran, paclitaxel-xylose). It should be understood to mention. Further, as will be apparent to those skilled in the art, while the above agents have been described in relation to a single class, many of the listed agents actually have multiple biological activities. Furthermore, multiple therapeutic agents can be used (ie, combined) or delivered sequentially.

H. Compositions and Methods for Generating Compositions Composed of Therapeutic Agents The present invention relates to various compositions used to inhibit fibrosis and / or tissue infection around a treatment site (eg, a surgical site). Offer things. Within various embodiments, fibrosis and / or infection is inhibited by local or systemic release of specific drugs that become localized at the treatment site. Within other embodiments, specific pharmacological agents are released locally or systemically to localize to the tissue adjacent to the device or graft introduced into the host, thereby forming fibrosis. And / or infection is inhibited. In certain embodiments, the composition is provided to inhibit fibrosis in and around the implanted device or prevent device / implant “stenosis” in situ and enhance efficacy. . In other embodiments, an anti-infective composition is provided to inhibit or prevent infection in and around the implanted device.

  A number of methods are available to optimize the delivery of therapeutic agents to the treatment site. Some of them are as described below.

1) Systemic, regional and local delivery of therapeutic agents A variety of drug delivery techniques can be utilized for systemic, regional and local delivery of anti-infective and / or fibrosis-inhibiting therapeutic agents .

  For systemic delivery of a therapeutic agent, there are several suitable routes of administration to provide systemic exposure of the therapeutic agent, including: (a) intravenous, (b) oral, (c) subcutaneous, (d ) Intraperitoneal, (e) subarachnoid, (f) inhalation and nostril, (g) sublingual gland or mouth, (h) rectum, (i) intrathecal, (j) intraarterial, (k) Intracardiac, (l) percutaneous, (m) intraocular and (n) intramuscular. Therapeutic agents can be administered continuously at low dosages to prevent disease progression, extend the remission phase of the disease, or relieve symptoms of an ongoing disease. Alternatively, the therapeutic agent can be continuously administered at high doses as pulse therapy to trigger relief of ongoing serious illness. The minimum dosage that can be used to achieve these goals may vary depending on the patient, the severity of the disease, the formulation of the drug being administered, the efficacy and tolerance of the therapeutic agent, and the route of administration.

  For regional and local delivery of therapeutic agents, several techniques may be suitable for preferentially increasing the level of therapeutic agent in the vicinity of the area to be treated, including: (a) a method of delivering a fibrosis inhibitor locally, regionally, systemically to a tissue surrounding a device or graft using a drug delivery catheter and / or syringe and needle (typically a drug delivery catheter is To be guided by circulation or inserted directly into the tissue under radiation guidance until the desired anatomical position is reached, after which the therapeutic drug dose is delivered to the tissue surrounding the device or implant And (b) drug localization techniques such as magnetic, ultrasound, or MRI (magnetic resonance imaging) -guided drug delivery, c) Chemical modification of a drug product designed to increase the uptake of the drug into the therapeutic or damaged tissue (macrophages, neutrophils, smooth muscle cells, fibroblasts, extracellular matrix components, neovascular tissue, etc.) Damaged or cured (D) chemical modifications of therapeutic agents or formulations designed to localize drugs at sites of bleeding or disruption of vasculature, and (e) direct injection (For example, subcutaneously, intramuscularly, intraarticularly, etc. of the therapeutic agent under standard or endoscopic observation).

2) Infiltration of the therapeutic agent into the tissue surrounding the device or graft As another method, the tissue cavity in which the device or graft is implanted or a pocket created by surgery may be anti-infected before, during or after treatment. It can be treated with drugs and / or fibrosis-inhibiting therapeutics. This can be achieved in several ways, including: (a) A method of locally applying a drug to the anatomical cavity or surface in which the device is placed (especially useful in this example, the fibrosis inhibitor is released over a period ranging from hours to weeks. Compositions that can be used in this application include, for example, fluids, fine granules, pastes, gels, microparticles, sprays, aerosols, individual implants, and therapeutic or drug release devices or implants. Other formulations that can be delivered to the site to be transplanted), (b) a particulate form of the therapeutic agent is also useful for delivery to the site of implantation, (c) at the site of the graft (or graft surface) A sprayable collagen-containing formulation such as COSTASIS, applied alone or loaded with a therapeutic agent, and covalently derivatized poly (ethylene glycol) -collagen compositions (eg, US Pat. Nos. 5,874,500 and 5,565) (Referred to herein as “CT3”) (both Angiotech Pharmaceuticals, Inc., Canada), (d) applied to the site of the graft (or the surface of the graft), alone or A sprayable PEG-containing formulation, such as COSEAL or ADHIBIT (Angiotech Pharmaceuticals, Inc.), SPRAYGEL or DURASEAL (both Confluent Surgical, Inc., Boston, Mass.) Carrying the therapeutic agent, (e) the site of the graft (Also on the surface of the graft), a fiven-containing formulation such as FLOSEAL or TISSEAL (both BaxterHealthcare Corporation, Fremont, Calif.), (F) applied to the site of the graft (or the surface of the graft) RESTYLANE or PERLANE (both Q-MedAB, Sweden), HYLAFORM (Inamed Corporation, Santa Barbara, CA), SYNVISC (Biomatrix, Inc., New Zealand) Ridgefield, New Zealand), SEPRAFILM or SEPRACOAT (both Genzyme Corporation, Cambridge, Mass.) And other hyaluronic acid-containing preparations, (g) applied to the site of the graft (or the surface of the graft / device) and loaded with the therapeutic agent A polymer gel for surgical implantation, such as REPEL (Life Medical Sciences, Inc., Princeton, NJ) or FLOGEL (Baxter Healthcare Corporation), (h) applied to the site of the graft (or the surface of the graft) and treated An orthopedic “cement” used to hold the prosthesis and tissue in place, carrying the drug, (i) applied to the implantation site (or the surface of the graft / device) and carrying the therapeutic agent Dermabond (Johnson & Johnson, Inc., New Brunswick, NJ, Indermil (US Surgical Company, Norwalk, Conn.), Glustitch (Blacklock Medical Products Inc., Canada), Tissu Emend II (Veterinary Products Laboratories, Phoenix, AZ), Vet Bond (3M Company, St. Paul, MN), Histoacryl BLUE (Davis & Geck, St. Louis, MO) and OrabaseSoothe-N-Seal liquid protection Surgical adhesives containing cyanoacrylates, such as agents (Colgate-Palmolive Company, New York, NY) and / or (j) applied to the site of the implant (or the surface of the implant / device) and loaded with the therapeutic agent Protein-based sealants or adhesives such as BIOGLUE (Cryolife, Inc.) and TISSUEBOND (TissueMed, Ltd.).

  Preferred polymeric substrates that can be used alone or in combination with a fiber formation inhibitor / composition to prevent the formation of fibrous tissue include pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl] (4 -Arm thiol PEG (including a structure having a linking group between the sulfhydryl group and the end of the polyethylene glycol backbone) and pentaerythritol poly (ethylene glycol) ether tetra-succinimidyl glutarate] (4-arm NHS (again NHS Including a structure having a linking group between the group and the end of the polyethylene glycol backbone)))}} formed from a reactant containing one or both. Another preferred composition is pentaerythritol poly (ethylene glycol) ether tetraamino] (4-arm amino PEG (including a structure having a linking group between the amino group and the end of the polyethylene glycol backbone)) as a reactive reagent. And pentaerythritol poly (ethylene glycol) ether tetra-succinimidyl glutarate] (4-arm NHS PEG (again including a structure having a linking group between the NHS group and the end of the polyethylene glycol backbone)) Or both. The chemical structure of these reactants is shown, for example, in US Pat. No. 5,874,500. Depending on the situation, collagen or a collagen derivative (eg methylated collagen) is added to a reactant containing poly (ethylene glycol) to form a preferred cross-linked substrate or independent composition that functions as a polymeric carrier for therapeutic agents. And helps prevent the formation of fibrous tissue.

3) Sustained release formulations of therapeutic agents As noted above, desirable therapeutic agents are polymeric components (which can be biodegradable or non-biodegradable) or non-polymeric compounds to release the therapeutic agent over time. And can be mixed, blended, compounded or otherwise modified. For many of the above examples, both localized and localized sustained release delivery of the fibrosis inhibitor and / or anti-infective agent may be necessary. For example, desirable therapeutic agents may be mixed, formulated, conjugated, or otherwise with a polymeric component (which may be biodegradable or non-biodegradable) or non-polymeric compounds to release the therapeutic agent over time. It can be modified by the method.

Representative examples of biodegradable polymers suitable for delivery of the therapeutic agent include albumin, collagen, gelatin, hyaluronic acid, starch, cellulose and fibrin derivatives (regenerated cellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, (Ruboxymethyl cellulose, cellulose acetate phthalate cellulose, cellulose acetate succinate cellulose, hydroxypropyl methylcellulose phthalate, etc.), casein, dextran, polysaccharides, fibrinogen, poly (ether ester) multi-block copolymer (poly (ethylene glycol)) And poly (butylene terephthalate)), polycarbonates derived from tyrosine (such as US Pat. No. 6,120,491), poly (hydroxyl acid), poly (D, L-lactide), poly (D, L-lactide-co- Glycolide) Poly (glycolide), poly (hydroxybutyrate), polydioxanone, poly (alkyl carbonate) and poly (orthoester), polyester, poly (hydroxyvaleric acid), polydioxanone, polyester, poly (malic acid), poly (tartronic acid) ), Poly (acrylamide), polyanhydride, polyphosphazene, poly (amino acid), poly (alkylene oxide) -poly (ester) block copolymer (XY, XYX, YXY, R- (YX) _n , or R- (XY) _{n and the} like, wherein X is a polyalkylene oxide and Y is a polyester (for example, poly (ethylene glycol, poly (propylene glycol) and poly (ethylene oxide) and poly (propylene oxide) block copolymers ( Example: BASFCorporation (Mount Olive, NJ), polymer PLURONIC and PLURONIC R series) and Y is polyester Polyester is a lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone, γ-decanolactone, δ- Decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one (eg, the residue of one or more monomers selected from PLGA, PLA, PCL, polydioxanone and copolymers thereof) R can be multifunctional inhibitors and copolymers, and mixtures thereof) and copolymers, and mixtures thereof (typically Illum, L., Davids, SS ( Edit) “Polymers in Controlled Drug Delivery” Wright, Bristol, 1987, Arshady, J. Controlled Release 17: 1-22, 1991. Pitt, Int. J. Phar. 59: 173-196, 1990. See Holland et al., J. Controlled Release 4: 155-0180, 1986).

  Representative examples of non-degradable polymers suitable for delivery of fiber formation inhibitors include poly (ethylene-co-vinyl acetate) (“EVA”) copolymers, aromatic polyesters, or poly (ethylene terephthalate), Silicone rubber, acrylic polymer (polyacrylic acid salt, polyacrylic acid, polymethylacrylic acid, polymethacrylic acid, poly (butyl methacrylate)), poly (alkylsinoacrylic acid) (eg poly (ethyl cyanoacrylate), Poly (butyl cyanoacrylate) Poly (hexyl cyanoacrylate) Poly (octyl cyanoacrylate)), acrylic resin, polyethylene, polypropylene, polyamide (nylon 6,6), polyurethane (eg CHRONOFLEXAL and CHRONOFLEX AR (both CardioTech International, Inc ., Woburn, Massachusetts), TECOFLEX, and BIONATE (Polymer Technology Group, Inc., Emeryville, CA)), poly (ester urethane), poly (ether urethane), poly (ester-urea), polyether (poly (ethylene oxide), poly (propylene oxide), PLURONIC polymers, and other ethylene oxide and propylene oxide Based polyoxyalkylene ether block copolymers (eg F-127 or F87) (BASF Corporation (Mount Olive, NJ)), and poly (tetramethylene glycol), styrene-based polymers (polystyrene, poly (styrene sulfonate) ), Poly (styrene) -block-poly (isobutylene) -block-poly (styrene), poly (styrene) -poly (isoprene) block copolymers), and vinyl polymers (polyvinylpyrrolidone, poly (vinyl alcohol), poly (Vinyl acetate) and its copolymers and their combinations Polymers can be anionic (alginate, carrageenan, carboxymethylcellulose, poly (acrylamido-2-methylpropane sulfonic acid) and copolymers thereof, poly (methacrylate) and copolymers thereof, Developed as poly (acrylic acid) and copolymers thereof, and mixtures thereof, or cationic (chitosan, poly-L-lysine, polyethyleneimine, and poly (allylamine)) and mixtures (generally Dunn Et al., J. Applied Polymer Sci. 50: 353-365, 1993. Cascone et al., J. Materials Sci .: Materials in Medicine 5: 770-774, 1994. Shiraishi et al., Biol. Pharm. Bull. 16 (11): 1164-1168, 1993. Thacharodi and Rao, Int’l J. Pharm. 120: 115-118, 1995. Miyazaki et al., Int’l J. Pharm. 118: 257-263, 1995).

Desirable polymeric carriers in the practice of the present invention include poly (ethylene-co-vinyl acetate), polyurethane, poly (D, L-lactic acid) oligomers and polymers, poly (L-lactic acid) oligomers and polymers, poly (glycolic acid) ), Lactic acid and glycolic acid copolymers, lactic acid and glycolic acid copolymers, poly (caprolactone), poly (valerolactone), polyanhydrides, poly (caprolactone) or poly (lactic acid) with polyethylene glycol. Polymers (such as MePEG), forms XY, XYX, YXY, R- (YX) _n , or R- (XY) _n block copolymers, etc., where X is a polyalkylene oxide (eg, poly ( Ethylene glycol, poly (polyethylene glycol) and block copolymers of poly (ethylene oxide) and poly (propylene oxide) (eg BASFCorporation (Mount Olive, NJ), (Limmer PLURONIC and PLURONIC R series) where Y is a polyester, where the polyester is lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ- Butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepane-2one, R is a multifunctional inhibitor), silicone rubber, poly (Styrene) block-poly (isobutylene) -block-poly (styrene), poly (acrylate) polymers and mixtures, admixtures, or copolymers of the above, other preferred polymers include collagen, poly (alkylene oxide) ) Based polymers, polysaccharides such as hyaluronic acid, chitosan and fucan, It is a copolymer of beauty polysaccharides degradable polymers.

  Other representative polymers capable of localized and sustained delivery of anti-infective and / or anti-fibrotic drugs include carboxylic acid polymers, polyacetates, polycarbonates, polyethers, polyethylenes, polyvinyl butyrals, polysilanes, polysilanes. Urea, polyoxide, polystyrene, polysulfide, polysulfone, polysulfonide, polyvinyl halide, pyrrolidone, rubber, thermosetting polymer, crosslinkable acrylic and methacrylic polymers, ethylene acrylic acid copolymer, styrene acrylic copolymer, vinyl acetate heavy Polymers and copolymers, vinyl acetal resins and copolymers, epoxies, melamines, other amino resins, phenolic acid polymers and their copolymers, water-insoluble cellulose ester polymers (cellulose cellulose propionate) , Cellulose acetate butyrate, cellulose nitrate, cellulose acetate phthalate, and mixtures thereof), polyvinyl pyrrolidone, polyethylene glycol, polyethylene oxide, polyvinyl alcohol, polyether, polysaccharides, hydrophilic polyurethane, polyhydroxyacrylate, Dextran, xanthan, hydroxypropylcellulose, and homopolymers and copolymers of N-vinyl pyrrolidone, N-vinyl lactam, N-vinyl butyrolactam, N-vinyl caprolactam, other vinyl compounds with polar pendant groups, hydrophilic esters Acrylates and methacrylates with groups, hydroxy acrylates, and acrylic acid, and combinations thereof, as well as cellulose esters and ethers, ethyl cellulose, hydroxyethyl Rulose, cellulose nitrate, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, natural and synthetic elastomers, rubber, acetal, styrene polybutadiene, acrylic resin, polyvinylidene chloride, polycarbonate, homopolymers and copolymers of vinyl compounds There are coalesced, polyvinyl chloride, and polyvinyl chloride acetate.

  Representative examples of patents related to drug delivery polymers and their formulations include PCT publication numbers WO 98/19713, WO 01/17575, WO 01/41821, WO 01/41822, and WO01 / 15526 (and corresponding No. 4,500,676, 4,582,865, 4,629,623, 4,636,524, 4,713,448, 4,795,741, 4,913,743, 5,069,899, 5,099,013, 5,128,326, 5,143,724,5,153,5 6,071,447, 6,090,995, 6,106,473, 6,110,483, 6,121,027, 6,156,345, 6,214,901, 6,368,611, 6,630,155, 6,528,080, RE37,950, 6,46,1631, 6,143,314, 5,990,194,5,759,5,759,5 5,340,849, 5,278,202, 5,278,201, 6,589,549, 6,287,588, 6,201,072, 6,117,949, 6,004,573, 5,702,717, 6,413,539, 5,714,159, 5,612,052, and U.S. Patent Application Publication Nos. 2003/0068377, 2002/0192286, 2002/007 6441, and 2002/0090398.

  It will also be apparent to those skilled in the art that the polymers described herein can be mixed or copolymerized in various compositions as needed to deliver therapeutic amounts of the bioactive agent.

  Depending on the composition used, the polymeric carrier for anti-infectives and / or fiber formation inhibition (gliosis inhibition) can be in various forms with desired release characteristics and specific properties. For example, polymeric carriers can be constructed to release therapeutic agents upon receipt of certain triggering events such as pH (Heller et al., Polymerin Medicine III "Chemically Self-Regulated Drug Delivery Systems", Elsevier Science Publishers BV, Amsterdam, 1988, pp. 175-188. Kang et al., J. Applied Polymer Sci. 48: 343-354, 1993. Dong et al., J. Controlled Release 19: 171-178, 1992. Dong and Hoffman, J. Controlled Release 15: 141-152, 1991. Kim et al., J. Controlled Release 28: 143-152, 1994. Cornejo-Bravo et al., J. Controlled Release 33: 223-229, 1995. Wu and Lee, Pharm. Res. 10 (10): 1544-1547. 1993. Serres et al., Pharm. Res. 13 (2): 196-201, 1996. Peppas, Gurny et al. (Ed.) "Fundamentals of pH- and Temperature-Sensitive Delivery Systems", Pulsatile. Drug Delivery, Wissenschaftliche Verlagsgesellschaft mbH, Stuttgart, 1993, pp. 41-55, Doelker, "Cellulose Derivatives" 1993, Peppas and Langer (ed), Biopolymers I, Springer-V See erlag, Berlin, etc.) Representative examples of pH sensitive polymers include poly (acrylic acid) and its derivatives, such as homopolymers (poly (aminocarboxylic acid), poly (acrylic acid), poly (methyl acid). Acrylic acid)), copolymers of such homopolymers, and copolymers of poly (acrylic acid) and acrylates, or acrylamide monomers (such as those described above). Other pH sensitive polymers include polysaccharides such as cellulose acetate phthalate cellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, trimellilate cellulose acetate, and chitosan. Further, other pH sensitive polymers include any mixture of pH sensitive polymers and water soluble polymers.

  Similarly, temperature sensitive anti-infectives and / or fibrogenesis inhibitors can be delivered via polymeric carriers (Chen et al., “Novel Hydrogels of a Temperature-Sensitive Pluronic Grafted to a Bioadhesive Polyacrylic Acid Backbone for Vaginal Drug Delivery "in Proceed. Intern. Symp. Control. Rel. Bioact. Mater. 22: 167-168, Controlled Release Society, Inc., 1995. Okano," Molecular Design of Stimuli-Responsive Hydrogels for Temporal Controlled Drug Delivery " Intern. Symp. Control. Rel. Bioact. Mater. 22: 111-112, Controlled Release Society, Inc., 1995. Johnston et al., Pharm. Res. 9 (3): 425-433, 1992, Tung, Int'l J. Pharm. 107: 85-90, 1994, Harsh and Gehrke, J. Controlled Release 17: 175-186, 1991, Bae et al., Pharm. Res. 8 (4): 531-537, 1991. Dinarvand And D'Emanuele, J. Controlled Release 36: 221-227, 1995. Yu and Grainger, "Novel Thermo-sensitive Amphiphilic Gels: Poly N-isopropylacrylamide-co-sodiumacryla te-co-n-N-alkylacrylamide Network Synthesis and Physicochemical Characterization ", Dept. of Chemical & Biological Sci., Oregon Graduate Institute of Science & Technology, Beaverton, OR, pp. 820-821. Zhou and Smid, “Physical Hydrogels of Associative Star Polymers”, Polymer Research Institute, Dept. of Chemistry, College of Environmental Science and Forestry, State Univ. Of New York, Syracuse, NY, pp. 822-823. Hoffman et al., “Characterizing Pore Sizesand Water‘ Structure ’in Stimuli-Responsive Hydrogels”, Center for Bioengineering, Univ. Of Washington, Seattle, Washington, p. 828. Yu and Grainger, “Thermo-sensitive Swelling Behavior in Crosslinked N-isopropylacrylamide Networks: Cationic, Anionic and Ampholytic Hydrogels”, Dept. of Chemical & Biological Sci, Oregon Graduate Institute of Science & Technology, Beaverton, Oregon, pp. 829-830 . Kim et al., Pharm. Res. 9 (3): 283-290, 1992. Bae et al., Pharm. Res. 8 (5): 624-628, 1991. Kono et al., J. Controlled Release 30: 69-75, 1994. Yoshida et al., J. Controlled Release 32: 97-102, 1994, Okano et al., J. Controlled Release 36: 125-133, 1995. Chun and Kim, J. Controlled Release 38: 39-47, 1996. D'Emanuele and Dinarvand, Int'l J. Pharm. 118: 237-242, 1995. Katono et al., J. Controlled Release 16: 215-228, 1991. Hoffman, “Thermally Reversible Hydrogels Containing Biologically Active Species”, Migliaresi et al. (Eds.), Polymersin Medicine III, Elsevier Science Publishers B.V., Amsterdam, 1988, pp. 161-167. Hoffman, “Applications of Thermally Reversible Polymers and Hydrogels in Therapeutics and Diagnostics”, Third International Symposium on Recent Advances in Drug Delivery Systems, Salt Lake City, Utah, February 24-27, 1987, pp. 297-305. Gutowska et al., J. Controlled Release 22: 95-104, 1992. Palasis and Gehrke, J. Controlled Release 18: 1-12, 1992. Paavola et al., Pharm. Res. 12 (12): 1997-2002, 1995, etc.).

  A representative example of a thermogelled polymer and its gelatin temperature (LCST (° C)) is poly (N-methyl-Nn-propylacrylamide), 19.8. Poly (N-n-propylacrylamide), 21.5. Poly (N-methyl-N-isopropylacrylamide), 22.3. Poly (N-n-propylmethacrylamide), 28.0. Poly (N-isopropylacrylamide), 30.9. Poly (N, n-diethylacrylamide), 32.0. Poly (N-isopropylmethacrylamide), 44.0. Poly (N-cyclopropylacrylamide), 45.5. Poly (N-ethylmethylacrylamide), 50.0. Poly (N-methyl-N-ethylacrylamide), 56.0. Poly (N-cyclopropylmethacrylamide), 59.0. There are homopolymers such as poly (N-ethylacrylamide), 72.0. In addition, thermogelled (thermogel) polymers can be produced by inter-monomer copolymers or homopolymers of acrylic monomers (acrylic acid and derivatives thereof (such as methylacrylic acid), acrylate monomers and derivatives thereof (butyl). In combination with other water-soluble polymers such as methacrylates), butyl acrylate, lauryl acrylate, and acrylamide monomers and derivatives thereof (N-butylacrylamide and acrylamide)).

  Another representative example of a heat gelled polymer is a cellulose ester derivative, which includes hydroxypropyl cellulose, 41 ° C. Methylcellulose, 55 ° C. Hydroxypropyl methylcellulose, 66 ° C. And ethyl hydroxyethyl cellulose with structure XY, YXY and XYX, polyalkylene oxide-polyester block copolymer, where X is polyalkylene oxide and Y is a biodegradable polyester (eg PLG-PEG-PLG) And PLURONIC (F-127, 10-15 ° C. L-122, 19 ° C. L-92, 26 ° C. L-81, 20 ° C. And L-61, 24 ° C, etc.).

  Representative examples of patents relating to thermally gelling polymers and their formulations include US Patent Nos. 6,451,346, 6,201,072, 6,117,949, 6,004,573, 5,702,717, and 5,484,610, and PCT Publication Nos. WO 99/07343, WO 99. / 18142, WO 03/17972, WO 01/82970, WO 00/18821, WO 97/15287, WO01 / 41735, WO 00/00222 and WO 00/38651.

Anti-infective agents and / or fibrosis inhibiting therapeutic agents can be attached by polymer occlusion, polymer dissolution, covalent attachment, attachment by ionic hydrophobic reaction, or encapsulation in microcapsules. In certain inventive embodiments, the composition of the therapeutic agent is provided as a non-encapsulated formulation, such as fine granules (nanometer to micrometer in size), pastes of various sizes, films, or sprays. In one embodiment, the anti-scarring agent can be incorporated into biodegradable magnetic nanospheres. Nanospheres can also be used to replenish endovascular devices implanted with anti-scarring agents, such as, for example, stents containing weakly magnetic alloys (see, eg, Z. Forbes, BB Yellen , G. Friedman, K. Barbee. “An approach to targeted drug delivery based on uniform magnetic fields,” EIEEE Trans. Magn. 39 (5): 3372-3377 (2003)).
In certain aspects of the invention, the composition of the antiinfective and / or fiber formation inhibitor is in the form of fine particles, microparticles, nanoparticles, etc. having a size ranging from 50 nm to 500 μm, depending on the application of the particles. Can be created. These compositions can be composed of: These compositions can be formed by spray drying, milling, colloid demixing, W / O emulsification, W / O / W emulsification, and solvent evaporation. In another aspect, these compositions include microemulsions, emulsions, liposomes and micelles. Alternatively, such a composition can be simply applied as a “spray”, which solidifies into a film or coating state for use in device / graft surface coating or tissue lining applications. Can be made. Such propellants can be formulated with a variety of microsphere sizes including, for example, 0.1 μm to 3 μm, 10 μm to 30 μm, and 30 μm to 100 μm.

  Therapeutic compositions containing anti-infectives and / or fibrosis inhibitors can be formulated in various “paste” or gel forms. The composition of the therapeutic agent is a liquid at one temperature (40 ° C, 45 ° C, 50 ° C, 55 ° C, 60 ° C, etc. at temperatures above 37 ° C), and another temperature solid or semi-solid (Such as ambient body temperature or any temperature below 37 ° C). Such “thermal paste” can be easily created by various techniques (see PCT publication WO 98/24427, etc.). Other pastes can be applied as liquids, whereby the water-soluble components of the paste dissolve and the encapsulated drug precipitates in the water-soluble body environment, causing in vivo coagulation. “Pastes” and “gels” containing these therapeutic agents are particularly useful for application to the surface of tissue in contact with an implant or device.

  Within the scope of further embodiments of the invention, hydrophobicity in combination with a polymeric carrier and / or carbohydrate, protein or polypeptide suitable for inclusion and release of hydrophobic anti-infective and / or fibrogenesis inhibitor compounds. A carrier containing the compound is provided. Within certain embodiments, the polymeric carrier contains or is comprised of one or more hydrophobic compound sites, pockets, or granules. For example, in one embodiment of the invention, the hydrophobic compound can be incorporated into a polymeric carrier after incorporation into the substrate containing the hydrophobic therapeutic compound. In this regard, a variety of substrates are available including, for example, carbohydrates and polysaccharides (such as starch, cellulose, dextran, methylcellulose, sodium alginate, heparin, chitosan and hyaluronic acid), proteins or polypeptides (albumin, collagen and Gelatin). Within another embodiment, a hydrophobic compound can be contained within the hydrophobic core, which core is included in the hydrophilic shell.

Anti-infective agents and / or fibrosis inhibitor therapeutic agents can also be delivered as solutions. The therapeutic agent can be incorporated directly into the solution to provide a solution or diffusion. Within certain embodiments, the solution is an aqueous solution. In addition to buffer salts, aqueous solutions further include agents that modify viscosity (hyaluronic acid, alginate, carboxymethylcellulose (CMC), and the like). In other embodiments of the present invention, the solution can include biocompatible solvents or liquid oligomers and / or polymers such as ethanol, DMSO, glycerol, PEG-200, PEG-300 or NMP. These compositions further comprise polymers such as biodegradable polymers, polyesters (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone From the residue of one or more monomers selected from γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one And block polymers having the structure of XY, YXY, R- (YX) _n , R- (XY) _n and XYX. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.) and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASF Corporation (Mount Olive, NJ)) , PLURONIC and PLURONIC R series of polymers), Y is a biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ- Residue of one or more monomers selected from butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one (PLG-PEG-PLG etc.)) and R is a multifunctional initiator.

In other embodiments of the invention, the anti-infective therapeutic and / or fibrosis inhibitor may further comprise a second carrier. The second carrier forms include fine particles (PLGA, PLLA, PDLLA, PCL, gelatin, polydioxanone, poly (alkyl cyanoacrylate), etc.), nanospheres (PLGA, PLLA, PDLLA, PCL, gelatin, polydioxanone, poly (Alkyl cyanoacrylate)), liposomes, emulsions, microemulsions, micelles (SDS, XY, YXY, R- (YX) _n , R- (XY) _n and XYX, where X is a polyalkylene oxide (poly (Ethylene glycol, poly (propylene glycol) and block copolymer of poly (ethylene oxide) and poly (propylene oxide), etc.)) (Example: Polymers PLURONIC and PLURONIC R series from BASF Corporation (Mount Olive, NJ)) Y is a biodegradable polyester, where the polyester is lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, Roxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepane-2one ( Example: PLG-PEG-PLG), where R can be in the form of a multifunctional initiator), zeolite or cyclodextrin.

  Other carriers that can also be used to contain and deliver the anti-infective and / or fibrosis inhibitor therapeutics described herein include hydroxypropylcyclodextrin (Cserhati and Hollo, Int. J. Pharm. 108 : 69-75, 1994), liposomes (eg, Sharma et al., Cancer Res. 53: 5877-5881, 1993. Sharma and Straubinger, Pharm. Res. 11 (60): 889-896, 1994. WO 93/18751, USA. Patent No. 5,242,073), liposome / gel (WO 94/26254), nanocascel (Bartoli et al., J. Microencapsulation 7 (2): 191-197, 1990), micelle (Alkan-Onyuksel et al., Pharm. Res. 11 (2 ): 206-212, 1994), grafts (Jampel et al., Invest. Ophthalm. Vis. Science 34 (11): 3076-3083, 1993. Walter et al., Cancer Res. 54: 22017-2212, 1994), nanoparticles (Violante and LanzafamePAACR), nanoparticle modification (US Pat.No. 5,145,684), nanoparticle (surface modification) (US Pat.No. 5,399,363), micelle (spherical activator) (US Pat.No. 5,403,858), synthetic Phospholipid compounds (US Pat.No. 4,534,899), gas-carrying dispersions (US Pat.No. 5,301,664), liquid emulsions, foams, sprays, gels, lotions, creams, ointments, dispersible blisters, particles or droplets Solid or liquid aerosols, microemulsions (US Pat. No. 5,330,756), polymer shells (nano and micro coatings) (US Pat. No. 5,439,686), emulsions (Tarr et al., Pharm Res. 4: 62-165, 1987) Nanosphere (Hagan et al., Proc. Intern. Symp. Control Rel. Bioact. Mater. 22, 1995. Kwon et al., Pharm Res. 12 (2): 192-195. Kwon et al., PharmRes. 10 (7): 970- 974. Yokoyama et al., J. Contr. Rel. 32: 269-277, 1994. Gref et al., Science 263: 1600-1603, 1994. Bazile et al., J. Pharm. Sci. 84: 493-498, 1994) and grafts (US Pat. No. 4,882,168).

  In another aspect of the present invention, the polymer carrier can be a material formed in situ. In one embodiment, precursors include monomers or macromers that contain unsaturated groups that can be polymerized or cross-linked. The monomer or macromer is then injected, for example, within or on the surface of the treatment area, and the source (visible light or ultraviolet light) or free system (potassium persulfate and ascorbic acid or iron peroxide and hydrogen peroxide). ) Can be polymerized in situ. The polymerization procedure can be performed immediately before, simultaneously with, or after the reagent is injected into the treatment site. For representative examples of compositions that undergo free radical polymerization reactions, see WO 01/44307, WO 01/68720, WO 02/072166, WO 03/043552, WO 93/17669, WO00 / 64977, U.S. Patent Nos. 5,900,245, 6,051,248. 6,083,524, 6,177,095, 6,201,065, 6,217,894, 6,639,014, 6,352,710, 6,410,645, 6,531,147, 5,567,435, 5,986,043, 6,602,975, U.S. patent application publication numbers 2002 / 012796A1, 2002 / 0127266A1, 2002/0120022003229, / 0059906A1.

  In certain embodiments, it may be desirable to use a composition that can be administered as a liquid, but the liquid may subsequently form a hydrogel at the site of administration. Such in situ hydrogel-forming compositions can be administered as liquids from a variety of devices and are not preformed and are therefore adaptable for administration to any site. Examples of forming the hydrogel in situ include a photoactive mixture of a water soluble copolyester prepolymer and polyethylene glycol that forms a hydrogel barrier. Block copolymers of polyalkylene oxide polymers (eg BASF Corporation (Mount Olive, NJ), polymers PLURONIC and PLURONIC R series) and poloxamers are designed to dissolve in cold water, but insoluble hydrogels And adheres to tissues at body temperature (Leach et al., Am. J. Obstet. Gynecol. 162: 1317-1319 (1990)).

  As mentioned elsewhere in this document, the present invention describes polymer crosslinkable substrates and polymeric carriers that can be used to help prevent the formation or growth of fibrous connective tissue. The composition contains a fibrosis inhibitor and can deliver the agent around the implanted device. The following compositions are particularly useful when it is desirable to infiltrate the periphery of the device regardless of the presence or absence of fiber formation inhibitors. Such polymeric materials can be prepared, for example, from (a) synthetic materials, (b) naturally occurring materials, or (c) mixtures of synthetic and naturally occurring materials. The substrate can be prepared, for example, from (a) one component (eg, a self-reactive compound) or (b) two or more compounds that react with each other. Typically, prior to delivery, these materials are flowable and can be sprayed or otherwise extruded from a delivery device (eg, a syringe) to deliver the composition. After delivery, the component materials react with each other and / or within the body to provide the desired effect. In some cases, the materials that react with each other must be separated prior to delivery to the patient and mixed prior to delivery to the patient prior to delivery to maintain fluidity. In a preferred embodiment of the present invention, the matrix components are delivered in liquid form to the desired site in the body where polymerization occurs in situ.

First and second synthetic polymers In one embodiment, a first synthetic polymer containing two or more nucleophilic groups is reacted with a second synthetic polymer containing two or more electrophilic groups. Thus, a crosslinkable polymer composition (in other words, a crosslinked substrate) can be prepared, wherein the electrophilic group can be covalently bonded to the nucleophilic group. In one example, both the first and second polymers are non-immunogenic. In another embodiment, the substrate is less susceptible to enzymatic cleavage by, for example, matrix metalloproteinases (eg, collagenase) and therefore has a longer duration in vivo than a collagen-based composition. It is expected to have.

  As used herein, the term “polymer” refers to polyalkyls, polyamino acids, polyalkylene oxides and polysaccharides, among others. Further, for external or oral use, the polymer may be polyacrylic acid or carbopol. As used herein, the term “synthetic polymer” refers to a polymer that is provided through chemical synthesis, not naturally occurring. Therefore, naturally occurring proteins such as collagen and naturally occurring polysaccharides such as hyaluronic acid are specifically excluded. Synthetic collagen and synthetic hyaluronic acid, and derivatives thereof are included. Synthetic polymers containing either nucleophilic groups or electrophilic groups are also referred to herein as “multifunctionally activated synthetic polymers”. The term “multifunctionally activated” (or simply “activated”) has two or more nucleophilic or electrophilic groups that can react with each other to covalently bond, or It means a synthetic polymer that has been scientifically modified to have (ie, a nucleophilic group reacts with an electrophilic group). Multifunctionally activated synthetic polymer types include bifunctional activated polymers, tetrafunctional activated polymers, and star-branched polymers.

  The multifunctionally activated synthetic polymer used in the present invention is at least two or more to form with a synthetic polymer containing a plurality of nucleophilic groups (ie, “multi-nucleophilic polymers”). Preferably it has at least three functional groups. In other words, it needs to be activated with at least difunctionality, more preferably with trifunctionality or tetrafunctionality. If the first synthetic polymer is a bifunctional activated synthetic polymer, the second synthetic polymer must contain a trifunctional or tetrafunctional group to obtain a three-dimensional crosslinked network. is there. Most preferably, both the first and second synthetic polymers contain at least trifunctional groups.

  Synthetic polymers containing multiple nucleophilic groups are also commonly referred to herein as “multi-nucleophilic polymers”. For use in the present invention, the multi-nucleophilic polymer should contain at least two, more preferably at least three nucleophilic groups. When a synthetic polymer containing only two nucleophilic groups is used, it is necessary to use a synthetic polymer containing three or four electrophilic groups to obtain a three-dimensional crosslinked network.

  Preferred multinucleophilic polymers for use in the compositions and methods of the present invention include synthetic polymers that contain or have been modified to contain multiple nucleophilic groups such as primary amino groups and thiol groups. Preferred polynucleophilic polymers include (i) synthetic polypeptides synthesized to contain two or more primary amino groups or thiols, and (ii) modified to contain two or more primary amino groups or thiol groups. Polyethylene glycol. In general, the reaction of a thiol group having an electrophilic group tends to proceed more slowly than the reaction of a primary amino group having an electrophilic group.

  In one example, the polynucleophilic polypeptide is a synthetic polypeptide synthesized to incorporate amino acid residues containing primary amino groups (such as lysine) and / or amino acids containing thiol groups (such as cysteine). is there. Poly (lysine), a synthetically produced polymer of the amino acid lysine (145 MW), is particularly preferred. Poly (lysine) has been prepared as having 6 to about 4,000 primary amino groups, corresponding to a molecular weight of about 870 to about 580,000.

  The poly (lysine) used in the present invention preferably has a molecular weight in the range of about 1,000 to about 300,000, more preferably in the range of about 5,000 to about 100,000, most preferably from about 8,000 to about Has a range of 15,000. Poly (lysine) with various molecular weights is commercially available from Peninsula Laboratories, Inc. (Belmont, Calif.) And Aldrich Chemical (Milwaukee, Wis.).

  Polyethylene glycol contains multiple primary amino or thiol groups, for example according to the method described in Chapter 22 of Poly (ethylene Glycol) Chemistry: Biotechnical and Biomedical Applications, J. Milton Harris, Ed., Plenum Press, New York (1992) Can be chemically modified. Polyethylene glycol modified to contain two or more primary amino groups is referred to herein as “multi-amino PEG”. Polyethylene glycol modified to contain more than one thiol group is referred to herein as “multi-thiol PEG”. As used herein, the term “polyethylene glycol” includes modified and / or derivatized polyethylene glycol.

  Various forms of multi-amino PEG are commercially available from Shear Water Polymers (Huntsville, Alab.) And Huntsman Chemical Company (Utah) under the name “Jeffamine”. Multi-amino PEGs useful in the present invention include Huntsman's Jeffamine diamine ("D" series) and triamine ("T" series), which contain two and three primary amino groups, respectively, per molecule. ing.

Ethylenediamine _{(H 2 N-CH 2 -CH} 2 -NH 2), tetramethylenediamine _{(H 2 N- (CH 2)} 4 -NH 2), pentamethylenediamine _{(cadaverine) (H 2 N- (CH 2} ) 5 -NH ₂ ), hexamethylene diamine (H ₂ N- (CH ₂ ) ₆ -NH ₂ ), di (2-aminoethyl) amine (HN- (CH ₂ -CH ₂ -NH ₂ ) ₂ ) and tris (2 - polyamines such as aminoethyl) amine _{(N- (CH 2 -CH 2 -NH} 2) 3) can also be used as a synthetic polymer containing multiple nucleophilic groups.

Synthetic polymers containing multiple electrophilic groups are also commonly referred to herein as “multi-electrophilic group polymers”. As used in the present invention, the multifunctionally activated synthetic polymer contains at least two, more preferably at least three electrophilic groups, in order to form a three-dimensional cross-linked network with a multi-nucleophilic polymer. There is a need to. Preferred multi-electrophilic polymers used as compositions of the present invention contain two or more succinimidyl groups that can form covalent bonds with nucleophilic groups in other molecules. Succinimidyl groups are highly reactive with substances containing primary amino (NH ₂ ) groups such as multi-amino PEG, poly (lysine), or collagen. Succinimidyl groups are slightly less reactive with substances containing synthetic polypeptides such as thiol (SH) groups such as multithiol PEG or multiple cysteine residues.

  As used herein, the term “containing two or more succinimidyl groups” refers to a polymer that is preferably commercially available that contains two or more succinimidyl groups, as well as a polymer that has been chemically derivatized to contain two or more succinimidyl groups. Is meant to be included. As used herein, the term “succinimidyl group” is intended to encompass sulfosuccinimidyl groups and other variants of “common” succinimidyl groups. The presence of a sodium sulfite moiety on the sulfosuccinimidyl group helps to increase the water solubility of the polymer.

Hydrophilic polymers and particularly a variety of derivatized polyethylene glycols are preferred for use in the compositions of the present invention. As used herein, the term “PEG” refers to a polymer (OCH ₂ —CH ₂ ) _n having a repeating structure. Some specific PEG shape structures activated with tetrafunctionality are shown in FIGS. 4-13 of US Pat. No. 5,874,500 and are incorporated herein by reference. Examples of suitable PEGs are PEG succinimidyl propionate (SE-PEG), PEG succinimidyl succinamide (SSA-PEG) and PEG succinimidyl carbonate (SC-PEG). In one embodiment of the present invention, the cross-linking substrate is pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl] (4-arm thiol PEG) and pentaerythritol poly (ethylene glycol) ether tetra-succinimidyl glutarate] (4- Arm NHS PEG) is formed in situ by reacting as a reactive reagent. US Pat. No. 5,874,500 shows the structure of these reactants. Each of these materials contains ethylene oxide to contain either thiol groups (to form 4-arm thiol PEG) or N-hydrosuccinimidyl groups (to form 4-arm NHS PEG). It has a core with a structure that becomes visible by adding a derived residue to each hydroxyl group in pentaerythritol and then derivatizing the terminal hydroxyl group (derived from ethylene oxide). There may be a linker group between the backbone and the reactive functional group, and this product is commercially available as COSEAL from Angiotech Pharmaceuticals Inc. Depending on the situation, as discussed in detail below, one or both groups “D” of these molecules may be present.

  As mentioned above, preferred activated polyethylene glycol derivatives used in the present invention contain a succinimidyl group as a reactive group. However, different activating groups can be attached along the PEG molecule. For example, functionally activated PEG propionaldehyde (A-PEG), or functionally activated PEG glycidyl ether (E-PEG), or functionally activated PEG-isocyanate (I-PEG) ), Or PEG can be derivatized to form functionally activated PEG-vinylsulfone (V-PEG).

  Hydrophobic polymers can also be used to prepare the compositions of the present invention. The hydrophobic polymer used in the present invention contains, or is derivatized to contain, two or more electrophilic groups such as succinimidyl groups, most preferably 2, 3 or 4 electrophilic groups. Is preferred. As used herein, the term “hydrophobic polymer” contains a relatively low proportion of elemental oxygen or nitrogen.

Hydrophobic polymers that already contain two or more succinimidyl groups include disuccinimidyl suberate (DSS), bis (sulfosuccinimidyl) suberate (BS ₃ ), dithiobis (succinimidyl propion) Acid salts) (DSP), bis (2-succinimidooxycarbonyloxy) ethyl sulfone (BSOCOES) and 3,3'-dithiobis (sulfosuccinimidyl propionate (DTSPP) and their analogs and derivatives The polymers described above are commercially available from Pierce (Rockford, Ill.) Under catalog numbers 21555, 21579, 22585, 21554, and 21577, respectively.

  Preferred hydrophobic polymers used in the present invention typically have carbon chains not exceeding about 14 carbons. Polymers with carbon chains much longer than 14 carbons are usually very poorly soluble in aqueous solutions, and therefore have very long reaction times when mixed with aqueous solutions of synthetic polymers containing multiple nucleophilic groups. become longer.

  Certain polymers such as polybasic acids can be derivatized to contain two or more functional groups such as succinimidyl groups. The polybase used in the present invention includes tricarboxylic acid based on trimethylolpropane group, tetracarboxylic acid based on di (trimethylolpropane), heptanedioic acid, octanedioic acid (suberic acid) and hexadecanedioic acid (tapsic acid). ), But is not limited to this. Many of these polybases are commercially available from DuPont Chemical Company (Wilmington, Delaware). A common method is to react with an appropriate molar amount of N-hydroxysuccinimide (NHS) in the presence of N, N'-dicyclohexylcarbodiimide (DCC) to contain more than one succinimidyl group. Bases can be chemically derivatized.

Polyhydric alcohols such as trimethylolpropane and di (trimethylolpropane) are converted to the carboxylic acid form using various methods, as described in US patent application Ser. No. 08 / 403,358, and then each trifunctional. And can be further derivatized by reaction with NHS in the presence of DCC to produce a tetrafunctional activated polymer. Polybases such as heptanedioic acid (HOOC- (CH ₂ ) ₅ -COOH), kutandioic acid (HOOC- (CH ₂ ) ₆ -COOH) and hexadecanedioic acid (HOOC- (CH ₂ ) ₁₄ -COOH) Succinimidyl groups can be added and derivatized to produce bifunctional and activated polymers.

  As described in U.S. Patent Application No. 08 / 403,358, ethylenediamine, tetramethylenediamine, pentamethylenediamine (cadaverine), hexamethylenediamine, bis (2-aminoethyl) amine, and tris (2-aminoethyl) amine, etc. Can be derivatized to contain more than one succinimidyl group by chemically derivatizing the polyamine to a polybasic acid and reacting with an appropriate molar amount of N-hydroxysuccinimide in the presence of DCC. Many of these polyamines are commercially available from DuPont Chemical Company.

In a preferred embodiment, the first synthetic polymer contains a plurality of nucleophilic groups (denoted below with “X”) and also contains a second plurality of electrophilic groups (denoted with “Y” below). ) To form a covalent polymer network as follows:
Polymer-X _m + Polymer-Y _n → Polymer-Z-Polymer
m ≤ 2, n ≤ 2 and m + n ≤ 5,
Exemplary X groups include —NH ₂ , —SH, —OH, —PH ₂ , CO—NH—NH _2, etc., where the X groups may be the same or different in the polymer —X _m .

Typical Y _{groups, -CO 2 -N (COCH 2)} 2, -CO 2 H, -CHO, -CHOCH 2 ( epoxide), - N = C = O , -SO 2 -CH = CH 2, - N (COCH) ₂ (eg, a hetero five-membered ring having a double bond existing between two CH groups), -SS- (C ₅ H ₄ N), etc., where the Y group is a polymer -Y _n may be the same or different.

  Z is a functional group resulting from the bond of a nucleophilic group (X) and an electrophilic group (Y).

  As described above, the present invention also considers cases where X and Y are the same or different (eg, the synthetic polymer may be two different electrophilic groups having glutathione or the like, or two different nucleophilic groups). is doing.

  In one embodiment, the backbone of at least one synthetic polymer includes alkylene oxide residues (eg, ethylene oxide, propylene oxide residues and mixtures thereof). The term “backbone” means a significant portion of the polymer.

For example, a synthetic macromolecule containing an alkylene oxide residue can be described by the formula X-polymer-X or Y-polymer-Y, where X and Y are defined as above and say “polymer” The term is-(CH ₂ CH ₂ O) _n- or-(CH (CH ₃ ) CH ₂ O) _n- or-(CH ₂ -CH ₂ -O) _n- (CH (CH ₃ ) CH ₂ -O) _n- means. In these cases, the synthetic polymer is bifunctional.

The required functional groups X or Y are commonly linked to the polymer backbone by a linking group (labeled “Q” below), many of which are known or possible. There are many ways to prepare a variety of functionalized polymers, some of which are listed below:
Polymer -Q ₁ -X + Polymer -Q ₂ -Y → Polymer -Q ₁ -ZQ ₂ -Polymer Typical Q groups include -O- (CH ₂ ) _n- , -S- (CH ₂ ) _n- , _{-NH- (CH 2) n -,} - O 2 C-NH- (CH 2) n -, - O 2 C- (CH 2) n -, - O 2 C- (CR 1 H) n - and oR ₂ -CO-NH- provides partial structure synthetic polymers: polymer-O- (CH ₂ ) _n- (X or Y), polymer-S- (CH ₂ ) _n- (X or Y), polymer _{-NH- (CH 2) n - (} X or Y), polymer _{-O 2 C-NH- (CH 2} ) n - (X or Y), polymer -O ₂ C- (CH _{2) n} - (X or Y), polymer ^{_{-O 2 C- (CR 1 H)}} n - (X or Y) and polymer -OR ₂ -CO-NH- (X or Y). In these structures, n = 1-10, R ¹ = H or alkyl (eg, CH ₃ , C ₂ H ₅ etc.), R ² = CH ₂ , or CO—NH—CH ₂ CH ₂ , and Q ₁ and Q ₂ may be the same or different.

For example, Q ₂ = OCH ₂ CH ₂ (Q ₁ is not present in this case), Y = —CO ₂ —N (COCH ₂ ) ₂ , and X = —NH ₂ , —SH or —OH. The resulting reaction and the Z group are as follows:
Polymer-NH ₂ + Polymer-O-CH ₂ -CH ₂ -CO ₂ -N (COCH ₂ ) ₂ →
Polymer _{-NH-CO-CH 2 -CH 2} -O- polymer.

Polymer-SH + Polymer-O-CH ₂ -CH ₂ -CO ₂ -N (COCH ₂ ) ₂ →
Polymer-S-COCH ₂ CH ₂ —O-polymer. And polymers -OH + polymer _{-O-CH 2 -CH 2 -CO 2} -N (COCH 2) 2 →
Polymer-O-COCH ₂ CH ₂ -O-polymer.

  Additional groups, indicated below with “D”, can be inserted between the polymer and the linking group (if present). One purpose of such D groups is to affect the rate of degradation of the crosslinkable polymer composition in vivo, for example to increase or decrease the rate of degradation. This is useful in many cases, for example, when incorporating a drug into a substrate, and it is desirable to increase or decrease the rate of degradation of the polymer to affect the nature of drug delivery in the desired direction. Cross-linking reactions involving first and second synthetic polymers, each having D and Q groups, are illustrated.

Polymer-DQ-X + Polymer-DQY → Polymer-DQZQD-Polymer Some of the useful biodegradable groups “D” include one or more α-hydroxy acids (eg, lactic acid), glycolic acid, and their There are polymers formed from cyclized products (eg lactide, glycolide), ε-caprolactone, and amino acids. Polymers include polylactide, polyglycolide, poly (co-lactide-glycolide), poly-ε-caprolactone, polypeptides (also known as polyamino acids, eg various di- or tri-peptides) and poly (anhydrides) And so on.

  In a general method of preparing a crosslinkable polymer composition for use in the context of the present invention, a first synthetic polymer containing a plurality of nucleophilic groups contains a second plurality of electrophilic groups. Mix with synthetic polymer. The formation of a three-dimensional crosslinked network occurs as a result of the reaction between the nucleophilic group on the first synthetic polymer and the electrophilic group on the second synthetic polymer.

  The concentration of the first synthetic polymer and the second synthetic polymer used in preparing the composition of the invention depends on the type and molecular weight of the specific synthetic polymer used and the desired final use. It depends on a number of factors including the application. In general, when using multi-amino PEG as the first synthetic polymer, it is preferred to use it at a concentration in the range of about 0.5 to about 20% of the final composition, The second synthetic polymer is used at a concentration ranging from about 0.5 to about 20% of the final composition. For example, a final composition having a total amount of 1 gram (1000 milligrams) contains about 5 to about 200 milligrams of multi-amino PEG and about 5 to about 200 milligrams of a second synthetic polymer.

  Using higher concentrations for the first and second synthetic polymers leads to the formation of a more closely crosslinked network, producing a harder and stronger gel. Compositions intended for use in tissue augmentation typically use concentrations close to the upper limit of the preferred concentration range for the first and second synthetic polymers. Compositions intended for use as bioadhesives or in anti-adhesion need not be hard and therefore contain lower polymer concentrations.

  Because polymers containing multiple electrophilic groups also react with water, the second synthetic polymer generally has the ability to crosslink by hydrolysis, which usually occurs when such electrophilic groups are exposed to an aqueous medium. Stored and used in a sterilized dry state to prevent loss. A process for preparing synthetic hydrophilic polymers containing multiple electrophilic groups in a sterilized dry state is described in US Pat. No. 5,643,464. For example, the dry synthetic polymer may be a thin sheet or compressed into a film, which can then be sterilized using gamma or more preferably e-beam irradiation. The resulting dried film or sheet can be cut to the desired size and chopped into smaller sized microparticles. In contrast, polymers containing multiple nucleophilic groups are not usually water reactions and can therefore be stored in aqueous solution.

  Within certain embodiments, one or both of the electrophilic or nucleophilic terminal polymers described above can be combined with a synthetic or naturally occurring polymer. The presence of a synthetic or naturally occurring polymer may enhance the mechanical properties and / or adhesive properties in forming the composition in situ. Naturally occurring polymers and polymers derived from naturally occurring polymers that can be involved in the formation of substances in situ include naturally occurring proteins such as collagen, collagen derivatives (such as methylated collagen), fibrinogen, thrombin, albumin, fibrin, and derivatives. And naturally occurring polysaccharides such as glycosaminoglycans, including deacetylated and desulfated glycosaminoglycan derivatives.

  In one embodiment, a composition comprising both a naturally occurring protein and a first and second synthetic polymer as described above is used to form a cross-linked substrate according to the present invention. In one embodiment, the composition comprising both collagen and the first and second synthetic polymers described above is used to form a cross-linked substrate in accordance with the present invention. In one embodiment, the composition comprising both methylated collagen and the first and second synthetic polymers described above is used to form a cross-linked substrate in accordance with the present invention. In one embodiment, a composition comprising both fibrinogen and first and second synthetic polymers as described above is used to form a cross-linked substrate according to the present invention. In one embodiment, the composition comprising both thrombin and the first and second synthetic polymers described above is used to form a crosslinked substrate in accordance with the present invention. In one embodiment, the composition comprising both albumin and the first and second synthetic polymers described above is used to form a crosslinked substrate according to the present invention. In one embodiment, the composition comprising fibrin and both the first and second synthetic polymers described above is used to form a cross-linked substrate according to the present invention. In one embodiment, a composition comprising both the naturally occurring polysaccharide and the first and second synthetic polymers described above is used to form a cross-linked substrate according to the present invention. In one embodiment, a composition comprising both a glycosaminoglycan and a first and second synthetic polymer as described above is used to form a crosslinked substrate according to the present invention. In one embodiment, the composition comprising both deacetylated glycosaminoglycan and the first and second synthetic polymers described above is used to form a cross-linked substrate according to the present invention. In one embodiment, a composition comprising both the desulfated glycosaminoglycan and the first and second synthetic polymers described above is used to form a crosslinked substrate according to the present invention.

  In one embodiment, a composition comprising a naturally occurring protein and a first synthetic polymer as described above is used to form a cross-linked substrate according to the present invention. In one embodiment, the composition comprising collagen and the first synthetic polymer described above is used to form a cross-linked substrate according to the present invention. In one embodiment, the composition comprising methylated collagen and the first synthetic polymer described above is used to form a cross-linked substrate according to the present invention. In one embodiment, the composition comprising fibrinogen and the first synthetic polymer described above is used to form a cross-linked substrate according to the present invention. In one embodiment, a composition comprising thrombin and a first synthetic polymer as described above is used to form a cross-linked substrate according to the present invention. In one embodiment, the composition comprising albumin and the first synthetic polymer described above is used to form a cross-linked substrate according to the present invention. In one embodiment, the composition comprising fibrin and the first synthetic polymer described above is used to form a crosslinked substrate according to the present invention. In one embodiment, the composition comprising the naturally occurring polysaccharide and the first synthetic polymer described above is used to form a cross-linked substrate according to the present invention. In one embodiment, a composition comprising a glycosaminoglycan and a first synthetic polymer as described above is used to form a crosslinked substrate according to the present invention. In one embodiment, a composition comprising a deacetylated glycosaminoglycan and a first synthetic polymer as described above is used to form a crosslinked substrate according to the present invention. In one embodiment, a composition comprising a desulfated glycosaminoglycan and a first synthetic polymer, as described above, is used to form a cross-linked substrate according to the present invention.

  In one embodiment, a composition comprising a naturally occurring protein and a second synthetic polymer as described above is used to form a cross-linked substrate according to the present invention. In one embodiment, the composition comprising collagen and a second synthetic polymer as described above is used to form a cross-linked substrate according to the present invention. In one embodiment, the composition comprising methylated collagen and a second synthetic polymer described above is used to form a cross-linked substrate according to the present invention. In one embodiment, the composition comprising fibrinogen and a second synthetic polymer as described above is used to form a cross-linked substrate according to the present invention. In one embodiment, the composition comprising thrombin and the second synthetic polymer described above is used to form a cross-linked substrate according to the present invention. In one embodiment, a composition comprising albumin and a second synthetic polymer as described above is used to form a cross-linked substrate according to the present invention. In one embodiment, the composition comprising fibrin and a second synthetic polymer as described above is used to form a cross-linked substrate according to the present invention. In one embodiment, a composition comprising a naturally occurring polysaccharide and a second synthetic polymer, as described above, is used to form a crosslinked substrate according to the present invention. In one embodiment, a composition comprising a glycosaminoglycan and a second synthetic polymer as described above is used to form a cross-linked substrate according to the present invention. In one embodiment, a composition comprising a deacetylated glycosaminoglycan and a second synthetic polymer as described above is used to form a cross-linked substrate according to the present invention. In one embodiment, a composition comprising a desulfated glycosaminoglycan and a second synthetic polymer, as described above, is used to form a crosslinked substrate in accordance with the present invention.

  The presence of a protein or polysaccharide component containing a functional group capable of reacting with a functional group on a plurality of activated synthetic macromolecules can be achieved by mixing and / or crosslinking the synthetic macromolecule with the naturally occurring polymer matrix. May result in the formation of a crosslinkable. In particular, if naturally occurring polymers (proteins or polysaccharides) also contain nucleophilic groups such as primary amino groups, electrophilic groups on the second synthetic polymer react with primary amino groups on these components, and Nucleophilic groups react on the first synthetic polymer, and these other components act to become part of the polymer substrate. For example, lysine-rich proteins such as collagen are particularly highly reactive with electrophilic groups on synthetic polymers.

  In one embodiment, the naturally occurring protein in the polymer can be collagen. As used herein, the term “collagen” or “collagen substance” means any form of collagen, including those that have been processed or otherwise modified, extracted from tissue or produced by recombinant techniques. It is intended to encompass all types of collagen from any source including, but not limited to, collagen, collagen analogs, collagen derivatives, modified collagen, and denatured collagen such as gelatin.

  In general, for example, collagen can be extracted and purified from humans or other mammalian sources such as bovine or porcine dermis and human placenta, or can be produced by recombinant or other techniques, or collagen from any source Is included in the composition of the present invention. Purified and substantially non-antigen collagen in solution obtained from bovine skin is well known in the art. US Pat. No. 5,428,022 discloses a method for extracting and purifying collagen from human placenta. US Pat. No. 5,667,839 discloses a method for producing recombinant human collagen in the milk of genetically modified animals including genetically modified cows. Any type of collagen can be used in the compositions of the present invention, including but not limited to type I, II, III, IV, or combinations thereof, but type I is usually preferred. Either atelopeptides or telopeptide-containing collagen can be used. However, since immunogenicity is reduced as compared to telopeptide-containing collagen, atelopeptide collagen is usually preferred when collagen obtained from a heterogeneous source such as bovine collagen is used.

  Collagens previously cross-linked by methods such as heat, irradiation, or chemical crosslinkers are preferred in the use of the compositions of the present invention, but previously cross-linked collagen can also be used. Uncrosslinked atelopeptide fibrillar collagen is commercially available from Innamed Aesthetics (Santa Barbara, Calif.) At concentrations of 35 mg / ml and 65 mg / ml under the trade names ZyderM I collagen and ZYDERMII collagen, respectively. Glutaraldehyde cross-linked atelopeptide fibrillar collagen is commercially available from Innamed Corporation (Santa Barbara, Calif.) At a concentration of 35 mg / ml under the trade name Zyplast Collagen.

  The collagen used in the present invention is usually an aqueous suspension at a concentration of about 20 mg / ml to about 120 mg / ml, preferably about 30 mg / ml to about 90 mg / ml.

  Due to the sticky concentration, non-fibrillar collagen is preferably used in compositions intended for use as a bioadhesive. The term “non-fibrillar collagen” means a modified or non-modified collagen material that is substantially non-fibrillar at a pH of 7 and is indicated by the optical clarity of an aqueous suspension of collagen.

  Collagen that is already non-fibrous can be used in the composition of the present invention. The term “non-fibrillar collagen” as used herein refers to the type of collagen that is natural and non-fibrous, and collagen that has been chemically modified to be non-fibrous at and around neutral pH values. Include. Types of collagen that are native and non-fibrillar (or fibril) include types IV, VI, and VII.

  Chemically modified collagens that are non-fibrous at neutral pH values include succinylated and methylated collagens, both described in US Pat. No. 4,164,559 issued to Miyata et al. On August 14, 1979. According to the method of, it can prepare. Due to its inherent tackiness, methylated collagen is particularly preferred for use in bioadhesive compositions, as disclosed in US patent application Ser. No. 08 / 476,825.

  The collagen used in the crosslinkable polymer composition of the present invention is initially fibrous and can then be rendered non-fibrous by adding one or more fiber degrading agents. As mentioned above, the fibrinolytic agent needs to be present in an amount sufficient to render it nonfibrous at pH 7 values. The fiber degrading agents used in the present invention include various biocompatible alcohols, amino acids (eg, arginine), inorganic salts (eg, sodium chloride and potassium chloride) and carbohydrates (eg, various sugars including sucrose). There are, but not limited to.

  In one embodiment, the polymer can be collagen or a collagen derivative, such as methylated collagen. Examples of in situ composition formation include pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl] (4-arm thiol PEG), pentaerythritol poly (ethylene glycol) ether tetra-succinimidyl glutarate] (4- Arm NHS PEG) and methylated collagen are used as reactive reagents. The composition produces a crosslinked hydrogel when mixed with a suitable buffer. (See US Pat. Nos. 5,874,500, 6,051,648, 6,166,130, 5,565,519, and 6,312,725}.

  In another embodiment, the naturally occurring polymer can be a glycosaminoglycan. Glycosaminoglycans, such as hyaluronic acid, include both anionic and cationic functional groups along each polymer chain, which can form intramolecular and / or intermolecular intersections, and hyaluronic acid Cause thixotropic properties (or shear fluidization).

  In certain embodiments, glycosaminoglycans can be derivatized. For example, glycosaminoglycans can be chemically derivatized, eg, by deacetylation, desulfation, or both, to include primary amino groups that can react with electrophilic groups on the synthetic polymer molecule. . Glycosaminoglycans derivatized according to any of the above methods or both include: hyaluronic acid, chondroitin sulfate A, chondroitin sulfate B (dermatan sulfate), chondroitin sulfate C, chitin (can be derivatized to chitotin) ), Keratan sulfate, kerato sulfate, and heparin. Further details of the derivatization of glycosaminoglycans by deacetylation and / or desulfation and the resulting covalent attachment of glycosaminoglycan derivatives to synthetic hydrophilic polymers are assigned and approved by the assignee of the present invention. US patent application Ser. No. 08 / 146,843 (filing date: November 3, 1993).

  Generally, the first synthetic polymer is added to the collagen, and then the collagen and the first synthetic polymer are thoroughly mixed to obtain a homogeneous composition. A second synthetic polymer is then added and mixed into the collagen / first synthetic polymer mixture, where the mixture contains primary amino or thiol groups on the first synthetic polymer and also on the collagen. The primary amino group is covalently bonded to the base to form a homogeneous cross-linked network. A variety of deacetylated and / or desulfated glycosaminoglycan derivatives can be incorporated into the composition in a manner similar to that described above for collagen. In addition, the introduction of hydrocolloids such as carboxymethylcellulose promotes tissue attachment and / or swelling capabilities.

Administration of the Crosslinked Synthetic Polymer Composition The composition of the present invention having two synthetic polymers can be administered before, during, or during the crosslinking of the first and second synthetic polymers. Certain applications, such as tissue augmentation, described in detail below, require the composition to be cross-linked prior to administration, and in other applications such as tissue adhesion, before cross-linking reaches "equilibrium" It is necessary to administer the composition. The point at which cross-linking reaches equilibrium is defined herein as the point at which the composition no longer feels sticky or does not stick to the touch.

  To administer the composition prior to cross-linking, the first synthetic polymer and the second synthetic polymer can be included in separate cylinders of a two-chamber syringe. In this case, the two synthetic polymers are not actually mixed until the two polymers are pushed out of the tip of the syringe needle into the patient's tissue. This allows the majority of the cross-linking reaction to occur in situ and has already progressed too much before the two synthetic polymers are prematurely mixed or the cross-link between the two components is delivered from the syringe needle. The problem of needle occlusion that often occurs can be avoided. As described above, the use of a needle with a smaller diameter is possible, and this is advantageous when soft tissue enhancement is performed in delicate facial tissues, for example, around the eyeball.

  Alternatively, the first synthetic polymer and the second synthetic polymer are mixed according to the method described above prior to delivery to the tissue site, and immediately after mixing (preferably within about 60 seconds) to the desired tissue site. ) Can be injected.

  In another embodiment of the invention, the first synthetic polymer and the second synthetic polymer were mixed and then extruded onto a sheet or other solid so that they could be crosslinked. The crosslinked solid is then dehydrated to remove substantially all unbound water. The resulting dry solid is ground or crushed into particles, then hyaluronic acid, dextran sulfate, dextran, succinylated non-crosslinked collagen, methylated non-crosslinked collagen, glycogen, glycerol, glucose, maltose, fatty acids Suspended in a non-aqueous liquid carrier including but not limited to triglycerides (corn oil, soybean oil, sesame oil) and egg yolk phospholipids. The particle suspension can be injected into the tissue site with a small gauge needle. Once inside the tissue, the crosslinkable polymer particles are hydrated and expanded to at least 5 times the size.

Hydrophilic polymer + a plurality of crosslinkable components As described above, the first and / or second synthetic polymer may be combined with a hydrophilic polymer such as collagen or methylated collagen to form a composition useful in the present invention. Can be formed. In one general example, a composition useful in the present invention includes a hydrophilic polymer combined with two or more crosslinkable components. Details of this embodiment are further described in this section.

Hydrophilic polymer component:
The hydrophilic polymer component can be a synthetic or naturally occurring hydrophilic polymer. Naturally occurring hydrophilic polymers include, but are not limited to: proteins such as collagen and its derivatives, fibronectin, albumin, globulin, fibrinogen, and fibrin (especially preferred in combination with collagen), polymannuronic acid and poly Carboxylic acid polysaccharides such as galacturonic acid, aminated polysaccharides, especially glycosaminoglycans such as hyaluronic acid, chitin, chondroitin sulfate A, B, or C, keratin sulfate, keratan sulfate and heparin, and dextran and starch derivatives Activated polysaccharide. Collagen (eg, methylated collagen) and glycosaminoglycans are preferred as naturally occurring hydrophilic polymers used herein.

  In general, for example, collagen can be extracted and purified from humans or other mammalian sources such as bovine or porcine dermis and human placenta, or can be produced by recombinant or other techniques, or collagen from any source Can be used in the composition of the process. Purified and substantially non-antigen collagen in solution obtained from bovine skin is well known in the art. See US Pat. No. 5,428,022 to Palefsky et al. Here, a method for extracting and purifying collagen from a mammalian source of human placenta is disclosed. See also US Pat. No. 5,667,839 to Berg. Here, a method for producing recombinant human collagen in milk of genetically modified animals including genetically modified cows is disclosed. Unless otherwise specified, the term “collagen” or “collagen material” as used herein means all forms of collagen, including those that have been processed or otherwise modified.

  Any type of collagen can be used in the compositions of the present invention, including but not limited to type I, II, III, IV, or combinations thereof, but type I is usually preferred. Either atelopeptides or telopeptide-containing collagen can be used. However, since immunogenicity is reduced compared to telopeptide-containing collagen, atelopeptide collagen is usually preferred when collagen obtained from a source such as bovine collagen is used.

Collagens that have been previously cross-linked by methods such as heat, irradiation, or chemical cross-linking agents are preferred in the use of the compositions of the present invention, but previously cross-linked collagen can also be used. Atelopeptide fibrillar collagen which is not crosslinked, under the respective trade name ZYDERM ^(R) I collagen and ZYDERM ^(R) II collagen, McGhan Medical Corporation (Santa Barbara, at a concentration of 35 mg / ml and 65 mg / ml ). Glutaraldehyde crosslinked atelopeptide fibrillar collagen is commercially available from under the tradename ZYPLAST ^(R), McGhan Medical Corporation at a concentration of 35 mg / ml (Santa Barbara, CA).

  The collagen used in the present invention is not necessary, but is usually an aqueous suspension at a concentration of about 20 mg / ml to about 120 mg / ml, and is about 30 mg / ml to about 90 mg / ml. ml is preferred.

  While intact collagen is preferred, deformed collagen, more commonly known as gelatin, can also be used in the compositions of the present invention. Gelatin has the added advantage of breaking down faster than collagen.

  Non-fibrillar collagen is usually preferred because of its larger surface area and higher concentration of reactive groups. The term “non-fibrillar collagen” means a modified or non-modified collagen material that is substantially non-fibrillar at a pH of 7 and is indicated by the optical clarity of an aqueous suspension of collagen.

  Collagen that is already non-fibrous can be used in the composition of the present invention. The term “non-fibrillar collagen” as used herein refers to the type of collagen that is natural and non-fibrous, and collagen that has been chemically modified to be non-fibrous at and around neutral pH values. Include. Types of collagen that are native and non-fibrillar (or fibril) include types IV, VI, and VII.

  Chemically modified collagens that are non-fibrous at neutral pH values include succinylated collagen, propylated collagen, ethylated collagen, methylated collagen and the like, both of which are U.S. patents issued to Miyata et al. It can be prepared according to the method described in US Pat. No. 4,164,559. Methylated collagen is particularly preferred due to its inherent stickiness, as disclosed in US Pat. No. 5,614,587 issued to Rhee et al.

  The collagen used in the crosslinkable composition of the present invention is initially fibrous and can then be rendered non-fibrous by adding one or more fiber degrading agents. As mentioned above, the fibrinolytic agent needs to be present in an amount sufficient to render it nonfibrous at pH 7 values. The fiber degrading agent used in the present invention includes, but is not limited to, various biocompatible alcohols, amino acids (eg, arginine), inorganic salts, and carbohydrates, and biocompatible alcohols are particularly preferable. Preferred biocompatible alcohols include glycerol and propylene glycol. Non-biocompatible alcohols such as ethanol, methanol and isopropanol are not preferred for use in the present invention because of the potential for adverse effects on the recipient patient's body. A preferred amino acid is arginine. Preferred inorganic salts include sodium chloride and potassium chloride. Although carbohydrates such as various sugars, including sucrose, can be used in the practice of the present invention, they are less preferred than other types of fibrinolytic agents because they can have cytotoxic effects in vivo.

  Fibrous collagen is less preferred because the surface area of fibrous collagen is narrower and the concentration of reactive groups is lower than non-fibrous. However, as disclosed in US Pat. No. 5,614,587, when visibility is not a requirement, fibrillar collagen or a mixture of non-fibrillar or fibrillar collagen is intended to have long-term persistence in vivo. It is preferable to use in the composition.

  Synthetic hydrophilic polymers can also be used in the present invention. Useful synthetic hydrophilic polymers include, but are not limited to, polyalkylene oxides, especially polyethylene glycols including block and random copolymers and poly (ethylene oxide) -poly (propylene oxide) copolymers, glycerol, etc. Polyols, polyglycerols (especially highly branched polyglycerols), propylene glycols and trimethylene glycols substituted with one or more polyalkylene oxides, such as mono-, di- and tri-polyoxyethylenated glycerol, mono- and Di-polyethyl oxide propylene glycol, and mono- and di-polyethyl trimethylene glycol, polyethyl sorbitol, polyethylglycolate, acrylic acid polymers and their analogs and copolymers (poly Crylic acid itself, polymethacrylic acid, poly (hydroxyethyl-methacrylate), poly (hydroxyethyl acrylate), poly (methyl alkyl sulfoxide methacrylate), poly (methyl alkyl sulfoxide acrylate) and any copolymer of the preceding sentence) And / or additional acrylate active species such as aminoethyl acrylate and mono-2- (acryloxy) -ethyl succinate, polymaleic acid, polyacrylamide itself, poly (methacrylamide), poly (dimethylacrylamide) and poly ( Poly (acrylamide) such as N-isopropyl-acrylamide), poly (olefin alcohol) such as poly (vinyl alcohol), poly (vinyl pyrrolidone), poly (N-vinylcaprolactam) and their copolymers (N -Vinyl lactam), poly ( Polyoxazolines including methyloxazoline) and poly (ethyloxazoline), and polyvinylamine. The polymers listed above are not exhaustive and a variety of other synthetic hydrophilic polymers can be used as appreciated by those skilled in the art.

Crosslinkable components:
The composition of the present invention also consists of a plurality of crosslinkable components. Each of the crosslinkable components participates in a reaction that results in a cross-linked substrate. Before the crosslinking reaction is complete, the crosslinkable component provides the necessary adhesive quality that allows the method of the present invention.

The crosslinkable component is crosslinkable with a biocompatible and non-immunogenic substrate useful in a variety of contexts including adhesion prevention, bioactive drug delivery, tissue augmentation, and other uses. Selected as The crosslinkable component of the present invention consists of: component A having m nucleophilic groups and m > 2. m Component B having an n electrophilic group capable of reacting with a nucleophilic group and n > 2 and m + n > 4. Any third group having at least one functional group that is either an electrophilic group and capable of reacting with the nucleophilic group of component A, or a nucleophilic group and capable of reacting with the electrophilic group of component B. Any component C which is a component of Therefore, components A, B and C the total number of functional groups present in the (if present) in total> 5, i.e., the total number of functional groups, m + n + p is> must be 5, Where p is the number of functional groups in component C and is > 1 as pointed out. Each component is biocompatible, non-immunogenic, and at least one component consists of a hydrophilic polymer. Also, of course, the composition can be additionally cross-linkable, having one or more reactive nucleophilic or electrophilic groups and thus participating in the formation of a cross-linked biomaterial through covalent bonds to other components. May contain various components D, E, F and the like.

  The m nucleophilic groups of component A can be the same or different; alternatively, A can contain two or more different nucleophilic groups. Similarly, the n electrophilic groups of component B may be the same or different, or two or more different electrophilic groups may be present. In the case of a nucleophilic group, the functional group of any component C may be the same as or different from the nucleophilic group of component A. Conversely, in the case of an electrophilic group, the functional group of any component C is It may be the same as or different from the electrophilic group.

Therefore, the component is structural formula
(I) R ¹ (-[Q ¹ ] _q -X) _m (component A),
(II) R ² (-[Q ² ] _r -Y) _n (component B), and
(III) R ³ (-[Q ³ ] _s -Fn) _p (optional component C),
Indicated by.

R ¹ , R ² and R ³ are selected independently of each other from the group consisting of C _{2 to} C ₁₄ hydrocarbyl, heteroatom-containing C _{2 to} C ₁₄ hydrocarbyl, hydrophilic polymer, and hydrophobic polymer, and at least One R ¹ , R ² and R ³ is a hydrophilic polymer, preferably a synthetic hydrophilic polymer.

X represents one of the nucleophilic groups of component A, and the various X moieties on A may be the same or different,
Y represents one of the electrophilic groups of component B, and the various Y moieties on A may be the same or different,
Fn represents a functional group of optional component C.

Q ¹ , Q ² and Q ³ are linking groups.

  m ≧ 2, n ≧ 2, m + n = ≧ 4, q and r are independent of each other and are 0 (zero) or 1, and in the presence of any component C, p ≧ 1, and Is irrelevant and is 0 (zero) or 1.

Reactive group:
X can be virtually any nucleophilic group as long as the reaction occurs with an electrophilic group Y. Similarly, Y can be virtually any electrophilic group as long as the reaction occurs with X. The only limitation is whether the reaction between X and Y is reasonably early mixed with the aqueous medium, regardless of the need for heat or the possibility of toxic or non-biodegradable reaction catalysts or other chemical reagents. A practical limitation that should occur automatically. It is preferred, but not essential, that the reaction occur without the need for ultraviolet or other radiation. Ideally, the reaction between X and Y should end within 60 minutes, with 30 minutes or less being preferred. Most preferably, the reaction occurs in about 5-15 minutes or less.

Examples of suitable nucleophilic groups as ^{_{X, -NH 2, -NHR 4,}} -N (R 4) 2, -SH, -OH, -COOH, -C 6 H 4 -OH, -PH 2, - ^{PHR 5, -P (R 5)} 2, -NH-NH 2, -CO-NH-NH 2, there are such -C ₅ H ₄ N, but are not limited to. Here, R ⁴ and R ⁵ are hydrocarbyl, usually alkyl or monocyclic allyl, preferably alkyl, most preferably lower alkyl. Organometallic moieties are also nucleophilic groups useful for purposes of the present invention, especially those that act as carbanion donors. However, organometallic nucleophilic groups are not preferred. Examples of organometallic moieties include: Grignard function in which R ⁶ is a carbon atom (substituted or unsubstituted) -R ⁶ MgHal, and Hal is halo, usually bromo, iodine or chloro, preferably bromo, and Lithium-containing functionality, usually alkyllithium groups, sodium-containing functionality.

One skilled in the art will recognize that certain nucleophilic groups need to be activated with a base so that they have the ability to react with electrophiles. For example, if nucleophilic sulfhydryls and hydroxyl groups are present in the crosslinkable composition, to remove protons to allow reaction with electrophiles and provide -S ^- or -O ^- species It is necessary to mix the composition with an aqueous base. Non-nucleophilic groups are preferred unless it is desirable for the group to participate in a crosslinking reaction. In some embodiments, groups can be present as a component of the buffer solution. Suitable groups and corresponding cross-linking reactions are described in Section E below.

  It is necessary to make a selection of the electrophilic group provided in the crosslinkable composition (eg component B) so that reaction with a specific nucleophilic group is possible. Thus, when the X moiety is an amino group, the Y group is selected to react with the amino group. Similarly, when the X moiety is a sulfhydryl moiety, the corresponding electrophilic group is a sulfhydryl reactive group and the like.

As an example, when X is amino (usually primary amino but not necessarily required), the electrophilic group present in Y includes, but is not limited to, amino reactive groups such as: 1) Carboxylic esters including cyclic esters and `` activated '' esters, (2) Acid chloride groups (-CO-Cl), (3) Anhydrides (-(CO) -O- (CO) -R) (4) ketones and aldehydes including α, β-unsaturated aldehydes and ketones such as -CH = CH-CH = O and -CH = CH-C (CH ₃ ) = O, (5) halogens, (6) Isocyanate (-N = C = O), (7) Isothiocyanate (-N = C = S), (8) Epoxide, (9) Activated hydroxyl groups (eg carbonyldiimidazole or sulfonyl chloride) Activated with a conventional activator) and (10) ethenesulfonyl (—SO ₂ CH═CH ₂ ) and acrylate (—CO ₂ —C═CH ₂ ), methacrylate (—CO ₂ —C) (CH ₃ ) = CH ₂ )), ethyl acetate Olefins containing conjugated olefins such as analog functional groups including acrylate (—CO ₂ —C (CH ₂ CH ₃ ) ═CH ₂ ) and ethyleneimino (—CH═CH—C═NH). Since the carboxylic acid group itself is easily affected by the reaction with the nucleophilic amine, it is necessary to activate the component containing the carboxylic acid group so that it undergoes an amine reaction. Activation can be accomplished in a variety of ways, but often involves reaction with a suitable hydroxyl-containing compound in the presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC) or dicyclohexyl (DHU). For example, to form a reactive electrophilic group, N-hydroxysuccinimide ester and N-hydroxysulfosuccinimide ester, respectively, carboxylic acid with alkoxy-substituted N-hydroxy-succinimide or N-hydroxysulfosuccinimide in the presence of DCC. Can be activated. To provide a reactive anhydride group, the carboxylic acid can be activated by reacting with an alkyl halogen such as acetyl chloride (eg, acetyl chloride). As a further example, a carboxylic acid can be converted to an acid chloride group using, for example, thionyl chloride or acryl chloride, which has the ability to exchange reactions. The specific reagents and procedures used to carry out such activation reactions are well known to those skilled in the art and are described in the relevant text and literature.

Similarly, when X is a sulfhydryl, the electrophilic group present in Y is a group that reacts with a sulfhydryl moiety. Some of these reactive groups form thioester linkages upon reaction with sulfhydryl groups, as described in PCT Publication No. WO 00/62827 issued to Wallace et al. As described in detail herein, such “sulfhydryl-reactive” groups include, but are not limited to: mixed anhydrides, ester derivatives of phosphorus, ester derivatives of p-nitrophenol, p-nitrothiophenol. And substituted hydroxylamine esters, including pentafluorophenol, N-hydroxyphthalimide ester, N-hydroxysuccinimide ester, N-hydroxysulfosuccinimide ester, and N-hydroxyglutarimide ester, esters of 1-hydroxybenzotriazole, 3-hydroxy- 3,4-dihydro-benzotriazin-4-one, 3-hydroxy-3,4-dihydro-quinazolin-4-one, carbonylimidazole derivatives, acid chlorides, ketenes, and isocyanates. With these sulfhydryl reactive groups, auxiliary reagents can also be used to promote bond formation (eg, 1-ethyl-3- [3-diethylaminopropyl] carbodiimide to promote binding to carboxyl-containing groups) Can be used.)
In addition to the sulfhydryl reactive groups that form thioester linkages, a variety of other sulfhydryl reactive functionalities that form other types of linkages can be used. For example, a compound containing a methyl imidate derivative has a sulfhydryl group and forms an amide-thioester linkage. Alternatively, a sulfhydryl reactive group that forms a disulfide bond with a sulfhydryl group can be employed, and such a group typically has a -SS-Ar structure, where Ar is substituted or non-substituted with an electron withdrawing moiety. Substituted nitrogen-containing heteroaromatic moiety or non-heteroaromatic group substitution, Ar is for example 4-pyridinyl, o-nitrophenyl, m-nitrophenyl, p-nitrophenyl, 2,4-dinitrophenyl, 2 -Nitro-4-benzoic acid, 2-nitro-4-pyridinyl and the like. In such cases, auxiliary reagents such as mild oxidants such as hydrogen peroxide can be used to promote the formation of disulfide bonds.

  In addition, other sulfhydryl reactive group groups form a thioether bond with a sulfhydryl group. Such groups include, inter alia, maleimides, substituted maleimides, haloalkyls, epoxies, iminos, and aziridinos, as well as olefins (conjugated olefins) such as ethenesulfonyl, ethenimino, acrylate, methacrylate, and α, β unsaturated aldehydes and ketones. Is included). This sulfhydryl reactive group is particularly preferred because the thioether bond provides faster crosslinkability and longer in vivo stability.

  When X is —OH, the electrophilic functional group on the residual component needs to react with the hydroxyl group. The hydroxyl group can be activated as described above for the carboxylic acid group or reacted directly in the presence of a group with sufficient reactive electrophile such as an epoxide group, aziridine group, an alkyl halogen, or an anhydride. Can do.

  Where X is a Grignard functionality or an organometallic nucleophile such as an alkyllithium group, electrophilic functional groups suitable for reaction therewith are, by way of example, carbonyl groups including ketones and aldehydes.

  Depending on the selected reaction partner and / or reaction situation, it is understood that certain functional groups react as nucleophiles or electrophiles. For example, a carboxylic acid group reacts as a nucleophile in the presence of a fairly strong group, but usually acts as an electrophile, so a hydroxyl group with a nucleophilic attack on the carbonyl carbon and a nucleophile that flows Can be exchanged simultaneously.

The covalent chain in the cross-linked structure that results from the covalent bond between a specific nucleophilic group component and a specific electrophilic group component in the crosslinkable composition is, as an example only, but includes the following ( For the sake of enhancement, the optional linking groups Q ¹ and Q ² are omitted):

Linking group:
Functional groups X and Y and optional FN on component C are either directly attached to the compound core (R ¹ , R ² or R ³ on optional component C, respectively) or indirectly through a linking group Longer linking groups are also referred to as “chain extenders”. In structural formulas (I), (II) and (III), any linking group is denoted as Q ¹ , Q ² and Q ³ and when q, r and s are equal to 1, a linking group is present (R , X, Y, Fn, mn and p have been defined so far).

  Suitable linking groups are well known in the art. See, for example, International Patent Publication No. WO 97/22371. Linking groups are useful in avoiding the problem of steric hindrance that sometimes is associated with the formation of direct linkages between molecules. Linking groups can additionally be used to link several polyfunctionally activated compounds together to form larger molecules. In preferred embodiments, linking groups can be used to alter the degradation characteristics of the composition after administration and after consequent gel formation. For example, a linking group can be incorporated into component A, B, or optional component C to promote hydrolysis, inhibit hydrolysis, or provide enzymatic degradation to the site.

  Examples of linking groups that provide hydrolyzable moieties include, among others: ester linkages, anhydride linkages obtained by incorporation of glutarate and succinate, orthoester linkages, orthocarbonate linkages such as trimethylene carbonate, amides Chain, phosphate ester chain, α-hydroxy acid chain obtained by mixing lactic acid and glycolic acid, chain of lactone group obtained by mixing caprolactone, valerolactone, γ-butyrolactone and p-dioxanone, and dimer, oligomer Or an amide linkage present in a poly (amino acid) segment. Examples of non-degradable linking groups are succinimide, propionic acid and carboxymethylated linkage. See, for example, PCT WO99 / 07417. Examples of enzymatically degradable linkages include Leu-Gly-Pro-Ala, which is degraded by collagenase, and Gly-Pro-Lys, which is degraded by plasmin.

  Linking groups can also enhance or subdue the reactivities of various nucleophilic and electrophilic groups. For example, an electron withdrawing group that is within one or two carbons of a sulfhydryl group can be expected to reduce its effect upon binding due to a decrease in nucleophilicity. Carbon-carbon double bonds and carbonyl groups also have similar effects. Conversely, an electron withdrawing group adjacent to the carbonyl group (eg, reactive carbonyl of glitalyl-N-hydroxysuccinimidyl) increases the reactivity of the carbonyl carbon in relation to the incoming nucleophile. Let In contrast, sterically large groups around functional groups can also be used in order to reduce reactivity and thus binding rate as a result of the steric hindrance rate.

  As an example, specific linking groups and corresponding component structures are shown in the following table:

In the above table, n is usually in the range of 1 to about 10, R ⁷ is usually hydrocarbyl, usually alkyl or allyl, preferably alkyl, and most preferably lower alkyl, R ⁸ is hydrocarbylene, Heteroatom-containing hydrocarbylene, substituted hydrocarbylene, or substituted heteroatom-containing hydrocarbylene) usually alkylene or arylene (again, optionally containing substituted and / or heteroatoms), preferably low alkylene (eg: Methylene, ethylene, n-propylene, n-butylene, etc.), phenylene, or amidoalkylene (eg, — (CO) —NH—CH ₂ ).

  Other general principles to consider in connection with linking groups are: If higher molecular weight components are to be used, no more than 20,000 mol. Wt. Fragments will occur during absorption into the body Thus, it is preferable to have a biodegradable chain as described above. Furthermore, it is desirable to add sufficient charge or hydrophilicity to promote water miscibility and / or solubility. A hydrophilic group can be easily introduced using known chemical synthesis, as long as it does not cause unwanted expansion or unwanted reduction in compressive strength. In particular, the polyalkoxy segment weakens the strength of the gel.

Core of ingredients:
The “core” of each crosslinkable component consists of a molecular structure to which a nucleophilic or electrophilic group is attached. For component A the formula (I) R ^1- [Q ¹ ] _q -X) _m , for component B (II) R ² (-[Q ² ] _r -Y) _n and for any component C Is (III)
Using R ³ (— [Q ³ ] _s —Fn) _p , the “core” groups are R ¹ , R ² and R ³ . Each molecular core of the reactive component of the crosslinkable composition is typically N, O and C under the condition that at least one of the crosslinkable components A, B, and optionally C, consists of the molecular core of the synthetic hydrophilic polymer. is selected from S, hydrophilic polymers of synthetic and naturally occurring, selected hydrophobic polymer, and from C ₂ -C ₁₄ hydrocarbyl group 0-2 heteroatoms. In a preferred embodiment, at least one of A and B consists of the molecular core of a synthetic hydrophilic polymer.

Hydrophilic crosslinkable component In one embodiment, the crosslinkable component is a hydrophilic polymer. The term “hydrophilic polymer” as used herein refers to a synthetic polymer having an average molecular weight and composition that is effective in making the polymer “hydrophilic” as defined above. As explained above, synthetic crosslinkable hydrophilic polymers useful herein include, but are not limited to: polyalkylene oxides, particularly polyethylene glycols and poly (( Ethylene oxide) -poly (propylene oxide) copolymers, polyols such as glycerol, polyglycerols (especially highly branched polyglycerols), propylene glycol and trimethylene glycols substituted with one or more polyalkylene oxides, such as mono-, Di- and tri-polyoxyethylenated glycerol, mono- and di-polyethyl oxide propylene glycol, and mono- and di-polyethyl trimethylene glycol, polyethyl sorbitol, polyethylglycolate, acrylic acid polymer And their analogs and copolymers (polyacrylic acid itself, polymethacrylic acid, poly (hydroxyethyl-methacrylate), poly (hydroxyethyl acrylate), poly (methylalkyl sulfoxide methacrylate), poly (methylalkyl) Sulfoxide acrylate) and any copolymer of the preceding sentence) and / or additional acrylate active species such as aminoethyl acrylate and mono-2- (acryloxy) -ethyl succinate, polymaleic acid, polyacrylamide itself, poly (methacryl Amido), poly (dimethylacrylamide) and poly (N-isopropyl-acrylamide) and other poly (acrylamide), poly (vinyl alcohol) and other poly (olefin alcohol), poly (vinyl pyrrolidone), poly (N-vinylcaprolactam) And them Copolymer poly (N- vinyl lactams) such as poly polyoxazoline, and poly vinyl amine containing (methyl oxazoline) and poly (ethyl oxazoline). The polymers listed above are not exhaustive and a variety of other synthetic hydrophilic polymers can be used as appreciated by those skilled in the art.

  The synthetic crosslinkable hydrophilic polymer can be a homopolymer, a block copolymer, a random copolymer, or a graft copolymer. Further, the polymer may be linear or branched, and if branched, minimum to high level branched, dendritic, hyperbranched, or star polymers. Polymers include degradable segments and blocks that are distributed throughout the molecular structure of the polymer or that exist as a single block, as in block copolymers. Biodegradable segments are those that break down to break covalent bonds. Typically, a biodegradable segment is a segment that is hydrolyzed when enzymatically cleaved in the presence of water and / or in situ. The biodegradable segment is composed of small molecule segments such as an ester chain, an anhydride chain, an ortho ester chain, an ortho carbonate chain, an amide chain, and a phosphonate chain. Larger biodegradable “blocks” generally consist of oligomers or polymer segments incorporated within the hydrophilic polymer. Exemplary oligomer and polymer segments having biodegradability include, by way of example, poly (amino acid) segments, poly (orthoester) segments, poly (orthocarbonate) segments, and the like.

  Other suitable synthetic crosslinkable hydrophilic polymers are synthesized to incorporate chemically synthesized polypeptides, especially amino acids containing primary amino groups (such as lysine) and / or amino acids containing amino acid thiol groups (such as cysteine). There are polynucleophilic group polypeptides that have been produced. Poly (lysine), which is a synthetically produced polymer of the amino acid lysine (145 MW), is particularly preferred. Poly (lysine) is prepared with 6 to about 4,000 primary amino groups, corresponding to a molecular weight of about 870 to about 580,000. The poly (lysine) used in the present invention preferably has a molecular weight in the range of about 1,000 to about 300,000, more preferably in the range of about 5,000 to about 100,000, and most preferably in the range of about 8,000 to about 15,000. is there. Poly (lysine) weights of various molecules are commercially available from Peninsula Laboratories, Inc. (Belmont, Calif.).

  The synthetic crosslinkable hydrophilic polymer can be a homopolymer, a block copolymer, a random copolymer, or a graft copolymer. Further, the polymer may be linear or branched, and if branched, minimum to high level branched, dendritic, hyperbranched, or star polymers. Polymers include degradable segments and blocks that are distributed throughout the molecular structure of the polymer or that exist as a single block, as in block copolymers. Biodegradable segments are those that break down to break covalent bonds. Typically, a biodegradable segment is a segment that is hydrolyzed when enzymatically cleaved in the presence of water and / or in situ. The biodegradable segment is composed of small molecule segments such as an ester chain, an anhydride chain, an ortho ester chain, an ortho carbonate chain, an amide chain, and a phosphonate chain. Larger biodegradable “blocks” generally consist of oligomers or polymer segments incorporated within the hydrophilic polymer. Exemplary oligomer and polymer segments having biodegradability include, by way of example, poly (amino acid) segments, poly (orthoester) segments, poly (orthocarbonate) segments, and the like.

  As mentioned above, a variety of different synthetic crosslinkable hydrophilic polymers can be used in the composition, but preferred synthetic crosslinkable hydrophilic polymers are polyethylene glycol (PEG) and polyglycerol (PG), especially highly branched. Polyglycerol. Since PEG is not toxic, antigenic and immunogenic (ie biocompatible), it can be formulated with a wide range of solubility and usually does not interfere with enzyme activity and / or peptide conformation, Various forms of PEG are widely used in the modification of biologically active molecules. A particularly preferred synthetic crosslinkable hydrophilic polymer for certain applications is polyethylene glycol (PEG) having a molecular weight in the range of about 100 to about 100,000 mol. Wt., But for highly branched PEGs, biodegradable sites are incorporated. Much higher molecular weight polymers (up to 1,000,000 or more) can be used to ensure that all degradation products have a molecular weight of about 30,000 or less. However, the preferred molecular weight for most PEGs is from about 1,000 to about 20,000, more preferably in the range of about 7,500 to about 20,000. Most preferably, the polyethylene glycol molecular weight is approximately 10,000.

  Naturally occurring crosslinkable polymers include, but are not limited to: proteins such as collagen, fibronectin, albumin, globulin, fibrinogen, and fibrin (especially preferred in combination with collagen), polymannuronic acid and polygalacturonic acid, etc. Activated carboxylic acid polysaccharides, aminated polysaccharides, especially glycosaminoglycans, such as hyaluronic acid, chitin, chondroitin sulfate A, B, or C, keratin sulfate, keratonic sulfate and heparin, and dextran and starch derivatives Polysaccharides. Collagen and glycosaminoglycans are examples of naturally occurring hydrophilic polymers used herein, with methylated collagen being the preferred hydrophilic polymer.

  Any hydrophilic polymer herein must contain functional groups, ie nucleophilic groups or electrophilic groups, or be activated in order to be crosslinkable. Although PEG activation is described below, it should be understood that the following description is for illustrative purposes and similar techniques can be employed with other polymers.

  First of all, for PEG, protein modifications (Abuchowski et al., Enzymes as Drugs, John Wiley & Sons: New York, NY (1981) pp. 367-383.) And Dreborg et al., Crit. Rev. Therap. Drug Carrier Syst. (1990) 6: 315), peptide chemistry (Mutter et al., The Peptides, Academic: New York, NY. 2: 285-332, and Zalipsky et al., Int. J. Peptide Protein Res. (1987) 30: 740), and Various functionalities in areas such as the synthesis of polymeric drugs (see Zalipsky et al., Eur. Polym. J. (1983) 19: 1177. And Ouchi et al., J. Macromol. Sci. Chem. (1987) A24: 1011). Base polyethylene glycol has been used effectively.

  Active forms of PEG, including polyfunctionally activated PEG, are commercially available and can be easily prepared using known methods. For example, Poly (ethylene Glycol) Chemistry: Biotechnical and Biomedical Applications, J. Milton Harris. Chapter 22 of Plenum Press (New York) (1992). And See Shearwater Polymers, Inc. Catalog, Polyethylene Glycol Derivatives (Huntsville, Alab.) (1997-1998).

  Several structures of specific tetrafunctional PEG active forms as systemic reactive products obtained by reacting activated PEG with multi-amino PEG, i.e. PEG having two or more primary amino groups, are described in U.S. Patent No. 5,874,500. Figures 1-10 of the issue. The illustrated activated PEG has a core of pentaerythritol (2,2-bis (hydroxymethyl) -1,3-propanediol). Such activated PEG, as understood in these techniques, converts the exposed hydroxyl group (ie, the terminal hydroxyl group on the PEG chain) in a PEGylated polyol to a carboxylic acid group (usually nitrogen). N-hydroxysuccinimide, N-hydroxysulfosuccinimide, so as to give a multifunctional activated PEG, by reacting with an anhydride in the presence of a containing base This is followed by esterification with, or the like.

Hydrophobic polymer:
The crosslinkable compositions of the present invention also have hydrophobic polymers, but hydrophilic polymers are preferred for most uses. Polylactic acid and polyglycolic acid are two examples of hydrophobic polymers that can be used. Along with other hydrophobic polymers, only short-chain oligomers containing up to about 14 carbon atoms should be used to avoid problems related to solubility during the reaction.

Low molecular weight components:
As noted above, one or more molecular nuclei of the crosslinkable component also includes C ₂ -C ₁₄ containing 0 to 2 heteroatoms selected from low molecular weight compounds, ie, N, O, S, and combinations thereof. It can also be a hydrocarbyl group. Such molecular cores can be substituted with nucleophilic or electrophilic groups.

When the low molecular weight molecular core is substituted with a primary amino group, the components are, for example, ethylenediamine (H ₂ N—CH ₂ CH ₂ —NH ₂ ), tetramethylenediamine (H ₂ N— (CH ₄ ) —NH ₂ ), Pentamethylenediamine (cadaverine) (H ₂ N- (CH ₅ ) -NH ₂ ), hexamethylenediamine (H ₂ N- (CH ₆ ) -NH ₂ ), bis (2-aminoethyl) amine (HN- [CH ₂ CH ₂ —NH ₂ ] ₂ ), or tris (2-aminoethyl) amine (N— [CH ₂ CH ₂ —NH ₂ ] ₃ ).

  Low molecular weight diols and polyols include trimethylolpropane, di (trimethylolpropane), pentaerythritol, and diglycerol, all of which are activated with a base to promote their reactivity as nucleophiles. I need. Such diols and polyols can also be functionalized to provide di- and poly-carboxylic acids, the functional groups noted hereinabove as being useful as nucleophiles in certain situations. Polybases used in the composition include tricarboxylic acid based on trimethylolpropane group, tetracarboxylic acid based on di (trimethylolpropane), heptanedioic acid, octanedioic acid (suberic acid) and hexadecanedioic acid (TAPS Acid), but is not limited to this.

For low molecular weight di- and poly-electrophiles, for example, polymers include disuccinimidyl suberate (DSS), bis (sulfosuccinimidyl) suberate (BS ₃ ), dithiobis (sc Cinimidyl propionate) (DSP), bis (2-succinimidooxycarbonyloxy) ethylsulfone (BSOCOES) and 3,3'-dithiobis (sulfosuccinimidylpropionate (DTSPP) and their analogs The compounds described above are commercially available from Pierce (Rockford, Ill.), Including but not limited to derivatives, such di- and poly-electrophiles are also eg in the presence of DCC. Can be synthesized from di- and polyacids by reacting with the appropriate molar amount of N-hydroxysuccinimide at 0. Using various known techniques, trimethylolpropane and Convert the polyol and di (trimethylol propane) to a carboxylic acid, it can then be further reacted with NHS derivative in the presence of DCC, to form an activated polymer of trifunctional and tetrafunctional groups.

Delivery system:
A suitable delivery system for a homogeneous dry powder composition (containing at least two crosslinkable polymers) and two buffer solutions involve a multi-tank spray device, where one or more vessels are Including the powder, one or more baths contain the buffer solution necessary to provide an aqueous environment so that the composition is exposed to the aqueous environment as it exits the bath. Many devices adapted for multi-component tissue sealant / hemostatic agent delivery are well known in the art and can be used in the practice of the invention. Alternatively, any type of controllable extrusion system can be used to deliver the composition, or it can be delivered manually in the form of a dry powder and exposed to an aqueous environment at the site of administration.

  A homogeneous dry powder composition and two buffer solutions can be conveniently formed under aseptic conditions by placing each of the three ingredients (dry powder, acid buffer solution and base buffer solution) in separate syringes . For example, the composition, the first buffer solution and the second buffer solution can be separately contained in a multi-tank tank syringe system having a plurality of cylinders, mixing heads, and exit holes. A first buffer solution can be added to the bath containing the composition to dissolve the composition to form a homogeneous solution, which is then extruded into a mixing head. The second buffer solution can be extruded simultaneously into the mixing head. Finally, the resulting composition can then be extruded from the exit hole to the surface.

  For example, a syringe barrel containing dry powder and basic buffer can be part of a dual syringe system. (Example: Double tank syringe described in US Pat. No. 4,359,049 issued to Redl et al.) In this example, an acid buffer is added to a syringe containing dry powder to produce a homogeneous solution. To do. In other words, an acid buffer can be added (eg, injected) to a syringe containing a dry powder to produce a homogeneous solution of the first and second components. This homogeneous solution can then be extruded into the mixing head while the basic buffer is simultaneously pushed out into the mixing head. In the mixing head, the homogeneous solution and the basic buffer are mixed to form a reaction mixture. The reaction mixture can then be extruded from the exit aperture to the surface (eg, tissue) where it forms a film that can function as a sealant or barrier or the like. As soon as the reaction mixture is formed by mixing the homogeneous solution and the basic buffer with a mixing head, it begins to form a three-dimensional substrate. Thus, it is preferred that the reaction mixture be quickly extruded from the mixing head on the tissue after it has been formed so that a three-dimensional substrate can be formed on and attached to the surface.

  Other systems for the coupling of two reaction liquids are well known in the art, including US Pat. No. 6,454,786 issued to Holm et al., 6,461,325 issued to Delmotte et al., Issued to Antanavich et al. Includes systems described in 5,585,007, 5,116,315 issued to Capozzi et al., And 4,631,055 issued to Redl et al.

Storage and processing:
Since crosslinkable components containing electrophilic groups react with water, the electrophilic group components or components are usually sterilized and stored and used in dry form to prevent hydrolysis. The process for preparing synthetic hydrophilic polymers containing multiple electrophilic groups in sterile and dry form is defined in US Pat. No. 5,643,464, assigned to the assignee of the present invention and issued to Rhee et al. For example, the dry synthetic polymer can be compression molded into a thin sheet or membrane and then sterilized using gamma radiation or preferably e-beam irradiation. The resulting dried film or sheet can be cut to the desired size and chopped into smaller sized particles.

  Components containing multiple nucleophilic groups are not usually water reactions and can therefore be stored in aqueous solution. When stored as dry, particulate, solid, the various components of the crosslinkable composition can be mixed and stored in a single container. Mixing of all ingredients with water, saline or other aqueous medium should not occur until just before use.

  In another example, the crosslinkable components can be mixed in a single aqueous medium (eg, a low pH buffer) that is neither reactive. The tissue site of interest can then be sprayed with a high pH buffer, after which the components react rapidly to form a gel.

  Suitable liquid media for storage of the crosslinkable composition include aqueous solutions such as monosodium phosphate / dibasic sodium phosphate, sodium carbonate / sodium bicarbonate, glutamine hydrochloride or acetic acid at a concentration of 0.5 to 300 mM. There is a buffer solution. In general, sulfhydryl reaction components such as PEG substituted with maleimide groups or succinimidyl esters can be prepared with water or dilution buffer and the pH is 5-6. In preparing a polysulfhydryl component such as sulfhydryl-PEG, a buffer having a pKs value of about 8 to 10.5 can be used to achieve faster gelation of a composition containing a mixture of sulfhydryl-PEG and SG-PEG. Useful. These include carbonate, borohydrochloric acid and AMPSO (3-[(1,1-dimethyl-2-hydroxyethyl) amino] 2-hydroxy-propane-sulfonic acid). In contrast, using a combination of maleimidyl PEG and sulfhydryl-PEG, a pH value of 5-9 is preferred as the liquid medium used in the preparation of sulfhydryl PEG.

Collagen + fibrinogen and / or thrombin (eg Costasis)
In another embodiment, the polymer composition can include collagen in combination with fibrinogen and / or thrombin. (See US Pat. Nos. 5,290,552, 6,096,309, and 5,997,811.) For example, aqueous compositions include fibrinogen and FXIII, particularly plasma, collagen in an amount sufficient to concentrate the composition, fibrinogen present in the composition. There is a sufficient amount of anti-solvent to delay the degradation of thrombin, and Ca ²⁺ and, in some cases, the resulting adhesive clot, in a sufficient amount to catalyze the polymerization of. The composition can be prepared as a two-part composition that can be mixed immediately prior to use, where fibrinogen / FXIII and collagen are the first component, and thrombin combined with an anti-solvent, and the Ca ²⁺ second component Become.

  Plasma, the source of fibrinogen, can be obtained from a patient who is the subject to whom the composition is delivered. After standard preparation involving centrifugation of blood cell components, plasma can be used “as is”. Alternatively, the fibrinogen can be concentrated to further process the plasma and prepare a plasma cryoprecipitate. A plasma cryoprecipitate can be prepared by freezing the plasma at about -20 ° C for at least about 1 hour, and then storing the frozen plasma overnight at about 4 ° C and thawing gently. The thawed plasma is centrifuged and the plasma cryoprecipitate is collected by removing approximately 4/5 of the plasma to provide a cryoprecipitate consisting of the remaining 1/5 of the plasma. Other fibrinogen / FXIII preparations such as cryoprecipitates, patient autologous fibrin sealants, fibrinogen analogs or other single donors or commercially available fibrin sealants can be used. Approximately 0.5 ml to about 1.0 ml of plasma or plasma cryoprecipitate provides about 1-2 ml of adhesive composition, which is sufficient for use in middle ear surgery. Other plasma proteins (eg, albumin, plasminogen, von Willebrand factor, or factor VIII, etc.) may or may not be present in the fibrinogen / FXII separation because of the variety of preparation or origin methods Good.

  Collagen, preferably hypoallergenic collagen, is present in the composition in an amount sufficient to concentrate the composition and enhance the adhesive properties of the preparation. The collagen can also be atelopeptide collagen or telopeptide collagen, such as natural collagen. To further concentrate the composition, collagen enhances fibrin by acting as a macromolecular lattice or scaffold where the fibrin network is absorbed. This provides greater utility and resistance to the resulting adherent clot at lower fibrinogen concentrations compared to autologous fibrinogen adhesive preparations at various concentrations (eg, AFG).

  The collagen forms that can be employed can be described as having at least “near-natural” structural properties. Still further, unless it is not crosslinkable or is part of a composite composition (eg, bone) as a product that produces insoluble fibers having a pH value of 5 or greater, usually from a volume percentage of about 1 to 25, the diameter It is composed of a small amount that is low in the proportion of fibers of 50 nm or more, and there is almost no substantial change even if there is a change to the helical structure of the fiber. Furthermore, the collagen composition needs to enhance gelation in the surgical adhesive composition.

  A number of commercially available collagen preparations can be used. Zyderm Collagen Implant (ZCI) has a fiber diameter distribution consisting of a fiber diameter of 5-10 nm with a 90% fiber volume content and the remaining 10% of the fiber diameter exceeding about 50 nm. As a fibrous slurry and solution in isotonic saline, it is available at pH 7.2 and can be injected with a fine gauge needle. Different from ZCI, crosslinkable collagen available from Zyplast can also be employed. Zyplast is essentially an externally crosslinked (glutaraldehyde) version of ZCI. The material has a somewhat higher fiber volume content of about 50 nm in diameter and remains insoluble over a wide pH range. The crosslinkability has the effect of imitating the crosslinkability from the outside seen in many tissues in vivo.

  Thrombin serves as a catalyst to provide fibrin, an insoluble polymer, and there is a sufficient amount of composition to catalyze the polymerization of fibrinogen present in the patient's plasma. Thrombin also activates FXIII, a plasma protein that catalyzes covalent crosslinking in fibrin, making the resulting clot insoluble. Usually thrombin is present in the adhesive composition at a concentration of about 0.01 to about 1000 or more NIH unit (NIHu), usually about i to about 500 NIHu, most usually about 200 to about 500 NIHu. Exists. Thrombin can be obtained from a variety of host animal sources, conveniently bovines. Thrombin is commercially available from a variety of sources including Parke-Davis and is usually lyophilized with buffer salts and stabilizers in vials to provide thrombin activity in the range of about 1000 NIHu to 10,000 NIHu . Thrombin is usually prepared by reconstitution of the powder with the addition of either sterile diluted water or isotonic saline. Alternatively, a coagulant sourced from thrombin analogs or reptiles can be used.

  The composition may further comprise an amount of anti-solvent effective to enhance the integrity of the adherent clot during the healing process. A number of anti-solvents are well known, including aprotinin, C1-esterase inhibitors and e-amino-n-caproic acid (EACA). E-amino-n-caproic acid, the only anti-solvent approved by the FDA, has an effective concentration of the final adhesive composition of about 5 mg / ml to about 40 mg / ml, more commonly about 20 to about 30 mg / ml. EACA is commercially available as a solution having a concentration of about 250 mg / ml. Conveniently, the commercial solution is diluted with diluting water to provide the desired concentration of solution. The solution is preferably used to reconstitute lyophilized thrombin at the desired thrombin concentration.

  Other examples of in situ formed materials that can be used include those based on protein cross-linking (US Patent Nos. RE38158, 4,839,345, 5,514,379, 5,583,114, 6,458,147, 6,371,975; 5,290,552, 6,096,309, US Publication No. 2002) / 0161399, and 2001/0018598 and PCT publication numbers WO 03/090683, WO01 / 45761, WO 99/66964 and WO 96/03159).

Self-reactive compound In one embodiment, the therapeutic agent is released from a cross-linked substrate formed at least in part by the self-reactive compound. As used herein, a self-reactive compound contains a core that is substituted with at least three reactive groups. The reactive group can be attached directly to the core of the compound or indirectly attached to the core of the compound (eg, the reactive group is attached at the core via one or more linking groups).

  The three reactive groups that are necessarily present in the self-reactive compound can react with at least one of the remaining two reactive groups to effect a bond-forming reaction. For clarity, it is noted that when these compounds react to form a cross-linked substrate, the reaction of the reactive group on one compound with the reactive group on the other compound occurs most frequently. In other words, the term “self-reaction” does not necessarily mean that each self-reactive compound reacts with the compound itself, but rather these form a substrate when a plurality of identical self-reactive compounds combine to perform a crosslinking reaction. Is intended to mean that the compounds react with each other. A compound “self-reacts” in the sense that it can react with other compounds having the same chemical structure.

Self-reactive compounds consist of at least four components: a core and three reactive groups. In one example, the self-reacting compound is characterized by formula (I), where R is the core, the reactive groups are represented by X ¹ , X ² and X ³ and the linker is optional (L) And present between the core and the functional group.
Core R is a polyvalent moiety attached to at least three groups (i.e. at least trivalent), for example, hydrophilic polymers, hydrophobic polymers, amphiphilic polymers, C _2-14 hydrocarbyl or heteroatom-containing C _{2, -14} hydrocarbyl or can include these. The linking groups L ¹ , L ² , and L ³ may be the same or different. The identifiers p, q and r are either 0 (if no linker is present) or 1 (if a linker is present). The reactive groups X ¹ , X ² and X ³ may be the same or different. Each of these reactive groups reacts with at least one other reactive group to form a three-dimensional substrate. Therefore, X ¹ can react with X ² and / or X ³ , X ² with X ¹ and / or X ³ , X ³ with X ¹ and / or X ^2, etc. The trivalent core is directly or indirectly bonded to the trifunctional group, and the tetravalent core is directly or indirectly bonded to the functional group.

  Each side chain usually has one reactive group. However, the present invention also includes self-reactive compounds whose side chains have one or more reactive groups. Thus, in another embodiment of the invention, the self-reactive compound has the formula (II):

Where a and b are integers from 0 to 1, c is an integer from 3 to 12, and R ′ is a hydrophilic polymer, hydrophobic polymer, amphiphilic polymer, C _2-14 hydrocarbyl, And heteroatoms containing C _2-14 hydrocarbyl, X ′ and Y ′ are reactive groups, which may be the same or different, and L ⁴ and L ⁵ are linking groups. Each reactive group interacts with other reactive groups to form a three-dimensional substrate. The first environment provides a modified environment in which the compound is substantially non-reactive in the initial environment, but multiple autoreactive compounds react in the modified environment to form a three-dimensional substrate When exposed to modification, it becomes reactive. In one preferred embodiment, R is a hydrophilic polymer. In other preferred embodiments, X ′ is a nucleophilic group and Y ′ is an electrophilic group.

  The following self-reactive compound is an example of a compound of formula (II):

R ⁴ formula:

That is, in Formula (II), a and b are 1, c is 4, and the core R ′ is a tetrafunctional group-activated polyethylene glycol, (C (CH ₂ —O—) _4, which is a hydrophilic polymer. X ′ is succinimidyl which is an electrophilic group reactive group, Y ′ is a nucleophilic group reactive group —CH—NH ₂ , L ⁴ is —C (O) —O—, and L ⁵ is — (CH ₂ -CH ₂ -O-CH ₂ ) _x -CH ₂ -OC (O)-(CH ₂ ) _2- .

  The self-reacting compounds of the present invention are easily synthesized by techniques well known in the art. A typical synthesis is described below:

The reactive groups are selected so that the compound is not substantially reactive in the initial environment. Upon exposure to a specific modification in the initial environment, a modified environment is provided, the compound becomes reactive, and then multiple autoreactive compounds interact in the modified environment to interact in three dimensions To form a substrate. Examples of modifications in the initial environment, described in detail below, include the addition of an aqueous medium, a change in pH, exposure to ultraviolet radiation, a change in temperature or contact with a redox initiator.

The core and reactive groups can also be selected to provide compounds with one or more of the following functions: biocompatible, non-immunogenic, and toxic, inflammation at the site of administration Do not leave products that react sexually or immunogenicly. Similarly, the core and reactive groups can also be selected to provide a resulting substrate having one or more of the following functions:
In one embodiment of the invention, the autoreactive compounds interact to form a three-dimensional substrate substantially immediately or upon exposure to a modified environment. The term “substantially immediate” is intended to mean within 5 minutes, preferably within 2 minutes, and the term “immediately” is meant within 1 minute, preferably within 30 seconds.

  In one example, the autoreactive compound and the resulting substrate are not affected by enzymatic cleavage by a matrix metalloprotease such as collagenase and therefore do not degrade immediately in vivo. Furthermore, from the standpoint of selection and amount of each component, the self-reactive compound can be readily adjusted to enhance specific identification, such as compressive strength, expansion, tackiness, hydrophilicity, visibility, and the like.

  In one preferred embodiment, R is a hydrophilic polymer. In other preferred embodiments, X is a nucleophilic group, Y is an electrophilic group, and Z is either an electrophilic group or a nucleophilic group. Additional examples are described below.

  High levels of interaction, such as crosslinkability, can be useful when a less swellable substrate is desired or when increased compressive strength is desired. In these embodiments, it is desirable to have an integer of 2-12. Further, when a plurality of self-reactive compounds are used, the compounds may be the same or different.

I. Reactive groups Prior to use, store the self-reactive compound in the original environment so that the compound remains substantially non-reactive until use. At the stage of modification to this environment, the compound becomes reactive and multiple compounds interact to form the desired substrate. The initial environment as well as the modified environment is determined by the nature of the reactive group.

  The number of reactive groups may be the same or different. However, in one embodiment of the invention, the number of reactive groups is approximately equal. As used in this context, the term “approximate” means that the ratio of moles of reactive groups to moles of reactive groups is from 2: 1 to 1: 2. A 1: 1 molar ratio of reactive groups is usually preferred.

  In general, the concentration of self-reactive compounds in the modified environment is in the range of about 1-50 wt%, usually about 2-40 wt%, if it is liquid in nature. The preferred concentration of the compound in the liquid depends on a number of factors, including the type of compound (eg, type of molecular core and reactive group), molecular weight, and the end use of the resulting three-dimensional substrate. For example, the use of higher concentrations of compounds or the use of multifunctional compounds leads to the formation of cross-linked networks more closely, producing a harder and stronger gel. Therefore, compositions intended for use in tissue augmentation typically use concentrations close to the upper limit of the preferred concentration range for autoreactive compounds. Compositions intended for use as bioadhesives or in anti-adhesion need not be hard and therefore contain lower concentrations of autoreactive compounds.

1) Electrophilic group and nucleophilic group reactive group In one embodiment of the present invention, the reactive group is an electrophilic group and a nucleophilic group, which performs a nucleophilic group substitution reaction, a nucleophilic group addition reaction, or both. . The term “electrophilic group” means a reactive group that is susceptible to nucleophilic attack, ie, that reacts with an incoming nucleophilic group. The electrophilic groups in this document are positively charged or electron deficient and are usually electron deficient. The term “nucleophilic group” means a reactive group rich in electrons, has an unshared electron pair that acts as a reactive site, and reacts with a positively charged or electron deficient site. For such reactive groups, the initial modification in the environment consists of adding an aqueous medium and / or changing the pH value.

  In one embodiment of the invention, X1 (also referred to herein as X) may be a nucleophilic group, X2 (also referred to herein as Y) may be an electrophilic group or vice versa, and X3 (herein referred to as Z Also referred to as electrophilic groups or nucleophilic groups.

When Z is an electrophilic group (Z _EL ), X can be virtually any nucleophilic group as long as reaction with the electrophilic groups Y and Z can occur. Similarly, when Z is an electrophilic group (Z _NU ), Y can be virtually any nucleophilic group as long as a reaction with the electrophilic groups X and Z can occur. The only limitation is between X and Y, and X and Z _EL , or Y and Z _NU , regardless of the need for heat or the possibility of toxic or non-biodegradable reaction catalysts or other chemical reagents A practical limitation is that the reaction should occur automatically and reasonably quickly when mixed with the aqueous medium. It is preferred, but not essential, that the reaction occur without the need for ultraviolet or other radiation. In one embodiment, the reaction of either X and Y and X and Z _EL or Y and Z _NU can be completed in 60 minutes or less, preferably 30 minutes or less. Most preferably, the reaction occurs in about 5-15 minutes or less.

Examples of suitable nucleophilic groups as X or Fn _NU has the following but are not limited ^{_{to: -NH 2, -NHR 1, -N}} (R 1) 2, -SH, -OH, -COOH, - C ₆ H ₄ —OH, —H, —PH ₂ , —PHR ¹ , —P (R ¹ ) ₂ , —NH—NH ₂ , —CO—NH—NH ₂ , —C ₅ H ₄ N, and the like. Here, R ¹ is a hydrocarbyl group, and each R ¹ may be the same or different. R ¹ is usually alkyl or monocyclic allyl, preferably alkyl, with low alkyl being most preferred. Organometallic moieties are also nucleophilic groups useful for purposes of the present invention, especially those that act as carbanion donors. Examples of organometallic moieties include: Grignard function -R ⁶ MgHal (where R ² is a carbon atom (substituted or unsubstituted), Hal is halo, usually bromo, iodine or chloro, preferably bromo), Lithium-containing functionality (usually alkyl lithium groups) and sodium-containing functionality.

It is understood by those skilled in the art that certain nucleophilic groups need to be activated with a base so that they have the ability to react with electrophilic groups. For example, if nucleophilic sulfhydryls and hydroxyl groups are present in the self-reacting compound, the compound may be removed to remove the protons to allow reaction with the electrophilic group and provide a —S 2 ^— or —O 2 ^— species. Must be mixed with the aqueous base. Non-nucleophilic groups are preferred unless it is desirable for the group to participate in a crosslinking reaction. In some embodiments, groups can be present as a component of the buffer solution. Suitable bases and crosslinkable reactions are described herein.

It is necessary to select the electrophilic group provided in the self-reactive compound so that reaction with a specific nucleophilic group is possible. Therefore, when the X reactive group is an amino group, the Y group and the Z _EL group are selected to react with the amino group. Similarly, when the X reactive group is a sulfhydryl moiety, the corresponding electrophilic group is a sulfhydryl-reactive group and the like. In general, examples of electrophilic groups suitable as Y or Z _EL include -CO-Cl,-(CO) -O- (CO) -R (R is an alkyl group), -CH = CH-CH = O and _{-CH = CH-C (CH 3} ) = O, halo, -N = C = O, -N = C = S, -SO 2 CH = CH 2, -O (CO) C = CH 2, - _{O (CO) -C (CH 3} ) = CH 2, -SS- (C 5 H 4 N), - O (CO) -C (CH 2 CH 3) = CH 2, -CH = CH-C = NH , -COOH,-(CO) ON (COCH ₂ ) ₂ , -CHO,-(CO) ON (COCH ₂ ) ₂ -S (O) ₂ OH, and N (COCH) ₂ .

When X is amino (usually primary amino but not necessarily required), the electrophilic group present in Y and Z _EL is an amino reactive group. Typical amine reactive groups include, by way of example, the following groups, or radicals thereof: (1) Carboxylic esters, including cyclic esters and “activated” esters, (2) Acid chloride group (-CO-Cl), (3) Anhydride (-(CO) -O- (CO) -R), where R is an alkyl group, (4) α, β unsaturated aldehyde And ketones and aldehydes, including ketones such as CH = CH-CH = O and CH = CH-C (CH ₃ ) = O, (5) halo groups, (6) isocyanates (-N = C = O), (7) Thioisocyanate groups (-N = C = S), (8) Epoxides, (9) Activated hydroxyl groups (eg activated with conventional activators such as carbonyldiimidazole or sulfonyl chloride) ) And (10) ethenesulfonyl (—SO ₂ CH═CH ₂ ), and acrylate (—O (CO) —C═CH ₂ ), methacrylate (—O (CO) —C (CH ₃ ) = CH _2), ethyl acrylate (-O (CO) -C (CH 2 CH 3) = CH 2) And ethyleneimino olefins containing conjugated olefins such as analog functional group containing (-CH = CH-C = NH).

  In one embodiment, the amine reactive group is a carbonyl group that undergoes an electrophilic reaction that is susceptible to nucleophilic attack by primary or secondary amines, such as the carboxylic esters and aldehydes described above, and carboxyl groups (-COOH). Is included.

  Since the carboxylic acid group itself is easily affected by the reaction with the nucleophilic amine, it is necessary to activate the component containing the carboxylic acid group so that the amine reaction occurs. Activation can be accomplished in a variety of ways, but often involves reaction with a suitable hydroxyl-containing compound in the presence of a dehydrating agent such as dicyclohexylcarbodiimide (DCC) or dicyclohexyl (DHU). For example, to form a reactive electrophilic group, N-hydroxysuccinimide ester and N-hydroxysulfosuccinimide ester, respectively, carboxylic acid with alkoxy-substituted N-hydroxy-succinimide or N-hydroxysulfosuccinimide in the presence of DCC. Can be activated. To provide a reactive anhydride group, the carboxylic acid can be activated by reacting with an alkyl halogen such as acetyl chloride (eg, acetyl chloride). As a further example, a carboxylic acid can be converted to an acid chloride group using, for example, thionyl chloride or acetyl chloride, which has the ability to exchange reactions. The specific reagents and procedures used to carry out such activation reactions are well known to those skilled in the art and are described in the relevant text and literature.

Thus, in one embodiment, the amine reactive group is succinimidyl ester (—O (CO) —N (COCH ₂ ) ₂ ), sulfosuccinimidyl ester (—O (CO) —N (COCH ₂ ) ₂ — It can be selected from S (O) ₂ OH), maleimide (—N (COCH) ₂ ), epoxy, isocyanate, thioisocyanate, and ethenesulfonyl.

Similarly, when X is a sulfhydryl, the electrophilic group present in Y and Z _EL is a group that reacts with the sulfhydryl moiety. Some of these reactive groups form thioester linkages upon reaction with sulfhydryl groups, as described in WO 00/62827 issued to Wallace et al. As described in detail herein, sulfhydryl reactive groups include, but are not limited to: mixed anhydrides, ester derivatives of phosphorus, ester derivatives of p-nitrophenol, p-nitrothiophenol and pentafluoro Substituted hydroxylamine esters, including phenols, N-hydroxyphthalimide esters, N-hydroxysuccinimide esters, N-hydroxysulfosuccinimide esters, and N-hydroxyglutarimide esters, esters of 1-hydroxybenzotriazole, 3-hydroxy-3,4 -Dihydro-benzotriazin-4-one, 3-hydroxy-3,4-dihydro-quinazolin-4-one, carbonylimidazole derivatives, acid chlorides, ketenes and isocyanates. With these sulfhydryl reactive groups, auxiliary reagents can also be used to promote bond formation (eg, 1-ethyl-3- [3-diethylaminopropyl] carbodiimide to promote binding to carboxyl-containing groups) Can be used).

  In addition to the sulfhydryl reactive groups that form thioester linkages, a variety of other sulfhydryl reactive functionalities that form other types of linkages can be used. For example, a compound containing a methyl imidate derivative has a sulfhydryl group and forms an amide-thioester linkage. Alternatively, a sulfhydryl reactive group that forms a disulfide bond with a sulfhydryl group can be employed, and such a group typically has a -SS-Ar structure, where Ar is substituted or non-substituted with an electron withdrawing moiety. Substituted nitrogen-containing heteroaromatic moiety or non-heteroaromatic group substitution, Ar is for example 4-pyridinyl, o-nitrophenyl, m-nitrophenyl, p-nitrophenyl, 2,4-dinitrophenyl, 2 -Nitro-4-benzoic acid, 2-nitro-4-pyridinyl and the like. In such cases, auxiliary reagents such as mild oxidants such as hydrogen peroxide can be used to promote the formation of disulfide bonds.

  In addition, other sulfhydryl reactive group groups form a thioether bond with a sulfhydryl group. Such groups include, inter alia, maleimides, substituted maleimides, haloalkyls, epoxies, iminos, and aziridinos, as well as olefins (conjugated olefins) such as ethenesulfonyl, ethenimino, acrylate, methacrylate, and α, β unsaturated aldehydes and ketones. Is included).

  When X is —OH, the electrophilic functional group on the residual component needs to react with the hydroxyl group. The hydroxyl group can be activated as described above for the carboxylic acid group or reacted directly in the presence of a group with sufficient reactive electrophilic groups such as an epoxide group, an aziridine group, an alkyl halogen, or an anhydride. Can do.

  When X is a Grignard functionality or an organometallic nucleophilic group such as an alkyllithium group, electrophilic functional groups suitable for reaction therewith are, by way of example, carbonyl groups including ketones and aldehydes.

  Depending on the chosen reaction partner and / or reaction situation, it is understood that certain functional groups react as nucleophilic or electrophilic groups. For example, a carboxylic acid group reacts as a nucleophilic group in the presence of a fairly strong group, but usually acts as an electrophilic group, so a hydroxyl group with a nucleophilic attack on the carbonyl carbon and an incoming nucleophilic group. Can be exchanged simultaneously.

  The above as well as other examples are illustrated below, where a substrate formed by the covalent linkage of a specific nucleophilic reactive group and a specific electrophilic reactive group on a self-reactive compound. The share chain in is also shown in the table below as an example only:

For autoreactive compounds and nucleophilic group reactive groups that contain electrophilic groups, the initial environment can usually be dry and sterilized. Since the electrophilic group reacts with water, hydrolysis is prevented by sterilization and storage in a dry form. The dried synthetic polymer can be compression molded into a thin sheet or membrane and then sterilized using gamma radiation or e-beam irradiation. The resulting dried film or sheet can be cut to the desired size and chopped into smaller sized particles. The initial dry environment modification usually consists of the addition of an aqueous medium.

  In one example, the initial environment can be an aqueous medium, such as in a low pH buffer (eg, a pH value of about 6.0 or less), where both electrophilic and nucleophilic groups are not reactive. Liquid media suitable for storage of such compounds include aqueous buffer solutions such as monosodium phosphate / dibasic sodium phosphate, sodium carbonate / sodium bicarbonate, glutamine hydrochloride or acetic acid at a concentration of 0.5-300 mM. . Modification of the initial aqueous environment with a low pH value usually consists of increasing the pH value to at least pH 7.0, more preferably to increase the pH value to at least pH 9.5.

  In other examples, the modification of the dried initial environment comprises dissolving the autoreactive compound in a first buffer solution having a pH range within about 1.0 to 5.5 to form a homogeneous solution, and (ii) about 6.0 to It consists of adding a second buffer solution having a pH range of 11.0 to the homogeneous solution. The buffer solution can be an aqueous, pharmaceutically acceptable base or acid composition. The term “buffer” means, in a general sense, an acidic or basic aqueous solution, where the solution is buffered in the composition of the present invention (eg resistance to pH change by addition of acid or base). It may or may not function to provide For example, the self-reactive compound can be in the form of a homogeneous dry powder. This powder is then mixed with a buffer solution having a pH value in the range of about 1.0 to 5.5 to form a homogeneous acidic aqueous solution, which is then mixed with a buffer solution having a pH value in the range of about 6.0 to 11.0. To form a reaction solution. For example, 0.375 grams of dry powder can be mixed with 0.75 grams of acid buffer and mixed to provide a homogenous solution, where this solution is mixed with 1.1 grams of base buffer to form a three-dimensional substrate substantially immediately. A reaction mixture can be provided that forms.

  Acidic buffer solutions having a pH in the range of about 1.0 to 5.5 include, but are not limited to, the following: citric acid, hydrochloric acid, phosphoric acid, sulfuric acid, AMPSO (3-[(1,1-dimethyl- 2-hydroxyethyl) amino] 2-hydroxy-propane-sulfonic acid), acetic acid, lactic acid solution, and combinations thereof. In a preferred embodiment, the acidic buffer solution is a citric acid, hydrochloric acid, phosphoric acid, sulfuric acid solution and combinations thereof. Regardless of the exact oxidant, the acidic buffer preferably has a pH that retards the reactivity of the nucleophilic group on the core. For example, a pH value of 2.1 is usually sufficient to delay the nucleophilicity of the thiol group. A low pH is usually preferred when the core contains an amine group as the nucleophilic group. In general, an acidic buffer is an acidic solution that renders these nucleophilic groups relatively non-nucleophilic when contacted with nucleophilic groups.

  A typical acidic buffer is a hydrochloric acid solution having a concentration of about 6.3 mM and a pH in the range of 2.1-2.3. This buffer can be prepared by combining concentrated hydrochloric acid with water, ie, diluting concentrated hydrochloric acid with water. Similarly, this buffer A dilutes 1.23 grams of concentrated hydrochloric acid to a volume of 2 liters, or 1.84 grams of concentrated hydrochloric acid to a volume of 3 liters, or 2.45 grams of concentrated hydrochloric acid to a volume of 4 liters. Alternatively, the buffer can be conveniently prepared by diluting 3.07 grams concentrated hydrochloric acid to a volume of 5 liters or diluting 3.68 grams concentrated hydrochloric acid to a volume of 6 liters. For safety reasons, it is preferred to add water to the concentrated acid.

  Basic buffer solutions having a pH within the range of about 6.0 to 11.0 include, but are not limited to, glutamic acid, acetic acid, carbonate and carbonate salts (eg, sodium carbonate, sodium carbonate) Monohydrate and sodium bicarbonate), boric acid, phosphoric acid and phosphate (eg monosodium phosphate monohydrate and dibasic sodium phosphate) and combinations thereof. In a preferred embodiment, the basic buffer solution is a carbonate salt, a phosphate salt solution, and combinations thereof.

  In general, a basic buffer is one in which the nucleophilic group on the core regains its nucleophilic properties (masked by the activity of the acidic buffer) and allows the nucleophilic group to interact with the electrophilic group on the core. Or an aqueous solution that neutralizes the effect of the acidic buffer when added to a homogeneous solution of the compound and the first buffer.

  A typical basic buffer is an aqueous solution of carbonate and phosphate salts. This buffer can be prepared by mixing the base solution with saline. 34.7 g monosodium phosphate monohydrate, 49.3 g sodium carbonate monohydrate, and enough water can be combined to prepare a 2 liter solution volume of saline. Similarly, a 6 liter solution can be combined with 104.0 g monosodium phosphate monohydrate, 147.94 g sodium carbonate monohydrate, and enough water to prepare 6 liters of saline. . A basic buffer can be prepared by combining 7.2 g of sodium hydroxide with 180.0 g of water. The basic buffer is usually prepared as a mixture with the final desired pH, eg pH value 9.65-9.75, adding saline to the base solution as needed.

  In general, the base species present in the basic buffer should be sufficiently basic to neutralize the acidity provided by the acidic buffer, but not substantially to the electrophilic group on the core. Itself should not be nucleophilic enough to react. For this reason, relatively “weak” bases such as carbonate and phosphoric acid are preferred in this embodiment of the invention.

  To demonstrate the preparation of the three-dimensional substrate used in this document, a mixture of one autoreactive compound is combined with a first acidic buffer (eg acid solution, eg dilute hydrochloric acid solution) to form a homogeneous solution be able to. This homogeneous solution can be mixed with a second basic buffer (eg, a base solution, eg, an aqueous solution containing phosphate and carbonate salts), and then on the core of the self-reactive compound. The reactive groups of each of them react substantially instantaneously to form a three-dimensional substrate.

2) Redox reactive group In one embodiment of the present invention, the reactive group is a vinyl group such as a styrene derivative, which undergoes radical polymerization upon initiation by a redox initiator. The term “redox” means a reactive group that is susceptible to redox activation. The term “vinyl” is a reactive group that is activated by a redox initiator and forms radicals upon reaction. X, Y and Z may be the same or different vinyl groups, for example methacrylic groups.

  For self-reactive compounds containing vinyl reactive groups, the initial environment is usually an aqueous environment. The first environmental modification involves the addition of a redox initiator.

3) Oxidative coupling reactive group In one embodiment of the present invention, the reactive group performs an oxidative coupling reaction. For example, X, Y and Z may be a halo group such as chloro with an adjacent electron withdrawing group on a halogen-supported carbon (eg, on an “L” linking group). Typical electron withdrawing groups include nitro, allyl and the like.

  For such reactive groups, the initial modification in the environment consists of a change in pH. For example, in the presence of a base such as KOH, the self-reacting compound then undergoes dehydration and chlorocoupling reactions to form double bonds between carbon atoms as illustrated below:

For self-reactive compounds containing oxidative coupling reactive groups, the initial environment can usually be dry and sterile or a non-basic medium. The initial environmental modification usually consists of the addition of a base.

4) Photoinitiated reactive group In one embodiment of the present invention, the reactive group is a photoinitiated group. For such reactive groups, the initial modification in the environment consists of ultraviolet radiation.

In one embodiment of the present invention, X can be an azido (—N ₃ ) group, Y can be an alkyl group such as —CH (CH ₃ ) ₂ , or vice versa. Exposure to ultraviolet radiation then forms a bond between the groups to provide the following linkage: —NH—C (CH ₃ ) ₂ —CH ₂ —. In another embodiment of the present invention, X is benzophenone _{(- (C 6 H 4)} -C (O) - (C 6 H 5)) group, Y is an alkyl group such as -CH (CH _{3) 2} or, The reverse may be true. Exposure to ultraviolet radiation then forms bonds between groups to provide the following linkage:

For self-reactive compounds containing photoinitiated reactive groups, the initial environment is usually an environment that blocks ultraviolet radiation. This can be, for example, storage in a container that does not transmit ultraviolet radiation.

  Initial environmental modifications usually consist of exposure to ultraviolet radiation.

5) Temperature-sensitive reactive group In one embodiment of the present invention, the reactive group is a temperature-sensitive group, which performs a thermochemical reaction. For such reactive groups, the initial modification in the environment consists of a change in temperature. The term “temperature sensitive” means a reactive group that is chemically inert at one temperature or temperature range and reactive at a different temperature or temperature range.

  In one embodiment of the present invention, X, Y, and Z can be the same or different vinyl groups.

  For self-reactive compounds containing reactive groups that are temperature sensitive, the initial environment is usually in the range of about 10-30 ° C.

  The initial environmental modification usually consists of a temperature change in the range of about 20-40 ° C.

B. Linking group:
The reactive group can be attached directly to the core or indirectly through a linking group, and longer linking groups are also referred to as “chain extenders”. In the above formula (I), optional linker groups are denoted L ¹ , L ² , and L ³ , and a linking group is present when p, q and r are equal to 1.

  Suitable linking groups are well known in the art. See, for example, WO 97/22371 to issued to Rhee et al. Linking groups are useful in avoiding the problem of steric hindrance that sometimes is associated with the formation of direct linkages between molecules. Linking groups can additionally be used to chain several self-reactive compounds together to form larger molecules. In one example, a linking group can be used to alter the degradation characteristics of the composition after administration and subsequent gel formation. For example, a linking group can be used to promote hydrolysis, inhibit hydrolysis, or provide a site for enzymatic degradation.

  Examples of linking groups that provide hydrolyzable moieties include, among others: ester linkages, anhydride linkages obtained by incorporation of glutarate and succinate, orthoester linkages, orthocarbonate linkages such as trimethylene carbonate, amides Chain, phosphate ester chain, α-hydroxy acid chain obtained by mixing lactic acid and glycolic acid, chain of lactone group obtained by mixing caprolactone, valerolactone, γ-butyrolactone and p-dioxanone, and dimer, oligomer Or an amide linkage present in a poly (amino acid) segment. Examples of non-degradable linking groups are succinimide, propionic acid and carboxymethylated linkage. For example, see WO99 / 07417 issued to Coury et al. Examples of enzymatically degradable linkages include Leu-Gly-Pro-Ala, which is degraded by collagenase, and Gly-Pro-Lys, which is degraded by plasmin.

  Linking groups can also be included to facilitate or prevent the reactivity of various reactive groups. For example, an electron withdrawing group within one or two carbons of a sulfhydryl group is expected to reduce its effect upon binding due to a decrease in nucleophilicity. Carbon-carbon double bonds and carbonyl groups also have similar effects. Conversely, an electron withdrawing group adjacent to the carbonyl group (eg, reactive carbonyl of glaryl-N-hydroxysuccinimidyl) increases the reactivity of the carbonyl carbon relative to the incoming nucleophilic group. Let In contrast, sterically large groups around reactive groups can also be used to reduce the reactivity and hence the binding rate as a result of the steric hindrance rate.

  As an example, specific linking groups and corresponding formulas are shown in the following table:

In the table above, x is usually in the range of 1 to about 10, R ² is usually hydrocarbyl, usually alkyl or allyl, preferably alkyl, and most preferably lower alkyl, R ³ is hydrocarbylene, Heteroatom-containing hydrocarbylene, substituted hydrocarbylene, or substituted heteroatom-containing hydrocarbylene) usually alkylene or arylene (again, optionally containing substituted and / or heteroatoms), preferably low alkylene (eg: Methylene, ethylene, n-propylene, n-butylene, etc.), phenylene, or amidoalkylene (eg, — (CO) —NH—CH ₂ ).

  Other general principles to consider in connection with linking groups are: When components of higher molecular weight self-reactive compounds are to be used, it is preferable to have a biodegradable chain as described above so that fragments of 20,000 mol. Wt. Or more do not occur during absorption into the body. Furthermore, it is desirable to add sufficient charge or hydrophilicity to promote water miscibility and / or solubility. A hydrophilic group can be easily introduced using known chemical synthesis, as long as it does not cause unwanted expansion or unwanted reduction in compressive strength. In particular, the polyalkoxy segment weakens the strength of the gel.

C. Core The “core” of each self-reactive compound consists of the molecular structure to which the reactive groups are attached. The molecules can be polymers, including synthetic polymers and naturally occurring polymers. In one embodiment, the core is a polymer containing repeating monomer units. The polymer can be hydrophilic, hydrophobic or amphiphilic. The molecule can also be a low molecular weight component such as C _2-14 hydrocarbyl or a heteroatom-containing C _2-14 hydrocarbyl. The heteroatom-containing C _2-14 hydrocarbyl can have 1 or 2 heteroatoms selected from N, O and S. In a preferred embodiment, the self-reactive compound consists of a molecule of a synthetic hydrophilic polymer.

1) Hydrophilic polymer:
As mentioned above, the term “hydrophilic polymer” as used herein refers to the average molecular weight and composition selected to naturally make the polymer “hydrophilic” or the polymer as a whole hydrophilic. Means a polymer having Preferred polymers are polymers that have been purified to a high purity or highly pure state such that the polymer is pharmaceutically pure or processed to be pure. By incorporating a sufficient number of oxygen (or less frequently nitrogen) atoms that can form hydrogen bonds into the aqueous solution, most hydrophilic polymers can be made water soluble.

  The synthetic hydrophilic polymer can be a homopolymer, a block copolymer including di-block and tri-block copolymers, a random copolymer, or a graft copolymer. Further, the polymer may be linear or branched, and if branched, minimum to high level branched, dendritic, hyperbranched, or star polymers. Polymers include degradable segments and blocks that are distributed throughout the molecular structure of the polymer or that exist as a single block, as in block copolymers. The biodegradable segment is preferably degraded to break the covalent bond. Typically, a biodegradable segment is a segment that is hydrolyzed when enzymatically cleaved in the presence of water and / or in situ. The biodegradable segment is composed of small molecule segments such as an ester chain, an anhydride chain, an ortho ester chain, an ortho carbonate chain, an amide chain, and a phosphonate chain. Larger biodegradable “blocks” generally consist of oligomers or polymer segments incorporated within the hydrophilic polymer. Exemplary oligomeric and polymer segments having biodegradability include, by way of example, poly (amino acid) segments, poly (orthoester) segments, poly (orthocarbonate) segments, and the like. Other biodegradable segments that form part of the core of the hydrophilic polymer include polyesters such as polylactide, polyethers such as polyalkylene oxide, polyamides such as proteins, and polyurethanes. For example, the core of the self-reactive compound can be a diblock copolymer of tetrafunctional group activated polyethylene glycol and polylactide.

  Synthetic hydrophilic polymers useful herein include, but are not limited to: polyalkylene oxides, particularly polyethylene glycols (PEG) and poly (ethylene oxide) -poly (propylene oxide) including block and random copolymers Copolymers, polyols such as glycerol, polyglycerol (PG) and especially highly branched polyglycerols, propylene glycol, poly (oxyalkylene) -substituted diols and mono-, di- and tri-polyethyl oxide glycerol, mono- and Di-polyethyl oxide propylene glycol, and mono- and di-polyethyl trimethylene glycol, polyethyl sorbitol, polyethyl glycolate, acrylic acid polymers and their analogs and copolymers (polyacrylic acid itself, poly Tacrylic acid, poly (hydroxyethyl-methacrylate), poly (hydroxyethyl acrylate), poly (methyl alkyl sulfoxide methacrylate), poly (methyl alkyl sulfoxide acrylate) and any copolymer of the preceding sentence) and / or aminoethyl Additional acrylate active species such as acrylate and mono-2- (acryloxy) -ethyl succinate, polymaleic acid, polyacrylamide itself, poly (methacrylamide), poly (dimethylacrylamide) and poly (N-isopropyl-acrylamide) ) Such as poly (acrylamide), poly (olefin alcohol) such as poly (vinyl alcohol), poly (vinyl pyrrolidone), poly (N-vinyl caprolactam) and copolymers thereof (poly (N-vinyl lactam)), Poly (methyloxazoline) And polyoxazolines, including poly (ethyloxazoline), and polyvinylamine, and copolymers of the preamble. The polymers listed above are not exhaustive and a variety of other synthetic hydrophilic polymers can be used as appreciated by those skilled in the art.

  Those skilled in the art cannot practically prepare synthetic polymers such as polyethylene glycol to have the correct molecular weight, and the term “molecular weight” as used herein is commonly used in the art. It is understood to mean the average weight of the molecular weight of multiple molecules in any sample. Thus, 2,000 PEG samples contain a mixture of statistical polymer molecules, for example in the weight range of 1,500 to 2,500 daltons, and one molecule is somewhat different from the neighboring molecule in that range. The specification for the molecular weight range indicates that the average molecular weight is any number within the specified limits and may include molecules outside these limits. Thus, a molecular weight range of about 800 to about 20,000 indicates that the average molecular weight is at least about 800 and ranges up to about 20 kDa.

  Other suitable synthetic hydrophilic polymers include chemically synthesized polypeptides, particularly those synthesized to incorporate amino acids containing primary amino groups (such as lysine) and / or amino acids containing amino acid thiol groups (such as cysteine). There are nucleophilic group polypeptides. Poly (lysine), which is a synthetically produced polymer of the amino acid lysine (145 MW), is particularly preferred. Poly (lysine) is prepared with 6 to about 4,000 primary amino groups, corresponding to a molecular weight of about 870 to about 580,000. The poly (lysine) used in the present invention preferably has a molecular weight in the range of about 1,000 to about 300,000, more preferably in the range of about 5,000 to about 100,000, and most preferably in the range of about 8,000 to about 15,000. is there. Poly (lysine) weights of various molecules are commercially available from Peninsula Laboratories, Inc. (Belmont, Calif.).

  Despite the variety of different synthetic hydrophilic polymers that can be used in current compounds, the preferred synthetic hydrophilic polymers are PEG and PG (especially highly branched PG). Since PEG is not toxic, antigenic and immunogenic (ie biocompatible), it can be formulated with a wide range of solubility and usually does not interfere with enzyme activity and / or peptide conformation, Various forms of PEG are widely used in the modification of biologically active molecules. A particularly preferred synthetic hydrophilic polymer for certain applications is PEG with a molecular weight in the range of about 100 to about 100,000 mol. Wt., But for highly branched PEG, it provides that biodegradable sites are incorporated, Much higher molecular weight polymers can be used (up to 1,000,000 or more) to ensure that all degradation products have a molecular weight of about 30,000 or less. However, the preferred molecular weight for most PEGs is from about 1,000 to about 20,000, more preferably in the range of about 7,500 to about 20,000. Most preferably, the polyethylene glycol molecular weight is approximately 10,000.

  Naturally occurring hydrophilic polymers include, but are not limited to: proteins such as collagen, fibronectin, albumin, globulin, fibrinogen, and fibrin and thrombin (especially preferred in combination with collagen), polymannuronic acid and polygalacturon Activities such as carboxylic polysaccharides such as acids, aminated polysaccharides, especially glycosaminoglycans such as hyaluronic acid, chitin, chondroitin sulfate A, B, or C, keratin sulfate, keratosulfate and heparin, and dextran and starch derivatives Polysaccharides. Collagen and glycosaminoglycan are preferred as naturally occurring hydrophilic polymers used herein.

  Unless otherwise specified, the term “collagen” as used herein means all forms of collagen, including those that have been processed or otherwise modified. Thus, for example, collagen from any source that can be extracted and purified from human or other mammalian sources such as bovine or porcine dermis and human placenta, or produced by recombinant or other techniques. It can be used in the compounds of the present invention. Purified and substantially non-antigen collagen in solution obtained from bovine skin is well known in the art. For example, US Pat. No. 5,428,022 issued to Palefsky et al. Discloses a method for extracting and purifying collagen from human placenta, and US Pat. No. 5,667,839 issued to Berg includes transgenic bovines. A method of producing recombinant human collagen in the milk of genetically modified animals is disclosed. Expression of recombinant collagen, which is not genetically modified in yeast and other cell lines, is described in US Pat. No. 6,413,742 issued to Olsen et al., 6,428,978 issued to Olsen et al. And issued 6,653,450 to Berg et al.

  Any type of collagen can be used in the compounds of the present invention, including but not limited to type I, II, III, IV, or combinations thereof, but type I is usually preferred. Either atelopeptides or telopeptide-containing collagen can be used. However, since immunogenicity is reduced compared to telopeptide-containing collagen, atelopeptide collagen is usually preferred when collagen obtained from natural sources such as bovine collagen is used.

  Collagens previously cross-linked by methods such as heat, irradiation, or chemical crosslinkers are preferred for use in the present invention, but previously cross-linked collagen can also be used.

  The collagen used in the present invention is not necessary, but is usually an aqueous suspension at a concentration of about 20 mg / ml to about 120 mg / ml, and is about 30 mg / ml to about 90 mg / ml. ml is preferred. Although intact collagen is preferred, deformed collagen, more commonly known as gelatin, can also be used. Gelatin has the added advantage of breaking down faster than collagen.

  Usually, the use of non-fibrillar collagen in the compounds of the present invention is preferred, but fibrillar collagen can also be used. The term “non-fibrillar collagen” refers to modified or unmodified collagen that is substantially non-fibrillar (ie, molecular collagen that is not closely related to other collagen to form fibers). Usually, a solution of non-fibrillar collagen is more transparent than a solution of fibrous collagen. Types of collagen that are native and non-fibrillar (or fibril) include types IV, VI, and VII.

  Non-fibrous chemically modified collagens with neutral pH include succinylated and methylated collagens, both of which can be prepared according to the method described in US Pat. No. 4,164,559 issued to Miyata et al. . Methylated collagen contains reactive amine groups and is a preferred nucleophile-containing component in the compositions of the present invention. In another embodiment, methylated collagen is present in addition to the first and second components in the substrate formation reaction of the present invention. Methylated collagen is described, for example, in US Pat. No. 5,614,587 issued to Rhee et al.

  The collagen used in the composition of the present invention is initially fibrous and can then be rendered non-fibrous by adding one or more fiber degrading agents. As mentioned above, the fibrinolytic agent needs to be present in an amount sufficient to render it nonfibrous at pH 7 values. The fiber degrading agent used in the present invention includes, but is not limited to, various biocompatible alcohols, amino acids, inorganic salts, and carbohydrates, and biocompatible alcohols are particularly preferable. Preferred biocompatible alcohols include glycerol and propylene glycol. Non-biocompatible alcohols such as ethanol, methanol and isopropanol are not preferred for use in the present invention because of the potential for adverse effects on the recipient patient's body. A preferred amino acid is arginine. Preferred inorganic salts include sodium chloride and potassium chloride. Although carbohydrates such as various sugars, including sucrose, can be used in the practice of the present invention, they are less preferred than other types of fibrinolytic agents because they can have cytotoxic effects in vivo.

  Fibrous collagen is less preferred for use with the compounds of the present invention. However, as disclosed in U.S. Pat.No. 5,614,587 issued to Rhee et al., Fibrillar collagen, or non-fibrous and Fibrous collagen may be preferred.

2) Hydrophobic polymer:
The core of the self-reacting compound may also consist of a hydrophobic polymer containing a low molecular weight multifunctional species, but for most uses a hydrophilic polymer is preferred. In general, a “hydrophobic polymer” herein includes a relatively small portion of oxygen and / or nitrogen atoms. Preferred hydrophobic polymers used in the present invention typically have carbon chains not exceeding about 14 carbons. Polymers with carbon chains much longer than 14 carbons are usually very poorly soluble in aqueous solutions, and thus, for example, reaction times when mixed with aqueous solutions of synthetic polymers containing multiple nucleophilic groups. Become very long. Thus, the use of short chain oligomers can avoid problems related to solubility during the reaction. Polylactic acid and polyglycolic acid are two particularly suitable examples of hydrophobic polymers.

3) Amphiphilic polymers In general, amphiphilic polymers have a hydrophilic part and a hydrophobic (or lipophilic) part. In order to form the amphiphilic polymer core of the self-reactive compound, the hydrophilic part is placed at one end of the core, the hydrophobic part at the opposite end, or the hydrophilic and hydrophobic parts are random Can be distributed (random copolymers), or in the form of arrays or grafts (block copolymers). The hydrophilic and hydrophobic moieties can include any of the hydrophilic and hydrophobic polymers described above.

  Alternatively, the amphiphilic polymer core is modified with a hydrophilic polymer modified with a hydrophobic moiety (eg, an alkylated PEG or hydrophilic polymer modified with one or more fatty chains), or a hydrophilic moiety. Hydrophobic polymers (eg, “PEGylated” phospholipids such as polyethylene glycolated phospholipids).

4) Low molecular weight component:
As noted above, the molecular core of the self-reactive compound can also be a C _2-14 hydrocarbyl or a low molecular weight compound as defined herein as a heteroatom-containing C _2-14 hydrocarbyl, which includes N, O, 1-2 heteroatoms selected from S and combinations thereof are included. Any of the reactive groups described herein can replace such molecular nuclei.

Alkanes are the appropriate C _2-14 hydrocarbyl molecular core. Typical alkanes substituted with a nucleophilic primary amino group and a Y electrophilic group include ethyleneamine (H ₂ N-CH ₂ CH ₂ -Y), tetramethyleneamine (H ₂ N- (CH ₄ )- Y), pentamethylene amine _{(H 2 N- (CH 5)} -Y) and hexamethylene amines _{(H 2 N- (CH 6)} -Y) is.

Low molecular weight diols and polyols are also suitable C _2-14 hydrocarbyls, including trimethylolpropane, di (trimethylolpropane), pentaerythritol, and diglycerol. Polyacids are also suitable C _2-14 hydrocarbyls, including trimethylolpropane group tricarboxylic acid, di (trimethylolpropane) group tetracarboxylic acid, heptanedioic acid, octanedioic acid (suberic acid) and hexadecanedioic acid (tapsic acid) ) Is included.

Low molecular weight di- and poly-electrophiles are also the core molecules of suitable heteroatom-containing C _2-14 hydrocarbyls. These include, for example, polymers such as disuccinimidyl suberate (DSS), bis (sulfosuccinimidyl) suberate (BS ₃ ), dithiobis (succinimidyl propionate) (DSP) , But is not limited to, bis (2-succinimidooxycarbonyloxy) ethylsulfone (BSOCOES) and 3,3'-dithiobis (sulfosuccinimidylpropionate (DTSPP) and their analogs and derivatives It is not a thing.

  In one embodiment of the present invention, the self-reactive compound of the present invention consists of the core of a low molecular weight material having a plurality of acrylate moieties and a plurality of thiol groups.

D. Preparation Self-reactive compounds are readily synthesized and functionalized with the desired functional groups (i.e. nucleophilic and electrophilic groups) to enable crosslinkability, the core of hydrophilic, hydrophobic or amphiphilic polymers or Includes a low molecular weight core. For example, the preparation of self-reactive compounds having a polyethylene glycol (PEG) core is discussed below. However, it is to be understood that the following description is for illustrative purposes and similar techniques can be employed with other polymers.

First of all, for PEG, various functionalized PEGs are effectively used in the following areas: PEG protein modification (Abuchowski et al., Enzymes as Drugs, John Wiley & Sons: (New York New York State (1981) pp. 367-383 and Dreborg et al. (1990) Crit. Rev. Therap. Drug Carrier Syst. 6 : 315), peptide chemistry (Mutter et al., ThePeptides, Academic: (New York, NY). 2: 285-332 and Zalipsky et al. (1987) Int. J. Peptide Protein Res. 30 : 740) and the synthesis of polymeric drugs (Zalipsky et al. (1983) Eur. Polym. J. 19 : 1177. And Ouchi et al. (1987) J. Macromol. Sci. Chem. A24 : 1011).

  Functional forms of PEG, including polyfunctionalized PEG, are commercially available and can be easily prepared using known methods. See, for example, Poly (ethylene Glycol) Chemistry: Biotechnical and Biomedical Applications, J. Milton Harris, Ed., Plenum Press (New York, NY) (1992), Chapter 22.

Polyfunctionalized forms of PEG are particularly noteworthy and include PEG succinimidyl glutarate, PEG succinimidyl propionic acid, succinimidyl butyrate, PEG succinimidyl acetate, PEG succinimidyl succinamide, PEG succinimidyl carbonate, PEG propionaldehyde, PEG Examples include glycidyl group ether, PEG-isocyanate, and PEG-vinylsulfone. Many forms of such PEG are described in US Pat. Nos. 5,328,955 and 6,534,591, both issued to Rhee et al. Similarly, the various shapes of various multi-amino PEGs can be found in PEG Shop (www.sunbio.com), a division of Sun Bio in Korea, Nippon Oil & Fat Co., Ltd. (Ebisu Garden Place, 4-20-3 Ebisu, Shibuya-ku, Tokyo) Tower), Nektar Therapeutics (San Carlos, Calif., Formerly Shearwater Polymers, Huntsville, Alab.) And Huntsman's PerformanceChemicals Group (Houston, Tex.) Under the name Jeffamine ^(R) polyoxyalkyleneamine. ing. Multiamino PEGs useful in the present invention include Jeffamine diamine ("D" series) and triamine ("T" series), which contain two and three primary amino groups per molecule. The analogue poly (sulfhydryl) PEG is also available from Nektar Therapeutics (eg in the form of pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl (molecular weight 10,000)). These polyfunctionalized PEG shapes can then be modified to contain other desired reactive groups.

Reaction with a succinimidyl group to convert a terminal hydroxyl group to a reactive ester is one technique for preparing a core with an electrophilic group. This core can then be modified to contain nucleophilic groups such as primary amines, thiols, and hydroxyl groups. Other agents that convert the hydroxyl group include carbonyldiimidazole and sulfonyl chloride. However, as discussed herein, a wide range of electrophilic groups can be advantageously employed for reaction with the corresponding nucleophilic group. Examples of such electrophilic groups include conjugates such as acid chloride groups, anhydrides, ketones, aldehydes, isocyanates, isothiocyanates, epoxides, and ethenesulfonyl (—SO ₂ CH═CH ₂ ) and analog functional groups. There are olefins including olefins.

Other in-situ crosslinkable materials In accordance with the present invention, a number of other types of in-situ formed materials that can be used in combination with an anti-scarring agent have been described. In situ forming materials can be biocompatible crosslinkable polymers formed from water soluble precursors with electrophilic and nucleophilic groups with the ability to react and crosslink in situ ( Example: see US Pat. No. 6,566,406). The in situ forming material can be a hydrogel that can be formed through a combination of physical and chemical crosslinkability processes, where physical crosslinkability results in the formation of a more elastic chemical crosslinkability. Mediated by one or more natural or synthetic components that stabilize the precursor solution that forms the hydrogel at the deposition site for a sufficient period of time (see, eg, US Pat. No. 6,818,018). In situ forming materials can be formed upon exposure to an aqueous liquid from the physiological environment from the dried hydrogel precursor (see, eg, US Pat. No. 6,703,047). The in-situ formed material can be first expanded or dissolved in a relatively hydrophilic proportion of the modifier to form a mixture to release the water-soluble therapeutic agent in a controlled manner. It can be a hydrogel matrix that provides controlled release of a relatively low molecular weight therapeutic species that forms the mixture into microparticles that diffuse into the bioabsorbable hydrogel (eg, 6,632,457). The in situ forming material can be a multi-component hydrogel system (see, eg, US Pat. No. 6,379,373). The in situ forming material can be a multi-arm block copolymer comprising a central core molecule, such as a polyol residue, and at least three copolymer arms covalently bonded to the central core molecule, each polymer being It consists of an inner hydrophobic polymer segment covalently bonded to the central core molecule and an outer hydrophilic polymer segment covalently bonded to the hydrophobic polymer segment, where the hydrophobic core site is bounded by the central core molecule and the hydrophobic polymer segment. Is defined (see, for example, 6,730,334). The in-situ forming material can be a gel-forming macromer comprising at least four polymer blocks (at least two of which are hydrophobic, at least one is hydrophilic and contains crosslinkable groups) (eg, No. 6,639,014). The in situ forming material can be a water-soluble macromer comprising at least one hydrolyzable chain formed from a carbonate or dioxanone group, at least one water-soluble polymer block, and at least one polymerisable group ( See, for example, US Pat. No. 6,177,095). In situ forming materials consist of polyoxyalkylene block copolymers that form physically weak crosslinks to provide a paste-like tacky gel at physiological temperatures (eg, US Pat. No. 4,911,926). See). The in situ forming material can be a heat irreversible gel made from a polyoxyalkylene polymer and an ionic polysaccharide (see, eg, US Pat. No. 5,126,141). In situ forming materials include chitin derivatives (see, eg, US Pat. No. 5,093,319), chitosan coagulation (see, eg, US Pat. No. 4,532,134), or hyaluronic acid (see, eg, US Pat. No. 4,141,973) It can be a gel-forming composition. The in situ forming material may be an in situ alginic acid modification (see, eg, US Pat. No. 5,266,326). In situ forming materials can be formed from ethylenically unsaturated water-soluble macromers that can contact and crosslink with tissues, cells, and bioactive molecules to form gels (eg, US Pat. No. 5,573,934). See). In situ forming materials can include urethane prepolymers used in combination with unsaturated cyano compounds containing cyano groups attached to carbon atoms such as cyano (meth) acrylic acid and their esters. (See, eg, US Pat. No. 4,740,534). The in situ forming material can be a biodegradable hydrogel that polymerizes by photoinitiated free radical polymerization from water soluble macromers (see, eg, US Pat. No. 5,410,016). The in-situ forming material consists of a first portion consisting of serum albumin protein in an aqueous buffer having a pH range of about 8.0-11.0 and a water-compatible or water-soluble bifunctional crosslinker. Can be formed from a binary mixture containing a second part (see, eg, US Pat. No. 5,583,114).

  In another embodiment, in situ forming materials that can be used include those based on cross-linking of proteins. For example, the in situ forming material can be a biodegradable hydrogel composed of recombinant or natural human serum albumin and a poly (ethylene) glycol polymer solution, thus cross-linking a mechanical solution that acts as a sealant. In this step, a coating structure that is not a liquid is formed. See, for example, US Pat. Nos. 6,458,147 and 6,371,975. The in-situ forming material is two separate fibrinogen and thrombin-based substances that are diffused together to form a bioadhesive material when mixed prior to application or upon application to the site to form a fibrin sealant. It can consist of a mixture. See, for example, US Pat. No. 6,764,467. In situ forming materials can be composed of sonicated collagen and albumin that form adhesive materials that develop adhesive properties when chemically crosslinked with glutaraldehyde and amino acids or peptides. See, for example, US Pat. No. 6,310,036. The in-situ forming material is a hydrated sticky gel consisting of an aqueous solution consisting essentially of a protein with an amino group (eg gelatin, albumin) in the side chain, crosslinked with an N-hydroxyimide ester compound. It is possible. See, for example, US Pat. No. 4,839,345. The in situ forming material can be a hydrogel prepared from a protein or polysaccharide backbone (eg, albumin or polymannuronic acid) conjugated to a crosslinker (eg, a polyvalent derivative of polyethylene or polyalkylene glycol). See, for example, US Pat. No. 5,514,379. The in situ forming material may consist of a polymerizable collagen composition that is applied to the tissue and then exposed to the initiator to polymerize the collagen and close the tissue wound. See, for example, US Pat. No. 5,874,537. The in situ forming material can be a binary mixture consisting of a cross-linking agent of a protein (eg, serum albumin) and an aqueous bifunctionalized polyethylene oxide species in an aqueous buffer having a pH range of about 8.0-11.0. This transforms the liquid into a strong and flexible binding composition that plugs the tissue in situ. See, for example, US Pat. No. 5,583,114 and RE38158 and PCT Publication No. WO96 / 03159. In situ forming materials can consist of proteins, surfactants, and lipids in liquid carriers, which can be cross-linked by the addition of crosslinkers and used as in situ sealants or binders. . See, for example, US Patent Application No. 2004 / 0063613A1 and PCT Publication Nos. WO 01/45761 and WO 03/090683. The in-situ formed material can consist of two enzyme-free liquid components that are mixed by diffusing the components into the catheter tube deployed at the vascular puncture site, where the two liquid components are mixed when mixed. Chemical cross-linking forms a mechanical non-liquid matrix that plugs the vascular puncture site. See US Patent Nos. 2002 / 0161399A1 and 2001 / 0018598A1. The in situ forming material can be a cross-linked albumin composition consisting of an albumin preparation and a carbodiimide preparation mixed in conditions permitting the use of the cross-linkability of albumin as a bioadhesive material or sealant. See, for example, PCT Publication No. WO99 / 66964. In situ forming material may be formed from collagen and peroxidase and hydrogen peroxide so that the collagen crosslinks to form a semi-solid gel that plugs the wound. See, for example, PCT Publication No. WO01 / 35882.

  In another embodiment, in situ forming materials that can be used include those based on crosslinking of isocyanate or isothiocyanate capped polymers. For example, the in-situ formed material is capped with an isocyanate, which is a liquid composition that is formed into a solid adhesive film by in-situ polymerization and crosslinking upon contact with bodily fluids or tissues. Can be formed from the polymer. See, for example, PCT Publication No. WO 04/021983. The in-situ forming material can be a moisture-curing sealant composition consisting of an active isocyanate-terminated isocyanate prepolymer containing a polyol component having a molecular weight of 2,000-20,000 and an isocyanuration catalyst. See US Pat. No. 5,206,331.

In other examples, the reagent can be subjected to an electrophilic-nucleophilic reaction to produce a cross-linked substrate. Polymers containing and / or terminating nucleophilic groups such as amines, sulfhydryls, hydroxyls, -PH ₂ or CO-NH-NH ₂ are used as nucleophilic reagents and as used in peptide synthesis, etc. Polymers terminated with electrophilic groups such as carboxylic acids, aldehydes, epoxides, isocyanates, vinyls, vinyl sulfones, maleimides, -SS- (C ₅ H ₄ N) or activated esters are used as electrophilic reagents. be able to. For example, under basic conditions (pH> about 8), 4-arm thiol derivatized poly (ethylene glycol) (pentaerythritol poly (ethylene glycol) ether tetra-succinimidyl) is converted to 4-arm NHS derivatized polyethylene glycol (penta Erythritol poly (ethylene glycol) ether tetra-sulfhydryl glutarate). For representative examples of compositions that cause such electrophilic-nucleophilic bridge reactions, see U.S. Pat.Nos. 6,610,033, 6,632,457, PCT application publication numbers WO 04/060405 and WO 04/060346.

  In other examples, the electrophilic or nucleophilic terminal polymer can further constitute a polymer that can enhance the mechanical and / or adhesive properties of the in-situ forming composition. The polymer can be a biodegradable or non-biodegradable polymer. For example, the polymer can be collagen or a collagen derivative, such as methylated collagen. Examples of in situ composition formation include pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl) (4-arm thiol PEG), pentaerythritol poly (ethylene glycol) ether tetra-succinimidyl glutarate) (4- Arm NHS PEG) and methylated collagen are used as reactive reagents. The composition produces a crosslinked hydrogel when mixed with a suitable buffer. (See, eg, US Pat. Nos. 5,874,500, 6,051,648, 6,166,130, 5,565,519, and 6,312,725).

In other embodiments, reagents that can form covalent bonds with the tissue to be applied can be used. Succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, _{maleimide, -SS- (C 5 H 4 N} ) or contains an electrophilic group such as an activated ester, and / or which polymers terminated in It can be used as a reagent. For example, solid or liquid 4-arm NHS derivatized polyethylene glycol (such as pentaerythritol poly (ethylene glycol) ether tetrasuccinimidyl glutarate) can be applied to the tissue. In a preferred embodiment, polyethylene glycol derived from 4-arm NHS is applied under basic conditions (pH> about 8). Other representative examples of compositions of this nature that can be used are disclosed in PCT Publication Nos. WO 04/060405 and WO 04/060346, and US Patent Application No. 10 / 749,123.

  In other embodiments, the in situ forming material polymer can be a polyester. Polyesters that can be used in the in situ forming composition include poly (hydroxyesters). In other examples, the polyester is lactide, lactic acid, glycolide, glycolic acid, e-caprolactin, γ-caprolactin, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone, γ It can consist of the residues of one or more monomers selected from -decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one. Representative examples of these types of compositions are described in US Pat. Nos. 5,874,500, 5,936,035, 6,312,725, 6,495,127, and PCT Publication No. WO2004 / 028547 WO 2004/028547.

  In other examples, the electrophilic end polymer can be partially or completely exchanged by a small molecule or oligomer composed of electrophilic groups (eg, disuccinimidyl glutarate).

  In other examples, the nucleophilic terminal polymer can be partially or completely exchanged by small molecules or oligomers composed of nucleophilic groups (eg, dicysteine, dilysine, triidine, etc.).

  Other examples of in situ formed materials that can be used include those based on protein cross-linking (U.S. Patent Nos. RE38158, 4,839,345, 5,514,379, 5,583,114, 6,310,036, 6,458,147, 6,371,975, U.S. Publication No. 2004 / 0063613A1). , 2002 / 0161399A1, and 2001 / 0018598A1, and PCT publication numbers WO 03/090683, WO01 / 45761, WO 99/66964, and WO 96/03159) and for crosslinking of isocyanate or isothiocyanate capped polymers. Based on it (see PCT Publication No. WO04 / 021983 etc.).

  Other examples of in situ forming materials include reagents composed of one or more cyanoacrylate groups. These reagents include poly (alkyl cyanoacrylate) or poly (carboxyalkyl cyanoacrylate) (eg, poly (ethyl cyanoacrylate), poly (butyl cyanoacrylate), poly (isobutyl cyanoacrylate), poly (hexyl cyanoacrylate), Poly (methoxypropyl cyanoacrylate), and poly (octyl cyanoacrylate)) can be used to prepare.

  Examples of commercially available cyanoacrylates that can be used in the present invention include Dermabond, Indermil, Glustitch, VetBond, histoacryl, TISSUMEND, Histoacryl BLUE and Orabase SOOTHE-N-Seal LIQUID PROTECTANT.

  In other embodiments, the cyanoacrylate composition further stabilizes the reagent and / or alters the reaction rate of the cyanoacrylate and / or plasticizes the poly (cyanoacrylate) and / or degrades the poly (cyanoacrylate). It can consist of additives that change the rate. For example, trimethylene carbonate polymer or poly (ethylene glycol) oxalate polymer or ε-caprolactin group copolymer can be mixed with 2-alkoxyalkyl cyanoacrylate (eg 2-methoxypropyl cyanoacrylate). . Representative examples of these compositions are described in US Pat. Nos. 5,350,798 and 6,299,631.

  In other examples, cyanoacrylate compositions can be prepared by covering the heterochain polymer with cyanoacrylate groups. Heterochain polymers covered with cyanoacrylate preferably have at least two cyanoacrylate ester groups per chain. Heterochain polymers can be composed of absorbable poly (ester), poly (ester-carbonate), poly (ether-carbonate) and poly (ether-ester). The poly (ether-esters) described in US Pat. Nos. 5,653,992 and 5,714,159 can also be used as heterochain polymers. Triaxial poly (ε-caprolactin-co-trimethylene carbonate) is an example of a poly (ester-carbonate) that can be used. The heterochain polymer may be a polyether. Examples of polyethers that can be used include, but are not limited to, poly (ethylene glycol), poly (propylene glycol) and poly (ethylene glycol) block copolymers and poly (propylene glycol) (eg, PLURONIC F127 or F68). Not PLURONICS-based polymers). Representative examples of these compositions are described in US Pat. No. 6,699,940.

In another aspect of the invention, the biologically active anti-infective and / or fibrosis inhibitor can be delivered with a non-polymeric compound (such as a carrier). Such non-polymeric carriers include sucrose derivatives (such as sucrose acetate isobutyrate and sucrose oleate), sterols (such as cholesterol, stigmasterol, β-sitosterol, and estradiol), cholesteryl esters (such as cholesteryl stearate) , C ₁₂ -C ₂₄ fatty acids (such as lauric acid, myristic acid, palmitic acid, stearic acid, arachidic acid, behenic acid, and lignoceric acid), C ₁₈ -C ₃₆ mono-, di- and triacylglycerides (glyceryl monoole) Art, glyceryl monolinoleate, glyceryl monolaurate, glyceryl monodocosanoate, glyceryl monomyristate, glyceryl monodisenoate, glyceryl dipalmitate, glyceryl didocosanoate, glyceryl dimyristate, glyceryl di Desenoate, glyceryl tridocosanoate, glyceryl trimyristate, glyceryl tridecenoate, glycerin tristearate, and mixtures thereof, sucrose fatty acid esters (such as sucrose distearate and sucrose palmitate), sorbitan fatty acid esters (sorbitan monostearate) Alerts, such as sorbitan monopalmitate and sorbitan tristearate), C ₁₆ -C ₁₈ fatty alcohols (such as cetyl alcohol, myristyl alcohol, stearyl alcohol, and cetostearyl alcohol), esters of fatty alcohols and fatty acids (cetyl palmitate and cetea) Lille palmitate, etc.), fatty acid anhydrides (stearic anhydride, etc.), phospholipids (phosphatidylcholine (lecithin), phosphatidyl seri , Phosphatidylethanolamine, phosphatidylinositol, and lyso derivatives thereof), sphingosine and its derivatives, spingomyelin (such as stearyl, palmitoyl, and tricosanyl spingomyelin), ceramide (such as stearyl and palmitoylceramide), glycosphingolipid Lanolin, lanolin alcohols, calcium phosphate, sintered and unsintered hydroxyapatite, zeolite, and combinations and mixtures thereof.

  Representative examples of patents relating to non-molecular delivery systems and their formulations include US Pat. Nos. 5,736,152, 5,888,533, 6,120,789, 5,968,542, and 5,747,058.

  In certain embodiments of the invention, there are provided therapeutic compositions comprising (i) a fibrosis inhibitor and / or (ii) an anti-infective agent. The therapeutic composition can include one or more additional therapeutic agents (as described above), for example, anti-inflammatory agents, antithrombotic agents, and / or antiplatelet agents. Other agents that can be combined with the therapeutic composition include, for example, surfactants (eg, PLURONICS such as F-127, L-122, L-101, L-92, L-81, and L-61) There are additional ingredients such as preservatives, antioxidants and the like.

In one embodiment, the present invention provides a composition comprising i) a fiber formation inhibitor and ii) a polymer or a compound that forms a polymer in situ. The following are some (but not all) desirable fiber formation inhibitors and classes of fiber formation inhibitors that are included in the following inventive compositions:
1a. A fiber formation inhibitor that inhibits cell regeneration.
2a. An inhibitor of fiber formation in which angiogenesis is inhibited.
3a. A fibrosis inhibitor that inhibits migration of fibroblasts.
4a. A fibrogenesis inhibitor that inhibits the proliferation of fibroblasts.
5a. An inhibitor of fiber formation in which the deposition of extracellular matrix (ECM) is inhibited.
6a. A fiber formation inhibitor that inhibits tissue remodeling.
7a. A fiber formation inhibitor that is an angiogenesis inhibitor.
8a. Fiber formation inhibitors that are 5-lipoxygenase inhibitors or antagonists.
9a. A fibril formation inhibitor that is a chemokine receptor antagonist.
10a. A fiber formation inhibitor that is a cell cycle inhibitor.
11a. A fibrogenesis inhibitor that is a taxane.
12a. Fiber formation inhibitor which is a microtubule inhibitor.
13a. A fibrosis inhibitor that is paclitaxel.
14a. A fiber formation inhibitor that is a cathepsin inhibitor.
15a. A fiber formation inhibitor that is an analog or derivative of paclitaxel.
16a. Fiber formation inhibitor which is a vinca alkaloid.
17a. A fibril formation inhibitor which is camptothecin, or an analogue or derivative thereof.
18a. A fiber formation inhibitor that is podophyllotoxin.
19a. A fibrosis inhibitor which is etoposide or an analogue or derivative thereof.
20a. An anthracycline fibrogenesis inhibitor.
21a. A fibrosis inhibitor which is doxorubicin, or an analogue or derivative thereof.
22a. A fibril formation inhibitor which is mitoxantrone, or an analogue or derivative thereof.
23a. A fiber formation inhibitor which is a platinum compound.
24a. An inhibitor of fiber formation, which is nitrosourea.
25a. A fibril formation inhibitor that is nitroimidazole.
26a. Fiber formation inhibitor which is a folic acid antagonist.
27a. A fibrogenesis inhibitor that is a cytidine analog.
28a. An inhibitor of fiber formation, which is a pyrimidine analogue.
29a. A fibrogenesis inhibitor which is a fluoropyrimidine analogue.
30a. A fiber formation inhibitor that is a purine analog.
31a. A fiber formation inhibitor which is a nitrogen mustard, or an analogue or derivative thereof.
32a. A fiber formation inhibitor which is hydroxyurea.
33a. A fibrosis inhibitor that is mitomycin, or an analog or derivative thereof.
34a. Fiber formation inhibitor which is an alkyl sulfonate.
35a. A fiber formation inhibitor that is benzamide, or an analog or derivative thereof.
36a. A fiber formation inhibitor that is nicotinamide, or an analog or derivative thereof.
37a. A fiber formation inhibitor which is a halogenated sugar, or an analogue or derivative thereof.
38a. Fiber formation inhibitor which is a DNA alkylating agent.
39a. A fiber formation inhibitor that is a microtubule inhibitor.
40a. Fiber formation inhibitor which is a topoisomerase inhibitor.
41a. Fiber formation inhibitor which is a DNA cleaving agent.
42a. An anti-fibrotic drug that is an antimetabolite.
43a. An inhibitor of fiber formation in which adenosine deaminase is inhibited.
44a. A fiber formation inhibitor that inhibits purine ring synthesis.
45a. Fiber formation inhibitor which is a nucleotide conversion inhibitor.
46a. A fiber formation inhibitor that inhibits the reduction of didihydrofolic acid.
47a. An inhibitor of fiber formation in which thymidine monophosphate is suppressed.
48a. An inhibitor of fiber formation that causes DNA damage.
49a. A fiber formation inhibitor that is a DNA intercalator.
50a. Fiber formation inhibitor which is an RNA synthesis inhibitor.
51a. A fibrogenesis inhibitor that is a pyrimidine synthesis inhibitor.
52a. Fiber formation inhibitors in which ribonucleotide synthesis or function is inhibited.
53a. An inhibitor of fiber formation in which thymidine monophosphate synthesis or function is inhibited.
54a. Fiber formation inhibitor that inhibits DNA synthesis.
55a. An inhibitor of fiber formation in which DNA adduct formation occurs.
56a. Fiber formation inhibitor that inhibits protein synthesis.
57a. An inhibitor of fiber formation in which microtubule function is inhibited.
58a. A fiber formation inhibitor that is a cyclin-dependent protein kinase inhibitor.
59a. Fibrosis inhibitor which is an epidermal growth factor kinase inhibitor.
60a. Fiber formation inhibitor which is an elastase inhibitor.
61a. Fiber formation inhibitor which is a factor Xa inhibitor.
62a. A fiber formation inhibitor which is a farnesyltransferase inhibitor.
63a. A fibrinogen antagonist which is a fibrinogen antagonist.
64a. A fiber formation inhibitor which is guanylate cyclase.
65a. Fiber formation inhibitor which is a heat shock protein 90 antagonist.
66a. A fibrogenesis inhibitor which is geldanamycin, or an analogue or derivative thereof.
67a. A fiber formation inhibitor which is guanylate cyclase.
68a. A fibrogenesis inhibitor which is an HMGCoA reductase inhibitor.
69a. A fibrosis inhibitor that is simvastatin, or an analog or derivative thereof.
70a. A fiber formation inhibitor that is a hydroorotic acid dehydrogenase inhibitor.
71a. A fiber formation inhibitor which is IKK2.
72a. A fibrosis inhibitor that is an IL-1 antagonist.
73a. An inhibitor of fiber formation, which is an ICE antagonist.
74a. An inhibitor of fiber formation, which is an IRAK antagonist.
75a. A fibrosis inhibitor that is an IL-4 agonist.
76a. A fiber formation inhibitor that is an immunomodulator.
77a. A fibrogenesis inhibitor which is sirolimus, or an analogue or derivative thereof.
78a. A fiber formation inhibitor which is a nitric oxide inhibitor.
79a. A fibrogenesis inhibitor which is everolimus, or an analogue or derivative thereof.
80a. A fibrogenesis inhibitor which is tacrolimus, or an analogue or derivative thereof.
81a. A fibrogenesis inhibitor which is a TNF alpha inhibitor.
82a. A fibrosis inhibitor that is biolimus or an analogue or derivative thereof.
83a. A fibrosis inhibitor that is tresperimus or an analogue or derivative thereof.
84a. A fibrosis inhibitor that is auranofin or an analogue or derivative thereof.
85a. An inhibitor of fiber formation which is 27-0-demethylrapamycin or an analogue or derivative thereof.
86a. A fiber formation inhibitor which is gusperimus or an analogue or derivative thereof.
87a. A fibrogenesis inhibitor which is pimecrolimus or an analogue or derivative thereof.
88a. A fibrosis inhibitor which is ABT-578 or an analogue or derivative thereof.
89a. A fiber formation inhibitor which is an inosine monophosphate dehydrogenase (IMPDH) inhibitor.
90a. A fiber formation inhibitor which is mycophenolic acid or an analogue or derivative thereof.
91a. A fibrosis inhibitor which is 1-α-25 dihydroxyvitamin D ₃ or an analogue or derivative thereof.
92a. A fiber formation inhibitor that is a leukotriene inhibitor.
93a. A fiber formation inhibitor that is an MCP-1 antagonist.
94a. A fiber formation inhibitor which is an MMP inhibitor.
95a. A fiber formation inhibitor which is an NFκB inhibitor.
96a. A fibril formation inhibitor that is an NFκB inhibitor, wherein the NFκB inhibitor is Bay 11-7082.
97a. A fibrosis inhibitor that is a NO antagonist.
98a. A fibrosis inhibitor that is a p38 MAP kinase inhibitor.
99a. A fibrogenesis inhibitor that is a p38 MAP kinase inhibitor, where the p38 MAP kinase inhibitor is SB 202190.
100a. A fiber formation inhibitor which is a phosphodiesterase inhibitor.

101a. A fiber formation inhibitor which is a TGFβ inhibitor.
102a. A fibrosis inhibitor that is a thromboxane A2 antagonist.
103a. A fibrogenesis inhibitor which is a TNFα antagonist.
104a. Fiber formation inhibitor which is a TACE inhibitor.
105a. A fiber formation inhibitor that is a tyrosine kinase inhibitor.
106a. Fiber formation inhibitor which is a vitronectin inhibitor.
107a. A fibrosis inhibitor that is a fibroblast growth factor inhibitor.
108a. A fiber formation inhibitor which is a protein kinase inhibitor.
109a. A fibrogenesis inhibitor that is a PDGF receptor kinase inhibitor.
110a. A fibrosis inhibitor which is an endothelial growth factor receptor kinase inhibitor.
111a. A fiber formation inhibitor that is a retinoic acid receptor antagonist.
112a. A fibrosis inhibitor that is a platelet-derived growth factor receptor kinase inhibitor.
113a. A fibrinogen antagonist which is a fibrinogen antagonist.
114a. Fiber formation inhibitor which is an antifungal agent.
115a. A fiber formation inhibitor which is an antifungal agent and the antifungal agent is sulconizole.
116a. Fiber formation inhibitor which is bisphosphonate.
117a. A fibril formation inhibitor which is a phospholipase A1 inhibitor.
118a. A fibrosis inhibitor that is a histamine H1 / H2 / H3 receptor antagonist.
119a. A fiber formation inhibitor that is a macrolide antibiotic.
120a. A fibrosis inhibitor that is a GPIIb / IIIa receptor antagonist.
121a. A fibrosis inhibitor that is an endothelin receptor antagonist.
122a. A fibrogenesis inhibitor that is an agonist of a peroxisome proliferator-responsive receptor.
123a. Fiber formation inhibitor which is an estrogen receptor drug.
124a. An inhibitor of fiber formation, which is a somatostatin analog.
125a. A fiber formation inhibitor that is a neurokinin 1 antagonist.
126a. Fiber formation inhibitor which is a neurokinin 3 antagonist.
127a. A fibrosis inhibitor that is a VLA-4 antagonist.
128a. A fiber formation inhibitor that is a bone cell inhibitor.
129a. A fiber formation inhibitor that is a DNA topoisomerase ATP hydrolysis inhibitor.
130a. Fiber formation inhibitor which is an angiotensin I converting enzyme inhibitor.
131a. A fibrosis inhibitor that is an angiotensin II antagonist.
132a. Fiber formation inhibitor which is an enkephalinase inhibitor.
133a. Fiber formation inhibitor which is a gamma agonist insulin sensitizer of peroxisome proliferator-responsive receptor.
134a. A fiber formation inhibitor that is a protein kinase C inhibitor.
135a. A fiber formation inhibitor that is a ROCK (rho kinase) inhibitor.
136a. A fiber formation inhibitor that is a CXCR3 inhibitor.
137a. Fiber formation inhibitor which is an Itk inhibitor.
138a. A fiber formation inhibitor that is a cytosolic phospholipase A ₂ α inhibitor.
139a. A fibrosis inhibitor that is a PPAR agonist.
140a. A fiber formation inhibitor that is an immunosuppressant.
141a. A fiber formation inhibitor which is an Erb inhibitor.
142a. An inhibitor of fiber formation, which is an apoptosis agonist.
143a. A fibrogenesis inhibitor which is a lipocortin agonist.
144a. A fibrosis inhibitor that is a VCAM-1 antagonist.
145a. A fiber formation inhibitor which is a collagen antagonist.

As noted above, the present invention provides a composition comprising each of the fiber formation inhibitors or classes of fiber formation inhibitors listed in the preceding sentence 146 (i.e., 1a-145a), each comprising the following 98 (i.e. 1b-97b) polymers and compounds:
1b. Cross-linked polymer.
2b. A polymer that reacts with mammalian tissues.
3b. A polymer that is a naturally occurring polymer.
4b. A polymer that is a protein.
5b. A polymer that is a carbohydrate.
6b. A polymer that is biodegradable.
7b. A polymer that is crosslinkable and biodegradable.
8b. Polymers that are not biodegradable.
9b. Collagen.
10b. Methylated collagen.
11b. Fibrinogen.
12b. Thrombin.
13b. Albumin.
14b. Plasminogen.
15b. Von Willebrand factor.
16b. Factor VIII.
17b. Hypoallergenic collagen.
18b. Atelopeptide collagen.
19b. Telopeptide collagen.
20b. Crosslinkable collagen.
21b. Aprotinin.
22b. Gelatin.
23b. Protein conjugates.
24b. Gelatin conjugate.
25b. Hyaluronic acid.
26b. Hyaluronic acid derivative.
27b. Synthetic polymer.
28b. A polymer formed from reactants composed of synthetic isocyanine-containing compounds.
29b. Synthetic isocyanine-containing compounds.
30b. A polymer formed from a reactant and composed of a synthetic thiol-containing compound.
31b. Synthetic thiol-containing compounds.
32b. A polymer formed from a reactant composed of a synthetic compound and containing at least two thiol groups.
33b. Synthetic compounds containing at least two thiol groups.
34b. A polymer formed from reactants composed of synthetic compounds and containing at least three thiol groups.
35b. Synthetic compounds containing at least three thiol groups.
36b. A polymer formed from reactants composed of synthetic compounds and containing at least four thiol groups.
37b. Synthetic compounds containing at least four thiol groups.
38b. Polymers formed from reactants composed of synthetic amino-containing compounds.
39b. Synthetic amino-containing compounds.
40b. A polymer formed from a reactant composed of a synthetic compound and containing at least two amino groups.
41b. Synthetic compounds containing at least two amino groups.
42b. A polymer formed from reactants composed of synthetic compounds and containing at least three amino groups.
43b. Synthetic compounds containing at least three amino groups.
44b. A polymer formed from reactants composed of synthetic compounds and containing at least four amino groups.
45b. Synthetic compounds containing at least four amino groups.
46b. A polymer formed from reactants composed of synthetic compounds and consisting of carbonyl-oxygen-succinimidyl groups.
47b. Synthetic compound consisting of carbonyl-oxygen-succinimidyl group.
48b. A polymer formed of reactants composed of synthetic compounds and consisting of at least two carbonyl-oxygen-succinimidyl groups.
49b. A synthetic compound consisting of at least two carbonyl-oxygen-succinimidyl groups.
50b. A polymer formed of reactants composed of synthetic compounds and consisting of at least three carbonyl-oxygen-succinimidyl groups.
51b. A synthetic compound consisting of at least three carbonyl-oxygen-succinimidyl groups.
52b. A polymer formed of reactants composed of synthetic compounds and consisting of at least four carbonyl-oxygen-succinimidyl groups.
53b. A synthetic compound consisting of at least four carbonyl-oxygen-succinimidyl groups.
54b. A polymer formed from a reactant and composed of a synthetic polyalkylene oxide-containing compound.
55b. Synthetic polyalkylene oxide-containing compounds.
56b. A polymer formed from reactants composed of synthetic compounds and consisting of both polyalkylene oxide and biodegradable polyester blocks.
57b. A synthetic compound consisting of both polyalkylene oxide and a biodegradable polyester block.
58b. A polymer composed of a reactive poly-alkylene-containing compound and formed from a reactive substance having a reactive amino group.
59b. Synthetic polyalkylene oxide-containing compounds containing reactive amino groups.
60b. A polymer composed of a synthetic polyalkylene oxide-containing compound and formed from a reactive substance having a reactive thiol group.
61b. Synthetic polyalkylene oxide-containing compounds containing reactive thiol groups.
62b. A polymer composed of a reactive polycarbonyl-oxygen-succinimidyl group and composed of a synthetic polyalkylene oxide-containing compound.
63b. A synthetic polyalkylene oxide-containing compound containing a reactive carbonyl-oxygen-succinimidyl group.
64b. A polymer composed of biodegradable polyester blocks formed from reactants composed of synthetic compounds.
65b. A synthetic compound consisting of a biodegradable polyester block.
66b. A polymer composed of a synthetic polymer formed from reactants and formed from all or part of lactic acid or lactide.
67b. Synthetic polymers formed with all or part of lactic acid or lactide.
68b. A polymer composed of a synthetic polymer formed from reactants and formed from all or part of glycolic acid or glycolide.
69b. Synthetic polymers formed with all or part of glycolic acid or glycolide.
70b. A polymer formed from reactants and composed of polylysine.
71b. Polylysine.
72b. A polymer formed from reactants and composed of a compound consisting of (a) a protein and (b) a polyalkylene oxide.
73b. A polymer formed from reactants and composed of (a) protein and (b) polylysine.
74b. A polymer formed from reactants and composed of (a) a protein and (b) a compound having at least four thiol groups.
75b. A polymer formed from reactants and composed of (a) a protein and (b) a compound having at least four amino groups.
76b. A polymer formed from reactants and composed of (a) a protein and (b) a compound having at least four carbonyl-oxygen-succinimide groups.
77b. A polymer composed of (a) a protein and (b) a compound having a biodegradable region formed from a reactant selected from (b) lactic acid, lactide, glycolic acid, glycolide, and epsilon-caprolactone. .
78b. A polymer formed from reactants and composed of a compound consisting of (a) collagen and (b) polyalkylene oxide.
79b. A polymer formed from reactants and composed of (a) collagen and (b) polylysine.
80b. A polymer formed from reactants and composed of (a) collagen and (b) a compound having at least four thiol groups.
81b. A polymer formed from reactants and composed of (a) collagen and (b) a compound having at least four amino groups.
82b. A polymer formed from reactants and composed of (a) collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.
83b. A polymer formed from a reactant and composed of (a) collagen and (b) a compound with a biodegradable region formed from a reactant selected from lactic acid, lactide, glycolic acid, glycolide, and epsilon-caprolactone .
84b. A polymer formed from a reactant and composed of a compound comprising (a) methylated collagen and (b) polyalkylene oxide.
85b. A polymer formed from reactants and composed of (a) methylated collagen and (b) polylysine.
86b. A polymer formed from reactants and composed of (a) methylated collagen and (b) a compound having at least four thiol groups.
87b. A polymer formed from reactants and composed of (a) methylated collagen and (b) a compound having at least four amino groups.
88b. A polymer formed from reactants and composed of (a) methylated collagen and (b) a compound having at least four carbonyl-oxygen-succinimide groups.
89b. Composed of (a) methylated collagen and (b) a compound with a biodegradable region formed from a reactant selected from lactic acid, lactide, glycolic acid, glycolide, and epsilon-caprolactone. Polymer.
90b. A polymer formed from reactants and composed of hyaluronic acid.
91b. A polymer formed from a reactant and composed of a hyaluronic acid derivative.
92b. A polymer composed of pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl formed from reactants and having an average molecular weight of 3,000 to 30,000.
93b. Pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight of 3,000 to 30,000.
94b. A polymer composed of pentaerythritol poly (ethylene glycol) ether tetra-amino formed from reactants and having an average molecular weight of 3,000 to 30,000.
95b. Pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight of 3,000 to 30,000.
96b. A synthetic compound formed from a reactant, (a) having an average molecular weight of 3,000 to 30,000, comprising a polyalkylene oxide region and a plurality of nucleophilic groups, and (b) having an average molecular weight of 3,000 to 30,000, Polymer composed of a synthetic compound composed of an alkylene region and a plurality of electrophilic groups.
97b. (A) a synthetic compound having an average molecular weight of 3,000 to 30,000, comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight of 3,000 to 30,000, having an average molecular weight of 3,000 to 30,000. Synthetic compound consisting of an electronic group A mixture of synthetic compounds.

As noted above, the present invention provides compositions comprising each of the fibrosis inhibitors or classes of fibrosis inhibitors listed in the preamble 146 (1a-145a), each of which includes the preceding sentence 98 (1b-97b). Thus, in another embodiment, the invention provides the described composition of 146x98 = 14,308. In other words, each of the following is a distinct aspect of the present invention. 1a + 1b; 1a + 2b; 1a + 3b; 1a + 4b; 1a + 5b; 1a + 6b; 1a + 7b; 1a + 8b; 1a + 9b; 1a + 10b; 1a + 11b; 1a + 12b; 1a + 13b; 1a + 14b; 1a + 15b; 1a + 16b; 1a + 17b; 1a + 18b; 1a + 19b; 1a + 20b; 1a + 21b; 1a + 22b; 1a + 23b; 1a + 24b; 1a + 25b; 1a + 26b; 1a + 27b; 1a + 28b; 1a + 29b; 1a + 30b; 1a + 31b; 1a + 32b; 1a + 33b; 1a + 34b; 1a + 35b; 1a + 36b; 1a + 37b; 1a + 38b; 1a + 39b; 1a + 40b; 1a + 41b; 1a + 42b; 1a + 43b; 1a + 44b; 1a + 45b; 1a + 46b; 1a + 47b; 1a + 48b; 1a + 49b; 1a + 50b; 1a + 51b; 1a + 52b; 1a + 53b; 1a + 54b; 1a + 55b; 1a + 55b; 1a + 57b; 1a + 58b; 1a + 59b; 1a + 60b; 1a + 61b; 1a + 62b; 1a + 63b; 1a + 64b; 1a + 65b; 1a + 66b; 1a + 67b; 1a + 68b; 1a + 69b; 1a + 70b; 1a + 71b; 1a + 72b; 1a + 73b; 1a + 74b; 1a + 75b; 1a + 76b; 1a + 77b; 1a + 78b; 1a + 79b; 1a + 80b; 1a + 81b; 1a + 82b; 1a + 83b; 1a + 84b; 1a + 85b; 1a + 86b; 1a + 87b; 1a + 88b; 1a + 89b; 1a + 90b; 1a + 91b; 1a + 92b; 1a + 93b; 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50a + 79b; 50a + 80b; 50a + 81b; 50a + 82b; 50a + 83b; 50a + 84b; 50a + 85b; 50a + 86b; 50a + 87b; 50a + 88b; 50a + 89b; 50a + 90b; 50a + 91b; 50a + 92b; 50a + 93b; 50a + 94b; 50a + 95b; 50a + 96b; 50a + 97b; 51a + 1b; 51a + 2b; 5 1a + 3b; 51a + 4b; 51a + 5b; 51a + 6b; 51a + 7b; 51a + 8b; 51a + 9b; 51a + 10b; 51a + 11b; 51a + 12b; 51a + 13b; 51a + 14b; 51a + 15b; 51a + 16b; 51a + 17b; 51a + 18b; 51a + 19b; 51a + 20b; 51a + 21b; 51a + 22b; 51a + 23b; 51a + 24b; 51a + 25b; 51a + 26b; 51a + 27b; 51a + 28b; 51a + 29b; 51a + 30b; 51a + 31b; 51a + 32b; 51a + 33b; 51a + 34b; 51a + 35b; 51a + 36b; 51a + 37b; 51a + 38b; 51a + 39b; 51a + 40b; 51a + 41b; 51a + 42b; 51a + 43b; 51a + 44b; 51a + 45b; 51a + 46b; 51a + 47b; 51a + 48b; 51a + 49b; 51a + 50b; 51a + 51b; 51a + 52b; 51a + 53b; 51a + 54b; 51a + 55b; 51a + 55b; 51a + 57b; 51a + 58b; 51a + 59b; 51a + 60b; 51a + 61b; 51a + 62b; 51a + 63b; 51a + 64b; 51a + 65b; 51a + 66b; 51a + 67b; 51a + 68b; 51a + 69b; 51a + 70b; 51a + 71b; 51a + 72b; 51a + 73b; 51a + 74b; 51a + 75b; 51a + 76b; 51a + 77b; 51a + 78b; 51a + 79b; 51a + 80b; 51a + 81b; 51a + 82b; 51a + 83b; 51a + 84b; 51a + 85b; 51a + 86b; 51a + 87b; 51a + 88b; 51a + 89b; 51a + 90b; 51a + 91b; 51a + 92b; 51a + 93b; 51a + 94b; 51a + 95b; 51a + 96b; 51a + 97b; 52a + 1b; 52a + 2b; 52a + 3b; 52a + 4b; 52a + 5b; 52a + 6b; 52a + 7b; 52a + 8b; 52a + 9b; 52a + 10b; 52a + 11b; 52a + 12b; 52a + 13b; 52a + 14b; 52a + 15b; 52a + 16b; 52a + 17b; 52a + 18b; 52a + 19b; 52a + 20b; 52a + 21b; 52a + 22b; 52a + 23b; 52a + 24b; 52a + 25b; 52a + 26b; 52a + 27b; 52a + 28b; 52a + 29b; 52a + 30b; 52a + 31b; 52a + 32b; 52a + 33b; 52a + 34b; 52a + 35b; 52a + 36b; 52a + 37b; 52a + 38b; 52a + 39b; 52a + 40b; 52a + 41b; 52a + 42b; 52a + 43b; 52a + 44b; 52a + 45b; 52a + 46b; 52a + 47b; 52a + 48b; 52a + 49b; 52a + 50b; 52a + 51b; 52a + 52b; 52a + 53b; 52a + 54b; 52a + 55b; 52a + 55b; 52a + 57b; 52a + 58b; 52a + 59b; 52a + 60b; 52a + 61b; 52a + 62b; 52a + 63b; 52a + 64b; 52a + 65b; 52a + 66b; 52a + 67b; 52a + 68b; 52a + 69b; 52a + 70b; 52a + 71b; 52a + 72b; 52a + 73b; 52a + 74b; 52a + 75b; 52a + 76b; 52a + 77b; 52a + 78b; 52a + 79b; 52a + 80b; 52a + 81b; 52a + 82b; 52a + 83b; 52a + 84b; 52a + 85b; 52a + 86b; 52a + 87b; 52a + 88b; 52a + 89b; 52a + 90b; 52a + 91b; 52a + 92b; 52a + 93b; 52a + 94b; 52a + 95b; 52a + 96b; 52a + 97b; 53a + 1b; 53a + 2b; 53a + 3b; 53a + 4b; 53a + 5b; 53a + 6b; 53a + 7b; 53a + 8b; 53a + 9b; 53a + 10b; 53a + 11b; 53a + 12b; 53a + 13b; 53a + 14b; 53a + 15b; 53a + 16b; 53a + 17b; 53a + 18b; 53a + 19b; 53a + 20b; 53a + 21b; 53a + 22b; 53a + 23b; 53a + 24b; 53a + 25b; 53a + 26b; 53a + 27b; 53a + 28b; 53a + 29b; 53a + 30b; 53a + 31b; 53a + 32b; 53a + 33b; 53a + 34b; 53a + 35b; 5 3a + 36b; 53a + 37b; 53a + 38b; 53a + 39b; 53a + 40b; 53a + 41b; 53a + 42b; 53a + 43b; 53a + 44b; 53a + 45b; 53a + 46b; 53a + 47b; 53a + 48b; 53a + 49b; 53a + 50b; 53a + 51b; 53a + 52b; 53a + 53b; 53a + 54b; 53a + 55b; 53a + 55b; 53a + 57b; 53a + 58b; 53a + 59b; 53a + 60b; 53a + 61b; 53a + 62b; 53a + 63b; 53a + 64b; 53a + 65b; 53a + 66b; 53a + 67b; 53a + 68b; 53a + 69b; 53a + 70b; 53a + 71b; 53a + 72b; 53a + 73b; 53a + 74b; 53a + 75b; 53a + 76b; 53a + 77b; 53a + 78b; 53a + 79b; 53a + 80b; 53a + 81b; 53a + 82b; 53a + 83b; 53a + 84b; 53a + 85b; 53a + 86b; 53a + 87b; 53a + 88b; 53a + 89b; 53a + 90b; 53a + 91b; 53a + 92b; 53a + 93b; 53a + 94b; 53a + 95b; 53a + 96b; 53a + 97b; 54a + 1b; 54a + 2b; 54a + 3b; 54a + 4b; 54a + 5b; 54a + 6b; 54a + 7b; 54a + 8b; 54a + 9b; 54a + 10b; 54a + 11b; 54a + 12b; 54a + 13b; 54a + 14b; 54a + 15b; 54a + 16b; 54a + 17b; 54a + 18b; 54a + 19b; 54a + 20b; 54a + 21b; 54a + 22b; 54a + 23b; 54a + 24b; 54a + 25b; 54a + 54a + 27b; 54a + 29b; 54a + 29b; 54a + 31b; 54a + 32b; 54a + 33b; 54a + 34b; 54a + 35b; 54a + 36b; 54a + 37b; 54a + 38b; 54a + 39b; 54a + 40b; 54a + 41b; 54a + 42b; 54a + 43b; 54a + 44b; 54a + 45b; 54a + 46b; 54a + 47b; 54a + 48b; 54a + 49b; 54a + 50b; 54a + 51b; 54a + 52b; 54a + 53b; 54a + 54b; 54a + 55b; 54a + 55b; 54a + 57b; 54a + 58b; 54a + 59b; 54a + 60b; 54a + 61b; 54a + 62b; 54a + 63b; 54a + 64b 54a + 65b; 54a + 66b; 54a + 67b; 54a + 68b; 54a + 69b; 54a + 70b; 54a + 71b; 54a + 72b; 54a + 73b; 54a + 74b; 54a + 75b; 54a + 76b; 54a + 77b; 54a + 78b; 54a + 79b; 54a + 80b; 54a + 81b; 54a + 82b; 54a + 83b; 54a + 84b; 54a + 85b; 54a + 86b; 54a + 87b; 54a + 88b; 54a + 89b 54a + 90b; 54a + 91b; 54a + 92b; 54a + 93b; 54a + 94b; 54a + 95b; 54a + 96b; 54a + 97b; 55a + 1b; 55a + 2b; 55a + 3b; 55a + 4b; 55a + 5b; 55a + 6b; 55a + 7b; 55a + 8b; 55a + 9b; 55a + 10b; 55a + 11b; 55a + 12b; 55a + 13b; 55a + 14b; 55a + 15b; 55a + 16b; 55a + 17b 55a + 18b; 55a + 19b; 55a + 20b; 55a + 21b; 55a + 22b; 55a + 23b; 55a + 24b; 55a + 25b; 55a + 26b; 55a + 27b; 55a + 28b; 55a + 29b; 55a + 30b; 55a + 31b; 55a + 32b; 55a + 33b; 55a + 34b; 55a + 35b; 55a + 36b; 55a + 37b; 55a + 38b; 55a + 39b; 55a + 40b; 55a + 41b; 55a + 42b 55a + 43b; 55a + 44b; 55a + 45b; 55a + 46b; 55a + 47b; 55a + 48b; 55a + 49b; 55a + 50b; 55a + 51b; 55a + 52b; 55a + 53b; 55a + 54b; 55a + 55b; 55a + 55b; 55a + 57b; 55a + 58b; 55a + 59b; 55a + 60b; 55a + 61b; 55a + 62b; 55a + 63b; 55a + 64b; 55a + 65b; 55a + 66b; 55a + 67b ; 55a + 6 8b; 55a + 69b; 55a + 70b; 55a + 71b; 55a + 72b; 55a + 73b; 55a + 74b; 55a + 75b; 55a + 76b; 55a + 77b; 55a + 78b; 55a + 79b; 55a + 80b; 55a + 81b; 55a + 82b; 55a + 83b; 55a + 84b; 55a + 85b; 55a + 86b; 55a + 87b; 55a + 88b; 55a + 89b; 55a + 90b; 55a + 91b; 55a + 92b; 55a + 93b; 55a + 94b; 55a + 95b; 55a + 96b; 55a + 97b; 56a + 1b; 56a + 2b; 56a + 3b; 56a + 4b; 56a + 5b; 56a + 6b; 56a + 7b; 56a + 8b; 56a + 9b; 56a + 10b; 56a + 11b; 56a + 12b; 56a + 13b; 56a + 14b; 56a + 15b; 56a + 16b; 56a + 17b; 56a + 18b; 56a + 19b; 56a + 20b; 56a + 21b; 56a + 22b; 56a + 23b; 56a + 24b; 56a + 25b; 56a + 26b; 56a + 27b; 56a + 28b; 56a + 29b; 56a + 30b; 56a + 31b; 56a + 32b; 56a + 33b; 56a + 34b; 56a + 35b; 56a + 36b; 56a + 37b; 56a + 38b; 56a + 39b; 56a + 40b; 56a + 41b; 56a + 42b; 56a + 43b; 56a + 44b; 56a + 45b; 56a + 46b; 56a + 47b; 56a + 48b; 56a + 49b; 56a + 50b; 56a + 51b; 56a + 52b; 56a + 53b; 56a + 54b; 56a + 55b; 56a + 55b; 56a + 57b; 56a + 58b; 56a + 59b; 56a + 60b; 56a + 61b; 56a + 62b; 56a + 63b; 56a + 64b; 56a + 65b; 56a + 66b; 56a + 67b; 56a + 68b; 56a + 69b; 56a + 70b; 56a + 71b; 56a + 72b; 56a + 73b; 56a + 74b; 56a + 75b; 56a + 76b; 56a + 77b; 56a + 78b; 56a + 79b; 56a + 80b; 56a + 81b; 56a + 82b; 56a + 83b; 56a + 84 b; 56a + 85b; 56a + 86b; 56a + 87b; 56a + 88b; 56a + 89b; 56a + 90b; 56a + 91b; 56a + 92b; 56a + 93b; 56a + 94b; 56a + 95b; 56a + 96b; 56a + 97b; 57a + 1b; 57a + 2b; 57a + 3b; 57a + 4b; 57a + 5b; 57a + 6b; 57a + 7b; 57a + 8b; 57a + 9b; 57a + 10b; 57a + 11b; 57a + 12b; 57a + 13b; 57a + 14b; 57a + 15b; 57a + 16b; 57a + 17b; 57a + 18b; 57a + 19b; 57a + 20b; 57a + 21b; 57a + 22b; 57a + 23b; 57a + 24b; 57a + 25b; 57a + 26b; 57a + 27b; 57a + 28b; 57a + 29b; 57a + 30b; 57a + 31b; 57a + 32b; 57a + 33b; 57a + 34b; 57a + 35b; 57a + 36b; 57a + 37b; 57a + 38b; 57a + 39b; 57a + 40b; 57a + 41b; 57a + 42b; 57a + 43b; 57a + 44b; 57a + 45b; 57a + 46b; 57a + 47b; 57a + 48b; 57a + 49b; 57a + 50b; 57a + 51b; 57a + 52b; 57a + 53b; 57a + 54b; 57a + 55b; 57a + 55b; 57a + 57b; 57a + 58b; 57a + 59b; 57a + 60b; 57a + 61b; 57a + 62b; 57a + 63b; 57a + 64b; 57a + 65b; 57a + 66b; 57a + 67b; 57a + 68b; 57a + 69b; 57a + 70b; 57a + 71b; 57a + 72b; 57a + 73b; 57a + 74b; 57a + 75b; 57a + 76b; 57a + 77b; 57a + 78b; 57a + 79b; 57a + 80b; 57a + 81b; 57a + 82b; 57a + 83b; 57a + 84b; 57a + 85b; 57a + 86b; 57a + 87b; 57a + 88b; 57a + 89b; 57a + 90b; 57a + 91b; 57a + 92b; 57a + 93b; 57a + 94b; 57a + 95b; 57a + 96b; 57a + 97b; 58a + 1b; 58a + 2b; 58a + 3b 58a + 4b; 58a + 5b; 58a + 6b; 58a + 7b; 58a + 8b; 58a + 9b; 58a + 10b; 58a + 11b; 58a + 12b; 58a + 13b; 58a + 14b; 58a + 15b; 58a + 16b; 58a + 17b; 58a + 18b; 58a + 19b; 58a + 20b; 58a + 21b; 58a + 22b; 58a + 23b; 58a + 24b; 58a + 25b; 58a + 26b; 58a + 27b; 58a + 28b 58a + 29b; 58a + 30b; 58a + 31b; 58a + 32b; 58a + 33b; 58a + 34b; 58a + 35b; 58a + 36b; 58a + 37b; 58a + 38b; 58a + 39b; 58a + 40b; 58a + 41b; 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59a + 2b; 59a + 3b; 59a + 4b; 59a + 5b; 59a + 6b; 59a + 7b; 59a + 8b; 59a + 9b; 59a + 10b; 59a + 11b; 59a + 12b; 59a + 13b; 59a + 14b; 59a + 15b; 59a + 16b; 59a + 17b; 59a + 18b; 59a + 19b; 59a + 20b; 59a + 21b; 59a + 22b; 59a + 23b; 59a + 24b; 59a + 25b; 59a + 26b; 59a + 27b; 59a + 28b; 59a + 29b; 59a + 30b; 59a + 31b; 59a + 32b; 59a + 33b; 59a + 34b; 59a + 35b; 59a + 36b; 59a + 37b; 59a + 38b; 59a + 39b; 59a + 40b; 59a + 41b; 59a + 42b; 59a + 43b; 59a + 44b; 59a + 45b; 59a + 46b; 59a + 47b; 59a + 48b; 59a + 49b; 59a + 50b; 59a + 51b; 59a + 52b; 59a + 53b; 59a + 54b; 59a + 55b; 59a + 55b; 59a + 57b; 59a + 58b; 59a + 59b; 59a + 60b; 59a + 61b; 59a + 62b; 59a + 63b; 59a + 64b; 59a + 65b; 59a + 66b; 59a + 67b; 59a + 68b; 59a + 69b; 59a + 70b; 59a + 71b; 59a + 72b; 59a + 73b; 59a + 74b; 59a + 75b; 59a + 76b; 59a + 77b; 59a + 78b; 59a + 79b; 59a + 80b; 59a + 81b; 59a + 82b; 59a + 83b; 59a + 84b; 59a + 85b; 59a + 86b; 59a + 87b; 59a + 88b; 59a + 89b; 59a + 90b; 59a + 91b; 59a + 92b; 59a + 93b; 59a + 94b; 59a + 95b; 59a + 96b; 59a + 97b; 60a + 1b; 60a + 2b; 60a + 3b; 60a + 4b; 60a + 5b; 60a + 6b; 60a + 7b; 60a + 8b; 60a + 9b; 60a + 10b; 60a + 11b; 60a + 12b; 60a + 13b; 60a + 14b; 60a + 15b; 60a + 16b; 60a + 17b; 60a + 18 b; 60a + 19b; 60a + 20b; 60a + 21b; 60a + 22b; 60a + 23b; 60a + 24b; 60a + 25b; 60a + 26b; 60a + 27b; 60a + 28b; 60a + 29b; 60a + 30b; 60a + 31b; 60a + 32b; 60a + 33b; 60a + 34b; 60a + 35b; 60a + 36b; 60a + 37b; 60a + 38b; 60a + 39b; 60a + 40b; 60a + 41b; 60a + 42b; 60a + 43b; 60a + 44b; 60a + 45b; 60a + 46b; 60a + 47b; 60a + 48b; 60a + 49b; 60a + 50b; 60a + 51b; 60a + 52b; 60a + 53b; 60a + 54b; 60a + 55b; 60a + 55b; 60a + 57b; 60a + 58b; 60a + 59b; 60a + 60b; 60a + 61b; 60a + 62b; 60a + 63b; 60a + 64b; 60a + 65b; 60a + 66b; 60a + 67b; 60a + 68b; 60a + 69b; 60a + 70b; 60a + 71b; 60a + 72b; 60a + 73b; 60a + 74b; 60a + 75b; 60a + 76b; 60a + 77b; 60a + 78b; 60a + 79b; 60a + 80b; 60a + 81b; 60a + 82b; 60a + 83b; 60a + 84b; 60a + 85b; 60a + 86b; 60a + 87b; 60a + 88b; 60a + 89b; 60a + 90b; 60a + 91b; 60a + 92b; 60a + 93b; 60a + 94b; 60a + 95b; 60a + 96b; 60a + 97b;

  Within certain embodiments of the present invention, the therapeutic composition also consists of a radiopaque sonogenic material and a magnetic resonance imaging (MRI) reactive material (eg, an MRI contrast agent) and ultrasound. Visualization of the composition under fluoroscopy and / or MRI can be assisted. For example, the composition can be (eg: powdered tantalum, tungsten, barium carbonate, bismuth oxide, barium sulfate, metrazimide, iopamidol, iohexol, iopromide, iobitridol, iomeprol, iopentol, ioversol, ioxirane, iodixanol, iotrolane, acetozolic acid derivatives , Diatrizoic acid derivatives, iotalamic acid derivatives, ioxitalamic acid derivatives, metrizoic acid derivatives, iodamides, lipophilic agents, iodopamides, and production of radiopaque materials, or microspheres that present sound absorbing surfaces Or it may be sonication (by addition of foam) or radiopaque. For visualization under MRI, a contrast agent (eg, gadolinium (III) chelate or iron oxide compound) can be incorporated into the composition.

  Alternatively, the composition can be further visualized under visible light using fluorescence or other spectroscopic means. Visualizing agents that can be included for this purpose include dyes, pigments, and other colorants. In one embodiment, the composition can further include a colorant to improve visualization of the composition in vivo and ex vivo. In most cases, visualization of the composition once delivered to the host is difficult, especially at the edge of the graft or tissue. Coloring agents can be incorporated into the composition to reduce or eliminate the occurrence or severity of this problem. Colorants provide the composition with a unique color, higher contrast, and a unique fluorescent color. In one embodiment, a composition is provided that contains a color that is readily visible (under visible light or using fluorescent techniques) and is easily distinguishable from the graft site. In another embodiment, the liquid or semi-solid composition can contain a colorant. For example, when one component composed of a mixture of two components is mixed in vitro or in vivo, the mixture can be colored so that the mixture is sufficiently colored.

  Coloring agents are, for example, endogenous compounds (eg amino acids or vitamins) or nutrients or foods, and can also be hydrophobic or hydrophilic compounds. Preferably, at the concentration used, the colorant has very little or no toxicity. Other preferred are colorants that are normally taken into the body through safe and absorption, such as β-carotene. Representative examples of colored nutrients (under visible light) include fat-soluble vitamins such as vitamin A (yellow), water-soluble vitamins such as vitamin B12 (pink-red) and folic acid (yellow-orange), β-carotene There are carotenoids such as (yellow-purple) and lycopene (red). Other examples of colorants include natural product (berry and fruit) extracts such as anthocyanins (purple) and saffron extracts (dark red). The colorant can be α-tocopherol quinol (vitamin E derivative) or L-tryptophan fluorescent or phosphorescent compound.

  In one embodiment, the compositions of the present invention also include one or more colorants, also called dyes, present in an effective amount that provides an observable color scheme for compositions such as gels. Examples of colorants include food-friendly dyes known as FD & C dyes, and natural coloring such as grape skin extract, red beetroot powder, beta-carotene, annatto, carmine, turmeric, paprika, etc. There is an agent. Derivatives, analogs, and isomers of the above colored compounds can also be used. The manner in which the colorant is incorporated into the implant or therapeutic composition varies depending on the colorant's characteristics and the desired location. For example, a hydrophobic colorant can be selected for a hydrophobic substrate. Coloring agents can be mixed into carrier substrates such as micelles. Furthermore, the pH value of the environment can be controlled to further control the color and its degree.

  In one embodiment, the composition of the present invention includes one or more preservatives or bacteriostatic agents present in an amount effective to protect the composition and / or inhibit bacterial growth within the composition. Agents such as bismuth tribromophenolate, methylhydroxybenzoic acid, bacitracin, ethylhydroxybenzoic acid, propylhydroxybenzoic acid, erythromycin, chlorocresol, benzalkonium chloride, and the like. Examples of preservatives include paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydrated acetic acid, sorbic acid and the like. In one embodiment, the composition of the present invention has one or more bactericidal (also known as bactericidal) agents.

  In one embodiment, the composition of the present invention has one or more antioxidants included in an effective amount. Examples of antioxidants are sulfites, α-tocopherol, β-carotene and ascorbic acid.

  Furthermore, the therapeutic composition of the present invention should preferably have a stable lifetime of at least several months and can be manufactured and maintained under sterile conditions. The composition can be sterilized by being prepared in a sterile environment and / or sterilized at the end using methods known in the art. A combination of these methods can also be used to prepare the composition in sterile form. Sterilization can also occur at the end using gamma radiation or electron beam sterilization methods.

  In one embodiment, the compounds and compositions of the invention are sterilized. Many pharmaceuticals are manufactured in sterile form, and this standard is defined in USP XXII <1211>. The term “USP” means the United States Pharmacopeia (see U.S. Pharmacopeia, www.usp.org, Rockville, MD). Sterilization in this example can be accomplished by a number of methods recognized in the industry and listed in USPXXII <1211>, including gas sterilization, ionizing radiation, and, where appropriate, filtration. Sterilization can be maintained in a way that the term aseptic processing is used, which is also defined in USPXXII <1211>. An acceptable gas used for gas sterilization is ethylene oxide. Acceptable radiation types used in ionizing radiation methods include gamma (eg, cobalt 60 source) and electron beams. The normal projection amount of gamma radiation is 2.5MRad. Filtration can be accomplished with a suitable material filter of polytetrafluoroethylene (such as Teflon, E.I. DuPont De Nemoursand Company (such as Wilmington, Del.)) With a suitable pore size (such as 0.22 μm).

  In another aspect, the composition of the present invention is encapsulated in a container for use for its intended purpose (ie, as a component of a drug). Important container characteristics include the ability to add water or other aqueous media, such as saline, and acceptable light transmission characteristics to prevent damage to the composition in the container by light energy (See USP XXII <661>), acceptable limit of extract in container material (see USP XXII), moisture (see USP XXII <671>) or acceptable barrier ability to oxygen. In the case of oxygen permeation, this can be controlled by including in the container a positive pressure of an inert gas such as high purity nitrogen or a rare gas such as argon.

  Common materials used in the manufacture of pharmaceutical containers include USP Type I-III and Type NP glass (see USP XXII <661>), polyethylene, Teflon, silicone and gray butyl rubber. For parenteral drugs, USPTypes I-III glass and polyethylene are preferred.

E. Methods Using Compositions The compositions of the present invention can be used in a variety of ways. For example, the composition comprises (a) prevention of tissue adhesion, (b) treatment or prevention of inflammatory arthritis, (c) prevention of cartilage loss, (d) treatment or prevention of hypertrophic scar / keloid, (e) Can be used for the treatment or prevention of vascular diseases and (f) medical devices and graft coatings. Some specific applications are described in detail below.

Adhesion prevention Adhesion prevention provides a device for use in preventing adhesions (surgical adhesion). The polymer composition has one or more pharmacologically active agents (such as anti-scarring agents), providing a pharmacological alternative to cellular and / or non-cellular processes involved in the growth and / or progression of surgical adhesions To do. Pharmacologically active agents have been described that can reduce surgical adhesions by inhibiting the formation of fibrous or scar tissue. In another aspect, the present invention provides a surgical adhesion barrier comprising a scarring inhibitor or a composition comprising a scarring inhibitor.

  Surgical adhesions are abnormal, fibrous bands of scar tissue, formed in the body as a result of the treatment process, including abdomen, gynecology, heart, spinal cord, plastic, blood vessels, ENT, ophthalmology, urine, nerves, orthopedics, and laparotomy Or a minimally invasive surgical procedure follows. Surgical adhesions are generally connective tissue structures formed between adjacent sites of injury within the body. Briefly, the site of injury causes an inflammatory and healing response that eventually leads to healing and scar tissue formation. When the scarring causes the attachment of the fibrous tissue band or adjacent anatomy (separable), the formation of a surgical adhesion is said to have occurred. Bonding ranges from thin, easily separable structures to dense, tough fibrous structures that can only be separated by surgical dissection. Although many adhesions are benign, some cause significant clinical problems and some are the primary cause of repeated surgical procedures. Because surgical trauma related to adhesion dissociation repeats the entire process, adhesion dissociation surgery (adhesion detachment) often fails and results in recurrence. Surgical dissection of adhesions is a serious clinical problem, and it is estimated that 473,000 adhesion detachments were performed in the United States in 2002. According to the DRG (diagnostic group classification), hospital charges charged for these treatments are estimated to be at least $ 10 billion annually.

  Because all procedures involve some degree of trauma to the surgical tissue, almost all procedures (including those that have been performed successfully) have the potential to cause clinically significant adhesion formation. Adhesions can be caused by surgical trauma such as incisions, manipulations, withdrawals or sutures, and from inflammation, infection (such as fungi and mycobacteria), bleeding or the presence of foreign bodies. Surgical trauma can also result from tissue desiccation, ischemia, or thermal damage. Due to the various causes of surgical adhesions, the operation is by so-called minimally invasive (catheter-based therapy, laparoscopic procedures, etc.) or by standard laparotomy techniques involving one or more relatively large incisions There is a possibility of formation regardless of whether or not. While surgical procedures have potential complexity, surgical adhesions include GI surgery (causing intestinal obstruction), gynecological surgery (causing pain and / or infertility), tendon repair (shortening and flexion deformity). Cause), joint capsule treatment (causing capsule contractures), and nerve and muscle repair procedures (causing loss and loss of function).

  Surgical adhesions can cause various, often serious and unpredictable clinical complications, some of which only appear several years after the completion of the original procedure. Surgical adhesion complications are a major cause of surgical failure and are a major cause of bowel obstruction and infertility. Other adhesion-related complications include chronic back and pelvic pain, bowel obstruction, urethral obstruction, and dysuria. To remove postoperative complications caused by adhesions, it is usually necessary to perform another operation. However, the next operation is further complicated by the adhesions formed as a result of the previous operation. In addition, the second operation causes further adhesions and is likely to be accompanied by surgical complications.

  The placement of medical devices and grafts also increases the risk of surgical adhesions. In addition to the above mechanism, if the immune system recognizes the graft as foreign, the implanted device can generate a “foreign” reaction that results in an inflammatory response, followed by the formation of scar tissue. is there. The particular form of foreign body response corresponding to the placement of the medical device is completely encapsulated (“walled off”) in the scar tissue coating (encapsulation). Fiber coating of implanted devices and grafts can complicate the procedure, but breast and breast reconstruction surgery, joint replacement surgery, hernia repair surgery, artificial blood vessel graft surgery, stent placement, and brain surgery Are particularly prone to this complication. In each case, the graft is coated with a fibrous connective tissue coating to fully perform the function of the surgical graft (breast augmentation implant, artificial joint, surgical mesh, vascular graft, stainless steel or dural patch). Missing or losing.

  Adhesions usually form within the first few days after surgery. In general, adhesion formation is an inflammatory response, releasing various factors and increasing vascular permeability, resulting in fibrinogen influx and fibrin deposition. This accumulation forms groups that crosslink adjacent tissues. Fibroblasts accumulate, attach to the group, deposit collagen, and induce angiogenesis. If this filming phenomenon is prevented within 4-5 days after surgery, adhesion formation is inhibited.

  Various models of adhesion prevention were discussed, including (1) prevention of fibrin deposition, (2) reduction of local tissue inflammation, and (3) removal of fibrin deposition. Fibrin deposition is prevented through the use of a physical barrier that is mechanical or a physical barrier consisting of a sticky solution. Barriers have the advantage of physically preventing adjacent tissues from contacting each other, thereby reducing the possibility of scarring each other. Many investigators and commercial products use anti-adhesion barriers, but there are countless technical difficulties and considerable defect rates have been reported. Inflammation is reduced by the administration of drugs such as corticosteroids and non-steroidal anti-inflammatory drugs. However, the use of these drugs in animal models has not been facilitated by dose limitations due to the extent of the inflammatory response and systemic side effects. Finally, the removal of fibrin deposition was investigated using proteolytic and fibrinolytic enzymes. The clinical use of these enzymes has potential complications and can cause a large amount of bleeding after surgery (surgical hemostasis is important for successful treatment).

  Many polymer compositions (such as surgical adhesion barriers) can be used alone or in combination with one or more anti-scarring agents in the practice of the present invention to prevent surgical adhesions. It should be noted that certain polymer compositions themselves can prevent the formation of fibrous tissue at the surgical site. In certain embodiments, the polymer composition can form a barrier between tissue surfaces and organs.

  For example, a surgical adhesion barrier can be coated on a tissue surface and is a hydrophilic polymeric material having a molecular weight of 50,000 or more and a concentration ranging from 0.01 to 15% by weight (eg, a polypeptide or polysaccharide). ). See US Pat. No. 6,464,970. The surgical adhesion barrier can be a crosslinkable system having at least three reactive compounds, each having a polymeric nucleus with at least one functional group. See US Pat. No. 6,458,889. The surgical adhesion barrier can be composed of a polyoxyalkylene composition that does not gel, with or without a therapeutic agent. See US Pat. No. 6,436,425. The surgical adhesion barrier can be composed of an anionic polymer with an acid sulfate and sulfur content of 5% or more to prevent monocyte or macrophage invasion. See US Pat. No. 6,417,173. The surgical adhesion barrier may be an aqueous composition comprising a surfactant, pentoxyphyllin and a polyoxyalkylene polyether. See US Pat. No. 6,399,624. Surgical adhesion barriers are two cross-linked syntheses, one with a nucleophilic group and the other with an electrophilic group, so that a usable substrate is formed to incorporate a biologically active compound. It can be composed of a polymer. See U.S. Patent Nos. 6,323,278, 6,166,130, 6,051,648, and 5,874,500. The surgical adhesion barrier can be composed of a hyaluronic acid composition, as described in US Pat. Nos. 6,723,709, 6,531,147, and 6,464,970. The surgical adhesion barrier may be a coating of polymer tissue formed by applying a polymerization initiator to the tissue and then covering with a water soluble macromer that can be polymerized using free radicals under the influence of ultraviolet light. See U.S. Patent Nos. 6,177,095 and 6,083,524. The surgical adhesion barrier is composed of a fluid prepolymer material that is emitted to the tissue surface and then exposed to activation energy in situ to initiate conversion of the applied material to a non-fluid polymer shape. You can also. See U.S. Patent Nos. 6,004,547 and 5,612,050. Surgical adhesion barriers may be hydrogel-forming copolymers, self-solvent copolymers and absorbable polyester copolymers that can be selectively and partially associated with dependent hydrogel populations upon contact with an aqueous environment. See US Pat. No. 5,612,052. Surgical adhesion barriers are anionic polymers that are effective in inhibiting cell invasion and fiber formation (eg, dermatan sulfate, dextran sulfate, pentosan polysulfide, or alginate), and pharmacologically effective carriers that are semi-solid It may be a carrier. See U.S. Patent Nos. 6,756,362, 6,127,348 and 5,994,325. The surgical adhesion barrier may be an acidified hydrogel consisting of carboxypolysaccharides and a polyether having a pH in the range of about 2.0 to about 6.0. See US Pat. No. 6,017,301. The surgical adhesion barrier is used to inhibit neurite by-products and can consist of dextran sulfate with a molecular weight of about 40,000 to 500,000 daltons. See US Pat. No. 5,705,178. The surgical adhesion barrier may be a fragmented biocompatible hydrogel that is at least partially hydrated and substantially free of aqueous phase, wherein the hydrogel is composed of gelatin and is absorbed when delivered to a wet tissue target site. See U.S. Patent No. 6,066,325. The surgical adhesion barrier may be a water-soluble, biodegradable macromer consisting of at least two crosslinkable substituents and crosslinks to other macromers at localized sites when under the influence of a polymerization initiator. See US Pat. No. 6,465,001. The surgical adhesion barrier may be a biocompatible adhesive composition consisting of at least one acrylic ester cyanoacrylate monomer and a polymerization initiator or accelerator. See US Pat. No. 6,620,846.

In one embodiment, polymers that can form covalent bonds with the tissue to be applied can be used. Succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, _{maleimide, -SS- (C 5 H 4 N} ) or contains an electrophilic group such as an activated ester, and / or which polymers terminated in It can be used as a reagent. For example, solid or liquid 4-arm NHS derivatized polyethylene glycol (such as pentaerythritol poly (ethylene glycol) ether tetrasuccinimidyl glutarate) can be applied to the tissue. In this example, 4-arm NHS derivatized polyethylene glycol is dissolved in an acidic solution (pH about 2-3) and then applied simultaneously to the tissue using a basic buffer (pH> about 8). The fiber formation inhibitor can be incorporated directly into either 4-arm NHS derivatized polyethylene glycol, acidic solution or basic buffer. In another example, the fiber formation inhibitor can be incorporated into a second carrier, and the second monomer can be incorporated into a 4-arm NHS derivatized polyethylene glycol, an acidic solution, and / or a basic buffer. The second simple substance may include fine particles and / or fine particles made of a biodegradable polymer. Biodegradable polymers include polyesters (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, can be composed of residues of one or more monomers selected from trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one), and XY , YXY, R- (YX) _n , R- (XY) _n and XYX block polymers are included. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.), and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASFCorporation (Mount Olive, NJ), Y is biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, etc.) From the residue of one or more monomers selected from γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one What can be configured, such as PLG-PEG-PLG), R is a multifunctional initiator.

In another example, the tissue-reactive polymer can be applied first and then the fiber formation inhibitor can be applied to the coated tissue. The fiber formation inhibitor can be applied directly to the tissue or mixed into the second simple substance. The second carrier includes fine particles (as described above), fine particles (as described above), gel (hyaluronic acid, carboxymethyl cellulose, dextran, poly (ethylene oxide) -poly (propylene oxide) block copolymer, mixture, association, Cross-linked composition, etc.), film (biodegradable polyester, lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone , Γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one can be composed of one or more monomer residues And block polymers having the structures XY, YXY, R- (YX) _n , R- (XY) _n and XYX. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.), and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASFCorporation (Mount Olive, NJ), Y is biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, etc.) From the residue of one or more monomers selected from γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one Can be constructed (PLG-PEG-PLG, etc.), R is a multifunctional initiator, hyaluronic acid, potassium Bo carboxymethylcellulose, dextran, poly (ethylene oxide) - poly (propylene oxide) block copolymers, mixtures, federation, a crosslinked composition.

  Preferred polymeric substrates that can be used alone or in combination with a fiber formation inhibitor / composition to prevent the formation of fibrous tissue include pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl (4 Arm thiol PEG, containing a structure with a linking group between the ends of the sulfhydryl group and the polyethylene glycol backbone) and pentaerythritol poly (ethylene glycol) ether tetra-succinimidyl glutarate (plus NHS group and polyethylene glycol backbone) Formed from reactants consisting of either or both of 4-arm NHS PE), including structures with linking groups between the ends. Another preferred composition is pentaerythritol poly (ethylene glycol) ether tetraamino] (4 arm amino PEG as a reactive reagent, including a structure having a linking group between the amino group and the end of the polyethylene glycol backbone) and Pentaerythritol poly (ethylene glycol) ether tetra-succinimidyl glutarate] (further including a structure with a linking group between the NHS group and the end of the polyethylene glycol backbone, 4 arm NHS PEG). The chemical structure of these reactants is shown, for example, in US Pat. No. 5,874,500. Depending on the situation, collagen or a collagen derivative (eg methylated collagen) is added to a reactant containing poly (ethylene glycol) to form a preferred cross-linked substrate or independent composition that functions as a polymeric carrier for therapeutic agents. And helps prevent the formation of fibrous tissue.

  Surgical adhesion barriers that can be combined with one or more anti-scarring agents according to the present invention include commercially available products. Examples of surgical adhesion barrier compositions that can incorporate fiber forming agents include the following. (a) Sprayable collagen-containing formulations such as COSTASIS or CT3 (Angiotech Pharmaceuticals, Inc., Canada), (b) COSEAL or ADHIBIT (Angiotech Pharmaceuticals, Inc.), SPRAYGEL or DURASEAL (both Confluent Surgical, Inc., Sprayable PEG-containing formulations such as Focalseal (Genzyme Corporation, Cambridge, Mass.), (C) RESTYLANE or PERLANE (both Q-Med AB, Sweden), HYLAFORM (Inamed Corporation, Santa Barbara, CA) Hyaluronic acid-containing preparations such as SYNVISC (Biomatrix, Inc., Ridgefield, NJ), SEPRAFILM or SEPRACOAT (both Genzyme Corporation), (d) fibrinogens such as FLOSEAL or TISSEAL (both Baxter Healthcare Corporation, Fremont, CA) Containing formulation, (e) REPEL (Life Medical Sciences, Inc. (Princeton, Jersey) or polymer gels such as FLOWGEL (Baxter Healthcare Corporation, Deerfield, Ill.), (F) Dermabond (Johnson & Johnson, Inc. New Brunswick, NJ), Indermil (US Surgical Company, Norwalk, Connecticut), Glustitch (Blacklock Medical Products Inc., Canada), Tissumend (Veterinary Products Laboratories, Phoenix, Arizona), VetBond (3M Company, St. Paul, MN), HistoacrylBLUE (Davis & Geck, St. Louis, MO) and OrabaseSoothe-N-Seal Liquid Protectant Surgical adhesive-containing cyanoacrylates such as (Colgate-Palmolive Company, New York, NY), (g) Dextran sulfate gels such as the Adcon product family (available at Wright Medical Technology, Inc., Arlington, Tennessee), (h) Lipid-based suites such as ADSURF (Britannia Pharmaceuticals Ltd., UK) Things and (j) INTERCEED (Ethicon, Inc., Somerville, NJ) and HYDROSORB (MacroPore Biosurgery, Inc., California San Diego / Medtronic Sofamor Danek, Memphis, Tennessee) film compositions such.

  For clarity, some specific uses and treatment details are described, including:

i) Spinal and neurosurgical anti-adhesion back pain is the leading cause of healthcare spending in the US and costs over $ 50 billion annually ($ 100 billion globally). More than 12 million people in the United States have some form of degenerative disc disease (DDD), of which 10% (1.2 million) may require surgery to correct this problem.

  In healthy individuals, the spinal column is made up of vertebral plates separated by an intervertebral disc that forms a strong joint and absorbs spinal cord compression during movement. The intervertebral disc consists of a gel-like internal substance called the nucleus pulposus surrounded by a strong fibrocartilage capsule called annulus fibrosus. The nucleus pulposus is composed of a loose framework of collagen fibrils and connective tissue cells (similar to fibroblasts and chondrocytes) embedded in a gelatin matrix of glycosaminoglycans and water. The annulus is composed of a number of concentric circles of fibrocartilage that are fixed to the vertebral body. The most common cause of DDD is the formation of locally weakened annulus fissures that allow the nucleus pulposus and annulus to rise to the spinal canal and / or spinal canal, hernia formation or ossification Occurs when Raised or herniated discs often compress nerve tissue such as spinal fibers or spinal nerve root fibers. Compression of the spinal cord or nerve root with an injured disc often results in neurological dysfunction (numbness, weakness, tingling sensation), catastrophic pain, rectal or bladder disorders and can cause long-term disability. Although many causes of DDD are resolved naturally, a significant number of patients can be treated with minimally invasive treatment, microscopic hernia removal, major surgical removal of the disc, spinal fusion surgery (with a variety of techniques and devices). Surgical procedures in the form of fixation of the adjacent vertebral plate used) and / or artificial disc implantation are required. The present invention provides for the application or adhesion of adhesion inhibitors or fibrosis inhibitors in the surgical treatment of DDD.

  Resection of the spinal disc is essential and urgent in cauda equina syndrome when there are significant neurological deficits, especially rectal or bladder disorders. It can also be done selectively to relieve pain and eliminate inferior neurological symptoms. The spinal nerve roots exit the spinal canal through the bony spinal canal (a hole in the bone between the upper and lower vertebrae), the common site of nerve constriction. In order to access the spinal foramen during lumbar surgery, vertebral tissue is often removed by a process known as laminectomy.

  For laparotomy (laminectomy) of a ruptured disc or mixed spinal nerve root canal, the patient is placed in a modified mid-lumbar position under general anesthesia. An incision is made in the posterior midline, the tissue is excised to expose the appropriate space, the ligamentum flavum is excised, and in some cases a portion of the bone membrane is removed to allow sufficient visualization. Carefully retract the nerve root to expose herniated fragments and ring defects. Usually, the disc cavity opens from a rupture in the annulus, and a loose section of the nucleus pulposus is removed with a pituitary forceps. Also, carefully remove additional sections of the intervertebral disc isolated from the inside and outside of the disc space and forcefully irrigate the disc space to remove all remaining sections. If a rupture is present in the dura, the dura is closed with sutures often augmented with fibrin glue. The tissue is then closed with absorbable sutures.

  Microlumbar discectomy (microscopic herniation) can be performed as an outpatient surgery and is a significant replacement for laminectomy as an option for disc herniation or radical strangulation. A 1-inch incision is made from the spinous process above the affected disc to the lower spinous process. Using a surgical microscope, an incision is made into the yellow ligament and the bone is removed from the membrane until the nerve root can be clearly identified. Carefully retract the nerve root so that the rupture in the annulus can be seen with a magnifying glass. A microdisc forceps is used to remove the disc section through an annular rupture, and the isolated disc section is also removed. Similar to laminectomy, the disc space is irrigated to remove the disc segment, any dura rupture is repaired, and the tissue is closed with absorbable sutures. It should be noted that an anterior (abdominal) approach can also be used in both laparotomy and endoscopic discectomy. Cervical and thoracic discectomy is similar to lumbar surgery, and posterior discectomy can also be performed by a posterior approach (in combination with laminectomy) or in conjunction with fixation.

  In lumbar surgery, such as laminectomy, discectomy, and microscopic herniation, the spinal dura is often exposed and left unprotected. As a result, scar tissue is often formed between the dura mater and the surrounding tissue. This scar is formed from a damaged spine and overlays the laminectomy site. As a result, adhesions occur between the muscle tissue and the brittle dura, which reduces the fluidity of the spinal cord and the nerve roots that exit the spinal cord, resulting in pain, persistent neurological symptoms, and postoperative recovery delay. Connected. Similarly, adhesions that occur in epidural and dural tissues cause complications in cases of spinal cord injury (eg, compression and crush trauma). Furthermore, intradural and perineural scarring and adhesion formation have been implicated in performing subsequent (corrected and repeated) spinal surgery, which is technically more difficult to perform.

  In order to avoid the occurrence of adhesions, a scar reducing barrier is inserted between the dural sleeve and the paravertebral muscle tissue after laminectomy. Alternatively (or in addition), alone or in a fibrosis inhibitor, the adhesion barrier can be removed from the spinal nerve where the spinal nerve exits the spinal canal and crosses the space between the vertebrae (i.e., the laminectomy site). Can be coated on top (or penetrate the surrounding tissue). This reduces the invasion of cells and blood vessels into the epidural space from overlying muscles and exposed cancellous bone, thereby complications associated with the vessel housing, spinal cord and / or nerve roots Is reduced. In microscopic herniactomy, it is important to be able to deliver the barrier as a spray, gel or liquid substance and administer it through the delivery port of the endoscope. Again, either alone or included in a fibrosis inhibitor, spray the adhesion barrier over the spinal nerve where the spinal nerve exits the spinal canal and crosses the space between the vertebrae (i.e., the laminectomy site). Can invade the surrounding tissue). The present invention discloses a barrier composition, used alone or in combination with a fibrosis inhibitor, to directly use special delivery catheters, endoscopes, or needles during discectomy and microscopic herniation Or it can be delivered by other applicators. When dural defects are present, the fibrosis inhibitor can cheen the dural healing and prevent complications such as CSF flow.

  In another embodiment, adhesion formation may be associated with neurosurgery (brain) surgery. Neurosurgery can be accompanied by severe postoperative complications, often resulting in surgical trauma and undesirable fibrosis and gliosis (gliosis is the formation of scar tissue that occurs in the brain as a result of glial cell activity) Cause. Intracranial hemorrhage, infection, cerebrospinal fluid leakage and increased pain cause complications due to adhesions after brain surgery. For example, if the scar tissue blocks the normal cerebrospinal fluid circulation (CSF) after brain surgery or spinal surgery, fluid accumulates and applies pressure to the surrounding tissue (which increases intracranial pressure) and severe complications Cause (involuntary incarceration, brain damage, and / or death). It can be used alone or in combination with fibrosis inhibitors to prevent excessive dural scars and adhesion formation in various neurosurgical procedures.

  In order to prevent surgical adhesions in neurosurgery, spinal or neurosurgical sites (or grafts placed in the spine, such as artificial discs, rods, screws, spinal cages, drug delivery pumps, nerve stimulators, etc.) Many coated with a therapeutic agent (such as a fibrosis inhibitor or an anti-infective agent) applied alone or on a therapeutic surface (such as a fibrosis inhibitor or an anti-infective agent) There are complications. It should be noted that certain polymer compositions themselves can prevent the formation of fibrous tissue at the site of spinal or neurosurgery. These complications are particularly useful in carrying out this example, either alone or in combination with a fibrosis inhibiting composition.

  Soaking various polymer compositions with or without additional therapeutic agents to prevent surgical adhesions at the spinal or neurosurgical site (eg, at the tissue at the surgical site or around the graft and tissue interface) Can do.

In one embodiment, polymers that can form covalent bonds with the tissue to be applied can be used. Succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, _{maleimide, -SS- (C 5 H 4 N} ) or contains an electrophilic group such as an activated ester, and / or which polymers terminated in It can be used as a reagent. For example, solid or liquid 4-arm NHS derivatized polyethylene glycol (such as pentaerythritol poly (ethylene glycol) ether tetrasuccinimidyl glutarate) can be applied to the tissue. In this example, 4-arm NHS derivatized polyethylene glycol is dissolved in an acidic solution (pH about 2-3) and then applied simultaneously to the tissue using a basic buffer (pH> about 8). The fiber formation inhibitor can be incorporated directly into either 4-arm NHS derivatized polyethylene glycol, acidic solution or basic buffer.

In another example, the fiber formation inhibitor can be incorporated into a second carrier, and the second monomer can be incorporated into a 4-arm NHS derivatized polyethylene glycol, an acidic solution, and / or a basic buffer. The second simple substance may include fine particles and / or fine particles made of a biodegradable polymer. Biodegradable polymers include polyesters (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, can be composed of residues of one or more monomers selected from trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one), and XY , YXY, R- (YX) _n , R- (XY) _n and XYX block polymers are included. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.), and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASFCorporation (Mount Olive, NJ), Y is biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, etc.) From the residue of one or more monomers selected from γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one What can be configured, such as PLG-PEG-PLG), R is a multifunctional initiator.

In another example, the tissue-reactive polymer can be applied first and then the fiber formation inhibitor can be applied to the coated tissue. The fiber formation inhibitor can be applied directly to the tissue or mixed into the second simple substance. The second carrier includes fine particles (as described above), fine particles (as described above), gel (hyaluronic acid, carboxymethyl cellulose, dextran, poly (ethylene oxide) -poly (propylene oxide) block copolymer, mixture, association, Cross-linked composition, etc.), film (biodegradable polyester, lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone , Γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one can be composed of one or more monomer residues And block polymers having the structures XY, YXY, R- (YX) _n , R- (XY) _n and XYX. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.) and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASF Corporation (Mount Olive, NJ)) , PLURONIC and PLURONIC R series of polymers), Y is a biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ- Residue of one or more monomers selected from butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one (PLG-PEG-PLG etc.), R is a multifunctional initiator, hyaluronic acid, potassium Ruboxymethylcellulose, dextran, poly (ethylene oxide) -poly (propylene oxide) block copolymers, mixtures, associations and cross-linked compositions.

  A preferred polymeric matrix that can be used alone or in combination with a fiber formation inhibitor / composition to prevent the formation of fibrous tissue leading to surgical adhesions is pentaerythritol poly (ethylene glycol) ether tetra as a reactive reagent. -Sulphhydryl (including 4-arm thiol PEG, including a structure with a linking group between the ends of the sulfhydryl group and polyethylene glycol backbone) and penerythritol poly (ethylene glycol) ether tetra-succinimidyl glutarate (plus NHS group) There are four-arm NHS PEGs containing structures with linking groups between the ends of the polyethylene glycol backbone. Another preferred composition is pentaerythritol poly (ethylene glycol) ether tetraamino] (4 arm amino PEG as a reactive reagent, including a structure having a linking group between the amino group and the end of the polyethylene glycol backbone) and Pentaerythritol poly (ethylene glycol) ether tetra-succinimidyl glutarate] (further including a structure with a linking group between the NHS group and the end of the polyethylene glycol backbone, 4 arm NHS PEG). The chemical structure of these reactants is shown, for example, in US Pat. No. 5,874,500. Depending on the situation, collagen or a collagen derivative (eg methylated collagen) is added to a reactant containing poly (ethylene glycol) to form a preferred cross-linked substrate or independent composition that functions as a polymeric carrier for therapeutic agents. And helps prevent the formation of fibrous tissue.

  Spinal or neurosurgical sites (eg, at the tissue at the surgical site or near the graft-tissue interface) with or without additional fibrosis inhibition (and / or anti-infection) therapies to prevent surgical adhesions Other examples of polymer compositions that can be immersed in are various commercial products. For example, ConfluentSurgical, Inc. manufactures DURASEAL, a synthetic hydrogel designed to enhance sutured dural closure after brain surgery. Products developed by Confluent Surgical, Inc. are described, for example, in US Pat. No. 6,379,373. FzioMed, Inc. (San Luis Obispo, Calif.) Manufactures OXIPLEX / SPGel, which is marketed as an adhesion barrier for spinal surgery. OXIPLEX / SP Gel has been used to reduce pain and radiculopathy in laminectomy, laminectomy, and discectomy. Products developed by FzioMed, Inc. are described, for example, in US Pat. Nos. 6,566,345 and 6,017,301. Anika Therapeutics, Inc. (Woburn, Mass.) Is developing INCERT-S to prevent internal adhesions and scarring after spinal surgery. INCERT-S is part of a bioabsorbable potential family that is chemically modified from hyaluronic acid. Products developed by Anika Therapeutics, Inc. are described, for example, in US Pat. Nos. 6,548,081, 6,537,979, 6,096,727, 6,013,679, 5,502,081 and 5,356,883. LifeMedical Sciences, Inc. (Little River, NJ) has developed RELIEVE as a bioresorbable polymer that is designed to prevent or reduce the formation of adhesions after spinal surgery. is there. Products developed by LifeMedical Sciences, Inc. are described in US Pat. Nos. 6,696,499, 6,399,624, 6,211,249, 6,136,333 and 5,711,958. Wright Medical Technology, Inc. sells the Adcon product family, which originally was Gliatech, Inc. (Beachwood, Ohio), a posterior lumbar laminectomy or laminectomy with exposed nerve pathways. A dextran sulfate gel developed to inhibit post-surgical dural fiber formation that occurs during incision. ADCON provides a barrier between the spinal cord and nerve roots and the surrounding muscles and bones after lumbar spine surgery. The ADCON product family is described, for example, in US Pat. Nos. 6,417,173, 6,127,348, 6,083,930, 5,994,325, and 5,705,178.

  Applied or immersed in spinal or neurosurgical sites (or graft surfaces) to prevent adhesions, used alone, or therapeutic agents (eg, fibrosis inhibitors and / or anti-infectives) Other commercially available materials that carry the carrier include (a) sprayable collagen-containing formulations such as COSTASIS or CT3, (b) sprayable PEG-containing formulations such as COSEAL, ADHIBIT, FocalSeal, or SPRAYGEL, (c) Fibrinogen-containing preparations such as FLOSEAL or TISSEAL (both Baxter Healthcare Corporation, Fremont, Calif.), (D) hyaluronic acid-containing preparations such as RESTYLANE, PERLANE, HYLAFORM, SYNVISC, SEPRAFILM or SEPRACOAT, (e) REPEL or FLOWGEL Polymer gel for surgical implantation, including cyanoacrylates such as (f) Dermabond, Indermil, Glustitch, Tissumend, VetBond, Histoacryl BLUE and Orabase Soothe-N-Seal Liquid Protectant Surgical adhesives, (h) lipid-based compositions such as ADSURF, and (j) INTERCEED (Ethicon, Inc., Summerville, NJ) and HYDROSORB (MacroPore Biosurgery, Inc., San Diego / Medtronic Sofamor Danek, Film compositions such as Memphis, Tennessee). For those skilled in the art, not only the commercially available compositions not specifically mentioned above but also the next generation and / or future developed commercial products are expected to be used according to the present invention. It must be clear that it is suitable.

  As described above, the composition for preventing surgical adhesions can be applied directly or jointly to the tissue at the spinal or neurosurgical site. The polymer composition (with or without a therapeutic agent) can be administered by any of the methods described herein. Typical methods include direct application during surgery, direct application by endoscope, ultrasound, CT, MRI, fluoroscopy, and / or application in conjunction with placement of the device or graft at the surgical site It is. Representative examples of devices or grafts for use in spinal or neurosurgery include dura mater patches, artificial spines (eg, artificial discs, intervertebral disc injectable filling or swelling agents, spinal implants , Spinal nucleus implants, intervertebral disc spacers), fixation cages, nerve stimulators, implantable drug delivery pumps, shunts, drains, electrodes, and bone fixation devices (eg, fixation plates and bone screws) Not.

  The polymer composition can be applied during the recovery procedure or endoscopic procedure with or without a fibrosis inhibitor. (a) Before, during, and after the surgical procedure, on the surface of the surgical site (eg, as an injection material, solution, paste, gel, in-situ formed gel or mesh), (b) Before, during, after, on the surface of the tissue around the surgical site (eg as injection material, solution, paste, gel, in situ formed gel or mesh), (c) at the surgical site (subdural space By topical application of the composition to the anatomical space (e.g. or within the sheath) (especially useful in this example is the use of a polymeric carrier that releases the fibrosis inhibitor over a period ranging from hours to weeks- Liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and other formulations that release the drug and can be delivered to the site where the device is inserted) (d) Solution to tissue in and around the surgical site Application by intradermal injection of injections, sustained-release preparations, and / or (e) combinations of the methods described above. Combination therapy (ie combination of therapeutic agents and antithrombotic, anti-infective, antiplatelet agents) can also be used.

  In certain applications involving the placement of medical devices and grafts, it is possible to apply a fibrosis inhibiting (and / or anti-infective) composition at a site adjacent to the graft (preferably near the graft-tissue interface). Sometimes desirable. This can be done during laparotomy or endoscopic treatment by applying a polymer composition with or without a fiber formation inhibitor. (a) Immediately before, during, and after the implantation procedure, (b) Immediately before implanting the implant on the surface of the implant (eg, as injection material, solution, paste, gel, gel formed in situ or mesh) Or during, or after, on adjacent tissue surfaces (eg, as injection material, solution, paste, gel, in situ gel, or mesh), (c) before, during, or (D) An anatomical space where the graft is placed on the surface of the graft and the surrounding tissue (eg, injection material, solution, paste, gel, gel or mesh formed in situ) after transplantation Topical application of the composition (such as in the subdural space or within the sheath) (especially useful in this example is the use of a polymeric carrier that releases the fibrosis inhibitor over a period ranging from hours to weeks— Liquid, suspension, emulsion, microemulsion (E) solutions in tissue surrounding the implant Application by intradermal injection of injections, infusions and sustained release formulations and / or (f) combinations of the methods described above. Combination therapy (ie combination of therapeutic agents and antithrombotic, anti-infective, antiplatelet agents) can also be used.

  In one embodiment, the polymer composition can be delivered to the tissue (or device / tissue interface) in the form of a laparotomy, endoscopic procedure or catheter-based procedure. The fibrosis inhibitor can be incorporated directly into the surgical adhesion barrier or can be incorporated into the second carrier (polymer or non-polymer) as described above and then incorporated into the adhesion barrier. Representative examples of spray or gel polymer compositions include poly (ethylene glycol) based systems, hyaluronic acid and crosslinked hyaluronic acid compositions. These compositions can be applied as final compositions or as materials that form a crosslinked gel in situ.

In another embodiment, the activated polymer is dissolved in a biologically acceptable buffer (pH is less than 6.8). If a second biologically acceptable buffer (pH is greater than 7.5) is present, the resulting solution is applied to the desired tissue surface. The reaction mixture is applied to the tissue site by extrusion, brushing, spraying, or other convenient method. After application of the composition to the surgical site, excess solution is removed from the surgical site as needed. At this point, the surgical site can be closed by conventional methods (sutures, staples, bioadhesive materials, etc.). In one embodiment, an activated polymer that can form a covalent bond with the tissue to be applied can be used. Succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, _{maleimide, -SS- (C 5 H 4 N} ) or contains an electrophilic group such as an activated ester, and / or which polymers terminated in It can be used as a reagent. For example, solid or liquid 4-arm NHS derivatized polyethylene glycol (such as pentaerythritol poly (ethylene glycol) ether tetrasuccinimidyl glutarate) can be applied to the tissue. In this example, 4-arm NHS derivatized polyethylene glycol is dissolved in an acidic solution (pH about 2-3) and then applied simultaneously to the tissue using a basic buffer (pH> about 8). The fiber formation inhibitor can be incorporated directly into either 4-arm NHS derivatized polyethylene glycol, acidic solution or basic buffer. In another example, the fiber formation inhibitor can be incorporated into a second carrier, and the second monomer can be incorporated into a 4-arm NHS derivatized polyethylene glycol, an acidic solution, and / or a basic buffer. The second simple substance may include fine particles and / or fine particles made of a biodegradable polymer. Biodegradable polymers include polyesters (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, can be composed of residues of one or more monomers selected from trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one), and XY , YXY, R- (YX) _n , R- (XY) _n and XYX block polymers are included. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.) and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASF Corporation (Mount Olive, NJ)) , PLURONIC and PLURONIC R series of polymers), Y is a biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ- Residue of one or more monomers selected from butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one (PLG-PEG-PLG etc.), R is a multifunctional initiator. In another example, the tissue-reactive polymer can be applied first and then the fiber formation inhibitor can be applied to the coated tissue. The fiber formation inhibitor can be applied directly to the tissue or mixed into the second simple substance. The second carrier includes fine particles (as described above), fine particles (as described above), gel (hyaluronic acid, carboxymethyl cellulose, dextran, poly (ethylene oxide) -poly (propylene oxide) block copolymer, mixture, association, Cross-linked composition, etc.), film (biodegradable polyester, lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone , Γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one can be composed of one or more monomer residues And block polymers having the structures XY, YXY, R- (YX) _n , R- (XY) _n and XYX. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.), and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASFCorporation (Mount Olive, NJ), Y is biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, etc.) From the residue of one or more monomers selected from γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one Can be constructed (PLG-PEG-PLG, etc.), R is a multifunctional initiator, hyaluronic acid, potassium Bo carboxymethylcellulose, dextran, poly (ethylene oxide) - poly (propylene oxide) block copolymers, mixtures, federation, a crosslinked composition.

In yet another aspect, the activated polymer can be applied to the surgical site in a solid form. The activated polymer can react to the tissue surface applied as a polymer hydrate. Biologically acceptable buffer (pH> 7.5) can be applied to the tissue before and / or after applying the solid activated polymer. In one embodiment, an activated polymer that can form a covalent bond with the tissue to be applied can be used. Succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, _{maleimide, -SS- (C 5 H 4 N} ) or contains an electrophilic group such as an activated ester, and / or which polymers terminated in It can be used as a reagent. For example, solid 4-arm NHS derivatized polyethylene glycol (such as pentaerythritol poly (ethylene glycol) ether tetrasuccinimidyl glutarate) can be applied to the tissue. Fibrosis inhibitors can be incorporated directly into either 4-arm NHS derivatized polyethylene glycol or basic buffer. In another example, the fiber formation inhibitor can be incorporated into a second carrier, and the second monomer can be incorporated into a 4-arm NHS derivatized polyethylene glycol and / or a basic buffer. The second simple substance may include fine particles and / or fine particles made of a biodegradable polymer. Biodegradable polymers include polyesters (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, can be composed of residues of one or more monomers selected from trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one), and XY , YXY, R- (YX) _n , R- (XY) _n and XYX block polymers are included. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.), and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASFCorporation (Mount Olive, NJ), Y is biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, etc.) From the residue of one or more monomers selected from γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one What can be configured, such as PLG-PEG-PLG), R is a multifunctional initiator. In another example, the tissue-reactive polymer can be applied first and then the fiber formation inhibitor can be applied to the coated tissue. The fiber formation inhibitor can be applied directly to the tissue or mixed into the second simple substance. The second carrier includes fine particles (as described above), fine particles (as described above), gel (hyaluronic acid, carboxymethyl cellulose, dextran, poly (ethylene oxide) -poly (propylene oxide) block copolymer, mixture, association, Cross-linked composition, etc.), film (biodegradable polyester, lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone , Γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one can be composed of one or more monomer residues And block polymers having the structures XY, YXY, R- (YX) _n , R- (XY) _n and XYX. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.), and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASFCorporation (Mount Olive, NJ), Y is biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, etc.) From the residue of one or more monomers selected from γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one Can be constructed (PLG-PEG-PLG, etc.), R is a multifunctional initiator, hyaluronic acid, potassium Bo carboxymethylcellulose, dextran, poly (ethylene oxide) - poly (propylene oxide) block copolymers, mixtures, federation, a crosslinked composition.

ii) Prevention of adhesions in gynecological procedures In one embodiment, adhesion formation may be associated with gynecological surgery. Postoperative adhesions occur in 60-90% of patients who have undergone major gynecological surgery and are one of the most common causes of infertility in industrialized countries. Adhesions are formed between the ovary, fallopian tube, intestinal tract, or pelvic wall. By tying the fiber band that normally binds to the mobile appendage structure (ovary or fallopian tube) to other tissues, the mobility, kinking or twisting of the mobile appendage structure is lost. When tightly tightening, compressing, or twisting the fallopian tube itself through adhesions, the passage of the ovum from the ovary to the fallopian tube may be blocked leading to infertility. Adhesion around the fallopian tube also interferes with sperm transport to the ovum, which also causes infertility. Other adhesion-related complications include chronic pelvic pain, sexual pain, urethral obstruction and dysuria.

  Several products for the management of gynecological adhesions are on the market and some are in development. Life Medical Sciences, Inc. is in various stages of development and produces products (REPEL, REPEL-CV, RESOLVE and RELIVE) that can be used to prevent surgical adhesions in gynecological and other surgeries. Products developed by LifeMedical Sciences, Inc. are described in US Patents 6,696,499, 6,399,624, 6,211,249, 6,136,333 and 5,711,958. ConfluentSurgical, Inc. is a unique sprayable adhesion barrier that produces SPRAYGEL, developed for use in pelvic and intrauterine surgical procedures. A product developed by ConfluentSurgical, Inc. is described in, for example, US Pat. No. 6,379,373. Closure Medical Corp. (Raleigh, NC) has developed a cyanoacrylate-based internal adhesive that can be used to seal internal surgical incisions and implants and is compatible with gynecological and common surgical professionals. It is. Products developed by Closure Medical, Corp. are described in US Pat. Nos. 6,620,846, 6,579,469, 6,565,840, 6,547,467 and 5,981,621.

  Applied or immersed in gynecological surgery site (or device or graft surface) to prevent adhesions in open or endoscopic gynecological surgery, used alone or as a therapeutic agent (eg, fibrosis inhibitor) Other commercially available substances carrying (and / or anti-infectives) include (a) sprayable collagen-containing formulations such as COSTASIS or CT3, and (b) sprayable PEGs such as COSEAL, ADHIBIT, FocalSeal or DURASEAL (C) fibrinogen-containing preparations such as FLOSEAL or TISSEAL, (d) hyaluronic acid-containing preparations such as RESTYLANE or PERLANE, HYLAFORM, SYNVISC, SEPRAFILM or SEPRACOAT, (e) surgical gels such as FLOWGEL, (f ) Surgical adhesives containing cyanoacrylates such as Dermabond, Indermil, Glustitch, Tissumend, VetBond, HistoacrylBLUE and Orabase Soothe-N-Seal Liquid Protectant; (g) Dextran sulfate such as ADCON group gels Le, and (h) AdSurf lipid-based compositions such as. For those skilled in the art, not only the commercially available compositions not specifically mentioned above but also the next generation and / or future developed commercial products are expected to be used according to the present invention. It must be clear that it is suitable.

  Gynecological procedures include hysterectomy (removal of uterus), myomectomy (removal of hysteromyoma), endometriosis (cauterization), infertility (in vitro fertilization, adhesion peeling), pregnancy control (fallopian tube ligation) ), Reverse contraceptive surgery, pain, dysmenorrhea, malformed uterine bleeding, ectopic pregnancy, ovarian cysts, gynecological malignancies and many other medical conditions. Although many procedures are still performed through open surgical techniques, gynecological surgery is increasingly performed through an endoscope inserted through the navel. Almost all manipulations of pelvic organs and pelvic sidewalls cause a cascade and can eventually lead to the formation of pelvic adhesions. In many cases, adhesions need to be removed during repeated surgical procedures to treat pain and infertility. Adhesion barriers, alone or containing fibrosis inhibitors (and / or anti-infectives), can be applied directly to the affected site (solid, film, paste, gel, liquid during laparotomy or endoscopic treatment) Or in other forms). In a preferred embodiment, the barrier (alone or including fibrosis inhibitors and / or anti-infectives) is within the pelvis during treatment, under direct mirror observation, during treatment, during surgery, or during manipulation. Sprayed into organs (and intestinal tract, pelvis and abdominal sidewall). Because adhesions often occur in areas that are distant from the tissue that is actually placed during the surgical procedure, the barrier (with or without therapeutic agents) can be used to block the wide area of the pelvis (in some cases, uterine appendages, pelvic side walls, and Application to the entire pelvic surface). Desirable barriers include liquids, gels that can be delivered by endoscope and remain in place for a sufficient time to adhere to the tissue to be treated and deliver the therapeutic agent or prevent formation of adhesions , Pastes, sprays and other forms. Alternatively, the drug may be injected directly into the peritoneum (prior to treatment) so that the dose and duration of the drug are sufficient to prevent adhesions and complications (preferably multiple doses and / or sustained release). , During, or later). An ideal adhesion procedure improves patient outcomes by reducing the incidence, number and persistence of adhesions, reducing pain, improving fertility, and limiting the need for repeated treatments.

  As described above, the composition for preventing surgical adhesions can be applied directly to the tissue at the gynecological site or to the joint. The polymer composition (with or without fibrosis inhibitors or anti-infectives) can be administered by any of the methods described herein. Typical methods include direct application during surgery or direct application by endoscope, ultrasound, CT, MRI, fluoroscopy. When implanting a device, a medical device or graft is placed at the surgical site and an anti-adhesion composition is applied to the implant surface or surrounding tissue. Representative examples of grafts for use in gynecological procedures include urogenital stents, expandable drugs, infertility devices (eg, valves, clips and clamps), and fallopian tube occlusion grafts and plugs However, it is not limited to these.

  The polymer composition can be applied during recovery procedures or endoscopic gynecological surgery with or without a fibrosis inhibitor. (a) During the surgical procedure, on the tissue surface of the pelvic sidewall, appendages, uterus and adjacent infected tissue (eg injection material, solution, gel, gel or mesh formed in situ), (b) the surgical procedure Before, during, or after, on the surface of the implanted device or graft, and / or the tissue surrounding the graft (eg, injection material, solution, gel, gel or mesh formed in situ), (c) by intraperitoneal or endoscopic injection of the composition into the anatomical space of the composition (i.e. peritoneum or pelvic cavity) at the surgical site (especially useful in this example comprises a polymeric carrier and is several hours to The use of implantable compositions that release fibrosis inhibitors over a period of weeks-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants Release the piece and the drug (E) by intradermal injection of solutions, infusions, and sustained-release preparations into tissues, (e) at the target fallopian tube location, By guided catheter or hysteroscopic injection of tissue into the lumen of the body (i.e. inserting the catheter or endoscope through the vagina, cervix and uterus until the lumen of the fallopian tube is reached) (especially in this example Useful is the use of an implantable composition comprising a polymeric carrier and releasing a fibrosis inhibitor over a period ranging from hours to weeks-liquids, suspensions, emulsions, microemulsions, microspheres Pastes, gels, microparticles, sprays, aerosols, solid implants and other formulations that can release the drug and be delivered to sites at risk of adhesion formation), and / or (f) by a combination of the methods described above. Combination therapy (ie, combination of therapeutic agents and antithrombotic, anti-infective, or antiplatelet agents) can also be used in the manner described above.

  Apply fibrosis inhibiting (and / or anti-infective) compositions at the site adjacent to the graft (preferably near the graft-tissue interface) in certain applications involving gynecological medical devices or graft placement It may be desirable. This can be done during laparotomy or endoscopic treatment by applying a polymer composition with or without a fiber formation inhibitor. (a) Immediately before, during, and after the implantation procedure, (b) Immediately before implanting the implant on the surface of the implant (eg, as injection material, solution, paste, gel, gel formed in situ, or mesh) (C) before, during, or after graft implantation on adjacent tissue surfaces (eg, as injection material, solution, paste, gel, gel formed in situ, or mesh) (D) the anatomical space (egg) where the graft is placed on the surface of the graft and the tissue surrounding the graft (eg injection material, solution, paste, gel, gel or mesh formed in situ) Topical application of the composition to the duct, uterine cavity, peritoneal cavity, or pelvic cavity (especially useful in this example is the use of a polymeric carrier that releases the fibrosis inhibitor over a period ranging from hours to weeks) -Liquid, suspension, emulsion, micro Marjons, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and other formulations that release the drug and can be delivered to the site where the device is inserted), (e) a solution in the tissue surrounding the implant Application by intradermal injection of injections, infusions and sustained release formulations and / or (f) combinations of the methods described above. Combination therapy (ie combination of therapeutic agents and antithrombotic, anti-infective, antiplatelet agents) can also be used.

  In one embodiment, the polymer composition can be delivered to female pelvic tissue (or device / tissue interface) in the form of a laparotomy, endoscopic procedure or catheter-based procedure. The fibrosis inhibitor can be incorporated directly into the surgical adhesion barrier or can be incorporated into the second carrier (polymer or non-polymer) as described above and then incorporated into the adhesion barrier. Representative examples of spray or gel polymer compositions include poly (ethylene glycol) based systems, hyaluronic acid and crosslinked hyaluronic acid compositions. These compositions can be applied as final compositions or as materials that form a crosslinked gel in situ.

In another embodiment, the activated polymer is dissolved in a biologically acceptable buffer (pH is less than 6.8). If a second biologically acceptable buffer (pH is greater than 7.5) is present, the resulting solution is applied to the desired tissue surface. The reaction mixture is applied to the tissue site by extrusion, brushing, spraying, or other convenient method. After application of the composition to the surgical site, excess solution is removed from the surgical site as needed. At this point, the surgical site can be closed by conventional methods (sutures, staples, bioadhesive materials, etc.). In one embodiment, an activated polymer that can form a covalent bond with the tissue to be applied can be used. Succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, _{maleimide, -SS- (C 5 H 4 N} ) or contains an electrophilic group such as an activated ester, and / or which polymers terminated in It can be used as a reagent. For example, solid or liquid 4-arm NHS derivatized polyethylene glycol (such as pentaerythritol poly (ethylene glycol) ether tetrasuccinimidyl glutarate) can be applied to the tissue. In this example, 4-arm NHS derivatized polyethylene glycol is dissolved in an acidic solution (pH about 2-3) and then applied simultaneously to the tissue using a basic buffer (pH> about 8). The fiber formation inhibitor can be incorporated directly into either 4-arm NHS derivatized polyethylene glycol, acidic solution or basic buffer. In another example, the fiber formation inhibitor can be incorporated into a second carrier, and the second monomer can be incorporated into a 4-arm NHS derivatized polyethylene glycol, an acidic solution, and / or a basic buffer. The second simple substance may include fine particles and / or fine particles made of a biodegradable polymer. Biodegradable polymers include polyesters (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, can be composed of residues of one or more monomers selected from trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one), and XY , YXY, R- (YX) _n , R- (XY) _n and XYX block polymers are included. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.), and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASFCorporation (Mount Olive, NJ), Y is biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, etc.) From the residue of one or more monomers selected from γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one What can be configured, such as PLG-PEG-PLG), R is a multifunctional initiator. In another example, the tissue-reactive polymer can be applied first and then the fiber formation inhibitor can be applied to the coated tissue. The fiber formation inhibitor can be applied directly to the tissue or mixed into the second simple substance. The second carrier includes fine particles (as described above), fine particles (as described above), gel (hyaluronic acid, carboxymethyl cellulose, dextran, poly (ethylene oxide) -poly (propylene oxide) block copolymer, mixture, association, Cross-linked composition, etc.), film (biodegradable polyester, lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone , Γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one can be composed of one or more monomer residues And block polymers having the structures XY, YXY, R- (YX) _n , R- (XY) _n and XYX. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.), and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASFCorporation (Mount Olive, NJ), Y is biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, etc.) From the residue of one or more monomers selected from γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one Can be constructed (PLG-PEG-PLG, etc.), R is a multifunctional initiator, hyaluronic acid, potassium Bo carboxymethylcellulose, dextran, poly (ethylene oxide) - poly (propylene oxide) block copolymers, mixtures, federation, a crosslinked composition.

In yet another aspect, the activated polymer can be applied to the surgical site in a solid form. The activated polymer can react to the tissue surface applied as a polymer hydrate. Biologically acceptable buffer (pH> 7.5) can be applied to the tissue before and / or after applying the solid activated polymer. In one embodiment, an activated polymer that can form a covalent bond with the tissue to be applied can be used. Succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, _{maleimide, -SS- (C 5 H 4 N} ) or contains an electrophilic group such as an activated ester, and / or which polymers terminated in It can be used as a reagent. For example, solid 4-arm NHS derivatized polyethylene glycol (such as pentaerythritol poly (ethylene glycol) ether tetrasuccinimidyl glutarate) can be applied to the tissue. Fibrosis inhibitors can be incorporated directly into either 4-arm NHS derivatized polyethylene glycol or basic buffer. In another example, the fiber formation inhibitor can be incorporated into a second carrier, and the second monomer can be incorporated into a 4-arm NHS derivatized polyethylene glycol and / or a basic buffer. The second simple substance may include fine particles and / or fine particles made of a biodegradable polymer. Biodegradable polymers include polyesters (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, can be composed of residues of one or more monomers selected from trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one), and XY , YXY, R- (YX) _n , R- (XY) _n and XYX block polymers are included. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.) and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASF Corporation (Mount Olive, NJ)) , PLURONIC and PLURONIC R series of polymers), Y is a biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ- Residue of one or more monomers selected from butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one (PLG-PEG-PLG etc.), R is a multifunctional initiator. In another example, the tissue-reactive polymer can be applied first and then the fiber formation inhibitor can be applied to the coated tissue. The fiber formation inhibitor can be applied directly to the tissue or mixed into the second simple substance. The second carrier includes fine particles (as described above), fine particles (as described above), gel (hyaluronic acid, carboxymethyl cellulose, dextran, poly (ethylene oxide) -poly (propylene oxide) block copolymer, mixture, association, Cross-linked composition, etc.), film (biodegradable polyester, lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone , Γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one can be composed of one or more monomer residues And block polymers having the structures XY, YXY, R- (YX) _n , R- (XY) _n and XYX. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.), and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASFCorporation (Mount Olive, NJ), Y is biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, etc.) From the residue of one or more monomers selected from γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one Can be constructed (PLG-PEG-PLG, etc.), R is a multifunctional initiator, hyaluronic acid, potassium Bo carboxymethylcellulose, dextran, poly (ethylene oxide) - poly (propylene oxide) block copolymers, mixtures, federation, a crosslinked composition.

iii) Prevention of adhesions in abdominal procedures In one embodiment, adhesions may be associated with abdominal surgical procedures. After abdominal surgery, the formation of adhesions causes the intestinal rings to twist or twist around the tissue fiber band, thus impairing the normal movement of intestinal fluid. Tangles interfere with partial or total flow through the intestine, causing the scar to compress around the intestine, causing intestinal twisting (twisting), or impeding blood flow through the intestine. Tangles, bowel twists or fibrosis can result in partial or total bowel obstruction that requires immediate decompression, necessitating surgery and possibly death. Infarct formation due to adhesions or intestinal twist (interruption of blood flow to the intestinal tract) is a medical emergency and usually requires surgical removal of the infected intestinal tract, which can be fatal if not treated immediately . Peritoneal adhesions (adhesion of the abdominal wall and underlying organs) mean another serious health care problem that causes pain, bowel obstruction and other serious postoperative complications, all types of abdominal surgery (50-90% incidence in case of abdominal wall incision).

  As mentioned above, adhesion barriers are frequently used to manage abdominal adhesions following laparotomy and endoscopic procedures. Various commercially available adhesion barriers can be used in combination with a fibrosis inhibitor (and / or anti-infection) in the management of abdominal adhesions. Confluent Surgical, Inc. is a unique sprayable adhesion barrier, producing SPRAYGEL, developed for use in abdominal and pelvic surgical procedures. A product developed by ConfluentSurgical, Inc. is described in, for example, US Pat. No. 6,379,373. Closure Medical Corp. (Raleigh, NC) can be used to seal internal surgical incisions and implants and uses cyanoacrylate-based internal adhesives that are compatible with gastrointestinal, oncology and common surgical professionals. We are developing. Products developed by Closure Medical, Corp. are described in US Pat. Nos. 6,620,846, 6,579,469, 6,565,840, 6,547,467 and 5,981,621. Genzyme Corporation has developed hyaluronic acid-containing biomaterials such as SEPRAFILM and SEPRACOAT to reduce the incidence of adhesions after abdominal and pelvic surgery. (See U.S. Patent Nos. 6,780,427, 6,531,147, 6,521,223 and 6,010,692.

  Applied or immersed in the abdominal site (or the surface of the implanted device or graft) to prevent adhesions during laparotomy or endoscopic abdominal procedures, used alone, or therapeutic agents (eg, fibers Other commercially available substances that carry (inhibitors of formation or anti-infectives) include: (a) sprayable collagen-containing preparations such as COSTASIS or CT3; (b) sprayables such as COSEAL, ADHIBIT, FocalSeal or DURASEAL PEG-containing preparations, (c) fibrinogen-containing preparations such as FLOSEAL or TISSEAL, (d) hyaluronic acid-containing preparations such as RESTYLANE or PERLANE, HYLAFORM, or SYNVISC, (e) surgical implant polymer gels such as REPEL or FLOWGEL, (f ) Surgical adhesives containing cyanoacrylates such as Dermabond, Indermil, Glustitch, Tissumend, VetBond, HistoacrylBLUE and Orabase Soothe-N-Seal Liquid Protectant, (g) Dextran sulfate gels such as ADCON group gels, And (h) a lipid-based composition such as AdSurf. For those skilled in the art, not only the commercially available compositions not specifically mentioned above but also the next generation and / or future developed commercial products are expected to be used according to the present invention. It must be clear that it is suitable.

  Abdominal surgery includes hernia repair (abdominal, anterior, inguinal, incision), intestinal obstruction, infectious colitis (ulcerative colitis, Crohn's disease), appendectomy, trauma (penetration wound, blunt trauma), tumor resection , Infection (abscess, peritonitis), cholecystectomy, gastroplasty (obesity surgery), esophageal and pyloric stenosis, colon fistula, detour ileostomy, anorectal fistula, hemorrhoid resection, splenectomy, liver cancer It is performed for a variety of symptoms, including resection, pancreatitis, bowel perforation, upper lower GI bleeding, and ischemic bowel. Although many procedures are still performed through open surgical techniques, abdominal surgery is increasingly performed through an endoscope inserted through the navel. Almost all manipulations of the abdominal organs and peritoneum can cause a cascade and eventually lead to the formation of abdominal adhesions. In many cases, adhesions need to be removed during repeated surgical procedures to treat pain and bowel obstruction. Adhesion barriers, alone or containing fibrosis inhibitors (and / or anti-infectives), can be applied directly to the affected site (solid, film, paste, gel, liquid during laparotomy or endoscopic treatment) Or in other forms). In a preferred embodiment, the barrier (alone or including a fibrosis inhibitor and / or an anti-infective) is the pelvis during treatment, directly or under a microscope, during treatment, during surgery, or during manipulation. Sprayed on internal organs (large and small intestines, stomach, liver, spleen, gallbladder, etc.), visceral peritoneum and abdominal (wall) peritoneum. Because adhesions often occur in areas that are distant from the tissue that is actually placed during the surgical procedure, the barrier (with or without therapeutic agents) can be extended to a large area of the abdomen (sometimes even the entire viscera and abdominal wall). It is necessary to apply. Desirable barriers can be delivered during an laparotomy or endoscopically and remain in place for a time sufficient to adhere to the tissue to be treated and deliver the therapeutic agent or prevent formation of adhesions Films, liquids, gels, pastes, sprays, and other forms that can be included. Alternatively, the drug may be injected directly into the peritoneum (prior to treatment) so that the dose and duration of the drug are sufficient to prevent adhesions and complications (preferably multiple doses and / or sustained release). , During, or later). An ideal adhesion procedure improves patient outcomes by reducing the incidence, number and persistence of adhesions, reducing pain, preventing bowel obstruction, and limiting the need for repeated treatments.

  As mentioned above, the composition for preventing surgical adhesions can be applied directly to the tissue of the abdominal procedure or to the joint. The polymer composition (with or without fibrosis inhibitors or anti-infectives) can be administered by any of the methods described herein. Typical methods include direct application during surgery or direct application by endoscope, ultrasound, CT, MRI, fluoroscopy. When implanting a device, a medical device or graft is placed at the surgical site and an anti-adhesion composition is applied to the implant surface or surrounding tissue. Representative examples for use in abdominal procedures include hernia meshes, obesity restriction devices, implantable sensors, implantable pumps, peritoneal dialysis catheters, peritoneal drug delivery catheters, for drainage or nutrition GI tract, portal vein shunt, ascites shunt, gastrostomy feeding tube or percutaneous feeding tube, percutaneous jejunostomy tube, colostomy device, drainage tube, gallbladder T tube, Hemostatic graft. Examples include, but are not limited to, enteral feeding devices, colon and gallbladder stents, low profile devices, gastroplasty implants, capsule endoscopes, antireflux devices, and esophageal stents.

  The polymer composition can be applied during recovery procedures or endoscopic abdominal surgery with or without a fibrosis inhibitor. (a) During the surgical procedure, on the tissue surface of the peritoneal cavity, visceral peritoneum, abdominal organs, abdominal wall and adjacent infected tissue (eg, injection material, solution, gel, in situ formed gel or mesh), ( b) Implanted device or implant, and / or tissue surrounding the implant (eg, injection material, solution, gel, in situ formed gel or mesh) before, during, or after the surgical procedure (C) by intraperitoneal or endoscopic injection of the composition into the anatomical space (i.e. peritoneum) at the surgical site (especially useful in this example comprises a polymeric carrier and can be The use of implantable compositions that release fibrosis inhibitors over a period of several weeks-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solids Releases and heals implants and drugs (E) by intradermal injection of solutions, infusions, and sustained-release formulations into tissues, (e) at the desired gastrointestinal tract location, By guided catheter or endoscope (gastroscope, ERCP, colon) injection of tissue into the lumen of the tissue (particularly useful in this example includes a polymeric carrier and forms fibers over a period ranging from hours to weeks Is the use of implantable compositions that release inhibitors-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and drug releases Other formulations that can be delivered to the site of the gastrointestinal at risk of adhesion formation), and / or (f) by a combination of the methods described above. Combination therapy (ie, combination of therapeutic agents and antithrombotic, anti-infective, or antiplatelet agents) can also be used in the manner described above.

  For certain applications involving abdominal or gastrointestinal medical devices or graft placement, apply fibrosis inhibiting (and / or anti-infective) compositions at the site adjacent to the graft (preferably near the graft-tissue interface) It may be desirable to do so. This can be done during laparotomy or endoscopic treatment by applying a polymer composition with or without a fiber formation inhibitor. (a) Immediately before, during, and after the implantation procedure, (b) Immediately before implanting the implant on the surface of the implant (eg, as injection material, solution, paste, gel, gel formed in situ, or mesh) (C) before, during, or after graft implantation on adjacent tissue surfaces (eg, as injection material, solution, paste, gel, gel formed in situ, or mesh) (D) the anatomical space (gastrointestinal tract) where the graft is placed on the surface of the graft and the surrounding tissue (eg injection material, solution, paste, gel, gel or mesh formed in situ) Topical application of the composition to the tube, peritoneal cavity, etc. (especially useful in this example is the use of a polymeric carrier that releases the fibrosis inhibitor over a period ranging from hours to weeks-liquid, suspension Liquid, emulsion, microemulsion, micro Fairs, pastes, gels, microparticles, sprays, aerosols, solid implants and other formulations that can be delivered to the site where the drug is released and the device is inserted), (e) solutions to the tissue surrounding the implant, injections And / or (f) application by a combination of the methods described above. Combination therapy (ie combination of therapeutic agents and antithrombotic, anti-infective, antiplatelet agents) can also be used.

  In one embodiment, the polymer composition can be delivered to the abdomen (or device / tissue interface) in the form of a laparotomy, endoscopic procedure or catheter-based procedure. The fibrosis inhibitor can be incorporated directly into the surgical adhesion barrier or can be incorporated into the second carrier (polymer or non-polymer) as described above and then incorporated into the adhesion barrier. Representative examples of spray or gel polymer compositions include poly (ethylene glycol) based systems, hyaluronic acid and crosslinked hyaluronic acid compositions. These compositions can be applied as final compositions or as materials that form a crosslinked gel in situ.

In another embodiment, the activated polymer is dissolved in a biologically acceptable buffer (pH is less than 6.8). If a second biologically acceptable buffer (pH is greater than 7.5) is present, the resulting solution is applied to the desired tissue surface. The reaction mixture is applied to the tissue site by extrusion, brushing, spraying, or other convenient method. After application of the composition to the surgical site, excess solution is removed from the surgical site as needed. At this point, the surgical site can be closed by conventional methods (sutures, staples, bioadhesive materials, etc.). In one embodiment, an activated polymer that can form a covalent bond with the tissue to be applied can be used. Succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, _{maleimide, -SS- (C 5 H 4 N} ) or contains an electrophilic group such as an activated ester, and / or which polymers terminated in It can be used as a reagent. For example, solid or liquid 4-arm NHS derivatized polyethylene glycol (such as pentaerythritol poly (ethylene glycol) ether tetrasuccinimidyl glutarate) can be applied to the tissue. In this example, 4-arm NHS derivatized polyethylene glycol is dissolved in an acidic solution (pH about 2-3) and then applied simultaneously to the tissue using a basic buffer (pH> about 8). The fiber formation inhibitor can be incorporated directly into either 4-arm NHS derivatized polyethylene glycol, acidic solution or basic buffer. In another example, the fiber formation inhibitor can be incorporated into a second carrier, and the second monomer can be incorporated into a 4-arm NHS derivatized polyethylene glycol, an acidic solution, and / or a basic buffer. The second simple substance may include fine particles and / or fine particles made of a biodegradable polymer. Biodegradable polymers include polyesters (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, can be composed of residues of one or more monomers selected from trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one), and XY , YXY, R- (YX) _n , R- (XY) _n and XYX block polymers are included. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.) and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASF Corporation (Mount Olive, NJ)) , PLURONIC and PLURONIC R series of polymers), Y is a biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ- Residue of one or more monomers selected from butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one (PLG-PEG-PLG etc.), R is a multifunctional initiator. In another example, the tissue-reactive polymer can be applied first and then the fiber formation inhibitor can be applied to the coated tissue. The fiber formation inhibitor can be applied directly to the tissue or mixed into the second simple substance. The second carrier includes fine particles (as described above), fine particles (as described above), gel (hyaluronic acid, carboxymethyl cellulose, dextran, poly (ethylene oxide) -poly (propylene oxide) block copolymer, mixture, association, Cross-linked composition, etc.), film (biodegradable polyester, lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone , Γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one can be composed of one or more monomer residues And block polymers having the structures XY, YXY, R- (YX) _n , R- (XY) _n and XYX. Where X is a polyalkylene oxide (such as poly (ethylene glycol) or poly (propylene glycol)) and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASF Corporation (Mount, New Jersey) Y) is a biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone) One or more monomers selected from γ-butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one (PLG-PEG-PLG etc.), R is a multifunctional initiator, hyaluro Acid, carboxymethylcellulose, dextran, poly (ethylene oxide) -poly (propylene oxide) block copolymer, mixture, association, cross-linked composition.

In yet another aspect, the activated polymer can be applied to the surgical site in a solid form. The activated polymer can react to the tissue surface applied as a polymer hydrate. Biologically acceptable buffer (pH> 7.5) can be applied to the tissue before and / or after applying the solid activated polymer. In one embodiment, an activated polymer that can form a covalent bond with the tissue to be applied can be used. Succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, _{maleimide, -SS- (C 5 H 4 N} ) or contains an electrophilic group such as an activated ester, and / or which polymers terminated in It can be used as a reagent. For example, solid 4-arm NHS derivatized polyethylene glycol (such as pentaerythritol poly (ethylene glycol) ether tetrasuccinimidyl glutarate) can be applied to the tissue. Fibrosis inhibitors can be incorporated directly into either 4-arm NHS derivatized polyethylene glycol or basic buffer. In another example, the fiber formation inhibitor can be incorporated into a second carrier, and the second monomer can be incorporated into a 4-arm NHS derivatized polyethylene glycol and / or a basic buffer. The second simple substance may include fine particles and / or fine particles made of a biodegradable polymer. Biodegradable polymers include polyesters (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, can be composed of residues of one or more monomers selected from trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one), and XY , YXY, R- (YX) _n , R- (XY) _n and XYX block polymers are included. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.), and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASFCorporation (Mount Olive, NJ), Y is biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, etc.) From the residue of one or more monomers selected from γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one What can be configured, such as PLG-PEG-PLG), R is a multifunctional initiator. In another example, the tissue-reactive polymer can be applied first and then the fiber formation inhibitor can be applied to the coated tissue. The fiber formation inhibitor can be applied directly to the tissue or mixed into the second simple substance. The second carrier includes fine particles (as described above), fine particles (as described above), gel (hyaluronic acid, carboxymethyl cellulose, dextran, poly (ethylene oxide) -poly (propylene oxide) block copolymer, mixture, association, Cross-linked composition, etc.), film (biodegradable polyester, lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone , Γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one can be composed of one or more monomer residues And block polymers having the structures XY, YXY, R- (YX) _n , R- (XY) _n and XYX. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.), and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASFCorporation (Mount Olive, NJ), Y is biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, etc.) From the residue of one or more monomers selected from γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one Can be constructed (PLG-PEG-PLG, etc.), R is a multifunctional initiator, hyaluronic acid, potassium Bo carboxymethylcellulose, dextran, poly (ethylene oxide) - poly (propylene oxide) block copolymers, mixtures, federation, a crosslinked composition.

iv) Prevention of heart treatment adhesions In one embodiment, adhesions may be associated with cardiac surgical procedures. For heart surgery, including transplantation, defect repair, coronary artery bypass graft (CABG), congenital heart defects, and valve replacement, step-by-step and reoperation (especially repetitive CABG surgery) is very common. Therefore, cardiac surgery often requires surgery to be performed on tissue that has been traumatically damaged by previous surgery, resulting in thicker fibrotic adhesions and difficult incisions. Postoperative pericardial adhesions (adhesion between the two surfaces of the pericardium) with the first surgery are common. Pericardial adhesions can cause symptoms by restricting normal movement and clogging the heart during the cardiac cycle, thereby increasing the risk of patients undergoing repeated cardiac surgery. A resternotomy (opening the chest wall and reopening the heart to expose the heart surgically) and subsequent adhesion incisions increase the risk of damaging the heart, large vessels and explants, and increase the risk of operative time (patient cardiopulmonary Increase the time to undergo bypass), and increase the morbidity and mortality of the treatment. Resteriotomy is associated with 6% of major vascular trauma outbreaks, and mortality rates of over 35% have been reported for patients who experienced major bleeding during resternotomy. A 50% mortality rate has been reported in relation to aortocoronary graft injury. Pediatric staged open-heart surgery (which requires repeated treatment as the heart grows) also causes a very high rate of complications due to reoperation.

  As previously mentioned, adhesion barriers are frequently used to manage adhesions following cardiac laparotomy procedures. A variety of commercially available adhesion barriers can be used in combination with fibrosis inhibitors (and / or anti-infections) in managing cardiac surgery adhesions. Life Medical Sciences, Inc. is in various stages of development and has developed products (REPEL, REPEL-CV, RESOLVE and RELIVE) that can be used to prevent surgical adhesions in cardiac laparotomy and other surgeries. Products developed by Life Medical Sciences, Inc. are described in US Pat. Nos. 6,696,499, 6,399,624, 6,211,249, 6,136,333 and 5,711,958. ClosureMedical Corp. (Raleigh, NC) develops cyanoacrylate-based internal adhesives that can be used to seal internal surgical incisions and implants and are compatible with lung and common surgical professionals . Products developed by Closure Medical, Corp. are described in US Pat. Nos. 6,620,846, 6,579,469, 6,565,840, 6,547,467 and 5,981,621. Genzyme Corporation has developed biomaterials containing hyaluronic acid, such as SEPRAFILM and SEPRACOAT, to reduce the incidence of adhesions after cardiac surgery. (See U.S. Patent Nos. 6,780,427, 6,531,147, 6,521,223 and 6,010,692.

  Applied or immersed in a cardiac surgery site (or the surface of an implanted device or graft) to prevent adhesions during laparotomy or endoscopic cardiac surgery, used alone, or a therapeutic agent (eg, fiber Other commercially available substances that carry (inhibitors of formation or anti-infectives) include: (a) sprayable collagen-containing preparations such as COSTASIS or CT3; (b) sprayables such as COSEAL, ADHIBIT, FocalSeal or DURASEAL PEG-containing preparations, (c) fibrinogen-containing preparations such as FLOSEAL or TISSEAL, (d) hyaluronic acid-containing preparations such as RESTYLANE or PERLANE, HYLAFORM, or SYNVISC, (e) surgical implant polymer gels such as REPEL or FLOWGEL, (f ) Surgical adhesives containing cyanoacrylates such as Dermabond, Indermil, Glustitch, Tissumend, VetBond, Histoacryl BLUE and Orabase Soothe-N-Seal Liquid Protectant, (g) Dextran sulfate gels such as ADCON group gels , And (h) AdSurf lipid-based compositions such as. For those skilled in the art, not only the commercially available compositions not specifically mentioned above but also the next generation and / or future developed commercial products are expected to be used according to the present invention. It must be clear that it is suitable.

  Almost all manipulations of the chest wall, pericardium, and heart cause a cascade that can ultimately lead to the formation of adhesions. In many cases, adhesions need to be removed during repeated cardiac laparotomy procedures. Adhesion barriers, either alone or containing fibrosis inhibitors (and / or anti-infectives), can be applied directly to affected sites (solids, films, pastes, gels, It is most suitable to apply (in liquid or other form). In a preferred embodiment, the barrier (alone or including a fibrosis inhibitor and / or anti-infective) is the heart during treatment, directly or under a microscope, during treatment, during surgery or during manipulation, Sprayed on pericardium, pleura and chest wall. Because adhesions often occur in areas that are distant from the tissue that is actually placed during the surgical procedure, barriers (with or without therapeutic agents) can extend the barrier to large areas of the rib cage (sometimes the entire cardiopulmonary viscera and pericardium). However, it is necessary to apply to the portion immersed therein. Desirable barriers can be delivered during an laparotomy or endoscopically and remain in place for a time sufficient to adhere to the tissue to be treated and deliver the therapeutic agent or prevent formation of adhesions Films, liquids, gels, pastes, sprays, and other forms that can be included. Alternatively, the therapeutic agent can be injected directly into the pericardium (treatment of the treatment) so that the dose and duration of the drug are sufficient to prevent adhesions and complications (preferably multiple doses and / or sustained release). Can be delivered (before, during, or after). An ideal adhesion procedure reduces the incidence, number and persistence of adhesions and improves patient outcomes by reducing the complications of repeated treatments.

  As mentioned above, compositions for preventing surgical adhesions can be applied directly to the tissue of a cardiac surgical procedure or to a joint. The polymer composition (with or without fibrosis inhibitors or anti-infectives) can be administered by any of the methods described herein. Typical methods include direct application during surgery or direct application by endoscope, ultrasound, CT, MRI, fluoroscopy. When implanting a device, a medical device or graft is placed at the surgical site and an anti-adhesion composition is applied to the implant surface or surrounding tissue. Representative examples of grafts for use in spinal or neurosurgery include heart valves (pigs, artificial), auxiliary artificial hearts, heart pumps, artificial hearts, stents, bypass grafts (artificial and endogenous), patches , But not limited to, cardiac leads, defibrillators and pacemakers.

  The polymer composition can be applied during recovery procedures or endoscopic cardiac surgery with or without a fibrosis inhibitor. (a) During surgery, the pericardium (or immersed in the pericardium), heart, large blood vessels, capsule, lung, chest wall and adjacent infected tissue (eg, injectable material, solution, gel, gel formed in situ) (B) the implanted device or graft, and / or the tissue surrounding the graft (eg, injectable material, solution, gel, raw material). The gel or mesh formed in position) is (c) particularly useful in this example by intraperitoneal or endoscopic injection of the composition into the anatomical space (i.e. pericardium) at the surgical site. Is the use of an implantable composition containing a polymeric carrier and releasing a fibrosis inhibitor over a period ranging from hours to weeks-liquids, suspensions, emulsions, microemulsions, microspheres, pastes , Gels, microparticles, sprays, aerosols, solid implants And other formulations that can release the drug and be delivered to sites at risk of adhesion formation), (d) by intradermal injection of solutions, infusions, and sustained release formulations into tissues (interpericardial infusion), (e) At the desired heart location, by guided catheter or endoscopic injection of tissue into the lumen of the atrium, ventricle, large blood vessel, coronary artery or pericardium (especially useful in this example is high The use of an implantable composition containing a molecular carrier and releasing a fibrosis inhibitor over a period ranging from hours to weeks-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels , Microparticles, sprays, aerosols, solid implants and other formulations that can release the drug and be delivered to sites at risk of adhesion formation), and / or (f) by a combination of the methods described above. Combination therapy (ie, combination of therapeutic agents and antithrombotic, anti-infective, or antiplatelet agents) can also be used in the manner described above.

  In certain applications involving placement of a cardiac medical device or graft, a fibrosis inhibiting (and / or anti-infective) composition is applied at a site adjacent to the graft (preferably near the graft-tissue interface). May be desirable. This can be done during laparotomy, endoscopic or catheter treatment by applying a polymer composition with or without a fibrosis inhibitor. (a) Immediately before, during, and after the implantation procedure (b) Immediately before implantation of the implant on the surface of the implant (eg, as injection material, solution, paste, gel, gel formed in situ, or mesh) (C) before, during, or after graft implantation on adjacent tissue surfaces (eg, as injection material, solution, paste, gel, gel formed in situ, or mesh) (D) the anatomical space (heart) where the graft is placed on the surface of the graft and the tissue surrounding the graft (eg injection material, solution, paste, gel, gel or mesh formed in situ) Topical application of the composition to the membrane (intraarteries) (especially useful in this example is the use of a polymeric carrier that releases the fibrosis inhibitor over a period ranging from hours to weeks-liquid, suspension , Emulsion, microemulsion, microsphere , Pastes, gels, microparticles, sprays, aerosols, solid implants and other formulations that release the drug and can be delivered to the site where the device is inserted), (e) solutions to the tissue surrounding the implant, injections, And / or (f) application by a combination of the methods described above by intradermal injection of a sustained release formulation. Combination therapy (ie combination of therapeutic agents and antithrombotic, anti-infective, antiplatelet agents) can also be used.

  In one embodiment, the polymer composition can be delivered to the heart (or device / tissue interface) in the form of a laparotomy, endoscopic procedure or catheter-based procedure. The fibrosis inhibitor can be incorporated directly into the surgical adhesion barrier or can be incorporated into the second carrier (polymer or non-polymer) as described above and then incorporated into the adhesion barrier. Representative examples of spray or gel polymer compositions include poly (ethylene glycol) based systems, hyaluronic acid and crosslinked hyaluronic acid compositions. These compositions can be applied as final compositions or as materials that form a crosslinked gel in situ.

In another embodiment, the activated polymer is dissolved in a biologically acceptable buffer (pH is less than 6.8). If a second biologically acceptable buffer (pH is greater than 7.5) is present, the resulting solution is applied to the desired tissue surface. The reaction mixture is applied to the tissue site by extrusion, brushing, spraying, or other convenient method. After application of the composition to the surgical site, excess solution is removed from the surgical site as needed. At this point, the surgical site can be closed by conventional methods (sutures, staples, bioadhesive materials, etc.). In one embodiment, an activated polymer that can form a covalent bond with the tissue to be applied can be used. Succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, _{maleimide, -SS- (C 5 H 4 N} ) or contains an electrophilic group such as an activated ester, and / or which polymers terminated in It can be used as a reagent. For example, solid or liquid 4-arm NHS derivatized polyethylene glycol (such as pentaerythritol poly (ethylene glycol) ether tetrasuccinimidyl glutarate) can be applied to the tissue. In this example, 4-arm NHS derivatized polyethylene glycol is dissolved in an acidic solution (pH about 2-3) and then applied simultaneously to the tissue using a basic buffer (pH> about 8). The fiber formation inhibitor can be incorporated directly into either 4-arm NHS derivatized polyethylene glycol, acidic solution or basic buffer. In another example, the fiber formation inhibitor can be incorporated into a second carrier, and the second monomer can be incorporated into a 4-arm NHS derivatized polyethylene glycol, an acidic solution, and / or a basic buffer. The second simple substance may include fine particles and / or fine particles made of a biodegradable polymer. Biodegradable polymers include polyesters (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, can be composed of residues of one or more monomers selected from trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one), and XY , YXY, R- (YX) _n , R- (XY) _n and XYX block polymers are included. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.), and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASFCorporation (Mount Olive, NJ), Y is biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, etc.) From the residue of one or more monomers selected from γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one What can be configured, such as PLG-PEG-PLG), R is a multifunctional initiator. In another example, the tissue-reactive polymer can be applied first and then the fiber formation inhibitor can be applied to the coated tissue. The fiber formation inhibitor can be applied directly to the tissue or mixed into the second simple substance. The second carrier includes fine particles (as described above), fine particles (as described above), gel (hyaluronic acid, carboxymethyl cellulose, dextran, poly (ethylene oxide) -poly (propylene oxide) block copolymer, mixture, association, Cross-linked composition, etc.), film (biodegradable polyester, lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone , Γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one can be composed of one or more monomer residues And block polymers having the structures XY, YXY, R- (YX) _n , R- (XY) _n and XYX. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.), and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASFCorporation (Mount Olive, NJ), Y is biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, etc.) From the residue of one or more monomers selected from γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one Can be constructed (PLG-PEG-PLG, etc.), R is a multifunctional initiator, hyaluronic acid, potassium Bo carboxymethylcellulose, dextran, poly (ethylene oxide) - poly (propylene oxide) block copolymers, mixtures, federation, a crosslinked composition.

In yet another aspect, the activated polymer can be applied to the surgical site in a solid form. The activated polymer can react to the tissue surface applied as a polymer hydrate. Biologically acceptable buffer (pH> 7.5) can be applied to the tissue before and / or after applying the solid activated polymer. In one embodiment, an activated polymer that can form a covalent bond with the tissue to be applied can be used. Succinimidyl, aldehyde, epoxide, isocyanate, vinyl, vinyl sulfone, _{maleimide, -SS- (C 5 H 4 N} ) or contains an electrophilic group such as an activated ester, and / or which polymers terminated in It can be used as a reagent. For example, solid 4-arm NHS derivatized polyethylene glycol (such as pentaerythritol poly (ethylene glycol) ether tetrasuccinimidyl glutarate) can be applied to the tissue. Fibrosis inhibitors can be incorporated directly into either 4-arm NHS derivatized polyethylene glycol or basic buffer. In another example, the fiber formation inhibitor can be incorporated into a second carrier, and the second monomer can be incorporated into a 4-arm NHS derivatized polyethylene glycol and / or a basic buffer. The second simple substance may include fine particles and / or fine particles made of a biodegradable polymer. Biodegradable polymers include polyesters (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, can be composed of residues of one or more monomers selected from trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one), and XY , YXY, R- (YX) _n , R- (XY) _n and XYX block polymers are included. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.), and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASFCorporation (Mount Olive, NJ), Y is biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, etc.) From the residue of one or more monomers selected from γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one What can be configured, such as PLG-PEG-PLG), R is a multifunctional initiator. In another example, the tissue-reactive polymer can be applied first and then the fiber formation inhibitor can be applied to the coated tissue. The fiber formation inhibitor can be applied directly to the tissue or mixed into the second simple substance. The second carrier includes fine particles (as described above), fine particles (as described above), gel (hyaluronic acid, carboxymethyl cellulose, dextran, poly (ethylene oxide) -poly (propylene oxide) block copolymer, mixture, association, Cross-linked composition, etc.), film (biodegradable polyester, lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone , Γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one can be composed of one or more monomer residues And block polymers having the structures XY, YXY, R- (YX) _n , R- (XY) _n and XYX. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.) and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASF Corporation (Mount Olive, NJ)) , PLURONIC and PLURONIC R series of polymers), Y is a biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ- Residue of one or more monomers selected from butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one (PLG-PEG-PLG etc.), R is a multifunctional initiator, hyaluronic acid, potassium Ruboxymethylcellulose, dextran, poly (ethylene oxide) -poly (propylene oxide) block copolymers, mixtures, associations and cross-linked compositions.

v) Prevention of orthopedic surgical adhesions In one embodiment, adhesions may be associated with orthopedic surgical procedures. Many orthopedic procedures are performed as a result of injury or trauma (fractures, ligament injuries, cartilage, tendons or muscles) and can cause severe tissue damage leading to excessive scarring and adhesion formation. As a result, orthopedic procedures can cause trauma with severe post-operative complications, which can cause injury or trauma from the surgery itself. In general, excessive scarring and adhesion formation of orthopedic symptoms continues with the following patterns: (a) Joint damage leads to malformations such as joints that do not fully extend, bend, or do not turn (spasticity), (b ) Tendon damage, impedes normal movement and causes capsule contracture, (c) Cartilage damage, hyaline cartilage changes to fibrocartilage, resulting in loss of function and joint instability, (d) muscle damage Adhesion occurs in adjacent tissues, causing loss of strength and loss of function, (e) nerve damage causes loss of conduction and function. Entrapment (encircled and tightened) by scarring causes pain, sensory impairment and loss of motor function, and (f) tendons and ligaments cause shortening, loss of range of motion and loss of function Sometimes. Adhesion complications can be widespread. For example, adhesions formed after spinal surgery can cause low back pain, leg pain and sphincter disorders (bladder and intestinal tract). For this reason, methods for reducing adhesion formation in musculoskeletal surgery are a major clinical problem. The very right administration of the anti-adhesion composition, alone or loaded with a fibrosis inhibitor, can be utilized in a variety of clinical conditions to improve patient outcomes following emergency or non-emergency orthopedic procedures.

  As mentioned above, adhesion barriers are frequently used to manage adhesions following orthopedic procedures. A variety of commercially available adhesion barriers can be used in combination with fibrosis inhibitors (and / or anti-infections) in the management of orthopedic adhesions. Closure Medical Corp. (Raleigh, NC) has developed a cyanoacrylate-based internal adhesive that can be used to seal internal surgical incisions and implants and is compatible with orthopedic and general surgical professionals. ing. Products developed by Closure Medical, Corp. are described in US Pat. Nos. 6,620,846, 6,579,469, 6,565,840, 6,547,467 and 5,981,621. LifeMedical Sciences, Inc. is in various stages of development and has developed products (REPEL, REPEL-CV, RESOLVE and RELIVE) that can be used to prevent surgical adhesions in orthopedic and spinal surgery. Products developed by LifeMedical Sciences, Inc. are described in US Pat. Nos. 6,696,499, 6,399,624, 6,211,249, 6,136,333 and 5,711,958.

  Laparotomy or endoscopic surgery is applied or immersed in an orthopedic site (or the surface of an implanted device or graft) to prevent adhesions during surgery, used alone, or a therapeutic agent (e.g. Other commercial substances that carry (: fiber formation inhibitors or anti-infectives) include (a) sprayable collagen-containing formulations such as COSTASIS or CT3, (b) COSEAL, ADHIBIT, FocalSeal, SPRAYGEL or DURASEAL Sprayable PEG-containing preparations, (c) fibrinogen-containing preparations such as FLOSEAL or TISSEAL, (d) hyaluronic acid-containing preparations such as RESTYLANE, HYLAFORM, PERLANE, SYNVISC, SEPRAFILM, SEPRACOAT, InterGel, or LUBRICOAT, (e) REPEL Or surgical gels such as FLOWGEL, prosthetics such as (f) Osteobond (Zimmer), LVC (Wright Medical Technology), SimplexP (Stryker), Palacos (Smith & Nephew), and Endurance (Johnson & Johnson, Inc.) And organization Orthopedic "cements" used to hold in place, (g) surgical adhesive containing cyanoacrylates such as Dermabond, Indermil, Glustitch, Tissumend, VetBond, HistoacrylBLUE and Orabase Soothe-N-SealLiquid Protectant, (g) grafts containing hydroxyapatite (or synthetic bone material such as calcium sulfate, VITOSS (Orthovita) and CORTOSS (Orthovita)), (h) other biocompatible tissues manufactured by BioCure, 3M Company and Neomend, etc. Fillers, (i) polysaccharide gels such as ADCON series gels, (j) films such as INTERCEED, VICRYL mesh, and GelFoam, sponges or meshes, (o) lipid-based compositions such as AdSurf, and (p) There are OSSIGEL, viscous forms of hyaluronic acid (HA) and basic fibroblast growth factor (bFGF) (Orquest, Inc.) designed to accelerate healing of fractured bones. For those skilled in the art, not only the commercially available compositions not specifically mentioned above but also the next generation and / or future developed commercial products are expected to be used according to the present invention. It must be clear that it is suitable.

  Orthopedic procedures include fractures (open and closed), sprains, joint dislocation, crush trauma, ligament and muscle laceration, nerve damage, congenital malformations and congenital abnormalities, total and partial joint replacement, and cartilage damage It is performed for various symptoms including. Many procedures are performed by open surgical techniques, but orthopedic procedures are also increasingly performed through arthroscopes inserted into joints. Almost any musculoskeletal (muscle, tendon, joint, bone, cartilage) injury, trauma, or orthopedic surgical procedure can ultimately cause a cascade of adhesion formation. In many cases, adhesions need to be removed during repeated surgical procedures (eg, incision, tendon release, nerve strangulation release, frozen joint, etc.). Adhesion barriers, either alone or containing fibrosis inhibitors (and / or anti-infectives), can be applied directly to the affected site (solid, film, paste, gel) during open or arthroscopic orthopedic procedures. (In liquid, or other form) is most suitable. In a preferred embodiment, the barrier (alone or including a fibrosis inhibitor and / or anti-infective) is sprayed directly or arthroscopically on the infected musculoskeletal during treatment. Because adhesions often occur in areas away from the tissue that is actually placed during the surgical procedure, barriers (with or without therapeutic agents) need to be applied around damaged or repaired tissue. Desirable barriers can be delivered during an laparotomy or endoscopically and remain in place for a time sufficient to adhere to the tissue to be treated and deliver the therapeutic agent or prevent formation of adhesions Films, liquids, gels, pastes, sprays, and other forms that can be included. Ideal adhesion treatment reduces the incidence, number and persistence of adhesions, reduces pain, weakness and sensory abnormalities, prevents spasticity, increases range of motion, improves function, reduces physical malformations and disabilities Improve patient outcomes by limiting and reducing the need for repeated treatments.

  As described above, compositions for preventing surgical adhesions can be applied directly to the tissue of an orthopedic surgical procedure or to a joint. The polymer composition (with or without fibrosis inhibitors or anti-infectives) can be administered by any of the methods described herein. Typical methods include direct application during surgery or direct application by arthroscope, ultrasound, CT, MRI, fluoroscopy. When implanting a device, a medical device or graft is placed at the surgical site and an anti-adhesion composition is applied to the implant surface or surrounding tissue. Representative examples of implants for use in orthopedic procedures include plates, rods, screws, pins, wires, total and partial prostheses (artificial hips, knees, shoulders, finger joints), reinforcing patches, tissue There are fillers, synthetic bone fillers, bone cements, synthetic graft materials, allograft materials, autograft materials, artificial discs, spinal cord cages, and spinal canals.

  The polymer composition can be applied during recovery procedures or arthroscopic orthopedic surgery with or without a fibrosis inhibitor. (a) During surgical procedures, bone, joints, muscles, tendons, ligaments, cartilage and tissue surface adjacent to infected tissue (eg injection material, solution, paste, gel, in situ formation) (As a gel or mesh); (b) the surface of the implanted orthopedic device or graft and / or tissue around the graft before, during, or after the surgical procedure (eg, injection material, solution, paste) , Gel, as an in-situ formed gel or mesh), (c) at the surgical site (eg joint space, tendon sheath, nerve root, spinal canal) composition intra-articular or endoscopic to anatomical space By administration (especially useful in this example is the use of a polymeric carrier that releases a fibrosis inhibitor over a period ranging from hours to weeks-liquids, suspensions, emulsions, microemulsions, microspheres , Paste, gel, fine particles, spray, aerosol Solid implants and other formulations that release the drug and can be delivered to the site where the device is inserted), (d) intradermal injections of solutions, infusions, and sustained release formulations into tissues (intramuscular or intraarticular) (E) guided catheter injection of the composition into the tissue and / or (f) application by a combination of the methods described above. Combination therapy (ie, combination of therapeutic agents and antithrombotic, anti-infective, or antiplatelet agents) can also be used in the manner described above.

  In certain applications involving the placement of orthopedic medical devices and grafts, it may be necessary to apply a fibrosis inhibiting (or anti-infective) composition at the site adjacent to the graft (preferably near the graft-tissue interface). Sometimes desirable. This can be done during an open surgery, endoscopic or catheter orthopedic procedure by applying a polymer composition with or without a fibrosis inhibitor. (a) before, during, and after the transplantation procedure, (b) transplant the orthopedic graft on the surface of the graft (eg as injection material, solution, paste, gel, in-situ gel or mesh) Immediately before, during, or after, to adjacent tissue surface (eg, as injection material, solution, paste, gel, gel formed in situ, or mesh), Or later (d) the anatomical space in which the implant is placed on the surface of the implant and the tissue surrounding the implant (eg, injection material, solution, paste, gel, gel or mesh formed in situ) Topical application of the composition to the joint capsule (vertebral canal, bone marrow, tendon sheath, etc.) (especially useful in this example is the use of a polymeric carrier that releases the fibrosis inhibitor over a period ranging from hours to weeks. -Liquid, suspension, emulsion, microphone Emulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and other formulations that release the drug and can be delivered to the site where the device is inserted), (e) to the tissue surrounding the orthopedic implant Application by intradermal injection of solutions, infusions, and sustained release formulations of and / or (f) combinations of the methods described above. Combination therapy (ie combination of therapeutic agents and antithrombotic, anti-infective, antiplatelet agents) can also be used.

  In one embodiment, the polymer composition can be delivered to musculoskeletal tissue (or device / tissue interface) in the form of laparotomy, endoscopic treatment or catheter-based treatment. The fibrosis inhibitor (and / or anti-infective agent) is mixed directly into the surgical adhesion barrier or mixed into the second carrier (polymer or non-polymer) as described above and then mixed into the adhesion barrier. be able to. Representative examples of spray or gel polymer compositions include poly (ethylene glycol) based systems, hyaluronic acid and crosslinked hyaluronic acid compositions. These compositions can be applied as final compositions or as materials that form a crosslinked gel in situ.

In another embodiment, the activated polymer is dissolved in a biologically acceptable buffer (pH is less than 6.8). If a second biologically acceptable buffer (pH is greater than 7.5) is present, the resulting solution is applied to the desired tissue surface. The reaction mixture is applied to the tissue site by extrusion, brushing, spraying, or other convenient method. After application of the composition to the surgical site, excess solution is removed from the surgical site as needed. At this point, the surgical site can be closed by conventional methods (sutures, staples, bioadhesive materials, etc.). In one embodiment, an activated polymer that can form a covalent bond with the tissue to be applied can be used. Polymers containing and / or terminating electrophilic groups such as succinimidyl, aldehydes, epoxides, isocyanates, vinyls, vinyl sulfones, maleimides, -SS- (C ₅ H ₄ N) or activated esters are It can be used as a reagent. For example, solid or liquid 4-arm NHS derivatized polyethylene glycol (such as pentaerythritol poly (ethylene glycol) ether tetrasuccinimidyl glutarate) can be applied to the tissue. In this example, 4-arm NHS derivatized polyethylene glycol is dissolved in an acidic solution (pH about 2-3) and then applied simultaneously to the tissue using a basic buffer (pH> about 8). The fiber formation inhibitor can be incorporated directly into either 4-arm NHS derivatized polyethylene glycol, acidic solution or basic buffer. In another example, the fiber formation inhibitor can be incorporated into a second carrier, and the second monomer can be incorporated into a 4-arm NHS derivatized polyethylene glycol, an acidic solution, and / or a basic buffer. The second simple substance may include fine particles and / or fine particles made of a biodegradable polymer. Biodegradable polymers include polyesters (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, can be composed of residues of one or more monomers selected from trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one), and XY , YXY, R- (YX) _n , R- (XY) _n and XYX block polymers are included. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.) and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASF Corporation (Mount Olive, NJ)) , PLURONIC and PLURONIC R series of polymers), Y is a biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ- Residue of one or more monomers selected from butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one (PLG-PEG-PLG etc.), R is a multifunctional initiator. In another example, the tissue-reactive polymer can be applied first and then the fiber formation inhibitor can be applied to the coated tissue. The fiber formation inhibitor can be applied directly to the tissue or mixed into the second simple substance. The second carrier includes fine particles (as described above), fine particles (as described above), gel (hyaluronic acid, carboxymethyl cellulose, dextran, poly (ethylene oxide) -poly (propylene oxide) block copolymer, mixture, association, Cross-linked composition, etc.), film (biodegradable polyester, lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone , Γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one can be composed of one or more monomer residues And block polymers having the structures XY, YXY, R- (YX) _n , R- (XY) _n and XYX. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.) and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASF Corporation (Mount Olive, NJ)) , PLURONIC and PLURONIC R series of polymers), Y is a biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ- Residue of one or more monomers selected from butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one (PLG-PEG-PLG etc.), R is a multifunctional initiator, hyaluronic acid, potassium Ruboxymethylcellulose, dextran, poly (ethylene oxide) -poly (propylene oxide) block copolymers, mixtures, associations and cross-linked compositions.

In yet another aspect, the activated polymer can be applied to the surgical site in a solid form. The activated polymer can react to the tissue surface applied as a polymer hydrate. Biologically acceptable buffer (pH> 7.5) can be applied to the tissue before and / or after applying the solid activated polymer. In one embodiment, an activated polymer that can form a covalent bond with the tissue to be applied can be used. Polymers containing and / or terminating electrophilic groups such as succinimidyl, aldehydes, epoxides, isocyanates, vinyls, vinyl sulfones, maleimides, -SS- (C ₅ H ₄ N) or activated esters are It can be used as a reagent. For example, solid 4-arm NHS derivatized polyethylene glycol (such as pentaerythritol poly (ethylene glycol) ether tetrasuccinimidyl glutarate) can be applied to the tissue. Fibrosis inhibitors can be incorporated directly into either 4-arm NHS derivatized polyethylene glycol or basic buffer. In another example, the fiber formation inhibitor can be incorporated into a second carrier, and the second monomer can be incorporated into a 4-arm NHS derivatized polyethylene glycol and / or a basic buffer. The second simple substance may include fine particles and / or fine particles made of a biodegradable polymer. Biodegradable polymers include polyesters (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, can be composed of residues of one or more monomers selected from trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one), and XY , YXY, R- (YX) _n , R- (XY) _n and XYX block polymers are included. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.) and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASF Corporation (Mount Olive, NJ)) , PLURONIC and PLURONIC R series of polymers), Y is a biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ- Residue of one or more monomers selected from butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one (PLG-PEG-PLG etc.), R is a multifunctional initiator. In another example, the tissue-reactive polymer can be applied first and then the fiber formation inhibitor can be applied to the coated tissue. The fiber formation inhibitor can be applied directly to the tissue or mixed into the second simple substance. The second carrier includes fine particles (as described above), fine particles (as described above), gel (hyaluronic acid, carboxymethyl cellulose, dextran, poly (ethylene oxide) -poly (propylene oxide) block copolymer, mixture, association, Cross-linked composition, etc.), film (biodegradable polyester, lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone , Γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one can be composed of one or more monomer residues And block polymers having the structures XY, YXY, R- (YX) _n , R- (XY) _n and XYX. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.) and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASF Corporation (Mount Olive, NJ)) , PLURONIC and PLURONIC R series of polymers), Y is a biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ- Residue of one or more monomers selected from butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one (PLG-PEG-PLG etc.), R is a multifunctional initiator, hyaluronic acid, potassium Ruboxymethylcellulose, dextran, poly (ethylene oxide) -poly (propylene oxide) block copolymers, mixtures, associations and cross-linked compositions.

vi) Reconstruction and cosmetic surgery adhesion prevention In one embodiment, adhesions may be associated with cosmetic or reconstructive surgical procedures. The use of soft tissue grafts in cosmetic applications (aesthetics and reconstruction) includes breast augmentation, breast reconstruction after cancer surgery, craniofacial surgery, reconstruction after trauma, and congenital craniofacial reconstruction. It is common in eye plastic surgery.

  The clinical function of a soft tissue graft depends on whether the graft can effectively maintain its shape over time. In many instances, these devices are susceptible to “foreign” reactions from surrounding host tissue, such as when implanted in the body. The implanted device is recognized as a foreign body in the body, which causes an inflammatory response, followed by grafting of the graft with fibrous connective tissue (adhesion formation). Encapsulation of surgical grafts complicates various reconstruction and cosmetic surgery, but is particularly problematic in breast augmentation where the breast implant becomes coated with a fibrous coating and changes its anatomy and function. A scar capsule that cures and contracts (known as “capsular contracture”) is the most common complication of breast augmentation or reconstruction surgery. Capsular (fiber) contractures can cause breast stiffening, loss of normal anatomy and breast contours, discomfort, weakening or rupture of the implant shell, asymmetry, infection, and patient dissatisfaction. Furthermore, if the device is manipulated or stimulated by the daily activities of the patient, fiber coating of any soft tissue graft may occur even after successful implantation. Bleeding within and around the graft also leads to the triggering of a biological cascade that ultimately leads to scar tissue hyperplasia. In addition, certain types of implantable prostheses (such as breast augmentation implants) tend to leak from the outer membrane of the graft and can cause a chronic inflammatory response in the surrounding tissues (with tissue encapsulating and Gel filler (e.g., silicone). Undesirable scar effects around the graft are the primary cause of defect correction, scar tissue destruction (incision or capsulectomy), graft replacement, or additional surgery to remove the graft . The very right administration of the anti-adhesion composition, alone or loaded with a fibrosis inhibitor, can be utilized in various cosmetic and reconstruction procedures to improve patient outcomes.

  Soft tissue grafts are used in a variety of cosmetic, plastic and reconstructive surgeries, and on different body parts including but not limited to the face, nose, breast, chin, hips, chest, lips and cheeks. Can be delivered. Soft tissue grafts are used for reconstruction of tissue cavities made by surgery or trauma, tissue or organ augmentation, tissue contouring, bulk recovery for aged tissue, and soft tissue grooves or rhytides The Among all soft tissue transplant procedures, augmentation breast graft placement or breast reconstruction after mastectomy is the most frequently performed cosmetic surgery graft procedure. For example, in 2002 alone, more than 300,000 women underwent breast augmentation. About 80,000 of these women underwent breast reconstruction after mastectomy with cancer.

  Among all soft tissue transplants, the failure process is similar despite anatomical placement. However, breast grafts are used to describe the present invention because they are the most widely studied soft tissue transplant year. In general, breast augmentation or reconstruction surgery involves placing a commercially available breast implant, consisting of a coating filled with either saline or silicone, into tissue under the mammary gland. For breast augmentation, the following four incisions have been used: the axilla (under the armpit), the circumference of the areola (around the areola), the lower breast (the base of the breast intersecting the chest wall) and the umbilical cross ( Around the navel). Tissue is often excised with a small incision using an endoscope (especially for axillary and transumbilical procedures that require drilling from the incision to the chest). Pockets for placing breast augmentation implants are created either in the subgland or subthoracic region. For grafts under the gland, the tissue is incised to create a space between the glandular tissue and the greater pectoral muscle that extends to the heel of the lower breast. For the pectoral muscle graft, the pectoral muscle fibers are carefully excised to create a space between the lower pectoral muscle layer and the surface of the rib cage. Careful hemostasis is essential (because it can contribute to complications such as capsule contractures), and minimally invasive treatment (axillary, transumbilical approach) is more restrictive if bleeding control is inadequate There is a need to change to fewer treatments (eg, areola areola). Depending on the type of surgical approach selected, breast augment implants are often contracted and rolled up for placement in the patient. After being accurately positioned, the implant is filled or expanded to the desired size.

  Although many patients are satisfied with the initial treatment, a high percentage of people suffer from complications that often require repeated treatments for correction. Encapsulation of a breast augmentation prosthesis, which forms a shell (called capsule contracture) around the prosthesis, is the most common complication reported after breast augmentation, accounting for 50% of patients Has reported some dissatisfaction. Calcification can occur inside the fibrous coating, increasing its hardness further, complicating the interpretation of mammograms. Multiple causes have been identified for capsule contractures, including: foreign body reaction, migration of silicone gel molecules across the capsule or within tissues, autoimmune disease, genetic predisposition, infection, hematoma, and prosthesis Surface properties. Although the specific etiology has not been identified repeatedly, at the cellular level, the activity of breast fibroblasts stimulated by foreign bodies is a consistent finding. The capsule tissue around the prosthesis contains macrophages and sometimes T- and B-lymphocytes, suggesting an inflammatory component to the process. The surface of the implant has both smooth and textured areas formed in an attempt to reduce the coating, but none has been demonstrated to produce consistently excellent results. In animal models, it has been suggested that on surfaces with a texture that promotes the ingrowth of fibrous tissue on the surface, there is an increased tendency for increased coating thickness and contracture. Placing the implant in a position below the pectoral muscle appears to reduce the rate of encapsulation in both smooth and open-grained grafts.

  From the patient's point of view, the biological processes described above lead to a series of commonly described complaints. Implant mispositioning, hardness and unfavorable shape are the most frequently cited complications and the biggest factor in causing capsule contractures. When the surrounding scar coating begins to harden and contract, it can cause discomfort, weakening of the shell, asymmetry, skin depression and misplacement. Actual capsule contractures occur in about 10% of patients after breast augmentation and 25-30% in cases of reconstruction surgery, but many patients report dissatisfaction with aesthetic results . Scarring leading to asymmetry occurs in 10% of breast augmentations and 30% of reconstructions and is a major cause of corrective surgery. Skin hatching (due to the skin being pulled in the direction of the graft due to contracture) is a complication reported in 10-20% of patients. When fibrous tissue ingrowth into the diaphragmatic valve (the contact site used to expand the graft) causes the graft to become self-controlling and leaking, scarring is caused by graft contraction (1- 6% of patients, even saline has leaked from the graft, causing the graft to “shrink”). In addition, more than 15% of patients undergoing breast augmentation suffer from chronic pain, and the majority of these ultimately contribute to the formation of scar tissue. Other complications of breast augmentation include late leaks, hematomas (about 1-6% of patients), seromas (2.5%), hypertrophic scars (2-5%) and infections (about cases) 1 to 4%).

  Correction can include graft resection, incision (capsule removal or surgical release), capsule resection (surgical removal of the fiber capsule), or placement of the graft in another location (eg, subgland to chest) Several options may be involved, including submuscular). Ultimately, additional surgery (correction, incision, resection, reimplantation) is needed in more than 20% of breast augmentation patients and more than 40% of reconstruction surgery patients, but scar formation and capsule contractures This is a common cause. Treatment to destroy the scar may not be sufficient, with about 8% for breast augmentation and 25% for reconstructive surgery, eventually with surgical removal of the graft.

  A fibrosis inhibitor or composition delivered locally from a soft tissue graft or administered locally to a tissue around a breast augmentation implant minimizes fibrous tissue formation, capsulation and capsular contracture Can do. When the fibrosis inhibiting composition is applied to the surface of a soft tissue graft or mixed into a soft tissue graft (eg, the drug is mixed into saline, gel or silicone inside the graft, and passively passes through the capsule to the surrounding tissue. Fiber diffusion), fiber contracture can be minimized or prevented. Infiltrating a fibrosis inhibitor or composition into the tissue around the soft tissue graft or into the pocket created by the surgical procedure in which the graft is placed can reduce the formation of scars and capsule contractures in breast and reconstructive surgery. Other ways to prevent.

  As mentioned above, graft adhesion and fiber formation coating for cosmetic surgery are common complications of cosmetic and reconstructive surgery. In the management of this complication, various commercially available adhesion barriers can be used in combination with a fibrosis inhibitor (and / or anti-infection). During cosmetic surgery, to prevent adhesions, soft tissue contained within a soft tissue graft “filler” (generally saline, silicone or gel) or immersed in tissue around the implantation site Commercially available materials that are applied to the surface of the implant, used alone, or that carry a therapeutic agent (eg, a fibrosis inhibitor or an anti-infective agent) include (a) sprayable collagen such as COSTASIS or CT3 Formulations, (b) Sprayable PEG-containing formulations such as COSEAL, ADHIBIT, Focal Seal, SPRAYGEL or DURASEAL, (c) Fibrinogen-containing formulations such as FLOSEAL or TISSEAL, (d) RESTYLANE or PERLANE, HYLAFORM, SYNVISC, SEPRAFILM or SEPRACOAT Hyaluronic acid-containing formulations such as (e) Surgical polymer gels such as REPEL or FLOWGEL, (f) DERMABOND, INDERMIL, GLUSTITCH, TISSUMEND, VETBOND, HISTOACRYLBLUE, and ORABASE SOOTHE-N-SEAL LIQUID PROTECTANT Surgical adhesives containing cyanoacrylate, (g) dextran sulfate gels such as ADCON group gels, and (h) AdSurf lipid-based compositions such as. Some of the above drugs (eg, formulations containing PEG, collagen or fibrinogen such as CoSeal, CT3, Adhibit, CoStasis, Focalseal, Spraygel, Duraseal, Tisseal and Floseal are hemostatic agents and vascular sealants as an additional benefit, It is also considered useful in the practice of the present invention, as insufficient is believed to play a role in the development of capsule contractures. For those skilled in the art, not only the commercially available compositions not specifically mentioned above but also the next generation and / or future developed commercial products are expected to be used according to the present invention. It must be clear that it is suitable.

  As described above, compositions for preventing surgical adhesions can be applied directly to the tissue around the aesthetic implant site or to the joint. The polymer composition (with or without a therapeutic agent) can be administered by any of the methods described herein. Typical methods include direct application during surgery or direct application by endoscope, ultrasound, CT, MRI, fluoroscopy, and application in conjunction with placement of aesthetic implants at the surgical site. Representative examples of grafts for use in cosmetic surgery include saline breast grafts, silicone breast implants, heel and lower jaw grafts, nasal grafts, buccal grafts, lip grafts, etc. Facial implants, pectoral muscle implants, buccal and subbuccal implants, tissue fillers, and buttocks fillers.

  The polymer composition can be applied during recovery procedures or endoscopic cosmetic surgery with or without a fibrosis inhibitor. (a) on the surface of the soft tissue graft (eg, as an injection material, solution, paste, gel, gel formed in situ, or mesh) before, during, or after the implantation procedure; (b) soft tissue graft Immediately before or during transplantation, (c) before or during soft tissue graft implantation, on the tissue surface of the implantation hole (eg, injection material, solution, paste, gel, gel or mesh formed in situ) Later, (d) the anatomy where the soft tissue graft is placed on the surface of the soft tissue graft and / or the tissue surrounding the graft (eg injection material, solution, paste, gel, gel or mesh formed in situ) Topical application of fibrosis inhibitors in a biological space (especially useful in this example is the use of a polymeric carrier that releases fibrosis inhibitors over a period ranging from hours to weeks-liquids, suspensions , Emulsions, microemulsions, Cross spheres, pastes, gels, microparticles, sprays, aerosols, solid implants and other formulations that can release the drug and deliver it to the site where the implant is inserted), (e) solutions and injections into the tissue surrounding the implant And / or (f) application by a combination of the methods described above. Combination therapy (ie combination of therapeutic agents and antithrombotic, anti-infective, antiplatelet agents) can also be used.

  A composition comprising an anti-scarring agent can infiltrate the space (pocket created by surgery) into which the soft tissue graft is implanted. In certain applications involving the placement of soft tissue grafts for cosmetic surgery, a fibrosis inhibiting (or anti-infective) composition is applied at the site adjacent to the graft (preferably near the graft-tissue interface). It may be desirable. This can be done during laparotomy, endoscopic or catheter cosmetic procedures by applying a polymer composition with or without a fiber formation inhibitor. (a) before, during, and after the transplantation procedure, (b) transplant the soft tissue graft onto the surface of the graft (eg as injection material, solution, paste, gel, in situ formed gel, or mesh) Immediately before, during, or after, to an adjacent tissue surface (eg, as an injection material, solution, paste, gel, gel formed in situ, or mesh), (c) before, during, or Later, (d) the anatomical where the soft tissue graft is placed on the surface of the soft tissue graft and the surrounding tissue (eg injection material, solution, paste, gel, gel or mesh formed in situ) Topical application of the composition in a space (pocket created by surgery, eg, in the case of breast transplant, this is the space below the gland or pectoral muscle) (especially useful for this example is hours to weeks Fiber formation over time The use of polymeric carriers that release harmful agents-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants, and drug release devices Other formulations that can be delivered to the site of insertion), (e) by intradermal injection of solutions, infusions, and sustained release formulations into the tissue surrounding the soft tissue graft and / or (f) of the methods described above Application by combination. Combination therapy (ie combination of therapeutic agents and antithrombotic, anti-infective, antiplatelet agents) can also be used.

  In one embodiment, the polymer composition can be delivered to the soft tissue graft (or graft / tissue interface) in the form of a laparotomy, endoscopic procedure or catheter-based procedure. The fibrosis inhibitor (and / or anti-infective agent) is mixed directly into the surgical adhesion barrier or mixed into the second carrier (polymer or non-polymer) as described above and then mixed into the adhesion barrier. be able to. Typical examples of spray or gel polymer compositions include poly (ethylene glycol) based systems, fibrinogen containing systems, hyaluronic acid and crosslinked hyaluronic acid compositions. These compositions can be applied as final compositions or as materials that form a crosslinked gel in situ.

In another embodiment, the activated polymer is dissolved in a biologically acceptable buffer (pH is less than 6.8). If a second biologically acceptable buffer (pH is greater than 7.5) is present, the resulting solution is applied to the desired tissue surface. The reaction mixture is applied to the tissue site by extrusion, brushing, spraying, or other convenient method. After application of the composition to the surgical site, excess solution is removed from the surgical site as needed. At this point, the surgical site can be closed by conventional methods (sutures, staples, bioadhesive materials, etc.). In one embodiment, an activated polymer that can form a covalent bond with the tissue to be applied can be used. Polymers containing and / or terminating electrophilic groups such as succinimidyl, aldehydes, epoxides, isocyanates, vinyls, vinyl sulfones, maleimides, -SS- (C ₅ H ₄ N) or activated esters are It can be used as a reagent. For example, solid or liquid 4-arm NHS derivatized polyethylene glycol (such as pentaerythritol poly (ethylene glycol) ether tetrasuccinimidyl glutarate) can be applied to the tissue. In this example, 4-arm NHS derivatized polyethylene glycol is dissolved in an acidic solution (pH about 2-3) and then applied simultaneously to the tissue using a basic buffer (pH> about 8). The fiber formation inhibitor can be incorporated directly into either 4-arm NHS derivatized polyethylene glycol, acidic solution or basic buffer. In another example, the fiber formation inhibitor can be incorporated into a second carrier, and the second monomer can be incorporated into a 4-arm NHS derivatized polyethylene glycol, an acidic solution, and / or a basic buffer. The second simple substance may include fine particles and / or fine particles made of a biodegradable polymer. Biodegradable polymers include polyesters (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, can be composed of residues of one or more monomers selected from trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one), and XY , YXY, R- (YX) _n , R- (XY) _n and XYX block polymers are included. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.) and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASF Corporation (Mount Olive, NJ)) , PLURONIC and PLURONIC R series of polymers), Y is a biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ- Residue of one or more monomers selected from butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one (PLG-PEG-PLG etc.), R is a multifunctional initiator. In another example, the tissue-reactive polymer can be applied first and then the fiber formation inhibitor can be applied to the coated tissue. The fiber formation inhibitor can be applied directly to the tissue or mixed into the second simple substance. The second carrier includes fine particles (as described above), fine particles (as described above), gel (hyaluronic acid, carboxymethyl cellulose, dextran, poly (ethylene oxide) -poly (propylene oxide) block copolymer, mixture, association, Cross-linked composition, etc.), film (biodegradable polyester, lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone , Γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one can be composed of one or more monomer residues And block polymers having the structures XY, YXY, R- (YX) _n , R- (XY) _n and XYX. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.), and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASFCorporation (Mount Olive, NJ), Y is biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, etc.) From the residue of one or more monomers selected from γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one Can be constructed (PLG-PEG-PLG, etc.), R is a multifunctional initiator, hyaluronic acid, potassium Bo carboxymethylcellulose, dextran, poly (ethylene oxide) - poly (propylene oxide) block copolymers, mixtures, federation, a crosslinked composition.

In yet another aspect, the activated polymer can be applied to the surgical site in a solid form. The activated polymer can react to the tissue surface applied as a polymer hydrate. Biologically acceptable buffer (pH> 7.5) can be applied to the tissue before and / or after applying the solid activated polymer. In one embodiment, an activated polymer that can form a covalent bond with the tissue to be applied can be used. Polymers containing and / or terminating electrophilic groups such as succinimidyl, aldehydes, epoxides, isocyanates, vinyls, vinyl sulfones, maleimides, -SS- (C ₅ H ₄ N) or activated esters are It can be used as a reagent. For example, solid 4-arm NHS derivatized polyethylene glycol (such as pentaerythritol poly (ethylene glycol) ether tetrasuccinimidyl glutarate) can be applied to the tissue. Fibrosis inhibitors can be incorporated directly into either 4-arm NHS derivatized polyethylene glycol or basic buffer. In another example, the fiber formation inhibitor can be incorporated into a second carrier, and the second monomer can be incorporated into a 4-arm NHS derivatized polyethylene glycol and / or a basic buffer. The second simple substance may include fine particles and / or fine particles made of a biodegradable polymer. Biodegradable polymers include polyesters (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, can be composed of residues of one or more monomers selected from trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one), and XY , YXY, R- (YX) _n , R- (XY) _n and XYX block polymers are included. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.) and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASF Corporation (Mount Olive, NJ)) , PLURONIC and PLURONIC R series of polymers), Y is a biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ- Residue of one or more monomers selected from butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one (PLG-PEG-PLG etc.), R is a multifunctional initiator. In another example, the tissue-reactive polymer can be applied first and then the fiber formation inhibitor can be applied to the coated tissue. The fiber formation inhibitor can be applied directly to the tissue or mixed into the second simple substance. The second carrier includes fine particles (as described above), fine particles (as described above), gel (hyaluronic acid, carboxymethyl cellulose, dextran, poly (ethylene oxide) -poly (propylene oxide) block copolymer, mixture, association, Cross-linked composition, etc.), film (biodegradable polyester, lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone , Γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one can be composed of one or more monomer residues And block polymers having the structures XY, YXY, R- (YX) _n , R- (XY) _n and XYX. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.) and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASF Corporation (Mount Olive, NJ)) , PLURONIC and PLURONIC R series of polymers), Y is a biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ- Residue of one or more monomers selected from butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one (PLG-PEG-PLG etc.), R is a multifunctional initiator, hyaluronic acid, potassium Ruboxymethylcellulose, dextran, poly (ethylene oxide) -poly (propylene oxide) block copolymers, mixtures, associations and cross-linked compositions.

vii) Agents and doses of fibrosis inhibitors In certain embodiments of the invention, compositions are provided that can release therapeutic agents that can reduce scarring at the surgical site (ie, fibrosis inhibitors). In one embodiment of the invention, the surgical adhesion barrier can be adapted to release an agent that inhibits one or more of the five general factors for the process of fibrosis (or scarring) including: Inflammatory response and inflammation of connective tissue cells (such as fibroblasts and smooth muscle cells), migration and proliferation, neovascularization (angiogenesis), extracellular matrix (ECM) accumulation, and remodeling (fibrotic tissue maturation) And organization). Suppression of one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce scar tissue overgrowth.

Examples of fiber formation inhibitors that can be used in the surgical adhesion barrier are listed below. Cell cycle inhibitors include (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, Taxotere and docetaxel), (C) podophyllotoxins (such as etoposide), (D) immune Modulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase inhibitors (such as simvastatin), (G) inosine monophosphate dehydrogenase Inhibitors (such as mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ ), (H) NHκB inhibitors (such as Bay11-7082), (I) Antifungal agents (such as sulconizol), (J) p38 MAP kinase inhibition Agents (such as SB202190), and analogs and derivatives as described above.

  The dose of drug administered from this composition to prevent surgical adhesions will depend on a variety of factors including the type of formulation, the site of healing, and the type of condition being treated. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), and the total drug dose administered can be measured and the appropriate surface concentration of the active agent can be determined. Drugs are generally used at concentrations ranging from several times the concentration used in single systemic applications up to 50%, 20%, 10%, 5%, or even less than 1%. In certain embodiments, the anti-scarring agent is released from the polymeric compound at an effective concentration over a period measured from the time of immersion in the tissue adjacent to the device, ranging from less than about 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, about 90 days The range is from day to about 180 days. In one embodiment, the drug is released at an effective concentration for 1 to 90 days.

A typical fibrosis inhibitor used alone or in combination should be administered according to the following dosage guidelines. The total amount (dose) of the anti-scarring agent in the composition is about 0.01 μg to 10 μg, 10 μg to 10 mg, 10 mg to 250 mg, 250 mg to 1000 mg, 1000 mg to 2500 mg. Can be a range. Scarring inhibitor dose per unit area of the surface to which drug is applied (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2, 1 μg / mm 2 ~10 μg / mm 2, 10 μg / mm 2 ~250μg / mm ^2, 250 may be one of a range of ^{μg / mm 2 ~1000 μg / mm} 2, 1000 μg / mm 2 ~2500μg / mm 2.

Listed below are exemplary dosage ranges for various anti-scarring agents that can be used in conjunction with a composition for treating or preventing surgical adhesions in accordance with the present invention. (A) A cell cycle inhibitor comprising doxorubicin and mitoxantrone. Doxorubicin analogs and derivatives thereof: The total dose should not exceed 25 mg (range 0.1 μg to 25 mg) and the preferred total dose is 1 μg to 5 mg. The dose per unit area was ^{0.01 μg / mm 2 ~100μg / mm} 2, preferred dosage is ^{0.1 μg / mm 2 ~10 μg /} mm 2. The lowest concentration of doxorubicin, 10 ⁻⁸ to 10 ⁻⁴ M, should be maintained on the graft or barrier surface. Mitoxantrone and its analogs and derivatives: The total dose should not exceed 5 mg (0.01 μg to 5 mg range), the preferred total dose being 0.1 μg to 1 mg. The dosage per unit area is 0.01 μg / mm ^{2 to} 20 μg / mm ² , and the preferred dosage is 0.05 μg / mm ^{2 to} 3 μg / mm ² . The lowest concentration of mitoxantrone, 10 ⁻⁸ to 10 ⁻⁴ M, should be maintained on the graft or barrier surface. (B) Cell cycle inhibitors including paclitaxel and analogs and derivatives thereof (eg docetaxel): The total dose should not exceed 10 mg (range 0.1 μg to 10 mg), the preferred total dose is 1 μg to 3 mg. The dose per unit area was ^{0.1 μg / mm 2 ~10μg / mm} 2, preferred dosage is ^{0.25 μg / mm 2 ~5 μg /} mm 2. The lowest concentration of paclitaxel, 10 ⁻⁸ to 10 ⁻⁴ M, should be maintained on the graft or barrier surface. (C) Cell cycle inhibitors such as podophyllotoxin (eg etoposide): The total dose should not exceed 10 mg (range 0.1 μg to 10 mg), and the preferred total dose is 1 μg to 3 mg To do. The dose per unit area was ^{0.1 μg / mm 2 ~10μg / mm} 2, preferred dosage is ^{0.25 μg / mm 2 ~5 μg /} mm 2. A minimum concentration of etoposide of 10 ⁻⁸ to 10 ⁻⁴ M should be maintained on the graft or barrier surface. (D) Immunosuppressive drugs including sirolimus and everolimus. Sirolimus (eg, rapamycin, rapamune): The total dose should not exceed 10 mg (range 0.1 μg to 10 mg), the preferred total dose being 10 μg to 1 mg. The dosage per unit area is 0.1 μg / mm ^{2 to} 100 μg / mm ² , and the preferred dosage is 0.5 μg / mm ² to 10 μg / mm ² . The lowest concentration of sirolimus, 10 ⁻⁸ to 10 ⁻⁴ M, should be maintained on the graft or barrier surface. Everolimus and its analogs and derivatives: the total dose should not exceed 10 mg (range 0.1 μg to 10 mg), the preferred total dose being 10 μg to 1 mg. The dosage per unit area of the surface area is 0.1 μg / mm ^{2 to} 100 μg / mm ² , and the preferred dosage is 0.3 μg / mm ² to 10 μg / mm ² . The lowest concentration of everolimus, 10 ⁻⁸ to 10 ⁻⁴ M, should be maintained on the graft or barrier surface. (E) Heat shock protein 90 antagonist (eg, geldanamycin) and analogs and derivatives thereof: the total dose should not exceed 20 mg (range 0.1 μg to 20 mg), the preferred total dose is 1 μg ˜5 mg. The dose per unit area was ^{0.1 μg / mm 2 ~10μg / mm} 2, preferred dosage is ^{0.25 μg / mm 2 ~5 μg /} mm 2. The lowest concentration of geldanamycin, 10 ⁻⁸ to 10 ⁻⁴ M, should be maintained on the graft or barrier surface. (F) HMGCoA reductase inhibitors (eg, simvastatin) and analogs and derivatives thereof: the total dose should not exceed 2000 mg (range 10.0 μg to 2000 mg), and the preferred total dose is 10 μg to 300 mg And The dose per unit area is ^{1.0μg / mm 2 ~1000 μg / mm} 2, a preferred dosage ^{2.5 μg / mm 2 ~500μg / mm} 2. The lowest concentration of simvastatin, 10 ⁻⁸ to 10 ⁻³ M, should be maintained on the graft or barrier surface. (G) Inosine monophosphate dehydrogenase inhibitors (eg, mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ ) and analogs and derivatives thereof: Total dose exceeds 2000 mg (range 10.0 μg to 2000 mg) The preferred total dose is 10 μg to 300 mg. The dose per unit area is ^{1.0μg / mm 2 ~1000 μg / mm} 2, a preferred dosage ^{2.5 μg / mm 2 ~500μg / mm} 2. The minimum concentration of mycophenolic acid, 10 ⁻⁸ to 10 ⁻³ M, should be maintained on the graft or barrier surface. (H) NFκB inhibitors (eg, Bay 11-7082) and analogs and derivatives thereof: the total dose should not exceed 200 mg (range 0.1 μg to 200 mg), and the preferred total dose is 1 μg to 50 mg. The dose per unit area is 1.0 μg / mm ^{2 to} 100 μg / mm ² , and the preferred dose is 2.5 μg / mm ² to 50 μg / mm ² . The minimum concentration of Bay 11-7082, 10 ⁻⁸ to 10 ⁻⁴ M, should be maintained on the graft or barrier surface. (I) Antifungal drugs (eg sulconizole) and analogues and derivatives thereof: The total dose should not exceed 2000 mg (range 10.0 μg to 2000 mg), the preferred total dose is 10 μg to 300 mg To do. The dose per unit area was ^{1.0 μg / mm 2 ~1000μg / mm} 2, a preferred dosage ^{2.5 μg / mm 2 ~500 μg /} mm 2. The graft or barrier surface to maintain a minimum concentration of Surukonizoru to 10 ^-8 ~10 ^-3 M. The same applies to (J) p38 MAP kinase inhibitors (such as SB202190), analogs and derivatives thereof. The total dose is not to exceed 2000 mg (range of 10.0 μg to 2000 mg), and the preferable total dose is 10 μg to 300 mg. The dose per unit area was ^{1.0 μg / mm 2 ~1000μg / mm} 2, a preferred dosage ^{2.5 μg / mm 2 ~500 μg /} mm 2. The lowest concentration of SB202190, 10 ⁻⁸ to 10 ⁻³ M, should be maintained on the graft or barrier surface.

  According to another aspect, any of the anti-infectives described above can be used in combination with the present composition to prevent surgical adhesions. Typical anti-infectives include (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) Dophilotoxins (such as etoposide), (E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin), and analogs and derivatives of the above.

  The dose of drug administered from this composition to prevent or inhibit infection according to the present invention will depend on various factors including the type of formulation, the site of healing, and the type of condition being treated. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), and the total drug dose administered can be measured and the appropriate surface concentration of the active agent can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective agent is released from the polymeric compound at an effective concentration in the range of less than about 1 day to about 180 days over a period measured from the time of immersion in the tissue adjacent to the device. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, about 90 days The range is from day to about 180 days.

  The dose of drug administered from this composition to prevent or inhibit infection according to the present invention will depend on various factors including the type of formulation, the site of healing, and the type of condition being treated. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), and the total drug dose administered can be measured and the appropriate surface concentration of the active agent can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective agent is released from the polymeric compound at an effective concentration in the range of less than about 1 day to about 180 days over a period measured from the time of immersion in the tissue adjacent to the device. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, about 90 days The range is from day to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following dosage guidelines. The total amount (dose) of the anti-infective agent in the composition is about 0.01 μg-1 μg, about 1 μg-10 μg, about 10 μg-1 mg, about 1 mg-10 mg, about 10 mg-100 mg , About 100 mg to 250 mg, about 250 mg to 1000 mg. The dosage (dose) of the drug per unit area of the device or tissue surface to which the anti-infective agent is applied is about 0.01 μg / mm ² to 1 μg / mm ² , about 1 μg / mm ² to 10 μg / mm ² , about 10 μg / mm ^{2 to} 100 μg / mm ² , about 100 μg / mm ² to 250 μg / mm ² , about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compounds which release an anti-infective agents in different proportions, administration parameters described above, a minimum concentration of about 10 ^-8 M to ^-7 M of the drug tissue surface, about 10 ^-7 M to ^-6 M, about 10 ^-6 M to ^-5 M, to be maintained at either about 10 ^-5 M to ^-4 M, it should be used in combination with the drug release rate from the composition.

Inflammatory Arthritis In one embodiment, the present invention provides a composition for the treatment and prevention of inflammatory arthritis. The composition of the present invention can be composed of one or more polymer carriers and an anti-scarring agent.

  Inflammatory arthritis is a serious health problem in developed countries due to the increasing number of elderly people. Inflammatory arthritis includes rheumatoid arthritis, systemic lupus, erythema, systemic sclerosis (scleroderma), mixed connective tissue disease, Sjogren's syndrome, ankylosing spondylitis, Behcet's syndrome, sarcoidosis, and osteoarthritis, It is not limited to them. These are all characterized by inflammatory and / or painful symptoms as prominent symptoms.

  In one embodiment, the composition can be used to treat or prevent osteoarthritis (OA). Osteoarthritis is a common, debilitating and expensive disease that is currently considered an incurable disease. The disease is characterized by abnormal functioning of chondrocytes, and finally its terminal differentiation leading to the initiation of OA, the destruction of the cartilage matrix in the articular cartilage of infected joints. While age is the strongest risk factor for OA, serious joint trauma, overweight and repeated joint use are important risk factors for OA. The pattern of OA joint involvement is also affected by excessive work and entertainment.

  OA consists of a primary (non-specific) type and a secondary type. Primary OA is most often associated with age. Repeated use of joints, particularly those that support the weight of the hips, knees and back, stimulates the joints and causes inflammation, causing joint pain and swelling. Eventually, the cartilage begins to deteriorate by peeling off and forming a small deterioration. As the disease progresses, the cartilage buffer between the bone and joint is completely gone. Loss of the cartilage buffer causes friction between the bones, causing pain and limiting joint movement. Cartilage inflammation promotes the growth of new bone around the joint (bone puncture).

  Secondary OA is pathologically indistinguishable from nonspecific OA, but causes other diseases and conditions. Diseases that lead to secondary OA include obesity, severe trauma (eg, ligament damage, cartilage damage), joint structure surgery (ligament repair, meniscal resection, cartilage removal), abnormal joints at birth (congenital) Abnormal), gout, diabetes, and other metabolic disorders.

  In one embodiment, the composition can be used to treat or prevent rheumatoid arthritis (RA). Rheumatoid arthritis is a multisystem chronic, recurrent, inflammatory disease of unknown cause. Although many organs are affected, RA is basically a severe form of chronic synovitis that leads to destruction and stiffness of inflamed joints (Robbins Pathological Basis of Disease, RS Cotran, V. Kumar And by SL Robbins, WBSaunders Co., 1989). Pathologically, the disease is characterized by significant hypertrophy of the synovium, forming villus-like processes and extending into the joint space, synovial alignment (synovial proliferation), leukocytes (macrophages, lymphocytes, plasma cells, and Lymphoid follicles (called “inflammatory synovitis”) infiltrate the synovium and form several layers of fibrinous deposits in which cells are necrotic. The tissue formed as a result of this process is called pannus and grows to eventually fill the joint space. Pannus creates an extensive network of new blood vessels that are essential for synovitis change through the process of angiogenesis. Digestive enzymes released from cells of pannus tissue (matrix metalloproteinases such as collagenase and stromelysin) and other mediators of inflammatory processes (eg, hydrogen peroxide, superoxide, lysosomal enzymes, and arachidonic acid metabolism) Product) destroys the cartilage matrix and causes progressive destruction of the cartilage. Pannus penetrates the articular cartilage, leading to erosion and degradation of the cartilage tissue. Eventually, the subchondral bone of the associated joint erodes with fibrous toughness and eventually with bone tonicity.

  RA is an autoimmune disease and is generally believed to stimulate many different joint stimuli to activate an immune response in immunogenetic susceptible hosts, but has not been conclusively proven. Neither exogenous infectious agents (EB virus, rubella virus, cytomegalovirus, herpes virus, human cell T-lymphotropic virus, mycoplasma, etc.) or endogenous proteins (collagen, proteoglycan, altered immunoglobulin) It has been done so far as a causative agent that causes an appropriate host immune response. Regardless of the inducer, autoimmunity plays a role in the progression to the disease. In particular, relevant antigens are taken up by antigen presenting cells (synovial macrophages or dendritic cells), processed and presented to T lymphocytes. T cells elicit cellular immune responses that stimulate the proliferation and differentiation of B lymphocytes and transmit them to plasma cells. As a result, an excessive and inappropriate immune response is directed against the host tissue (eg antitoxin directed against type II collagen, against the Fc portion of autologous IgG (called “rheumatic factor”) Directed antitoxin). This further amplifies the immune response and accelerates the destruction of the cartilage tissue. When this cascade is initiated, many mediators that destroy cartilage cause rheumatoid arthritis to progress.

  When a rheumatoid joint is invaded by pannus tissue (composed of inflammatory cells, blood vessels, and connective tissue), the articular cartilage is destroyed. In general, chronic inflammation by itself is not sufficient to damage the interface, but permanent defects can be created when fibrotic vascular tissue digests cartilage arrest. Abnormal growth of blood vessels and pannus tissue may inhibit treatment with a fibrosis inhibitor composition or fibrosis inhibitor. Incorporation of scar suppressants into these compositions and other intra-articular formulations provides an approach that can slow the rate of disease progression.

  Thus, within one embodiment of the present invention, a method comprising the step of administering to a patient in need a composition containing a therapeutically effective amount of an anti-scarring or fibrosis inhibitor, wherein inflammatory arthritis is A method of treating or preventing is provided. Inflammatory arthritis includes rheumatoid arthritis, systemic lupus, erythema, systemic sclerosis (scleroderma), mixed connective tissue disease, Sjogren's syndrome, ankylosing spondylitis, Behcet's syndrome, sarcoidosis, and osteoarthritis It is not limited to. These are all characterized by inflammatory and / or painful symptoms as prominent symptoms.

  Effective anti-scar therapy for inflammatory arthritis accomplishes one or more of the following: (i) Symptoms (pain, swelling and tenderness of the infected joint, morning stiffness, weakness, malaise, loss of appetite, weight (Ii) reduction of severity of (symptoms), (ii) reduction of severity of clinical symptoms (concentration of joint covering, synovial hypertrophy, joint exudates, soft tissue spasticity, reduction of range of motion, stiffness and fixed joint malformations), ( iii) reduction of extra-articular symptoms (rheumatic nodules, vasculitis, pulmonary nodules, interstitial fibrosis, pericarditis, episclerosis, iritis, Ferti syndrome, osteoporosis), (iv) period of disease remission / Increase the frequency and interval at which symptoms do not occur, (v) prevent fixed defects and disabilities, and / or (vi) prevent / reduce chronic progression of symptoms.

  In accordance with the present invention, any of the above scarring inhibitors can be utilized in the practice of this invention. In certain embodiments of the invention, the composition is associated with inflammatory arthritis and releases an agent that inhibits one or more of the general factors for the process of fiber formation (or scarring), including: (a) new Angiogenesis (angiogenesis), (b) migration and / or proliferation of connective tissue cells (fibroblasts and synovium), (c) destruction of cartilage matrix by metalloproteinase activity, (d) cytokines (IL-1, Inflammatory reaction caused by TNFα, FGF, VEGF, etc. By inhibiting one or more elements of fibrosis (or scarring), cartilage loss can be inhibited or reduced.

  In one embodiment, the composition comprises a scarring inhibitor and a polymeric carrier that can be applied to treat inflammatory arthritis. A number of polymeric and non-polymeric delivery systems containing anti-scarring agents for the treatment of inflammatory arthritis have already been described above. The anti-scarring agent can be administered systemically at the lowest dose to obtain the above results (orally, intravenously, or by intramuscular or subcutaneous injection). For patients with few infected joints, or patients with significant symptoms in a limited number of joints, through needle insertion into the percutaneous joint capsule or as part of an orthopedic procedure performed on the joint As such, the scarring inhibitor can be injected directly into the infected joint (intra-articular injection). In a preferred embodiment, an intra-articular formulation containing a fibrosis inhibitor is administered to the joint after an injury that is likely to induce arthritis (such as an injury to the cruciate ligament or knee meniscus) occurs. The drug is administered for a sufficient period of time (through sustained release formulations and / or repeated infusions) so that the cartilage is not destroyed as a result of injury (or a surgical procedure to treat it).

  The anti-scarring agent can be administered by any method described herein. However, preferred administration methods include intravenous, oral, subcutaneous or intramuscular injection. Particularly preferred examples include administration of a fibrosis-inhibiting compound as an intra-articular injection (directly under arthroscopy or radiation guidance or irrigated into the joint as part of an open surgical procedure). Scarring inhibitors can be administered chronically at low dosages to prevent disease progression, extend the remission phase of the disease, or alleviate symptoms of an ongoing disease. Alternatively, the therapeutic agent, for example, in the case of acute inflammation following traumatic joint injury (as described below, intra-articular fracture, ligament injury, knee meniscus injury, etc.), to trigger the relief of ongoing serious disease As a “pulse” therapy, it can be administered continuously at high doses. The minimum dosage that can be used to achieve these goals may vary depending on the patient, the severity of the disease, the formulation of the drug being administered, the efficacy and / or tolerance of the drug, the clearance of the drug from the joint, and the route of administration.

  In one embodiment, the fibrosis inhibiting composition may be a hyaluronic acid composition that can be injected into a joint. Hyaluronic acid, a normal component of synovial joint fluid, lubricates the joint surface during normal activity (rest, walk) to prevent physical damage and shocks the joint with high impact activity (running, jumping, etc.) Reduce. In patients with OA, the elasticity and viscosity of synovial fluid and synovial hyaluronic acid concentrations are reduced. This is believed to promote the destruction of the articular cartilage within the connection. HA (typically sodium hyaluronate) administered intra-articularly penetrates the articular cartilage surface, synovial tissue, and joint capsule for a period of time after injection. By injecting hyaluronic acid into the joint (known as adding viscosity), it is possible to open the normal environment of synovial fluid, reduce pain, and prevent damage and disability. Representative examples of hyaluronic acid compositions used with viscosity addition are described in US Pat. Nos. 6,654,120, 6,645,945, and 6,635,287. Thus, HA-containing substances can be used as intra-articular injections (either as a single treatment or as a series of repeated treatment cycles) to treat knee osteoarthritis in patients whose conventional treatment cannot sufficiently relieve pain. As). Sometimes other joints such as the hips (injected under fluoroscopy), ankles, shoulders and elbow joints are also injected with HA to alleviate the symptoms of those specific joints. Depending on the particular commercial product, the HA substance is injected into the joint once a week for 5-6 weeks. If effective, the patient reports a reduction in symptoms over 6 months. At that point, the cycle is repeated to prolong treatment activity. Although some patients have sustained effects, infused hyaluronan is rapidly lost from joints in the body within a few days. Prolonging the residence time of hyaluronan in the joint by inhibiting the destruction of hyaluronan is expected to increase its efficiency and increase the duration of symptom relief. By adding a fibrosis inhibitor to hyaluronan, intra-articular injection has the added benefit of preventing cartilage damage (eg, “cartilage protection”).

  In the treatment of inflammatory arthritis, various commercially available HA compositions can be used according to the present invention in combination with one or more agents, including the following: Hylan (sodium hyaluronate ( Synvisc (Biomatrix, Inc., Ridgefield, NJ), Hyalgan (Sanofi-Synthelabo Inc., New York, NY), a highly elastic liquid chicken crown derived polymer containing derivatives of hyaluronan), and highly purified ORTHOVISC (Ortho Biotech Products, Bridge, NJ), used to relieve pain and improve joint mobility and range of motion in patients with high molecular weight, high viscosity HA and osteoarthritis (OA) in the knee Water). ORTHOVISC is injected into the knee to restore the elasticity and viscosity of the synovial fluid. HYVISC is a high molecular weight injectable HA product developed by Anika Therapeutics (Woburn, Mass.) And is currently used to treat osteoarthritis and racehorse legs. Other high-viscosity products for osteoarthritis treatment by HA include SUPERTZ from Seikagaku Corporation (Japan), Suplasyn from Bioniche Life Sciences, Inc. (Canada), DePuyOrthopaedics, Inc. (Indiana) There are ARTHREASE from Warsaw and Durolane from Q-Med AB (Sweden).

  In one embodiment, the compositions of the invention can be used to manage osteoarthritis in animals (such as horses). Some HA products (especially HYVISC, Boehringer Ingelheim Vetmedica, St. Joseph, MO) are also used for veterinary applications (usually equine osteoarthritis and legs). .

  Other intra-articular compositions used to treat arthritis include corticosteroids. The most common corticosteroids currently used for inflammatory arthritis are methylprednisolone acetate (DEPO-MEDROL, Pharmacia & Upjohn Company, Kalamazoo, MI), and triamcinolone acetonide (KENALOG, Bristol-Myers Squibb, NY) New York). With the addition of fibrosis inhibitors to intra-articular corticosteroid injection, intra-articular injection has the added benefit of preventing cartilage damage (such as “cartilage protection”).

  Formulations that can be used for these applications include solutions, topical formulations (eg, solutions, creams, ointments, gels), emulsions, micelle solutions, gels (crosslinkable and non-crosslinkable), test solutions and pastes. One form of formulation is an injectable composition. Hyaluronic acid (cross-linked, derivatized and / or non-cross-linked) is a typical material in compositions that further contain a polymer to increase the viscosity of the formulation. Such preparations can further include polymers (collagen, poly (ethylene glycol), dextran, etc.) and biocompatible solvents (ethanol, DMSO, NMP, etc.). In one embodiment, the fibrosis inhibitor therapeutic agent can be incorporated directly into the formulation. In another example, the fibrosis inhibiting therapeutic can be incorporated into a second carrier (such as the micelles, liposomes, emulsions, fines, nanospheres, etc. described above). Fines and nanospheres can be composed of biodegradable polymers. Degradable polymers that can be used include poly (hydroxyl esters) (such as PLGA, PLA, PCL, and the like) and polyanhydrides, polyorthoesters, and polysaccharides (such as chitosan and alginate).

In one embodiment, the fiber formation inhibitor is further comprised of a biodegradable polymer. Biodegradable polymers include polyesters (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, can be composed of residues of one or more monomers selected from trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one), and XY , YXY, R- (YX) _n , R- (XY) _n and XYX block polymers are included. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.), and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASFCorporation (Mount Olive, NJ), Y is biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, etc.) From the residue of one or more monomers selected from γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one What can be configured, such as PLG-PEG-PLG), R is a multifunctional initiator. In another example, the fiber formation inhibitor / polymer composition may further comprise a solvent, liquid oligomer, or liquid polymer such that the final composition passes through an 18G needle. Reagents used include ethanol, NMP, PEG 200, PEG 300 and low molecular weight liquid polymers having the structures XY, YXY, R- (YX) _n, R- (XY) _n and XYX. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.), and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASFCorporation (Mount Olive, NJ), Polymers such as PLURONIC and PLURONIC R series) and Y is a biodegradable polyester. Here, the polyester is lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, Those composed of residues of one or more monomers selected from trimethylene carbonate, 1,4-dioxan-2-one or 1,5 dioxepan-2-one (eg PLG-PEG-PLG). R is a multifunctional initiator.

In another example, the fiber formation inhibitor can be in the form of a solution or suspension of an organic solvent, a liquid oligomer or a liquid polymer. In this example, there are reagents such as ethanol, NMP, PEG200, PEG300 and low molecular weight liquid polymers having the structure of XY, YXY, R- (YX) _n, R- (XY) _n and XYX. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.), and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASFCorporation (Mount Olive, NJ), Polymers such as PLURONIC and PLURONIC R series) and Y is a biodegradable polyester. Here, the polyester is lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, Those composed of residues of one or more monomers selected from trimethylene carbonate, 1,4-dioxan-2-one or 1,5 dioxepan-2-one (eg PLG-PEG-PLG). R is a multifunctional initiator.

Examples of fiber formation inhibitors that can be used in the treatment of inflammatory arthritis are given below. Cell cycle inhibitors include (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, Taxotere and docetaxel), (C) podophyllotoxins (such as etoposide), (D) immune Modulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase inhibitors (such as simvastatin), (G) inosine monophosphate dehydrogenase Inhibitors (such as mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ ), (H) NHκB inhibitors (such as Bay11-7082), (I) Antifungal agents (such as sulconizol), (J) p38 MAP kinase inhibition Agents (such as SB202190), and analogs and derivatives as described above.

  The drug dosage administered from the current composition for the treatment of inflammatory arthritis depends on various factors including the type of formulation and the healing site. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), and the total drug dose administered can be measured and the appropriate surface concentration of the active agent can be determined. For topical application, drugs are generally in concentrations ranging from several times the concentration used in single systemic applications to less than 50%, 20%, 10%, 5%, or even 1%. used. In certain embodiments, the anti-scarring agent is released from the polymeric compound at an effective concentration over a period measured from the time of immersion in the tissue adjacent to the device, ranging from less than about 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, about 90 days The range is from day to about 180 days. In one embodiment, the drug is released at an effective concentration for 1 to 90 days.

A typical fibrosis inhibitor used alone or in combination should be administered according to the following dosage guidelines. The total amount (dose) of the anti-scarring agent in the composition ranges from about 0.01 μg to 10 μg, 10 μg to 10 mg, 10 mg to 250 mg, 250 mg to 1000 mg, 1000 mg to 2500 mg. Can be. Scarring inhibitor dose per unit area of the surface to which drug is applied (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2, 1 μg / mm 2 ~10 μg / mm 2, 10 μg / mm 2 ~250μg / mm ^2, 250 may be one of a range of ^{μg / mm 2 ~1000 μg / mm} 2, 1000 μg / mm 2 ~2500μg / mm 2.

Listed below are exemplary dosage ranges for various scarring inhibitors that can be used in conjunction with compositions for the treatment of inflammatory arthritis according to the present invention. The following dosages are particularly useful for intra-articular administration. (A) A cell cycle inhibitor comprising doxorubicin and mitoxantrone. Doxorubicin analogs and derivatives thereof: The total dose should not exceed 25 mg (range 0.1 μg to 25 mg) and the preferred total dose is 1 μg to 5 mg. The dose per unit area was ^{0.01 μg / mm 2 ~100μg / mm} 2, preferred dosage is ^{0.1 μg / mm 2 ~10 μg /} mm 2. In joints, the minimum concentration of doxorubicin is maintained at ^10-8 to ^10-4M . Mitoxantrone and its analogs and derivatives: The total dose should not exceed 5 mg (0.01 μg to 5 mg range), the preferred total dose being 0.1 μg to 1 mg. The dosage per unit area is 0.01 μg / mm ^{2 to} 20 μg / mm ² , and the preferred dosage is 0.05 μg / mm ^{2 to} 3 μg / mm ² . In joints, the minimum concentration of mitoxantrone is maintained at ^10-8 to ^10-4M . (B) Cell cycle inhibitors including paclitaxel and its analogs and derivatives (eg docetaxel): The total dose should not exceed 10 mg (range 0.1 μg to 10 mg), the preferred total dose is 1 μg to 3 mg. The dose per unit area was ^{0.1 μg / mm 2 ~10 μg /} mm 2, preferred dose is ^{0.25μg / mm 2 ~5 μg / mm} 2. The joint maintains a minimum concentration of paclitaxel in 10 ^-8 ~10 ^-4 M. (C) Cell cycle inhibitors such as podophyllotoxin (eg etoposide): The total dose should not exceed 10 mg (range 0.1 μg to 10 mg), and the preferred total dose is 1 μg to 3 mg To do. The dose per unit area was ^{0.1 μg / mm 2 ~10 μg /} mm 2, preferred dose is ^{0.25μg / mm 2 ~5 μg / mm} 2. In joints, maintain a minimum concentration of etoposide between 10 ^{-8 and} 10 ^-4 M. (D) Immunosuppressive drugs including sirolimus and everolimus. Sirolimus (eg, rapamycin, rapamune): The total dose should not exceed 10 mg (range 0.1 μg to 10 mg), the preferred total dose being 10 μg to 1 mg. The dosage per unit area is 0.1 μg / mm ^{2 to} 100 μg / mm ² , and the preferred dosage is 0.5 μg / mm ² to 10 μg / mm ² . Maintain a minimum concentration of sirolimus between ^{10-8 and 10-4} M in the joints. Everolimus and its analogs and derivatives: the total dose should not exceed 10 mg (range 0.1 μg to 10 mg), the preferred total dose being 10 μg to 1 mg. The dosage per unit area of the surface is 0.1 μg / mm ^{2 to} 100 μg / mm ² , and the preferred dosage is 0.3 μg / mm ² to 10 μg / mm ² . In joints, the lowest concentration of everolimus is maintained at ^10-8 to ^10-4M . (E) Heat shock protein 90 antagonist (eg, geldanamycin) and analogs and derivatives thereof: the total dose should not exceed 20 mg (range 0.1 μg to 20 mg), the preferred total dose is 1 μg ˜5 mg. The dose per unit area was ^{0.1 μg / mm 2 ~10 μg /} mm 2, preferred dose is ^{0.25μg / mm 2 ~5 μg / mm} 2. In joints, the minimum concentration of geldanamycin is maintained at ^10-8 to ^10-4M . (F) HMGCoA reductase inhibitors (eg simvastatin) and analogs and derivatives thereof: the total dose should not exceed 2000 mg (range 10.0 μg to 2000 mg), the preferred total dose is 10 μg to 300 mg And The dose per unit area is 1.0 μg / mm ^{2 to} 1000 μg / mm ² , and the preferred dose is 2.5 μg / mm ^{2 to} 500 μg / mm ² . The joint maintains a minimum concentration of simvastatin 10 ^-8 ~10 ^-3 M. (G) Inosine monophosphate dehydrogenase inhibitor (eg: mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ ) and its analogs and derivatives: total dose of 2000 mg (range 10.0 μg to 2000 mg) The total dose is preferably 10 μg to 300 mg. The dose per unit area is ^{1.0μg / mm 2 ~1000 μg / mm} 2, a preferred dosage ^{2.5 μg / mm 2 ~500μg / mm} 2. In joints, the minimum concentration of mycophenolic acid is maintained at ^10-8 to ^10-3M . (H) NFκB inhibitors (eg, Bay 11-7082) and analogs and derivatives thereof: the total dose should not exceed 200 mg (range 1.0 μg to 200 mg) and the preferred total dose is 1 μg to 50 mg. The dose per unit area is 1.0 μg / mm ^{2 to} 100 μg / mm ² , and the preferred dose is 2.5 μg / mm ² to 50 μg / mm ² . The joint maintains a minimum concentration of Bay 11-7082 in 10 ^-8 ~10 ^-4 M. (I) Antifungal drugs (eg, sulconizole) and analogs and derivatives thereof: The total dose should not exceed 2000 mg (range 10.0 μg to 2000 mg), and the preferred total dose should be 10 μg to 300 mg . The dose per unit area is 1.0 μg / mm ^{2 to} 1000 μg / mm ² , and the preferred dose is 2.5 μg / mm ^{2 to} 500 μg / mm ² . The joint maintains a minimum concentration of Surukonizoru to 10 ^-8 ~10 ^-3 M. The same applies to (J) p38 MAP kinase inhibitors (such as SB202190), analogs and derivatives thereof. The total dose is not to exceed 2000 mg (range of 10.0 μg to 2000 mg), and the preferable total dose is 10 μg to 300 mg. The dose per unit area was ^{1.0 μg / mm 2 ~1000μg / mm} 2, a preferred dosage ^{2.5 μg / mm 2 ~500 μg /} mm 2. The joint maintains a minimum concentration of SB202190 to 10 ^-8 ~10 ^-3 M.

In another embodiment, systemic treatment is given when the condition worsens or a systemic disease (such as RA) is present. Systemically delivered anti-scarring agents, as described above, need to be administered according to the level of drug required to inhibit the pathology of inflammatory arthritis. Systemic dosage will vary depending on the patient, the severity of the disease, the formulation of the drug being administered, the potency and / or tolerance of the drug, and the route of administration. For example, paclitaxel, in the case of doxorubicin or geldanamycin, if preferred embodiment of 10~175mg / m ² once every 1-4 weeks, acceptable, or if symptoms are 10 to 75 mg / m ^2, the allowable daily 10 to 175 mg / m ² weekly until healed. To treat acute malignant symptoms, paclitaxel as a “pulse” systemic therapy can be administered in excess of 50-250 mg / m ² . Other anti-scarring agents can be administered in the same amount to adjust for drug efficacy and tolerance.

  According to another aspect, any of the anti-infectives described above can be used in conjunction with a composition for the treatment of inflammatory arthritis. Typical anti-infectives include (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) Dophilotoxins (such as etoposide), (E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin), and analogs and derivatives of the above.

  The dose of drug administered from this composition to prevent or inhibit infection according to the present invention will depend on various factors including the type of formulation, the site of healing, and the type of condition being treated. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), and the total drug dose administered can be measured and the appropriate surface concentration of the active agent can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective agent is released from the polymeric compound at an effective concentration in the range of less than about 1 day to about 180 days over a period measured from the time of immersion in the tissue adjacent to the device. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, about 90 days The range is from day to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following dosage guidelines. The total amount (dose) of the anti-infective agent in the composition is about 0.01 μg-1 μg, about 1 μg-10 μg, about 10 μg-1 mg, about 1 mg-10 mg, about 10 mg-100 mg , About 100 mg to 250 mg, about 250 mg to 1000 mg. The dosage (dose) of the drug per unit area of the device or tissue surface to which the anti-infective agent is applied is about 0.01 μg / mm ² to 1 μg / mm ² , about 1 μg / mm ² to 10 μg / mm ² , about 10 μg / mm ^{2 to} 100 μg / mm ² , about 100 μg / mm ² to 250 μg / mm ² , about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compounds which release an anti-infective agents in different proportions, administration parameters described above, a minimum concentration of about 10 ^-8 M to ^-7 M of the drug tissue surface, about 10 ^-7 M to ^-6 M, about 10 ^-6 M to ^-5 M, to be maintained at either about 10 ^-5 M to ^-4 M, it should be used in combination with the drug release rate from the composition.

Prevention of cartilage loss ("cartilage protection")
In another embodiment, the polymer composition can be used to prevent or reduce cartilage loss following injury (eg, cruciate ligament damage and / or meniscal damage). It has long been known that joint damage tends to cause osteoarthritis in a patient's joint over time and there is no effective treatment to prevent it. Instead, the medical community and researchers have focused on treating established arthritis. Treatment of established diseases includes anti-inflammatory agents (nonsteroidal and steroidal), lubricants or synovial fluid substitutes, surgery and joint replacement in the case of severe disease.

  There are many forms of joint trauma, ranging from simple sprains that heal naturally to many bone fragments, and fractures where joint reconstruction is almost impossible. The treatment of these injuries is focused on restoring the joints to normal anatomical conditions and restoring normal operation. Risk factors that spread arthritis are related to the characteristics of the joint itself, whether it is the degree of trauma, the degree of joint rupture, the degree of fracture or dislocation, whether it is a weight bearing joint. In general, the greater the joint trauma, the greater the risk that the patient will develop osteoarthritis in the future. Surgical reduction of the damaged tissue does not always prevent arthritis. In the case of intra-articular fractures, for example in the case of split fractures of the tibia, the treatment involves surgically reconstructing the joints to return them to a proper, smooth, intact joint surface, and “step defects” Otherwise, all bone fragments fit together and prevent the femoral globular joint from being obstructed on its face. Although surgical repair techniques for these fractures have improved, it is very likely that fractured patients will develop osteoarthritis in the future.

  Injuries to the anterior cruciate ligament (ACL) of the knee represent a typical example of an injury that a patient is likely to cause severe osteoarthritis. The ACL is a ligament that connects the anterior tibial plateau to the posterior intercondylar groove. Composed of multiple non-parallel fibers of various lengths, it provides tension and mechanical stability over the entire range of movement of the knee as a unitary function. ACL stabilization has four main roles: (a) inhibition of tibial anterior conversion, (b) prevention of knee overextension, (c) functioning as a secondary stabilizer for valgus pressure, strengthening the central collateral ligament, and (d) Controls the rotation of the femur's tibia while pulling the femur, thereby controlling movements such as side steps and rotation. Generally, ACL deficiency causes failure of the femur's tibia, extending the covered capsular ligament to the limit and causing abnormal shear forces on the meniscus and articular cartilage. Diagnosis and treatment delay not only increases intra-articular damage, but also stretches the secondary stable coating structure to the limit.

  In spite of the known high risk of osteoarthritis, patients have only routine X-ray examination at the time of presentation after ACL injury if no associated fracture is seen. However, it has already been demonstrated that patients with ACL injury have a high probability of developing arthritis. After surgery, the incidence is 50% in 10 years and 80% in 20 years. Generally, after an ACL rupture, the patient must suffer from an unstable condition because the ligament is not stable at the joint while pivoting or rotating normally. It is necessary not only for sports that move the pivot, but also for daily activities such as the mother holding the baby moving the pivot to take something out of the refrigerator.

  A typical ACL rupture treatment and management is to replace and reconstruct a torn ACL using a graft. The graft can be taken from anywhere on the patient's limb (autograft). It may be extracted from a cadaver (allograft) or made from a synthetic material. Autograft is the most widely performed orthopedic ACL reconstruction. Techniques include removal of the patient's own tissue (the middle third of the patella tendon with bone attached to both ends), one or two medial hamstring muscles, or a quadriceps tendon with bone attached to one side Is included. Synthetic materials have the advantage of being ready to use, but vascular grafts have a higher failure rate than autografts and allografts, and their mechanical properties are not very similar to normal ligaments. The success of ACL reconstruction depends on many factors, including surgical techniques, post-operative rehabilitation, and associated secondary ligament instability. Surgical procedures where arthroscopy is used to determine whether there is any other related damage during the surgical procedure, or whether such damage can be treated simultaneously, such as meniscal injury or cartilage trauma, is a small accessory Performed through the incision, the tunnel is pierced through the tibia and femur, allowing the graft to be inserted and secured.

  Surgical reconstruction was initially thought to provide a permanent solution to rebuild a stable knee and prevent degeneration. However, other studies have shown that joints can be devastated once the cascade of inflammatory activity begins after joint injury. This explains whether surgical repair alone can affect the degeneration of traumad joints. Simply stabilizing a joint or rebuilding a joint on a large scale does not address the fundamentals of biology. Unfortunately, even though long-term data show that surgery could stabilize the knee and restore the patient's activity, what did the surgery do to the subsequent growth rate of osteoarthritis? There is no influence. As a result, to date, standard care has been to completely repair the joint and treat it as arthritis grows. It should be noted that all joints (including knees) can become arthritis after trauma, but commonly involved joints include fingers, thumbs, metacarpal bones (wrists), elbows, shoulders, bones, There are spinal joints (small joint surfaces, sacroiliac joints), temporal mandibles, ear bones, lumbar region, ankles, tarsal bones and toes, especially the first heel.

  Fibrosis inhibitors such as paclitaxel have been shown in animal experiments to have the ability to prevent cartilage destruction after cruciate ligament tears. The effect was seen in both inflammatory and biomechanical models that suffered joint damage. In a rabbit inflammatory carrageenan-induced arthritis model, paclitaxel showed cartilage. Hartley guinea pigs undergoing anterior cruciate ligament surgery show a deformity model of arthritis. In general, animals developed arthritis within a few weeks after the anterior cross became severe. When the fibrosis inhibitor paclitaxel was introduced into the joint, the arthritic process was greatly delayed, preventing not only the cartilage but also the underlying bone from being destroyed.

  The present invention addresses significant medical unmet needs. Prevention of progressive joint degeneration after trauma. When a composition comprising a fibrosis inhibitor is introduced into an injured joint immediately after injury (eg, through intra-articular injection, peri-articular administration, through an arthroscope, during joint surgery during open surgery) It can affect the cascade of events and prevent destruction of the cartilage matrix. Because most ligament injuries are severe or severely painful, patients seek immediate medical attention long before the irreversible change occurs in the joint (within the first 24-48 hours). When first shown to medical professionals, intra-articular injections of fibrosis inhibitors (in the joint and surrounding tissue) are administered to the joint to stop or slow down its destructive activity, protecting the articular cartilage from destruction . Initial introduction of the agents of the present invention slows, reduces or eliminates the cascade of events leading to osteoarthritis. The invention can be administered immediately after injury, repeated for the period until stabilization surgery, and / or administered after the surgery is complete.

  Thus, within one embodiment of the present invention, treating cartilage loss with a method comprising administering to a patient in need thereof a composition containing a therapeutically effective amount of a scar or fibrosis inhibitor. Or a method to prevent is provided.

  Scar suppressant therapy effective for cartilage loss accomplishes one or more of the following: (i) reduction in the severity of symptoms (pain, bumps and tenderness of the infected joint), (ii) clinical signs of the disease Reduced severity of articular cartilage (hyperarticular cartilage enlargement, synovial fluid enlargement, joint exudates, soft tissue spasticity, reduced range of motion, stiff and fixed joint malformations), (iii) frequency and duration of disease recovery and absence of symptoms Increased duration, (iv) delayed or prevented the occurrence of clinically serious arthritis in previously damaged joints, and / or (v) prevented or reduced fixed defects and dysfunction.

  In accordance with the present invention, any of the above scarring inhibitors can be utilized in the practice of this invention. In certain embodiments of the invention, the composition can release an agent that inhibits one or more of the general factors for the process of fibrosis (or scarring) associated with joint damage, including: ) Formation of new blood vessels (angiogenesis), (b) migration and proliferation of connective tissue cells (fibroblasts or synovial cells), (c) extracellular matrix (ECM) accumulation and remodeling by matrix metalloproteinase activity (D) Inflammatory reaction by cytokines (IL-1, TNFα, FGF, VEGF, etc.). By inhibiting one or more of the fibrosis (or scarring) components, joint damage and osteoarthritic growth are reduced or prevented in previously damaged joints.

  In one embodiment, the composition comprises an anti-scarring agent and a polymeric carrier suitable for application in the treatment of damaged joints. A number of polymeric and non-polymeric delivery systems and compositions comprising anti-scarring agents for use in preventing cartilage loss have already been described above. The anti-scarring agent can be administered systemically at the lowest dose to obtain the above results (orally, intravenously, or by intramuscular or subcutaneous injection). For patients who have only a small number of joints or who have significant disease in a limited number of joints, anti-scarring agents can be applied to tissues inside the joint or injected directly into the infected joint Yes (intra-articular injection).

  The anti-scarring agent can be administered by any method described herein. However, preferred methods of administration include intravenous, oral, or subcutaneous, intramuscular or intraarticular injection. Scarring inhibitors can be injected directly into the joint capsule of the infected joint via percutaneous needle insertion (intra-articular injection) or as part of an arthroscopic procedure performed on the joint it can. In a preferred embodiment, an intra-articular formulation containing a fibrosis inhibitor is administered to the joint after an injury that is likely to induce arthritis (such as an injury to the cruciate ligament or knee meniscus) occurs. A fibrosis inhibitor can be administered for a sufficient period of time (through sustained release formulations and / or repeated infusions) to prevent cartilage from being destroyed as a result of damage (or the surgical procedure used for treatment). Scarring inhibitors can be administered chronically at low dosages to prevent disease progression, extend the remission phase of the disease, or alleviate symptoms of an ongoing disease. Alternatively, therapeutic agents can be administered at high doses as “pulse” therapy to induce recovery of ongoing disease (such as the period immediately following joint injury). The lowest dose that can achieve these goals can be used, but the amount depends on the patient, the severity of the illness, the formulation of the drug to be administered, the distance to the joint, the interval, the effectiveness and / or tolerance of the drug, It depends on the route.

  Various HA compositions for intra-articular injection that can be combined with one or more drugs in accordance with the present invention are commercially available: Hylan (a derivative of sodium hyaluronate (hyaluronan)) Synvisc (Biomatrix, Inc., Ridgefield, NJ), Hyalgan (Sanofi-Synthelabo Inc., New York, NY), and highly purified high molecular weight, high ORTHOVISC (Ortho Biotech Products, Bridgewater, NJ) used to relieve pain and improve joint mobility and range of motion in patients with viscous HA and knee osteoarthritis (OA). ORTHOVISC is injected into the knee to restore the elasticity and viscosity of the synovial fluid. HYVISC is a high molecular weight injectable HA product developed by Anika Therapeutics (Woburn, Mass.) And is currently used to treat osteoarthritis and racehorse legs. Other HA-based additional viscosity products for intra-articular injection include SUPERTZ from Seikagaku Corporation (Japan), Suplasyn from BionicheLife Sciences, Inc. (Canada), DePuyOrthopaedics, Inc. (Warsaw, IN) ARTHREASE and Durolane made by Q-Med AB (Sweden). By adding a fibrosis inhibitor to hyaluronan, intra-articular injection has the added benefit of preventing cartilage damage (eg, “cartilage protection”).

  In one embodiment, the compositions of the invention can be used to manage osteoarthritis in animals (such as horses). Some HA products (especially HYVISC, Boehringer Ingelheim Vetmedica, St. Joseph, MO) are also used for veterinary applications (usually equine osteoarthritis and legs). .

  Fibrosis inhibitor preparations that can be used to treat or prevent cartilage loss include solutions, topical preparations (eg, solutions, creams, ointments, gels) emulsions, micelle solutions, gels (crosslinkable and non-crosslinkable), test solutions and / or pastes. It is a form. One formulation is in the form of an injectable composition for intra-articular or arthroscopic delivery. Hyaluronic acid (cross-linked, derivatized and / or non-cross-linked) is a typical material in compositions that further contain a polymer to increase the viscosity of the formulation. Such preparations can further include polymers (collagen, poly (ethylene glycol), dextran, etc.) and biocompatible solvents (ethanol, DMSO, NMP, etc.). In one embodiment, the fibrosis inhibitor therapeutic agent can be incorporated directly into the formulation. In another example, the fibrosis inhibiting therapeutic can be incorporated into a second carrier (such as the micelles, liposomes, emulsions, fines, nanospheres, etc. described above). Fines and nanospheres can be composed of biodegradable polymers. Degradable polymers that can be used include poly (hydroxyl esters) (such as PLGA, PLA, PCL, and the like) and polyanhydrides, polyorthoesters, and polysaccharides (such as chitosan and alginate).

In one embodiment, the fiber formation inhibitor is further comprised of a biodegradable polymer. Biodegradable polymers include polyesters (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, can be composed of residues of one or more monomers selected from trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one), and XY , YXY, R- (YX) _n , R- (XY) _n and XYX block polymers are included. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.) and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASF Corporation (Mount Olive, NJ)) , PLURONIC and PLURONIC R series of polymers), Y is a biodegradable polyester (lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ- Residue of one or more monomers selected from butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one (PLG-PEG-PLG etc.), R is a multifunctional initiator. In another example, the fiber formation inhibitor / polymer composition may further comprise a solvent, liquid oligomer, or liquid polymer such that the final composition passes through an 18G needle. In this example, there are reagents such as ethanol, NMP, PEG 200, PEG 300 and low molecular weight liquid polymers having the structure of XY, YXY, R- (YX) _n, R- (XY) _n and XYX. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.) and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASF Corporation (Mount Olive, NJ)) , PLURONIC and PLURONIC R series of polymers), and Y is a biodegradable polyester. Here, the polyester is lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, Those composed of residues of one or more monomers selected from trimethylene carbonate, 1,4-dioxan-2-one or 1,5 dioxepan-2-one (eg PLG-PEG-PLG). R is a multifunctional initiator.

In another example, the fiber formation inhibitor can be in the form of a solution or suspension of an organic solvent, a liquid oligomer or a liquid polymer. In this example, there are reagents such as ethanol, NMP, PEG200, PEG300 and low molecular weight liquid polymers having the structure of XY, YXY, R- (YX) _n, R- (XY) _n and XYX. Where X is a polyalkylene oxide (poly (ethylene glycol), poly (propylene glycol), etc.), and a block copolymer of poly (ethylene oxide) and poly (propylene oxide) (BASFCorporation (Mount Olive, NJ), Polymers such as PLURONIC and PLURONIC R series) and Y is a biodegradable polyester. Here, the polyester is lactide, lactic acid, glycolide, glycolic acid, e-caprolactone, γ-caprolactone, hydroxyvaleric acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, Those composed of residues of one or more monomers selected from trimethylene carbonate, 1,4-dioxan-2-one or 1,5 dioxepan-2-one (eg PLG-PEG-PLG). R is a multifunctional initiator.

Examples of fibrosis inhibitors for use in the treatment or prevention of cartilage loss after trauma include the following: cell cycle inhibitors include (A) anthracyclines (such as doxorubicin and mitoxantrone), ( B) Taxanes (such as paclitaxel, Taxotere and docetaxel), (C) Podophyllotoxins (such as etoposide), (D) Immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) Heat shock protein 90 antagonists (gel) (Danamycin etc.), (F) HMGCoA reductase inhibitor (simvastatin etc.), (G) Inosine monophosphate dehydrogenase inhibitor (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NHκB inhibitors (such as Bay11-7082), (I) antifungal agents (such as sulconizole), (J) p38 MAP kinase inhibitors (such as SB202190), and analogs and derivatives as described above.

  The dose of drug administered from this composition to treat cartilage loss depends on various factors including the type of formulation and the site of healing. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), and the total drug dose administered can be measured and the appropriate surface concentration of the active agent can be determined. For topical application (such as intra-articular or endoscopic administration), drugs may be 50%, 20%, 10%, 5%, or even less than 1%, several times higher than those normally used for single systemic administration It shall be used in the concentration range. In certain embodiments, the anti-scarring agent is released from the polymeric compound at an effective concentration over a period measured from the time of immersion in the tissue adjacent to the device, ranging from less than about 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, about 90 days The range is from day to about 180 days. In one embodiment, the drug is released at an effective concentration for 1 to 90 days.

A typical fibrosis inhibitor used alone or in combination should be administered according to the following dosage guidelines. The total amount (dose) of the anti-scarring agent in the composition ranges from about 0.01 μg to 10 μg, 10 μg to 10 mg, 10 mg to 250 mg, 250 mg to 1000 mg, 1000 mg to 2500 mg. Can be. Scarring inhibitor dose per unit area of the surface to which drug is applied (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2, 1 μg / mm 2 ~10 μg / mm 2, 10 μg / mm 2 ~250μg / mm ^2, 250 may be one of a range of ^{μg / mm 2 ~1000 μg / mm} 2, 1000 μg / mm 2 ~2500μg / mm 2.

Listed below are exemplary dosage ranges for various anti-scarring agents that can be used in conjunction with compositions for the treatment of cartilage loss in accordance with the present invention. (A) A cell cycle inhibitor comprising doxorubicin and mitoxantrone. Doxorubicin analogs and derivatives thereof: The total dose should not exceed 25 mg (range 0.1 μg to 25 mg) and the preferred total dose is 1 μg to 5 mg. The dose per unit area was ^{0.01 μg / mm 2 ~100μg / mm} 2, preferred dosage is ^{0.1 μg / mm 2 ~10 μg /} mm 2. In joints, the minimum concentration of doxorubicin is maintained at ^10-8 to ^10-4M . Mitoxantrone and its analogs and derivatives: The total dose should not exceed 5 mg (range 0.01 μg to 5 mg), the preferred total dose being 0.1 μg to 1 mg. The dose per unit area of the surface is 0.01 μ~20 μg / mm ^2, preferred dosage is ^{0.05 μg / mm 2 ~3μg / mm} 2. In joints, the minimum concentration of mitoxantrone is maintained at ^10-8 to ^10-4M . (B) Cell cycle inhibitors including paclitaxel and analogs and derivatives thereof (eg docetaxel): The total dose should not exceed 10 mg (range 0.1 μg to 10 mg), the preferred total dose is 1 μg to 3 mg. The dose per unit area of the surface is 0.1 μg~10 μg / mm ^2, preferred dosage is ^{0.25 μg / mm 2 ~5μg / mm} 2. The joint maintains a minimum concentration of paclitaxel in 10 ^-8 ~10 ^-4 M. (C) Cell cycle inhibitors such as podophyllotoxin (eg, etoposide): The total dose should not exceed 10 mg (range 0.1 μg to 10 mg), and the preferred total dose is 1 μg to 3 mg To do. The dose per unit area of the surface is 0.1 μg~10 μg / mm ^2, preferred dosage is ^{0.25 μg / mm 2 ~5μg / mm} 2. In joints, maintain a minimum concentration of etoposide between 10 ^{-8 and} 10 ^-4 M. (D) Immunosuppressive drugs including sirolimus and everolimus. Sirolimus (eg, rapamycin, rapamune): The total dose should not exceed 10 mg (range 0.1 μg to 10 mg), the preferred total dose being 10 μg to 1 mg. The dosage per unit area is 0.1 μg / mm ^{2 to} 100 μg / mm ² , and the preferred dosage is 0.5 μg / mm ² to 10 μg / mm ² . Maintain a minimum concentration of sirolimus between ^{10-8 and 10-4} M in the joints. Everolimus and its analogs and derivatives: the total dose should not exceed 10 mg (range 0.1 μg to 10 mg), the preferred total dose being 10 μg to 1 mg. The dosage per unit area of the surface is 0.1 μg / mm ^{2 to} 100 μg / mm ² , and the preferred dosage is 0.3 μg / mm ² to 10 μg / mm ² . In joints, the lowest concentration of everolimus is maintained at ^10-8 to ^10-4M . (E) Heat shock protein 90 antagonist (eg, geldanamycin) and analogs and derivatives thereof: the total dose should not exceed 20 mg (range 0.1 μg to 20 mg), the preferred total dose is 1 μg ˜5 mg. The dose per unit area of the surface is 0.1 μg~10 μg / mm ^2, preferred dosage is ^{0.25 μg / mm 2 ~5μg / mm} 2. In joints, the minimum concentration of geldanamycin is maintained at ^10-8 to ^10-4M . (F) HMGCoA reductase inhibitors (eg, simvastatin) and analogs and derivatives thereof: the total dose should not exceed 2000 mg (range 10.0 μg to 2000 mg), and the preferred total dose is 10 μg to 300 mg And The dose per unit area is 1.0 μg / mm ^{2 to} 1000 μg / mm ² , and the preferred dose is 2.5 μg / mm ^{2 to} 500 μg / mm ² . The joint maintains a minimum concentration of simvastatin 10 ^-8 ~10 ^-3 M. (G) Inosine monophosphate dehydrogenase inhibitor (eg: mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ ) and its analogs and derivatives: total dose of 2000 mg (range 10.0 μg to 2000 mg) The total dose is preferably 10 μg to 300 mg. The dose per unit area is ^{1.0μg / mm 2 ~1000 μg / mm} 2, a preferred dosage ^{2.5 μg / mm 2 ~500μg / mm} 2. In joints, the minimum concentration of mycophenolic acid is maintained at ^10-8 to ^10-3M . (H) NFκB inhibitors (eg, Bay 11-7082) and analogs and derivatives thereof: the total dose should not exceed 200 mg (range 1.0 μg to 200 mg) and the preferred total dose is 1 μg to 50 mg. The dose per unit area is 1.0 μg / mm ^{2 to} 100 μg / mm ² , and the preferred dose is 2.5 μg / mm ² to 50 μg / mm ² . The joint maintains a minimum concentration of Bay 11-7082 in 10 ^-8 ~10 ^-4 M. (I) Antifungal drugs (eg, sulconizole) and analogs and derivatives thereof: The total dose should not exceed 2000 mg (range 10.0 μg to 2000 mg), and the preferred total dose should be 10 μg to 300 mg . The dose per unit area is 1.0 μg / mm ^{2 to} 1000 μg / mm ² , and the preferred dose is 2.5 μg / mm ^{2 to} 500 μg / mm ² . The joint maintains a minimum concentration of Surukonizoru to 10 ^-8 ~10 ^-3 M. The same applies to (J) p38 MAP kinase inhibitors (such as SB202190), analogs and derivatives thereof. The total dose is not to exceed 2000 mg (range of 10.0 μg to 2000 mg), and the preferable total dose is 10 μg to 300 mg. The dose per unit area was ^{1.0 μg / mm 2 ~1000μg / mm} 2, a preferred dosage ^{2.5 μg / mm 2 ~500 μg /} mm 2. The joint maintains a minimum concentration of SB202190 to 10 ^-8 ~10 ^-3 M.

  According to another aspect, the anti-infectives described above can be used in combination with a formulation for treating or preventing cartilage loss. Typical anti-infectives include (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) Dophilotoxins (such as etoposide), (E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin), and analogs and derivatives of the above.

  The dose of drug administered from this composition to prevent or inhibit infection according to the present invention will depend on various factors including the type of formulation, the site of healing, and the type of condition being treated. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), and the total drug dose administered can be measured and the appropriate surface concentration of the active agent can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective agent is released from the polymeric compound at an effective concentration in the range of less than about 1 day to about 180 days over a period measured from the time of immersion in the tissue adjacent to the device. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, about 90 days The range is from day to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following dosage guidelines. The total amount (dose) of the anti-infective agent in the composition is about 0.01 μg-1 μg, about 1 μg-10 μg, about 10 μg-1 mg, about 1 mg-10 mg, about 10 mg-100 mg , About 100 mg to 250 mg, about 250 mg to 1000 mg. The dosage (dose) of the drug per unit area of the device or tissue surface to which the anti-infective agent is applied is about 0.01 μg / mm ² to 1 μg / mm ² , about 1 μg / mm ² to 10 μg / mm ² , about 10 μg / mm ^{2 to} 100 μg / mm ² , about 100 μg / mm ² to 250 μg / mm ² , about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compounds which release an anti-infective agents in different proportions, administration parameters described above, a minimum concentration of about 10 ^-8 M to ^-7 M of the drug tissue surface, about 10 ^-7 M to ^-6 M, about 10 ^-6 M to ^-5 M, to be maintained at either about 10 ^-5 M to ^-4 M, it should be used in combination with the drug release rate from the composition.

In another aspect of the hypertrophic scar / keloid invention, compositions (eg, fibrosis inhibitors) and methods comprising pharmacologically active agents are provided for the treatment of hypertrophic scars and keloids.

  Hypertrophic scars and keloids are densely overgrown fibrous tissues as a result of an excessive fibroproliferative healing response to the wound. Hypertrophic scars and keloids usually grow after healing of skin damage. Briefly, wound healing and scar formation occur in three stages: inflammation, proliferation, and maturation. The first stage, inflammation, occurs in response to trauma that is severe enough to damage the skin. In this stage, lasting 3-4 days, blood and tissue fluids form an adhesive coagulation and fibrinous network that serves to join the wound surfaces together. This is followed by a proliferative phase in which there is ingrowth of capillaries and connective tissue from the wound edge and closure of skin defects. Finally, after the growth of capillaries and fibroblasts, the maturation process begins, the scar contracts, the cellularity and vascularity decrease, and becomes flat and white. This last stage can take 6-12 months.

  If the connective tissue is excessively formed and the wound cellularity remains persistent, the scar will turn red and bulge. When the scar stays within the boundary of the original scar, it is called a hypertrophic scar, but when the scar extends beyond the original scar to the surrounding tissue, the lesion is called a keloid. Hypertrophic scars and keloids are formed in the second and third stages of scar formation. Some wounds are particularly prone to excessive endothelial and fibroblast proliferation, including burns, open wounds, and infected wounds. In hypertrophic scars, a degree of maturation occurs and a gradual recovery occurs. However, in the case of keloids, an actual tumor is formed, which can be quite large. In these cases, natural improvements rarely occur.

  Keloids and hypertrophic scars in most parts are inherently cosmetic concerns, but some keloids and hypertrophic scars can cause spasticity, and covering the joints can lead to loss of function or occur on the face Then, the appearance will be severely damaged. Keloids and hypertrophic scars can cause pain and itching.

  In one embodiment of the invention, the polymer composition can be directly injected into a hypertrophic scar or keloid to prevent the progression of these lesions. The frequency of injection will depend on the release rate of the polymer used and the clinical response. This treatment is particularly effective in preventing symptoms that are recognized as resulting in hypertrophic scars and keloids (burns, excision sites of keloids and hypertrophic scars, predisposed patients' chest and back). Scratches). It is also desirable to start before or during the proliferative phase (from day 1) and before hypertrophic scars and keloids begin to develop (within the first 3 months after injury).

  In one embodiment, the present invention provides a topical or injectable composition comprising a scarring inhibitor suitable for application on or within a hypertrophic scar or keloid and a polymeric carrier. A number of polymeric and non-polymeric delivery systems for use in the treatment of hypertrophic scars or keloids have already been described above.

  Incorporating a fibrosis inhibitor into a topical or injectable formulation is one way to treat this condition. A topical formulation can be in the form of a solution, suspension, emulsion, gel, ointment, cream, film or mesh. Injectable preparations may be in the form of solutions, suspensions, emulsions or gels. Polymers and non-polymeric components that can be used to prepare these topical or injectable compositions are as described above.

  In another example, the fibrosis inhibiting therapeutic can be incorporated into a second carrier (such as the micelles, liposomes, emulsions, fines, nanospheres, etc. described above). Fine granules and nanospheres include degradable polymers. Degradable polymers that can be used include poly (hydroxyl esters) (such as PLGA, PLA, PCL, and the like) and polyanhydrides, polyorthoesters, and polysaccharides (such as chitosan and alginate).

  In addition, a variety of other compositions and approaches for the treatment of hypertrophic scars and keloids can be used in accordance with the present invention. For example, treatment includes administration of an angiogenesis inhibitor (such as fumagillol, thalidomide) that is effective as a systemic or local therapy to reduce excessive scarring. See US Pat. No. 6,638,949. The treatment can be a copolymer made of a hydrophilic polymer such as polyethylene glycol combined with a polymer (such as phenylboronic acid) that is easily absorbed by the surface of the body tissue. See US Pat. No. 6,596,267. The treatment includes a cryoprobe that includes a cryogen, thereby placing it in a hypertrophic scar or keloid to freeze the tissue. See US Pat. No. 6,503,246. Treatment may be a method of locally administering an amount of botulinum toxin within or near the skin wound so as to promote healing. See US Pat. No. 6,447,787. The treatment can be a liquid composition composed of a film-forming carrier (such as collodion) containing one or more active ingredients such as topical steroids, silicone gels and vitamin E. See U.S. Patent No. 6,337,076. Treatment may be a method of inhibiting or treating the formation of scar tissue by administering an amount of fluoroquinolone that inhibits fiber formation. See US Pat. No. 6,060,474. The treatment can be a composition of an effective amount of calcium antagonist and protein synthesis inhibitor sufficient to cause substrate degradation at the site of the scar and modulate scar formation. See US Pat. No. 5,902,609. The treatment can be a composition of non-biodegradable granules with a substantial surface charge in a pharmaceutically acceptable carrier. See US Pat. No. 5,861,149. The treatment can be a composition of endothelial growth factor and heparin that can be administered locally or injected intralesionally. See US Pat. No. 5,500,409.

  Treatments for hypertrophic scars and keloids that can be combined with one or more therapeutic agents according to the present invention include commercially available products. Representative products include, for example, PROXIDERM, an external tissue expansion product for wound healing (Progressive Surgical Products (Westbury, NY)), CICA-CARE gel sheet dressing product (Smith & Nephew Healthcare Ltd. (India)), MEPIFORM self-adhesive silicone dressing (Molnlycke Health Care (Eddie Stone, PA)).

  In one embodiment, the present invention relates to a topical hypertrophic scar or keloid that is prone to form hypertrophic scars or keloids or a topical carrier comprising a scarring inhibitor suitable for application on or within a site and a polymeric carrier. Alternatively, an injectable composition is provided.

  In one embodiment of the present invention, the anti-scarring agent alone or the anti-scarring composition may be injected directly into the hypertrophic scar or keloid to prevent the progression of these lesions as described above. it can. The frequency of injection will depend on the release rate of the polymer used (if present) and the clinical response. This treatment is particularly effective in preventing symptoms that are recognized as resulting in hypertrophic scars and keloids (burns, excision sites of keloids and hypertrophic scars, predisposed patients' chest and back). Scratches). It is also desirable to start before or during the proliferative phase (from day 1) and before hypertrophic scars and keloids begin to develop (within the first 3 months after injury).

  In accordance with the present invention, any of the fiber formation inhibitors described above can be utilized alone or in combination in the practice of this example. In one embodiment of the invention, intravascular to release an agent that inhibits one or more of the following four general components that comprise a composition for the treatment of hypertrophic scars and keloids: The device can be adapted. That is, the formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), accumulation of extracellular matrix (ECM), and remodeling (maturation and organization of fibrous tissue) .

Examples of fiber formation inhibitors used in compositions for the treatment of hypertrophic scars and keloids include cell cycle inhibitors including (A) anthracyclines (such as doxorubicin and mitoxantrone), (B ) Taxanes (such as paclitaxel, Taxotere and docetaxel), (C) Podophyllotoxins (such as etoposide), (D) Immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) Heat shock protein 90 antagonists (geldana) (F) HMGCoA reductase inhibitors (simvastatin, etc.), (G) inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NHκB Inhibitors (such as Bay11-7082), (I) antifungal agents (such as sulconizole), (J) p38 MAP kinase inhibitors (such as SB202190), and analogs and derivatives as described above.

  The dose of drug administered from this composition for treating hypertrophic scars and keloids depends on a variety of factors including the type of formulation and the type of condition being treated. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), and the total drug dose administered can be measured and the appropriate surface concentration of the active agent can be determined. Drugs are generally used at concentrations ranging from several times the concentration used in single systemic applications up to 50%, 20%, 10%, 5%, or even less than 1%. In certain embodiments, the anti-scarring agent is released from the polymeric compound at an effective concentration over a period measured from the time of immersion in the tissue adjacent to the device, ranging from less than about 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, about 90 days The range is from day to about 180 days. In one embodiment, the drug is released at an effective concentration for 1 to 90 days.

A typical fibrosis inhibitor used alone or in combination should be administered according to the following dosage guidelines. The total amount (dose) of the anti-scarring agent in the composition ranges from about 0.01 μg to 10 μg, 10 μg to 10 mg, 10 mg to 250 mg, 250 mg to 1000 mg, 1000 mg to 2500 mg. Can be. Scarring inhibitor dose per unit area of the surface to which drug is applied (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2, 1 μg / mm 2 ~10 μg / mm 2, 10 μg / mm 2 ~250μg / mm ^2, 250 may be one of a range of ^{μg / mm 2 ~1000 μg / mm} 2, 1000 μg / mm 2 ~2500μg / mm 2.

Listed below are exemplary dosage ranges for various scarring inhibitors that can be used in conjunction with compositions for the treatment of hypertrophic scars and keloids in accordance with the present invention. (A) A cell cycle inhibitor comprising doxorubicin and mitoxantrone. Doxorubicin analogs and derivatives thereof: The total dose should not exceed 25 mg (range 0.1 μg to 25 mg) and the preferred total dose is 1 μg to 5 mg. The dose per unit area was ^{0.01 μg / mm 2 ~100μg / mm} 2, preferred dosage is ^{0.1 μg / mm 2 ~10 μg /} mm 2. The lowest concentration of doxorubicin, 10 ⁻⁸ to 10 ⁻⁴ M, should be maintained with wounds, keloids or hypertrophic scars. Mitoxantrone and its analogs and derivatives: The total dose should not exceed 5 mg (range 0.01 μg to 5 mg), the preferred total dose being 0.1 μg to 1 mg. The dose per unit area of the surface is 0.01 μ~20 μg / mm ^2, preferred dosage is ^{0.05 μg / mm 2 ~3μg / mm} 2. The lowest concentration of mitoxantrone, 10 ⁻⁸ to 10 ⁻⁴ M, should be maintained with wounds, keloids or hypertrophic scars. (B) Cell cycle inhibitors including paclitaxel and analogs and derivatives thereof (eg docetaxel): The total dose should not exceed 10 mg (range 0.1 μg to 10 mg), the preferred total dose is 1 μg to 3 mg. The dose per unit area of the surface is 0.1 μg~10 μg / mm ^2, preferred dosage is ^{0.25 μg / mm 2 ~5μg / mm} 2. The lowest concentration of paclitaxel, 10 ⁻⁸ to 10 ⁻⁴ M, should be maintained with wounds, keloids or hypertrophic scars. (C) Cell cycle inhibitors such as podophyllotoxin (eg, etoposide): The total dose should not exceed 10 mg (range 0.1 μg to 10 mg), and the preferred total dose is 1 μg to 3 mg To do. The dose per unit area of the surface is 0.1 μg~10 μg / mm ^2, preferred dosage is ^{0.25 μg / mm 2 ~5μg / mm} 2. The lowest concentration of etoposide, 10 ⁻⁸ to 10 ⁻⁴ M, should be maintained with wounds, keloids or hypertrophic scars. (D) Immunosuppressive drugs including sirolimus and everolimus. Sirolimus (eg, rapamycin, rapamune): the total dose should not exceed 10 mg (range 0.1 μg to 10 mg), the preferred total dose being 10 μg to 1 mg. The dose per unit area is ^{0.1μg / mm 2 ~100 μg / mm} 2, preferred dosage is ^{0.5 μg / mm 2 ~10μg / mm} 2. The lowest concentration of sirolimus, 10 ⁻⁸ to 10 ⁻⁴ M, should be maintained with wounds, keloids or hypertrophic scars. Everolimus and its analogs and derivatives: The total dose should not exceed 10 mg (range 0.1 μg to 10 mg), the preferred total dose being 10 μg to 1 mg. The dosage per unit area of the surface is 0.1 μg / mm ^{2 to} 100 μg / mm ² , and the preferred dosage is 0.3 μg / mm ² to 10 μg / mm ² . The lowest concentration of everolimus, 10 ⁻⁸ to 10 ⁻⁴ M, should be maintained with wounds, keloids or hypertrophic scars. (E) Heat shock protein 90 antagonist (eg, geldanamycin) and analogs and derivatives thereof: the total dose should not exceed 20 mg (range 0.1 μg to 20 mg), the preferred total dose is 1 μg ˜5 mg. The dose per unit area of the surface is 0.1 μg~10 μg / mm ^2, preferred dose is ^{0.25μg / mm 2 ~5 μg / mm} 2. The lowest concentration of geldanamycin, 10 ⁻⁸ to 10 ⁻⁴ M, should be maintained with wounds, keloids or hypertrophic scars. (F) HMGCoA reductase inhibitors (eg, simvastatin) and analogs and derivatives thereof: the total dose should not exceed 2000 mg (range 10.0 μg to 2000 mg), and the preferred total dose is 10 μg to 300 mg And The dose per unit area is ^{1.0μg / mm 2 ~1000 μg / mm} 2, a preferred dosage ^{2.5 μg / mm 2 ~500μg / mm} 2. The lowest concentration of simvastatin, 10 ⁻⁸ to 10 ⁻³ M, should be maintained with wounds, keloids or hypertrophic scars. (G) Inosine monophosphate dehydrogenase inhibitors (eg, mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ ) and analogs and derivatives thereof: Total dose exceeds 2000 mg (range 10.0 μg to 2000 mg) The preferred total dose is 10 μg to 300 mg. The dose per unit area is ^{1.0μg / mm 2 ~1000 μg / mm} 2, a preferred dosage ^{2.5 μg / mm 2 ~500μg / mm} 2. The lowest concentration of mycophenolic acid, 10 ⁻⁸ to 10 ⁻³ M, should be maintained with wounds, keloids or hypertrophic scars. (H) NFκB inhibitors (eg, Bay 11-7082) and analogs and derivatives thereof: the total dose should not exceed 200 mg (range 1.0 μg to 200 mg) and the preferred total dose is 1 μg to 50 mg. The dose per unit area is 1.0 μg / mm ^{2 to} 100 μg / mm ² , and the preferred dose is 2.5 μg / mm ² to 50 μg / mm ² . The minimum concentration of Bay 11-7082, 10 ⁻⁸ to 10 ⁻⁴ M, should be maintained with wounds, keloids or hypertrophic scars. (I) Antifungal drugs (eg, sulconizole) and analogs and derivatives thereof: The total dose should not exceed 2000 mg (range 10.0 μg to 2000 mg) and the preferred total dose should be 10 μg to 300 mg . The dose per unit area is ^{1.0μg / mm 2 ~1000 μg / mm} 2, a preferred dosage ^{2.5 μg / mm 2 ~500μg / mm} 2. Wounds, the keloid or hypertrophic scars to maintain a minimum concentration of Surukonizoru to 10 ^-8 ~10 ^-3 M. The same applies to (J) p38 MAP kinase inhibitors (such as SB202190), analogs and derivatives thereof. The total dose is not to exceed 2000 mg (range of 10.0 μg to 2000 mg), and the preferable total dose is 10 μg to 300 mg. The dose per unit area was ^{1.0 μg / mm 2 ~1000μg / mm} 2, a preferred dosage ^{2.5 μg / mm 2 ~500 μg /} mm 2. The lowest concentration of SB202190, 10 ⁻⁸ to 10 ⁻⁴ M, should be maintained with wounds, keloids or hypertrophic scars.

  According to another aspect, the anti-infectives described above can be used in combination with formulations for the treatment or prevention of hypertrophic scars and keloids. Typical anti-infectives include (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) Dophilotoxins (such as etoposide), (E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin), and analogs and derivatives of the above.

  The dose of drug administered from this composition to prevent or inhibit infection according to the present invention will depend on various factors including the type of formulation, the site of healing, and the type of condition being treated. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), and the total drug dose administered can be measured and the appropriate surface concentration of the active agent can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective agent is released from the polymeric compound at an effective concentration in the range of less than about 1 day to about 180 days over a period measured from the time of immersion in the tissue adjacent to the device. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, about 90 days The range is from day to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following dosage guidelines. The total amount (dose) of the anti-infective agent in the composition is about 0.01 μg-1 μg, about 1 μg-10 μg, about 10 μg-1 mg, about 1 mg-10 mg, about 10 mg-100 mg , About 100 mg to 250 mg, about 250 mg to 1000 mg. The dosage (dose) of the drug per unit area of the device or tissue surface to which the anti-infective agent is applied is about 0.01 μg / mm ² to 1 μg / mm ² , about 1 μg / mm ² to 10 μg / mm ² , about 10 μg / mm ^{2 to} 100 μg / mm ² , about 100 μg / mm ² to 250 μg / mm ² , about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compounds which release an anti-infective agents in different proportions, administration parameters described above, a minimum concentration of about 10 ^-8 M to ^-7 M of the drug tissue surface, about 10 ^-7 M to ^-6 M, about 10 ^-6 M to ^-5 M, to be maintained at either about 10 ^-5 M to ^-4 M, it should be used in combination with the drug release rate from the composition.

In another embodiment of a vascular disease, the present invention provides a polymer composition comprising a polymeric carrier for treating a vascular disease such as (e.g., stenosis, restenosis or atherosclerosis) and one or more fiber formations. The use of inhibitors is also provided.

Another aspect of the invention for perivascular delivery provides a composition of a therapeutic agent. With this composition, around the blood vessels (eg, on the outer part of the blood vessel or directly on the outer membrane of the blood vessel) to treat or prevent vascular diseases (eg, stenosis, restenosis, or atherosclerosis) Deliver.

  Perivascular drug delivery uses a needle or catheter directed through ultrasound, CT, fluoroscopy, MRI or endoscopic guidance, and a localized (often sustained release) therapeutic formulation through the skin Administration to the epicardial surface of the target vessel (artery, vein, autologous bypass graft, synthetic bypass graft, AV fistula). Alternatively, the procedure can be performed during surgery under direct vision or under additional image guidance (eg, during bypass surgery, hemodialysis access surgery). Such procedures can also be performed in conjunction with endovascular procedures such as angioplasty, atherectomy, stent implantation, or in conjunction with surgical arterial procedures such as endarterectomy, vascular or graft repair insertion, etc. .

  For example, in one embodiment, the polymer concentration of paclitaxel can be injected into the vessel wall or applied to the outer membrane surface of the vessel to keep the drug concentration highest in the area where the biological activity is most needed. Can do. This may reduce the local “outflow” of the drug, highlighted by the continuous blood flow that flows through the surface of an intravascular drug delivery device (such as a drug coated stent). Administering effective fibrosis inhibitors to the outer surface of the duct reduces arterial, venous or graft obstruction, and endovascular manipulation (restenosis, arterial embolization, thrombosis, plaque rupture, systemic drug addiction) Etc.) can be reduced.

  For example, in patients with shallow superficial femoral artery narrowing, balloon angioplasty is performed as usual (i.e., a balloon angioplasty catheter is passed along the guide line to the artery and the balloon is inflated into the lesion site). . When the needle is inserted through the skin under ultrasound, fluoroscopy, or CT guidance before, during, or after angioplasty, a fibrosis inhibitor or composition (eg, sustained release polymer) in the needle or catheter The paclitaxel impregnated into the blood is directly infiltrated around the circumference of the narrowed area of the artery. This is done around an artery, vein or graft, but this procedure is also for diseases such as the carotid artery, thrombosis, iliac artery, common thigh, superficial femur and popliteal artery, and graft It is desirable to carry out at the joining site. The logical venous site includes immersion around the tube into which the indwelling catheter is inserted. Similarly, during endoscopic or open coronary bypass surgery, peripheral bypass surgery, or hemodialysis access surgery, a fibrosis inhibitor or composition (eg, paclitaxel impregnated with sustained release polymer) causes restenosis. Wetting, spraying or wrapping around in the joining area where there is an increase. This is performed around an artery, vein or graft, but this procedure is for diseases such as the carotid artery, thrombosis, iliac artery, common thigh, superficial thigh and popliteal artery, and AV This is preferably done at the graft anastomosis site.

  In accordance with the present invention, any of the above scarring inhibitors can be utilized in the practice of this invention. In one example, a composition for perivascular drug delivery is adapted to release an agent that inhibits one or more of the five general factors for the process of fiber formation (or scarring) including: Can: connective tissue cells (such as fibroblasts and smooth muscle cells) inflammatory response and inflammation, migration and proliferation, neovascularization (angiogenesis), extracellular matrix (ECM) accumulation, and remodeling (fibrotic) Organization maturity and organization). Suppressing one or more of the components that make up fibrosis (or scarring) can inhibit or reduce neointimal tissue overgrowth.

  The dose of fibrosis inhibitor drug administered from this composition for perivascular delivery depends on a variety of factors including the type of formulation, the site of healing, and the type of condition being treated. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), and the total drug dose administered can be measured and the appropriate surface concentration of the active agent can be determined. Drugs are generally used at concentrations ranging from several times the concentration used in single systemic applications up to 50%, 20%, 10%, 5%, or even less than 1%. In certain embodiments, the anti-scarring agent is released from the polymeric compound at an effective concentration over a period measured from the time of immersion in the tissue adjacent to the device, ranging from less than about 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, about 90 days The range is from day to about 180 days. In one embodiment, the drug is released at an effective concentration for 1 to 90 days.

Some examples of fiber formation inhibitors that can be used in perivascular drug delivery compositions are listed below. Cell cycle inhibitors include (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, Taxotere and docetaxel), (C) podophyllotoxins (such as etoposide), (D) immune Modulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase inhibitors (such as simvastatin), (G) inosine monophosphate dehydrogenase Inhibitors (such as mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ ), (H) NHκB inhibitors (such as Bay11-7082), (I) Antifungal agents (such as sulconizol), (J) p38 MAP kinase inhibition Agents (such as SB202190), and analogs and derivatives as described above.

A typical fibrosis inhibitor used alone or in combination should be administered according to the following dosage guidelines. The total amount (dose) of the anti-scarring agent in the composition ranges from about 0.01 μg to 10 μg, 10 μg to 10 mg, 10 mg to 250 mg, 250 mg to 1000 mg, 1000 mg to 2500 mg. Can be. Scarring inhibitor dose per unit area of the surface to which drug is applied (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2, 1 μg / mm 2 ~10 μg / mm 2, 10 μg / mm 2 ~250μg / mm ^2, 250 may be one of a range of ^{μg / mm 2 ~1000 μg / mm} 2, 1000 μg / mm 2 ~2500μg / mm 2.

Listed below are exemplary dosage ranges for various scarring inhibitors that can be used in conjunction with perivascular administration in accordance with the present invention. (A) A cell cycle inhibitor comprising doxorubicin and mitoxantrone. Doxorubicin analogs and derivatives thereof: The total dose should not exceed 25 mg (range 0.1 μg to 25 mg) and the preferred total dose is 1 μg to 5 mg. The dosage per unit area of the graft is 0.01 μg / mm ^{2 to} 100 μg / mm ² , and the preferred dosage is 0.1 μg / mm ² to 10 μg / mm ² . The minimum concentration of doxorubicin, 10 ⁻⁸ to 10 ⁻⁴ M, should be maintained on the outer membrane surface. Mitoxantrone and its analogs and derivatives: The total dose should not exceed 5 mg (0.01 μg to 5 mg range), the preferred total dose being 0.1 μg to 1 mg. The dosage per unit area of the graft is 0.01 μg / mm ^{2 to} 20 μg / mm ² , and the preferred dosage is 0.05 μg / mm ^{2 to} 3 μg / mm ² . The minimum concentration of mitoxantrone, 10 ⁻⁸ to 10 ⁻⁴ M, shall be maintained on the outer membrane surface. (B) Cell cycle inhibitors including paclitaxel and its analogs and derivatives (eg docetaxel): The total dose should not exceed 10 mg (range 0.1 μg to 10 mg), the preferred total dose is 1 μg ~ 3 mg. The dosage per unit area of the graft is 0.1 μg / mm ^{2 to} 10 μg / mm ² , and the preferred dosage is 0.25 μg / mm ^{2 to} 5 μg / mm ² . The minimum concentration of paclitaxel, 10 ⁻⁸ to 10 ⁻⁴ M, should be maintained on the outer membrane surface. (C) Cell cycle inhibitors such as podophyllotoxin (eg etoposide): The total dose should not exceed 10 mg (range 0.01 μg to 10 mg), and the preferred total dose is 1 μg to 3 mg To do. The dose per unit area of the implant is ^{0.1 μg / mm 2 ~10 μg /} mm 2, preferred dose is ^{0.25μg / mm 2 ~5 μg / mm} 2. The minimum concentration of etoposide, 10 ⁻⁸ to 10 ⁻⁴ M, shall be maintained on the outer membrane surface. (D) Immunosuppressive drugs including sirolimus and everolimus. Sirolimus (ie Rapamune): the total dose should not exceed 10 mg (range 0.1 μg to 10 mg), the preferred total dose being 10 μg to 1 mg. The dose per unit area was ^{0.1 μg / mm 2 ~100μg / mm} 2, preferred dosage is ^{0.5 μg / mm 2 ~10 μg /} mm 2. The lowest concentration of sirolimus, 10 ⁻⁸ to 10 ⁻⁴ M, should be maintained on the outer membrane surface. Everolimus and its analogs and derivatives: The total dose should not exceed 10 mg (range 0.1 μg to 10 mg), the preferred total dose being 10 μg to 1 mg. The dosage per unit area of the surface is 0.1 μg / mm ^{2 to} 100 μg / mm ² , and the preferred dosage is 0.3 μg / mm ² to 10 μg / mm ² . The lowest concentration of everolimus, 10 ⁻⁸ to 10 ⁻⁴ M, shall be maintained on the outer membrane surface. (E) Heat shock protein 90 antagonist (eg, geldanamycin) and analogs and derivatives thereof: The total dose should not exceed 20 mg (range 0.1 μg to 20 mg), and the preferred total dose is 1 μg to 5 mg. The dosage per unit area of the graft is 0.1 μg / mm ^{2 to} 10 μg / mm ² , and the preferred dosage is 0.25 μg / mm ^{2 to} 5 μg / mm ² . The minimum concentration of geldanamycin, 10 ⁻⁸ to 10 ⁻⁴ M, should be maintained on the outer membrane surface. (F) HMGCoA reductase inhibitors (eg, simvastatin) and analogs and derivatives thereof: The total dose should not exceed 2000 mg (range 10.0 μg to 2000 mg), and the preferred total dose is 10 μg to 300 mg. The dosage per unit area of the graft is 1.0 μg / mm ^{2 to} 1000 μg / mm ² , and the preferred dosage is 2.5 μg / mm ^{2 to} 500 μg / mm ² . The lowest concentration of simvastatin, 10 ⁻⁸ to 10 ⁻³ M, should be maintained on the outer membrane surface. (G) Inosine monophosphate dehydrogenase inhibitor (eg: mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ ) and its analogs and derivatives: total dose of 2000 mg (range 10.0 μg to 2000 mg) The total dose is preferably 10 μg to 300 mg. The dose per unit area of the implant is ^{1.0μg / mm 2 ~1000 μg / mm} 2, a preferred dosage ^{2.5 μg / mm 2 ~500μg / mm} 2. The minimum concentration of mycophenolic acid, 10 ⁻⁸ to 10 ⁻³ M, shall be maintained on the outer membrane surface. (H) NFκB inhibitors (eg, Bay 11-7082) and analogs and derivatives thereof: The total dose should not exceed 200 mg (range 1.0 μg to 200 mg) and the preferred total dose is 1 μg to 50 mg. The dosage per unit area of the graft is 1.0 μg / mm ^{2 to} 100 μg / mm ² , and the preferred dosage is 2.5 μg / mm ² to 50 μg / mm ² . The minimum concentration of Bay 11-7082, 10 ⁻⁸ to 10 ⁻⁴ M, should be maintained on the outer membrane surface. (I) Antifungal drugs (eg sulconizole) and analogues and derivatives thereof: The total dose should not exceed 2000 mg (range 10.0 μg to 2000 mg), the preferred total dose is 10 μg to 300 mg . The dosage per unit area of the graft is 1.0 μg / mm ^{2 to} 1000 μg / mm ² , and the preferred dosage is 2.5 μg / mm ^{2 to} 500 μg / mm ² . The minimum concentration of sulconizole is maintained at 10 ⁻⁸ to 10 ⁻³ M on the epicardial surface, vein or graft. The same applies to (J) p38 MAP kinase inhibitors (such as SB202190), analogs and derivatives thereof. The total dose is not to exceed 2000 mg (range of 10.0 μg to 2000 mg), and the preferable total dose is 10 μg to 300 mg. The dosage per unit area of the graft is 1.0 μg / mm ^{2 to} 1000 μg / mm ² , and the preferred dosage is 2.5 μg / mm ^{2 to} 500 μg / mm ² . The minimum concentration of SB202190, 10 ⁻⁸ to 10 ⁻³ M, shall be maintained on the outer membrane surface.

  According to another aspect, any of the anti-infectives described above can be used in the practice of this example, either alone or with a fiber forming agent. Typical anti-infectives include (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) Dophilotoxins (such as etoposide), (E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin), and analogs and derivatives of the above.

  The dose of drug administered from this composition to prevent or inhibit infection according to the present invention will depend on various factors including the type of formulation, the site of healing, and the type of condition being treated. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), and the total drug dose administered can be measured and the appropriate surface concentration of the active agent can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective agent is released from the polymeric compound at an effective concentration in the range of less than about 1 day to about 180 days over a period measured from the time of immersion in the tissue adjacent to the device. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, about 90 days The range is from day to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following dosage guidelines. The total amount (dose) of the anti-infective agent in the composition is about 0.01 μg-1 μg, about 1 μg-10 μg, about 10 μg-1 mg, about 1 mg-10 mg, about 10 mg-100 mg , About 100 mg to 250 mg, about 250 mg to 1000 mg. The dosage (dose) of the drug per unit area of the device or tissue surface to which the anti-infective agent is applied is about 0.01 μg / mm ² to 1 μg / mm ² , about 1 μg / mm ² to 10 μg / mm ² , about 10 μg / mm ^{2 to} 100 μg / mm ² , about 100 μg / mm ² to 250 μg / mm ² , about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compounds which release an anti-infective agents in different proportions, administration parameters described above, a minimum concentration of about 10 ^-8 M to ^-7 M of the drug tissue surface, about 10 ^-7 M to ^-6 M, about 10 ^-6 M to ^-5 M, to be maintained at either about 10 ^-5 M to ^-4 M, it should be used in combination with the drug release rate from the composition.

Medical device and implant coating materials The fiber formation inhibitors and compositions of the present invention can be used in implants or implantable medical devices (eg, artificial joints such as metals, plastics and / or other materials, retaining pins, skull plates, etc.) ), Breast grafts (eg silicone gel envelope, foam foam, etc.), implanted catheters and cannulas for long-term use (3 days or more), artificial organs and blood vessels (eg artificial heart, spleen, kidney, blood vessels) ), Monolithic implants such as drug delivery devices (Alzet Minipon) (DURECT Corporation, Cupertino, Calif.), Steroid granules for protein growth and contraception, including pumps and controlled release devices, dermal or internal sutures, periodontal ligaments, It can also be combined with ophthalmic shields, corneal lenses, and the like.

  Another use of the fiber formation inhibiting compounds and compositions is for synthetic implant coating materials. In a general method of coating the surface of a synthetic implant, the multifunctional compound is exposed to the modified environment, so that a thin layer of the composition is applied to the surface of the implant, and then substantially interacted. Will occur. In one example, a compound is selected to minimize cellular and fiber responses to the coated implant and the substrate is given a pure neutral charge. The compound is applied to the surface of the graft by extrusion, brushing, spraying, or other convenient method. When the compound is applied to the surface of the implant, the interaction continues and a complete three-dimensional substrate is formed.

  Although this method can be used to coat the surface of any type of synthetic graft, reduced thrombus formation is a prosthetic or heart valve, vascular graft, vascular stent, anastomosis, coupling device, and stent / graft Especially useful for grafts that are important to consider, such as combinations. This method can also be used to coat an implantable surgical membrane (eg, monofilament yarn polypropylene) or mesh (eg, for hernia repair). Breast augmentation implants can also be coated in the manner described above to minimize capsule contracture.

  Compounds and compositions that inhibit fiber formation can also be covered with suitable fibrous materials so that they can be covered with bone and provide structural integrity to the bone. The term “appropriate fibrous material” as used herein is substantially non-water soluble, non-immunogenic, biocompatible and mixed with the crosslinkable composition of the present invention. do not do. Fibrous materials may include a variety of materials with these characteristics, and can be combined with crosslinkable materials herein, and / or various implants and devices related to medical or pharmaceutical use Provides structural integrity.

  Lenses can also be coated with compounds and compositions that inhibit fiber formation of the present invention, which are made of naturally occurring or synthetic polymers.

  Typical medical devices that can be coated with the polymer composition of the present invention include vascular stents, gastrointestinal stents, tracheal / bronchial stents, urogenital stents, ENT stents, endovascular grafts, intraocular lenses, hypertrophic scars.・ Keloid grafts, vascular grafts, anastomotic coupling devices, implantable sensors, implantable pumps, implantable nerve stimulators, implantable electrical devices such as implantable electrical leads, surgical adhesive barriers Glaucoma drainage device, film or mesh, prosthetic heart valve, middle ear ventilation tube, penile graft, endotracheal tube and tracheal cannula, peritoneal dialysis catheter, intracranial pressure monitor, aortic filter, CVC, auxiliary artificial heart ( LVAD), artificial spine, urinary catheter (foley) catheter, prosthetic bladder sphincter, orthopedic implant, and There is such as gastrointestinal drainage tubes.

Infiltration of the polymeric compound around the medical device and the graft Another use of the polymer composition described herein is to infiltrate the composition into tissue adjacent to the medical device. The subject polymer composition may comprise a fiber formation inhibitor and / or an anti-infective agent.

  Polymeric compounds can be found in (a) tissue adjacent to a medical device, (b) near the interface between the medical device and tissue, (c) near a site around the medical device, and (d) in tissue around the medical device. The medical device can be infiltrated by application to the composition directly and / or indirectly in and / or on the surface. Methods by which the subject polymer composition can infiltrate tissue adjacent to the medical device include delivering the polymer composition in the following manner: (a) to the surface of the medical device during the implantation procedure (eg, injection) (As substance, paste, gel or mesh), (b) Implant material, paste, gel, in situ gel or mesh just before or during implantation of medical device implant (C) Immediately after implantation of the medical device, on the surface of the medical device and / or on the surface of the implanted medical device (eg, injection material, paste, gel, gel or mesh formed in situ) (d) Topical application of the composition to the anatomical space in which the medical device is placed (especially useful in this example is the use of a polymeric carrier that releases the fibrosis inhibitor over a period ranging from hours to weeks. is there- Bodies, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and other formulations that can release the drug and be delivered to the site where the device is inserted) (e) Delivery by a combination of the methods described above, by intradermal injection of a solution, infusion or sustained release formulation into the tissue surrounding the medical device. Combination therapy (eg, combination of therapeutic agents and combination with antithrombotic and / or antiplatelet agents) can also be used. In any case, the subject polymer composition can be immersed in tissue adjacent to the entire device or a portion thereof.

  Representative examples of polymeric compounds that can invade tissues adjacent to medical devices include: (a) formulations containing sprayable collagen such as COSTASIS (Angiotech Pharmaceuticals, Inc., Canada) and Cross-linked poly (ethylene glycol) -methylated collagen composition (e.g., as described in U.S. Patent Nos. 5,874,500 and 5,565,519) alone or with a therapeutic agent (e.g., anti-scarring agent and / or anti-infective agent), And infiltrate the tissue adjacent to the medical device, (b) a spray such as COSEAL (Angiotech Pharmaceuticals, Inc.), FocalSeal (Genzyme Corporation, Cambridge, Mass.), SPRAYGEL or DURASEAL (both Confluent Surgical, Inc., Boston, Massachusetts). Drugs containing possible PEGs alone or with therapeutic agents (eg, anti-scarring and / or anti-infectives) and medical Infiltrate the tissue adjacent to the device, and (c) carry a fibrinogen-containing drug, such as FLOSEAL or TISSEAL (both Baxter Healthcare Corporation, Fremont, California) alone or with a therapeutic agent (eg, anti-scarring and / or Anti-infectives) and infiltrate the tissue adjacent to the medical device, (d) RESTYLANE or PERLANE (both Q-Med AB, Sweden), HYLAFORM (Inamed Corporation, Santa Barbara, CA), SYNVISC (Biomatrix, Inc., Ridgefield, New Jersey), drugs containing hyaluronic acid, such as SEPRAFILM or SEPRACOAT (both Genzyme Corporation), either alone or with therapeutic agents (eg, anti-scarring and / or anti-infectives) and in medical devices Infiltrate adjacent tissue, (e) REPEL (Life Medical Sciences, Inc., Princeton, NJ) or FLOWGEL (B axter Healthcare Corporation) or other therapeutic polymer gel alone or with a therapeutic agent (eg, anti-scarring and / or anti-infective agent) and infiltrate the tissue adjacent to the medical device, (f) Osteobond ( Zimmer, Inc., Warsaw, Indiana), Low Viscosity Cement (LVC) (Wright Medical Technology, Arlington, Tennessee), SimplexP (Stryker Corporation, Kalamazoo, MN), Palacos (Smith & Nephew Corporation, UK) and Endurance (Johnson & Johnson, Inc) , New Brunswick, NJ) and other surgical “cements” that hold the organs and tissues in place, either alone or with therapeutic agents (eg, anti-scarring and / or anti-infectives), and medical Infiltrate tissue adjacent to the device, (g) Dermabond (Johnson & Johnson, Inc.), Indermil (US Surgical Company, Norwalk, Conn.), Glusti tch (Blacklock Medical Products Inc., Canada), TissuEmend (Veterinary Products Laboratories, Phoenix, AZ), VetBond (3M Company, St. Paul, MN), HistoacrylBLUE (Davis & Geck, St. Louis, MO), and Orabase Soothe-N- A surgical adhesive containing cyanoacrylate, such as Seal Liquid Protectant (Colgate-Palmolive Company, New York, NY), alone or with a therapeutic agent (eg, anti-scarring and / or anti-infective agent) and medical device Infiltrate the tissue adjacent to the bone, (h) grafts containing hydroxyapatite (or synthetic bone material such as calcium sulfate), VITOSS and CORTOSS (both Orthovita, Inc., Malvern, PA) alone or as a therapeutic agent Carrying (eg, scarring inhibitors and / or anti-infectives) and infiltrate tissue adjacent to the medical device, (i) BioCure, Inc (Norcross, Georgia), other biocompatible tissue fillers such as 3M Company (St. Paul, MN), and Neomend, Inc. (Sunnyvale, CA), alone or with therapeutic agents (eg, scars) And / or anti-infective agents) and infiltrate tissues adjacent to medical devices, (j) polysaccharide gels such as ADCON series gels (Gliatech, Inc., Cleveland, Ohio) alone or as therapeutic agents (E.g., scarring inhibitors and / or anti-infectives) and infiltrate tissues adjacent to medical devices, (k) INTERCEED (a division of Ethicon, Inc., Gynecare Worldwide, Somerville, NJ), VICRYL Films, sponges or meshes such as mesh (Ethicon, Inc.) and GelFoam (Pfizer, Inc., New York, NY) can be used alone or with therapeutic agents. (Eg scarring inhibitors and / or anti-infective agents), and invade adjacent tissue to the medical device.

  Other examples of polymer compositions that can invade tissues adjacent to medical devices include pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl (4-arm thiol PEG, sulfhydryl groups and polyethylene glycol backbone) as a reactive reagent. And a structure having a linking group between the NHS group and the end of the polyethylene glycol backbone, and pentaerythritol poly (ethylene glycol) ether tetra-succinimidyl glutarate. 4-arm NHS PE). Another preferred composition is pentaerythritol poly (ethylene glycol) ether tetraamino] (4-arm amino PEG, comprising a structure having a linking group between the amino group and the end of the polyethylene glycol backbone) as a reactive reagent, and Pentaerythritol poly (ethylene glycol) ether tetra-succinimidyl glutarate] (further including a structure having a linking group between the NHS group and the end of the polyethylene glycol backbone, 4-arm NHS PEG) . The chemical structure of these reactive groups is shown in US Pat. No. 5,874,500. Optionally, collagen or a collagen derivative (eg, methylated collagen) is added to a reactive group comprising poly (ethylene glycol) to form a preferred cross-linked substrate.

  Representative examples of medical devices that can be used with the subject compositions are shown below.

In one embodiment of the endovascular device, the subject polymer composition can infiltrate tissue adjacent to the intravascular device. The subject polymer composition can include therapeutic agents (such as anti-scarring agents and / or anti-infective agents). An “intravascular device” is a device that is at least partially implanted within a vasculature (such as a blood vessel). Examples of intravascular devices that can be used with the present invention include catheters, balloon catheters, balloons, stents, stent-coated stents, stent grafts, anastomotic connections, and guide wires.

  In another embodiment, the subject polymer composition can infiltrate tissue adjacent to the endovascular stent. A “stent” is a cylindrical tube (metal, textile, non-degradable or degradable polyester, or other suitable material (such as ecological tissue) that maintains blood flow from one part of a blood vessel to another. )). In one embodiment, a stent is an intravascular scaffold that maintains the lumen of a body pathway (such as an artery) and allows blood flow. Representative examples of stents that benefit from infiltration of adjacent tissue with the subject polymer compositions include intravascular stents such as vascular stents, peripheral stents, and coated stents.

  Stents that can be used in the present invention include metal stents, polymer stents, biodegradable stents and coated stents. Stents are self-expandable and expandable with balloons, composed of various metal compounds and polymer materials, manufactured with a myriad of designs, used in coronary and peripheral blood vessels, and disassembled There are those composed of non-degradable and non-degradable components, completely or partially covered with vascular graft material (so-called “coated stent”), “sleeve”, etc., and may be bare metal or drug eluate .

  Stents include stainless steel, spring tempered stainless steel, stainless steel alloys, gold, platinum, superelastic alloys, cobalt chromium alloys and other cobalt-containing alloys (ELGILOY (Combined Metals of Chicago, Grove Village, Illinois), PHYNOX ( Alloy WireInternational, UK) and CONICHROME (Carpenter Technology Corporation, Wyomissing, PA), etc.), titanium-containing alloys, platinum-tungsten alloys, nickel-containing alloys, nickel-titanium alloys (such as Nitinol), and malleable metals (such as tantalum) In addition to metal and metal alloys, composite materials or coated composite materials, other functionally equivalent materials, and polymer (non-biodegradable or biodegradable) materials can be used. Typical examples of polymers that can be included in stent construction include polyethylene, polypropylene, polyurethane, polyester (such as polyethylene terephthalate (such as Dacron or Mylar (EI DuPont De Nemoursand Company, Wilmington, Del.)), Polyamide, polyaramid (KEVLAR). (Manufactured by EI DuPont De Nemours and Company), polyfluorocarbon (poly (tetrafluoroethylene) with or without copolymerized hexafluoropropylene (eg, trade name Teflon (EI DuPont De Nemours and Company) ), Raw silk as well as blends, blends and copolymers of these polymers, etc. Also, stents can be made from engineering plastics (thermotropic liquid crystal polymers (LCP), p, p'-dihydroxy polynuclear aromatics or di- Carboxy polynuclear aromatic What etc.) formed from compound may be one as a raw material.

  Additional stent types that can be used in the present invention include, for example, PCT Publication No. WO 01/01957 and U.S. Pat.Nos. 5,851,231,5,843,172,5,837,008,5,766,237,5,769,883,5,735,811,5,700,286,5,683,448,5,679,400,5,665,115,5,649,977,5,637,113,5,591,5,5,419,5,4 A removable drug eluting stent is described in Lambert, T. (1993) J. Am. Coll. Cardiol .: 21: 21: 483A. In addition, the stent can be adapted to release therapeutic agents. For example, it can be adapted to release the therapeutic agent only at the distal end or along the entire stent.

  A balloon over stent device, such as that described in Wilensky, RL (1993) J. Am. Coll. Cardiol .: 21: 185A, is also suitable for infiltrating the target polymer composition into adjacent tissues. .

  In addition to conventional stents, stents specifically designed for drug delivery can also be used. These specialized drug delivery stents and conventional stents include Conor Medsystems (Palo Alto, Calif.) (Eg, US Pat. Nos. 6,527,799, 6,293,967, 6,290,673, 6,241,762, US Patent Publication Nos. 2003/0199970, 2003). / 0167085 and PCT Publication No. WO 03/015664 etc.).

  Examples of intravascular stents in which the subject polymer composition invades adjacent tissue in accordance with the present invention include commercially available products. Stents include self-expandable or balloon-expandable stents (such as STRECKER stents (Medi-Tech / Boston Scientific Corporation)), and implants that change with temperature (such as Nitinol stents). Self-expanding stents that can be used include the Coronary Artery WALLSTENT and SciMED RADIUS stents from Boston Scientific Corporation (Natick, Mass.) And the Gianturco stent from Cook Group, Inc. (Bloomington, Indiana). Available balloon expandable stents include CROSSFLEX stent, BX-VELOCITY stent, PALMAZ-SCHATZ crown and spiral stent (Cordis Corporation, Miami Lakes, FL), V-FLEX PLUS stent (Cook Group, Inc.), NIR Stents, EXPRESS stents and LIBRERTE stents (Boston Scientific Corporation), ACS MULTILINK stents, MULTILINK PENTA stents, SPIRIT stents, CHAMPION stents (Guidant Corporation), and coronary stents S670 and S7 from Medtronic, Inc. (Minneapolis, MN) There is.

Other examples of stents that can immerse the polymer composition of interest in adjacent tissue in accordance with the present invention include those manufactured by Boston Scientific Corporation (drug-eluting TAXUSExpress ² paclitaxel-eluting coronary stent system, over-the-wire stent type stent ( Express ² coronary stent system and NIR Elite OTW stent system), rapid exchange stents (such as Express ² coronary stent system and NIR Elite Monorail stent system), and self-expanding stents (such as Magic WALLSTENT and Radius self-expanding stents)) , Medtronic, Inc. (Minneapolis, MN) (DriverABT578-eluting stent, Driver Zipper MXMulti-Exchange coronary stent system, and Driver over-the-wire coronary stent system, S7 Zipper MX Multi-Exchange coronary stent system, S7, S670, S6 60, and BeStent2 with DiscreteTechnology over-the-wire coronary stent system, manufactured by Guidant Corporation (Cobalt chromium stent (MULTI-LINK VISION coronary stent system, MULTI-LINK ZETA coronary stent system, MULTI-LINKPIXEL coronary stent system, MULTI-LINK ULTRA coronary artery) (E.g. stent systems and MULTI-LINK FRONTIER), Johnson & Johnson / Cordis Corporation (e.g. CYPHER sirolimus-eluting stent, PALMAZ-SCHATZ balloon expandable stent, SMART room temperature stent), AbbottVascular (Redwood, CA) (Matrix) LO stents, TriMaxx stents, and Dexamet stents), Conor Medsystems (Menlo Park, CA) (MedStent and COSTAR stents), AMG GmbH (Germany) (PICO elite stents, etc.), Biosensors International (Singapore) (Matrix stent, Champion stent (formerly S stent), Challenge stent, etc.), Biotronik (Switzerland) (Magic AMS stent, etc.), Clearstream Technologies (Ireland) (ClearFLEX stent, etc.), CookInc. (Bloomington, IN) (V-Flex Plus stent, Zilver PTX self-expanding vascular stent coating, Logix PTX stent (under development)), Devax (Irvine, CA) (Axxess stent, etc.), DISA Vascular (Pty) Ltd (South Africa) ( ChromoFlex stents, S-Flex stents, S-Flex micro-stents, and TaxochromeDES), Intek Technology (Bar, Switzerland) (Apollo stents), OrbusMedical Technologies (Hoevelaken, Netherlands) (Genous, etc.), SorinBiomedica (Italy, Saluggia) (Janus and Carbostent) and Bard / Angiomed GmbH Medizintechnik KG Maryhill, Jersey, and Blue Medical Supply & Equipment (Marietta, Georgia), Aachen Resonance GmbH (Germany), Eucatech AG (Germany), Eurocor GmbH (Germany, Bonn), Prot, Goodman, Terumo (Japan), TransluminaGmbH (Germany) ), MIV Therapeutics (Canada), Occam International BV (Eindhoven, The Netherlands), SahajanandMedical Technologies PVT LTD. (India), stents, AVI Biopharma / Medtronic / Interventional Technologies (Oregon, Portland) (RestenNG coated stents, etc.) ), And Jomed (Sweden) (such as Flexmaster drug-eluting stents).

  In general, stents are inserted in a similar manner regardless of the site or disease being treated. In brief, usually, pre-insertion inspections such as diagnostic imaging procedures during surgery, endoscopy, or direct visualization are first performed for the purpose of determining the proper position for stent insertion. The guide wire is then advanced through the lesion site or the site to be inserted, over which the delivery catheter passes, thereby inserting the folded form of the stent. Intravascular stents are inserted into arteries, such as the femoral artery in the groin, and are advanced through the circulation until they reach the anatomical site of the plaque in the coronary or peripheral circulation under radiological guidance. In general, a stent can be compressed through a catheter, inserted through a very small cavity, and then expanded to a larger diameter once it is in the desired location. The delivery catheter is then removed and the stent remains as a scaffold. Once expanded, the stent physically pushes the path walls apart and holds them open. Inspection after insertion (usually x-rays) is often used to confirm proper placement.

  In general, the stent is manipulated in place with particular consideration by radiological or direct visual control, and is placed accurately within the vessel to be treated. In certain embodiments, the stent may further include radiopaque, echogenic material, or MRI-responsive material (such as an MRI contrast agent) to aid in visualization of the device, such as by ultrasound, fluoroscopy, and / or magnetic resonance imaging. Can be included. The radiopaque or MRI visible material can also be in the form of one or more markers (bands of material placed on both ends of the stent) that can be used to orient and guide the device during the implantable procedure.

  In another aspect, the subject polymer composition can infiltrate tissue adjacent to the anastomotic coupling device.

  An anastomosis coupling device refers to an anastomosis of blood vessels (ie, arteries and arteries, veins and arteries, arteries and veins, arteries and artificial blood vessels, artificial arteries, without the manual sutures commonly performed in anastomosis formation). Any vascular device that mechanizes the formation of blood vessels and arteries, veins and artificial blood vessels, and artificial blood vessels and veins. The term also means an anastomotic coupling device (described below) designed to facilitate semi-automated vascular anastomoses without the use of sutures and to significantly reduce coupling times (sometimes down to a few seconds) There are many types and designs of such devices. The term also refers to a device that facilitates the binding of a vascular graft to a hole or orifice (side or end of the blood vessel) in the target vessel. The anastomosis connection device can be fixed outside the blood vessel or inside the blood vessel wall (inside the outer membrane of the tissue, in the wall, or in the inner membrane layer), and keep a part of the device inside the lumen of the blood vessel You can also.

  An anastomotic coupling device can also be used to create a new flow from one structure to another through a channel or bypass branch. Thus, in general, such devices (also referred to herein as “bypass devices”) have at least one tubular structure that defines a lumen. An anastomotic coupling device can include a tubular structure or a plurality of tubular structures through which blood can flow. At least a portion of the tubular structure remains outside of the blood vessel (ie, outside the blood vessel) to provide a bypass path. Also, a portion of the device can remain in the lumen or in the vascular tissue.

  An example of an anastomotic coupling device is described in a co-pending application (US patent application Ser. No. 10 / 853,023) entitled “Anastomotic coupling device” (Filing date: May 24, 2004). Representative examples of anastomotic coupling devices include, but are not limited to, vascular clips, vascular sutures, vascular staples, vascular clamps, suturing devices, anastomotic coupling devices (ie, anastomotic couplers) (to carry blood) Couplers including a tubular segment), anastomotic rings, and percutaneous in situ coronary artery bypass (PISCAB and PICVA) devices. Broadly speaking, anastomotic coupling devices can be classified into three categories: (1) automatic and corrective suture methods and devices, (2) micromechanical devices, and (3) anastomotic coupling devices.

(1) Automatic and correction suturing methods and devices Automatic suturing and corrective suturing methods generally speed up the formation of multiple sutures (usually one stage). The use of is lost. The suturing device is minimally invasive so that anastomosis is formed between the blood vessel and the hollow organ structure by applying surgical fasteners through sutures and other device ports and other small openings. Devices adapted to be included are also included. With these devices, sutures and other fasteners are applied in a relatively quick and automated manner in body parts with limited access. By taking a minimally invasive approach to forming the anastomosis, blood loss is reduced and there is no need to temporarily stop blood flow distal to the surgical site. For example, the suturing device may comprise a blood vessel held by a shaft adapted for anastomosis, and a collar slidable on the shaft configured to hold a plurality of needles and a suture passing through the blood vessel. it can. See US Pat. No. 6,709,441. The suturing device includes a carrier portion for insertion of an arm portion of the “graft” that extends to hold the graft in place, a needle assembly for holding and advancing the coil fastener to engage the vessel wall It can also consist of a graft flange for completing the anastomosis. See US Pat. No. 6,709,442. The suturing device can also include two oblong couplings that include a separate bushing adapted for suturing (eg, US Pat. No. 4,350,160).

  One typical example of a suturing device is the Heartflow device by Perclose-Abbott Labs, Redwood City, Calif. (U.S. Pat. (See 01/19257).

  The Nitinol U-Clip suture clip device (Coalescent Surgical, Sunnyvale, Calif.) Consists of a self-closing Nitinol wire loop attached to a soft material and a needle with a quick release mechanism. This device facilitates suture management and promotes the formation of anastomoses by eliminating knot tying (for general information see US Pat. Nos. 6,074,401 and 6,149,658 and PCT publication numbers WO 99/62406, WO 99/62409). , WO 00/59380, see WO 01/17441).

  The Enclose anastomosis assist device (Novare Surgical Systems, Cupertino, Calif.) Allows surgeons to perform anastomosis with sutures without using a partially occluded side-mounted aortic clamp while using standard suturing techniques. Wall distortion is avoided (see US Pat. Nos. 6,312,445 and 6,165,186).

  In one embodiment, automatic and modified suturing methods and devices can result in surgical fasteners (such as sutures or suture clips) suitable for infiltrating adjacent tissue with the subject polymer composition. In another embodiment, automatic and modified suturing methods and devices may result in surgical fasteners (such as sutures or suture clips) infiltrating adjacent tissue with the subject polymer composition to complete the anastomosis.

(2) Micromechanical device The micromechanical device is used to form an anastomosis and / or to fix a graft blood vessel at the anastomotic site. Typical examples of micromechanical devices include staples (both penetrating and non-penetrating) and clips.

  There are various forms of anastomosis staples and clip devices and can be constructed of a variety of materials. For example, the staples and clips can be formed of a metal or metal alloy (titanium, nickel-titanium alloy, stainless steel, etc.), a polymeric material (silicone, poly (urethane), rubber, etc.), or a thermoplastic elastomer.

  The polymeric material may be an absorbable or biodegradable material designed to dissolve after completion of the anastomosis. The biodegradable polymer is composed of, for example, a homopolymer or copolymer composed of one or a plurality of monomers, and this monomer includes lactide, lactic acid, glycolide, glycolic acid, ε-caprolactone, γ-caprolactone, hydroxy Selected from herbic acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepane-2one The

  There are also descriptions of various devices for guiding staples and clips to predetermined positions.

  A manufacturer of non-penetrating staples used for anastomosis is United States Surgical Corp. (Norwalk, Connecticut). The VCS system (Autosuture) is an automatic stapling device that applies a non-penetrating titanium vascular clip, which is normally used intermittently to flip the tissue edge over with high compression force. (For a description of the U.S. Surgical anastomotic coupling device, see U.S. Pat. Nos. 6,440,146, 6,391,039, 6,024,748, 5,833,698, 5,799,857, 5,779,718, 5,725,538, 5,725,537, 5,720,756, 5,360,154, 5,193,731).

  The anastomotic clip may be composed of a shape memory material (such as Nitinol) that automatically closes between an open U-shaped structure and a closed shape. See US Pat. No. 6,641,593. An anastomotic clip has a shape memory that defines a substantially helical closed shape, and may consist of a wire with a removable needle attached to the clip. See US Pat. No. 6,551,332. Other anastomotic clips are described in US Pat. Nos. 6,461,365 and 6,514,265.

  Automatic stapling devices are also available from Bypass / Ethicon, Inc. (Summerville, NJ), which includes US Patent Nos. 6,193,129, 5,632,433, 5,609,285, 5,533,661, 5,439,156, 5,350,104, 5,333,773, 5,312,024, 5,292,053, 5,285,322, 5,275 5,271,544, 5,271,543 and 5,205,459 and WO03 / 02016. Resorbable surgical staples containing a polymer mixture having a high glycolide content (ie containing 65-85% by weight polymerized glycolide) are described in US Pat. Nos. 4,741,337 and 4,889,119. A surgical staple made from a mixture of a lactide / glycolide copolymer and poly (p-dioxanone) is described in US Pat. No. 4,646,741. Other types of stapling apparatus are described in US Pat. Nos. 5,234,447, 5,904,697 and 6,565,582, and US Publication No. 2002 / 0185517A1.

  In another aspect, the micromechanical device can be an anastomosis clip. For example, an anastomotic clip may be composed of a shape memory material (such as Nitinol) that automatically closes between an open U-shaped structure and a closed shape. See US Pat. No. 6,641,593. An anastomotic clip has a shape memory that defines a substantially helical closed shape, and may consist of a wire with a removable needle attached to the clip. See US Pat. No. 6,551,332. Other anastomotic clips are described in US Pat. Nos. 6,461,365, 6,187,019, 6,514,265, and the like.

  In one embodiment, the present invention provides a micromechanical anastomosis device (staple or clip) comprising a subject polymer composition that infiltrates adjacent tissue.

(3) Anastomotic coupling device The anastomotic coupling device can be used to join the first blood vessel to the second blood vessel for the completion of the anastomosis (with or without graft vessels) ). In one embodiment, the anastomotic coupling device facilitates the automatic coupling of a graft or vessel to a hole or orifice (side or end of the vessel) in the target vessel without the use of sutures or staples. In another aspect, the anastomotic coupling device consists of a tubular structure that defines a lumen (described below) through which blood can flow.

  An anastomotic coupling device that facilitates the automatic coupling of a graft or blood vessel to a hole or orifice in a target vessel can take a variety of forms and can be manufactured from a variety of raw materials. In general, such devices are made of a polymer or a biocompatible material such as a metal or metal alloy. For example, equipment includes fluoropolymers such as expanded poly (tetrafluoroethylene) (ePTFE), fluorinated ethylene propylene (FEP), polyurethane, sold by WL Gore & Associates, Inc. under the GORE-TEX trade name, polyurethane, It can be formed of a synthetic material such as polyethylene, polyamide (nylon), silicon, polypropylene, polysulfone, or polyester.

  The anastomotic coupling device can include an absorbable or biodegradable material designed to dissolve after completion of the anastomosis. The biodegradable polyester is composed of, for example, a homopolymer or copolymer composed of one or a plurality of monomers, and these monomers include lactide, lactic acid, glycolide, glycolic acid, ε-caprolactone, γ-caprolactone, hydroxy Selected from herbic acid, hydroxybutyric acid, β-butyrolactone, γ-butyrolactone, γ-valerolactone, γ-decanolactone, δ-decanolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepane-2one The

  Equipment includes metals and metal alloys (such as nitinol, stainless steel, titanium, iron, nickel, nickel-titanium, cobalt, platinum, tungsten, tantalum, silver, gold, molybdenum, chromium, and chromium), or metal and polymer Combinations can be included.

  The device can be anchored outside the blood vessel in tissue around the lumen of the blood vessel, or a portion of the device can be retained within the lumen of the blood vessel.

  In one embodiment, the anastomotic coupler may be an artificially shaped open coupling device and is placed on the side wall of the target vessel so that the tubular graft conduit can extend from the target vessel. The coupling device can include a plurality of concentrically arranged tissue penetrating members and retaining fingers that pass through the sidewalls of the tubular graft conduit to fluidly seal the graft to the coupling device. It can also be fixed and held. See US Pat. Nos. 6,702,829, 6,699,256, and the like.

  In another embodiment, the anastomotic coupler can be in the form of a frame. For example, the frame can be deformed and placed in the shape of a scissors, and the expansion member moves so that the graft vessel is secured to the target vessel upon insertion. See US Pat. No. 6,179,849.

  In another embodiment, the anastomotic coupler can be an annular device used as an anastomosis interface between the graft lumen and the target vessel lumen opening. For example, the anastomosis ring can be composed of a stainless steel alloy, a titanium alloy, or a cobalt alloy and can have a flange that is expandable in diameter. See US Pat. No. 6,699,257. The anastomotic ring is described in US Pat. No. 6,248,117.

  In another embodiment, the anastomotic coupler is resorbable. Resorbable anastomotic coupling devices include, for example, those containing a high glycolide content (ie, containing 65-85% by weight polymerized glycolide) (see US Pat. Nos. 4,741,337, 4,889,119, etc.) Or a mixture of lactide / glycolide copolymer and poly (p-dioxanone) (see, for example, US Pat. No. 4,646,741).

  In another embodiment, the anastomotic coupler includes a bioabsorbable elastomeric material. Representative examples of elastomeric materials used in resorbable devices are described in US Pat. No. 5,468,253.

  In another embodiment, an anastomotic coupler can be used to connect a first blood vessel to a second blood vessel (with or without a graft vessel). For example, an anastomotic coupler can be a device that serves to interconnect two blood vessels in a side-to-side anastomosis, such as when implanting two parallel cardiac conduits. The anastomosis coupler is configured as two partially open cylindrical segments interconnected along the perimeter with a flow opening so that the device can be inserted in a minimally invasive surgical manner And then, consistently, in the original configuration, pressure is provided against the inner wall to prevent leakage. See the following US patents. 6,464,709, 6,458,140, 6,251,116, and US Patent Application Publication No. 2003 / 0100920A1.

  In another embodiment, the anastomotic coupler can be incorporated into the design of the vascular graft to eliminate the attachment procedure to the interface prior to deployment. For example, an anastomotic coupler is configured for attachment of a leading and posterior petaloid portion for expanding a vascular opening as it is advanced, and a graft, while forming a base for the vascular opening seal Can be given. See US Pat. No. 6,702,828.

  In another embodiment, the anastomotic coupler can be in the form of a frame. For example, the anastomotic coupler can be configured as a scissor-shaped structure that can be deformed by using an expandable member inserted into a target blood vessel. See US Pat. No. 6,179,849.

  In another aspect, the anastomotic coupling device may include a graft that incorporates a fixation mechanism (such as a collet or grommet) at its opposite end and a heating element that forms a thermal bond between the graft and the blood vessel ( (See US Pat. Nos. 6,652,544 and 6,293,955, etc.).

  In another aspect, the anastomotic coupling device can include a compressible and expandable fitting to secure the end of the bypass graft to two vessels. This fitting can also be incorporated into the bypass graft design to eliminate the procedure of attaching the graft to the fitting prior to deployment (see, eg, US Pat. No. 6,494,889).

  The anastomotic coupling device can include a pair of coupling disk members for coupling two blood vessels in an end-to-end manner. One of these members can include a hook member, while the other member has a recess for receiving to align and secure the turned vascular tissue together in the hook position. (See U.S. Pat. No. 4,523,592).

  Representative examples of coupling devices by anastomosis of Bypass / Ethicon, Inc. are described in U.S. patent application publication numbers US2002 / 0082625A1, 2003 / 0100910A1, and U.S. Pat. Has been.

  Other anastomotic coupling devices are those described in the following US patents and the like. U.S. Patents 6,036,702, 6,508,822, 6,599,303, 6,673,084, 5,695,504, 6,569,173, 4,931,057, 5,868,763, 4,624,257, 4,917,090, 4,917,091,5,697,943,5,562,695,5,454,514 0120293A1, 2004 / 0030348A1.

  The anastomotic coupling device can include a proximal aortic coupling device and a distal coronary coupling device. For example, aortic anastomotic coupling devices include devices such as the SYMMETRY bypass aortic connection device (from St. Jude Medical, Inc., Maple Grove, MN), which can be used from an aortic cutter or hole punch assembly and graft delivery system. Composed. An aortic hole punch is a cylindrical cutter with a protruding needle that provides an anchor and back pressure for a rotating cutter, which cuts a round hole in the wall of the aorta. The graft delivery system is a radially expandable Nitinol device in which the vein graft is held by a small hook that penetrates the vein graft wall. The graft is secured to the aorta using the inner or outer rings of struts or flanges. This device and other St. Jude anastomosis coupling devices are described in US Pat. Nos. 6,309,416, 6,302,905, 6,152,937, PCT Publication Nos. WO00 / 27312, WO 00/27311, and the like.

  The CorLInk automatic anastomosis connector manufactured by CardioVations Division of Ethicon, Inc. (Johnson & Johnson, Somerville, NJ) uses Nitinol metal alloy fasteners to connect blood vessels implanted in the aorta. It consists of a central cylindrical body consisting of interconnected elliptical arches, and two sets of pins, each of which is radial from each end. The graft is loaded into a CorLink insertion instrument and placed in a single procedure to form an anastomosis.

  Other examples of anastomotic coupling devices include Cardica (see US Pat. Nos. 6,719,769, 6,419,681 and 6,537,287), ConvergeMedical (formerly Advanced Bypass Technologies), Onux Medical (PCT Publication No. WO 01/34037, etc.) And Ventrica (Menlo Park, Calif.) (VENTRICA Magnetic Vascular Positioner) (see US Pat. Nos. 6,719,768, 6,517,558, 6,352,543, etc.).

  As described above, the anastomotic coupling device comprises a tubular structure that defines a lumen through which blood can flow. These types of devices (also referred to herein as “bypass devices”) can serve as artificial pathways or conduits for fluid communication between blood vessels, and can be used from a portion of a blood vessel (such as an artery) to the same blood vessel. Can be used to divert (ie, shunt) blood to another part of the blood vessel, to a second blood vessel (such as an artery or vein), or to multiple blood vessels (venous and arterial). In one embodiment of the invention, the anastomosis device is a bypass device.

  The bypass device can be used in a variety of end-to-end anastomosis procedures. The bypass device can be placed in patients where it is desirable to route between two or more vasculatures or between two different parts of the same vasculature. For example, bypass devices allow blood to flow around an artery (such as a coronary artery, a carotid artery, or an artery that feeds the lower limb) when it is damaged or completely or partially blocked Can be used to form a passageway. The bypass device can be used in coronary artery bypass surgery to short blood flow from an artery, such as the aorta, from the occlusion site of the artery to the downstream portion of the coronary artery.

  Certain types of anastomotic coupling devices are configured to join two adjacent blood vessels. The device can further include a tubular segment to short circuit blood flow to another blood vessel. These types of coupling devices are often used for end-to-end anastomoses when blood vessels are severed or damaged.

  The bypass device includes at least one tubular structure having a first end and a second end, thereby defining a single lumen through which blood can flow or a plurality of A plurality of lumens having a tubular structure and through which blood can flow are defined. The tubular structure includes an extravascular portion, and may optionally include an intravascular portion. The extravascular portion is outside the adventitial tissue of the blood vessel, while the intravascular portion is in the vessel lumen or inside the intimal tissue, intermediate tissue, outer membrane tissue, and the like.

  The arrangement of the tubular segments can take a variety of forms. For example, the tubular portion is generally straight, curved (such as L-shaped or helical), tapered, bifurcated (such as bifurcated or trifurcated), or includes a network of conduits through which blood can flow. There is also. In general, straight or curved devices have a single lumen through which blood can flow, while branched conduits (generally T and Y devices) and conduit networks (described below) There are multiple lumens through which blood can flow. The tubular structure takes the form of a hollow cylinder, for example, and may or may not include a support structure such as a mesh or porous framework. Depending on the procedure, the device may be biodegradable or non-biodegradable, expandable or rigid, metal or polymer, and may be assembled with a shape memory material (such as nitinol). In certain embodiments, the device includes a self-expanding stent structure.

  The bypass device is generally made of a biocompatible material. Any of the materials described above for other types of coupling devices (such as synthetic or naturally derived polymers, or metals or metal alloys) can be used to create the bypass device. For example, the device may be a fluoropolymer such as expanded poly (tetrafluoroethylene) (ePTFE) or fluorinated ethylene propylene (FEP), an artificial material such as polyurethane, polyethylene, polyamide (nylon), silicone, polypropylene, polysulfone, or polyester. In addition, it can be formed from naturally derived substances such as collagen and polysaccharides. Equipment includes metals and metal alloys (such as Nitinol, stainless steel, titanium, nickel, nickel-titanium, cobalt, platinum, iron, tungsten, tantalum, silver, gold, molybdenum, chromium, and chrome plating), or metals and polymers May be included. Other types of devices include natural graft materials (autologous blood vessels, allovascular vessels, xenografts, etc.) or a combination of synthetic and natural graft materials. In another aspect, the bypass device can be formed of an absorbable or biodegradable material (polylactic acid, polyglycolide, and a copolymer of lactide and glycolide) designed to dissolve after completion of the anastomosis. In another embodiment, demineralized water bone can be used to provide a tubular conduit that is easy to mold (see US Pat. No. 6,290,718).

  The tubular structure has a proximal end that can be arranged for coupling to a proximal vessel and a distal end that can be arranged for coupling to a distal vessel. As described above, the anastomosis may be depicted as either “proximal” or “distal” depending on its relative position with respect to the vascular occlusion. A “proximal” anastomosis is formed in the proximal vessel, and a “distal” anastomosis is formed in the distal vessel, which may be the same vessel as the proximal vessel or a different vessel There is also. The terms “distal” and “proximal” may also be used to describe the direction of blood flow from one blood vessel to another in the tubular structure. For example, blood may flow from a proximal vessel (such as the aorta) to a distal vessel (such as the coronary artery) to bypass occlusions in the coronary artery.

  The tubular structure can be directly coupled to a proximal or distal blood vessel. Alternatively, the bypass device can further include a graft vessel or be configured to receive a graft vessel, which can be coupled to the same or another vessel to complete the anastomosis. . Representative examples of graft blood vessels include, for example, grafts used for vascular grafts or hemodialysis applications (such as arteriovenous grafts, arteriovenous anastomoses, or arteriovenous grafts).

  In one embodiment, the tubular anastomosis coupler has a proximal end that connects to the proximal vessel and a distal end that is used to connect to the bypass graft. The bypass graft can be secured to the distal vessel to complete the anastomosis. The direction of blood flow can be from the proximal blood vessel into the proximal end of the tubular structure. Blood can be allowed to flow into the graft vessel through the distal end of the tubular structure.

  In another aspect, the tubular anastomotic coupler has a proximal end that couples to a graft vessel that anchors to the proximal vessel and a distal end that is configured to couple to a distal vessel. The direction of blood flow can be from the proximal vessel to the graft vessel and into the proximal end of the tubular structure. Blood can be allowed to flow into the distal vessel through the distal end of the tubular structure.

  The anastomosis bypass device can be secured to the vessel in a variety of ways and can be coupled to the vessel for the formation of an anastomosis with or without the use of sutures. The bypass device can be coupled to the outside of the blood vessel, or a portion of the device can be implanted within the blood vessel. For example, placing a portion of the implanted device inside the lumen of the blood vessel (ie, within the lumen), or placing a portion of the implanted device within the blood vessel (ie, within the intimal tissue of the blood vessel, tissue within the wall) It can also be placed in the inner or outer membrane tissue. In one embodiment, at least one tubular structure, or a portion thereof, can be inserted into the end of a blood vessel or the side of a blood vessel. The device can be fixed directly to the blood vessel using, for example, fasteners such as sutures, staples, clips, or adhesives. The bypass device can also include an interface that secures the conduit to the target vessel without using sutures. The interface may be, for example, a hook, hook, pin, clamp, or a flange or lip shape for coupling the device to the anastomosis site.

  Representative examples of anastomotic coupling devices having at least one tubular portion include, but are not limited to, end-to-end anastomosis procedures (such as anastomosis stents and anastomosis sleeves) and end-to-end anastomosis procedures (single lumen and multiple lumens). Devices used for bypass devices, etc.).

  In one embodiment of the invention, the anastomotic coupling device consists of a single tubular portion that can be used as a shunt to divert blood from the original vessel to a graft vessel (such as in an end-to-side anastomosis procedure). In one embodiment, one end of the tubular portion can be coupled directly or indirectly to the target vessel as described above. The opposite end of the tubular portion can be attached to a graft vessel, which can be secured to the target vessel to complete the anastomosis.

  The tubular portion can be straight, curved (such as L-shaped or helical), and the direction can be orthogonal or a relative angle associated with the blood vessel. In one embodiment, the conduit can be secured, for example, with fasteners such as staples, clamps, hooks, or by adhesives, high frequency seals, or other methods well known to those skilled in the art.

  In one embodiment, as an anastomotic coupling device, for example, there is a graft knitted with a tubular metal, and a suture ring is welded to a distal end, and a method for fixing a target blood vessel at a predetermined position is provided. The See US Pat. No. 6,235,054. Other types of conduits secured to the site include those described in US Pat. Nos. 4,368,736 and 4,366,819.

  In certain types of single lumen coupling devices, the conduit is a flange whose end remains within the lumen of the blood vessel. For example, the conduit may have a tubular body with a coupling device, which has a plurality of extensions and is configured to be annularly disposed within the tubular vessel. See US Pat. No. 6,660,015. In other devices, the flange may be bonded in or on the outer membrane tissue of the blood vessel.

  For other types of single lumen bypass devices, U.S. Pat.Nos. Publication numbers 2004 / 0015180A1, 2003 / 0065344A1, 2002 / 0116018A1, and the like.

  In one embodiment of the present invention, the anastomotic coupling device comprises a plurality of lumens through which blood can move. A multi-lumen bypass device may include two or more tubular portions configured to interconnect multiple (two or more) blood vessels. Multiple lumen coupling devices can be used for a variety of anastomosis procedures. For example, such devices divert blood from a closed proximal vessel (such as an artery) to one or more target (ie, distal) vessels (such as an artery or vein) in a coronary artery bypass graft (CABG) procedure. Can be used for.

  In one embodiment, the at least one tubular portion can also be used as a shunt to divert blood between the original vessel and the target vessel. In another aspect, the device can be configured as an interface to secure the graft vessel to the target vessel and complete the anastomosis. Depending on the procedure, the tubular arm can be either equal length and diameter or unequal length and diameter, and can include an expandable tubular portion or a shape memory material (such as Nitinol). Further, the tubular portion can be made of the same material or different materials.

  In one embodiment, one or more ends of the tubular portion can be inserted into the ends or sides of one or more blood vessels. In other embodiments, one or more tubular portions of the device can remain within the lumen of a blood vessel or graft vessel. The device can optionally be secured to the blood vessel using fasteners or adhesives or otherwise known to those skilled in the art.

  At least one arm of the plurality of luminal bonds can be bonded to the graft vessel. The graft vessel can be an artificial vessel such as ePTFE or polyester graft, or can be a natural graft material (autologous, allovascular, xenograft, etc.) or a combination of synthetic and natural graft materials. In certain embodiments, the graft vessel can be coupled to the end of the tubular portion of the device and the second graft vessel can be coupled to the opposite end of the same tubular portion or to the end of another tubular portion. can do. The graft vessel can be further bonded to the target vessel to complete the anastomosis.

  In one embodiment, the device can include three or more tubular arms extending from the junction site. For example, a multi-lumen device can be generally T-shaped or Y-shaped (ie, have two or three lumens, respectively). For example, the multi-lumen device can be a T-shaped tubular graft bond with a longitudinal member extending into the target vessel and a second portion outside the vessel and providing a connection with an alternative tubular structure. . See the following US patents. Nos. 6,152,945 and 5,972,017. Other multi-lumen devices are described in US Pat. Nos. 6,152,945, 6,451,033, 5,755,778, 5,922,022, 6,293,965, 6,517,558 and 6,626,914, and US Publication No. 2004 / 0015180A1.

  In another aspect, the device may be a tube that bypasses blood flow directly from a portion of the heart (left ventricle) to the coronary artery. For example, the device can be a one-way valve that is a hollow tube that can be partially closed during the relaxation phase in response to cardiac tissue movement, while allowing blood flow during the systole ( (See US Pat. No. 6,641,610). The device can be an elongated rigid branch body consisting of a bypass tube, which has two openings, one can be placed in the myocardium of the left ventricle and the other can be placed in the coronary artery (See WO00 / 15146 and US Application Publication No. 2003 / 0055371A1, etc.). The device can be a tubular instrument with a valve in the shape of L or T, which is adapted for insertion into the heart wall and provides blood communication from the heart to the coronary vessels ( (See US Pat. No. 6,123,682).

  In another aspect, the device may include an interconnected tubular conduit network. For example, the device can include two tubular portions that are generally axially or orthogonally oriented relative to each other. See U.S. Patent Nos. 6,241,761 and 6,241,764. Communication between the two annular structures can be achieved by a flow path that facilitates blood flow between the holes in each tube.

  In another aspect, the anastomotic coupling device may be a resorbable device and may be configured with two or three ends that provide a vascular interface without the need for suturing, such as a bypass graft or an alternative vessel Fluid communication is provided by the intersecting lumens. See US Patent Application Publication No. 2002 / 0052572A1, PCT Publication No. WO 02 / 24114A2, etc. The anastomotic coupling device can also be formed of a resorbable tubular structure and is hemostatic with a snap coupling device or other component for securing to tissue and a sealing ring to prevent blood leakage. Composed. See US Pat. No. 6,056,762. The anastomotic coupling device can be designed with three legs, where the two legs are adapted to expand and fit snugly after being inserted into a continuous vessel in a contracted state. The three legs are adapted to be connected and sealed with the third conduit. See US Pat. No. 6,019,788.

  One example of a commercially available multi-lumen anastomotic coupling device is the Solem graft coupling device (Jomed, Sweden). This device is described in further detail in PCT Publication No. WO 01/13820 and US Pat. Nos. 6,179,848, D438618 and D429334, which include nitinol and ePTFE grafts to complete a distal anastomosis. Includes a T-shaped bond consisting of

  Another example of anastomotic coupling is the Holly Graft system (under development) used by CABG Medical, Inc. (Minneapolis, MN) for bypass surgery, which is described in US Pat. Nos. 6,241,761 and 6,241,764, etc. is there.

  In one aspect, the present invention provides an anastomotic coupling device that infiltrates a subject polymer composition into adjacent tissue. In one embodiment, the anastomotic coupling device can be coupled to a blood vessel for the formation of an anastomosis without the use of sutures or staples. In certain embodiments, the anastomotic coupling device may be comprised of a tubular structure defining a lumen through which blood can flow and an anti-scarring agent. The device includes one, two, three, or more lumens defined by one, two, three, or more tubular structures, depending on the number of blood vessels to be joined be able to.

  Intravascular devices can be introduced into or within the walls, lumens, or adventitia of the blood vessel, causing inflammation or damage to the endothelial tissue of the blood vessel or altering the natural hemodynamic flow within the blood vessel. Infection may occur or be promoted in or around intravascular devices. This inflammation and damage stimulates a phased biological phenomenon that can result in a fibrotic response that can lead to the formation of scar tissue in the blood vessels or make it more susceptible to infection. There is. In accordance with the present invention, the subject polymer composition (alone or comprising a scarring inhibitor and / or an anti-infective) is a device, or a portion of a device that is in direct contact with a blood vessel (such as the end portion or end of the device). ) Inhibits one or more of the scarring processes described above (smooth muscle cell proliferation, cell migration, inflammation, etc.) and is less likely to form intimal proliferation or stenosis in the blood vessel. And can inhibit or prevent infection on the surface and surroundings of the connecting device by anastomosis.

  Thus, in one embodiment, the subject polymer composition can only be associated with the portion of the intravascular device that is in contact with blood or endothelial tissue. For example, the anti-scarring agent can be incorporated into tissue adjacent to all or part of the intravascular portion of the device. In another aspect, the subject polymer composition can be infiltrated into tissue adjacent to all or a portion of the extravascular portion of the device.

  In another aspect, the subject polymer composition can be infiltrated into tissue adjacent to part or all of the surface of the device. In another aspect, the subject polymer composition can be associated (such as infiltrating adjacent tissue) with a fixation member (a fastener such as a staple or clip) that secures the device to the blood vessel.

  As described above, the anastomotic coupling device can include a polymer composition comprising a fibrosis inhibitor or an anti-infective agent as a means of increasing the clinical effectiveness of the device. In another method, the fibrosis inhibitor and / or anti-infective is applied to a film or mesh (described in detail below) that is applied in a perivascular manner to an anastomosis site (such as the intersection of a graft vessel and a vessel). Or can be incorporated on its surface. These films or wraps can be used with any of the anastomotic coupling devices described above and are generally placed around the outside of the anastomosis during surgery. In other examples, the drug can be delivered to the anastomosis site in a spray, paste, gel, or the like. In another method, the drug can be infiltrated into tissue adjacent to a graft vessel that is secured to the vessel within the coupling device.

  In yet another aspect, the subject polymer composition can infiltrate tissue adjacent to other specialized intravascular devices. The apparatus includes a coronary drug injection guide wire (manufactured by TherOx, Inc., etc.), a graft, and a stent device with a balloon (as described in Wilensky, RL (1993) J. Am. Coll. Cardiol .: 21: 185A). Etc. are included.

  As described above, the present invention provides a polymer composition infiltrated into tissue adjacent to an intravascular device (an anastomotic coupling device, stent, drug delivery balloon, intravascular catheter, etc.). The polymer composition can include therapeutic agents (such as anti-scarring agents and anti-infective agents). Many polymer compositions that infiltrate the tissue adjacent to the device (preferably near the device-tissue interface) and are used in conjunction with an intravascular device have already been described above.

  The polymer composition is applied to (a) the tissue adjacent to the intravascular device, (b) around the interface between the intravascular device and tissue, (c) the site around the intravascular device, and (d) the tissue around the intravascular device. Application directly and / or indirectly can infiltrate around the implanted intravascular device. Methods for infiltrating a tissue adjacent to an endovascular device with a subject polymer composition include delivery of the polymer composition to: (a) on the surface of the intravascular device (eg, as an infusion material, paste, gel or mesh) during the implantation procedure; (b) immediately before or during the implantation of the intravascular device (eg: infusion material, (C) Immediately after implantation of the intravascular device, the surface of the tissue around the intravascular device and / or the implanted intravascular device (eg, injection material) (D) topical application of the composition to the anatomical space in which the endovascular device is placed (especially useful in this example from several hours The use of polymeric carriers that release therapeutic agents over a period of several weeks-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants, and Drug Other formulations that can be delivered to the site where the dispensing device is inserted), (e) by intradermal injection of solutions, infusions, and sustained release formulations into the tissue surrounding the intravascular device, and / or (f) Application by a combination of methods. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In any case, the subject polymer composition can be immersed in tissue adjacent to the entire device or a portion thereof.

  According to certain embodiments, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the present invention. In one embodiment of the present invention, the subject polymer composition infiltrated into tissue adjacent to an intravascular device inhibits one or more of four general factors for the process of fiber formation (or scarring) including: Inhibitors can be included: new blood vessel formation (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) accumulation, and remodeling (fibers) Sexual maturity and organization). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of the fiber formation inhibitor that can be used in the present invention are listed below. Cell cycle inhibitors include (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, Taxotere and docetaxel), (C) podophyllotoxins (such as etoposide), (D) immune Modulators (sirolimus, everolimus, tacrolimus, etc.), (E) heat shock protein 90 antagonists (eg geldanamycin), (F) HMGCoA reductase inhibitors (simvastatin, etc.), (G) inosine monophosphate dehydrogenase Inhibitors (such as mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ ), (H) NHκB inhibitors (such as Bay11-7082), (I) Antifungal agents (such as sulconizole), (J) p38 MAP kinase inhibition Agents (such as SB202190), and analogs and derivatives as described above.

  The dose of drug administered from this composition for preventing or inhibiting fibrosis according to the present invention will depend on a variety of factors including the type of formulation, the site of healing, and the type of condition being treated. Because intravascular devices are manufactured in a variety of shapes and sizes, the exact dose to be administered also depends on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), the total drug dose administered can be measured, and the appropriate surface concentration of the active agent can be determined. The drug is used in the range of several times the concentration normally used in a single systemic administration of chemotherapy to less than 50%, 20%, 10%, 5%, or 1%. In certain embodiments, the anti-scarring agent is released from the polymeric compound at an effective concentration over a period measured from the time of immersion in the tissue adjacent to the device, ranging from less than about 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, about 90 days The range is from day to about 180 days.

A typical fibrosis inhibitor used alone or in combination should be administered according to the following dosage guidelines. The total amount (dose) of the anti-scarring agent in the composition is about 0.01 μg to 10 μg, about 10 μg to 10 mg, about 10 mg to 250 mg, about 250 mg to 1000 mg, about 1000 mg to 2500 mg. It can be any range. Scarring inhibitor dose per unit area of the device or tissue surface agent is applied (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2, about ^{1 μg / mm 2 ~10 μg /} mm 2, about ^{10 μg / mm 2 ~250μg / mm} 2, about ^{250 μg / mm 2 ~1000 μg /} mm 2, can be either in the range of about ^{1000 μg / mm 2 ~2500μg / mm} 2.

  According to another aspect, any of the anti-infectives described above can be used in the present invention. Typical anti-infectives include (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) Dophilotoxins (such as etoposide), (E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin), and analogs and derivatives of the above.

  The dose of drug administered from this composition to prevent or inhibit infection according to the present invention will depend on various factors including the type of formulation, the site of healing, and the type of condition being treated. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), and the total drug dose administered can be measured and the appropriate surface concentration of the active agent can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective agent is released from the polymeric compound at an effective concentration in the range of less than about 1 day to about 180 days over a period measured from the time of immersion in the tissue adjacent to the device. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, about 90 days The range is from day to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following dosage guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose (amount) of anti-infective drug per unit area of the device or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² , or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compounds release anti-infectives at different rates, the above administration parameters are such that the minimum concentration of drug on the tissue surface is about 10 ⁻⁸ to 10 ⁻⁷ , about 10 ⁻⁷ to 10 ⁻⁶ , about 10 ^It should be used in combination with the drug release rate from the composition so that it is maintained at any of ^-6 to 10 ^-5 , about 10 ^-5 to 10 ^-4 .

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate) and / or podophyllotoxins (etoposide) are It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

Gastrointestinal Stent In one embodiment, the subject polymer composition can infiltrate the tissue surrounding the gastrointestinal (GI) stent. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents). The term “GI” stent refers to devices located in the gastrointestinal tract, including the bile duct, pancreatic duct, colon, and esophagus. GI stents are or consist of scaffold materials used to treat intraluminal pathways blocked by illnesses and injuries, including malignant tumors and benign diseases.

  In one embodiment, the GI stent is an esophageal stent that is used to keep the esophagus open and thereby allow food to move from the mouth to the stomach. For example, an esophageal stent can be composed of a cylindrical retaining mesh inner layer, a retaining mesh outer layer, and a semi-permeable membrane sandwiched therebetween. See US Pat. No. 6,146,416. An esophageal stent is a coarsely knitted radial self-expanding stent with an elastomeric film formed to prevent tissue ingrowth along the stent and a distal cuff that inhibits stent migration. It can be. See US Pat. No. 5,876,448. An esophageal stent can be constructed of a soft wire structure that forms a cylindrical tube that has a deformed end that is increased in diameter to provide a fixed pressure. See US Pat. No. 5,876,445. The esophageal stent can be a flexible, self-expandable tubular wall that incorporates at least one cut conical segment along the longitudinal axis. See US Pat. No. 6,533,810.

  In another aspect, a GI stent is a gallbladder stent used to keep the bile duct open, thereby allowing bile to drain into the small intestine. For example, a gallbladder stent can be composed of a shape memory alloy. See US Pat. No. 5,466,242. The gallbladder stent can be a wing that expands radially with a number of grooves protruding from a helical core. See U.S. Pat. Nos. 5,776,160 and 5,486,191.

  In another embodiment, the GI stent may be a colon stent. For example, a colonic stent can radially expand and become a hollow tube that is secured to the inner wall of the organ with a loose fit. See European patent application number EP1092400A2, etc.

  In another aspect, the GI stent is a splenic stent that keeps the pancreatic duct open and facilitates secretion of secretions into the small intestine. For example, a splenic stent can be composed of a flexible biocompatible material suitable for elastic surfaces with perforations that facilitate drainage, as well as for tube curvature. See US Pat. No. 6,132,471.

  In accordance with the present invention, GI stents that can be effective by infiltrating the surrounding tissue with the polymer composition of interest include commercially available products such as the NIR bile stent system and the WALLSTENT endoprosthesis (Boston Scientific Corporation).

  In one embodiment, the present invention provides a GI device comprising a subject polymer composition that infiltrates surrounding tissue, the polymer composition may comprise a therapeutic agent (a scarring inhibitor and / or an anti-infective agent). A number of polymeric and non-polymeric delivery systems for use with GI stents have already been described above.

  The polymer compound directly and / or indirectly surrounds the composition (a) tissue adjacent to the GI stent, (b) around the interface between the GI stent and the tissue, (c) around the GI stent, and (d) surrounding the GI stent. Application within and / or on the tissue can invade around the implanted GI stent. Methods of infiltrating the tissue adjacent to the GI stent with the polymer composition of interest include delivery of the polymer composition: (a) the surface of the GI stent during the implantation procedure (eg, injection material, paste, gel or mesh) (B) immediately before or during implantation of the GI stent (eg as injection material, paste, gel, in situ gel or mesh), (c) immediately after implantation of the GI stent (D) the anatomical where the GI stent is placed on the surface of the tissue surrounding the GI stent and / or the implanted GI stent (eg injection material, paste, gel, gel or mesh formed in situ) Topical application of fiber formation inhibitor in space (especially useful in this example is the use of a polymeric carrier that releases the fiber formation inhibitor over a period ranging from hours to weeks-liquid, suspension , Emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and other formulations that can release the drug and be delivered to the site where the implant is inserted), (e) GI (F) Application by a combination of the methods described above via intradermal injection of solution, infusion, and sustained release formulation into the tissue surrounding the stent. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the subject polymer composition can be wetted to the entire device or to some surrounding tissue.

  According to one embodiment, any fiber formation inhibitor and / or anti-infective agent described above can be used in the practice of the present invention. In one embodiment of the invention, the subject polymer composition infiltrating the tissue adjacent to the GI stent releases an agent that inhibits one or more of the four general factors for the process of fiber formation (or scarring), including: Can be adapted to: new blood vessel formation (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) accumulation, and remodeling (fibers) Sexual maturity and organization). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (such as simvastatin), (G) inosine monophosphate dehydrogenase inhibitors (such as mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ ), (H) NFκB inhibitors (such as Bay11-7082), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Since GI stents are made in a variety of shapes and sizes, the exact dose administered will also depend on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site) and the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the specified period of time that the anti-scarring agent can be measured from the time of infiltration into the tissue surrounding the device is released from the polymer composition at a concentration that ranges from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Drug scarring inhibitor dosage per unit area of the device or tissue surface of a subject to be coated (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm, ² or from about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,,.

  According to another aspect, all of the anti-infective agents described above can be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site) and the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose (amount) of anti-infective drug per unit area of the device or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² , or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

Tracheal Stent and Bronchial Stent The present invention infiltrates the polymer composition of interest adjacent to tissue adjacent to the tracheal stent and bronchial stent device. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  A typical example of a tracheal stent or bronchial stent that is effective by infiltrating adjacent tissues with the polymer composition of interest is a tracheal stent or bronchial stent. Bronchial stents, or tracheal or bronchial stents with an outer coating (such as polyurethane, poly (ethylene terephthalate), tetrafluoroethylene resin (PTFE), or silicone rubber) are included.

  Tracheal and bronchial stents can be composed of, for example, an elastic plastic shaft with a metal fastener, which creates a lumen along the axial direction to create a clearance in the affected area of the trachea, and There are three parts that mimic the natural shape of the trachea. See US Pat. No. 5,480,431. The tracheal / bronchial stent can be T-shaped with a tubular section for tracheostomy that protrudes outwardly from the tracheostomy and is configured to close and seal fluid. See U.S. Pat. Nos. 5,184,610 and 3,721,233. The tracheal / bronchial stent is a flexible with tracheostomy tube that is attached to the wall and has a bifurcated bronchial end arranged as a TY shape with a unique curve at the intersection to minimize tissue damage It can be composed of an artificial polymer resin. See U.S. Pat. No. 4,795,465. The tracheal / bronchial stent may be a scaffold material with a geometric pattern and a structure that is substantially cylindrical and has a shape memory frame, with a coating that is thick enough to prevent epithelialization. it can. See, for example, US Patent Application Publication No. 2003 / 0024534A1.

  In accordance with the present invention, tracheal / bronchial stents that are effective by infiltrating adjacent tissues with the polymer composition of interest are WALLSTENT bronchial endoprosthesis and ULTRAFLEX bronchial stent system (Boston Scientific Corporation) and DUMON bronchial silicone stent (Bryan Corporation). (Made in Woburn, Mass.)).

  In one embodiment, the present invention provides trachea and bronchial stents comprising a subject polymer composition that infiltrates surrounding tissue, which polymer composition may comprise a therapeutic agent (an anti-scarring agent and / or an anti-infective agent). is there. A number of polymeric and non-polymeric delivery systems for tracheal and bronchial stents have already been described above.

  The polymer compound directly and / or indirectly (a) tissue adjacent to the tracheal / bronchial stent, (b) around the tracheal / bronchial stent-tissue interface, (c) around the tracheal / bronchial stent, d) It can infiltrate around the implanted trachea / bronchial stent by applying it in and / or on the tissue surrounding the trachea / bronchial stent. Methods of infiltrating the polymer composition of interest into the tissue adjacent to the tracheal / bronchial stent include delivery of the polymer composition: (a) the surface of the tracheal / bronchial stent during the implantation procedure (eg, injection material, paste) (B) as a gel or mesh), (b) immediately before or during implantation of the trachea / bronchus, on the tissue surface (eg as injection material, paste, gel, gel or mesh formed in situ), (c) trachea / Immediately after transplantation of the bronchus, (d) the trachea on the surface of the trachea / bronchi and / or the tissue surrounding the transplanted trachea / bronchus (eg injection material, paste, gel, gel or mesh formed in situ) / Local application of fibrosis inhibitor to the anatomical space where the bronchus is placed (especially useful in this example is release of fibrosis inhibitor over a period ranging from hours to weeks The use of polymeric carriers-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants, and the site where the drug is released and the implant is inserted (E) Application by a combination of the methods described above via intradermal injection of solutions, infusions, and sustained release formulations into the tissue surrounding the trachea / bronchi). Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the subject polymer composition can be wetted to the entire device or to some surrounding tissue.

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the present invention, the subject polymer composition that invades the tissue adjacent to the tracheal / bronchial stent inhibits one or more of the four general factors for the fibrosis (or scarring) process including: Can be adapted to release: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), accumulation of extracellular matrix (ECM), and remodeling (Maturation and organization of fibrous tissue). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (such as simvastatin), (G) inosine monophosphate dehydrogenase inhibitors (such as mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ ), (H) NFκB inhibitors (such as Bay11-7082), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Because tracheal and bronchial stents are made in a variety of shapes and sizes, the exact dose administered will also depend on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site) and the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the specified period of time that the anti-scarring agent can be measured from the time of infiltration into the tissue surrounding the device is released from the polymer composition at a concentration that ranges from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Drug scarring inhibitor dosage per unit area of the device or tissue surface of a subject to be coated (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm, ² or from about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,,.

  According to another aspect, all of the anti-infective agents described above can be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site) and the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose (amount) of anti-infective drug per unit area of the device or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² , or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compounds which release an anti-infective agents in different proportions, administration parameters described above, a minimum concentration of about 10 ^-8 M to ^-7 M of the drug tissue surface, about 10 ^-7 M to ^-6 M, about 10 ^-6 M to ^-5 M, to be maintained at either about 10 ^-5 M to ^-4 M, it should be used in combination with the drug release rate from the composition.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

Urogenital Stent In one embodiment, the subject polymer composition can invade tissue adjacent to the urogenital (GU) stent device. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  Typical examples of genitourinary (GU) stents that are effective by infiltrating adjacent tissues with the polymer composition of interest include ureteral stents, urethral stents, fallopian tube stents, and prostate stents. GU stents made of metal or polymer, or GU stents with external coatings (such as polyurethane, poly (ethylene terephthalate), tetrafluoroethylene resin (PTFE), or silicone rubber) are included.

  In one embodiment, urogenital stents include ureteral stents and urethral stents. A ureteral stent is a hollow tube with holes along the sides to prevent migration and coils on both sides. Ureteral stents are used to relieve obstruction (caused by stones or malignant tumors), facilitate the passage of stones, or promote healing of ureteral anastomoses or leaks after surgery or trauma . These are placed percutaneously via the bladder using an endoscope or via the kidney.

  Urethral stents are used for the treatment of recurrent urethral constriction, detrusor sphincter ataxia and bladder urinary opening obstruction due to benign prostatic hypertrophy. Furthermore, treatments performed on the prostate, such as external radiation and brachytherapy, can lead to fibrosis and / or infection due to tissue injury caused by those treatments. In prostate cancer patients treated with external beam radiation, the incidence of urethral squeezing is about 2%. The onset of urethral squeezing can also occur in other conditions, such as after urinary catheterization or surgery, resulting in damage to the epithelium of the urethra. Clinical signs of urinary tract obstruction include decreased urinary gland power and caliber, intermittent, post-urine drip, sputum and nocturia. When the urethra is completely closed, a number of problems can occur, including ultimate renal failure. A urethral stent can be used to maintain urethral patency. Stents are generally self-expanding and consist of a metal superalloy, titanium, stainless steel or polyurethane.

  For example, a ureteral / urethral stent can be composed of a main catheter body made of a flexible polymer material with a distal end that is widened and has a hydrophilic tip that dissolves when contacted with bodily fluids. See U.S. Pat. No. 5,401,257. A ureteral / urethral stent may consist of multiple sections at the distal end of the bladder, including a closed portion that has no fluid passage and serves as a backflow prevention device to prevent backflow of urine to the kidney. it can. See US Pat. No. 5,647,843. A ureteral / urethral stent can consist of a central catheter tab made of a shape memory material that forms a stent with a retention coil to secure the ureter. See US Pat. No. 5,681,274. The ureter / urethral stent is composed of an elongate flexible tubular stent that is pre-curled at both ends and an end-attached elongate tubular rigid extension that can be combined as an external ureteral catheter. obtain. See U.S. Pat. Nos. 5,221,253 and 5,116,309. The ureter / urethral stent is comprised of an elongated member, a proximal retention structure, and a resilient portion with a slidable portion that joins them together, thereby fluidly communicating with each other and providing a retracted and expanded position it can. See US Pat. No. 6,685,744. The ureter / urethral stent can be a hollow cylindrical tube with flexible coupling and positioning means that can be expanded and selectively contracted. See US Pat. No. 5,322,501. A ureter / urethral stent can be composed of a rigid polymer body with excellent column and shaft strength to advance in the ureter and a relatively soft bladder coil portion to reduce the risk of inflammation. See U.S. Pat. No. 5,141,502. A ureteral / urethral stent can be composed of an elongated tubular segment with a flexible wall at the base and a number of members that prevent clogging of waste fluids that occur during compression. See US Pat. No. 6,676,623. The ureter / urethral stent may be a catheter comprised of a conduit that is part of an assembly that allows non-contaminated insertion into the urinary tract by providing a sealing member that surrounds the catheter during the dismantling operation. See, for example, US Patent Application Publication No. 2003 / 0060807A1.

  In another embodiment, the urogenital stent includes a prostate stent. For example, a prostate stent can be composed of two polymer rings constructed of tubes with multiple arm members connecting the rings in parallel. See US Pat. No. 5,269,802. Prostate stents are composed of a thermoplastic and a coil spring that reinforces the periphery so that it has strong mechanical support but is flexible enough to accommodate the natural anatomical flexion of the urethral prostate can do. See US Pat. No. 5,069,169.

  In another aspect, urogenital stents include Fallopian stents and other female urogenital devices. For example, a genitourinary device is designed for women with a flexible and flexible vaginal insert that can be held on its own by extending against the vaginal wall and extending against the urethral opening. A device for urinary incontinence. See U.S. Pat. No. 3,661,155. Urogenital devices include urinary devices consisting of an oval spherical concave wall with an opening to the peripheral edge that hits the body that is integral with the wall, and a tubular member with a pleated portion. See US Pat. No. 6,041,448.

  According to the present invention, the urogenital stent that is effective when the polymer composition of interest invades adjacent tissue includes the UROLUME endoprosthesis stent (American Medical Systems, Inc. (Minnetonka, MN)), RELIEVE prostate / Urethral endoscope device (InjecTx, Inc. (San Jose, CA)), PERCUFLEX urethral stent (Boston Scientific Corporation), and TARKINGTON urethral stent and FIRLIT-KLUGE urethral stent (Cook Group Inc (Bloomington, IN)) ) And other commercial products.

  In one embodiment, the present invention provides a GU stent comprising a subject polymer composition that infiltrates surrounding tissue, the polymer composition may comprise a therapeutic agent (a scarring inhibitor and / or an anti-infective agent). A number of polymeric and non-polymeric delivery systems for use with GU stents have already been described above.

  The polymeric compound directly and / or indirectly surrounds the composition (a) tissue adjacent to the GU stent, (b) around the GU stent-tissue interface, (c) around the GU stent, and (d) surrounding the GU stent. Application within and / or on the tissue can infiltrate around the implanted GU stent. Methods for infiltrating the tissue adjacent to the GU stent with the polymer composition of interest include delivery of the polymer composition: (a) The surface of the GU stent during the implantation procedure (eg, injection material, paste, gel or mesh) (B) immediately before or during implantation of the GU stent (eg as injection material, paste, gel, in-situ gel or mesh), (c) immediately after implantation of the GU stent (D) the anatomy where the GU stent is placed on the surface of the tissue surrounding the GU stent and / or the implanted GU stent (eg injection material, paste, gel, gel or mesh formed in situ) Topical application of fiber formation inhibitor in space (especially useful in this example is the use of a polymeric carrier that releases the fiber formation inhibitor over a period ranging from hours to weeks-liquid, suspension , Emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and other formulations that can release the drug and be delivered to the site where the implant is inserted), (e) GU (F) Application by a combination of the methods described above via intradermal injection of the solution, infusion, and sustained release formulation into the tissue surrounding the stent. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the subject polymer composition can be wetted to the entire device or to some surrounding tissue.

According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the invention, the subject polymer composition infiltrating the tissue adjacent to the GU stent releases an agent that inhibits one or more of the four general factors for the process of fiber formation (or scarring) including: Can be adapted to: new blood vessel formation (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) accumulation, and remodeling (fibers) Sexual maturity and organization). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth. Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (such as simvastatin), (G) inosine monophosphate dehydrogenase inhibitors (such as mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ ), (H) NFκB inhibitors (such as Bay11-7082), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Because GU stents are made in a variety of shapes and sizes, the exact dose to be administered also depends on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site) and the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from the polymer composition, the concentration of which is effective for a specific period of time that can be measured from the time of infiltration into the surrounding tissue, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Drug scarring inhibitor dosage per unit area of the device or tissue surface of a subject to be coated (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm, ² or from about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,,.

  According to another aspect, all of the anti-infective agents described above can be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site) and the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose (amount) of anti-infective drug per unit area of the device or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² , or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

Ear Stent and Nasal Stent In one embodiment, the subject polymer composition infiltrates tissue adjacent to an ENT stent device (such as lacrimal stent, ear canal stent, nasal stent, sinus stent, etc.). obtain. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  The paranasal sinuses are four pairs of hollow regions housed within the skull skeleton, named after the bone in which they are located (ethmoid sinus, maxillary sinus, frontal sinus, and sphenoid sinus). All are lined up with respiratory mucosa attached directly to the bone. Purulent forms of sinusitis may develop after inflammatory injury such as upper respiratory tract infection or allergic rhinitis. Occasionally, secretions may remain in the sinuses due to changes in ciliary function or obstruction of the ostea drainage. If drainage is incomplete, the sinuses are generally more susceptible to infection with Haemophilus influenzae, pneumococci, Moraxellacatarrhalis, Bayonella, Peptococcus, acne, and certain fungi. Become.

  When initial treatments such as antibiotics, intranasal steroid sprays and antinasal closure are ineffective, surgical drainage of the infected sinuses is required. Surgical treatment often involves ostea debridement to remove anatomical obstruction and partial removal of the mucosa. Sometimes, stents (cylindrical tubes that physically keep the ostea lumen open) remain in the osta so that drainage is ensured even in the presence of post-operative swelling. ENT stents are typically made of stainless steel or plastic, but remain in place for several days or weeks before removal.

  Representative examples of ENT stents that are effective when the polymer composition of interest infiltrates adjacent tissue in accordance with the present invention include lacrimal stents, ear canal stents, nasal stents, sinus stents, and the like.

  In one embodiment, the present invention provides a lacrimal stent having a polymer composition comprising a therapeutic agent (scarring inhibitor and / or anti-infective agent) infiltrating adjacent tissue.

  In another aspect, the present invention provides an eustachian stent having a polymer composition comprising a therapeutic agent (scarring inhibitor and / or anti-infective agent) that has infiltrated adjacent tissue.

  In yet another aspect, the present invention provides a sinus stent having a polymer composition comprising a therapeutic agent (an anti-scarring agent and / or an anti-infective agent) that has infiltrated adjacent tissue.

  In yet another aspect, the present invention provides a nasal stent having a polymer composition comprising a therapeutic agent (an anti-scarring agent and / or an anti-infective agent) that has infiltrated adjacent tissue.

  ENT stents are also posterior nasal closure stents composed of two long hollow tubes that are bridged by soft transverse tubules. See US Pat. No. 6,606,995. ENT stents are also expandable nasal stents for post-operative nasal obturators that are made of an absorbent foam material that is very multi-hole and easy to mold, expands outwardly and has a non-stick surface. See U.S. Pat. No. 5,336,163. ENT stents are also nasal stents that consist of a deformable cylinder with a smooth outer non-absorbable surface that is used to fill the nasal cavity after surgery and has a ventilation path. See US Pat. No. 5,601,594. The ENT stent also has a ventilation tube that is used in the paranasal sinuses after endoscopic sinus fistula formation and consists of a flexible plastic tubular vent with a square bendable flange. See US Pat. No. 5,246,455. The ENT stent also has a vent tube consisting of a shaft and an expansion knob that is used to equalize the pressure between the middle and outer ears. See US Pat. No. 6,042,574. The ENT stent also has a middle ear ventilation tube consisting of an incompressible tubular base and an eccentric flange. See US Pat. No. 5,047,053.

  Examples of ENT stents that are effective by infiltrating adjacent tissue with a polymer composition of interest according to the present invention include SEPRAGEL sinus stents from Genzyme Corporation (Ridgefield, NJ), Medtronic Xomed Surgical Products, Commercial products such as MEROGEL nasal dressings and sinus stents from Inc. (Jacksonville, Florida) are included.

  In one embodiment, the present invention provides an ENT stent comprising a subject polymer composition that infiltrates surrounding tissue, the polymer composition may comprise a therapeutic agent (a scarring inhibitor and / or an anti-infective agent). A number of polymeric and non-polymeric delivery systems for use with ENT stents have already been described above.

  The polymeric compound directly and / or indirectly surrounds the composition (a) tissue adjacent to the ENT stent, (b) around the interface between the ENT stent and tissue, (c) around the ENT stent, and (d) surrounding the ENT stent. Application within and / or on the tissue can infiltrate around the implanted ENT stent. Methods of infiltrating the tissue adjacent to the ENT stent with the polymer composition of interest include delivery of the polymer composition: (a) the surface of the ENT stent during the implantation procedure (eg, injection material, paste, gel or mesh) (B) immediately before or during implantation of the ENT stent (eg as injection material, paste, gel, in situ gel or mesh), (c) immediately after implantation of the ENT stent (D) the anatomical where the ENT stent is placed on the surface of the tissue surrounding the ENT stent and / or the implanted ENT stent (eg injection material, paste, gel, gel or mesh formed in situ) Topical application of a fiber formation inhibitor in space (especially useful in this example is the use of a polymeric carrier that releases the fiber formation inhibitor over a period ranging from hours to weeks-liquid, Suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and other formulations that can release the drug and be delivered to the site where the implant is inserted), (e A) Application by combination of the methods described above, via intradermal injection of solution, infusion, and sustained release formulation into the tissue surrounding the ENT stent. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the subject polymer composition can be wetted to the entire device or to some surrounding tissue.

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the present invention, the subject polymer composition infiltrating the tissue adjacent to the ENT stent releases an agent that inhibits one or more of the four general factors for the process of fiber formation (or scarring) including: Can be adapted to: new blood vessel formation (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) accumulation, and remodeling (fibers) Sexual maturity and organization). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (such as simvastatin), (G) inosine monophosphate dehydrogenase inhibitors (such as mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ ), (H) NFκB inhibitors (such as Bay11-7082), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Because ENT stents are made in a variety of shapes and sizes, the exact dose to be administered also depends on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site) and the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from the polymer composition, the concentration of which is effective for a specific period of time that can be measured from the time of infiltration into the surrounding tissue, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Drug scarring inhibitor dosage per unit area of the device or tissue surface of a subject to be coated (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm, ² or from about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,,.

  According to another aspect, all of the anti-infective agents described above can be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site) and the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose (amount) of anti-infective drug per unit area of the device or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² , or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

In another embodiment, the subject polymer composition may infiltrate tissue adjacent to the ear ventilation tube (also referred to as the middle ear cavity ventilation tube). The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents). Acute otitis media is the most common bacterial infection, is the most frequent indicator of surgical treatment, is a major cause of hearing loss, and is a common cause of language developmental injury in children. The cost of treating this condition in children younger than 5 years is expected to be $ 5 billion annually in the United States alone. In fact, every year 85% of children develop otitis media at least once and 600,000 require surgical treatment. The prevalence of otitis media is increasing, and in severely injured cases, surgical treatment is more cost effective than traditional treatment.

  Acute otitis media (bacterial infection of the middle ear) is characterized by dysfunction of the ear canal, leading to a failure of the middle ear clearance action. The most common causes of otitis media are Streptococcus pneumoniae (30%), Haemophilus influenzae (20%), Branhamella catarrhali (12%), Streptococcus pyogenes (3%), and Staphylococcus aureus (1.5%) It is. Eventually, bacteria, leukocytes and fluid accumulate, which leads to an increase in pressure in the middle ear when there is no capacity to drain through the ear canal. In many cases, antibiotic therapy is sufficient treatment and the condition is resolved. However, in a significant number of patients, the condition may recur frequently or may not be completely resolved. In recurrent otitis media or chronic otitis media with exudation, there is a continuous accumulation of fluid and bacteria, creating a pressure gradient across the tympanic membrane, causing distress and hearing impairment. Tympanic fenestration (generally with the placement of a middle ear ventilation tube) eliminates the pressure differential and facilitates drainage of the middle ear (by the outer ear, not by the ear canal— “Eustal Bypass”) One form).

  Recurrent otitis media or otitis media with exudation can also be treated using the middle ear cavity ventilation tube or artificial youth tachytube / stent described above. These ventilation ducts are indicated with chronic otitis media with exudation in children, recurrent acute otitis media, tympanic membrane atelectasis, and complications of acute otitis media. If granulation tissue is excessively formed around these devices, the function of these devices will be reduced. This may then result in a second treatment, either removing the occlusion or inserting a new device. Incorporation of a fibrosis inhibitor into the ventilation tube or on its surface can also prevent granulation tissue overgrowth.

  Surgical placement of the middle ear cavity ventilation tube is most widely used for chronic otitis media, although it is not curative, because it improves hearing (which improves language development) and reduces the incidence of acute otitis media It has been a treatment. The placement of the middle ear cavity ventilation tube is one of the most common surgical procedures in the United States, with 1.3 million surgical replacements performed annually.

  Typical examples of ear ventilation tubes that are effective by infiltrating adjacent tissues with the polymer composition of interest include grommet tubes, T tubes, middle ear ventilation tubes, drainage tubes, tympanic tubes, otolaryngology Tubes, tympanostomy tubes, European tubes, European prostheses, European stents, but are not limited to these. Ear ventilation tubes are made from polytetrafluoroethylene (such as TEFLON), silicone, nylon, polyethylene, as well as other polymers, stainless steel, titanium, gold-plated steel, and the like.

  In one embodiment, the ear ventilation tube may be a middle ear cavity ventilation tube used to provide an alternative conduit for ventilating the middle ear cavity via the ear canal. Generally, the middle ear is ventilated by performing a tympanic incision, where the eardrum slit or opening is used to reduce accumulation and pressure drop in the middle ear cavity and to drain the accumulated fluid. Is created surgically. The middle ear cavity ventilation tube can be inserted into a surgical slit in the tympanic membrane to serve as a bypass for a normal ear canal that drains the middle ear cavity sinus under normal conditions. For example, the middle ear cavity ventilation tube may be an elongated, uniform tubular member made of pure titanium or a titanium alloy with indentations spaced inwardly from one end forming the flange. See US Pat. No. 5,645,584. The middle ear cavity ventilation tube can be composed of an outer surface made of titanium that is used to ventilate the middle ear and does not have a flange and has a small depression. See U.S. Pat. No. 4,971,076. The middle ear cavity ventilation tube can be composed of a shaft with tabs extending outwardly from the bottom surface of the shaft. See US Pat. No. 6,042,574. The middle ear cavity ventilation tube may comprise a permanent ear ventilation device consisting of an elongate tubular base with a flange made of an incompressible material and eccentrically connected. See US Pat. No. 5,047,053. The middle ear cavity ventilation tube can be composed of a cap plug, a central body and an end cap that together form a number of lumens within the duct. See US Pat. No. 5,851,199. The middle ear cavity ventilation tube can be composed of a microporous resin that is coined to form a gas permeable substrate, which has the ability to migrate to the surface of the tube sidewall to provide antimicrobial activity. In which silver particles are dispersed. See US Pat. No. 6,361,526. The middle ear cavity ventilation tube can be comprised of a tubular body and a rib structure that defines an outwardly projecting channel that spirals around the tubular body. See US Pat. No. 5,775,336. The middle ear cavity ventilation tube can be composed of an integral cutting blade extending from one of two flanges of a grommet for incising the eardrum. See U.S. Pat. Nos. 5,827,295 and 5,643,280. The middle ear cavity ventilation tube can be constructed of a tubular member having two opposing flanges, and the insertion of the tube is facilitated by the cutting edge of the flange that causes incision of the tympanic membrane. See U.S. Pat. Nos. 5,489,286, 5,466,239, 5,254,120, and 5,207,685. Other middle ear cavity ventilation tubes are described in US Pat. Nos. 6,406,453, 5,178,623, 4,808,171, 4,744,792, and the like.

  In another embodiment, the ear ventilation tube can be used in an attempt to eliminate stenosis that interferes with normal functioning to establish normal functioning of the European tube. Since fluid in the middle ear cavity is normally secreted out of the eardrum, normal functioning of the European canal is restored and optimal ventilation and drainage can be achieved. For example, a ventilation tube is a hollow with a compressible core with two parallel arms connected and radially arranged flanges placed in a European tube to maintain patency. It can be a European tube stent composed of a tubular body. See US Pat. No. 6,589,286. The ventilation tube can be an eustachian prosthesis comprised of a flexible tube with a radially extending flange for positioning in the eustachian passage. See U.S. Pat. No. 4,015,607.

  According to the present invention, commercially available products are also included in the middle ear cavity ventilation tube that can be effective by infiltrating the adjacent tissue with the polymer composition of interest. For example, Medtronic Xomed, Inc. (Jacksonville, Florida) sells a variety of ear ventilation tubes, including long-term ventilation tubes and grommet-type ventilation tubes, including ARMSTRONG grommets, GOODET grommets, and VENTURI-type ventilation. Tubes, SHEEHY type color buttons, REUTER bobbins, COHEN T grommets, and SOILEAU TYTAN titanium tubes. Micromedics, Inc. (Eagan, Minnesota) also sells a variety of ear ventilation tubes, including BAXTER bevel buttons, TINY TOUMA, SPOONER, TOUMA T tubes, SHOEHORN bobbins, SHAH, and SILVERSTEINMICROWICK ear tubes. Gyrus ENT LLC (Bartlett, TN) also sells a variety of ear ventilation tubes, including ULTRASIL ventilation tubes, RICHARDSCOLLAR bobbins, BALDWIN BUTTERFLY ventilation tubes and PAPARELLA 2000 tubes.

  In another aspect, the device includes an ear ventilation tube that includes the polymer composition of interest, the polymer composition comprising a scarring inhibitor and / or an anti-wetting agent that is moistened to tissue surrounding the site where the device is implanted. Contains infectious agents. A number of polymeric and non-polymeric delivery systems for use in ear ventilation tubes have already been described above.

  The polymer compound directly and / or indirectly (a) tissue adjacent to the ear ventilation tube device, (b) around the ear ventilation tube device and the tissue interface, (c) around the ear ventilation tube device, (d) When applied inside and / or on the tissue surrounding the ear ventilation tube device, it may infiltrate around the implanted ear ventilation tube device. Methods of infiltrating the subject polymer composition into tissue adjacent to the ear ventilation tube device include delivery of the polymer composition: (a) The surface of the ear ventilation tube device (eg, injectable material, paste) during the implantation procedure (B) on the tissue surface (eg as injection material, paste, gel, in-situ gel or mesh) immediately before or during implantation of the ear ventilation tube device (c) Immediately after implantation of the ear ventilation tube device, (d) on the surface of the ear ventilation tube device and / or tissue around the ear ventilation tube device (eg injection material, paste, gel, gel or mesh formed in situ) Topical application of fibrosis inhibitor in the anatomical space where the ear ventilation tube device is placed (especially useful in this example is fibrosis inhibition over a period ranging from hours to weeks) Is the use of polymeric carriers that release agents-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants, and drug releasing implants Other formulations that can be delivered to the site of insertion), (e) via intradermal injection of solutions, injections, and sustained release formulations into the tissue surrounding the ear ventilation tube device (f) of the method described above Application by combination. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the subject polymer composition can be wetted to the entire device or to some surrounding tissue.

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the present invention, the subject polymer composition that invades the tissue adjacent to the ear ventilation tube comprises an agent that inhibits one or more of the four general factors for the process of fibrosis (or scarring) including: Can be adapted to release: new blood vessel formation (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) accumulation, and remodeling ( Fibrous tissue maturation and organization). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (such as simvastatin), (G) inosine monophosphate dehydrogenase inhibitors (such as mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ ), (H) NFκB inhibitors (such as Bay11-7082), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Since ear ventilation tubes are made in a variety of shapes and sizes, the exact dose to be administered also depends on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site) and the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from the polymer composition, the concentration of which is effective for a specific period of time that can be measured from the time of infiltration into the surrounding tissue, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Drug scarring inhibitor dosage per unit area of the device or tissue surface of a subject to be coated (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm, ² or from about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,,.

  According to another aspect, all of the antiinfectives described above can be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site) and the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose (amount) of anti-infective drug per unit area of the device or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² , or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

In another aspect of the intraocular graft, the subject polymer composition can invade tissue adjacent to the intraocular graft. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  In one embodiment, the intraocular implant is an intraocular lens device for preventing opacity of a lens (such as an anterior chamber lens or an posterior chamber lens). Visual deficiencies that can be treated with intraocular lenses include, but are not limited to, cataracts, myopia, hyperopia, astigmatism and other eye diseases. Intraocular lenses are most commonly used in place of natural lenses that are removed during cataract surgery. Cataracts are due to changes in the transparency of the normal lens in the eye. When a lens becomes opaque due to calcium deposits (yellow or cloudy), light does not enter the eye properly and vision is impaired.

  Implanting an intraocular lens into the eye is one of the standard techniques for restoring effective vision of a sick or damaged eye. The number of intraocular lenses implanted in the United States has increased exponentially over the past decade. At present, more than 1 million intraocular lenses are implanted annually, the majority (90%) being placed in the posterior chamber of the eye. The intention of the intraocular lens is to replace the natural lens (that is, the aphakic eye) or to assist or correct the refractive error (that is, the phakic eye or the natural lens is not removed).

  Implanted intraocular lenses can cause complications due to mechanical trauma, inflammation, infection or eye problems. Mechanical and inflammatory damage can lead to vision loss, chronic pain, secondary cataracts, corneal decompensation, cystoid macular edema, anterior chamber bleeding, uveitis or glaucoma. One common problem that arises in cataract extraction is opacity, which is due to a surgical procedure or tissue response to an artificial lens. Opacification leads to opacity of the intraocular lens, thus reducing long-term benefits. Opacification generally occurs when epithelial cell proliferation and migration occurs along the posterior capsule behind the intraocular lens. Correcting this response may require subsequent surgery, which involves complex technical processes and can lead to complications that can lead to severe blindness. Therefore, such complications can be reduced by applying or incorporating a fiber formation inhibitor on the intraocular lens.

  Representative examples of intraocular lenses that can be effective by infiltrating adjacent tissues with the polymer composition of interest include, but are not limited to, polymethyl methacrylate (PMMA) intraocular lenses, silicone intraocular lenses, achromatic lenses Including lenses, pseudophakic lenses, phakic lenses, aphakic lenses, multifocal intraocular lenses, hydrophilic and hydrophobic acrylic intraocular lenses, intraocular implants, optical lenses and gas permeable hard (RGP) lenses, This is not a limitation.

  In one embodiment, the intraocular lens is foldable or solid. A foldable lens can be inserted into a small incision site using a very small tube, while a hard lens is inserted through a relatively large incision site. The foldable lens can be composed of silicone, acrylic or hydrogel, and the hard lens can be composed of a rigid polymer compound (PMMA).

  In one embodiment, the intraocular lens can be used as an implant for the treatment of cataracts from which the natural lens of the eye has been removed (ie, a lens lens). For example, an intraocular lens can be composed of two lenses with different refractive indices and different light outputs joined together as an achromatic lens that can be coupled into the posterior or anterior chamber of the eye. See US Pat. No. 5,201,762. The intraocular lens can be fixed to the posterior chamber by a system consisting of struts protruding through an iris attached to a retaining ring. See U.S. Pat. No. 4,053,953. The intraocular lens can be deformed for insertion into the eye and can be a shape memory rigid lens that cures at normal body temperature. See U.S. Pat. No. 4,946,470. Intraocular lenses can be coated with proteins, polypeptides, polyamino acids, polyamines or carbohydrates attached to the surface of the implant. See U.S. Pat. Nos. 6,454,802 and 6,106,554. Other examples of phakic intraocular lenses are described in US Pat. Nos. 6,599,317, 6,585,768, 6,558,419, 6,533,813, 6,210,438, 5,266,074, 4,753,654, 4,718,904, 4,704,123, and the like.

  In another embodiment, the intraocular lens can be used as a vision impairment correction implant where the natural lens of the eye has not been removed (ie, a phakic lens). For example, the intraocular lens should be a thin sided phasic anterior lens that can be composed of a visual area and a transition zone with a curved shape to minimize direct glare. Can do. See US Pat. No. 6,596,025, etc. The intraocular lens can be a self-centered phakic lens inserted into the posterior chamber lens, extending outward and projecting through the pupil so that the iris provides centripetal force to keep the lens in place There is an arm (ie tactile sense). See US Pat. No. 6,015,435. The intraocular lens can be composed of two haptics extending from a peripheral edge and a transverse member that is bent substantially linearly or inwardly in the lens direction from its edge. See US Pat. No. 6,241,777. Examples of other phakic intraocular lenses are described in US Pat. Nos. 6,228,115, 5,480,428, 5,222,981, and the like.

  In another aspect, the intraocular lens can be a multifocal lens that can be variably adapted so that a user can see through different portions of the lens to achieve different levels of focusing. For example, an intraocular lens can be a variable focus lens composed of two lens parts, with an optical zone between which a liquid container containing a charged solution and a channel can be placed. . See US Pat. No. 5,443,506.

In another aspect, the intraocular lens can be a deformable lens so that the lens can be folded for insertion through a tunnel incision. For example, an intraocular lens can be composed of a lens with a fixing member for fixing the lens in the eye, and is inserted from a normal optical state so that the lens can pass through the incision and enter the eye. A structure that can be bent or rolled into a ring is possible. See US Pat. No. 5,476,513. An intraocular lens can be composed of a resilient, deformable, silicone-based lens with a means for securing the lens to the lens to hold it in the eye. See US Pat. No. 5,201,763. The intraocular lens can be composed of a three-component copolymer that can be deformed from its original shape. See US Pat. No. 5,359,021, etc. An intraocular lens can consist of a transparent flexible membrane with a sac inside and a bladder attached to it, where the optical fluid medium is shorted from the optical element to the bag. The See US Pat. No. 6,048,364. The intraocular lens can be a biocomposite composed of a lens part made of a hydrogel with high water content that can be bent and a tactile part made of a hydrogel with low water content and strength and rigidity. See US Pat. No. 5,211,662. Examples of other deformable intraocular lenses are described in US Pat. Nos. 6,267,784, 5,507,806, US Patent Application No. 2003 / 0114928A1 , and the like.

  For other related devices and compositions that can be used in combination with intraocular lenses (such as insertion devices), see US Pat. 2003 / 0187455A1 etc.

  Intraocular implants that become effective when the polymer composition of interest invades adjacent tissue in accordance with the present invention include commercial products. For example, Alcon Laboratories, Inc. (Fort Worth, Texas) sells a foldable ACRYSOF intraocular lens. Bausch & Lomb Surgical, Inc. (San Dimas, CA) sells foldable SOFLEX SE intraocular lenses. Advanced Medical Optics, Inc (Santa Ana, Calif.) Sells CLARIFLEX foldable intraocular lenses, SENSAR acrylic intraocular lenses, and PHACOFLEXII SI40NB and SI30NB.

  The intraocular implant of the present invention can be used in a variety of surgical procedures. For example, intraocular implants can be used in conjunction with corneal transplants. Artificial corneas can be used for patients who are about to lose vision due to the modified cornea. Implanted synthetic cornea can restore a patient's vision, but often induces a fibrous foreign body reaction that limits its use. The intraocular graft of the present invention can prevent foreign body reaction to the artificial cornea and prolong the corneal life. In another example, the artificial cornea itself can be coated with the polymer composition of the present invention, thereby minimizing tissue response to corneal transplantation.

  In another embodiment, the intraocular lens can be used in conjunction with the treatment of secondary cataracts after extracapsular cataract extraction.

  As described above, the present invention provides intraocular lenses and other implants comprising a subject polymer composition that infiltrates adjacent tissue, the polymer composition comprising a therapeutic agent (an anti-scarring agent and / or an anti-infective agent). )including. In one embodiment, the anti-scarring agent may not be paclitaxel or a derivative thereof.

  A number of polymeric and non-polymeric delivery systems for intraocular implants have already been described above.

  The polymer compound directly and / or indirectly (a) tissue adjacent to the intraocular implant, (b) around the interface between the intraocular implant and tissue, (c) around the intraocular implant, ( d) When applied inside and / or on the tissue surrounding the intraocular graft, it may infiltrate around the implanted intraocular graft. Methods of infiltrating the tissue adjacent to the intraocular implant with the polymer composition of interest include delivery of the polymer composition: (a) The surface of the intraocular implant during the implantation procedure (eg, injection material, paste) (B, as a gel or mesh), (b) on the tissue surface (eg as an injection material, paste, gel, gel or mesh formed in situ) immediately before or during implantation of the intraocular implant (c ) Immediately after implantation of the intraocular implant, (d) on the surface of the intraocular implant and / or tissue surrounding the intraocular implant (eg, injection material, paste, gel, gel or mesh formed in situ) ) Topical application of fibrosis inhibitor in the anatomical space where the intraocular implant is placed (especially useful in this example is a polymeric carrier that releases the fibrosis inhibitor over a period ranging from hours to weeks) Is the use of-liquid, Suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and other formulations that can release the drug and be delivered to the site where the implant is inserted), (e ) Via intradermal injection of solutions, infusions, and sustained release formulations into the tissue surrounding the intraocular implant and / or (f) application by a combination of the methods described above. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the subject polymer composition can be wetted to the entire device or to some surrounding tissue.

  The process of infiltrating the tissue adjacent to these implants with the polymer composition of interest and the substances selected in these processes significantly change the refractive index of the intraocular implant or the visible light transmission of the implant or lens. It doesn't let you.

  According to certain embodiments, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the present invention. In one aspect of the invention, the subject polymer composition that invades the tissue adjacent to the intraocular implant inhibits one or more of the four general factors for the process of fibrosis (or scarring) comprising: Can be adapted to release: new blood vessel formation (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) accumulation, and remodeling (Maturation and organization of fibrous tissue). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (such as simvastatin), (G) inosine monophosphate dehydrogenase inhibitors (such as mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ ), (H) NFκB inhibitors (such as Bay11-7082), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Because intraocular implants are made in a variety of shapes and sizes, the exact dose administered will also depend on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site) and the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from the polymer composition, the concentration of which is effective for a specific period of time that can be measured from the time of infiltration into the surrounding tissue, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Drug scarring inhibitor dosage per unit area of the device or tissue surface of a subject to be coated (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm, ² or from about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,,.

  According to another aspect, all of the antiinfectives described above can be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site) and the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose (amount) of anti-infective drug per unit area of the device or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² , or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

In another embodiment of hypertrophic scars and keloids, the subject polymer composition can infiltrate tissue adjacent to the device to be used to treat hypertrophic scars and keloids. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  Various devices have been described for treating hypertrophic scars and keloids. For example, the device can be an external tissue expansion device consisting of two stitched steel plates with an adhesive foam foam cushion, which is a constant and continuous to remove hypertrophic scars and keloids A low gradient force is applied to the skin and tissue. See US Pat. No. 6,254,624. The device can be an element for a mask that compresses scar tissue with an adjustable force, which is by means of a pressure control unit and is connected to an inflatable or suction member within the element for the mask. See U.S. Patent No. 6,013,094. The treatment can be a device with a locking element and a structure to grip, but the dermal and epidermal layers of the skin wound are adjacent to the tissue edge so that the wound can be closed with minimal scarring. Can be pressed against each other. See US Pat. No. 5,591,206.

  In another aspect, a hypertrophic scar or keloid uses the device to deliver a scarring inhibitor and / or an anti-infective agent alone, or to deliver a composition of a scarring inhibitor as described above. It can also be treated in combination with the resulting coating or sheet. For example, the coating or sheet can be a copolymer made of a hydrophilic polymer such as polyethylene glycol combined with a polymer (such as phenylboronic acid) that is easily absorbed by the surface of the body tissue. See US Pat. No. 6,596,267. The coating or sheet can be a self-adhesive silicone sheet impregnated with an antioxidant or antibacterial agent. See US Pat. No. 6,572,878. The coating or sheet can be a garment with a wound dressing composed of an outer formable layer that acts as a bandage in contact with the wound and an inner self-adhesive gel lining. See US Pat. No. 6,548,728. The coating or sheet can be a liquid composition composed of a film-forming carrier (such as collodion) containing one or more active ingredients such as topical steroids, silicone gels and vitamin E. See U.S. Patent No. 6,337,076. The coating or sheet can also be dressed with a scar treatment pad with a layer of silicone elastic resin or silicone gel. See U.S. Pat. Nos. 6,284,941 and 5,891,076.

  The treatments and devices used for hypertrophic scars and keloids according to the present invention that may combine the polymer composition of interest with infiltration into adjacent tissue or hypertrophic scars and keloid tissue include commercially available products. included. Representative products include, for example, PROXIDERM, an external tissue expansion product for wound healing (Progressive Surgical Products (Westbury, NY)), CICA-CARE gel sheet dressing product (Smith & Nephew Healthcare Ltd. (India)), MEPIFORM self-adhesive silicone dressing (Molnlycke Health Care (Eddie Stone, PA)).

  In another aspect, a device for treating hypertrophic scars and keloids may include a subject polymer composition that invades adjacent tissue, the polymer composition being a therapeutic agent (a scarring inhibitor and / or an anti-infective agent). Can be included. The polymer composition is a topical or injectable polymer composition and comprises a scarring inhibitor and / or an anti-infective agent and a polymeric carrier suitable for application on or in a hypertrophic scar or keloid. Incorporating fibrosis inhibitors or / and anti-infectives into topical or injectable formulations is one way to treat this condition. A topical formulation can be in the form of a solution, suspension, emulsion, gel, ointment, cream, film or mesh. Injectable preparations may be in the form of solutions, suspensions, emulsions or gels. Polymers and non-polymeric components that can be used to prepare these topical or injectable compositions are as described above.

  The polymeric compound may directly and / or indirectly (a) tissue adjacent to the device used for hypertrophic scars and keloids, (b) around the device-tissue interface used for hypertrophic scars and keloids, (c) Peripheral site for devices used for hypertrophic scars and keloids, (d) Used for transplanted hypertrophic scars and keloids when applied to and / or on tissues surrounding devices used for hypertrophic scars and keloids Can infiltrate around the device. Methods of infiltrating a tissue adjacent to a device used for hypertrophic scars and keloids with a polymer composition of interest include delivery of the polymer composition: (a) used for hypertrophic scars and keloids during an implantation procedure The surface of the device (eg as injection material, paste, gel or mesh), (b) the tissue surface (eg injection material, paste, gel, raw material) just before or during implantation of the device used for hypertrophic scars and keloids. (As a gel or mesh formed in position), (c) device used for hypertrophic scar and keloid and / or device used for hypertrophic scar and keloid immediately after implantation of the device used for hypertrophic scar and keloid On the surface of surrounding tissues (eg injection material, paste, gel, gel or mesh formed in situ), (d) on hypertrophic scars and keloids Topical application of a fibrosis inhibitor in the anatomical space where the device to be used is placed (especially useful in this example is the use of a polymeric carrier that releases the fibrosis inhibitor over a period ranging from hours to weeks -Liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants, and others that can release the drug and be delivered to the site where the implant is inserted (E) application via a combination of the methods described above, (e) via intradermal injection of solutions, infusions, and sustained release formulations into the tissue surrounding the device used for hypertrophic scars and keloids. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the subject polymer composition can be wetted to the entire device or to some surrounding tissue.

  According to certain embodiments, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the present invention. In one embodiment of the present invention, the subject polymer composition that infiltrates the tissue adjacent to the hypertrophic scar and keloid treatment device is one of four general factors for the fibrosis (or scarring) process comprising: Or can be adapted to release drugs that inhibit more than one: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) Accumulation and remodeling (fibrotic tissue maturation and organization). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (such as simvastatin), (G) inosine monophosphate dehydrogenase inhibitors (such as mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ ), (H) NFκB inhibitors (such as Bay11-7082), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Because devices for treating hypertrophic scars and keloids are made in a variety of shapes and sizes, the exact dose administered will also depend on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site) and the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from the polymer composition, the concentration of which is effective for a specific period of time that can be measured from the time of infiltration into the surrounding tissue, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Drug scarring inhibitor dosage per unit area of the device or tissue surface of a subject to be coated (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm, ² or from about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,,.

  According to another aspect, all of the antiinfectives described above can be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site) and the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose (amount) of anti-infective drug per unit area of the device or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² , or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

Vascular Graft In one embodiment, the present invention infiltrates the subject polymer composition into tissue adjacent to the vascular graft. Vascular graft devices with polymer compositions containing fibrosis inhibitors and / or anti-infective agents that infiltrate adjacent tissues have the ability to inhibit or reduce granulation tissue overgrowth, so the clinical effectiveness of these devices The degree can be increased. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  Vascular grafts include extra vascular grafts or endovascular (ie, intraluminal) grafts. Vascular grafts include, but are not limited to, forms of peripheral bypass applications or coronary artery bypass applications. Vascular grafts can be used to replace or replace damaged or diseased veins and arteries, including but not limited to blood vessels damaged by aneurysms, intimal proliferation and thrombosis, and the like. Vascular grafts can also be used to provide access to blood vessels, for example, hemodialysis access. Vascular grafts provide alternative conduits for blood flow through damaged or affected areas of veins and arteries, such as, but not limited to, blood vessels damaged by aneurysms, intimal proliferation and thrombosis, etc. Although transplanted, transplantation can lead to further complications including, but not limited to, inflammation, thrombosis and intimal proliferation. The lack of long-term patency of the vascular graft may be, for example, surgical damage and abnormal hemodynamics and material incompatibility in the suture line. In general, further vascular diseases (restenosis, etc.) occur along the floor of the artery.

  In an attempt to reduce the restenosis that occurs at the site of anastomosis, several forms of improvement to vascular grafts have been made. Improvements include the following: (a) the use of a mirror cuff, a small piece of natural vein, to form a short cuff joined by stitching to an arterial opening or prostate graft; (b) thereby having a hem or cuff at the end of the graft Use of flanged grafts to facilitate end-to-side anastomosis, (c) use of grafts with large diameter and enlarged lumens for sutures at the anastomosis site, and (d) prevent thrombosis and intimal proliferation For example, the use of grafts to dispense drugs.

  Representative examples of vascular grafts include, but are not limited to, synthetic bypass grafts (such as femur popliteal, interfemoral, axillary femur, and the like), venous grafts (such as peripheral and coronary), internal There are breast (such as coronary) grafts, branched vascular grafts, endoluminal grafts, endovascular grafts and prostate grafts. Artificial blood vessels can be produced from, for example, polytetrafluoroethylene (ePTFE, etc.), polyesters such as DACRON, polyurethane, various polymer materials, and combinations of polymer materials.

  Intraluminal vascular grafts can be used to treat aneurysms. For example, a vascular graft can consist of a tubular graft with two tubular self-expanding stents that can be implanted to treat an aneurysm by means of a less invasive surgical procedure. See US Pat. No. 6,168,620. Vascular grafts can be composed of a flexible tubular body and a compressible frame that is in position relative to hold the tubular body and has pores on the surface to promote ingrowth. See US Pat. No. 5,693,088. The vascular graft can be a branched endovascular graft with a tubular trunk and two tubular limbs. See US Pat. No. 6,454,796. The vascular graft can be a kink-resistant intraluminal branch graft with two separate lumens in contact at a single lumen portion. See US Pat. No. 6,551,350. A vascular graft can be an intraluminal tube composed of ePTFE with seams formed at the ends so that the microstructured fibrils are perpendicular to each other. See US Pat. No. 5,718,973.

  In another aspect, the vascular graft can be used as a conduit for bypassing vascular stenosis or other vascular abnormalities. For example, a vascular graft can be composed of a multi-porous material that has a multi-hole hollow fiber layer disposed along the inner surface and that allows for tissue growth during the healing process while inhibiting bleeding. See US Pat. No. 5,024,671. The vascular graft can be a flexible single reinforced polymer tube with a microporous ePTFE tubular material and an external ePTFE braid projecting outwardly from the outer wall. See US Pat. No. 5,609,624. A vascular graft can be composed of a tubular wall with longitudinally extending pleats that bend and react to changes in blood pressure while maintaining high flexibility to reduce kinking. See US Pat. No. 5,653,745. Vascular grafts can consist of radially held ePTFE tubes reinforced with dense annular regions. See U.S. Pat. No. 5,747,128. The vascular graft can be a multi-hole PTFE tubing consisting of microstructured nodes interconnected by fibrils with an elastomeric coating on the outer wall. See U.S. Patent Nos. 5,152,782 and 4,955,899. A vascular graft can be a number of polymeric fibers knitted together, consisting of at least three different fibers, two of which are absorbent and one is non-absorbable. See U.S. Pat. Nos. 4,997,440, 4,871,365, 4,652,264, and the like.

  In another embodiment, the vascular graft can be modified to reduce thrombus formation or intimal proliferation at the anastomosis site. For example, a vascular graft can have an enlarged lumen with a first diameter parallel to the axis of the tubular wall and a second diameter transverse to the axis of the tube. See US Pat. No. 6,589,278. The vascular graft may have a flange-like hem or cuff that facilitates end-to-end direct anastomosis between the artery and the end of the flanged bypass graft. See US Pat. No. 6,273,912. A vascular graft can be comprised of a tubular wall having a non-thrombogenic agent and a thrombogenic layer in the luminal layer that forms the exterior of the vascular graft. See US Pat. No. 6,440,166. A vascular graft can be composed of a smooth lumen surface made of small pore size ePTFE that reduces the sticking of occlusive blood components. See US Pat. No. 6,517,571. A vascular graft can consist of a hollow tube containing a drug that spirally wraps the outer wall of a multi-hole ePTFE implant, thereby being injected through the multi-hole gap in the graft wall. Drug is dispensed. See US Pat. No. 6,355,063.

  In another embodiment, the vascular graft may be a harvested blood vessel used for a bypass graft. For example, a vascular graft can be composed of arterial blood vessels taken from a host, such as the internal thoracic artery or the lower abdominal wall artery. See US Pat. No. 5,797,946. Vascular grafts can consist of saphenous veins that can be harvested from the host and used for coronary artery bypass or peripheral bypass procedures. See US Pat. No. 6,558,313.

  Other examples of vascular grafts are described in the following U.S. patent numbers: 3,096,560, 3,805,301, 3,945,052, 4,140,126, 4,323,525, 4,355,426, 4,475,972, 4,530,113, 4,550,447, 4,562,596, 4,601,718, 116,116,116,116,5 5,151,105, 5,197,977, 5,282,824, 5,405,379, 5,609,624, 5,693,088, 5,910,168.

  In accordance with the present invention, vascular grafts that can infiltrate adjacent tissue with adjacent polymer compositions also include commercially available products. GORE-TEX vascular grafts and GORE-TEX INTERING vascular grafts are available from Gore Medical Division (WL Gore & Associates, Inc., Newark, Del.) CR Bard, Inc. (Mary Hill, NJ) We sell bypass grafts and IMPRA CARBOFLO vascular grafts.

  In one aspect, the present invention provides a vascular graft comprising a subject polymer composition to be implanted in adjacent tissue, the polymer composition may comprise a therapeutic agent (an anti-scarring agent and / or an anti-infective agent). ).

  A number of polymeric and non-polymeric delivery systems for use with vascular grafts have already been described above.

  The polymer compound directly and / or indirectly surrounds the composition (a) tissue adjacent to the vascular graft, (b) around the interface between the vascular graft and tissue, (c) surrounding the vascular graft, (d) surrounding the vascular graft. When applied inside and / or on tissue, it may infiltrate around the grafted vascular graft. Methods of infiltrating the polymer composition of interest into the tissue adjacent to the vascular graft include delivery of the polymer composition: (a) the surface of the vascular graft during the implantation procedure (eg, injection material, paste, gel or mesh) (B) Immediately before or during implantation of the vascular graft (eg as injection material, paste, gel, gel or mesh formed in situ), (c) Immediately after implantation of the vascular graft (D) into the anatomical space where the vascular graft is placed on the surface of the vascular graft and / or the tissue surrounding the vascular graft (eg injection material, paste, gel, gel or mesh formed in situ) Topical application of fibrosis inhibitors (especially useful in this example is the use of a polymeric carrier that releases fibrosis inhibitors over a period ranging from hours to weeks-liquid, Suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and other formulations that can release the drug and be delivered to the site where the implant is inserted), (e ) Via intradermal injection of solutions, infusions, and sustained release formulations into the tissue surrounding the vascular graft and / or (f) application by a combination of the methods described above. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the subject polymer composition can be wetted to the entire device or to some surrounding tissue.

  In addition to fibrosis inhibitors and / or anti-infectives, target polymer compositions that infiltrate tissues adjacent to vascular graft devices can be further combined with anti-inflammatory drugs (such as dexamethasone or aspirin) and antithrombotic drugs (heparin, heparin complexes, Hydrophobic heparin derivatives, dipyridamole, or aspirin can also be included. The drug combination can be included in a polymer composition that infiltrates the tissue adjacent to the vascular graft so that thrombus formation or fiber formation is reduced or inhibited. In certain examples, these agents can be included in a biodegradable polymer. For example, polymeric materials in the form of gels in and on the pores of the implant can also be used, including alginate, chitosan and chitosan sulfate, hyaluronic acid, dextran sulfate, pluronic polymer, long chain Pluronic polymers, polyester-polyether block copolymers (MePEG-PLA, PLA-PEG-PLA, and the like) of various configurations.

  According to one embodiment, the anti-scarring agents and / or anti-infective agents described above can be used in the practice of the present invention. In one aspect of the present invention, a subject polymer composition that infiltrates tissue adjacent to a vascular graft comprises an agent that inhibits one or more of four general factors for the process of fibrosis (or scarring), including: Can be adapted to release: new blood vessel formation (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) accumulation, and remodeling ( Fibrous tissue maturation and organization). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (such as simvastatin), (G) inosine monophosphate dehydrogenase inhibitors (such as mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ ), (H) NFκB inhibitors (such as Bay11-7082), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Because vascular grafts are made in a variety of shapes and sizes, the exact dose administered will also depend on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site) and the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from the polymer composition, the concentration of which is effective for a specific period of time that can be measured from the time of infiltration into the surrounding tissue, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Drug scarring inhibitor dosage per unit area of the device or tissue surface of a subject to be coated (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm, ² or from about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,,.

  According to another aspect, all of the antiinfectives described above can be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site) and the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose (amount) of anti-infective drug per unit area of the device or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² , or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

Hemodialysis access device In one embodiment, the subject polymer composition can infiltrate tissue surrounding the hemodialysis access device. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents). Hemodialysis access devices containing fibrosis inhibitors and / or anti-infectives have the ability to inhibit or reduce granulation tissue overgrowth and to inhibit or prevent infection, thereby allowing clinical use of these devices. Can increase the effectiveness.

  The hemodialysis access device can be used when blood needs to be removed and purified and then returned to the body. Hemodialysis adjusts body fluid balance and chemical balance, and removes waste products from the bloodstream that cannot be purified by a normally functioning kidney due to disease or injury. Blood for hemodialysis can be obtained via hemodialysis access or vascular access, with a minor operation being made accessible through a pulmonary arteriovenous fistula or an arteriovenous access graft. These hemodialysis access devices may develop complications including associated vascular infection, inflammation, thrombosis and intimal proliferation. The lack of long-term patency of hemodialysis may be due to surgical damage and abnormal hemodynamics and material incompatibility in the suture line. In general, further vascular diseases (restenosis, etc.) occur along the arterial floor and anastomosis sites.

  In addition to the pulmonary arteriovenous fistula and arteriovenous access graft described above, implantable subcutaneous hemodialysis access systems such as commercially available catheters, ports, and bifurcations can also be used for hemodialysis patients. These access systems can also consist of small metal or polymer devices or devices implanted under the skin. These devices can also be connected to a flexible tube inserted into a blood vessel for flowing blood access.

  Representative examples of hemodialysis access devices include, but are not limited to, arteriovenous access grafts, venous catheters, vascular grafts, implantable ports, and arteriovenous shunts. Synthetic hemodialysis access devices can be made of metals or polymers such as polytetrafluoroethylene (such as ePTFE), polyester (such as Dacron), polyurethane, or combinations of these materials.

  In one embodiment, the hemodialysis access device can be an arteriovenous access graft. For example, an arteriovenous access graft is an implantable self-expanding, flexible percutaneous structure that has a coarse structure that is compressible at the ends and has an elastic layer aligned along a portion of its length. It can consist of a stent graft. See the following US patent number. Nos. 5,755,775 and 5,591,226. An arteriovenous access graft can be composed of a tubular portion that has a generally constant diameter and tapers toward the end of the vein. See US Pat. No. 6,585,762. Two arteriovenous access grafts are placed in a circumferential manner so that the graft is self-sealing and resistant to the tensile strength of the upper radius and the stretch of the suture hole, with two polymer layers in between. Can be composed of microporous ePTFE tube. See US Pat. No. 6,428,571. The arteriovenous access graft can consist of a coaxial dual lumen tube with inner and outer tubes with a self-sealing non-biodegradable polymer adhesive between the tubes. See U.S. Pat. No. 4,619,641. An arteriovenous access graft is a synthetic fiber with a high velor outer profile that is woven or knitted to form a tubular prosthesis with elastic fibers that can self-seal after puncture. Can be configured. See US Pat. No. 6,547,820. The arteriovenous access graft should have a tubular shape with a base tube covered with a deflectable material, such as a multi-hole film, on the surface opposite to the luminal side and arranged adjacent to each other for movement Can do. See US Pat. No. 5,910,168.

  In another aspect, the hemodialysis access device may be a catheter system. For example, a catheter system can be composed of a suction tube and a return tube adapted for placement in the vasculature of the body and connected to a subcutaneous connection port. See the following US patent number. 6,620,118 and 5,989,206. The catheter system can also be a device used to arterize a vein by forming a pulmonary arteriovenous fistula by inserting one catheter into a vein and one catheter into an adjacent artery. See US Pat. No. 6,464,665. The catheter system may be constructed of a hollow outer tube in which a fistula vascular catheter is introduced percutaneously through a vascular wall perforation so that an artificial vascular fistula is formed between adjacent blood vessels by the catheter as required. it can. See U.S. Patent Nos. 6,099,542 and 5,830,224.

  In another aspect, the hemodialysis access device can be used for pulmonary arteriovenous fistulas. For example, the hemodialysis access device may be a pulmonary arteriovenous fistula assembly with a gap that is composed of a spirally wound coiled synthetic stent graft and used to enhance the function of the pulmonary arteriovenous fistula . See US Pat. No. 6,585,760.

  In another aspect, the hemodialysis access device can be an implantable access port, shunt or valve. These devices can be implanted subcutaneously in communication with the blood supply and are accessed using percutaneous puncture. For example, a hemodialysis access device may consist of a housing having an inlet port and an outlet port to the passage, which includes an elastomeric sealing valve that provides a needle access port to the outlet port. See US Pat. No. 5,741,228. The hemodialysis access device can be a shunt consisting of a slidable valve with a fluid transfer tube between the ends of the artery and vein and a soft lid. See US Pat. No. 5,879,320. The hemodialysis access device can be a shunt in the form of a junction with a coupling device with two legs inserted into a natural blood vessel so that one leg can be sealed without puncturing the other blood vessel Have been adapted. See US Pat. No. 6,019,788. The hemodialysis access device can be a surface access double hemostasis valve that can be attached to the wall of an arteriovenous graft for hemodialysis access. See U.S. Patent Nos. 6,004,301 and 6,090,067.

  Hemodialysis access devices that can benefit from having the subject polymer composition infiltrated into adjacent tissue in accordance with the present invention include commercial products. For example, hemodialysis access devices include LIFESITE (Vasca Inc., Chukesbury, Mass.) And DIALOCK catheter (Biolink Corp., Middleboro, Mass.), VECTRA vascular access graft and VENAFLO vascular graft (CRBard, Inc. , Murray Hill, NJ), and GORE-TEX vascular grafts and stretchable vascular grafts (Gore Medical Division, WL Gore & Associates, Inc., Newark, Del.).

  In one aspect, the invention provides a hemodialysis access device comprising a subject polymer composition infiltrated into adjacent tissue, the polymer composition containing a therapeutic agent (such as an anti-scarring agent and / or an anti-infective agent). Can be included. A number of polymeric and non-polymeric delivery systems for use with hemodialysis access devices have already been described above.

  The polymer composition comprises (a) tissue adjacent to the hemodialysis access device, (b) around the interface between the hemodialysis access device and the tissue, (c) a site around the hemodialysis access device, and (d) the hemodialysis access device. By applying directly and / or indirectly to the surrounding tissue, it can infiltrate around the implanted hemodialysis access device. Methods for infiltrating a tissue adjacent to a hemodialysis access device with a subject polymer composition include delivery of the polymer composition to: (a) on the surface of the hemodialysis access device during the implantation procedure (eg as infusate, paste, gel or mesh), (b) on the tissue surface immediately before or during implantation of the hemodialysis access device (eg: Infusion material, paste, gel, in situ formed gel or mesh), (c) Immediately after implantation of the hemodialysis access device, the surface of the tissue around the hemodialysis access device and / or the implanted hemodialysis access device (Eg: injection substance, paste, gel, gel or mesh formed in situ), (d) topical application of the composition to the anatomical space where the hemodialysis access device is located (especially in this example Useful is the use of polymeric carriers that release therapeutic agents over a period ranging from hours to weeks-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, , Microparticles, sprays, aerosols, solid implants and other formulations that release the drug and can be delivered to the site where the device is inserted), (e) solutions, infusions into the tissue surrounding the hemodialysis access device, and Application by intradermal injection of a sustained release formulation and / or (f) a combination of the methods described above. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the subject polymer composition can be wetted to the entire device or to some surrounding tissue.

  In addition to the fibrosis inhibitor and / or anti-infective agent, the subject polymer composition infiltrated into tissue adjacent to the hemodialysis access device may also include anti-inflammatory agents (such as dexamethasone or aspirin) and anti-thrombotic agents (heparin, Heparin complexes, hydrophobic heparin derivatives, dipyridamole, or aspirin).

  According to one aspect, the anti-scarring agents and / or anti-infective agents described above can be used in the practice of the present invention. In one embodiment of the present invention, the subject polymer composition infiltrated into tissue adjacent to the hemodialysis access device inhibits one or more of four general factors for the process of fibrosis (or scarring) including: It can be adapted to release the drug. In the formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), accumulation of extracellular matrix (ECM), and remodeling (maturation and organization of fibrous tissue) is there. Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (such as simvastatin), (G) inosine monophosphate dehydrogenase inhibitors (such as mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ ), (H) NFκB inhibitors (such as Bay11-7082), (I) Antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Also, because hemodialysis access devices are manufactured in a variety of shapes and sizes, the exact dose administered will vary depending on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Scarring inhibitor dose per unit area of the device or tissue surface of the object to which drug is applied (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2, or about 1 μg / mm ² ~10 μg / mm ² or can be from about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The anti-infective drug dose per unit area of the surface of the device or tissue to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² , or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

Film and Mesh In one embodiment, the subject polymer composition can infiltrate the tissue adjacent to the film or mesh. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents). By infiltrating the tissue adjacent to the film or mesh with a subject polymer composition containing a fibrosis inhibitor and / or an anti-infective agent, fiber formation (or scarring) in the vicinity of the graft is minimized, and the graft In addition to reducing or preventing the formation of adhesions between the tissue and the surrounding tissue, it may be possible to inhibit or prevent infection near the transplant site. In certain embodiments, the film or mesh can be used as a drug delivery vehicle (such as as a perivascular delivery device to prevent neointimal hyperplasia at the site of anastomosis).

  The film or mesh can take a variety of forms including, but not limited to, surgical barriers, surgical adhesive barriers, membranes (such as a septum), surgical sheets, surgical patches (such as a dural patch), Surgical wrap (such as vascular, perivascular, adventitia, pericardial wrap, and adventitia sheet), mesh (such as perivascular mesh), bandage, liquid bandage, suture, gauze, textile, There are tapes, surgical membranes, polymer matrices, shells, envelopes, tissue covers, and other types of surgical substrates, scaffolds, and coatings.

In one embodiment, the device can have a film or be in the form of a film. The film can be formed into one or multiple geometric shapes. Depending on the application, the film can be tube shaped or a thin elastic sheet made of polymer. In general, the film is desirably less than 5, 4, 3, 2, or 1 mm in thickness, and more desirably less than 0.75 mm, 0.5 mm, 0.25 mm, or 0.10 mm in thickness. The film can also be formed with a thickness of 50 μm, 25 μm or 10 μm or less. Such films have good tensile strength (eg 50 or more, preferably 100 or more, more preferably 150 or 200 N / cm ² or more), good adhesive properties (eg wet or wet surfaces) Also has a flexible property of adhering to each other, and the transmittance is controlled. Polymer films (which can be either multi-hole or non-multi-hole) are particularly useful for application to the surface of a device or implant, as well as to the surface of a tissue, cavity or organ.

  The film can be manufactured in a number of processes, for example, by casting, by application, or formed in situ at the treatment site. For example, a sprayable formulation can be applied to the treatment site and then molded into a solid film.

  In another aspect, the device can include or be in the form of a polymer, wherein at least a portion of the polymer takes the form of a mesh. A material composed of a large number of fibers or filaments (ie, fibrous materials), where the fibers or filaments are formed in such a way as to form a multi-hole structure (weaving, tying, braiding, layering) Generally meshed, looped, knitted, interwoven, entangled, knitted, felted, and the like, etc. It is a material that is easy to mold, such as having sufficient flexibility to wrap a part of it. The mesh is capable of retaining the structure (blood vessel or cavity wall) and can also be adapted to release a certain amount of therapeutic agent.

  The mesh material can take a variety of forms. For example, the mesh can be in the form of a woven, knitted or non-woven fabric and can include fibers or filaments that are oriented in a random direction relative to each other or arranged in an ordered array or pattern. . In one embodiment, for example, the mesh can be in the form of fibers such as knitted, braided, keyed, woven, non-woven (such as meltblown or wet) mesh knitted fibers. In one embodiment, the mesh includes a natural or synthetic biodegradable polymer that can be formed into a knitted mesh, a woven mesh, a coated mesh, a mesh mesh, a braided mesh, a looped mesh, and the like. Can do. The mesh or wrap preferably has intertwined yarns that form a porous structure such as, for example, knitted, woven, or netted.

  The structure and properties of the mesh used in the device will depend on the application of the selected therapeutic agent and the desired mechanical properties (ie, flexibility, tensile and elastic), degradation properties, and desired additional and release properties. The mesh should have mechanical properties that keep the device strong enough until the surrounding tissue heals. Factors affecting the flexibility and mechanical strength of the mesh include, for example, porosity, fiber thickness, fiber diameter, polymer compounds (such as monomer and activator type), process conditions, and materials There are additives used to prepare.

  In general, the mesh has sufficient porosity to allow fluid flow through the pores of the fiber network and promote tissue ingrowth. In general, the mesh gap should be wide enough to allow visible light or fluid to pass through the pores. However, a material having a smaller structure can also be used. The flow of fluid through the mesh gap depends on various factors such as the number of meshes and the yarn density. The porosity of the mesh means that the mesh gap is filled with another material (such as particles or polymer) or the mesh is treated (such as by heating) to reduce the pore size and form non-fibrous regions. You can make further adjustments. The flow of fluid through the mesh of the present invention varies with the nature of the fluid, such as viscosity, hydrophilicity / hydrophobicity, ionic concentration, temperature, elasticity, pseudoplasticity, particle content, and the like. Desirably, the gap does not prevent the release of impregnated or coated therapeutic agent from the mesh, and the gap does not prevent the exchange of tissue fluid at the site of application.

  The mesh material should be sufficiently flexible and capable of enveloping the body passageway or the entire exterior surface of the cavity or part thereof. The flexible mesh material generally takes the form of a flexible woven or knitted sheet, has a thickness in the range of about 25 microns to about 3000 microns, and is preferably about 50 to 1000 microns. Mesh materials suitable for wrapping arteries and veins generally range in thickness from about 100 to 400 microns.

  The diameter and length of the fiber or filament will vary depending on the form of the material (such as knitted, woven or non-woven) and the desired elasticity, porosity, surface area, flexibility and tensile strength. The fibers can be of any length, from short filaments to long fibers (ie, a few microns to hundreds of meters in length). Depending on the application, the fibers can have a single fiber or multi-fiber structure.

  The mesh can include fibers of the same or different dimensions, and the fibers can be formed from the same or different types of biodegradable polymers. For example, the textile material can include a regular or irregular arrangement of warp and weft yarns, and one type of polymer in the weft direction and another type (same or different from the first polymer). With a degradation profile). The degradation profile of the weft polymer can be different or the same as the degradation profile of the warp polymer. Similarly, the knitted material can include one or more types (single fibers, multiple fibers, etc.) and sizes of fibers, including fibers made from the same or different types of biodegradable polymers. You can also.

  The structure of the mesh (such as fiber density and porosity) can affect the amount of therapeutic agent that can be loaded into the device or on its surface. For example, coarsely woven fibers characterized by low fiber density and high porosity reduce the number of threads, resulting in a reduction in total fiber content and surface area. As a result, the amount of drug loaded into or on the fiber at a constant carrier: therapeutic ratio is lower than a fabric with high fiber density and low porosity. The mesh should not cause biologically harmful inflammation or toxic reactions, should have full metabolic capacity in the body, should have an acceptable shelf life and be easily sterilized.

  The device can include a plurality of mesh materials in any combination or arrangement. For example, a part of the apparatus may be a knitted material and another part may be a woven material. In another embodiment, the device is a plurality of layers (such as merging a layer of woven material into a layer of knitted material or another layer of woven material of the same or different types). be able to. In some embodiments, for example, to enhance the performance characteristics of the device (such as increasing the stiffness of the device or changing the porosity, elasticity, or tensile strength of the device) or to increase drug loading Multi-layer structures (such as devices with two or more layers of material) can also be used.

  The multilayer structure is considered useful in devices including multiple types of therapeutic agents. For example, the first layer of mesh material may be loaded with one type of drug and the second layer may be loaded with another type of drug. The two layers can be unbonded or bonded (for example, fused together by heat welding or ultrasonic welding), and can also form the same type of fiber, with different polymer compounds or Different types of fibers having a structure can also be formed.

  In certain aspects, the mesh can include portions that are not in the form of a mesh. For example, the device can include films, sheets, pastes, and the like or combinations thereof. For example, the device can have a multilayer structure with a therapeutic agent and a film layer with one or more layers of mesh material. For example, the film layer can be sandwiched between two layers of mesh or placed only on one side of the mesh material. The film layer can include a first therapeutic agent, while one or more meshes can include the same or different agents. In another example, the device can include at least two layers of mesh. In one aspect, at least two of the at least two layers of mesh can be fused together.

  In one aspect, a multilayer device is provided that can further include a film layer. The film layer can be placed between two of the at least two layers of mesh. In yet another example, the delivery device is depicted as including a mesh, where the mesh includes a biodegradable polymer and a first therapeutic agent. The device can further include a film comprising a second therapeutic agent, which can be the same or different composition as the first therapeutic agent. For example, in one embodiment, a device suitable for wrapping veins or arteries can include a layer of mesh and a film layer loaded with a therapeutic agent. The device can also wrap the body passage or cavity such that the film layer contacts the exterior surface of the passage or cavity. In this way, the device can deliver an appropriate dosage of the drug and can provide sufficient mechanical strength to improve and maintain the structural integrity of the body passage or cavity.

  In one embodiment, the mesh or film includes a polymer. The polymer can be a biodegradable polymer. Biodegradable compositions that can be used to prepare the mesh include albumin, collagen, hyaluronic acid and its derivatives, sodium alginate and its derivatives, chitosan and its derivatives, gelatin, starch, cellulose polymers (methylcellulose, hydroxypropylcellulose, Hydroxypropylmethylcellulose, ruboxymethylcellulose, cellulose acetate phthalate, cellulose acetate succinate, hydroxypropylmethylcellulose phthalate, etc.), casein, dextran and its derivatives, polysaccharides, poly (caprolactone), fibrinogen, poly (hydroxyl acid ), Poly (L-lactide) poly (D, L-lactide), poly (D, L-lactide-co-glycolide), poly (L-lactide-co-glycolide), copolymer of lactic acid and glycolic acid, ε -Capro Tonne and lactide copolymer, glycolide and ε-caprolactone copolymer, lactide and 1,4-dioxane-2-one copolymer, monomer with one or more residue units (D-lactide, L-lactide, D, L-lactide, glycolide, ε-caprolactone, trimethylene carbonate, 1,4-dioxan-2-one or 1,5-dioxepan-2-one, poly (glycolide), poly (hydroxybutyrate) , Poly (alkyl carbonate) and poly (orthoester), polyester, poly (hydroxyvalerate), polydioxanone, poly (ethylene terephthalate), poly (malic acid), poly (tartronic acid), polyanhydride, polyphosphazene In addition to the above-mentioned polymer copolymer, these compositions include a mixture or combination of the above-mentioned polymers. (Usually see below. Illum, L., Davids, SS (ed.) "Polymers in Controlled Drug Delivery" Wright, Bristol, 1987. Arshady, J. Controlled Release 17: 1-22, 1991 Pitt, Int. J. Phar. 59: 173-196, 1990. Holland et al., J. Controlled Release 4: 155-0180, 1986).

  In one aspect, the mesh or film includes lactide, glycolide, e-caprolactone, trimethylene carbonate, 1,4-dioxan-2-one, 1,5-dioxepan-2-one, 1,4-dioxepan-2-one, Biodegradable or resorbable polymers composed of one or more monomers selected from the group consisting of hydroxyvalerate and hydroxybutyrate are included. In one embodiment, the polymer can include, for example, a copolymer of lactide and glycolide. In another embodiment, the polymer includes poly (caprolactone). In another embodiment, the polymer includes poly (lactic acid), a mixture of poly (L-lactide) / poly (D, L-lactide), or a copolymer of L-lactide and D, L-lactide. In yet another embodiment, the polymer includes a copolymer of lactide and e-caprolactone. In yet another embodiment, the polymer includes polyester (such as poly (lactide-co-glycolide)). Poly (lactide-co-glycolide) has a lactide: glycolide ratio of about 20:80 to about 2:98, a lactide: glycolide ratio of about 10:90, or a lactide: glycolide ratio of about 5:95. Has a ratio of lactide: glycolide. In one embodiment, the poly (lactide-co-glycolide) is poly (L-lactide-co-glycolide). Other examples of biodegradable materials include polyglactin, polyglycolic acid, autogenous, heterogeneous, and xenogeneic tissues (such as pericardium or small intestinal submucosa), and oxidized regenerated cellulose. These meshes can be knitted, woven or non-woven meshes. Examples of nonwovens include electrospun materials.

  Meshes and films can be prepared from non-biodegradable polymers. Representative examples of non-biodegradable compositions include ethylene-co-vinyl acetate copolymers, acrylic and methacrylic based polymers (poly (acrylic acid), poly (methylacrylic acid), poly (methyl methacrylate) , Poly (hydroxyethyl methacrylic acid), poly (alkyl sinoacrylic acid), poly (alkyl acrylate), poly (alkyl methacrylate), etc.), polyolefin (such as poly (ethylene) or poly (propylene)), polyamide (nylon) 6,6), poly (urethane) (poly (ester urethane), poly (ether urethane), poly (urethane carbonate), poly (ester-urea), etc.), polyester (PET, polybutylene terephthalic acid, and poly Xylene terephthalic acid), polyether (poly (ethylene oxide), poly (propylene oxide), poly (ethylene oxide) -poly (oxidized) (Lopylene) copolymers, diblock and triblock copolymers, poly (tetramethylene glycol), etc., silicone-containing polymers and vinyl-based polymers (polyvinylpyrrolidone, poly (vinyl alcohol), poly (vinyl acetate phthalate)) , Poly (styrene-co-isobutylene-co-styrene), etc.), fluoropolymer (such as fluorinated ethylene propylene (FEP)) or polytetrafluoroethylene (such as expanded PTFE).

  The mesh or film material can be composed of a combination of the biodegradable and non-degradable polymers described above. Other examples of polymers that can be used are anionic (such as alginate, carrageenan, hyaluronic acid, dextran sulfate, chondroitin sulfate, carboxymethyldextran, carboxymethylcellulose and poly (acrylic acid)), or cationic (Such as chitosan, poly-l-lysine, polyethyleneimine, and poly (allylamine)) (generally Dunn et al., J. Applied Polymer Sci. 50: 353, 1993. Cascone et al., J. Materials Sci .: Materials in Medicine 5: 770, 1994. Shiraishi et al., Biol. Pharm. Bull. 16: 1164, 1993. Thacharodi and Rao, Int'l J. Pharm. lJ. Pharm. 118: 257, 1995, etc.). Desirable polymers (including copolymers and mixtures of these polymers) include poly (ethylene-co-vinyl acetate), poly (urethane carbonate), poly (hydroxyl acid) (eg, poly (D, L-lactic acid)) Oligomers and polymers, poly (L-lactic acid) oligomers and polymers, poly (D-lactic acid) oligomers and polymers, poly (glycolic acid), copolymers of lactic acid and glycolic acid, copolymers of lactide and glycolide, poly (caprolactone) ), Lactide or a copolymer of glycolide and ε-caprolactone), poly (valerolactone), poly (anhydride), and copolymers prepared from caprolactone, lactide, glycolide, polyethylene glycol, and the like.

  A variety of polymeric and non-polymeric films and meshes have been described and can be combined with anti-scarring agents. For example, the film or mesh can be a biodegradable polymeric matrix that conforms to the tissue and releases the drug in a controlled release manner. See US Pat. No. 6,461,640. The film or mesh can be a self-adhesive silicone sheet that is permeable to antioxidants and antimicrobial agents. See US Pat. No. 6,572,878. The film or mesh can be an easy to mold shield with connecting ports and fenestrations adapted to cover the spinal bone incision. See U.S. Patent No. 5,868,745 and U.S. Patent Application No. 2003/0078588. The film or mesh can be a resorbable microcoat having a single layer poly-lactide non-porous polymer substrate. See, for example, US Pat. No. 6,531,146 and US Patent Application No. 2004/0137033. The film or mesh can be a flexible nerve decompression device having an outer surface calibrated with a microstructure to reduce fiber growth when wrapped around nerves in the duct. See US Pat. No. 6,106,558. The film or mesh can be a resorbable collagen capsule that wraps around the spinal cord to prevent cell adhesion. See US Pat. No. 6,221,109. The film or mesh can be a garment with a wound dressing composed of an outer formable layer that acts as a bandage in contact with the wound and an inner self-adhesive gel lining. See US Pat. No. 6,548,728. The film or mesh can also be dressed with a scar treatment pad with a layer of silicone elastic resin or silicone gel. See the following US patent number. Nos. 6,284,941 and 5,891,076. The film or mesh can be a crosslinkable system with at least three reactive compounds, each with a polymer core with at least one functional group. See US Pat. No. 6,458,889. The film or mesh has a three-dimensional structure that separates the two faces, one face being open for post-operative cell colonization and the other face being connected to a collagenous film. It can be a prosthetic fiber. See US Pat. No. 6,451,032. Films or meshes are two cross-linked syntheses, one with a nucleophilic group and the other with an electrophilic group, to form a substrate that can be used to incorporate biologically active compounds. It can be composed of a polymer. See the following US patent number. Nos. 6,323,278, 6,166,130, 6,051,648 and 5,874,500. The film or mesh can be a film composed of a heterobifunctional adhesive bond inhibitor that acts to covalently link a matrix material, such as collagen, to a receptive tissue. See US Pat. No. 5,580,923. The film or mesh can be an assimilable warp knitted oxidized regenerated cellulose or other bioabsorbable material that acts as a physical barrier to prevent post-surgical adhesions. See US Pat. No. 5,007,916. The mesh used in the practice of the present invention is also disclosed in US Pat. No.).

  In one embodiment, the mesh may be suitable for use in hernia repair surgery or another type of surgical procedure. Mesh fibers used in connection with hernia repair are disclosed in US Pat. Nos. 6,638,284, 5,292,328, 4,769,038 and 2,671,444. Surgical meshes can be knitted, woven, braided, or a large number of yarns (such as single or multifilament yarns made of polymeric materials such as polypropylene or polyester) in a holding grid. It can be manufactured by other methods. U.S. Pat.Nos. 3,054,406, 3,124,136, 4,193,137, 4,347,847, 4,452,245, 4,520,821, 4,633,873, 4,652,264 for knitted and woven fibers composed of various synthetic fibers and used in surgical repair 4,655,221, 4,838,884 and 5,002,551, and European Patent Application No. 334,046. Implantable hernia meshes are described in US Pat. Nos. 6,610,006, 6,368,541 and 6,319,264. A hernia mesh for repairing hiatal hernia is described in US Pat. No. 6,436,030. A hernia mesh for repairing an abdominal region (such as the ventral side or the navel) is described in US Pat. No. 6,383,201. The mesh for anti-infection hernia is described in US Pat. No. 6,375,662. Hernia meshes, such as those described in the patents listed above, are suitable for forming a mesh that promotes the growth of fibrous tissue in combination with a fiber inducer.

  In one embodiment, the fiber formation inhibitor can be incorporated into a biodegradable or dissolvable film or mesh and applied to the treatment site before or after implantation of the artificial aid / implant. Exemplary materials for the production of these films and meshes include hyaluronic acid (cross-linked or non-cross-linked), fibrin derivatives (such as hydroxypropylcellulose), PLGA, collagen and cross-linked poly (ethylene glycol).

  The film or mesh can take the form of a tissue graft, including autografts, allografts, biografts, biogenic grafts or xenografts. Some tissue grafts are derived from various tissues. Representative examples of tissues that can be used to prepare a biograft include, but are not limited to, a rectus sheath, peritoneum, bladder, pericardium, vein, artery, diaphragm, and pleura. A biological graft can be applied by a perivascular method to a site (such as an anastomosis site) where a lesion or intimal proliferation can proceed after collection from a host administered with a scarring inhibitor. After implantation, a drug (such as paclitaxel) can be released from the graft and penetrate the vessel wall to prevent the formation of intimal growth at the treatment site. The biograft can be used as a backing layer to seal the composition (gel or paste with an anti-scarring agent).

  Films and meshes that can benefit from having the subject polymer composition infiltrated into adjacent tissue according to the present invention include commercial products. Examples of films and meshes that can incorporate fiber formers include INTERCEED (Johnson & Johnson, Inc.), Preclude (WL Gore), and PolyActive (poly (ether ester) multiblock copolymers (Osteotech, Inc.). , Shrewsbury, NJ), based on poly (ethylene glycol) and poly (butylene terephthalate)), and SURGICAL absorbable hemostatic gauze-like sheets (Johnson & Johnson). Another mesh is a prosthetic polypropylene mesh with a bioabsorbable coating called SEPRAMESH Biosurgical Composite (Genzyme Corporation, Cambridge, Mass.). One side of the mesh is coated with a bioabsorbable layer of sodium hyaluronate and ruboxymethylcellulose to provide a temporary physical barrier that separates the underlying cell and organ surfaces from the mesh. The other side of the mesh is uncovered and a complete tissue ingrowth similar to a bare polypropylene mesh is made. In one example, the fiber inducer can be applied only to the uncoated side of SEPRAMESH, not the side coated with sodium hyaluronate / ruboxymethylcellulose. Other films and meshes include: (a) BARD MARLEX mesh (CR Bard, Inc.) with very dense knitted fiber structure and low porosity, (b) Monofilament polypropylene mesh such as PROLENE available from Ethicon, Inc. (Summerville, NJ) U.S. Pat. Nos. 5,634,931 and 5,824,082), (c) SURGISIS GOLD and SURGISISIHM soft tissue, specially configured devices to be used to reinforce soft tissue for inguinal hernia repair in laparotomy and laparoscopic surgery Implants (both Cook Surgical, Inc.), (d) Thin wall polypropylene surgical mesh from Atrium Medical Corporation (Hudson, NH) sold under the trade names PROLITE, PROLITE ULTRA, and LITEMESH, (e) Flat Mesh patch containing filaments (the patch contains two layers of inert synthetic mesh) to cure and maintain the device in a COMPOSIX hernia mesh (CR Bard, Murray Hill, NJ), which is generally made of polypropylene and described in US Pat. No. 6,280,453), (f) Polypropylene mesh composed of monofilament polypropylene VISILEX mesh (CRBard, Inc.), (g) other meshes available from CR Bard, Inc. (PERFIX plug, Kugel hernia patch, 3D max mesh, LHI mesh, Dulex mesh, and Ventralex hernia patch), and (H) Other types of polypropylene monofilaments Hernia mesh and plug products (Hernia Mesh USA, Inc., Great Neck, NY) HERTRA mesh 1, 2, and 2A, HERMESH3, 4 & 5 and HERNIAMESH plugs T1, T2 , And T3.

  Other examples of commercially available meshes that can benefit from infiltrating the target polymer composition into adjacent tissues are as described below. An example is a prosthetic polypropylene mesh with a bioabsorbable coating sold under the name SEPRAMESH Biosurgical Composite (Genzyme Corporation). One side of the mesh is coated with a bioabsorbable layer of sodium hyaluronate and ruboxymethylcellulose to provide a temporary physical barrier that separates the underlying cell and organ surfaces from the mesh. The other side of the mesh is uncovered and a complete tissue ingrowth similar to a bare polypropylene mesh is made. In one example, a subject polymer composition comprising a fiber inducer and / or an anti-infective agent can invade tissue adjacent only to the uncoated side of SEPRAMESH, not the side coated with sodium hyaluronate / carboxymethylcellulose. Boston Scientific Corporation sells TRELEX NATURAL mesh made of uniquely knitted polypropylene material. Ethicon, Inc. manufactures absorbent VICRYL (polyglactin 910) mesh (knitted and woven) and MERSILENE polyester fiber mesh. DowCorning Corporation (Midland, Michigan) sells a mesh material made of a silicone elastic resin known as SILASTIC Rx Medical Seating (Platinized). United States Surgical / Syneture (Norwalk, Conn.) Sells mesh made from absorbent polyglycolic acid as the DEXON mesh product. Membrana Accurel Systems (Obernburg, Germany) sells CELGARD microporous polypropylene fibers and membranes. Gynecare Worldwide, a division of Ethicon, Inc., sells mesh materials made of oxidized regenerated cellulose known as INTERCEED TC7. IntegraLifeSciences Corporation (Plainsboro, NJ) manufactures a DURAGENPLUS adhesive barrier substrate that can be used as a barrier to adhesives after spinal and cranial surgery and for dural repair. The HYDROSORB shield from MacroPore Biosurgery, Inc. (San Diego, Calif.) Is a temporary trauma-holding membrane that inhibits adhesive formation in certain spinal applications.

  A number of polymeric and non-polymeric carrier systems that can be used in conjunction with films and meshes have already been described above. Examples of the method for incorporating the fiber formation inhibiting composition into or on the surface of the film or mesh include the following methods. (A) a method of directly or indirectly attaching a fiber formation inhibiting composition to a film or mesh (regardless of the presence or absence of a carrier by any of the spraying or dipping processes described above), (b) a film Or a method of incorporating or impregnating the fiber formation inhibiting composition into the mesh (with or without a carrier by any of the spraying or dipping processes described above), (c) the desired fiber formation inhibiting composition in the film or mesh A method by coating with a substance such as a hydrogel that absorbs, (d) a method of making the film or mesh itself or part of the film or mesh with a fiber formation inhibiting composition, (e) a fiber formation inhibitor, Linker applied or attached directly to the surface of the mesh or to the surface of the film or mesh It is covalently bound to method (small molecules or polymers). For coated equipment, the coating process may be carried out in such a way that (a) only one side of the film or mesh is coated, or (b) all or part of the sides of the film or mesh. it can.

  In one embodiment, the present invention provides a film or mesh comprising a subject polymer composition infiltrated into adjacent tissue, the polymer composition comprising a therapeutic agent (such as an anti-scarring agent and / or an anti-infective agent). be able to. In some embodiments, the polymer composition is a polymer composition that can function as a surgical adhesion barrier.

  Various polymeric compositions that can be used in conjunction with the film mesh of the present invention have been described. Such composition forms are, for example, gels, sprays, liquids, and pastes, or can be polymerized from in situ monomer or prepolymer components. For example, the composition may be a coating of a polymer tissue formed by applying a polymerization initiator to the tissue and then covering with a water soluble macromer capable of polymerization using free radicals under the influence of ultraviolet light. See U.S. Patent Nos. 6,177,095 and 6,083,524. The composition may be an aqueous composition comprising a surfactant, pentoxyphyllin and a polyoxyalkylene polyether. See US Pat. No. 6,399,624. The composition may be a hydrogel-forming copolymer, self-solvent copolymer, and absorbent polyester copolymer that can be selectively and partially associated with a dependent hydrogel population upon contact with an aqueous environment. See U.S. Pat. No. 5,612,052. The composition is composed of a flowable prepolymer material that is emitted to the tissue surface and can then be exposed to activation energy in situ to initiate conversion of the applied material to a non-flowing polymer shape. it can. See the following US patent number. Nos. 6,004,547 and 5,612,050. The composition can also consist of a gas mixture of oxygen present in a volume ratio of 1-20%. See US Pat. No. 6,428,500. The composition can be composed of an anionic polymer having an acid sulfate and sulfur content of 5% or more to prevent monocyte or macrophage invasion. See US Pat. No. 6,417,173. The composition can be composed of a polyoxyalkylene composition that does not gel, with or without a therapeutic agent. See US Pat. No. 6,436,425. The composition can be coated on the tissue surface and consists of an aqueous solution of a hydrophilic polymer substance (such as a polypeptide or polysaccharide) having a molecular weight of 50,000 or more and a concentration range of 0.01% to 15% by weight. can do. See US Pat. No. 6,464,970.

  Other representative examples of polymer compositions that can infiltrate the tissue adjacent to the film or mesh include poly (ethylene glycol) based systems, hyaluronic acid and crosslinked hyaluronic acid compositions. These compositions can be applied as final compositions or as materials that form a crosslinked gel in situ.

  Other compositions that can be used with film and mesh include, but are not limited to: (a) sprayable PEG-containing formulations such as COSEAL, SPRAYGEL, focalseal or DURASEAL; (b) RESTYLANE, HYLAFORM, PERLANE , SYNVISC, SEPRAFILM, SEPRACOAT, InterGEL, and other hyaluronic acid-containing preparations, (c) polymer gels such as REPEL or FLOWGEL, (d) dextran sulfate gels such as Adcon group products, and (e) AdSurf (Brittania Pharmaceuticals) Lipid-based composition of.

  Films or meshes (or devices containing films or meshes) are well-known in the art, such as by adjusting and sterilizing under aseptic environment, sterilization by gamma radiation or electron beam, or a combination of both. Can be sterilized for a certain period of time.

  Films and meshes can be applied to physical conduits or tissues that are prone to develop fibrosis or intimal proliferation. Prior to embedding, cut or shape the film or mesh, or cut from a sheet of inflatable material to match the structure of the wider pore, tube, or cut area, or at a minimum, the exposed tissue The area can be covered. The film or mesh can be bent or shaped to match the particular structure of the placement area. The film or mesh can also be extended in a cuff or cylinder shape and placed around the outer periphery of the desired tissue. The film or mesh can be provided in a relatively large bulk sheet and cut into a shape to shape the particular structure or surface shape of the tissue or device to be wrapped. Alternatively, the film or mesh can be preformed into one or more patterns for subsequent use. Film and mesh shapes are typically rectangular and can be placed at a desired location within the surgical site by direct surgical placement or endoscopic techniques. The film or mesh can be fixed in place by wrapping itself (ie self-adhesive) or by fixing with sutures, staples, sealants and the like. Alternatively, the film or mesh can easily adhere to the tissue so that no separate fixation mechanism is required.

  The film or mesh of the present invention can be used for various indicators including, but not limited to, the following. (a) Prevention of surgical adhesions between tissues after surgery (gynecological surgery, vasectomy, hernia repair, nerve root decompression, laminectomy, etc.), (b) prevention of hypertrophic scars and keloids (tissue) (C) resulting in burns and other wounds), (c) prevention of intimal proliferation and / or restenosis (such as those resulting from insertion of a vascular graft or hemodialysis access device), (d) described in this document Available for devices and grafts that lead to scarring (eg used as a sleeve or mesh around breast grafts to reduce or inhibit scarring), (e) prevention of infection (tissue burns, surgery , Or as a result of other wounds), or (f) may be used with any device or graft that results in the infection described in this document.

  In one embodiment, the film or mesh can be used to prevent adhesions between tissues following surgery, injury, or disease. The formation of adhesions is usually a complex process in which separate body tissues grow together and most commonly occurs as a result of surgery and / or trauma. Usually, the formation of adhesions is an inflammatory reaction in which factors are released, and vascular permeability increases, causing fibrinogen influx and fibrin accumulation. This accumulation forms a cross-linked matrix of adjacent tissue. Fibroblasts accumulate, adhere to the matrix, deposit collagen, and induce angiogenesis. This phased event can be prevented within 4-5 days after surgery and can inhibit the formation of adhesions. The formation of adhesions or the accumulation or inclusion of unwanted scar tissue complicates a variety of surgical procedures, as well as nearly all open or endoscopic abdominal or pelvic surgical procedures. In addition, the inclusion of surgical grafts complicates breast reconstruction, joint replacement, hernia repair, artificial vascular grafts, and neurosurgery. In either case, the graft reduces or weakens the function of the surgical graft (such as breast augmentation implants, artificial joints, surgical meshes, vascular grafts, dural patches) and is coated with fibrous connective tissue. . Chronic inflammation and scarring also occur during surgery, correcting for chronic sinusitis and removal of other chronic inflammatory sites (foreign, infected, fungal, mycobacteria, etc.). Surgical procedures that can lead to surgical adhesions include heart, spine, neuropathy, pleura, chest, gynecological surgery. However, adhesions can occur as a result of other treatments. This includes, but is not limited to, mechanical damage other than surgery, ischemia, bleeding, radiation therapy, infectious inflammation, pelvic inflammatory disease, and foreign body reaction. This abnormal scarring interferes with normal physiological functions, and in the case of coma may force or interfere with follow-up, correction, or other surgical procedures. For example, post-surgical surgical adhesions occur in 60-90% of patients undergoing major gynecological surgery and are one of the most common causes of intestinal obstruction in developed countries. Such adhesions are a major cause of surgical failure and are a major cause of bowel obstruction and infertility. Other adhesion treatment complications include chronic pelvic pain, urethral obstruction, and dysuria.

  Currently, prophylactic therapy is performed 4-5 days after surgery and is used to inhibit adhesion formation. As various methods for preventing adhesion, methods such as (1) prevention of fibrin accumulation, (2) reduction of local tissue inflammation, and (3) removal of fibrin accumulation were examined. Fibrin accumulation is prevented using a mechanical physical adhesion barrier or a physical adhesion barrier that includes an adhesive solution. Many investigators use anti-adhesion barriers, but there are many technical difficulties.

  In one embodiment, the present invention provides films and meshes with a subject polymer composition. The subject polymer composition includes an anti-scarring agent that has infiltrated adjacent tissue for use as a surgical adhesion barrier.

In one embodiment, films and meshes with a subject polymer composition that includes an anti-scarring agent infiltrated into adjacent tissue can be used to prevent surgical adhesions of epidural and dural tissue. The tissue can cause back surgery failures and complications associated with spinal injury (such as compression or crushing damage). The formation of scars within the dura and around the nerve root has resulted in technically more difficult movements of the spine. Vertebral tissue is frequently destroyed to allow access to the foramina during back surgery. Back surgery such as laminectomy and discectomy frequently exposes the spinal dura mater and remains unprotected. As a result, scar tissue is often formed between the dura mater and the surrounding tissue. This scar covers the laminectomy site,
Formed from damaged spine standing muscle. As a result, adhesion occurs between the muscular tissue and the weak dura mater, the mobility of the spine and nerve roots is reduced, pain occurs, and postoperative recovery is delayed. To prevent adhesion development, a scarring reduction barrier can be inserted between the dural sleeve and the paraspinal muscle tissue after laminectomy. This reduces the possibility of cells and blood vessels entering the dural space from overlapping muscles and exposed porous bones, and complications related to the canal that houses the spinal cord and / or nerve roots. decrease.

  In another aspect, use a film and mesh with a polymer composition of interest that includes a scarring inhibitor that has infiltrated adjacent tissue to prevent fibrosis between the hernia repair mesh and the surrounding tissue. it can. Hernias are abnormal processes in organs and other body tissues that protrude through capsules, muscles, bone defects or natural openings. The hernia itself is not dangerous, but an incarcerated hernia can be a major problem. Surgical prostheses (referred to herein as “hernia meshes”) used to repair hernias include mesh or gauze-like materials. The substance retains hernia and other body tissues that have been repaired during the healing process. Hernias are often repaired surgically to prevent infection. Medical conditions that require the use of a hernia mesh include inguinal hernia (ie, hernia at the thigh), umbilical hernia, abdominal wall hernia, femoral hernia, abdominal hernia, diaphragmatic hernia, upper abdominal wall hernia, gastroesophageal hernia, hiatal hernia Repairs such as, but not limited to, intermuscular hernia, mesenteric hernia, peritoneal hernia, rectal vaginal hernia, rectal hernia, uterine hernia and bladder hernia. Hernia repair usually involves returning the internal organs to their normal position, and wall defects are mainly closed by stitching, but if the hiatus is large, a mesh is placed over the defect to position the hernia opening. close. Infiltrating the tissue adjacent to the hernia repair mesh with the subject polymer composition containing the anti-scarring agent may reduce or prevent fibrosis adjacent to the implanted hernia mesh, and the abdominal wall and other tissues. The possibility of adhesion between the mesh and the mesh can be minimized, and further complications and abdominal pain can be reduced.

  In another aspect, the film or mesh infiltrated into adjacent tissue with the subject polymer composition containing an anti-scarring agent may have hypertrophic scars or keloids (such as those caused by tissue burns or other wounds). Sometimes used to prevent. Hypertrophic scars and keloids are the result of an excessive fibroproliferative healing response to the wound. Briefly, wound healing and scar formation occur in three stages: inflammation, proliferation, and maturation. The first stage, inflammation, occurs in response to trauma that is severe enough to damage the skin. In this stage, lasting 3-4 days, blood and tissue fluids form an adhesive coagulation and fibrinous network that serves to join the wound surfaces together. This is followed by a proliferative phase in which there is ingrowth of capillaries and connective tissue from the wound edge and closure of skin defects. Finally, after the growth of capillaries and fibroblasts, the maturation process begins, the scar contracts, the cellularity and vascularity decrease, and becomes flat and white. This last stage can take 6-12 months. If the connective tissue is excessively formed and the wound cellularity remains persistent, the scar will turn red and bulge. When the scar stays within the boundaries of the original wound, it is called a hypertrophic scar, but when the scar extends beyond the original scar to the surrounding tissue, this lesion is called a keloid. Hypertrophic scars and keloids are formed in the second and third stages of scar formation. Some wounds are particularly prone to excessive endothelial and fibroblast proliferation, including burns, open wounds, and infected wounds. In hypertrophic scars, a degree of maturation occurs and a gradual recovery occurs. However, in the case of keloids, an actual tumor is formed, which can be quite large. In these cases, natural improvements rarely occur. Films or meshes infiltrated into adjacent tissues with the target polymer composition containing a scarring inhibitor can be placed in contact with the wound or burn site to prevent hypertrophic scars and keloids.

  In yet another aspect, films and meshes infiltrating adjacent tissue with a subject polymer composition comprising an anti-scarring agent are used to deliver the anti-scarring agent to the exterior (surface) of a body passage or cavity. Sometimes. Arteries, veins, heart, esophagus, stomach, duodenum, small intestine, large intestine, bile duct, ureter, bladder, urethra, lacrimal duct, trachea, bronchi, bronchial treetop, nasal respiratory tube, ear canal, ear canal , Vas deferens and fallopian tube. Examples of cavities include the abdominal cavity, buccal oral cavity, abdominal cavity, pericardial cavity, pelvic cavity, internal peripheral cavity, thoracic cavity and uterine cavity.

  Symptoms treated or blocked using films and meshes infiltrating adjacent tissues with the subject polymer composition containing an anti-scarring agent include iatrogenic complications of arterial and venous catheterization, complications of vascular incision , Gastrointestinal tract rupture and incision complications, restenosis complications associated with vascular surgery (such as bypass surgery), and intimal proliferation.

  In one embodiment, the anti-scarring agent may be delivered from the subject polymer composition infiltrated into tissue adjacent to the film or mesh to the passageway in the body or the outer wall of the cavity. This is intended to prevent and / or reduce biological proliferative responses that may interfere with or inhibit the optimal functioning of the passageway and cavity. These include iatrogenic complications from arterial and venous catheterization, aortic incision, heart rupture, aneurysm, cardia valve tear, graft placement (AV bypass, peripheral bypass, CABG, etc.), fistula Includes formation, passage rupture, and surgical wound repair.

  The film or mesh can be used in the form of a perivascular wrap to prevent restenosis at the anastomotic site that results from the insertion of a vascular graft or hemodialysis access device. In this case, the perivascular wrap in which the target polymer composition containing a scarring inhibitor is infiltrated into the adjacent tissue can be used in combination with the vascular graft in order to inhibit scarring at the anastomosis site. These films or mesh materials can be placed or wrapped in a perivascular (perivascular) manner near the outside of the anastomosis during surgery. Film and mesh grafts infiltrated adjacent tissues with the polymer composition of interest containing an anti-scarring agent include synthetic bypass grafts (femoral popliteal, interfemoral, axillary thigh, etc.), vein grafts (peripheral and coronal) ), Internal breast (coronary) graft or hemodialysis graft (pulmonary arteriovenous fistula, arteriovenous access graft).

  In order to further understand these symptoms, typical complications that lead to abnormalities in the body passages or cavities are described in detail below.

  In one embodiment, the subject polymer composition can invade tissue adjacent to a coronary artery bypass graft (CABG). The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  In one embodiment, the subject polymer composition can infiltrate the tissue surrounding the peripheral bypass surgical site. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  In one embodiment, the subject polymer composition can invade tissue adjacent to the arteriovenous fistula. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  In one embodiment, the subject polymer composition can infiltrate the tissue surrounding the peripheral bypass surgical site. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  In one embodiment, the subject polymer composition can invade tissue adjacent to the anastomotic closure device. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  In one embodiment, the subject polymer composition can infiltrate tissue adjacent to the surgical site for implantation. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  According to one embodiment, the anti-scarring agents described above can be used in the practice of the present invention. In one embodiment of the invention, the subject polymer composition infiltrated into the tissue adjacent to the film and mesh inhibits one or more of the four general elements in the process of fibrosis (or scarring) including: Can be adapted to contain and / or release drugs: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), accumulation of extracellular matrix (ECM) And reformation (maturation and organization of fibrous tissue).

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (such as simvastatin), (G) inosine monophosphate dehydrogenase inhibitors (such as mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ ), (H) NFκB inhibitors (such as Bay11-7082), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Since films and meshes are made in a variety of shapes and sizes, the exact dose administered will depend on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Agent is the target of the device or per unit area scarring inhibitor administration of tissue surface coating (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm 2, or it may be about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplanted or tissue surface of the subject to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² Or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

Glaucoma drainage device In one embodiment, the subject polymer composition can infiltrate tissue adjacent to the glaucoma drainage device. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  Various types of glaucoma drainage devices can be used in the practice of this aspect. Some glaucoma drainage devices include plates and tubes. The function of the tube is to deliver an aqueous liquid from within the eye to the upper surface of the scleral plate. The scleral plate is securely sutured to the sclera and covered with a thick Tenon tissue flap and conjunctiva. The function of the plate is to form a large circular bleb. The bleb develops a bleb inner layer consisting of special fibrous and vascular tissue and is inflated with a watery liquid. This vascular bleb lining controls the leakage of aqueous fluid from the eye and determines the final level of intraocular pressure (IOP) achieved after insertion of the graft. If the vascular response is too great, the drainage capability of the device is reduced. In one embodiment of the invention, the polymer composition comprising the fibrosis inhibitor is adjacent to the entire device or a portion of the device so that the released fibrosis inhibitor modulates the healing response and the device functions properly. Infiltrated into tissue. In another aspect of the invention, a polymer composition comprising an anti-infective agent (alone or in combination with a fibrosis inhibitor) is used for the entire device or part of the device so that the released anti-infective agent inhibits or prevents infection. Infiltrate the tissue adjacent to the part.

  A glaucoma drainage device may be, for example, a conduit attached to a scleral drainage plate. The plate has a porous rear end surface for cell ingrowth and scleral adhesion. See US Pat. No. 5,882,327. The glaucoma drainage device is composed of a foldable and rotatable scleral plate and a drainage tube and can be delivered to the implantation site by an injection delivery system. See US Pat. No. 6,589,203. A glaucoma drainage device may be a pressure regulator having a mounting housing made of a thin and flexible base material made of a rubber material (such as silicone rubber) and attached to a tube. See US Pat. No. 5,752,928. A glaucoma drainage device can consist of an elastomeric plate with a sealing element that fits into the sclera to restrict the secretions, and is fitted with an elastomer drainage tube without a valve. See US Pat. No. 5,476,445. The glaucoma drainage device can consist of a plate that is raised and extends outward. The plate is adapted to dent on one side to conform to the curvature of the sclera and attach side by side with the sclera, and a communication tube extends between the raised plates. See U.S. Pat. No. 4,457,757. The glaucoma drainage device can consist of a thin elliptical elastomeric plate. The plate has a central hole for scar tissue growth and an elastomer drainage tube attached to allow fluid transfer to the eye. See U.S. Pat. No. 5,397,300. The glaucoma drainage device can be composed of a tube with an outer peripheral hole. A disk is connected to the outlet of the tube for placement on the eyeball surface. See US Pat. No. 5,868,697. The glaucoma drainage device can be composed of a tube having a flow control structure. The structure suppresses the movement of fluid in the tube, and there is at least one outer peripheral hole in the tube that is temporarily blocked by an absorbent material. See US Pat. No. 6,203,513. The glaucoma drainage device can be composed of a tube having a fixing means and having a porous plug that absorbs liquid. Filamentous extensions are attached that significantly restrict the flow of liquid. See US Pat. No. 5,300,020. The glaucoma drainage device may be an elastic polymer drain implant. The graft has a conduit extending between the ends and a flange projecting radially from the body. See U.S. Pat. No. 4,968,296. The glaucoma drainage device may be a shunt that diverts the aqueous humor in the eye from the anterior chamber to the part of the branching device that transfers fluid in either direction along the Schlemm's canal. See US Pat. No. 6,626,858.

  Glaucoma drainage devices that can be combined with one or more anti-scarring agents according to the present invention include commercially available products. For example, cylindrical tubes such as the Aquaflow Collagen Glaucoma Drainage Device (STAAR Surgical Company, Monrovia, Calif.) Can be used in the practice of the present invention. Examples of other glaucoma drainage devices include Molteno glaucoma grafts (single plate Molteno grafts, pressure ridge single plate Morteno grafts (D1), microplate Molteno grafts (M1), double plate Molteno grafts (R2 / L2), and Pressure Ridge Double Play Molteno graft (DR2 / DL2), MoltenoOpthalmic Limited (New Zealand), BAERVELDT glaucoma grafts (models BG-101-350, BG-102-350, BG-103-250) , Pfizer (New York, NY)), and Ahmed glaucoma valves (models FP7, S2, S3, PS2, PS3, B1, NewWorld Medical, Inc. (Rancho Cucamonga, Calif.)).

  In one aspect, the present invention provides a glaucoma drainage device in which the subject polymer composition is infiltrated into adjacent tissue. The polymer composition may include a therapeutic agent (a scarring inhibitor and / or an anti-infective agent). A number of polymeric and non-polymeric delivery systems for use in glaucoma drainage devices have already been described above.

  The polymer composition can be applied to (a) tissue adjacent to the glaucoma drainage device, (b) around the interface between the glaucoma drainage device and the tissue, (c) a site around the glaucoma drainage device, and (d) tissue around the glaucoma drainage device. Direct and / or indirect application can infiltrate the implanted glaucoma drainage device. Methods of infiltrating a subject polymer composition into tissue adjacent to a glaucoma drainage device include delivery of the polymer composition to: (a) on the surface of the glaucoma drainage device (eg as infusion material, paste, gel or mesh) during the implantation procedure, (b) on the tissue surface (eg infusion material, infusion material, just before or during implantation of the glaucoma drainage device) (C) Immediately after implantation of the glaucoma drainage device, and / or the tissue around the implanted glaucoma drainage device (eg injection material, paste) (D) Topical application of the composition to the anatomical space where the glaucoma drainage device is placed on the surface of the gel, gel or mesh formed in situ (particularly useful in this example is from a few hours The use of polymeric carriers that release therapeutic agents over a period of several weeks-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, , Microparticles, sprays, aerosols, solid implants and other formulations that release the drug and can be delivered to the site where the device is inserted), (e) solutions, infusions, and gradual solutions to the tissue surrounding the glaucoma drainage device Application by intradermal injection of a releasable formulation and / or (f) a combination of the methods described above. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the polymer composition of interest can infiltrate the entire device or some surrounding tissue.

  In one embodiment, the above method can be used to infiltrate the subject polymer composition into tissue adjacent to the entire plate of the device or a portion thereof.

  In another aspect, the method described above can be used to infiltrate the subject polymer composition into tissue adjacent to the entire device tube or a portion thereof.

  In yet another aspect, the above-described method can be used to infiltrate the subject polymer composition into tissue adjacent to all or part of both the plate and tube of the device.

In accordance with the present invention, any of the fiber formation inhibitors and / or anti-infectives described above can be utilized in the practice of the present invention. In one embodiment of the invention, the subject polymer composition infiltrated into tissue adjacent to the glaucoma drainage device inhibits one or more of the four general factors for the fibrosis (or scarring) process comprising: Can be adapted to release: new blood vessel formation (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) accumulation, and remodeling (Maturation and organization of fibrous tissue). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth. Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (such as simvastatin), (G) inosine monophosphate dehydrogenase inhibitors (such as mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ ), (H) NFκB inhibitors (such as Bay11-7082), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Also, because glaucoma drainage devices are manufactured in a variety of shapes and sizes, the exact dose to be administered depends on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fibrosis inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Agent is the target of the device or per unit area scarring inhibitor administration of tissue surface coating (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm 2, or it may be about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplanted or tissue surface of the subject to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² Or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

Prosthetic Heart Valve In one embodiment, the subject polymer composition can infiltrate tissue adjacent to the prosthetic heart valve. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  A prosthetic heart valve is a device used to replace a defective natural heart valve due to congenital malformations or infection, partial obstruction, or wear. Prosthetic heart valves typically consist of an occluder attached to the base of the occluder. The base is attached to a suture ring that secures the device to the heart tissue. The base of the occluder is annular and provides a blood flow path. One or more occluders may alternately open and close to control blood flow. To secure the prosthetic heart valve to the heart tissue, a suture ring (usually composed of a knitted tube) is rolled into a donut shape and secured around the base of the prosthetic heart valve occluder. The fixation of the suture ring to the heart tissue is usually performed by using sutures, sealants, adhesives, staples, or tightening with a metal or polymer wire.

  Although the design of prosthetic heart valves has been improved gradually, complications continue to occur. Because suture rings are often made of synthetic materials, thrombosis, fibrosis, and pannus frequently occur around prosthetic heart valves. This scarring frequently interferes with the function of the heart valve and may require a second surgical procedure and replacement over time. The suture ring is usually composed of a synthetic polymer, including but not limited to polyester (such as Dacron), polytetrafluoroethylene (such as Teflon), silicone, polypropylene, and the like. The suture ring is often made of a filler, which is woven with a woven material. The surface of the suture ring is covered with a cloth material and rough. For this reason, the suture ring tends to form scarring at an early stage after surgery, and severe pannus and fibrosis develop in the months after transplantation. The consequences of fibrosis invading the prosthetic heart valve are enormous and can lead to tragic consequences. For example, fibrosis may impede its function by limiting the proper opening and closing of the heart valve occluder. Fibrosis can extend from the suture ring to the valve membrane. Such fibrosis fuses the valve membrane at the joint, deforms the individual valve membranes, or stiffens the valve membranes, so that they cannot be opened and closed properly. As a result of such fibrosis, the heart valve usually becomes stenotic and does not function sufficiently. The prosthetic heart valve is also a source of infection around the implantation site.

  There are two types of prosthetic heart valves: mechanical and biological prosthetic. In general, both mechanical and biological prosthetic heart valves use synthetic suture rings. The difference between the two is mainly the type of occluder used. The mechanical prosthetic heart valve occluder consists of a ball and cage assembly, a single valve disc valve, or a double valve disc valve. Biological prosthetic heart valve occluders are composed of animal or human tissue that looks and functions similar to the natural heart valve to be replaced. The leaflets of biological prosthetic heart valves usually consist of chemically processed tissue. The harvested valve is fixed with glutaraldehyde or similar fixative to make it suitable for human implantation.

  In one embodiment, a prosthetic heart valve is a mechanical prosthesis that typically consists of a hard valve membrane made of a biologically compatible material (pyrolytic carbon, titanium, Dacron, etc.). The mechanical prosthetic heart valve can be a ball and cage assembly, a double leaflet, a triple leaflet, or a tilted disc. The most common is the double valve membrane. This is because the hemodynamics of this valve is better, and the blood flow is smoother and less rough. For example, a mechanical prosthetic heart valve can be constructed with a base with an external suture ring and an internal rim and at least two closure valve membranes for blood flow. See US Pat. No. 6,068,657. The mechanical prosthesis may consist of an annular valve housing with an opening in the center, and the first and second valve valve membranes may be attached to the center of the valve housing. See the following US patent number. Nos. 4,808,180 and 5,026,391. Mechanical prostheses may be designed in an annular shape with at least one leaflet attached centrally. The valve membrane can be opened and closed by a magnet that applies force to the valve membrane at a predetermined pressure. See US Pat. No. 6,638,303. The mechanical prosthesis may have an annular shape with a plurality of hinges. The hinge forms an inlet ramp and assists at least one valve membrane relative to the valve body. See U.S. Patent Nos. 6,645,244 and 5,919,226. A mechanical prosthesis can consist of a flexible cylindrical support frame, a cover forming a tip support stent for a valve triple valve device, and a sewing ring as an attachment surface. See US Pat. No. 5,258,023. The mechanical prosthesis has an increased valve lumen consisting of a single valve opening housing. The housing has at least one movable occluder associated with the housing and a suture cuff to attach the housing to heart tissue. See U.S. Patent Nos. 6,007,577 and 6,391,053. The mechanical prosthesis can be comprised of a sewing ring and a removable valve assembly that slides into the core of the ring. See US Pat. No. 5,032,128. The mechanical prosthesis may be a very flexible cylindrical stent. The stent is composed of a plurality of stent members adjacent to each other. The tip and the joint are alternately arranged, and the stent moves in a radial direction to assist a large number of flexible valve membranes. See the following US patent number. 6,558,418 and 6,338,740. Other mechanical prosthetic heart valves are described in US Pat. Nos. 6,395,025, 6,358,278, 6,176,877, 6,139,575 and 5,984,958.

  In another aspect, the prosthetic heart valve is a biological device, typically a flexible valve made of biological material (such as a porcine valve or a bovine pericardial valve). The tissue valve can be assisted with a stent frame that provides greater valvular structure and durability. A porcine valve with the porcine aorta attached can also be harvested to implant a tissue valve without a stent. For example, biological prosthetic heart valves can be obtained from donors (such as pigs) and processed to reduce antigen to prevent post-transplant inflammatory responses. See US Pat. No. 6,592,618. A biological prosthetic heart valve can be composed of biological tissue material disposed around a mechanical annular support to provide at least a portion of the sewing ring. See US Pat. No. 6,582,464. Biological prosthetic heart valves can consist of a xenograft mitral valve (such as a pig) and a sewing tube, a cover of flexible material attached to the mitral stool. See US Pat. No. 5,662,704. Biological prosthetic heart valves can consist of natural heart tissue attached to a prosthetic stent frame covered with a fabric cover. See the following US patent number. 3,983,581, 4,035,849, 5,861,028, 6,350,282 and 6,585,766. Biological prosthetic heart valves may be free standing stentless valves. The self-supporting valve can be composed of a tubular portion originating from a mammal. See the following US patent number. Nos. 5,156,621 and 6,342,070.

  In another aspect, the prosthetic heart valve can be inserted in place using minimally invasive techniques. For example, a prosthetic heart valve is an expandable device that is adapted to be delivered to an implantation site in a debilitated state and can be expanded to a number of leaflets attached to a stent system. See US Pat. No. 6,454,799.

  In another aspect, the device may be a component of a heart valve. For example, the device is an implantable annular ring that receives a prosthetic heart valve. See US Pat. No. 6,106,550. The device may be a suture ring with a tapered peripheral thread for attaching a prosthetic heart valve. See US Pat. No. 6,113,632 and the like. The device may be a mechanical heart valve suture ring composed of a reinforcing ring attachment, a knitting sewing cuff, and a fixation ring. See US Pat. No. 5,071,431.

  Prosthetic heart valves and their components (such as annulus) can be combined with one or more drugs according to the present invention, including the Carpentier-Edwards PERIMOUNT (CEP) pericardial biovalve, Carpentier-Edwards SAV aortic bioprosthesis and Edwards PRIMA PLUS STENTLESS BIOPROSTHESIS (Edwards Lifesciences, Irvine, Calif.), SJM REGENT valve (St. Jude Medical, St. Paul, Minn.), And MOSAIC bioprosthetic heart valve (Medtronic, Minneapolis, MN) And other commercial products.

  In another aspect, the present invention provides a prosthetic heart valve in which adjacent tissue is infiltrated with the subject polymer composition. The polymer composition includes a therapeutic agent (such as an anti-scarring agent and / or an anti-infective agent). A number of polymeric and non-polymeric delivery systems for use in prosthetic heart valves have already been described above.

  The polymer composition is applied to (a) the tissue adjacent to the prosthetic heart valve, (b) around the interface between the prosthetic heart valve and the tissue, (c) the site around the prosthetic heart valve, and (d) the tissue around the prosthetic heart valve. Application directly and / or indirectly can infiltrate around the implanted prosthetic heart valve. A method of infiltrating a tissue adjacent to a prosthetic heart valve with a subject polymer composition includes delivery of the polymer composition to: (a) on the surface of a prosthetic heart valve (eg, as an infusion material, paste, gel or mesh) during the implantation procedure, and (b) the tissue surface (eg, infusion material, just before or during implantation of the prosthetic heart valve). (C) immediately after implantation of the prosthetic heart valve, and / or tissue around the implanted prosthetic heart valve (eg, injection material, paste) (D) Topical application of the composition to the surface of the anatomical space where the prosthetic heart valve is placed (especially useful in this example from several hours The use of polymeric carriers that release therapeutic agents over a period of several weeks-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants, and Drug Other formulations that can be delivered to the site where the dispensing device is inserted), (e) by intradermal injection of solutions, infusions, and sustained release formulations into the tissue surrounding the prosthetic heart valve, and / or (f) Application by a combination of methods. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the subject polymer composition can be wetted to the entire device or to some surrounding tissue.

  In some embodiments, the subject polymer composition can invade the tissue adjacent to: (a) Annular ring surface (especially for mechanical prosthetic heart valves), (b) Valve surface (especially for biological prosthetic heart valves), and / or (c) a combination of the above.

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the present invention, the subject polymer composition infiltrated into tissue adjacent to a prosthetic heart valve inhibits one or more of the four general factors for the process of fiber formation (or scarring) comprising: Can be adapted to release: new blood vessel formation (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) accumulation, and remodeling (Maturation and organization of fibrous tissue). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (such as simvastatin), (G) inosine monophosphate dehydrogenase inhibitors (such as mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ ), (H) NFκB inhibitors (such as Bay11-7082), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Since prosthetic heart valves are manufactured in a variety of shapes and sizes, the exact dose administered depends on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Agent is the target of the device or per unit area scarring inhibitor administration of tissue surface coating (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm 2, or it may be about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplanted or tissue surface of the subject to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² Or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

Penis Graft In one embodiment, the subject polymer composition can invade tissue adjacent to the penis graft device. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents). In one embodiment, the subject polymer composition infiltrated into tissue adjacent to the penile implant is loaded with a scarring inhibitor to prevent fiber coating. In another embodiment, the subject polymer composition infiltrated into the tissue adjacent to the penile graft is loaded with an anti-infective agent (alone or in combination with an anti-scarring agent) to prevent fiber infection and / or coating. To do.

  Penile grafts are used to treat erectile dysfunction and are usually flexible rods, hinged rods, or devices with pumps that can be inflated. Penile implants consist of rods, coils, inflatable tubes and / or pressure chambers, and can be used to provide erectile function, expand, deform or deform a damaged penis. For example, penile grafts are implantable polymeric materials that can be injected into the lamina propria of the glans to enlarge the male genital glans. See US Pat. No. 6,418,934. The penile implant can be composed of a pair of elongated, arched silicone rubbers. This is symmetrical, and the thickness of the outer peripheral wall is different. See US Pat. No. 6,537,204. Penis implants can be used to increase penis volume. This is done by covering and adapting the outer sides without covering the upper and lower parts of the corpus cavernosum. See US Pat. No. 6,015,380. The penile graft may be a self-contained graft that can be inflated. The implant includes a cylindrical main portion with a pump that moves liquid from a storage organ to a pressure chamber (with a pressure relief valve). See U.S. Pat. Nos. 4,898,158 and 4,823,779. Penile implants can consist of stretched bars with a relatively short backbone. The backbone includes a number of openings and is covered with a layer of hydrophilic material that expands upon absorbing moisture. See U.S. Pat. No. 4,611,584. The penile graft can consist of at least one tube that can be inflated. The tube exchanges fluid with a mounting base controlled by a manual pump implanted in the scrotum. See US Pat. No. 6,475,137. The penile implant may be a double-walled sleeve that is flexible and partially cylindrical. The sleeve is structured like a bellows to suit penile malformations. See US Pat. No. 5,669,870. Penis implants can be used to correct inability to erect. In this case, at least one flexible main part is included which has a pressure chamber connected by a tube to a reservoir containing liquid so that the flow of bodily fluid is pressurized when the valve is opened. See U.S. Pat. No. 4,917,110. A penile implant may consist of a stainless steel pad assisted by a number of filaments. The pad is surrounded by a cylinder with a silicone ring that moves vertically in response to penile dilation or contraction. See U.S. Pat. No. 5,433,694. The penis graft can be increased in outer circumference and length by comprising a cylindrical sleeve with a stretchable outer sheet and a non-stretchable inner sheet. The inner sheet receives pressure from a body fluid source to form a closed fluid sac that receives the body fluid. See US Pat. No. 5,445,594. The penile implant may be composed of a braided sleeve having an outer elastomeric surface and an inner surface. The inner surface has helical grooves and folds so that the implant has a bendable configuration and a non-bent fixed configuration and remains adaptable. See US Pat. No. 5,512,033. The penile implant is composed of a polymeric matrix and can have isolated chondrogenic cells deposited on the matrix. Cartilage structures are formed after implantation and have controlled biomechanical properties and tension. See US Pat. No. 6,547,719. The penile implant can be composed of an implantable delivery pump, a deformable reservoir, and a conductor / distribution catheter such that a vasodilator is delivered to the erection site to treat impotence. See US Pat. No. 6,679,832. Other penile grafts are described in the following US patents. Nos. 6,579,230, 5,704,895, 5,250,020, 5,048,510 and 4,875,472.

  The fiber forming agent can be incorporated within, near, or near the device. Penis implants that can be combined with one or more agents in accordance with the present invention include, for example, TITAN Inflatable Penile Prosthesis (Mentor Corporation, Santa Barbara, Calif.), And AMS700 CX CXM, Commercial products such as AMS AMBICOR and AMS artificial penis product line (American Medical Systems, Inc., Minnetonka, MN) including artificial penis such as AMS Malleable 600M are included.

  In one embodiment, the present invention provides a penile transplant device in which a subject polymer composition is infiltrated into adjacent tissue, the subject polymer composition comprising a therapeutic agent (an anti-scarring agent and / or an anti-infective agent). A number of polymeric or non-polymeric delivery systems have been described above in the use of penile grafts.

  The polymer composition is applied to (a) the tissue adjacent to the penis graft, (b) around the interface between the penis graft and tissue, (c) the area around the penis graft, and (d) the tissue around the penis graft. Application directly and / or indirectly can infiltrate around the implanted penile graft. Methods for infiltrating a subject polymer composition into tissue adjacent to a penile implant include delivery of the polymer composition to: (a) on the surface of the penis graft (eg as injection material, paste, gel or mesh) during the transplantation procedure; (b) on the tissue surface (eg injection material, (C) Immediately after transplanting the penis graft, and / or the tissue surrounding the transplanted penis graft (eg, injection material, paste) (D) Topical application of the composition to the anatomical space in which the penile implant is placed (especially useful in this example from a few hours) The use of polymeric carriers that release therapeutic agents over a period of several weeks-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants, and Drug Other formulations that can be delivered to the site where the dispensing device is inserted), (e) by intradermal injection of solutions, infusions, and sustained release formulations into the tissue surrounding the penile graft and / or (f) Application by a combination of methods. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the subject polymer composition can be wetted to the entire device or to some surrounding tissue.

  Penile graft placement can be complicated by coagulase-negative staphylococcal infections (including Staphylococcus epidermidis), staphylococcus aureus, Pseudomonas aeruginosa, enterococci, Serratia, and Candida (usually first after surgery) For 6 months). Infection is characterized by fever, erythema, induration, and drainage from the surgical site. The common route of infection is an incision at the time of surgery, and infection occurs with up to 3% penile transplants using the best sterile surgical technique. To deal with this, surgical cleaning with antibiotic solutions is frequently performed.

  When a polymer composition containing an anti-infective agent is infiltrated into tissue adjacent to a penile graft, it achieves a level of bactericide locally and the incidence of bacterial transplantation (and consequently local infection and device failure) And systemic exposure to drugs is negligible.

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the present invention, a subject polymer composition infiltrated into tissue adjacent to a penile implant inhibits one or more of four general factors for the process of fibrosis (or scarring) including: Can be adapted to release drugs: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), accumulation of extracellular matrix (ECM), and regeneration Formation (maturation and organization of fibrous tissue). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (such as simvastatin), (G) inosine monophosphate dehydrogenase inhibitors (such as mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ ), (H) NFκB inhibitors (such as Bay11-7082), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Because penile implants are manufactured in a variety of shapes and sizes, the exact dose administered depends on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Agent is the target of the device or per unit area scarring inhibitor administration of tissue surface coating (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm 2, or it may be about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplanted or tissue surface of the subject to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² Or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

Endotracheal Tube and Tracheal Cannula In one embodiment, the subject polymer composition can invade tissue adjacent to the endotracheal tube and tracheal cannula device. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents). The combination of an anti-scarring agent with an endotracheal or tracheal cannula (such as a chest tube) or adjacent tissue can be used to prevent stenosis and / or infection of the artificial airway.

  Endotracheal tubes and tracheal cannulas are used to maintain the airway when respiratory assistance is needed. Endotracheal tubes tend to be used to secure the airway in the acute case, and the tracheal cannula is used when long-term ventilation is required or when the upper airway is obstructed.

  In one embodiment, the endotracheal tube can be used to provide a mechanical air passage when needed for lung ventilation during injury or surgery. Endotracheal tubes have a single or double lumen and are equipped with a flange or balloon to fix the position within the trachea. For example, the endotracheal tube can be composed of flexible inner and outer tubes. The tube is provided with a radially extending flange so as not to go beyond the larynx. See US Pat. No. 5,259,371. The endotracheal tube may have a double lumen secured for removal. The first lumen can be removed from the airway, while the second lumen remains in place. See US Pat. No. 6,443,156. An endotracheal tube has a tracheal portion and a bronchial portion, and can be attached at an angle to form a single lumen. When the balloon placed in the tube is inflated, this impedes gas flow to the bronchial portion. See US Pat. No. 6,609,521. The endotracheal tube can be made up of two cylindrical parts with different diameters connected by a non-circular tapered part to assist the glottis. The connecting portion is provided with a number of thin and flexible sealing gils extending from the tapered portion. See US Pat. No. 5,429,127. The endotracheal tube can be composed of a tubular portion with a visual indicator. This is for instructing the rotational orientation of the distal end, which is inclined along the airway, at the end of the bevel. See US Pat. No. 6,568,393. The endotracheal tube may have an inner diameter that is coated with a light reflective material to facilitate image transmission. There are also a number of flexible conduits, one adapted to receive a fiber optic bundle and another connected to a cuff that can be inflated. Another conduit is adapted to accept a flexible stylet to assist in insertion and removal. See US Pat. No. 6,629,924. The endotracheal tube can be composed of a flexible hollow cylindrical tube. The tube has an annular flange at the tip and a connector with an annular internal ridge attached concentrically to the base surface outside the tube. See US Pat. No. 5,251,617. The endotracheal tube can consist of a main tube with a cuff that can be inflated for sealing. The tube is equipped with a double lumen for irrigation and an inhalation tube for removing secretions that may accumulate in the trachea. See US Pat. No. 5,143,062. Other endotracheal tubes are described in the following US patents. Nos. 6,321,749, 5,765,559, 5,353,787, 5,291,882 and 4,977,894.

  An endotracheal tube can be used to bypass and supply air when the throat is blocked. A tracheal cannula is used in conjunction with an obturator for percutaneous insertion into the trachea from the fistula of the neck between adjacent cartilages for the purpose of assisting breathing. For example, the tracheal cannula may be a tubular cannula made of a soft plastic material. The tapered end is beveled and angled and curved downward so that it can be fixed in the trachea. See US Pat. No. 5,058,580. A tracheal cannula can consist of a tube attached to the exposed end (which can be sealed to the tube) of a removable instrument. See US Pat. No. 5,606,966. The tracheal cannula can be comprised of an arcuate cannula with a laterally outwardly extending flange and a tubular elbow joint that is rotatable and connects fluid to the cannula. See the following US patent number. Nos. 5,259,376 and 5,054,482. A tracheal cannula can consist of two airways with air vibrators. The vibrator generates a sonic vibration so that sound can be heard. See U.S. Pat. No. 4,773,412. The tracheal cannula can consist of a removable internal cannula. The cannula is between the outer cannula and the trachea and is received within the outer cannula with a sealing cuff. This can greatly prevent leakage of air from the trachea and allow it to be generated by the second passage formed between the inner and outer cannulas. See U.S. Pat. No. 4,573,460. The tracheal cannula consists of a first port for adjustment outside the wearer's neck, a second port for adjustment inside the trachea, and a third connection port that provides and controls the flow of gas through the valve can do. See US Pat. No. 5,957,978. The tracheal cannula can consist of a hollow tube, an inflatable balloon (with an orthogonal ridge), and a flange that is used for fixation outside the throat. See US Pat. No. 6,612,305. The tracheal cannula can consist of a very flexible material with wire reinforcement and a neck plate with a collar that can slide along the tube. See US Pat. No. 5,443,064. Other tracheal cannulas are described in the following US patents and the like. Nos. 6,662,804, 6,135,110 and 5,983,895.

  Endotracheal tubes can be combined with one or more agents in accordance with the present invention, including HI-LO tracheal tubes, LASER-FLEX tracheal tubes, and ENDOTROL trachea (Nellcor Puritan Bennett Inc. (Pleasanton, Calif.)). )), SHERIDAN endotracheal tube (Hudson RCI (Temecula, CA)), and cuffed BARD endotracheal tube (CRBard, Inc. (Murray Hill, NJ)).

  A tracheal cannula can be combined with one or more agents in accordance with the present invention, including SHILEY TRACHEOSOFT XLT tracheal cannula, PHONATE vocalization valve, and reusable cannula caffres tracheal cannula (NellcorPuritan Bennett Inc. (California Pleasanton, USA), PER-FIT percutaneous dilatation tracheal opening kit, PORTEX BLUE LINE cuff tracheal cannula, and BIVONA cuffless tracheal cannula (Portex, Inc. (Kean, NH)) and CRYSTALCLEAR tracheal cannula ( There are commercial products such as Rusch (Germany).

  In one aspect, the invention provides an endotracheal tube and tracheal cannula device comprising a subject polymer composition infiltrated into adjacent tissue, the polymer composition comprising a therapeutic agent (an anti-scarring agent and / or an anti-infective agent). Etc.). A number of polymeric and non-polymeric delivery systems for use in endotracheal tubes and tracheal cannula devices have already been described above.

  The polymer composition comprises (a) tissue adjacent to the endotracheal tube or tracheal cannula device, (b) around the interface of the endotracheal tube or tracheal cannula device and tissue, (c) a site around the endotracheal tube or tracheal cannula device. (D) can infiltrate around the implanted endotracheal tube and tracheal cannula device by applying directly and / or indirectly to the tissue surrounding the endotracheal tube or tracheal cannula device. Methods for infiltrating a subject polymer composition into tissue adjacent to an endotracheal tube or tracheal cannula device include delivery of the polymer composition to: (b) during or immediately before or during implantation of the endotracheal tube or tracheal cannula device on the surface of the endotracheal tube or tracheal cannula device during the implantation procedure (eg, as infusate, paste, gel or mesh), (C) Immediately after implantation of the endotracheal tube or tracheal cannula device and / or on the tissue surface (eg as infusion material, paste, gel, in situ formed gel or mesh) (D) The endotracheal tube or tracheal cannula device is placed on the surface of the tissue around the implanted endotracheal tube or tracheal cannula device (eg, injectable material, paste, gel, gel or mesh formed in situ) Topical application of the composition to an anatomical space (especially useful in this example is healing over a period of hours to weeks). The use of polymeric carriers that release therapeutics-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants, and drug release and device insertion Other formulations that can be delivered to the site to be delivered), (e) by intradermal injection of solutions, infusions, and sustained release formulations into the tissue surrounding the endotracheal tube or tracheal cannula device and / or (f) Application by a combination of methods. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the subject polymer composition can be wetted to the entire device or to some surrounding tissue.

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the invention, the subject polymer composition infiltrated into tissue adjacent to the endotracheal tube and tracheal cannula device is one or more of four general elements for the process of fiber formation (or scarring) comprising: Can be adapted to release drugs that inhibit: new blood vessel formation (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), accumulation of extracellular matrix (ECM) And reformation (maturation and organization of fibrous tissue). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (such as simvastatin), (G) inosine monophosphate dehydrogenase inhibitors (such as mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ ), (H) NFκB inhibitors (such as Bay11-7082), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Because endotracheal and tracheal cannula devices are fabricated in a variety of shapes and sizes, the exact dose to be administered depends on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Agent is the target of the device or per unit area scarring inhibitor administration of tissue surface coating (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm 2, or it may be about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplanted or tissue surface of the subject to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² Or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

Peritoneal Dialysis Catheter In one embodiment, the subject polymer composition can invade tissue adjacent to the peritoneal dialysis catheter or peritoneal graft to deliver the drug. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  Peritoneal dialysis catheters are typically tunnel-like catheters with double cuffs that provide access to the peritoneum. The most common peritoneal dialysis catheter designs are the Tenchkhoff catheter, the Swan Neck Missouri catheter, and the Toronto Western catheter. In peritoneal dialysis, the peritoneum acts as a semipermeable membrane and the solute can be exchanged for a lower concentration gradient. Continuous peritoneal access catheters are permanently implanted in patients who need repeated access to the peritoneum. Implanted peritoneal catheters can be used for peritoneal dialysis or as a means of delivering drugs to the peritoneum. Such catheters can be constructed of synthetic materials such as silicone, rubber, polyurethane, and other polymers that provide flexibility. The catheter can be designed as a straight tube, or bent or molded into various shapes to have different shapes (such as spirals or coils). The peritoneal catheter can be configured as a single continuous element, or it can be separated into multiple sections with flanges, cuffs, beads, and disks at the ends to secure the catheter in place.

  For example, a peritoneal catheter is an elastic, collapsible T-shaped containment vessel that may be provided with an access port having a flexible, elongated liquid channel for collecting or dispensing a fluid such as dialysate. See US Pat. No. 5,322,519. A peritoneal catheter can consist of two straight inflow / outflow conduits. The conduit is shaped as a circular intersection connecting fluted liquid transfer branches. See US Pat. No. 6,659,134. A peritoneal catheter can be composed of a plurality of tube lines with holes for fluid, and can be surrounded by a liquid permeable sheath structure with elongated cuts so that fluid flows but does not stick to tissue. See US Pat. No. 5,254,084. Peritoneal catheters have a semi-helical bend to provide radial flow, and consist of a number of inlet and outlet ports placed around and perimeter, with ultra-low temperature isotropic carbon coatings in the abdominal cavity Can have. See US Pat. No. 5,098,413. A peritoneal catheter is a flexible elongated tube that can be connected at one end to a pair of spaced sheets. The tube has at least one cuff to prevent catheter infection and extends into the body cavity. See U.S. Pat. No. 4,368,737. The peritoneal catheter can consist of two sections, including a maintenance device that grows permanently into the abdominal wall and a flexible elongated section for delivering and retrieving dialysate. See U.S. Pat. No. 4,278,092. Peritoneal catheters are flexible tubes that can have a naturally bent portion between the base and the distal end. This includes a flange that extends to the outer periphery at an angle that is not perpendicular to the axis of the catheter tube. See U.S. Pat. No. 4,687,471. A peritoneal catheter is a percutaneous access device that has a cylindrical connection for the protruding portion of the skin, an annular skirt for fixation to the dermis / subcutaneous tissue, and a flexible bellows (90 degrees through the neck and skirt). It can be constructed from a catheter tube having a looseness. See U.S. Pat. No. 4,886,502. A peritoneal catheter is an elongate flexible tube with a hole in the tube wall to allow fluid to pass through and can be formed into a cylindrical spiral wound tightly around the center of the tube. See U.S. Pat. No. 4,681,570. Other peritoneal catheters are described in US Pat. Nos. 6,290,669, 5,752,939, 5,171,227, and the like.

  In another aspect, the peritoneal catheter can be used to administer drugs to the peritoneum. For example, a peritoneal catheter is a hypodermic catheter device that has a receiving chamber of a penetrable member to accommodate an injection needle and can be connected to the abdominal cavity by a hollow shaft. See U.S. Pat. No. 4,400,169. The peritoneal catheter can be constructed with a porous outer casing. The casing defines the interior space with an inlet / outlet catheter made of material without holes that maintains communication with the opening of the outer casing to form two passages. See US Pat. No. 5,100,392.

  If a peritoneal catheter is used for a long time, infection may occur or the catheter may become clogged due to fibrin formation. Synthetic peritoneal catheters and delivery devices that incorporate a subject polymer composition containing an anti-scarring agent into adjacent tissue can prevent stenosis. Synthetic peritoneal catheters and delivery devices that incorporate a subject polymer composition containing an anti-infective agent into adjacent tissue can prevent or inhibit infection.

  Examples of peritoneal catheters that can be combined with one or more therapeutic agents according to the present invention include commercially available products. For example, Cook Critical Care (Bloomington, Ind.) Sells spinal chronic peritoneal dialysis catheters and Tenchkhoff chronic peritoneal dialysis catheters. BardAccess Systems (Salt Lake City, Utah) sells Tenchkhoff catheters and HEMOSPLIT peritoneal dialysis catheters. CardioMedSupplies, Inc (Ontario, Canada) sells single and double cuff linear peritoneal dialysis catheters and single and double cuff coiled peritoneal dialysis catheters. Other companies that sell single-cuff and double-cuff linear and coiled Tenchkoff catheters and other types of peritoneal catheters include Baxter International, Inc. (Deerfield, Ill.), Fresenius Medical Care (Lexington, Mass.) And GambroAB (Sweden).

  In one embodiment, the present invention provides a peritoneal access catheter and graft comprising a subject polymer composition infiltrated into adjacent tissue, the polymer composition comprising a therapeutic agent (such as a scarring inhibitor and / or an anti-infective agent). ) Can be included. A number of polymeric or non-polymeric delivery systems have been described above in the use of peritoneal dialysis grafts and catheters.

  The polymer composition comprises (a) tissue adjacent to the peritoneal access catheter or graft, (b) around the peritoneal access catheter or graft-tissue interface, (c) a site around the peritoneal access catheter or graft, (d ) It can infiltrate around the implanted peritoneal access catheter and graft by applying directly and / or indirectly to the tissue surrounding the peritoneal access catheter or graft. Methods of infiltrating a subject polymer composition into tissue adjacent to a peritoneal access catheter or graft include delivery of the polymer composition to: (a) on the surface of the peritoneal access catheter or graft during the implantation procedure (eg as infusion material, paste, gel or mesh), (b) the tissue surface just before or during the implantation of the peritoneal access catheter or graft (E.g., as infusion material, paste, gel, in situ formed gel or mesh), (c) immediately after implantation of peritoneal access catheter or graft, peritoneal access catheter or graft and / or implanted peritoneum (D) To the anatomical space where the peritoneal access catheter or graft is placed on the surface of the tissue around the access catheter or graft (eg, injection material, paste, gel, gel or mesh formed in situ) (Especially useful in this example is a polymeric carrier that releases a therapeutic agent over a period ranging from hours to weeks) -Can be delivered to liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and the site where the drug is released and the device is inserted Other formulations), (e) by intradermal injection of solutions, infusions, and sustained release formulations into the tissue surrounding the peritoneal access catheter or graft, and / or (f) application by a combination of the methods described above. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the subject polymer composition can be wetted to the entire device or to some surrounding tissue.

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the present invention, the subject polymer composition infiltrated into the tissue adjacent to the peritoneal dialysis graft and catheter comprises one or more of four general elements for the fibrosis (or scarring) process including: Can be adapted to release inhibitory drugs: new blood vessel formation (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), accumulation of extracellular matrix (ECM), And remodeling (maturation and organization of fibrous tissue). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (such as simvastatin), (G) inosine monophosphate dehydrogenase inhibitors (such as mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ ), (H) NFκB inhibitors (such as Bay11-7082), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Because peritoneal dialysis implants and catheters are manufactured in a variety of shapes and sizes, the exact dose administered depends on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Agent is the target of the device or per unit area scarring inhibitor administration of tissue surface coating (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm 2, or it may be about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplanted or tissue surface of the subject to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² Or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

Central Nervous System Shunt and Pressure Monitoring Device In one embodiment, the subject polymer composition can invade tissue adjacent to a central nervous system (CNS) device (CNS shunt or pressure monitoring device). The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents). A CNS device infiltrating adjacent tissue with a target polymer composition containing an anti-scarring agent can prevent stenosis and device obstruction leading to increased brain edema and intracranial pressure. A CNS device infiltrating adjacent tissue with a polymer composition of interest containing an anti-infective agent can prevent or inhibit infection of tissue surrounding the device.

  Cerebral edema, or cerebrospinal fluid (CSF) accumulation in the brain, is a frequent neurosurgical symptom and is caused by congenital malformations, infections, bleeding, or malignant tumors. Incompressible fluids can cause pressure in the brain, damage the brain, and if not treated can lead to death. A CNS shunt is a conduit placed in the ventricle that changes the flow of CSF from the brain to other parts of the body, relieving fluid pressure. The ventricular CSF is routed to multiple drainage sites by artificial bifurcation. This includes the pleura (ventricular thoracic branch), jugular vein, aorta (VA shunt), gallbladder and peritoneum (VP shunt, most common).

  Examples of CNS devices include CNS shunts such as ventricular thoracic branch, jugular vein, and aorta (VA) shunt), ventricular abdominal branches such as gallbladder and peritoneal branch (VP shunt), external ventricular drainage (EVD) devices and intracranial pressure (ICP) monitoring devices. Other CNS devices include dural patches and grafts that prevent dural fiber formation after laminectomy, and devices for continuous subarachnoid injection.

  In one embodiment, the CNS device may be a drainage shunt that drains fluid in the brain. For example, the CNS device is a bifurcated cerebrospinal bifurcation where the inner tube supplies fluid from the ventricle to the abdominal cavity and the outer tube applies pressure to the inner tube as the amount of fluid in the tube increases. Can be arranged to add. See US Pat. No. 5,405,316. A CNS device is a ventricular drainage system that is adapted to connect to a ventricular drainage catheter to receive cerebrospinal fluid, and may include a valve to control fluid flow. See US Pat. No. 5,772,625. The CNS device is a ventricular bifurcation system and can consist of a check valve to prevent backflow of cerebrospinal fluid and a flow switching mechanism that allows cerebrospinal fluid to flow from the ventricular catheter to the abdominal cavity or auricular catheter. . See U.S. Pat. No. 4,781,673. The CNS device is a branch member having a flow restriction path connected to a catheter, and can drain cerebrospinal fluid from the ventricle to the sagittal sinus. See US Pat. No. 6,283,934. The CNS device is the ventricular end of the ventricular heart bifurcation and may have a closed end with an adjacent lateral passage. The passageway is porous and inflatable to provide an umbrella-like liner for liquid flow while preventing obstruction. See U.S. Pat. No. 3,690,323. The CNS device is a cerebral edema valve and can consist of a chamber with inlet and outlet valves for delivering cerebrospinal fluid from the brain with controlled pressure. See US Pat. No. 5,069,663. The CNS device may be a cerebral edema device composed of a flexible outer shell. In addition to forming a liquid reservoir, the shell houses a non-disturbing self-regulating valve with a folded member that forms a slit-like opening and inlet and outlet tubes. See U.S. Pat. No. 5,728,061. The CNS device is a cerebrospinal fluid drainage shunt consisting of a main implantable control unit, which can connect a catheter that drains fluid to the cavity in the body and a cerebrospinal catheter. See US Pat. No. 6,585,677. The CNS device is a cerebrospinal fluid branch and can consist of a ventricular catheter connected to a flexible drainage tube. The tube has a flexible tubular cover on the outside from which the drainage tube can be pulled. See U.S. Pat. No. 4,950,232. The CNS device is an intracranial branch tube and can be composed of a thin film that extends radially outward from the opening at the end of the ventricular tube. The tube has a large number of holes on the side, and bypasses the cerebrospinal fluid of the ventricle under the dura mater on the surface of the brain. See US Pat. No. 5,000,731, etc. Other CNS shunts are described in the following US patents. Nos. 6,575,928, 5,437,626, and 4,631,051.

  In another embodiment, the CNS device may be a pressure monitoring device. For example, the pressure monitoring device can be an intracranial pressure sensor mounted in situ in the skull, where pressure is monitored and can be a means of transferring pressure out of the skull. See U.S. Pat. No. 4,003,141. The pressure monitoring device is a remote instrument that responds to differential pressure and can be composed of a thin planar conductive closed loop. The loop moves using a flexible diaphragm when the difference between the two pressures on the opposite side of the body changes. See U.S. Pat. No. 4,593,703. The pressure monitoring device can be composed of a positive contrast liquid contained in a compressible, elastic, silastic material container. The amount of liquid will vary depending on the function of pressure and force applied to the container. See U.S. Pat. No. 3,877,137. The pressure monitoring device may be a probe consisting of a threaded shaft with a lumen and a fixed locknut. The probe is inserted into the space under the arachnoid from the opening of the scalp. See U.S. Pat. No. 4,600,013. The pressure monitoring device can consist of an external transceiver unit and an implantable cavity resonator. The resonator has a cavity filled with a derivative at a predetermined resonance frequency for high frequency electromagnetic waves. See US Pat. No. 5,873,840. The pressure monitoring device may be an implantable sensor that senses a physiological parameter (such as cerebrospinal fluid flow) and then generates, processes, and forwards the signal to an external receiver. See US Pat. No. 6,533,733. Other CNS pressure monitoring devices are described in US Pat. Nos. 6,248,080 and 6,210,346.

  CNS shunts that can be combined with one or more agents in accordance with the present invention include commercial products such as Codman HAKIM programmable valves (manufactured by Johnson & Johnson Company affiliate Codman & Shurtleff, Inc., Raynham, Mass.). Other examples include the HEYER-SCHULTE neurosurgical shunt from IntegraNeuro Sciences (Plainsboro, NJ), the HERMETIC CSF drainage system, and the OSVII SMART VALVE system, as well as the shunt assembly from Medtronic, Inc. (Minneapolis, MN) This includes STRATA, DELTA, CSF-Snap and CSF-Flow management shunt assemblies.

  A pressure monitor CNS device can be combined with one or more agents in accordance with the present invention, such as the VENTRIX pressure monitor kit and CAMINO micro ventricular bolt ICP monitoring catheter (from Integra Neuro Sciences, Plainsboro, NJ). There are commercial products.

  In one embodiment, the invention provides a CNS device comprising a subject polymer composition infiltrated into adjacent tissue, the polymer composition comprising a therapeutic agent (such as an anti-scarring agent and / or an anti-infective agent). Can do. A number of polymeric and non-polymeric delivery systems for use in CNS devices have already been described above.

  The polymer composition can be (a) tissue adjacent to the CNS device, (b) around the interface between the CNS device and tissue, (c) a site around the CNS device, (d) directly and / or on the tissue around the CNS device. Indirect application can infiltrate the implanted CNS device. Methods for infiltrating a tissue adjacent to a CNS device with a subject polymer composition include delivery of the polymer composition to: (a) on the surface of the CNS device (eg as injection material, paste, gel or mesh) during the implantation procedure; (b) immediately before or during the implantation of the CNS device (eg injection material, paste, Gel, as an in-situ formed gel or mesh), (c) Immediately after implantation of the CNS device, the surface of the tissue around the CNS device and / or the implanted CNS device (eg injection material, paste, gel, Gel or mesh formed in situ), (d) topical application of the composition to the anatomical space where the CNS device is placed (especially useful in this example over a period ranging from hours to weeks) The use of polymeric carriers that release therapeutic agents-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants, and drug release devices Inserted part Other formulation) can be delivered to, (e) solution into the tissue surrounding the CNS system, implants, and intradermal injection of a sustained release formulation, and / or (f) coating with a combination of the above-described method. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the subject polymer composition can be wetted to the entire device or to some surrounding tissue.

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the invention, the subject polymer composition infiltrated into tissue adjacent to the CNS device comprises an agent that inhibits one or more of the four general factors for the process of fibrosis (or scarring), including: Can be adapted to release: new blood vessel formation (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) accumulation, and remodeling ( Fibrous tissue maturation and organization). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (such as simvastatin), (G) inosine monophosphate dehydrogenase inhibitors (such as mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ ), (H) NFκB inhibitors (such as Bay11-7082), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Since CNS devices are manufactured in a variety of shapes and sizes, the exact dose administered depends on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Agent is the target of the device or per unit area scarring inhibitor administration of tissue surface coating (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm 2, Or about 10 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² , or about 1000 μg / mm ^{2 to} 2500 μg / mm ² .

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplanted or tissue surface of the subject to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² Or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

Inferior vena cava filter In one embodiment, the subject polymer composition can infiltrate tissue adjacent to the inferior vena cava filter device. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents). The inferior vena cava filter is a device for capturing emboli and preventing them from moving through the bloodstream. Examples of inferior vena cava filters include vascular filters, blood filters, implantable blood filters, vena cava filters, vena cava filtering devices, thrombosis filters, thrombus filters, anti-migration filters, filtering devices, transcutaneous filter systems, Examples include, but are not limited to, intravascular traps, intravascular filters, clot filters, venous filters, and body vascular filters.

  The inferior vena cava filter captures clots and prevents them from moving to other parts of the body to form emboli. Plaques and clots can travel through the bloodstream and reach the lungs, causing pulmonary embolism and can be life threatening. To prevent this situation, the inferior vena cava filter is placed in a large vein in the body to prevent pulmonary embolism in patients with deep vein thrombosis (or patients at risk for such thrombosis). Such filters are most often composed of synthetic polymers or metals. The filter has various shapes, such as, but not limited to, a basket, a cone, an umbrella, and a loop shape. The shape of the filter must provide adequate trapping capacity while allowing adequate blood flow. In addition to its functional shape, the filter also has other design features such as a peripheral loop for adjustment and a locking function to prevent movement (bumps, braces, sharp points, etc.). A fiber-forming reaction can occur where the filter contacts the vessel wall for fixation. As a result of this fiber formation reaction, removal of the filter can be difficult. This is particularly a problem with filters that are to be placed for a relatively short period of time. The filter can also be a site where infection occurs. Infiltrating the tissue adjacent to the filter with a polymer composition containing a fibrosis inhibitor and / or an anti-infective agent can reduce or prevent stenosis and obstruction of the device due to a fiber proliferative reaction, and infection at the site of filter placement Can be prevented or inhibited.

In one embodiment, the inferior vena cava filter can be designed in a variety of shapes. For example, the inferior vena cava filter can be composed of a number of endoluminal elements supported by a maintenance device within the filter shape. The element is released into an open stent-like shape. See US Pat. No. 6,267,776. The inferior vena cava filter can consist of an embolus capture portion with multiple elongated filter wires and a fixed portion with multiple braces. The wire branches in a spiral to form a conical surface. See US Pat. No. 6,391,045. The inferior vena cava filter can be configured with a coarse echogenic function so that the position of the filter can be visually determined with ultrasound. See US Pat. No. 6,436,120. The inferior vena cava filter can consist of a number of core wire braces. The braces are fixed radially outwardly and are connected to each other with a compressive material to form a filter basket. See US Pat. No. 5,370,657. The inferior vena cava filter can consist of a tip head with a number of legs with hooks and pads that diverge into a cone and can be fixed to the blood vessel. See US Pat. No. 5,059,205. The inferior vena cava filter can be composed of a filtering device made of shape memory / superelastic material. The device is formed with a distal end of the deployment and retrieval wire so that the invasiveness of the deployment is minimized. See U.S. Pat. No. 5,893,869. The inferior vena cava filter can consist of a number of endoluminal elements tied with a maintenance device. When the maintenance device is released, the endoluminal filter element changes to an open shape in the blood vessel. See U.S. Pat. Nos. 6,517,559 and 6,267,776. The inferior vena cava filter can consist of an external catheter and an internal catheter with a mesh-like filter basket that folds to the end. The basket is made of spring wire or plastic monofilament. See US Pat. No. 5,549,626. The inferior vena cava filter can consist of multiple radial braces. The braces attach to physical elements and provide endothelial cell growth and antiproliferative properties through bilayer surface treatment. See US Pat. No. 6,273,901. The inferior vena cava filter can be composed of a metallic fabric. The fabric is formed as a screen to trap particles and can slide along the guide wire. See US Pat. No. 6,605,102. The inferior vena cava filter may be non-permanent using a single high memory coil wire with cylindrical and conical portions. See US Pat. No. 6,059,825. Other inferior vena cava filters are described in the following US patents. 6,623,506, 6,391,044, 6,231,589, 5,984,947, 5,695,518 and 4,817,600.

  Inferior vena cava filters that can benefit from having the subject polymer composition infiltrated into adjacent tissue in accordance with the present invention include commercial products. Examples of inferior vena cava filters that can benefit from incorporating fiber formation inhibitors include the GUNTHER TULIP vena cava filter and GIANTURCO-ROEHMBIRD'S NEST filter sold by Cook, Inc. (Bloomington, Ind.). Not limited to. C.R. Bard (Murray Hill, NJ) sells SIMON-NITINOL and RECOVERY filters. Cordis Endovascular, a subsidiary of Cordis Corporation (Miami Lakes, Florida), sells TrapEase Permanent vena cava filters. B. Braun Medical Inc. (Bethlehem, PA) sells VenaTech LP vena cava filters and Vena TecH- LGM vena cava filters. Boston Scientific Corporation (Natick, Mass.) Sells Over-the-Wire GREENFIELD vena cava filters.

  In one embodiment, the present invention provides an inferior vena cava filter comprising a subject polymer composition infiltrated into adjacent tissue, the polymer composition containing a therapeutic agent (such as an anti-scarring agent and / or an anti-infective agent). Can be included. A number of polymeric or non-polymeric delivery systems have been described above in the use of inferior vena cava filters. These polymer compositions contain one or more fibrosis inhibitors to inhibit or reduce granulation tissue overgrowth and / or contain one or more anti-infectives for infection. Is inhibited or reduced.

  The polymer composition consists of (a) tissue adjacent to the inferior vena cava filter device, (b) around the interface between the inferior vena cava filter device and tissue, (c) a site around the inferior vena cava filter device, and (d) inferior vena cava filter device. By applying directly and / or indirectly to the tissue surrounding the venous filter device, it can infiltrate around the implanted inferior vena cava filter device. A method of infiltrating a tissue adjacent to the inferior vena cava filter device with a subject polymer composition includes delivery of the polymer composition to: (a) on the surface of the inferior vena cava filter device (eg as infusion material, paste, gel or mesh) during the transplantation procedure; (b) on the tissue surface (eg, immediately before or during implantation of the inferior vena cava filter device) : As injection material, paste, gel, in situ formed gel or mesh), (c) Immediately after implantation of the inferior vena cava filter device, and / or implanted inferior vena cava filter device (D) Topical application of the composition to the anatomical space where the inferior vena cava filter device is placed on the surrounding tissue surface (eg injection material, paste, gel, gel or mesh formed in situ) (Especially useful in this example is the use of polymeric carriers that release therapeutic agents over a period ranging from hours to weeks-liquids, suspensions, emulsions, microemulsions, microspheres. Pastes, gels, microparticles, sprays, aerosols, solid implants and other formulations that release the drug and can be delivered to the site where the device is inserted), (e) solutions, injections into the tissue surrounding the inferior vena cava filter device And / or (f) application by a combination of the methods described above. Combination therapy (ie combination of therapeutic agents and antithrombotic or antiplatelet agents) can also be used. In all cases, it is understood that the subject polymer composition can be wetted to the entire device or to some surrounding tissue.

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the invention, the subject polymer composition infiltrated into tissue adjacent to a vena cava filter (such as the inferior vena cava filter) is one of four general factors for the process of fibrosis (or scarring) including: Can be adapted to release drugs that inhibit one or more: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) ) Accumulation and remodeling (fibrotic tissue maturation and organization). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. In addition, since the inferior vena cava filter device is manufactured in a variety of shapes and sizes, the exact dose administered will depend on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site) and the total administered drug dose can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Agent is the target of the device or per unit area scarring inhibitor administration of tissue surface coating (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm 2, or it may be about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplanted or tissue surface of the subject to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² Or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

Gastrointestinal Device In one embodiment, the subject polymer composition can infiltrate tissue adjacent to a gastrointestinal (GI) device. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents). There are many gastrointestinal tube devices used for replenishment and drainage. The function of such a tube is not sufficiently exerted when the fiber growth response to the device is excessive or when infection occurs at a certain site of the device. Infiltration of tissue adjacent to the device with a polymer composition comprising a fibrosis inhibitor and / or an anti-infective agent can modulate this fiber proliferative response (such as to prevent stenosis and / or device interference) It can maintain performance and prevent or inhibit infection at certain parts of the device.

  In the present invention, various GI tubes for drainage or replenishment can be used. Such devices include drainage or supplemental GI tubes, portal vein venous shunts, ascites shunts, nasal or nasal intestinal tubes, gastrostomy feeding tubes or transcutaneous feeding tubes, air conditioning systems. Vaginal endoscope tube, colostomy device, drainage tube, gallbladder T tube, biopsy forceps, gallstone removal device, endoscopic retrograde cholangiopancreatography (ERCP) device, dilatation balloon, enteral feeding device, This includes, but is not limited to, stents, low profile devices, virtual colonoscopy (VC) devices, capsule endoscopes, and retrieval devices.

  GI devices can be constructed of synthetic materials, including but not limited to stainless steel, metal, nitinol, glass, resin or polymer.

  In another aspect, the GI device can be a tool used to examine or provide access to the gastrointestinal tract. This includes optical imaging for diagnostic purposes in the form of still images or video recording. Procedures using such devices include rectal microscopy, colonoscopy, or esophagogastroduodenoscopy in which an endoscope is inserted into the esophagus or anal canal to assess part of the GI tract. Not limited to this. For example, the GI device may be an endoscope having a tubular shaft that receives a vision lens and a treatment instrument. See US Pat. No. 5,421,323. A GI device is an endoscopic catheter with multiple lumens that can be inserted through an endoscope to perform endoscopic retrograde cholangiopancreatography. The first lumen has a threaded wire, and the second lumen provides a conduit for injecting positive contrast agent to identify obstructions. The third lumen also provides a conduit for inflating the balloon. See U.S. Pat. Nos. 5,788,681 and 5,843,028. The GI device may be a video endoscope system composed of a capsule that can be swallowed, a transmitter, and a receiving system. See US Pat. No. 5,604,531, etc. The GI device may be an endoscope composed of an ultrasonic exchanger encapsulated. It has a self-contained electromechanical sector scanner and can be used for esophageal echocardiography. See U.S. Pat. Nos. 4,977,898 and 4,834,102. The GI device is a sterilizable endoscope and can have a disposable channel separable from an image sensor attached to a cylindrical capsule. See US Pat. No. 5,643,175. The GI device is a body conduit intrusion device and can be configured with bi-directional surface friction. The friction reduces the risk of puncture and secures the tissue during operation to reduce the time it takes to insert the catheter, guidewire, and endoscope through the body cavity and conduit. See US Pat. No. 6,589,213. The GI device may be a colon access device composed of a flexible tube and with a tether for discharge from the colonoscope. Can be placed in the colon for up to several days to monitor and treat colon disease. See US Pat. No. 6,149,581. The GI device includes a parent endoscope that is inserted into the duodenum and a child endoscope that is inserted into the papillary process through a forceps channel, and can be adapted for a bile duct or a pancreatic duct. See U.S. Pat. No. 4,979,496.

  In another embodiment, the GI device can be used as a conduit for long-term feeding with tubes. Such GI devices include, but are not limited to, transcutaneous feeding tubes, enteral feeding devices / catheters, gastrostomy feeding tubes, low profile devices, nasal tubes. Such long-term feeding tubes can be inserted through the GI tract of the nasal canal or the abdominal wall by gastrostomy. For example, the GI device may be an enteral feeding catheter adapted to function as a conduit for moving nutrients through the abdominal wall into the body. It has a maintenance device and a telescopic fixing means. See US Pat. No. 4,826,481, etc. The GI device may be an enteral feeding tube having a tapered guide tube and a balloon bolster, and having a catheter that can be easily inserted and removed. See US Pat. No. 6,582,395. The GI device may be an enteral feeding device for administering liquid to the stomach. It consists of a female connector, flexible feeding tube, liquid discharge tube, and probe, and is connected to the male side of the guide wire. See U.S. Pat. No. 5,242,429. The GI device may be a thin hollow cylinder with a spring bias valve. It is maintained from the surgical opening in the stomach wall by a fixed extension coaxial flange. See U.S. Pat. No. 4,344,435. The GI device may be a nasal tube with a flexible additive sheath extending longitudinally along the tube and having an opening at the end. See US Pat. No. 5,334,167. Other GI devices used as nutritional tubes or related devices are described in the following US patents and the like. 6,582,395, 5,989,225, 5,720,734, 5,716,347, 5,503,629, 5,342,321, 4,861,334, 4,758,219 and 4,057,065.

  In another embodiment, the GI device can be used for irrigation or aspiration of the GI tract. Such GI devices include, for example, removal of ingested toxicants and blood, treatment of symptoms related to absorption, decompression of the stomach, confirmation before surgery that the GI tract is empty, removal of gas after surgery, bowel obstruction and paralysis Can be used to treat diseases such as sexual ileus. For example, a GI tube may have a liquid reservoir connected to the tube with a therapeutic device that is elongate for insertion into the GI tube and slidable to control bleeding. See US Pat. No. 5,947,926. The GI tube may be a flexible nasal tube. Anatomically adapted to the esophagus and stomach, the ends are curved or bent to facilitate insertion. See US Pat. No. 5,690,620. The GI tube may be an elongated nasal tube. To prevent pressure necrosis in the nose due to forced operation, it can be fixed without being fixed from the nostril and bent. See U.S. Pat. No. 4,363,323. GI devices can consist of aspiration, nutrition, and inflation lumens and are surgically inserted through the abdominal and stomach walls. See U.S. Pat. No. 4,543,089. The GI device consists of a drain tube and an irrigation tube and can have a cuffed liquid sealing used for one-way irrigation of the intestine. See U.S. Pat. No. 4,637,814. The GI device may be a balloon-like tube with an open end and a thin wall. Shaped to extend through at least a portion of the feeding tube to allow digested food solids to pass through and treat absorption-related illnesses. See U.S. Pat. Nos. 4,315,509 and 4,134,405.

  In another aspect, the GI device may be a prosthetic angioplasty device. For example, the colostomy device may be a colostomy constructed with a hollow tubular support and a cylindrical main portion and having a pair of radially extending flanges to secure the member. See U.S. Pat. No. 4,781,176. The colostomy device can consist of an annular support plate for attachment to internal and external balloons, fistulas and rectum connected by tubes. See U.S. Pat. No. 5,569,216.

  In another aspect, the GI device may be a mechanical hemostasis device used to control GI bleeding. Hemostasis devices used to suppress blood flow include but are not limited to clamps, clips, staples, and sutures. For example, the hemostatic device may be a compression clip composed of a fixing device, a shaft with a lateral hole, and a bolster that can be fixed and moved along the shaft. See US Pat. No. 6,387,114. The hemostatic device may be an endoscopic clip consisting of a deformable material and a pair of hollow jaws that penetrate tissue. See US Pat. No. 5,989,268.

  In another embodiment, the GI device provides a means for cleaning a clogged GI tube. For example, the GI device may be a dilatation catheter consisting of a shroud tube with a strain relief tube used to change the shape of the dilatation balloon. See US Pat. No. 6,537,247.

  In another embodiment, the GI device functions to deliver a drug to the GI tract. For example, a GI device can be administered orally and can consist of two chamber parts that are permeable to water. The first chamber has an opening that releases liquid drug when subjected to pressure, and the second chamber includes an electrical circuit that generates gas to apply pressure so that the first chamber releases the drug. It is. See US Pat. No. 5,925,030. The GI device may be a foldable and oval gastric fixation device. It includes a tether and a long, thin intestinal payload module that contains sustained-release drugs, conjugated enzymes, or non-pathogenic microorganisms. See U.S. Pat. No. 4,878,905. The GI device may be an ingestible device for delivering a substance to a selected site within the GI. This includes a receiver of electromagnetic radiation for feeding the opening of the device for inserting or dispensing the substance. See U.S. Pat. No. 6,632,216.

  In another aspect, the GI device may be a shunt device that communicates between two body systems. The short-circuit device can be used to treat abnormal conditions such as bypassing passages in the body or moving unwanted fluid accumulation from the cavity to a site where the body can handle it. For example, a short circuit device can be used to replace fluid in the peritoneal cavity with systemic venous blood circulation as a treatment for ascites. Short circuit devices include, but are not limited to, portal vein vein shunts and peritoneal vein shunts. For example, the short circuit may be an implantable pump consisting of a cylindrical chamber and port, with pump means for aspirating and discharging liquid. See U.S. Pat. No. 4,725,207. The shunt is an implantable peritoneal venous shunt system that consists of a two-chamber ascites collection device and pump (such as magnet or pressure actuation) and an anti-reflux catheter, all connected with flexible tubing. See U.S. Pat. Nos. 4,657,530 and 4,610,658. The shunt can consist of a peritoneal tube connected to an implantable hollow plastic valve assembly. The assembly passes fluid through the venous tube when subjected to pressure. See U.S. Pat. No. 5,520,632. The shunt may be a collapsible shape memory metal fabric with a number of metal strands. A central fluid passage is provided and delivered in a collapsed manner in the body's pathway to produce a portal vein venous shunt. See US Pat. No. 6,468,303. The GI device may be a hollow laparoscopic tunnel dissection instrument consisting of an inflatable balloon and an obturator with a sharp tip. The obturator is used to drill holes that provide the anatomical workspace necessary for laparoscopic procedures. See U.S. Pat. Nos. 5,836,961 and 5,817,123.

  Examples of GI devices that may benefit from infiltrating the subject polymer composition into adjacent tissue in accordance with the present invention include commercial products.

  In one embodiment, the GI device used for nutritional support includes a variety of devices. For example, gastrostomy tubes such as DURA-GPolyurethane Gastrostomy Tubes and MAGNA-PORT Gastrostomy Tubes sold by Ross Products (Columbus, Ohio) under Abbott Laboratories. MossTubes, Inc. (West Sandlake, NY) sells MossG-Tube Percutaneous Endoscopic Gastrostomy Kits. Other tubes include, for example, EASY-FEED Enteral Feeding Sets sold by Ross Products (Columbus, Ohio) under AbbottLaboratories. COMPATEnteral Delivery Systems is sold by Novartis AG (Basel, Switzerland). CORFLO Feeding Tubes are sold by VIASYS Healthcare Medsystems Division (Wheeling, IL). ENDOVIVE Enteral FeedingSystems is sold by Boston Scientific Corporation. Nasal tubes such as Mark IV Nasal (SIL) Tubes are sold by MossTubes, Inc. (West Sandlake, NY). Bard Medical Division (Covington, Georgia) and AndersenProducts Limited (UK), affiliated with C.R. Bard, Inc., also sell a variety of nasal feeding tubes. Low-profile devices such as Low-Profile Replacement Gastrostomy Devices and Bard Button Replacement Gastrostomy Devices are sold by Bard Endoscopic Technologies (Billerica, Mass.) Under the umbrella of C.R. Bard, Inc.

  In another embodiment, the GI device includes irrigated or aspiration gastrointestinal tubes such as LAVACUATOR Gastro Intestinal Tubes and VENTROLLevine Tubes sold by Nellcor Puritan Bennett Inc. (Pleasanton, Calif.).

  In another aspect, GI devices include those used as portal vein vein shunts and other shunt devices. Such as VIATORR TIPS Endoprostheses sold by W.L.Gore & Associates, Inc. (Newark, Delaware). DenverAscites Shunts is sold by Denver Biomedical, Inc. (Golden, Colorado). LEVEEN Shunts is sold by Becton, Dickinson and Company (Franklin Lakes, NJ).

  In another embodiment, the GI device includes colostomy devices such as ASSURA Pouches and COLOPLAST Pouches sold by Coloplast Corporation (Marietta, GA). ESTEEMSYNERGY Standard Closed-End Pouches and SUR-FIT NATURA Closed-End Pouches are sold by ConvaTec (Princeton, NJ), a division of Bristol-MyersSquibb Company. Cymed Ostomy Company (Berkeley, Calif.) Sells MICROSKIN Colostomy Pouching Systems. KARAYA 5 One-Piece Pouching Systems, CONTOUR IOne-Piece Ostomy Pouching Systems, and CENTERPOINTLOCK (CPL) Two-Piece Pouching Systems are sold by Hollister Inc. (Liberty Building, Illinois). The Bard Medical Division (Covington, GA), a subsidiary of C.R. Bard, Inc., also sells a variety of colostomy bags.

  In another aspect, the GI device includes an inflation catheter. These include ELIMINATOR Multi-Stage Balloon Dilators sold by Bard Endoscopic Technologies (Billerica, Mass.) Of C.R. Bard, Inc. and CREFixed Wire and Wireguided Balloon Dilators sold by Boston Scientific Corporation (Natick, Massachusetts).

  In one embodiment, the invention provides a GI device comprising a subject polymer composition infiltrated into adjacent tissue, the polymer composition comprising a therapeutic agent (such as an anti-scarring agent and / or an anti-infective agent). Can do. A number of polymeric and non-polymeric delivery systems for use in GI devices have already been described above. These polymer compositions contain one or more fibrosis inhibitors to inhibit or reduce granulation tissue overgrowth and / or contain one or more anti-infectives for infection. Is inhibited or reduced.

  The polymer composition can be (a) tissue adjacent to the GI device, (b) around the interface between the GI device and the tissue, (c) a site around the GI device, Indirect application can infiltrate around the implanted GI device. Methods for infiltrating a subject polymer composition into tissue adjacent to a GI device include delivery of the polymer composition to: (a) on the surface of the GI device (eg as injection material, paste, gel or mesh) during the implantation procedure; (b) immediately before or during the implantation of the GI device (eg injection material, paste, Gel, as an in-situ formed gel or mesh) (c) Immediately after implantation of the GI device, the surface of the GI device and / or the tissue surrounding the implanted GI device (eg injection material, paste, gel, Gel or mesh formed in situ) (d) Topical application of the composition to the anatomical space where the GI device is placed (especially useful in this example over a period ranging from hours to weeks) The use of polymeric carriers that release therapeutic agents-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants, and drug release devices At the site to be inserted Other formulations may reached), (e) solution into the tissue surrounding the GI system, implants, and intradermal injection of a sustained release formulation, and / or (f) coating with a combination of the above-described method. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the subject polymer composition can be wetted to the entire device or to some surrounding tissue.

  According to one embodiment, the anti-scarring agents and / or anti-infective agents described above can be used in the practice of the present invention. In one embodiment of the present invention, the subject polymer composition infiltrated into the tissue adjacent to the GI device comprises an agent that inhibits one or more of the four general factors for the process of fiber formation (or scarring) including: Can be adapted to release: new blood vessel formation (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) accumulation, and remodeling ( Maturation and organization of fibrous tissue). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Since GI devices are manufactured in a variety of shapes and sizes, the exact dose administered depends on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Agent is the target of the device or per unit area scarring inhibitor administration of tissue surface coating (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm 2, or it may be about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplanted or tissue surface of the subject to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² Or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

Central venous catheter In one embodiment, the subject polymer composition can invade tissue adjacent to a central venous catheter (CVC) device. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents). For purposes of the present invention, a “central venous catheter” delivers fluid to large (central) veins in the body (jugular vein, pulmonary vein, femoral vein, iliac vein, inferior vena cava, superior vena cava, axillary vein, etc.) Should be construed to include all catheters and lines used to do this. A CVC device is typically a tubular hollow cannula that is inserted into a body passageway for injection and withdrawal of bodily fluids. CVCs can be inserted into large veins such as the superior vena cava. A portion of the catheter is placed within the body and a connection port extends outside the body to allow access to the circulatory system. CVCs can be used for drug administration (such as chemotherapy or antibiotic treatment), intravenous nutrition, pressure monitoring, and regular blood tests.

  CVC may or may not have a cuff or flange. The cuff is used to prevent the catheter from coming off and infected. CVCs have one or more lumens and come in various sizes as needed. Made of synthetic materials, including but not limited to polyurethane, polyethylene, silicone, copolymers, and other polymer compositions.

  Because CVC is usually left in the body for a long time, infection and inflammation may occur in response to the catheter. The CVC access lumen can be blocked by the formation of clots and blood clots. Some CVCs have been coated or surface treated to minimize the risk of infection and / or inflammation. When a polymer composition containing a fibrosis inhibitor and / or an anti-infective agent is infiltrated into tissue adjacent to the device, this fiber proliferative response is modulated to prevent stenosis and / or device obstruction, Can prevent or inhibit infection.

  In one embodiment, the CVC can be designed with special access to the circulatory system for specific symptoms and purposes. For example, a needle-shaped double lumen can be used to elongate the CVC and create a CVC specifically for hemodialysis. The lumen can be used as a conduit for administering drugs and additives into the body through AV access fistulas and grafts. See US Pat. No. 5,876,366. The CVC can consist of an indwelling cannula adapted to be placed in the superior vena cava. An exit port is provided at the end for delivery of the drug solution primarily to the subcutaneous tissue surrounding the cannula. See U.S. Pat. No. 5,817,072.

  In another aspect, the CVC can be designed to provide multiple conduits to access the circulatory system. For example, the CVC may be a flexible elongated synthetic catheter. A number of independent lumens are provided and can be adapted to be attached to individual liquid transfer devices. For this reason, the liquid is injected into the vein separately without mixing. In addition, blood can be collected at the same time as the liquid is injected, and the pressure in the vein can be monitored. See U.S. Pat. No. 4,072,146. The CVC may be a multi-lumen catheter with a flexible central lumen. With a shaped liquid passage, a number of collapsible lumens are attached to the periphery of the central lumen, which also has a shaped liquid passage. See U.S. Pat. No. 4,406,656.

  In another aspect, the CVC can have a means of preventing infection that occurs as a result of long-term use. For example, CVC can be composed of polyurethane with a hydrophilic thin layer on the surface. The surface is loaded with a Ramoplanin antibiotic to inhibit bacterial colonization of the catheter after insertion. See US Pat. No. 5,752,941. CVC can be composed of a polymer material with an outer surface embedded with germicidal metal (such as silver) atoms. The atoms also spread to subsurface layers to form a non-leaching surface treatment. See US Pat. No. 5,520,664.

  In another aspect, the CVC can be used in conjunction with a device that provides a means of controlling injection and fluid withdrawal through the CVC. For example, a CVC device can consist of a syringe with two separate liquid conduits, two syringes with independent plungers, and a single valve body. See U.S. Pat. No. 5,411,485. The CVC device can consist of upper and lower molded sheets and a number of syringe channels and barrels (which can be individually operated by syringe plungers). See U.S. Pat. No. 5,417,667. The CVC device may be a synthetic molded base that forms opposing slide valve walls. A number of syringes are attached to the valve wall so that liquid can be transferred to the inlet port. See U.S. Pat. No. 5,454,792. A CVC device can be configured with an access device for easier access. A connector is used to allow fluid to flow in both directions between the manifold and the CVC. See US Pat. No. 5,308,322. The CVC device can be provided with a valve assembly at the end of the CVC to control the passage of fluid from the catheter to the blood flow passageway (where the catheter is inserted). See U.S. Pat. No. 5,030,210.

  Other examples of central venous catheters include complete parenteral feeding catheters, central venous catheters inserted around, pulmonary artery catheters with flow control and balloons at the tip, long-term central venous access catheters (Hickman line and Broviac catheters) and so on. Representative examples of these catheters are described in the following US patents: 3,995,623, 4,072,146, 4,096,860, 4,099,528, 4,134,402, 4,180,068, 4,385,631, 4,406,656, 4,568,329, 4,960,409, 5,176,661, and 5,916,208.

  Examples of CVCs that may benefit from infiltrating the subject polymer composition into adjacent tissue in accordance with the present invention include commercial products. For example, Bard Access Systems (Salt Lake City, Utah), a division of C.R. Bard, sells HICKMAN, BROVIAC and LEONARDCentral Venous Catheters, including the SureCuff Organization Internal Growth Cuff and the VitaCuff Antimicrobial Cuff model. EdwardLifesciences (Irvine, CA) sells VANTEX catheters and PRESEP CENTRAL VENOUS OXIMETRY catheters. CookCritical Care (Bloomington, Ind.) Sells SPECTRUM Antibiotic Impregnated catheters and other CVC sets and trays. Arrow International (Reading, PA) sells ARROWGARDBLUE catheters with one or more lumens.

  Various central venous catheters can be used in hemodialysis. This includes, but is not limited to, fully implanted catheters such as Lifesite (Vasca Inc., Chukesbury, Mass.) And Dialock (Biolink Corp., Middleboro, Mass.). Although central venous catheters are vulnerable to infection, aspects of the invention for preventing or inhibiting infection are described above.

  In one embodiment, the present invention provides a CVC device comprising a subject polymer composition infiltrated into adjacent tissue, the polymer composition comprising a therapeutic agent (such as an anti-scarring agent and / or an anti-infective agent). Can do. A number of polymeric and non-polymeric delivery systems for use in CVC devices have already been described above. When these polymer compositions contain one or more fibrosis inhibitors and / or one or more anti-infectives, granulation tissue overgrowth is inhibited or reduced or infection at the site of the CVC device Is inhibited or prevented.

  The polymer composition can be (a) tissue adjacent to the CVC device, (b) around the interface between the CVC device and tissue, (c) a site around the CVC device, (d) directly and / or on the tissue around the CVC device. Indirect application can infiltrate the implanted CVC device. Methods for infiltrating a tissue adjacent to a CVC device with a subject polymer composition include delivery of the polymer composition to: (a) on the surface of the CVC device (eg as injection material, paste, gel or mesh) during the implantation procedure; (b) immediately before or during the implantation of the CVC device (eg injection material, paste, Gel, as an in-situ formed gel or mesh), (c) Immediately after implantation of the CVC device, the surface of the tissue surrounding the CVC device and / or the implanted CVC device (eg injection material, paste, gel, Gel or mesh formed in situ), (d) topical application of the composition to the anatomical space where the CVC device is placed (especially useful in this example over a period ranging from hours to weeks) The use of polymeric carriers that release therapeutic agents-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants, and drug release devices Inserted part Other formulation) can be delivered to, (e) solution into the tissue surrounding the CVC system, implants, and intradermal injection of a sustained release formulation, and / or (f) coating with a combination of the above-described method. Combination therapy (ie combination of therapeutic agents and antithrombotic or antiplatelet agents) can also be used. In all cases, it is understood that the subject polymer composition can be wetted to the entire device or to some surrounding tissue.

  In some embodiments, the subject polymer composition can invade the tissue adjacent to: (a) the outer surface of the intravascular portion of the CVC device and / or the portion of the CVC device that crosses the skin; (b) the inner surface of the CVC device and / or the outer surface of the portion of the CVC device that crosses the skin; And / or a portion whose outer surface is coated with a polymer composition containing a therapeutic agent (such as an anti-infective agent), (c) the surface of the subcutaneous “cuff” around the CVC device, (d) the other surface of the CVC device, and ( e) Any combination of the above.

  According to one aspect, the anti-scarring agents and / or anti-infective agents described above can be used in the practice of the present invention. In one embodiment of the present invention, the subject polymer composition infiltrated into tissue adjacent to the CVC device comprises an agent that inhibits one or more of the four general factors for the process of fiber formation (or scarring), including: Can be adapted to release: new blood vessel formation (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) accumulation, and remodeling ( Fibrous tissue maturation and organization). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Because CVC devices are manufactured in a variety of shapes and sizes, the exact dose administered depends on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Agent is the target of the device or per unit area scarring inhibitor administration of tissue surface coating (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm 2, or it may be about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplanted or tissue surface of the subject to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² Or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

In one embodiment, the subject polymer composition can infiltrate tissue adjacent to the auxiliary artificial heart (VAD). The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  VAD is intended to help the natural heart pump blood into the body. Examples of VAD and other related devices include assistive left ventricle, assistive right ventricle, assistive biventricle, cardiac assist device, mechanical assist device, artificial heart assist device, implantable cardiac assist system, implantable Examples include but are not limited to ventricular assist devices, cardiac assist pumps, and ventricular assist devices.

  VAD is used to treat cardiac dysfunction, where the heart cannot pump blood into the body at the heart rate necessary to maintain adequate blood flow. Cardiac dysfunction includes, but is not limited to, acute myocardial infarction, cardiomyopathy, valvular dysfunction, extensive cardiac surgery, and uncontrollable arrhythmias. VAD assists a malfunctioning heart by improving pump function and resting the heart to restore normal pump function. The VAD generally includes a blood pump mounted between the ventricle and the aorta, a cannula that connects the pump and the heart, and a drive control device that supplies power to the device to control it. The most common existing VAD is left ventricular VAD. This is because the left ventricle is more susceptible to disease than the right ventricle. However, the assistive heart can be used to pump blood from the left ventricle, the right ventricle, or both ventricles. VAD can be classified as a pump drive. It functions as either pulsatile (such as a balloon pump in the aorta) or continuous (such as a piston pump or a centrifugal pump of the centrifugal or medium axis spiral type).

  However, in VAD, in addition to tissue damage, complications related to transplantation and long-term use, such as infection, septic embolism, bleeding, and inflammation, may occur in response to blood clotting and thrombosis due to congestion. There is. These complications can interfere with the usefulness of VAD and can lead to life-threatening situations. Infiltration of tissue adjacent to VAD with a polymer composition containing an anti-scarring agent and / or an anti-infective agent prevents stenosis and / or device obstruction or prevents or inhibits infection at a site of the device I can do it.

  In one embodiment, the VAD may be a pulsatile pump. Such devices have flexible bags and diaphragms that are compressed and released to perform pulsatile pumping. One type of pulsatile pump is the intra-aortic balloon pump (IABP). This is a pouch-like pulsatile device that can be performed with minimally invasive procedures and works best when the left ventricle can drain blood and maintain systemic arterial pressure. For example, VAD may be IABP, which is a removable primary support within the aortic arch. This is maintained by a pump and a block balloon and descends in the aorta where there are both decompressed and pressurized parts. See US Pat. No. 6,228,018. VADs can be IABP catheters and pump chambers, both large and small in diameter, separated by flexible diaphragms and membranes. See U.S. Pat. No. 5,928,132. A VAD is a pulsatile pump that can consist of a cannula with an outer sheath and lumen, inlet and outlet valves, a fluid reservoir, and a hydraulic pump (which generates pulsatile pumping of blood through the cannula). See US Pat. No. 6,007,479.

  In another embodiment, the VAD is a continuous pump and can provide a nearly stable blood flow. This can include fine pulsatile elements. Continuous pumps include piston pumps such as devices driven by air and devices operated by magnets, as well as rotary pumps such as centrifugal or medium shaft propulsors. For example, the VAD may be an implantable device with a stator part and a rotating part (functioning as a centrifugal pump) attached with a magnet. A vortex pump draws blood from the left ventricle and sends it into the aorta to reduce left ventricular pressure. See US Pat. No. 5,928,131. The VAD can consist of an implantable piston to drive the implanted blood pump mechanism and is controlled by an external electromagnet. See US Pat. No. 5,089,017.

  In another embodiment, the VAD may be a device that assists in either left or right ventricular pumping capacity. For example, a VAD has a pair of chambers that can consist of a housing device with an inlet / outlet port, at least one ventricular outflow conduit, and an actuator, with one chamber deflated and the other expanded. Replacement pump is provided. See US Pat. No. 6,264,601. A VAD can consist of a pump, a chamber on the pump, and a tube that connects the pump and the chamber using liquid and gas as the transmission means. See US Pat. No. 6,146,325, etc.

  In another embodiment, the VAD is a device designed specifically for the left ventricle. For example, a VAD is a blood pump adapted to be incorporated into the blood flow between the left ventricle and the aorta using a controller that can adjust the pump speed based on the response of the sensor and an inflow fluid pressure sensor. See US Pat. No. 6,623,420. A VAD can consist of a bag adapted to fill and expand blood, release blood and contract, and means to change the resistance of the bag using gas from the conduit to the containment casing. See US Pat. No. 6,569,079. A VAD is a pump system consisting of a deformable bag with an inlet and an outlet, and a pair of plates can be placed on the opposite side of the bag to deform the bag. See US Pat. No. 5,599,173.

  In another embodiment, the VAD is a device designed as a biventricular assist device. For example, a VAD is a biventricular assist device made up of self-supporting cup-shaped parts and can have an annular diaphragm that forms a fluid chamber around the heart cavity. Positive and negative pressure can also be controlled by a pressure inlet / port communicating with the liquid chamber. See U.S. Pat. Nos. 5,908,378, 5,749,839, and 5,738,627.

  In another embodiment, the VAD can be used in an implanted system to supplement blood circulation pump function from outside the heart. For example, a VAD is an extracardiac pump system that can consist of an inflow / outflow conduit connected to a pump (such as a pulsatile or rotary pump) and a control panel for synchronously operating the pump. See U.S. Patent Nos. 6,610,004, 6,428,464, 6,200,260, and the like.

  In another embodiment, the VAD-related device can be used in conjunction with VAD or used independently to treat heart failure patients. For example, a VAD-related device is a stiffening device and can consist of a jacket that is applied to the heart to limit the expansion of the heart to a predetermined limit. See, for example, US Patent Nos. 6,582,355, 6,567,699, 6,241,654, and 6,169,922.

  Examples of VAD that may benefit from infiltrating the subject polymer composition into adjacent tissue in accordance with the present invention include commercial products. For example, Thoratec Corporation (Pleasanton, California) sells HEARTMATELeft Ventricular Assist Systems. WorldHeart Corporation (Ontario, Canada) sells WORLDHEARTNOVACOR Left Ventricular Assist System. Arrow International (Reading, PA) sells the LIONHEARTLeft Ventricular Assist System.

  In one embodiment, the present invention provides an LVAD comprising a subject polymer composition infiltrated into adjacent tissue, the polymer composition can comprise an anti-scarring agent and / or an anti-infective agent. A number of polymeric and non-polymeric delivery systems for use in VAD have already been described above. When these polymer compositions contain one or more fibrosis inhibitors and / or one or more anti-infectives, granulation tissue overgrowth is inhibited or reduced or infection at the site of VAD is prevented. Be inhibited or blocked.

  The polymer composition can be applied directly and / or indirectly to (a) the tissue adjacent to the VAD, (b) around the VAD-tissue interface, (c) the site around the VAD, (d) the tissue around the VAD Can infiltrate around the transplanted VAD. Methods of infiltrating a subject polymer composition into tissue adjacent to a VAD include delivery of the polymer composition to: (a) on the surface of the VAD (eg as injection material, paste, gel or mesh) during the implantation procedure, (b) on the tissue surface (eg injection material, paste, gel, mesh) just before or during implantation of the VAD. (As in situ gel or mesh); (c) Immediately after VAD implantation, VAD and / or tissues surrounding the implanted VAD (eg injection material, paste, gel, gel formed in situ) Or mesh) (d) Topical application of the composition to the anatomical space where the VAD is placed (especially useful in this example is a high release of therapeutic agent over a period ranging from hours to weeks. The use of molecular carriers-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and drug delivery and delivery to the site where the device is inserted Others that can be Formulation), (e) by intradermal injection of solutions, infusions, and sustained release formulations into the tissue surrounding VAD, and / or (f) application by a combination of the methods described above. Combination therapy (ie combination of therapeutic agents and antithrombotic or antiplatelet agents) can also be used. In all cases, it is understood that the subject polymer composition can be wetted to the entire device or to some surrounding tissue.

  According to one aspect, the anti-scarring agents and / or anti-infective agents described above can be used in the practice of the present invention. In one embodiment of the invention, the subject polymer composition infiltrated into tissue adjacent to VAD (such as LVAD) inhibits one or more of four general factors for the process of fiber formation (or scarring) including: Can be adapted to release drugs: new blood vessel formation (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) accumulation, and Remodeling (fibrotic tissue maturation and organization). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Since VADs are manufactured in a variety of shapes and dimensions, the exact dose administered will depend on the size, surface area and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Agent is the target of the device or per unit area scarring inhibitor administration of tissue surface coating (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm 2, or it may be about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplanted or tissue surface of the subject to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² Or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

In one embodiment, the subject polymer composition can invade tissue adjacent to a spinal implant (such as an artificial spine). The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents). As used herein, “artificial spine” means a device that is located within, on or near the spine and enhances the ability of the spine to perform its function in the host. An artificial spine can be used to treat the spinal column after the spine or composition, or part thereof, has degenerated or damaged. In a healthy host, the spinal column is composed of vertebral plates that are separated by an intervertebral disc that forms a strong joint and absorbs spinal cord compression. The intervertebral disc is composed of a gel-like internal substance called the nucleus pulposus together with a strong fibrocartilage capsule called the annulus fibrosus. If the disc is damaged, the host can suffer from spinal dysfunction, severe pain, and long-term disability. Disc damage usually requires surgery, and adjacent vertebral discs are often fixed using a variety of techniques and devices. Spinal segment fixation relieves pain by constraining spinal motion to the injured disc. When one spine segment is fixed, the host is not subject to noticeable movement limitations. However, if more than one segment is fixed, normal movement of the back is limited and more pressure is applied to the rest of the spinal joint, which may not alleviate the pain.

  In one embodiment, an artificial spine that facilitates fixation between spinal plates can be used to treat a damaged spinal segment. This can only be done if there is a single damaged spine segment. In another aspect, an artificial spine that maintains spinal motion within the spinal joint can be used to treat a damaged spinal segment. This can be done when multiple spine segments occur.

  Examples of artificial spines include spinal implants, artificial discs, intervertebral disc implants, cervical disc implants, intervertebral discs, implantable artificial spines, artificial spines, artificial discs, artificial implants, artificial spinal discs, vertebrae There are spinal discs and related devices including, but not limited to, intervertebral disc implants, implantable spinal grafts, implantable bone graphs, and artificial discs, spinal nucleus implants, and intervertebral disc spacers. In addition, the artificial spine includes a fixing cage and related devices (such as a fixing basket), a fixing cage device, an interbody cage, an interbody graft, a fixing device, a fixing cage fixing device, a bone fixing device, Includes bone fixation devices, bone fixation devices, fixation stabilization chambers, fixation plates for fixation cages, fixation bone plates, bone screws.

  Artificial vertebrae according to the present invention may comprise allograft bone material (see, eg, US Pat. No. 6,143,033), metal (see US Pat. No. 4,955,908), and / or synthetic material (US Pat. Nos. 6,264,695, 6,419,706, (See 5,824,093 and 4,911,718, etc.)), but can be composed of a single substance or various substances. The prosthesis must be biocompatible. It can also be composed of biodegradable or non-biodegradable components, depending on the intended function of the device. See U.S. Pat. No. 4,772,287. The artificial spine has no biological activity and functions as a mechanical means to stabilize the spinal column (see US Pat. Nos. 4,955,908 and 5,716,415, etc.) or has biological activity and facilitates fixation by the adjacent vertebral plate (See US Pat. Nos. 5,489,308 and 6,520,993).

  In one embodiment, the prosthesis may be a fixation cage designed to facilitate spinal fixation to limit movement between adjacent vertebrae. An anchoring cage is an interbody device that fits within an intervertebral space, or an interbody device that surrounds both the intervertebral space and the interior of the anterior portion of the spinal column. There are various shapes for the fixing cage. For example, the fixing cage may be rectangular or cylindrical, and may have a large number of openings and helical threads. The anchoring cage can have an outer body cavity and a cavity in the cavity that may or may not be used for insertion of a bone promoting material to stimulate bone anchoring. For example, the prosthesis may be an interbody fusion cage that protrudes from a hemispherical outer end that is secured using a plate, fastener and bone screw assembly and has an externally threaded axis. See US Pat. No. 6,156,037. The prosthesis may be a fixation cage with a threaded outer surface adapted to facilitate fixation with the bone structure when a bone growth inducing agent is implemented in the cage body. See U.S. Pat. Nos. 4,961,740, 5,015,247, 4,878,915 and 4,501,269. The prosthesis may be a tubular shell with helical threads protruding through a plurality of perforated columns to facilitate bone ingrowth and mechanical fixation. See U.S. Patent Nos. 6,071,310 and 5,489,308. Other US patents that describe threaded spinal grafts include US Pat. Nos. 5,263,953, 5,458,638, and 5,026,373.

  In another aspect, the prosthesis may be a bone fixation device designed to facilitate spinal fixation to limit movement between adjacent vertebrae. For example, bone dowels, rods, hooks, wires, wedges, plates, screws, and other components can be used to secure the spinal segment in place. The fixation may be contained within the intervertebral space, or may encompass both the intervertebral space and the anterior portion of the spinal column, or may include only the anterior portion of the spinal column. A bone fixation device can be used in conjunction with a fixation cage to assist in stabilizing the device within the intervertebral region. For example, the prosthesis can take the form of a ring-shaped solid having a plurality of discrete teeth meshing with bones protruding from the upper and lower surfaces and a central opening filled with a bone promoting substance. See US Pat. No. 6,520,993. The prosthesis can have a disc-shaped body with a welded raised portion that is placed on the opposite surface to increase lateral stability in situ. See U.S. Pat. No. 4,917,704. The prosthesis can be constructed from the opposite end that maintains the height of the intervertebral space by a synthetic central element with a smaller diameter, where the osteogenic material is placed inside the distal annular pocket Is done. See US Pat. No. 6,146,420. A prosthesis can be constructed from first and second sides extending parallel to the top and bottom surfaces that bite adjacent spines. See US Pat. No. 5,716,415. The prosthesis may be a fixed stabilization chamber composed of a hollow intervertebral spacer and an end with at least one hole for attachment to the surrounding bone. See US Pat. No. 6,066,175. The prosthesis can be constructed from a metal body having a plurality of seam plates that taper conically from the abdomen to the back and have bone screw openings and extend from opposite sides. See U.S. Pat. No. 4,955,908. The prosthesis may consist of a pair of plates with protrusions that engage adjacent vertebrae to maintain the plates in a prone arrangement and an alignment device disposed between the engaging plates to separate the plates. it can. See US Pat. No. 6,576,016. The prosthesis may be a plurality of implants inserted side by side in the disc space that promote bone fixation throughout the intervertebral space. See U.S. Pat. No. 5,522,899. A prosthesis consists of a fixation plate with a central portion configured to attach to a spinal implant (eg, a fixation cage) and an end adapted to be secured to a bone segment of a vertebra It may be a device. See US Pat. No. 6,306,170. The prosthesis may be a bone fixation device composed of a bone plate and a fastener device (such as a bone screw). See U.S. Pat. Nos. 6,342,055, 6,454,769, 6,602,257 and 6,620,163.

  In another aspect, the prosthesis can be an alternative to spinal fixation. The prosthesis may be an intervertebral disc designed to provide normal movement between vertebral plates. The purpose of the artificial disc is to simulate the natural shock absorbing function of the natural disc. An artificial disc can be constructed from the core and end elements that support the disc with respect to adjacent vertebrae, or it can be intended to replace only a portion of a natural disc (such as the nucleus pulposus). For example, the artificial disc may be in the form of an elastomeric section sandwiched between two rigid plates. See U.S. Patent Nos. 6,162,252, 5,534,030, 5,017,437 and 5,031,437. The intervertebral disc may be an elongated artificial intervertebral disc nucleus composed of a hydrogel core and a contrasting flexible jacket capable of deforming and improving the core. See US Pat. No. 5,824,093. An artificial intervertebral disc can be composed of robust upper and lower concavo-convex elements and a nucleus located between concave surfaces to allow movement. See US Pat. No. 6,156,067. The artificial disc may be a partial artificial spine composed of a core made of an elastic material such as a silicone polymer or elastomer covered by a housing made of a rigid material in contact with the adjacent spine. See US Pat. No. 6,419,706. The prosthetic disc uses only spinal nucleus tissue, using a spinal nucleus implant made of an expandable, biomimetic plastic with a hydrophobic and hydrophilic phase that can be expanded in situ to fit its natural size and shape Can be exchanged. See US Pat. No. 6,264,695. An artificial intervertebral disc can consist of a core formed from a biocompatible elastomer encased in a multi-layered thin film made of elastomer and fibers. See U.S. Pat. No. 4,911,718. An artificial intervertebral disc can consist of an inner bladder filled with a liquid with an outer layer of strong, inert fibers that intermingles with bioabsorbable materials that promote tissue ingrowth. See U.S. Pat. No. 4,772,287.

  In another aspect, the spinal implant may be a device that reduces spinal compression and reduces adhesions resulting from spinal surgery and / or trauma. For example, a protective device comprising a shield with at least one thin film on the rear surface can prevent adhesion formation on the spinal dura after surgery. See U.S. Patent Nos. 5,437,672 and 5,868,745, U.S. Patent Application No. 2003/0078588, and the like. The device may be a prosthesis having a patch flange and a suture flange extending around the patch so that the tissue under the patch is shielded and does not effectively adhere to the scar growth. See US Pat. No. 5,634,944. The device may be a protective intervention barrier consisting of a biocompatible shield used after intra- or spinal surgery to prevent post-surgical adhesion to the spinal nerve. See U.S. Pat. No. 4,013,078. The device can be used for nerve decompression. On the other hand, fiber growth around nerve tissue is reduced by roughening the surface using a microstructure extending outward. See U.S. Patent No. 6,106,558, U.S. Patent Application No. 2003/0078673, and the like.

  Prosthetic spines and other spinal implants that can benefit from having the subject polymer composition infiltrated into adjacent tissue in accordance with the present invention include commercial products. Medtronic Sofamor Danek (Memphis, Tennessee) sells the fixed cage product INTERFIX Threaded FusionDevice. Centerpulse Spine-Tech (Minneapolis, Minnesota) sells BAK / C Cervical Interbody Fusion System fixation cage products and CERVI-LOK Cervical Fixation System fixation devices. SpinalConcepts (Austin, Texas) sells the SC-ACUFIX Anterior Cervical Plate System. DePuySpine, Inc. (Rainham, MA) sells the spinal disc ACROFLEX TDR prosthesis and CHARITE Artificial Disc. Synthes-Stratec (Switzerland) sells PRODISC systems (including PRODISCCervical-C IDE replacement disks). Raymedica, Inc. (Minneapolis, Minnesota) sells PDN (PROSTHETICDISC NUCLEUS).

  In one embodiment, the present invention provides a spinal implant comprising a subject polymer composition infiltrated into adjacent tissue, the polymer composition comprising a therapeutic agent (such as an anti-scarring agent and / or an anti-infective agent). be able to. A number of polymeric and non-polymeric carrier systems that can be used with spinal grafts have already been described above. By infiltrating the tissue adjacent to the spinal graft with a subject polymer composition comprising a fibrosis inhibitor and / or an anti-infective agent, fiber formation (or scarring) in the vicinity of the graft is minimized, and the graft Can reduce or prevent the formation of adhesions with the surrounding tissue, or can inhibit or prevent infection in the vicinity of the implantation site.

  In one embodiment, the present invention provides a spinal graft in which adjacent tissue is infiltrated with the subject polymer composition. The subject polymer compositions include therapeutic agents (scarring inhibitors and / or anti-infections) to inhibit scarring or adhesion between the device and surrounding bone, or to inhibit or prevent infection at the implantation site. Medicine).

  The polymer composition is applied to (a) the tissue adjacent to the spinal graft, (b) around the interface between the spinal graft and tissue, (c) the site around the spinal graft, (d) the tissue around the spinal graft. Direct and / or indirect application can infiltrate around the implanted spinal graft. Methods for infiltrating a tissue adjacent to a spinal graft with a subject polymer composition include delivery of the polymer composition to: (a) on the surface of the spinal graft (eg as injection material, paste, gel or mesh) during the implantation procedure, (b) on the tissue surface (eg injection material, injection material, just before or during implantation of the spinal graft) Pastes, gels, as in situ formed gels or meshes) (c) Immediately after the implantation of the spinal graft, the spinal graft and / or the tissue surrounding the implanted spinal graft (eg, injection material, paste) (D) topical application of the composition to the anatomical space in which the spinal implant is placed (especially useful in this example from several hours The use of polymeric carriers that release therapeutic agents over a period of several weeks-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants, and Drug Other formulations that can be delivered to the site where the dispensing device is inserted), (e) by intradermal injection of solutions, infusions, and sustained release formulations into the tissue surrounding the spinal implant and / or (f) above Application by a combination of methods. Combination therapy (ie combination of therapeutic agents and antithrombotic or antiplatelet agents) can also be used. In all cases, it is understood that the subject polymer composition can be wetted to the entire device or to some surrounding tissue.

  In one embodiment, a subject polymer composition comprising an anti-scarring agent and / or an anti-infective agent is infiltrated into tissue adjacent to a spinal graft (such as an implantable cage or spinal disc). In certain embodiments, the spinal implant is coated with (or adapted to contain) a fiber inducer (such as silk or talc) at a portion of the device. Also, a subject polymer composition comprising an anti-scarring agent can invade tissue adjacent to another location of the device. For example, the outer surface of a graft (such as a spinal graft) can be coated with a fiber inducer to promote adhesion between the device and surrounding tissue. On the other hand, the subject polymer composition comprising an anti-scarring agent will infiltrate the tissue adjacent to the inside of the device to minimize tissue adhesion to the inside of the graft. Examples of fiber inducers and methods of using fiber inducers in combination with spinal implants are described in co-pending applications (US Application No. 60, filed November 20, 2003, entitled “Medical Implants and Fibrosis-Inducing Agents”). / 524,023) and the application filed on June 9, 2004 (US Application No. 60 / 578,471).

  According to one embodiment, any adhesion or fibrosis inhibitor and / or anti-infective agent described above can be used in the practice of the present invention. In one embodiment of the present invention, the subject polymer composition infiltrated into the tissue adjacent to the spinal graft inhibits one or more of the four general factors for the process of fiber formation (or scarring) comprising: Can be adapted to release: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), accumulation of extracellular matrix (ECM), and remodeling (Maturation and organization of fibrous tissue). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Because spinal implants are made in a variety of shapes and sizes, the exact dose to be administered depends on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Agent is the target of the device or per unit area scarring inhibitor administration of tissue surface coating (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm 2, or it may be about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplanted or tissue surface of the subject to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² Or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

Nerve Stimulation Device In one embodiment, the subject polymer composition can infiltrate tissue adjacent to the nerve stimulation device. Pulse generators transmit electrical shocks to neural tissue (CNS, peripheral nerves, autonomic nerves, etc.) to regulate their activity. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  There are a number of neurostimulators that have an adverse effect on the function of the device, or the ecological problems in which it is implanted or used, by the occurrence of a fibrous response. In general, fiber coating of the lead wire (or growth of fibrous tissue between the lead wire and the target tissue) delays, impairs or blocks the transfer of impact from the device to the tissue. This causes the device to perform at its best or not at all, or requires increased energy to overcome the electrical resistance imposed by the intervening scar (or glial) tissue, resulting in reduced battery life. Excessive wear may occur. Implanting a neurostimulator may cause or promote infection around the implantation site.

  Neurostimulators are used as an alternative or adjunct therapy for chronic, neurodegenerative diseases and are generally treated with drug therapy, invasive therapy, or behavioral / lifestyle changes. Neural stimulation blocks, masks, or stimulates the body's electrical signals to cause pain, seizures, anxiety disorders, depression, ulcers, deep vein thrombosis, muscle atrophy, obesity, joint stiffness, muscle spasms, osteoporosis, spinal side Used to treat dysfunctions including, but not limited to, manic, spinal disc degeneration, spinal cord injury, hearing loss, urinary dysfunction, gastric failure. Neural stimulation can be delivered to many different parts of the nervous system, such as the spinal cord, brain, vagus nerve, sacral nerve, gastric nerve, auditory nerve, and organs, bones, muscles, tissues, and the like. Thus, neural stimulators are developed to match different anatomical structures and characteristics of the nervous system. Representative examples of neurological and neurosurgical grafts and devices that can benefit from infiltrating a subject polymer composition into adjacent tissue in accordance with the present invention include neurostimulators, continuous arachnoids that reduce pain There are infusion devices, implantable electrodes, stimulation electrodes, implantable pulse generators, leads, stimulation catheter leads, nerve stimulation systems, electrical stimulation devices, implanted cochlear stimulation devices, auditory stimulation devices and micro stimulation devices .

  Neural stimulators can also be classified based on power sources including: Battery type, radio frequency type or a combination of both. In the case of a battery-powered neurostimulator, an implanted, non-rechargeable battery is used as a power source. Since the battery and leads are all surgically implanted, the nerve stimulator is completely covered inside. The setting of the fully implanted neurostimulator is controlled by the patient through an external magnet. The life of the implant is generally limited by the life of the battery and can range from 2 to 4 years depending on usage and power requirements. In the case of a radio frequency neurostimulator, radio frequency is transmitted from a worn source to an implanted passive receiver. Since the power supply can be quickly charged or replaced, large battery capacities can be used in radio frequency systems, and multiple leads can be used in these systems. A specific example is a nerve stimulation device that has a built-in power supply and supplies power for 8 hours or more. In this case, the power is controlled by an external radio frequency coupling device (see U.S. Pat.No. 5,807,397) or an external transmitter using a data signal and powered by radio frequency (US Pat. No. 6,061,596). To replenish.

  An example of a commercially available nerve stimulation product is a radiofrequency nerve stimulation device consisting of 3272 MATTRIX Receiver, 3210 MATTRIXTransmitter and 3487A PISCES-QUAD Quadripolar Leads from Medtronic, Inc. (Minneapolis, MN). Medtronic also sells battery-powered ITREL3 and SYNERGY nerve stimulators, and 3998 SPECIFY and 3587A RESUME II leads for sacral nerve stimulation to control the urology.

  Another example of a nerve stimulator is a stomach pacemaker. In a gastric pacemaker, a plurality of electrodes are placed along the digestive tract to deliver electrical stimulation in stages and regulate the peristaltic movement of the material through the digestive tract. See US Pat. No. 5,690,691. A typical example of gastric stimulation is ENTERRA Gastric Electrical Stimulation (GES) manufactured by Medtronic, Inc. (Minneapolis, MN).

  In particular, nerve stimulation devices such as leads must be accurately positioned to ensure that the stimulation is delivered to the correct anatomical location of the nervous system. All or some of the neurostimulators may migrate after surgery, or excessive scar (glia) tissue growth may occur around the graft (as described above), leading to reduced efficacy of these devices. A neurostimulator in which the subject polymer composition is infiltrated into tissue adjacent to the electrode-tissue interface can be used to increase the effectiveness and / or duration of the implant (especially a fully implanted battery). Type device). For neurostimulators, it is also effective to release therapeutic agents that prevent or reduce infection around the implantation site. The present invention provides a nerve stimulation lead infiltrated with the polymer composition of interest in adjacent tissue. The subject polymer composition may include a therapeutic agent (such as an anti-scarring agent and / or an anti-infective agent). A number of polymeric and non-polymeric delivery systems for use in neurostimulators have already been described above.

  The polymer composition is applied to (a) the tissue adjacent to the nerve stimulator, (b) around the interface between the nerve stimulator and the tissue, (c) the site around the nerve stimulator, (d) Direct and / or indirect application can infiltrate the implanted nerve stimulator. Methods for infiltrating a subject polymer composition into tissue adjacent to a neurostimulator include delivery of the polymer composition to: (a) on the surface of the neurostimulator during the implantation procedure (eg as an injection substance, paste, gel or mesh), (b) immediately before or during the implantation of the nerve stimulation apparatus (eg injection substance, (C) immediately after implantation of the nerve stimulator, and / or the surface of the tissue surrounding the implanted nerve stimulator (eg, injection material) (D) topical application of the composition to the anatomical space in which the neurostimulator is placed (especially useful in this example from several hours The use of polymeric carriers that release therapeutics over a period of several weeks-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants And other formulations that can release the drug and be delivered to the site where the device is inserted), (e) by intradermal injection of solutions, infusions, and sustained release formulations into the tissue surrounding the nerve stimulation device, and / or Or (f) Application by a combination of the methods described above. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the polymer composition of interest can wet the surrounding tissue of the entire device or a portion (device only, lead only, electrode only, and / or combinations thereof).

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the present invention, the subject polymer composition infiltrated in tissue adjacent to the nerve stimulator inhibits one or more of the four general factors for the process of fibrosis (or scarring) comprising: Can be adapted to release: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), accumulation of extracellular matrix (ECM), and remodeling (Maturation and organization of fibrous tissue). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Since neurostimulators are made in a variety of shapes and sizes, the exact dose administered depends on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Agent is the target of the device or per unit area scarring inhibitor administration of tissue surface coating (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm 2, or it may be about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplanted or tissue surface of the subject to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² Or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxins (eg, etoposide)) It should be immediately apparent that can be used to enhance the antimicrobial activity of the composition.

  For more clarity, some specific nerve stimulation devices and treatments are detailed below.

(1) Nerve stimulating device for treatment of chronic pain In one embodiment, the subject polymer composition can invade tissue adjacent to the nerve stimulating device to manage chronic pain. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  Chronic pain is one of the most important clinical problems of all drugs. For example, it is estimated that more than 5 million people in the United States suffer from back pain. The economic cost of chronic back pain is enormous, estimated to cost $ 50 billion to $ 100 billion, losing 100 million working days per year. About 40 million Americans suffer from recurrent headaches, and the cost of drugs spent on this is over $ 4 billion annually. In addition, 8 million Americans are reported to experience chronic neck or facial pain and spend approximately $ 2 billion annually on treatment. The cost of treating pain in tumor patients is expected to reach $ 12 billion. Chronic pain powers more people than cancer and heart disease, forcing the American population to pay more than cancer and heart disease combined. In addition to physical effects, chronic pain costs many other things, including job loss, marital discord and prescription drug addiction. Thus, it is clear that reducing the costs associated with morbidity and persistent pain will continue to be an important challenge for healthcare systems.

  Due to injury, disease, scoliosis, spinal disc degeneration, spinal cord injury, malignant tumor, arachnoiditis, chronic disease, pain syndrome (eg iatrogenic postoperative instability low back pain, complex local pain syndrome) and other causes The stubborn severe pain that causes a weakening has become a common medical problem. For many patients, continued use of drugs such as analgesics, especially narcotics, is a viable solution because of the potential for tolerance, loss of efficacy, and addiction. To combat this, neurostimulators have been developed to treat stubborn severe pain that is resistant to other traditional treatment therapies such as drug therapy, invasive therapy (surgery), or behavioral / lifestyle changes.

  Basically, neural stimulation works by delivering low voltage electrical stimulation to the spinal cord or certain peripheral nerves to block pain. “Gate Control Theory of Pain” (co-authored by Ronald Melzack / Patrick Wall) hypothesizes that there is a “gate” in the spinal dorsal horn that controls the flow of pain signals from peripheral receptors to the brain. The body appears to be able to block the signal ("close the gate") by activating other (non-pain) fibers in the dorsal area. The neural device is implanted into the epidural space of the spinal cord, stimulating the nociceptive nerve fibers in the dorsal horn to mask pain. As a result, patients generally experience a tingling sensation (known as illusion) instead of pain. With neurostimulators, the majority of patients should report improved pain relief (50% reduction), increased activity levels, and reduced use of narcotics.

  A pain management neural stimulation system consists of a power source that generates electrical stimulation, a lead (typically 1 or 2) that delivers electrical stimulation to the spinal cord or target peripheral nerve, and an electrical connection that connects the power source to the lead. The neural stimulation system can be battery powered, radio frequency, or a combination of both. In general, there are two types of nerve stimulation devices: A neurostimulator implanted by surgery and fully implanted in the body (i.e., the battery and lead are implanted), an internal (lead and radio frequency receiver) composition, and an external (power and antenna) composition It is a nerve stimulation device consisting of things. In the inner case, the battery powered neurostimulator, implanted, non-rechargeable battery and lead are all implanted surgically. The setting of a fully implanted neurostimulator is controlled by the host using an external magnet, and the graft has a lifetime of 2-4 years. In the case of a radio frequency neurostimulator, radio frequency is transmitted from a worn source to an implanted passive receiver. Since a larger battery capacity can be used in a radio frequency system, multiple leads can be used.

  There are a number of neurostimulators that can be used for spinal cord stimulation for pain management, position positioning and other disorder management. Examples of specific neurostimulators include sensors that detect the position of the spine and stimulators that automatically emit pulses that decrease in amplitude when supine. See U.S. Pat. Nos. 5,031,618 and 5,342,409. The nerve stimulation apparatus includes an electrode and a control circuit, and the control circuit includes a rest period at intervals corresponding to physical activity and a regeneration period as a treatment for pain. See U.S. Pat. No. 5,354,320. A neurostimulator implanted in the epidural space parallel to the spinal axis transmits data to the receiver to generate spinal stimulation pulses that are delivered through the combined multi-electrode. See US Pat. No. 6,609,031, etc. The neurostimulator consists of a stimulation catheter lead with a sheath and at least three electrodes, and delivers the stimulation to the neural tissue. See US Pat. No. 6,510,347. The neurostimulator is a self-rescue epidural spinal lead with a pivot region to stabilize the lead and expands when injected with a sclerosing agent. See US Pat. No. 6,308,103. Other neurostimulators used to induce electrical activity in the spinal cord are described in US Pat. Nos. 6,546,293, 6,236,892, 4,044,774, and 3,724,467.

  In accordance with the present invention, neurostimulators for chronic pain management that may benefit from infiltrating the subject polymer composition into adjacent tissue include commercial products. Commercially available neurostimulators for chronic pain management include SYNERGY, INTREL, X-TREL and MATTRIX neurostimulation systems from Medtronic, Inc. The percutaneous leads of this system can be quadrupole (4 electrodes) such as PISCES-QUAD, PISCES-QUADPLUS and PISCES-QUAD Compact, or octupole (8 electrodes) such as OCTAD lead. The surgical lead itself is a quadrupole type such as SPECIFY lead, RESUME II lead, RESUME TL lead, and ON-POINT PNS lead, creating a wide range of multiple stimulus combinations and illusions. Such neural stimulation systems and related leads are described in US Pat. Nos. 6,671,544, 6,654,642, 6,360,750, 6,353,762, 6,058,331, 5,342,409, 5,031,618, and 4,044,774. Such neurostimulation leads benefit from the release of therapeutic agents, reduce scarring at the electrode-tissue interface, improve the efficiency of shock transmission, and extend the period during which the lead is clinically functional be able to. For such nerve stimulation leads, the release of therapeutic agents that prevent or inhibit infection around the implantation site is also effective. In one embodiment, the device is infiltrated with a polymer composition of interest comprising an anti-scarring agent and / or an anti-infective agent in the tissue adjacent to the site where the device or lead is present or the site to be implanted. Neurostimulators and / or leads for chronic pain management. In another aspect, the present invention provides a subject polymer composition comprising a scarring inhibitor and / or an anti-infective agent in tissue adjacent to the epidural space where the lead is or will be implanted. Provide infiltrated leads. Other commercial systems that may be useful in the practice of the invention as described above include the rechargeable PRECISION Spinal Cord Stimulation System (a subsidiary of Boston Scientific Company, Advanced Bionics Corporation, Schirmer, Calif.) That can drive up to 16 electrodes. (See US Pat. Nos. 6,735,474, 6,735,475, 6,659,968, 6,622,048, 6,516,227 and 6,052,624). GENESIS XP Spinal Cord Stimulator from AdvancedNeuromodulation Systems, Inc. (Plano, Texas) (see US Pat. Nos. 6,748,276, 6,609,031, and 5,938,690) and Vagus Nerve Stimulation (VNS) TherapySystem from Cyberonics, Inc. (Houston, Texas) (See US Pat. Nos. 6,721,603 and 5,330,515) can also benefit from infiltrating the subject polymer composition into adjacent tissue in accordance with the present invention.

  Regardless of the specific design function, for nerve stimulation to be effective in reducing pain, nerves that require the lead to be accurately placed adjacent to the electrically stimulated spinal cord segment or target peripheral nerve Stimulators may migrate after surgery, or excessive tissue growth or extracellular matrix accumulation may occur around the nerve stimulator, resulting in reduced function of these devices. Nerve stimulating devices in which the polymer composition of interest is infiltrated into tissue adjacent to the electrode-tissue interface can be used to increase the period during which these devices function clinically. For neurostimulators, it is also effective to release therapeutic agents that prevent or inhibit infection around the implantation site. In one aspect, the present invention provides a neurostimulator for chronic pain management in which the subject polymer composition is infiltrated into tissue adjacent to the grafted portion (particularly the lead). The subject polymer composition includes a therapeutic agent (such as an anti-scarring agent and / or an anti-infective agent). A number of polymeric and non-polymeric delivery systems for use in neurostimulators for chronic pain management have already been described above.

  The polymer composition comprises: (a) tissue adjacent to a nerve stimulation device for chronic pain management; (b) around the interface between the nerve stimulation device and tissue for chronic pain management; and (c) nerve for chronic pain management. The area around the stimulator, (d) around the implanted neurostimulator for chronic pain management by applying directly and / or indirectly to the tissue surrounding the neurostimulator for chronic pain management Can infiltrate. A method of infiltrating a subject polymer composition into tissue adjacent to a neurostimulator for chronic pain management includes delivery of the polymer composition to: (a) Immediately before implanting a neurostimulator for chronic pain management on the surface of a neurostimulator for chronic pain management (e.g., as an injection material, paste, gel or mesh) or In the process, chronic pain management on the tissue surface (eg as injection material, paste, gel, gel or mesh formed in situ) (c) Immediately after implantation of a neurostimulator for chronic pain management (D) on the surface of the tissue surrounding the neurostimulator for surgery and / or the implanted nerve stimulator for chronic pain management (eg injection material, paste, gel, gel or mesh formed in situ) Topical application of the composition to the anatomical space where a neurostimulator for chronic pain management is placed (especially useful in this example is a polymeric carrier that releases the therapeutic agent over a period ranging from hours to weeks Is the use of-liquid, suspension , Emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants, and other formulations that release drugs and can be delivered to the site where the device is inserted), (e) chronic Application by intradermal injection of solutions, infusions, and sustained release formulations to the tissue surrounding the nerve stimulator for pain management and / or (f) by a combination of the methods described above. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the polymer composition of interest can infiltrate the surrounding tissue of the entire device or a portion (device only, lead only, electrode only, and / or combinations thereof).

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the invention, the subject polymer composition infiltrated into tissue adjacent to a neurostimulator for chronic pain management is one of four general factors for the process of fiber formation (or scarring) comprising: Or can be adapted to release drugs that inhibit more than one: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) Accumulation and remodeling (fibrotic tissue maturation and organization). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Because neurostimulators for chronic pain management are manufactured in a variety of shapes and sizes, the exact dose administered depends on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Agent is the target of the device or per unit area scarring inhibitor administration of tissue surface coating (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm 2, or it may be about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplanted or tissue surface of the subject to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² Or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

(2) Nerve stimulation for treatment of Parkinson's disease In one embodiment, the subject polymer composition can invade tissue adjacent to a nerve stimulation device for treatment of Parkinson's disease. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  Neurostimulators implanted in the brain are used to control symptoms associated with Parkinson's disease or essential tremor. In general, these devices are two-chamber neurostimulators (similar to cardiac pacemakers) that deliver both stimuli to the part of the brain that controls motor function. Electrical stimulation to relieve muscular symptoms due to Parkinson's disease itself (tremors, stiffness, slow movements, inability to move) or symptoms that occur as a result of the side effects of drugs used to treat the disease (movement disorders) used. Two stimulation electrodes are implanted into the brain (usually between the subthalamic nucleus or pallidal bulb) for the treatment of Parkinson's disease, which responds to levodopa, and one stimulation electrode is used for the treatment of tremor (middle ventral side of the thalamus) Transplanted into the nucleus). Electrodes are implanted into the brain by stereotaxic surgery using a stereotaxic head frame or MRI or CT guidance. The electrodes are connected through an extension (running under the scalp and neck skin) to a nerve stimulation (pulse generating) device implanted under the skin near the clavicle. A neurologist can optimize symptom control by adjusting stimulation parameters while using a non-invasive controller that communicates with the neurostimulator via telemetry. The patient can also use a magnet to turn the system on and off and use the controller to control device settings (within limits set by the neurologist). This form of deep brain stimulation has also been investigated for pain, epilepsy, mental status (obsessive compulsive disorder) and ataxia.

  For such applications involving implantable electrodes, for example used for tissue monitoring and stimulation of the cortical tissue of the brain and other tissues with a neurostimulator and a flexible, non-conductive coating material, Several devices have been described. See US Pat. No. 6,024,702. A nerve stimulator (pulse generator) is composed of an electrical control module that can be implanted in the cranium and a large number of electrodes, and stimulates brain tissue with electrical signals of a certain frequency. See US Pat. No. 6,591,138. A neural signal device is a system that consists of at least two electrodes adapted to the skull, a control module adapted to be implanted under the scalp to transmit output electrical signals, and an external device for two-way communication. is there. See U.S. Patent No. 6,016,449. A neurostimulator is an implantable assembly of one sensor and two electrodes that is used to alter the electrical activity of the brain. See US Pat. No. 6,466,822.

  In accordance with the present invention, neurostimulators for the treatment of Parkinson's disease that may benefit from infiltrating the subject polymer composition into adjacent tissue include commercial products. Commercially available examples of devices used to treat Parkinson's disease and essential tremor include the ACTIVA System from Medtronic, Inc. (see, for example, US Pat. Nos. 6,671,544 and 6,654,642). This system consists of a KINETRADual Chamber neurostimulator, SOLETRA neurostimulator or INTREL neurostimulator, connected to an extension (insulated wire) and further connected to a DBS lead. The DBS lead consists of four thin, insulated and polyurethane coiled wires. Each of the four wires is a 1.5mm long electrode. In one embodiment, the present invention provides a nerve stimulator and / or a lead for treating Parkinson's disease, wherein the nerve is infiltrated with a polymer composition of interest in a tissue adjacent to a site to be implanted or to be implanted. A stimulator is provided. The subject polymer composition may include a therapeutic agent (such as an anti-scarring agent and / or an anti-infective agent). In another aspect, the present invention has infiltrated a subject polymer composition comprising an anti-scarring agent and / or an anti-infective agent into tissue adjacent to the tissue in which the lead has been or will be implanted. Provide lead wires (DBS lead wires, etc.). In another aspect, the invention provides a subject polymer composition comprising a scarring inhibitor and / or an anti-infective agent in brain tissue adjacent to a site where a lead electrode is or is to be implanted. Provide infiltrated DBS leads.

  A number of polymeric and non-polymeric delivery systems for use in neurostimulators for the treatment of Parkinson's disease have already been described above.

  The polymer composition comprises (a) a tissue adjacent to a nerve stimulator for treating Parkinson's disease, (b) around the interface between the nerve stimulator for treating Parkinson's disease and the tissue, and (c) a nerve stimulator for treating Parkinson's disease. It can infiltrate around the implanted nerve stimulator for treating Parkinson's disease by applying directly and / or indirectly to the surrounding site, (d) the tissue surrounding the nerve stimulator for treating Parkinson's disease. A method of infiltrating a subject polymer composition into tissue adjacent to a neurostimulator for treating Parkinson's disease includes delivery of the polymer composition to: (b) Immediately before or after implantation of a nerve stimulator for treatment of Parkinson's disease on the surface of the nerve stimulation device for treatment of Parkinson's disease (eg, as an injection material, paste, gel or mesh) during the transplantation procedure. (C) Neural stimulation for treatment of Parkinson's disease immediately after implantation of the neural stimulation device for treatment of Parkinson's disease on the tissue surface (eg as injection material, paste, gel, gel or mesh formed in situ) (D) for treatment of Parkinson's disease on the surface of the tissue surrounding the device and / or the implanted neurostimulation device for treatment of Parkinson's disease (eg injection material, paste, gel, gel or mesh formed in situ) Topical application of the composition to the anatomical space in which the neurostimulator is placed (especially useful in this example is a polymeric carrier that releases the therapeutic agent over a period ranging from hours to weeks -Can be delivered to liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and the site where the drug is released and the device is inserted Other formulations), (e) intradermal injection of solutions, infusions, and sustained release formulations into tissues surrounding a nerve stimulator for treatment of Parkinson's disease and / or (f) application by a combination of the methods described above. . Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the polymer composition of interest can wet the surrounding tissue of the entire device or a portion (device only, lead only, electrode only, and / or combinations thereof).

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the invention, the subject polymer composition infiltrated into tissue adjacent to a neurostimulator for treating Parkinson's disease is one of four general factors for the process of fibrosis (or scarring) comprising: Can be adapted to release drugs that inhibit multiple: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) Accumulation and reformation (fibrotic tissue maturation and organization). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Since neurostimulators for treating Parkinson's disease are manufactured in a variety of shapes and sizes, the exact dose administered depends on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Agent is the target of the device or per unit area scarring inhibitor administration of tissue surface coating (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm 2, or it may be about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplanted or tissue surface of the subject to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² Or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

(3) Vagus nerve stimulation for treatment of epilepsy In one embodiment, the subject polymer composition may infiltrate tissue adjacent to the neurostimulator to treat epilepsy. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  Nerve stimulators are also used to stimulate the vagus nerve in the management of drug-resistant sputum (ie sputum that is not suppressed despite proper medication with antidepressants). Despite various attempts to control illness with medication, about 30% of epilepsy patients continue to have seizures and cannot tolerate the side effects of those medications. Approximately 2.5 million patients in the United States suffer from treatment-resistant epilepsy and are estimated to benefit from vagus nerve stimulation therapy. Thus, improper seizure control not only leaves important medical problems, but many patients suffer from limited self-esteem, poor academic performance, and limited lifestyle as a result of the disease.

  The vagus nerve (also called the tenth cranial nerve) contains primarily afferent sensory fibers, from the neck, thorax and abdomen to the brainstem nucleus cortex sortarius and multiple noradrenergic and serotonergic neuromodulators of the brain and spinal cord Carry information to the system. Vagus nerve stimulation (VNS) has been shown to induce progressive EEG changes and alter blood flow on both sides of the brain. Although the exact mechanism of seizure control is not known, VNS ends seizures after they begin, reduces seizure intensity and frequency, and prevents seizures when used prophylactically over time, It has been clinically shown that it can improve quality of life and reduce dosage, number and side effects of antiepileptic drugs (resulting in improved agility, mood and memory).

  In the VNS, bipolar leads are surgically implanted to deliver electrical stimulation from the pulse generator to the left vagus nerve of the neck. The pulse generator is an implanted lithium carbonate monofluoro battery powered device that delivers a precise stimulation pattern to the vagus nerve. Although the pulse generator can be programmed by a neurologist (using programming software) to suit the patient's individual symptoms, the patient can use an external magnet to switch the device on and off. Chronic electrical stimulation that can be used as a direct treatment for epilepsy is described, for example, in US Pat. No. 6,016,449, whereby an implantable neurostimulator is coupled to a semi-permanent deep brain electrode. An implantable neurostimulator consists of an implantable lead having a bifurcated, split, or distal portion at two or more separate end portions. Each separate end portion includes at least one detection or stimulation electrode and is used to treat epilepsy and other neurological disorders. See US Pat. No. 6,597,953.

  In accordance with the present invention, neurostimulators for acupuncture that may benefit from infiltrating the subject polymer composition into adjacent tissue include commercially available products. Examples of commercially available VNS systems include Model 300 and Model 302 leads from Cyberonics, Inc., Model 101 and Model 102R pulse generators, Model 201 programming software and Model 250 programming software, and Model 220 magnets. Product included. These products manufactured by Cyberonics, Inc. are described in US Pat. Nos. 5,540,730 and 5,299,569.

  Regardless of the specific design function, in order for vagus nerve stimulation to have an effect on epilepsy, the lead must be accurately placed adjacent to the left vagus nerve. If excessive scar tissue growth or extracellular matrix accumulation occurs around the VNS lead, it can lead to reduced device effectiveness. VNS devices that infiltrate adjacent tissue with the polymer composition of interest can improve the efficiency of shock transmission and extend the period during which these devices function clinically. VNS devices are also effective in releasing therapeutic agents that prevent or reduce infection around the implantation site. In one embodiment, the device includes a VNS device and / or lead that includes the polymer composition of interest, and the polymer composition is applied to tissue at or near the site where the VNS device and / or lead is implanted. Contains moist scarring inhibitors and / or anti-infectives. In another aspect, the present invention provides a lead comprising a subject polymer composition, the polymer composition being a scarring inhibitor moistened in the tissue surrounding the vagus nerve into which the lead is implanted and / or Contains anti-infectives.

  In another aspect, the invention provides a neurostimulator for acupuncture comprising a subject polymer composition infiltrated into adjacent tissue, the polymer composition comprising a therapeutic agent (an anti-scarring agent and / or an anti-infective agent). Etc.). A number of polymeric and non-polymeric delivery systems for use in neurostimulators for acupuncture have already been described above.

  The polymer composition comprises (a) tissue adjacent to the nerve stimulator for acupuncture, (b) around the interface between the nerve stimulator and tissue for the acupuncture, and (c) a site around the nerve stimulator for the acupuncture (D) It can infiltrate around the implanted nerve stimulator for acupuncture treatment by applying directly and / or indirectly to the tissue surrounding the nerve stimulation device for acupuncture treatment. A method of infiltrating a subject polymer composition into tissue adjacent to a nerve stimulator for acupuncture includes delivery of the polymer composition to: (a) on the surface of the neurostimulator for acupuncture treatment during the transplantation procedure (eg, as an injection material, paste, gel or mesh), (b) immediately before or during the implantation of the neurostimulator for acupuncture treatment, (C) Immediately after implantation of the nerve stimulator for acupuncture treatment and / or on the tissue surface (eg as injection material, paste, gel, gel or mesh formed in situ) (D) Acupuncture nerve stimulator is placed on the surface of the tissue surrounding the implanted nerve stimulator for acupuncture (eg injection material, paste, gel, gel or mesh formed in situ) Topical application of the composition to an anatomical space (especially useful in this example is the use of a polymeric carrier that releases the therapeutic agent over a period ranging from hours to weeks-liquids, suspensions, milk Suspension, microemulsion, Rosspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and other formulations that release drugs and can be delivered to the site where the device is inserted), (e) to the tissue surrounding the nerve stimulator for acupuncture Application by intradermal injection of solutions, infusions, and sustained release formulations of and / or (f) combinations of the methods described above. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the polymer composition of interest can wet the surrounding tissue of the entire device or a portion (device only, lead only, electrode only, and / or combinations thereof).

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the present invention, the subject polymer composition infiltrated into tissue adjacent to the nerve stimulator for acupuncture treatment is one or more of four general elements for the process of fibrosis (or scarring) comprising: Can be adapted to release drugs that inhibit blood: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), accumulation of extracellular matrix (ECM) , And remodeling (maturation and organization of fibrous tissue). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Since neurostimulators for acupuncture are manufactured in a variety of shapes and sizes, the exact dose administered depends on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Agent is the target of the device or per unit area scarring inhibitor administration of tissue surface coating (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm 2, or it may be about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplanted or tissue surface of the subject to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² Or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

(4) Vagus nerve stimulation for treatment of other disorders In one embodiment, the subject polymer composition may infiltrate the tissue adjacent to the nerve stimulation device to treat the neuropathy. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  While using VNS in the treatment of sputum, it was found that some patients experienced improved mood during treatment. Therefore, VNS is currently being tested for use in the management of treatment-resistant mood disorders such as depressed anxiety. In Europe and the United States, depression continues to be a major clinical problem, with more than 1% of the population (25 million in the United States) suffering from depression due to inappropriate drug therapy. Vagus nerve stimulation is tested in the management of various symptoms such as anxiety (panic disorder, obsessive-compulsive disorder, post-traumatic disorder), obesity, migraine, sleep disorder, dementia, Alzheimer's disease and other chronic or degenerative neuropathies I came. VNS has also been examined for use in the treatment of medically important obesity.

  An implantable neurostimulator for the treatment of psychiatric disorders consists of an implantable lead having a bifurcated, split, or distal portion at two or more separate end portions. Each separate end portion includes at least one detection or stimulation electrode. See US Pat. No. 6,597,953. An implantable neurostimulator is a device for treating Alzheimer's disease and dementia, especially neuromodulation, or stimulating the left vagus nerve, consisting of an implantable lead and receiver, an external stimulator, and a primary coil . See US Pat. No. 6,615,085.

  In accordance with the present invention, neurostimulators for the treatment of neurological disorders that may benefit from infiltrating the subject polymer composition into adjacent tissue include commercially available products. Cyberonics, Inc. manufactures and markets VNS systems, including Model 300 and Model 302 leads, Model 101 and Model 102R pulse generators, Model 201 and Model 250 programming software, and Model 220 magnets. . These and other products developed by Cyberonics, Inc. include depression (US Patent 5,299,569), dementia (US Patent 5,269,303), migraine (US Patent 5,215,086), sleep disorders (US Patent No. 5,335,657) and obesity (US Pat. Nos. 6,587,719, 6,609,025, 5,263,480 and 5,188,104) are used to treat neurological disorders.

  It is important to note that the basics of treatment are the same as those described above for sputum. The equipment used and the basics of therapy are the same. As explained above for the treatment of hemorrhoids, if excessive scar tissue growth or extracellular matrix accumulation occurs around the VNS lead, it can lead to reduced device effectiveness. VNS devices benefit from the release of therapeutic agents that can reduce scarring at the electrode-tissue interface, improving the efficiency of shock transmission, and these devices treat depression, anxiety, obesity, sleep disorders and dementia Can be extended clinically functional period. VNS devices are also effective in releasing therapeutic agents that prevent or reduce infection around the implantation site. In one embodiment, the device includes a VNS device and / or lead that includes the polymer composition of interest, and the polymer composition is applied to tissue at or near the site where the VNS device and / or lead is implanted. Contains moist scarring inhibitors and / or anti-infectives. In another aspect, the present invention provides a lead comprising a subject polymer composition, the polymer composition being a scarring inhibitor moistened in the tissue surrounding the vagus nerve into which the lead is implanted and / or Contains anti-infectives.

  In another aspect, the invention provides a neurostimulator for treatment of a neurological disorder comprising a subject polymer composition infiltrated into adjacent tissue, the polymer composition comprising a therapeutic agent (a scarring inhibitor and / or an anti-infection). Medicine). A number of polymeric and non-polymeric delivery systems for use in neurostimulators for the treatment of neurological disorders have already been described above.

  The polymer composition comprises (a) a tissue adjacent to a nerve stimulator for treating a neurological disorder, (b) a periphery of the nerve stimulator for treating the neuropathy and the tissue, (c) a nerve stimulator for treating the neuropathy. By applying directly and / or indirectly to the surrounding site, (d) the tissue surrounding the neurostimulator for treating a neuropathy, it is possible to infiltrate around the implanted neurostimulator for treating a neuropathy. Methods of infiltrating a tissue adjacent to a nerve stimulation device for treating a neurological disorder with a subject polymer composition include delivery of the polymer composition to: (a) (b) Immediately before or at the time of transplanting a nerve stimulator for treating nerve damage on the surface of the nerve stimulator for treating nerve damage (eg, as an injection material, paste, gel or mesh) during the transplantation procedure. (C) Neural stimulation for neuropathy treatment immediately after implantation of a neurostimulator for treatment of neuropathy (eg, as injection material, paste, gel, gel or mesh formed in situ) (D) for the treatment of neuropathy on the surface of the tissue around the device and / or the implanted nerve stimulation device for treatment of the neuropathy (eg injection material, paste, gel, gel or mesh formed in situ) Topical application of the composition to the anatomical space in which the neurostimulator is located (especially useful in this example is the use of a polymeric carrier that releases the therapeutic agent over a period ranging from hours to weeks-liquid , Suspensions, emulsions, Microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and other formulations that release drugs and can be delivered to the site where the device is inserted), (e) nerve stimulation for the treatment of neurological disorders Application by intradermal injection of solutions, infusions, and sustained release formulations into the tissue surrounding the device and / or (f) by a combination of the methods described above. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the polymer composition of interest can wet the surrounding tissue of the entire device or a portion (device only, lead only, electrode only, and / or combinations thereof).

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the present invention, the subject polymer composition infiltrated into tissue adjacent to a neurostimulator for treating a neurological disorder is one of four general factors for the process of fiber formation (or scarring) comprising: Can be adapted to release drugs that inhibit multiple: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) Accumulation and reformation (fibrotic tissue maturation and organization). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Since neurostimulation devices for the treatment of neurological disorders are manufactured in a variety of shapes and sizes, the exact dose administered depends on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Agent is the target of the device or per unit area scarring inhibitor administration of tissue surface coating (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm 2, or it may be about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplanted or tissue surface of the subject to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² Or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

(5) Sacral nerve stimulation for bladder control problems In one embodiment, the subject polymer composition can infiltrate tissue adjacent to the nerve stimulation system to treat bladder symptoms. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  Sacral nerve stimulation is used to manage patients with urinary problems, such as urge incontinence, non-obstructive urinary retention, or frequent tightness. Millions of people are suffering from bladder control problems, and a significant percentage of people (expected to exceed 60%) have other available therapies such as medications, absorption pads, external collection devices or bladder enlargement Not receiving proper treatment by This is debilitating, causing serious social anxiety and causing people to become isolated and depressed.

  Light electrical stimulation of the sacral nerve is used to influence the function of the bladder, urinary sphincter, and pelvic floor muscles (all structures that receive nerve supply from the sacral nerve). The lead is surgically implanted adjacent to the sacral nerve and the nerve stimulator is implanted subcutaneously in the upper buttocks or abdomen. The use of tin-coated leads allows for non-sutured fixation of the lead and minimal invasive placement of the lead under local anesthesia. The attending physician can adjust the device with a portable programmer, or the programmer operated by the patient can adjust the settings and switch the device on / off. Pulses are provided to provide bladder control and relieve patient symptoms.

  For stimulation of the sacral nerve by electrical stimulation, several neural stimulation systems have been described that target the bladder, pelvic floor muscles, rectum and / or genitals. For example, a nerve stimulation device is an electrical stimulation system consisting of an electrical stimulation device including an insulator sheath and a lead wire, and is fixed to the sacrum using a minimally invasive surgical procedure. See US Pat. No. 5,957,965. In another aspect, the neurostimulator is used to properly place the pelvis, sphincter or bladder muscle tissue. For example, the nerve stimulation device is a muscle electrical stimulation device including a pulse generator and an elongated medical lead, and is used for electrical stimulation or detection of an electrical signal derived from muscle tissue. See US Pat. No. 6,434,431. Another neural stimulation system consists of a leadless, tubular micro stimulator that is implanted into connective nerve tissue that needs to be stimulated to treat pelvic floor muscles or urinary incontinence. See US Pat. No. 6,061,596.

  In accordance with the present invention, neurostimulation systems for the treatment of bladder symptoms that benefit from having the subject polymer composition infiltrated into adjacent tissue include commercial products. An example of a commercially available nerve stimulation system for treating bladder disorders is the INTERSTIM Sacral Nerve Stimulation System manufactured by Medtronic, Inc. See, for example, US Pat. Nos. 6,104,960, 6,055,456, and 5,957,965.

  Regardless of the specific design function, for bladder control therapy to be effective, the lead must be accurately placed adjacent to the sacral nerve, bladder, sphincter or pelvic muscle (depending on the particular system used) There is. If excessive scar tissue growth or extracellular matrix accumulation occurs around the lead, efficacy may not be fully exploited. Sacral nerve stimulators (such as INTERSTIM) that infiltrate the target polymer composition into the tissue adjacent to the electrode-tissue interface can improve the efficiency of shock transmission and extend the period during which these devices function clinically. . In such a nerve stimulation apparatus, it is also effective to release a therapeutic agent that prevents or inhibits infection around the transplant site. In one embodiment, the device includes a polymer composition of interest comprising an anti-scarring agent and / or an anti-infective agent adjacent to the site where or where the sacral nerve stimulation device and / or lead is implanted or is scheduled for implantation. A sacral nerve stimulator and / or lead that has infiltrated the tissue to be infiltrated. In another aspect, the invention includes a lead infiltrated with a polymer composition of interest comprising an anti-scarring agent and / or an anti-infective agent in tissue adjacent to the sacral nerve to which the lead is to be implanted.

  For devices designed to directly stimulate bladder or pelvic muscle tissue, a slightly different embodiment is required. In this aspect, the device includes a bladder or pelvic muscle stimulator, leads, and / or sensors. A subject polymer composition comprising an anti-scarring agent and / or an anti-infective agent is infiltrated into the tissue adjacent to the site where the sacral nerve stimulator and / or lead is implanted or the site to be implanted. In another aspect, the present invention provides leads and / or sensors that transmit shock or monitor muscle activity. A subject polymer composition comprising an anti-scarring agent and / or an anti-infective agent is infiltrated into a tissue adjacent to the tissue (such as muscle) to be implanted with the lead and / or sensor.

  In another aspect, the invention provides a neural stimulation system for treating bladder conditions comprising a subject polymer composition infiltrated into adjacent tissue, the polymer composition comprising a therapeutic agent (an anti-scarring agent and / or Or anti-infectives). A number of polymeric and non-polymeric delivery systems for use in neural stimulation systems for treating bladder symptoms have already been described above.

  The polymer composition comprises (a) tissue adjacent to the nerve stimulation system for treating bladder symptoms, (b) around the interface of the nerve stimulation system and tissue for treating bladder symptoms, and (c) nerves for treating bladder symptoms. Site around the stimulation system, (d) around the nerve stimulation system for the treatment of transplanted bladder symptoms by applying directly and / or indirectly to the tissue surrounding the nerve stimulation system for the treatment of bladder symptoms Can infiltrate. A method of infiltrating a tissue adjacent to a neural stimulation system for treating a bladder with a subject polymer composition includes delivery of the polymer composition to: (a) on the surface of the neurostimulation system for treatment of the bladder during the implantation procedure (eg as infusion material, paste, gel or mesh), (b) immediately before or during the implantation of the neurostimulation system for treatment of the bladder, (C) Immediately after implantation of the bladder treatment nerve stimulation system on the tissue surface (eg, infusion material, paste, gel, in situ formed gel or mesh) and / or bladder treatment nerve stimulation system and / or (D) The bladder treatment nerve stimulation system is placed on the surface of the tissue around the implanted bladder treatment nerve stimulation system (eg, injection material, paste, gel, gel or mesh formed in situ). Topical application of the composition to an anatomical space (especially useful in this example is the use of a polymeric carrier that releases the therapeutic agent over a period ranging from hours to weeks-liquids, suspensions, milk Suspension, Macroemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and other formulations that release drugs and can be delivered to the site where the device is inserted), (e) a neurostimulation system for the treatment of the bladder Application by intradermal injection of solutions, infusions, and sustained release formulations into the tissue surrounding the and / or (f) a combination of the methods described above. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the polymer composition of interest can wet the surrounding tissue of the entire device or a portion (device only, lead only, electrode only, and / or combinations thereof).

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the present invention, the subject polymer composition infiltrated into tissue adjacent to the nerve stimulation system for treating bladder symptoms is one of four general factors for the process of fibrosis (or scarring) comprising: Can be adapted to release drugs that inhibit multiple: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) Accumulation and reformation (fibrotic tissue maturation and organization). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Since the neurostimulation system for the treatment of bladder symptoms is manufactured in a variety of shapes and sizes, the exact dose administered will depend on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site) and the total administered drug dose can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Agent is the target of the device or per unit area scarring inhibitor administration of tissue surface coating (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm 2, or it may be about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplanted or tissue surface of the subject to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² Or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

(6) Gastric nerve stimulation for treatment of gastrointestinal disorders In one embodiment, the subject polymer composition can invade tissue adjacent to a device for treating GI disorders. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  Nerve stimulators of the gastric nerve (supplied to the stomach and other parts of the upper gastrointestinal tract) affect gastric emptying and satiety in managing clinically important problems related to obesity or decreased gastrointestinal motility. Used to give. Morbid obesity is spreading like a pandemic, affecting more than 25 million Americans and is thought to lead to important health problems such as diabetes, heart attack, stroke and death. Light electrical stimulation of the gastric nerve is used to affect the function of the upper gastrointestinal tract and stomach (all structures that receive nerve supply from the gastric nerve). The lead is surgically implanted in the immediate vicinity of the gastric nerve and the nerve stimulator is implanted subcutaneously. The two devices are connected by a connecting line. The attending physician can adjust the device with a portable programmer, or the programmer operated by the patient can adjust the settings and switch the device on / off. The pulses are adjusted to provide the feeling of fullness and hunger that the patient experiences. This makes it possible to reduce the intake of meals (ie calories) and the patient succeeds in losing weight. Related devices include neural stimulators used to stimulate gastric emptying of patients due to reduced gastric motility, neurostimulators that stimulate bowel emptying of patients suffering from constipation (stimulation delivered to the colon), and There are devices that target the intestines of patients who suffer from other gastrointestinal motility abnormalities.

  Several such devices are described, including, for example, sensors coupled to pulse generators that detect and inhibit gastrointestinal electrical activity that emits and inhibits asynchronous stimulation pulse trains based on natural gastrointestinal electrical activity. Has been. See US Pat. No. 5,995,872. Other neurostimulators deliver shock to the colon and rectum to manage constipation and consist of leads, electrodes and implanted stimulus generators. See US Pat. No. 6,026,326. The neurostimulator may be a pulse generator and electrodes that electrically stimulate the visceral neuromuscular tissue to treat obesity. See US Pat. No. 6,606,523. The neurostimulator is a sealed, implantable pulse generator that is electrically coupled to the gastrointestinal tract to release two stages of electrical stimulation to treat gastric paresis in patients with reduced gastric emptying. Yes. See US Pat. No. 6,091,992. The nerve stimulator consists of an electrical signal controller, connecting wires, and attached leads that generate continuous low-voltage electrical stimulation at the bottom of the stomach to control appetite. See US Pat. No. 6,564,101. Other nerve stimulation devices used to electrically stimulate the gastrointestinal tract are described in US Pat. Nos. 6,453,199, 6,449,511, 6,243,607, and the like.

  Examples of GI disorder treatment devices that may benefit from infiltrating the subject polymer composition into adjacent tissue in accordance with the present invention include commercial products. An example of a commercially available gastric nerve stimulator used in the present invention is the TRANSCEND Implantable Gastric Stimulator (IGS), which is currently being developed at Transneuronix, Inc. (Mount Arlington, NJ). IGS is a programmable bipolar pulse generator that delivers a small amount of electrical pulses through the lead to the stomach wall to treat obesity. See U.S. Pat. Nos. 6,684,104 and 6,165,084.

  Regardless of the specific design function, for gastric nerve stimulation to be effective in satiety control (or gastric paresis), the lead must be accurately placed adjacent to the gastric nerve. If excessive scar tissue growth or extracellular matrix accumulation occurs around the lead, efficacy may not be fully exploited. A gastric nerve stimulator (and other implants designed to affect GI motility) that infiltrate the target polymer composition into the tissue adjacent to the electrode-tissue interface improves the efficiency of shock transmission The period during which these devices function clinically can be extended. In gastric nerve stimulation devices (and other transplant devices designed to affect GI motility), the release of therapeutic agents that can prevent or inhibit infection around the transplant site is also effective. In one embodiment, the device includes a subject polymer composition comprising an anti-scarring agent and / or an anti-infective agent adjacent to a site where a gastric nerve stimulator and / or lead is implanted or is intended for implantation. A gastric nerve stimulator and / or lead that has infiltrated the tissue to be treated. In another aspect, the present invention provides a lead infiltrated with a subject polymer composition comprising an anti-scarring agent and / or an anti-infective agent into tissue surrounding the gastric nerve into which the lead is implanted.

  In another aspect, the invention provides a device for treating a GI disorder comprising a subject polymer composition infiltrated into adjacent tissue, the polymer composition comprising a therapeutic agent (such as an anti-scarring agent and / or an anti-infective agent). May be included. A number of polymeric and non-polymeric delivery systems for use in GI disorder treatment devices have already been described above.

  The polymer composition comprises (a) tissue adjacent to the GI disorder treatment device, (b) around the interface between the GI disorder treatment device and the tissue, (c) a site around the GI disorder treatment device, (d) GI disorder By applying directly and / or indirectly to the tissue surrounding the treatment device, it can infiltrate around the implanted GI disorder treatment device. Methods of infiltrating a subject polymer composition into tissue adjacent to a device for treating a GI disorder include delivery of the polymer composition to: (a) The surface of the GI disorder treatment device (eg, as an injection material, paste, gel, or mesh) during the implantation procedure (b) Immediately before or during the implantation of the GI disorder treatment device (eg, the tissue surface (eg, : As injection material, paste, gel, gel or mesh formed in situ), (c) Immediately after implantation of GI disorder treatment device and / or implanted GI disorder treatment device (D) Topical application of the composition to the anatomical space where the device for treating GI disorders is placed on the surrounding tissue surface (eg injection material, paste, gel, gel or mesh formed in situ) (Especially useful in this example is the use of polymeric carriers that release therapeutic agents over a period ranging from hours to weeks-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels , Fine particles, spray, air Sols, solid implants, and other formulations that release the drug and can be delivered to the site where the device is inserted), (e) solutions, infusions, and sustained release formulations into the tissue surrounding the device for treating GI disorders Application by intradermal injection and / or (f) a combination of the methods described above. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the polymer composition of interest can wet the surrounding tissue of the entire device or a portion (device only, lead only, electrode only, and / or combinations thereof).

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the present invention, a subject polymer composition infiltrated into tissue adjacent to a device for treating GI disorders inhibits one or more of four general factors for the process of fibrosis (or scarring) including: Can be adapted to release drugs: new blood vessel formation (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) accumulation, and Remodeling (fibrotic tissue maturation and organization). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Since GI disorder treatment devices are manufactured in a variety of shapes and sizes, the exact dose administered will depend on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site) and the total administered drug dose can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Agent is the target of the device or per unit area scarring inhibitor administration of tissue surface coating (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm 2, or it may be about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplanted or tissue surface of the subject to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² Or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

(7) Implanted cochlear stimulator for the treatment of hearing loss In one embodiment, the subject polymer composition can infiltrate tissue adjacent to the implanted cochlear stimulator. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  Nerve stimulation is also used in the form of a transplanted cochlear stimulator to stimulate the auditory nerve to correct sensorineural hearing loss. A sound processor captures sound from the environment, processes the sound into a digital signal, and transfers it from the skin to the transplanted cochlear stimulator via the antenna. The digital information is converted into electrical signals and transmitted to the auditory nerve via the electrode array. Effectively, the transplanted cochlear stimulator bypasses the non-functional cochlear transducer and serves to directly depolarize afferent auditory nerve fibers. This stimulates the nerve to send a signal to the auditory center of the brain so that the patient can “hear” the sound detected by the sound processor. Treatment is for adults with hearing loss of 70 dB or more (and understanding up to 50% in one sentence using a hearing aid), or children over 12 months with 90 dB hearing loss in both ears Used.

  Although many transplants are performed without problems, about 12-15% of patients have some complications. Histological evaluation of the transplanted cochlear stimulator reveals that several forms of damage and scarring can occur. Surgical trauma can induce cochlear fiber formation, cochlear ossification and damage (including loss of sensory elements) in the membrane cochlea. A foreign body reaction along the implant and the electrode can cause a fiber tissue reaction along the electrode array associated with electrode failure. Implanting a neurostimulator may cause or promote infection around the implantation site.

  Various implantable cochlear stimulator systems or “artificial ears” for use in connection with the present invention have been described in various ways. For example, the nerve stimulation apparatus includes a plurality of transducers, detects vibrations, and generates stimulation signals for corresponding nerves connected to the cranial nerves. See US Pat. No. 5,061,282. The nerve stimulation device is a transplanted cochlear stimulation device comprising a voice-to-electrical stimulation encoder, a receiving stimulation device that can be implanted in the body, and an electrode, and generates a pulse based on the received electrical signal. See U.S. Pat. No. 4,532,930. The nerve stimulation device is a cochlear device, and includes a transducer that converts voice progression into an electrical signal and an electrode array that electrically stimulates a predetermined location of the auditory nerve. See U.S. Pat. No. 4,400,590. A nerve stimulator is typically a stimulus generator that applies electrical stimulation to an eighth nerve branch at a constant rate, independent of audio modulation. For this reason, sound modulation is perceived as actual silence. See US Pat. No. 6,175,767. A nerve stimulator is an electromechanical system comprising an input transducer and an output stimulator implanted under the skull, and converts mechanical sound vibrations into electrical signals. See US Pat. No. 6,235,056. The nerve stimulator is a transplanted cochlear stimulator that houses a rechargeable battery for storing and supplying power within the implant. See US Pat. No. 6,067,474. Other neurostimulators used as transplanted cochlear stimulators are described in US Pat. Nos. 6,358,281, 6,308,101, and 5,603,726.

  Examples of transplanted cochlear stimulators that may benefit from infiltrating the subject polymer composition into adjacent tissue in accordance with the present invention include commercial products. Several commercially available devices can be used to treat patients with significant sensorineural hearing loss and are suitable for use in the present invention. For example, the HIRESOLUTION Bionic Ear System (Boston Scientific Corp., Natick, Mass.) Consists of a HIRESAURIA processor that processes the sound and sends digital signals to a HIRES 90K implant surgically implanted in the inner ear. See U.S. Pat. Nos. 6,636,768, 6,309,410, 6,259,951, and the like. Electrode arrays that deliver the impact generated by the HIRES90K implant to the nerve can benefit from infiltrating the subject polymer composition into tissue adjacent to the electrode-nerve interface. PULSARci transplanted cochlear stimulator (MED-ELGMBH, (Innsbruck, Austria), see US Pat. Nos. 6,556,870 and 6,231,604, etc.) and NUCLEUS 3 transplanted cochlear stimulator system (Cochlear Corp., Lane Cove, Australia, US Pat. No. 6,807,445) 6788,790, 6,554,762, 6,537,200, and 6,394,947) are also commercially available cochlear stimulators with electrodes that can benefit from infiltrating the polymer composition of interest into tissue adjacent to the electrode-nerve interface It is an example of goods.

  Regardless of the specific design function, in order for the transplanted cochlear stimulator to be effective in sensorineural hearing loss, the electrode array must be accurately placed adjacent to the afferent auditory nerve fibers. If excessive scar tissue growth or extracellular matrix accumulation occurs around the lead, efficacy may not be fully exploited. Implanted cochlear stimulation devices in which the target polymer composition is infiltrated into tissue adjacent to the electrode-tissue interface can improve the efficiency of shock transmission and extend the period during which these devices function clinically. The transplanted cochlear stimulator is also effective in releasing therapeutic agents that prevent or reduce infection around the transplant site. In one embodiment, the device comprises a transplanted cochlear stimulator and / or lead comprising a polymer composition of interest, wherein the polymer composition is the site of implantation or the site of implantation of the implanted cochlear stimulator and / or lead. Contains scarring inhibitors and / or anti-infectives moistened in surrounding tissues. In another aspect, the invention provides a lead in which a subject polymer composition comprising an anti-scarring agent and / or an anti-infective agent is infiltrated into tissue adjacent to the implanted cochlear stimulator around the lead. .

  In another aspect, the present invention provides a transplanted cochlear stimulator comprising a subject polymer composition infiltrated into adjacent tissue, the polymer composition containing a therapeutic agent (such as an anti-scarring agent and / or an anti-infective agent). Can be included. A number of polymeric or non-polymeric delivery systems have been described above in the use of implanted cochlear stimulators.

  The polymer composition consists of (a) tissue adjacent to the transplanted cochlear stimulator, (b) around the interface between the transplanted cochlear stimulator and the tissue, (c) the area around the transplanted cochlear stimulator, (d) the transplanted cochlear stimulator By applying directly and / or indirectly to the surrounding tissue, it can infiltrate around the implanted cochlear stimulator. Methods for infiltrating a subject polymer composition into tissue adjacent to a transplanted cochlear stimulator include delivery of the polymer composition to: (a) on the surface of the transplanted cochlear stimulator (eg as an injection material, paste, gel or mesh) during the transplantation procedure; (b) immediately before or during the implantation of the transplanted cochlear stimulator (eg: injection) (C) Immediately after implantation of the transplanted cochlear stimulator, the surface of the tissue around the transplanted cochlear stimulator and / or the transplanted cochlear stimulator (E.g. injection material, paste, gel, gel or mesh formed in situ) (d) topical application of the composition to the anatomical space where the implanted cochlear stimulator is placed (especially in this example Useful is the use of polymeric carriers that release therapeutic agents over a period ranging from hours to weeks-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, Allosols, solid implants and other formulations that release the drug and can be delivered to the site where the device is inserted), (e) solutions, infusions, and sustained release formulations in the tissue surrounding the implanted cochlear stimulator Application by internal injection and / or (f) a combination of the methods described above. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the polymer composition of interest can wet the surrounding tissue of the entire device or a portion (device only, lead only, electrode only, and / or combinations thereof).

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the present invention, the subject polymer composition infiltrated into tissue adjacent to the transplanted cochlear stimulator inhibits one or more of the four general factors for the process of fiber formation (or scarring) including: Can be adapted to release drugs: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), accumulation of extracellular matrix (ECM), and regeneration Formation (fibrotic tissue maturation and organization). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Since implantable cochlear stimulation devices are manufactured in a variety of shapes and sizes, the exact dose administered depends on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Agent is the target of the device or per unit area scarring inhibitor administration of tissue surface coating (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm 2, or it may be about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site) and the total administered drug dose can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplanted or tissue surface of the subject to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² Or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

(8) Electrical stimulation to promote bone growth In one embodiment, the subject polymer composition can infiltrate tissue adjacent to the electrical bone stimulator. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  Electrical stimulation can also be used to stimulate bone growth. For example, the stimulator is an electrode and generator with strain-reacting piezoelectric material that generates changes and reacts to the strain by facilitating fixation of the implanted artificial bone to natural bone. See US Pat. No. 6,143,035. If excessive scar tissue growth or extracellular matrix accumulation occurs around the lead, efficacy may not be fully exploited. Electric bone stimulation devices infiltrated with the polymer composition of interest in tissue adjacent to the electrode-tissue interface can improve the efficiency of shock transmission and extend the period during which these devices function clinically. The electrical bone stimulator is also effective in releasing therapeutic agents that prevent or inhibit infection around the implantation site. In one embodiment, the device includes a subject polymer composition comprising an anti-scarring agent and / or an anti-infective agent adjacent to the site where the electrical bone stimulator and / or lead is implanted or is intended for implantation. An electrical bone stimulator and / or lead that has infiltrated the tissue to be removed. In another aspect, the invention provides a lead in which a subject polymer composition comprising an anti-scarring agent and / or an anti-infective agent is infiltrated into tissue adjacent to bone tissue surrounding the lead.

  In another aspect, the present invention provides an electrical bone stimulator comprising a subject polymer composition infiltrated into adjacent tissue, the polymer composition containing a therapeutic agent (such as an anti-scarring agent and / or an anti-infective agent). Can be included. A number of polymeric and non-polymeric delivery systems for use in electric bone stimulators have already been described above.

  The polymer composition comprises (a) tissue adjacent to the electric bone stimulator, (b) around the interface between the electric bone stimulator and the tissue, (c) a region around the electric bone stimulator, (d) the electric bone stimulator By applying directly and / or indirectly to the surrounding tissue, it can infiltrate around the implanted electrical bone stimulator. Methods for infiltrating a tissue adjacent to an electrical bone stimulator with a subject polymer composition include delivery of the polymer composition to: (a) on the surface of the electric bone stimulator (eg as injection material, paste, gel or mesh) during the implantation procedure, (b) immediately before or during the implantation of the electric bone stimulator (eg: injection) (As a substance, paste, gel, gel or mesh formed in situ) (c) Immediately after implantation of the electrical bone stimulator, the surface of the tissue around the implanted electrical bone stimulator and / or the implanted electrical bone stimulator (E.g. injection material, paste, gel, gel or mesh formed in situ) (d) topical application of the composition to the anatomical space where the electrical bone stimulator is placed (especially in this example Useful is the use of polymeric carriers that release therapeutic agents over a period ranging from hours to weeks-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols , Body grafts and other formulations that release the drug and can be delivered to the site where the device is inserted), (e) intradermal injection of solutions, injections, and sustained release formulations into the tissue surrounding the electrical bone stimulator And / or (f) Application by a combination of the methods described above. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the polymer composition of interest can wet the surrounding tissue of the entire device or a portion (device only, lead only, electrode only, and / or combinations thereof).

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the present invention, the subject polymer composition infiltrated into tissue adjacent to the electrical bone stimulator inhibits one or more of the four general factors for the process of fiber formation (or scarring) including: Can be adapted to release drugs: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), accumulation of extracellular matrix (ECM), and regeneration Formation (fibrotic tissue maturation and organization). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Because electrical bone stimulators are fabricated in a variety of shapes and sizes, the exact dose administered depends on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site) and the total administered drug dose can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Agent is the target of the device or per unit area scarring inhibitor administration of tissue surface coating (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm 2, or it may be about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site), the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplanted or tissue surface of the subject to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² Or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

A number of neurostimulators have been described above, all of which have similar design features, causing undesirable similar tissue reactions after transplantation, causing or promoting infection at the site of implantation. For those skilled in the art, not only commercially available neurostimulators not specifically cited herein, but also next generation and / or future developed commercially available neurostimulator products are expected to be used in accordance with the present invention, and It must be clear that it is suitable for its use. In particular, nerve stimulation devices such as leads must be accurately positioned to ensure that the stimulation is delivered to the correct anatomical location of the nervous system. All or some of the neurostimulators may migrate after surgery, or excessive scar (glia) tissue growth may occur around the graft, leading to reduced performance of these devices. A neurostimulator with a polymer composition of interest infiltrated into tissue adjacent to the electrode / tissue interface can be used to increase the effectiveness and / or duration of the implant (especially fully implanted battery-operated). For equipment). For neurostimulators, it is also effective to release therapeutic agents that prevent or inhibit infection around the implantation site. In one aspect, the invention provides a neurostimulator comprising a subject polymer composition infiltrated into adjacent tissue, the polymer composition comprising a therapeutic agent (such as an anti-scarring agent and / or an anti-infective agent). be able to. A number of polymeric and non-polymeric delivery systems for use in neurostimulators have already been described above. These compositions may be further supplemented with one or more fibrosis inhibitors to inhibit or reduce overgrowth of granulation, fiber and glio tissue, or one or more anti-infectives may be added to the transplant site. Can inhibit or prevent nearby infections.

Cardiac Rhythm Management (CRM) Device In one embodiment, the subject polymer composition can infiltrate tissue adjacent to the cardiac rhythm management device. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  The electrical device is a cardiac pacemaker device whose pulse generator can deliver electrical shock to the myocardial tissue (often a special conducting fiber) via the implanted lead to regulate the cardiac rhythm. In general, an electrical lead consists of a connection assembly, a lead body (ie, a conductor) and an electrode. The electrical leads are monopolar and can be adapted to provide effective treatment with only one electrode. Multipolar lead wires such as bipolar lead wires, tripolar lead wires, and quadrupole lead wires can also be used. The electrical lead also has an insulating sheath, which includes a polyurethane or silicone rubber coating. Representative examples of electrical leads include, but are not limited to, medical leads, cardiac leads, pacer leads, pacing leads, pacemaker leads, endocardial leads, endocardial pacing leads, Cardioverter / Defibrillator Lead, Cardioverter Lead, Epicardial Lead, Epicardial Defibrillator Lead, Patch Defibrillator, Patch Lead, Electrical Patch, Transvenous Lead Wire, active fixed lead wire, inactive fixed lead wire and detection lead wire. Representative examples of CRM devices that utilize leads include pacemakers, LVADs, defibrillators, implantable sensors, and other electrical heart stimulators.

  There are many pacemaker devices where the occurrence of a fibrotic reaction can adversely affect device function or cause damage to myocardial tissue. In general, fiber coating of the pacemaker lead (or growth of fibrous tissue between the lead and the target myocardial tissue) delays, impairs or blocks the delivery of shock from the device to the myocardium. For example, fiber formation is often found at the heart electrode / myocardium interface, causing electrical damage from the focal point of the electrical lead. Fibrous damage can affect the tricuspid valve and cause perforation. Fibrosis can lead to life-threatening subclavian vein thrombosis. Electrical leads in which the polymer composition of interest is infiltrated into tissue adjacent to the electrode-tissue interface can help extend the clinical performance of these devices. Not only does the device fail to perform best or fail at all due to fibrosis alone, but it requires increased energy to overcome the electrical resistance imposed by the intervening scar tissue, resulting in reduced battery life. It may be consumed excessively. Similarly, fiber coating the detection composition for rate-responsive pacemakers (described below) identifies and corrects rhythm abnormalities that lead to the pacemaker being improperly paced or unable to function properly when needed. May impair your ability to do. Cardiac pacemaker devices and / or electrical leads are also effective in releasing therapeutic agents that prevent or reduce infection around the implantation site.

  Several different electrical pacing devices include pacemakers, implantable tachycardia defibrillators (ICDs), left auxiliary artificial heart (LVAD), and vagus nerve stimulation (stimulates vagal nerve fibers and then the heart Used in the treatment of various heart rhythm abnormalities. The pulsing portion of the device sends electrical signals to the muscle (myocardium) or conduction tissue via the implanted lead, affecting the vibration rhythm or contraction. Pacing can be directed to one or more ventricles. Cardiac pacemakers can be used to block, mask, or stimulate the heart's electrical signals to treat dysfunctions including but not limited to atrial rhythm abnormalities, conduction abnormalities, ventricular rhythm abnormalities, and the like. When ventricular arrhythmias (such as systolic failure or ventricular hypertrophy) occur and LVAD is used to support ventricular contraction in heart failure, ICD is used to depolarize the ventricle and restore rhythm.

  Representative examples of patents describing pacemakers and pacemaker leads include: U.S. Pat.Nos. There is. Representative examples of patents describing electrical leads include vibration stimulators (see U.S. Patent Nos. 6,584,351 and 6,115,633), pacemakers (see U.S. Patent Nos. 6,564,099, 6,246,909 and 5,876,423), implantable Defibrillators (ICD), other defibrillator devices (see U.S. Pat.No. 6,327,499), defibrillators or required pacer catheters (see U.S. Pat.No. 5,476,502) and left auxiliary prosthesis There are leads found on various heart devices, such as the heart (see US Pat. No. 5,503,615).

  The cardiac rhythm device, and particularly the lead that delivers the electrical pulse, needs to be positioned very accurately so that the stimulus is delivered to the correct anatomical location of the heart. All or some of the pacing devices may migrate after surgery, or excessive scar tissue growth may occur around the lead (described above), leading to reduced performance of these devices. Cardiac rhythm management devices in which the polymer composition of interest is infiltrated into tissue adjacent to the electrode-tissue interface (especially in the case of fully implanted battery-operated devices) Can be used to increase the period. The cardiac rhythm management device is also effective in releasing therapeutic agents that prevent or reduce infection around the transplant site. In one embodiment, the invention provides a cardiac rhythm management device and / or lead comprising a subject polymer composition, the polymer composition comprising a scarring inhibitor and / or an anti-infective agent, Wet tissue adjacent to the site where the device and / or lead is implanted. In another aspect, the present invention provides a lead comprising a subject polymer composition, the polymer composition comprising a scarring inhibitor and / or an anti-infective agent, and tissue adjacent to the site where the lead is implanted. Moisten.

  In another aspect, the present invention provides a cardiac rhythm management device wherein the subject polymer composition is wetted in adjacent tissue, the subject polymer composition comprising a therapeutic agent (an anti-scarring agent and / or an anti-cancer agent). May contain infectious drugs). A number of polymeric and non-polymeric delivery systems for use in connection with cardiac rhythm management devices have already been described above.

  The polymer composition comprises: (a) tissue adjacent to the heart rhythm management device, (b) around the tissue interface of the heart rhythm management device, (c) the region around the heart rhythm management device, and (d) By applying directly and / or indirectly to and in and around the tissue surrounding the cardiac rhythm management device, the periphery of the implanted cardiac rhythm management device can be moistened. Methods of wetting the subject polymer composition to tissue adjacent to the cardiac rhythm management device include a method of delivering the polymer composition to: (a) on the surface of the cardiac rhythm management device In contrast (for example: as injection material, paste, gel or mesh), (b) immediately before or during implantation of the heart rhythm management device graft (eg, injection material, paste, gel, (As a gel or mesh formed in situ), (c) Immediately after implantation of the cardiac rhythm management device, the surface of the cardiac rhythm management device and / or the implanted cardiac rhythm management device (eg injection material, paste, gel) (D) Topical application of the composition to the surface of the anatomical space where the cardiac rhythm management device is placed (especially useful in this example is several hours to several Week span Is the use of a polymeric carrier that releases a fibrosis inhibitor over a ~ liquid, suspension, emulsion, microemulsion, microsphere, paste, gel, microparticle, spray, aerosol, solid implant and drug release Other formulations that can be delivered to the site where the device is inserted), (e) by intradermal injection of solutions, infusions, and sustained release formulations into the tissue surrounding the cardiac rhythm management device and / or (f) Application by a combination of methods. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the polymer composition of interest can wet the surrounding tissue of the entire device or a portion (device only, lead only, electrode only, and / or combinations thereof).

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the invention, the subject polymer composition wetted in tissue adjacent to the cardiac rhythm management device is one of four general factors for the fibrosis (or scarring) process comprising: Can be adapted to release drugs that inhibit multiple: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) Accumulation and remodeling (maturation and organization of fibrous tissue). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Since heart rhythm management devices are manufactured in a variety of shapes and sizes, the exact dose administered will also vary depending on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site) and the total administered drug dose can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg. Can be in the range of ~ 2500 mg. Scarring inhibitor dosage (amount) per unit area of the device or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ^{2 to} 10 μg / mm ² or it may be about ^{10 μg / mm 2 ~250 μg /} mm 2 or about ^{250 μg / mm 2 ~1000μg / mm} 2 , or about ^{1000 μg / mm 2 ~2500 μg /} mm 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site) and the total administered drug dose can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (dose) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg. It can range from ˜100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplant or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ^{2 to} 10 μg / mm ² , or it may be about ^{10 μg / mm 2 ~100 μg /} mm 2 or about ^{100 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2,,. Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

For clarity, some specific cardiac rhythm management devices and treatment details are described below.

(1) Cardiac pacemaker In one embodiment, the subject polymer composition can invade tissue adjacent to the cardiac pacemaker. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  Cardiac rhythm abnormalities are not uncommon in standard treatments, and the incidence is increased when both elderly and underlying coronary artery disease or myocardial infarction are present. Arrhythmias appear repeatedly but are generally very slow (arrhythmic arrhythmias-heart block, sinus node dysfunction, etc.) or very fast (tachyarrhythmias-atrial fibrillation, WPW syndrome, ventricular fibrillation, etc.) It is classified into the state. By sending an electrical pulse (pacing pulse) that travels through the electrical lead to the electrode (at the tip of the lead), the pacemaker function delivers an electrical shock to the heart to beat the heartbeat. The lead and electrode can be located in one chamber (either the right atrium or the right ventricle to the one-chamber pacemaker). Or there may be electrodes in both the right atrium and the right ventricle (called a two-chamber pacemaker). Electrical leads can be surgically implanted outside the heart (eg, epicardial leads) or connected to the endocardial surface of the heart via a catheter, guidewire or stylet. In some pacemakers, the device assumes a rhythm that generates cardiac function and operates at a constant speed. In the case of other pacemakers, the device simply increases the pacing function of the heart itself, and operates “on demand” to provide pacing assistance as needed (referred to as an “adaptive speed pacemaker”). The pacemaker receives feedback on the heart rhythm (and when it operates) from the electrode sensor on the lead. Other pacemakers, called velocity-responsive pacemakers, have special sensors that detect changes in physical activity (such as arm and leg movements, respiratory rate, etc.) and adjust pacing rise or fall accordingly.

  Many pacemakers and pacemaker leads are suitable for use with the present invention. For example, a pacing lead may be electrically connected to a standard conductor because it is constructed from an elongated coil conductor embedded within the lumen of the lead body to increase resistance and bend easily. See U.S. Patent Nos. 6,061,598 and 6,018,683. The pacing lead is resistant because it has an insulated sheath on its coil conductor and fatigues in the area between the ribs and the collarbone. See U.S. Patent No. 5,800,496. The pacing lead can be expanded from a first, short configuration to a second, long configuration by comprising a slidable inner and outer overlapping tube containing conductors. See US Pat. No. 5,897,585. For pacing leads, there is a way to temporarily harden the first part of the lead body using a cavity magnet rheological fluid that hardens when exposed to a magnetic field. See US Pat. No. 5,800,497. The pacing lead may be a coil configuration consisting of a plurality of wires or a bundle of wires made of a double layer titanium alloy. See US Pat. No. 5,423,881. The pacing lead consists of a wire made of stainless steel with a composition of at least 22% nickel and 2% molybdenum and wound around a coil. See U.S. Patent No. 5,433,744. Other pacing leads are described in US Pat. Nos. 6,489,562, 6,289,251, and 5,957,967.

  In another aspect, electrical leads used in the practice of the present invention may have active fixation elements for attachment to tissue. For example, electrical leads have a narrow needle groove rigid fixation helix and are sized to minimize foreign body reaction after implantation. See U.S. Patent No. 6,078,840. The electrical lead has an electrode / fixed part with a double-tapered self-propelled spiral electrode for attachment to the vessel wall. See US Pat. No. 5,871,531. An electrical lead may have a rigid insulating electrode head that carries a helical electrode. See U.S. Patent No. 6,038,463. The electrical lead may have a fixation sleeve designed with an additive sheath to minimize blood flow through the sheath upon introduction. See U.S. Patent No. 5,827,296. The electrical lead comprises an insulated electrical conductor portion and a longitudinally rigid helical member, and an introductory fixation portion screwed into the tissue. See US Patent No. 4,000,745.

  Lead wires suitable for use in the practice of the present invention include multipolar lead wires having a plurality of electrodes connected to the lead wire body. For example, since the electrical lead wire is a multi-electrode lead wire, the lead wire has two internal conductors and three electrodes, and the two electrodes are connected by a capacitor integrated with the lead wire. See U.S. Patent No. 5,824,029. An electrical lead is a lead body with two straight sections and a bent third section tied to a conductor or a bipolar electrode. See U.S. Patent No. 5,995,876. In another aspect, the electrical lead may be implanted using a catheter, guidewire or stylet. For example, the electrical lead comprises a resilient seal including an elongated insulative lead body including a conductor and lumen embedded within the lead wire unit and an expandable portion through which the guide wire passes. See US Pat. No. 6,192,280.

  In accordance with the present invention, cardiac pacemakers that may benefit from infiltrating adjacent tissue with the subject polymer composition also include commercially available products. Commercially available pacemakers suitable for carrying out the invention include the KAPPA SR 400 series one-chamber speed responsive pacemaker system from Medtronic, Inc., the KAPPA DR 400 series two-chamber speed responsive pacemaker system, the KAPPA 900 and 700 series one There are room velocity responsive pacemaker systems, and KAPPA 900 and 700 series two chamber velocity responsive pacemaker systems. Medtronic's pacemaker system utilizes a variety of leads including CAPSUREZ Novus, CAPSUREFIX Novus, CAPSUREFIX, CAPSURE SP Novus, CAPSURE SP, CAPSURE EPI and CAPSUREVDD, which are targeted polymer compositions for adjacent tissues May benefit from infiltration. Medtronic pacemaker systems and related leads are described in the following US Patent Numbers. 6,741,893, 5,480,441, 5,411,545, 5,324,310, 5,265,602, 5,265,601, 5,241,957 and 5,222,506. Medtronic also manufactures a variety of steroid eluting leads, including those described in the following US patent numbers. 5,987,746, 6,363,287, 5,800,470, 5,489,294, 5,282,844 and 5,092,332. INSIGNIA 1- and 2-chamber systems, PULSAR MAXII DR two-chamber responsive pacemaker, PULSAR MAX II SR single-chamber responsive pacemaker, DISCOVERY II DR two-chamber responsive pacemaker, manufactured by Guidant Corp. (Indianapolis, IN) DISCOVERYII SR single chamber speed responsive pacemakers, DISCOVERY II DDD two chamber pacemakers and DISCOVERY II SSI single chamber pacemaker systems are also suitable pacemaker systems for use with the present invention. Leads from the Guidant pacemaker system may also benefit from infiltrating the subject polymer composition into adjacent tissue. Guidant's pacemaker system and related leads are described in the following US Patent Numbers, etc. 6,473,648, 6,345,204, 6,321,122, 6,152,954, 5,769,881, 5,284,136, 5,086,773 and 5,036,849. St. Jude Medical, Inc. (St. Paul, MN) AFFINITY DR, AFFINITY VDR, AFFINITY SR, AFFINITY DC, ENTITY, IDENTITY, IDENTITY ADX, INTEGRITY, INTEGRITY DR, INTEGRITY ADx, MICRONY, REGENCY, TRILOGY, and VERITY ADx pacemaker The system and lead are also suitable for use with the present invention to improve transmission and detection on pacemaker leads. St. Jude Medical's pacemaker system and related leads are described in the following US patent numbers and the like. 6,763,266, 6,760,619, 6,535,762, 6,246,909, 6,198,973, 6,183,305, 5,800,468 and 5,716,390. Alternatively, the fiber formation inhibitor may be immersed in a region around the interface between the electrode and the myocardium under the present invention. For those skilled in the art, not only the commercially available pacemakers not specifically cited herein but also the next generation and / or future developed commercially available pacemaker products are expected to be used in accordance with the present invention. It must be clear that it is suitable.

  Regardless of the specific design function, in order for a pacemaker to be effective in cardiac rhythm disorders, the lead needs to be accurately placed adjacent to the target cardiac muscle tissue. If excessive scar tissue growth or extracellular matrix accumulation occurs around the lead, efficacy may not be fully exploited. A pacemaker lead infiltrating the polymer composition of interest into the electrode and tissue interface and / or the tissue adjacent to the sensor and tissue interface increases the efficiency of shock transmission and rhythm detection, thereby increasing effectiveness. Extends battery life. Pacemaker leads are also effective in releasing therapeutic agents that prevent or reduce infection around the implantation site. In a cardiac pacemaker device and / or lead comprising a polymer composition of interest, the polymer composition comprises an anti-scarring agent and / or an anti-infective agent, or the site of implantation of the cardiac pacemaker device and / or lead or The tissue around the site to be transplanted is moistened. In another aspect, the present invention provides a pacemaker lead comprising a subject polymer composition, the polymer composition comprising an anti-scarring agent and / or an anti-infective agent, adjacent to the site where the lead is implanted. Moisten muscle tissue.

  In another aspect, the invention provides a cardiac pacemaker wherein the subject polymer composition is wetted in adjacent tissue, the subject polymer composition comprising a therapeutic agent (an anti-scarring agent and / or an anti-infective agent). Etc.). A number of polymeric and non-polymeric delivery systems for use in connection with cardiac pacemakers have already been described above.

  The composition of the polymer can be applied to (a) tissue adjacent to a cardiac pacemaker, (b) around the tissue interface of the cardiac pacemaker, (c) around the cardiac pacemaker, and (d) around the heart pacemaker. By applying directly and / or indirectly and in and on it, the periphery of the implanted cardiac pacemaker can be moistened. Methods of wetting the subject polymer composition to the tissue adjacent to the cardiac pacemaker include delivering the polymer composition to: (a) against the surface of the cardiac pacemaker (eg: (B) Implant material, paste, gel, or mesh) (b) Immediately before or during implantation of a cardiac pacemaker implant (eg, injection material, paste, gel, gel formed in situ) Or as a mesh) (c) Immediately after implantation of the cardiac pacemaker, the surface of the cardiac pacemaker and / or the surface of the implanted cardiac pacemaker (eg, injectable material, paste, gel, in situ formed gel or mesh) (D) Topical application of the composition to the anatomical space in which the cardiac pacemaker is placed (especially useful in this example are hours to weeks Is the use of a polymer carrier that releases a fibrosis inhibitor over a period of time--liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants, and Other formulations that can release the drug and be delivered to the site where the device is inserted), (e) by intradermal injection of solutions, infusions, and sustained release formulations into the tissue surrounding the cardiac pacemaker and / or (f ) Application by a combination of the methods described above. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the polymer composition of interest can wet the surrounding tissue of the entire device or a portion (device only, lead only, electrode only, and / or combinations thereof).

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the present invention, the subject polymer composition wetted in tissue adjacent to the cardiac pacemaker has one or more of four general components for the process of fiber formation (or scarring) including: Can be adapted to release inhibitory drugs: new blood vessel formation (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), accumulation of extracellular matrix (ECM), And remodeling (maturation and organization of fibrous tissue). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Since cardiac pacemakers are manufactured in a variety of shapes and sizes, the exact dose to be administered also depends on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site) and the total administered drug dose can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg. Can be in the range of ~ 2500 mg. Scarring inhibitor dosage (amount) per unit area of the device or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ^{2 to} 10 μg / mm ² or it may be about ^{10 μg / mm 2 ~250 μg /} mm 2 or about ^{250 μg / mm 2 ~1000μg / mm} 2 , or about ^{1000 μg / mm 2 ~2500 μg /} mm 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site) and the total administered drug dose can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (dose) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg. It can range from ˜100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplant or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ^{2 to} 10 μg / mm ² , or it may be about ^{10 μg / mm 2 ~100 μg /} mm 2 or about ^{100 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2,,. Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

(2) Implantable tachycardia defibrillator (ICD) system In one embodiment, the subject polymer composition is adjacent to an implantable tachycardia defibrillator (ICD) system. Can invade tissues. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  An implantable tachycardia defibrillator (ICD) system is similar to a pacemaker (and many features are included in the pacemaker system), but it treats tachyarrhythmias such as ventricular hypertension or ventricular fibrillation Used for. The ICD consists of an electronic minicomputer that is connected to a battery to charge the ICD and store enough power to deliver it when treatment is needed. The ICD uses sensors to monitor heart activity, and the computer analyzes the data to determine when and whether an arrhythmia is present. ICD leads inserted through veins (referred to as “transvenous” leads. In some systems, the leads are surgically implanted-called the epicardial leads ~ sewn to the surface of the heart Connected to a pacing / computer device. The lead that is normally placed in the right ventricle consists of an insulated wire and the tip of an electrode, and includes a detection composition (detecting cardiac rhythm) and an impact coil. In the 1-chamber ICD, a single lead wire is placed in the ventricle, stopping the ventricular fibrillation and adjusting the speed, and the 2-chamber ICD stopping the atrium and ventricle fibrillation and adjusting the speed. In some cases, additional leads are required and placed under the skin adjacent to the chest or on the surface of the heart. For patients requiring ventricular and atrial tachyarrhythmia management, a second coil is placed in the atrium to treat tachycardia, atrial fibrillation and other arrhythmias. When a tachyarrhythmia is detected, a pulse is generated and propagated through the lead wire to the shock coil, depolarizing muscle and heart conversion and stopping fibrillation of the heart.

  Several ICD systems have been described that are suitable for use in the practice of the present invention. Representative examples of these ICD and related compositions are described in U.S. Pat.Nos. ing. Multiple ICD leads are suitable for use with the present invention. For example, a defibrillator lead is a linear assembly of sensors and coils formed in a loop and includes a conductor system for coupling the loop system to a pulse generator. See U.S. Patent No. 5,897,586. Since the defibrillator lead includes an elongated lead body with an elongated electrode extending from the lead body, the insulating tubular sheath is slidably embedded around the electrode. See U.S. Patent No. 5,919,222. A defibrillator lead is a temporary lead with a mounting pad that temporarily attaches a conductor to an insulating sleeve, thereby attaching a plurality of wire electrodes. See U.S. Patent No. 5,849,033. Other defibrillator leads are described in US Pat. No. 6,052,625. In another aspect, the electrical leads are suitable for use in pacing, defibrillation or both applications. For example, an electrical lead is an electrically isolated, elongated, lead body sheath that surrounds a plurality of lead conductors separated so as not to contact each other. See U.S. Patent No. 6,434,430. The electrical lead consists of a lumen suitable for receiving a stiffening member (eg, a guide wire) and delivers a fluorovisible medium. See U.S. Patent No. 6,567,704. The electrical lead consists of an elongate, flexible, electrically non-conductive probe contained within an electrically conductive path, and depending on the needs detected by the dominant element, defibrillation pulses and Send electrical signals such as pacer pulses. See U.S. Patent No. 5,476,502. Electrical leads form a conductive wire core in a helical coil and are covered with a layer of sheath coating that is electrically insulated from the electrically conductive material, resulting in low electrical resistance and excellent resistance to cyclic stress Has a mechanical resistance. See U.S. Patent No. 5,330,521. Other electrical leads suitable for use in pacing and / or defibrillation applications are described in US Pat. No. 6,556,873.

  In accordance with the present invention, ICDs that may benefit from infiltrating adjacent tissue with the subject polymer composition include commercial products. Commercially available ICDs suitable for the practice of the invention include Medtronic, Inc. GEM III DR 2-chamber ICD, GEMIII VR ICD, GEM II ICD, GEM ICD, GEM III AT Atrial and Ventricular Arrhythmia ICD arrhythmia, JEWEL AF 2-chamber ICD, There are MICROJEWEL ICD, MICRO JEWEL II ICD, JEWEL Plus ICD, JEWEL ICD, JEWEL ACTIVE CAN ICD, JEWELPLUS ACTIVE CAN ICD, MAXIMO DR ICD, MAXIMO VR ICD, MARQUIS DR ICD, MARQUIS VR system, and INTRINSIC2 room ICD. The Medtronic ICD system utilizes a variety of leads, including SPRINT FIDELIS, SPRINT QUATRO SECURE steroid-eluting bipolar leads, SubcutaneousLead System Model 6996SQ subcutaneous leads, TRANSVENE 6937A transvenous leads, and 6492 Unipolar AtrialPacing leads. May benefit from infiltrating the subject polymer composition into adjacent tissue. Medtronic's ICD system and associated leads are described in the following US Patent Numbers, etc. It is described in 6,038,472, 5,849,031, 5,439,484, 5,314,430, 5,165,403, 5,099,838 and 4,708,145. Manufactured by Guidant Corp. VITALITY 2 DR 2 room ICD, VITALITY 2 VR 1 room ICD, VITALITY AVT 2 room ICD, VITALITYDS 2 room ICD, VITALITY DS VR 1 room ICD, VITALITY EL 2 room ICD, VENTAK PRIZM 2 DR 2 room ICD The VENTAKPRIZM 2 VR 1 room ICD system is also an ICD system suitable for the practice of the present invention. Leads from the Guidant ICD system may also benefit from infiltrating the target polymer composition into adjacent tissue. Guidant's FLEXTENDBipolar lead, EASYTRAK Lead System, FINELINE lead and ENDOTAK RELIANCE ICD lead. Guidant's ICD system and associated leads are described in the following US patent numbers, etc. 6,574,505, 6,018,681, 5,697,954, 5,620,451, 5,433,729, 5,350,404, 5,342,407, 5,304,139 and 5,282,837. Biotronik, Inc. (Germany) sells POLYROX Epicardial leads, KENTROX SLQuadripolar ICD leads, AROX Bipolar leads and MAPOX Bipolar Epicardial leads (eg, US Pat. Nos. 6,449,506, 6,421,567, 6,418,348, 6,236,893) No. and 5,632,770. CONTOUR MD ICD, PHOTON μ DR ICD, PHOTON μ VR ICD, ATLAS + HF ICD, EPICHF ICD, EPIC + HF ICD systems and leads from St. Jud Medicale are transmitted and detected by ICD leads Can be benefited by infiltrating the adjacent polymer composition with the subject polymer composition (U.S. Patent Nos. 5,944,746, 5,722,994, 5,662,697, 5,542,173, 5,456,706 and 5,330,523). Alternatively, the fibrosis inhibitor may be immersed in the area surrounding the electrode-myocardial interface under the present invention, for those skilled in the art, commercially available ICDs not specifically cited herein. Become not the next generation and / or commercial ICD products to be developed in the future may also be expected to be used according to the invention, also must be clear that suitable for its use.

  Regardless of the specific design function, in order for ICD to be effective in cardiac rhythm disorders, the lead must be accurately placed adjacent to the target cardiac muscle tissue. If excessive scar tissue growth or extracellular matrix accumulation occurs around the lead, efficacy may not be fully exploited. ICD leads that infiltrate the polymer composition of interest into the electrode and tissue interface and / or the tissue adjacent to the sensor and tissue interface increase the efficiency of shock transmission and rhythm detection, resulting in improper electrical removal. Prevents fibrillation and extends battery life. ICD is also effective in releasing therapeutic agents that prevent or reduce infection around the transplant site. In one embodiment, the device comprises an ICD and / or lead comprising a polymer composition of interest, the polymer composition comprising an anti-scarring agent and / or an anti-infective agent, and implanting the ICD and / or lead. The tissue around the site to be transplanted or transplanted is moistened. In another aspect, the present invention provides an ICD lead comprising a subject polymer composition, the polymer composition comprising an anti-scarring agent and / or an anti-infective agent to wet muscle tissue adjacent to the lead. To do.

  In another aspect, the present invention provides an ICD wherein the subject polymer composition is wetted in adjacent tissue, the subject polymer composition comprising a therapeutic agent (such as an anti-scarring agent and / or an anti-infective agent). ) May be included. A number of polymeric and non-polymeric delivery systems for use in connection with ICD have already been described above.

  The composition of the polymer comprises: (a) the tissue adjacent to the ICD, (b) around the tissue interface of the ICD, (c) the region around the ICD, and (d) directly against the tissue around the ICD. Application around and / or indirectly and on it can wet the periphery of the implanted ICD. Methods for wetting the polymer composition of interest to the tissue adjacent to the ICD include delivering the polymer composition to: (a) against the surface of the ICD (eg, injection material) (As paste, gel or mesh), (b) Immediately before or during implantation of the ICD graft, as a tissue surface of the implantation hole (eg injection material, paste, gel, in situ formed gel or mesh) (C) Immediately after implantation of the ICD, (d) ICD on the surface of the ICD and / or the surface of the implanted ICD (eg, injection material, paste, gel, in situ formed gel or mesh) Topical application of the composition to the anatomical space in which it is placed (especially useful in this example is the use of a polymeric carrier that releases the fibrosis inhibitor over a period ranging from hours to weeks-liquid, suspension Suspension, emulsion, microemulsion, Microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants, and other formulations that release drugs and can be delivered to the site where the device is inserted), (e) solutions and injections into the tissue surrounding the ICD And / or (f) application by a combination of the methods described above. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the polymer composition of interest can wet the surrounding tissue of the entire device or a portion (device only, lead only, electrode only, and / or combinations thereof).

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the present invention, the subject polymer composition moistened in tissue adjacent to the ICD inhibits one or more of four general factors for the process of fiber formation (or scarring) including: Can be adapted to release drugs: new blood vessel formation (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) accumulation, and Remodeling (maturation and organization of fibrous tissue). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Because ICDs are manufactured in a variety of shapes and sizes, the exact dose administered will also depend on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site) and the total administered drug dose can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg. Can be in the range of ~ 2500 mg. Scarring inhibitor dosage (amount) per unit area of the device or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ^{2 to} 10 μg / mm ² or it may be about ^{10 μg / mm 2 ~250 μg /} mm 2 or about ^{250 μg / mm 2 ~1000μg / mm} 2 , or about ^{1000 μg / mm 2 ~2500 μg /} mm 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site) and the total administered drug dose can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (dose) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg. It can range from ˜100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplant or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ^{2 to} 10 μg / mm ² , or it may be about ^{10 μg / mm 2 ~100 μg /} mm 2 or about ^{100 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2,,. Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

(3) Vagus nerve stimulation for the treatment of arrhythmias In one embodiment, the subject polymer composition can invade tissue adjacent to the vagus nerve stimulation (VNS) device. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  Nerve stimulators may also be used to stimulate the vagus nerve and affect the rhythm of the heart. The vagus nerve, including conduction systems (including SA), provides nerve distribution to the heart, and vagus nerve indications include supraventricular arrhythmia, angina, atrial tachycardia, atrial flutter, atrial fibrillation and others It may be used to treat symptoms such as arrhythmia that cause low cardiac output.

  As described above, in VNS, bipolar electrical leads are surgically implanted to deliver electrical stimulation from the pulse generator to the left vagus nerve of the neck. The pulse generator is an implanted lithium carbonate monofluoro battery powered device that delivers a precise stimulation pattern to the vagus nerve. The pulse generator can be programmed (using programming software) by a cardiologist to treat a specific arrhythmia.

  Such products are described, for example, in US Pat. Nos. 6,597,953 and 6,615,085. For example, the nerve stimulation device is a vagus nerve stimulation device that generates pulses with a frequency that automatically changes based on the excitement rate of the vagus nerve. See US Pat. Nos. 5,916,239 and 5,690,681. A nerve stimulator is a device for detecting the characteristics of tachycardia based on an electrogram and delivering the current electrical stimulus to the nervous system to reduce the heart rate. See U.S. Patent No. 5,330,507. The neurostimulator is an implantable cardiac stimulation system that consists of two sensors (one for atrial signals and one for ventricular signals), a pulse generator and a controller to balance the sympathetic and vagal stimulation. to be certain. See U.S. Patent No. 6,477,418. A nerve stimulator is a device that applies electrical pulses to the vagus nerve at a programmable frequency and is tuned to maintain a low heart rate. See U.S. Patent No. 6,473,644. The neurostimulator provides electrical stimulation to the vagus nerve to induce changes in electroencephalogram measurements as a treatment for epilepsy, while controlling the heart's behavior within normal parameters. See, for example, US Pat. No. 6,587,727.

  VNS devices that may benefit from infiltrating adjacent tissue with the subject polymer composition in accordance with the present invention include commercial products. Examples of commercially available VNS systems include Model 300 and Model 302 leads from Cyberonics, Inc., Model 101 and Model 102R pulse generators, Model 201 programming software and Model 250 programming software, and Model 220 magnets. Product included. These products manufactured by Cyberonics, Inc. are described in US Pat. Nos. 5,928,272, 5,540,730 and 5,299,569.

  Regardless of the specific design function, in order for vagus nerve stimulation to be effective in treating arrhythmias, the lead must be accurately placed adjacent to the left vagus nerve. If excessive scar tissue growth or extracellular matrix accumulation occurs around the VNS lead, it can lead to reduced device effectiveness. VNS devices moistened with a polymer composition of interest at the tissue adjacent to the electrode-tissue interface can improve the efficiency of shock transmission and extend the period during which these devices function clinically. . VNS devices are also effective in releasing therapeutic agents that prevent or reduce infection around the implantation site. In one embodiment, the device includes a VNS device and / or lead that includes the polymer composition of interest, and the polymer composition is applied to tissue at or near the site where the VNS device and / or lead is implanted. Contains moist scarring inhibitors and / or anti-infectives. In another aspect, the present invention provides a lead comprising a subject polymer composition, the polymer composition being a scarring inhibitor moistened in the tissue surrounding the vagus nerve into which the lead is implanted and / or Contains anti-infectives.

  In another aspect, the invention provides a VNS device in which a subject polymer composition is wetted to adjacent tissue, the subject polymer composition comprising a therapeutic agent (an anti-scarring agent and / or an anti-infective agent). Etc.). A number of polymeric and non-polymeric delivery systems for use in connection with VNS devices have already been described above.

  The polymer composition can be applied to (a) the tissue adjacent to the VNS device, (b) around the tissue interface of the VNS device, (c) the region around the VNS device, and (d) the tissue around the VNS device. By applying directly and / or indirectly and in and on it, the periphery of the implanted VNS device can be moistened. Methods of wetting the subject polymer composition to the tissue adjacent to the VNS device include delivering the polymer composition to: (a) against the surface of the VNS device (eg: (B) Implant material, paste, gel, or mesh) (b) Immediately before or during implantation of the VNS device graft (eg, injection material, paste, gel, gel formed in situ) Or as a mesh) (c) Immediately after implantation of the VNS device, the surface of the VNS device and / or the surface of the implanted VNS device (eg injection material, paste, gel, gel or mesh formed in situ) (D) Topical application of the composition to the anatomical space in which the VNS device is placed (especially useful in this example is a polymer carrier that releases the fibrosis inhibitor over a period ranging from hours to weeks). Is used ~ liquid, suspension, milk Suspensions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and other formulations that release the drug and can be delivered to the site where the device is inserted), (e) surround the VNS device Application by intradermal injection of solutions, infusions, and sustained release formulations into tissues and / or (f) a combination of the methods described above. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the polymer composition of interest can wet the surrounding tissue of the entire device or a portion (device only, lead only, electrode only, and / or combinations thereof).

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the present invention, the subject polymer composition wetted in tissue adjacent to the VNS device comprises one or more of four general elements for the process of fiber formation (or scarring) including: Can be adapted to release inhibitory drugs: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), accumulation of extracellular matrix (ECM), And remodeling (maturation and organization of fibrous tissue). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Because VNS devices are manufactured in a variety of shapes and sizes, the exact dose administered will also vary depending on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site) and the total administered drug dose can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg. Can be in the range of ~ 2500 mg. Scarring inhibitor dosage (amount) per unit area of the device or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ^{2 to} 10 μg / mm ² or it may be about ^{10 μg / mm 2 ~250 μg /} mm 2 or about ^{250 μg / mm 2 ~1000μg / mm} 2 , or about ^{1000 μg / mm 2 ~2500 μg /} mm 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site) and the total administered drug dose can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (dose) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg. It can range from ˜100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplant or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ^{2 to} 10 μg / mm ² , or it may be about ^{10 μg / mm 2 ~100 μg /} mm 2 or about ^{100 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2,,. Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

A number of cardiac rhythm management (CRM) devices have been described above, all of which have similar design features, cause undesirable similar tissue reactions after transplantation, and introduce or promote infection at the transplant site Sometimes. For those skilled in the art, not only commercially available CRM equipment not specifically cited herein, but also the next generation and / or future developed commercially available CRM products are expected to be used in accordance with the present invention and their use. It should be clear that it is suitable for. In particular, CRM devices such as leads must be accurately positioned to ensure that the stimulus is delivered to the correct anatomical location within the atrium and / or ventricle. All or some of the CRM devices may migrate after surgery, or excessive scar tissue growth may occur around the graft, leading to reduced performance of these devices. CRM devices in which the polymer composition of interest is infiltrated into tissue adjacent to the electrode-tissue interface (especially for fully implanted battery-operated devices) can improve the effectiveness and / or duration of the implant. Can be used to enhance. The CRM device is also effective in releasing therapeutic agents that prevent or reduce infection around the implantation site. In one embodiment, the present invention provides a CRM device wherein the subject polymer composition is wetted to adjacent tissue, the subject polymer composition comprising a therapeutic agent (an anti-scarring agent and / or an anti-infective agent). Etc.). These compositions include one or more fibrosis inhibitors to inhibit or reduce granulation tissue overgrowth or gliosis tissue and / or include one or more anti-infective agents. This inhibits or reduces infection at the transplant site.

Implantable Sensor In one embodiment, the subject polymer composition can infiltrate tissue adjacent to the implantable sensor. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  Implantable sensors are provided for detecting physiological levels or changes in the body. There are a number of sensor devices where the occurrence of a fibrous response has an adverse effect on the function of the device, or the ecological problems in which it is implanted or used. The appropriate clinical function of the transplanted tissue depends on intimate anatomical contact with the target tissue and / or body fluid. If scarring occurs around the implanted device, the electrical components and properties at the device-tissue interface may deteriorate and the device may not function properly. When a scar is formed between the detection device and the adjacent (target) tissue, the sensor's detection mechanism includes physical, chemical and / or biological information (eg, fluid level, drug level, Metabolite levels, glucose levels, pressure, etc.) may not reach. Similarly, when a “foreign” reaction occurs and the implanted sensor is covered with scars (ie, the body “blocks” the sensor with fibrous tissue), the sensor receives biological information that does not reflect the entire organism. If the sensor detects conditions within the capsule (ie, levels detected in the microenvironment) and these conditions are not consistent with conditions outside the capsule (ie, consistent throughout the body and within the microenvironment) Record information that is not representative of the systemic level. Implantation of an implantable sensor can cause or promote infection around the implantation site.

  Sensors or transducers are located deep in the body, temperature, pressure, strain, fluid flow, metabolite levels (eg electrolysis, glucose), drug levels, chemical properties, electrical properties, Physiological properties such as magnetic properties may be monitored. Representative examples of implantable sensors used to practice the present invention include blood and tissue sugar monitors, electrolyte sensors, blood concentration sensors, temperature sensors, pH sensors, light sensors, amperometric sensors, pressure sensors. Sensors, biosensors, detection transponders, strain sensors, activity sensors and magnetoresistive sensors.

  A number of implantable sensors and transducers have been described. For example, implantable sensors include microelectronic devices implanted around the large intestine that detect anal content as needed and stimulate peristaltic contractures. See US Pat. No. 6,658,297. An implantable sensor can be used to measure the pH of the GI tract. A typical example of such a pH detector is the BRAVO pH Monitoring System manufactured by Medtronic, Inc. (Minneapolis, MN). An implantable sensor is a part of a GI catheter or probe that contains a sensitive polymeric material that undergoes an irreversible change when it encounters the cumulative activity of a sensor site and external media connected to an electrical or optical measurement device. . See U.S. Patent No. 6,006,121. The implantable sensor can be a component of a central venous catheter (CVC) (eg, jugular vein catheter) system. For example, the device consists of one or more oxygen sensors and a catheter body consisting of a refrigerant supply and return lumen that exchanges heat within the body to prevent heating due to ischemia caused by severe brain trauma or stroke Can comprise a distal heat exchange region. See US Pat. No. 6,652,565. A CVC may include a heat and temperature sensor to measure blood temperature. See US Pat. No. 6,383,144.

  In one embodiment, the present invention provides an implantable sensor in which the subject polymer composition is wetted into adjacent tissue, the subject polymer composition comprising a therapeutic agent (an anti-scarring agent and / or an anti-cancer agent). May contain infectious drugs). A number of polymeric and non-polymeric delivery systems for use in connection with implantable sensors have already been described above.

  The polymeric composition comprises (a) tissue adjacent to the implantable sensor, (b) around the tissue interface of the implantable sensor, (c) the area around the implantable sensor, and (d) By applying directly and / or indirectly to and in and on the tissue surrounding the implantable sensor, the periphery of the implanted implantable sensor can be moistened. Methods of wetting the polymer composition of interest to the tissue adjacent to the implantable sensor include delivering the polymer composition to: (a) against the surface of the implantable sensor (E.g. as injection material, paste, gel or mesh) (b) Immediately before or during implantation of the implantable sensor implant (e.g. injection material, paste, gel, mesh) (As a gel or mesh formed in place) (c) Immediately after implantation of the implantable sensor, the surface of the implantable sensor and / or the implanted implantable sensor (eg, injection material, paste, gel, (D) Topical application of the composition to the anatomical space where the implantable sensor is placed (in particular in this example, several hours to weeks) Is the use of a polymer carrier that releases a fibrosis inhibitor over a period of time--liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants, and Other formulations that can release the drug and be delivered to the site where the device is inserted), (e) by intradermal injection of solutions, infusions, and sustained release formulations into the tissue surrounding the implantable sensor and / or (f) Application by a combination of the above methods. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the polymer composition of interest can be wetted into the surrounding tissue of the entire device or a portion (device only, sensor only, detector only, and / or combinations thereof).

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the present invention, the subject polymer composition wetted in tissue adjacent to the implantable sensor is one of four general factors for the process of fiber formation (or scarring) comprising: Can be adapted to release drugs that inhibit multiple: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) Accumulation and remodeling (maturation and organization of fibrous tissue). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Because implantable sensors are made in a variety of shapes and sizes, the exact dose to be administered also depends on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site) and the total administered drug dose can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg. Can be in the range of ~ 2500 mg. Scarring inhibitor dosage (amount) per unit area of the device or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ^{2 to} 10 μg / mm ² or it may be about ^{10 μg / mm 2 ~250 μg /} mm 2 or about ^{250 μg / mm 2 ~1000μg / mm} 2 , or about ^{1000 μg / mm 2 ~2500 μg /} mm 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site) and the total administered drug dose can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (dose) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg. It can range from ˜100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplant or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ^{2 to} 10 μg / mm ² , or it may be about ^{10 μg / mm 2 ~100 μg /} mm 2 or about ^{100 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2,,. Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

Details of some specific implantable sensor devices and treatments are described below.

(1) Blood and glucose monitoring In one embodiment, the subject polymer composition can invade tissue adjacent to the glucose monitor. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  A glucose monitor is used to detect changes in glucose in the blood and is used in particular for the management and treatment of diabetic patients. Diabetes is a metabolic disorder of glucose metabolism that afflicts many people in the world's developing countries. This disease is characterized by the body's inability to utilize and metabolize carbohydrates, particularly glucose. Normally, a delicate balance between glucose in the blood and glucose in body tissue cells is maintained by a hormone called insulin produced by the pancreas. The pancreas malfunctions and produces an inappropriate amount of insulin to reduce the level of glucose in the blood (diabetes type I), or the pancreas is producing insulin properly When it stops responding to glucose-lowering effects (diabetes type II), it results in diabetes. Because the administration and timing of insulin and / or other hypoglycemic agents varies with changes in glucose levels relative to the drug, accurate detection of glucose levels in the blood is essential for the management of diabetics. Too much dosage can cause glucose levels in the blood to be too low, causing confusion and unconsciousness. If the dosage is too low, the level of glucose in the blood will be too high, resulting in excessive thirst, frequent urination and metabolism, known as ketoacidosis. Improper timing of drug administration can cause blood glucose levels to change drastically between the two extremes, which may lead to long-term complications from diabetes such as heart disease, kidney failure and blindness. ing. In the event of extreme symptoms, careful and continuous monitoring of glucose levels is important in life-threatening diabetes management. In diabetic patients, one method of detecting changes in glucose levels and continuously detecting when glucose levels are too high or too low is to implant a glucose monitor. Since the glucose monitor detects changes in glucose levels in the blood, insulin can be administered via an external injection or an implantable insulin pump to maintain the glucose level in the blood within the appropriate physiological range.

  There are several blood and tissue glucose monitors suitable for use in the practice of the present invention. For example, a glucose monitor can be delivered transluminally into the vasculature using a catheter or stent platform. See US Pat. No. 6,442,413. A glucose monitor may consist of a biological cell that is sensitive to glucose that monitors glucose levels in the blood and generates a detectable electrical or optical signal in response to changes in glucose concentration. See U.S. Patent Nos. 5,101,814 and 5,190,041. The glucose monitor can be a flexible electrode of small diameter, implanted subcutaneously, containing an analytically reactive enzyme designed as an electrochemical glucose monitor. See U.S. Patent Nos. 6,121,009 and 6,514,718. An implantable sensor is a closed loop insulin delivery system that detects glucose levels in a patient's blood based on electrical signals and then stimulates an insulin pump or pancreas to provide insulin. It is possible. See U.S. Patent Nos. 6,558,345 and 6,093,167. Other glucose monitors are described in US Pat. Nos. 6,579,498, 6,565,509 and 5,165,407. A minimally invasive glucose monitor is GLUCOWATCH G2BIOGRAPHER from Cygnus Inc. (see cygn.com). See U.S. Patent Nos. 6,546,269, 6,687,522, 6,595,919 and U.S. Patent Application Nos. 20040062759A1, 20030195403A1 and 20020091312A1.

  Glucose monitors that may benefit from infiltrating adjacent tissue with the subject polymer composition in accordance with the present invention include commercial products. There are a number of commercially available blood and tissue glucose monitoring devices suitable for the practice of the present invention. Almost any glucose monitor can be used, but for clarity, several specific commercial and development phase examples are described below.

  CONTINUOUS GLUCOSE MONITORING SYSTEM (CGMS) manufactured by Medtronic MiniMed, Inc. (Northbridge, California, see minimed.com), US Patent Nos. 6,520,326, 6,424,847, 6,360,888, 5,605,152, 6,804,544 See 20040167464A1. The CGMS system is surgically implanted into the subcutaneous tissue of the abdomen and stores tissue glucose measurements every 5 minutes. Since the sensitivity decreases due to the local tissue response to the device, it often needs to be removed after a few days (about 3 days), so infiltrating the tissue adjacent to the sensor with the polymer composition of interest May increase device activity.

  CONTINUOUS GLUCOSE MONITORING DEVICE, manufactured by Thera Sense (Alameda, Calif., See terasense.com), uses a small disposable electrochemical sensor that is inserted into the patient's skin using a spring-loaded insertion device. . The sensor measures interstitial glucose levels every 5 minutes and can store the results for future analysis. See US20040186365A1, US20040106858A1 and US20030176183A1. The device stores data for up to 1 month and has alarm functions for high and low glucose levels, but the accuracy is reduced due to foreign body reaction to the graft, so it must be replaced every few days. By infiltrating the polymer composition of interest into the tissue adjacent to this sensor, its activity can be extended and the frequency of replacement can be reduced. One electrochemical sensor that may benefit from the present invention is a multilayer electrochemical sensor manufactured by Isense (Portland, Oreg.). This system has a semi-permeable membrane, a catalytic membrane that generates an electric current in the presence of glucose, and a special membrane to reduce interference from other substances.

  SMSI glucosesensor (Sensors for Medicine and Sciences, Inc., Montgomery County, MD) can be implanted subcutaneously with a short outpatient procedure. This sensor automatically measures interstitial glucose every few minutes without user intervention. The sensor implant communicates wirelessly with a small external reader, allowing the user to monitor glucose levels continuously or as needed. The reader tracks the rate of change in glucose level and alerts the user to hypoglycemia and hyperglycemia. The operating life of the sensor graft is about 6-12 months and can be replaced afterwards.

  AnimasCorporation (animascorp.com, Westchester, PA) is developing an implantable glucose sensor that measures near-infrared by blood absorption based on a spectroscopic or optical sensor placed around the blood vessel. The Animas Glucose Monitor attaches to an insulin infusion pump and provides glow loop control of glucose levels in the blood. Sensors benefit from the present invention because the scar tissue on the sensor compromises the ability of the device to collect information correctly with the optical sensor.

  DexCom, Inc. (see San Diego, Calif., See dexcom.com)) has developed a self-made continuous glucose monitoring system that allows wireless measurement of glucose in blood continuously to an external receiver. An implantable sensor that transmits. The receiver displays the current glucose value every 30 seconds (and also displays trend values over 1 hour, 3 hours and 9 hours) and raises an alarm when the glucose level is high and low. This device consists of an implantable sensor placed in the subcutaneous tissue and continuously monitors the glucose level in the tissue (interstitial fluid) for both diabetic type 1 and type 2 patients. The device also includes a micro-architecture arrangement that is unique to the sensor area, which provides accurate data over time. Glucose monitoring devices and related systems developed by DexCom, Inc are described in US Pat. Nos. 6,741,877, 6,702,857 and 6,558,321. However, although the battery and circuitry of the monitoring device can function for a long time, foreign body reaction and / or graft encapsulation can affect the ability of the device to accurately detect glucose levels over time in some percent of the graft. I will give it. Infiltrating the tissue adjacent to the device with the polymer composition of interest allows for accurate detection of glucose levels longer after implantation, reducing the number of failed devices and reducing replacement frequency .

  Also of particular interest in the present invention is a glucose monitoring system that uses a glucose reactive polymer as part of the detection mechanism. M-Biotech (Salt Lake City, Utah) is developing a continuous monitoring system that includes subcutaneous implantation of glucose-responsive hydrogels in combination with pressure transducers. See the following US patent number. As the hydrogel shrinks or enlarges, it responds to changes in glucose concentration, and the expansion or contraction is detected by the pressure transducer. The converter converts information into an electrical signal and transmits a wireless signal to the display device. Cybersensors (Berkshire, UK) manufactures external receivers / transmitters that capture sensors and data, such as subcutaneously implanted capsules, and supply the capsules via RF signals (eg, GB2335496 and the United States) (See patent number 6,579,498) Issued by UK Patent and Trademark Office}. The sensor coating contains a glucose-affinity polymer, there are physical sensors and RF microchips, and the entire coating is further covered by a semi-permeable membrane. Glucose-affinity polymers, when in contact with glucose, become thinner and less sticky as the glucose concentration increases (range 3-15 nM). This reversible reaction is detected by a physical sensor and converted into a signal. The system described above is suitable for infiltrating a tissue of interest adjacent to a graft sensor, as provided in the present invention.

  The glucose detector under development by Advanced Biosensors (Mentow, Ohio) is small (150 μm wide, 2 mm long), biocompatible, includes a silicone-based needle, and is implanted subcutaneously. The device detects dermal glucose levels and transmits data wirelessly. However, due to foreign body reaction and / or encapsulation on the graft, the device is unable to accurately detect glucose levels beyond 7 days. Infiltration of the polymer composition of interest into the tissue adjacent to the device can accurately detect glucose levels over a longer period of time and extend the effective life span of the device.

  Regardless of the implantable blood, tissue or interstitial fluid glucose monitoring device, accurate detection of physical, chemical and / or physiological properties requires the device to be accurately placed next to the tissue . In particular, the detector of the detection mechanism needs to measure glucose levels that are the same (or representative) as in blood. If excessive scar tissue formation or extracellular matrix accumulation occurs around the device, this impairs glucose movement from the tissue to the detector, rendering it ineffective. Similarly, if a “foreign” reaction occurs and the implanted glucose sensor is encapsulated in fibrous tissue, the sensor will detect the glucose level in the coating. If the glucose level in the capsule is not the same as the glucose level outside the capsule (ie, throughout the body), information that is not representative of the systemic level is recorded. This can lead to serious consequences for doctors or patients prescribing hypoglycemic agents (such as insulin) in the wrong amount. A glucose monitoring device for blood, tissue or interstitial fluid infiltrating the polymer composition of interest into the tissue adjacent to the graft reduces the scarring and / or sealing of the graft, and glucose Increase detection efficiency and accuracy, minimize insulin prescribing errors, help maintain correct blood glucose levels, extend the clinical function of these devices, and / or reduce graft replacement frequency. Such a glucose monitoring device is also effective in releasing a therapeutic agent that prevents or reduces infection around the transplant site. In one embodiment, the device is a glucose monitoring device for blood, tissue, and interstitial fluid that includes a polymer composition of interest, the polymer composition being wetted around the tissue where the device is implanted. Contains anti-scarring agents and / or anti-infectives. In another aspect, the present invention provides a glucose monitoring device wherein the subject polymer composition is wetted in adjacent tissue, the subject polymer composition comprising a therapeutic agent (an anti-scarring agent and / or an anti-infection). Medicine). A number of polymeric and non-polymeric delivery systems for use in conjunction with glucose monitoring devices have already been described above.

  The composition of the polymer comprises: (a) tissue adjacent to the glucose monitoring device, (b) around the tissue interface of the glucose monitoring device, (c) the region around the glucose monitoring device, and (d) the glucose monitoring device. By applying directly and / or indirectly to and around the surrounding tissue, the periphery of the implanted glucose monitoring device can be moistened. Methods of wetting the subject polymer composition to the tissue adjacent to the glucose monitoring device include delivering the polymer composition to: (a) against the surface of the glucose monitoring device ( Example: as injection material, paste, gel or mesh) (b) Immediately before or during transplantation of the glucose monitoring device graft surface (eg injection material, paste, gel, in situ formed) Formed as a gel or mesh) (c) Immediately after implantation of the glucose monitoring device, formed on the surface of the glucose monitoring device and / or implanted glucose monitoring device (eg, injectable material, paste, gel, in situ) (D) Topical application of the composition to the anatomical space where the glucose monitoring device is placed (especially useful in this example is The use of polymer carriers that release fiber formation inhibitors over a period ranging from hours to weeks-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solids Grafts and other formulations that can release the drug and be delivered to the site where the device is inserted), (e) by intradermal injection of solutions, infusions, and sustained release formulations into the tissue surrounding the glucose monitoring device, And / or (f) Application by a combination of the methods described above. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the polymer composition of interest can be wetted into the surrounding tissue of the entire device or a portion (device only, sensor only, detector only, and / or combinations thereof).

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the present invention, the subject polymer composition wetted in the tissue adjacent to the glucose monitoring device is one or more of four general elements for the process of fiber formation (or scarring) including: Can be adapted to release drugs that inhibit: new blood vessel formation (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), accumulation of extracellular matrix (ECM) And remodeling (fibrotic tissue maturation and organization). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Because glucose monitoring devices are manufactured in a variety of shapes and sizes, the exact dose administered will also vary depending on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site) and the total administered drug dose can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg. Can be in the range of ~ 2500 mg. Scarring inhibitor dosage (amount) per unit area of the device or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ^{2 to} 10 μg / mm ² or it may be about ^{10 μg / mm 2 ~250 μg /} mm 2 or about ^{250 μg / mm 2 ~1000μg / mm} 2 , or about ^{1000 μg / mm 2 ~2500 μg /} mm 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. Examples of typical anti-infectives include (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) Podophyllotoxins (such as etoposide), (E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin) are included, as well as analogs and derivatives of the other day.

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site) and the total administered drug dose can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (dose) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg. It can range from ˜100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplant or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ^{2 to} 10 μg / mm ² , or it may be about ^{10 μg / mm 2 ~100 μg /} mm 2 or about ^{100 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2,,. Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

(2) Pressure and stress sensor In one embodiment, the polymer composition of interest can invade tissue adjacent to the pressure and / or stress sensor. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  A pressure and stress monitor is used to detect an increase in body pressure or stress. Implantable transducers and sensors are used to temporarily or chronically use and record absolute pressure on an organ, tissue or blood vessel. A number of different designs and operating systems have been proposed and are temporarily or chronically deployed for patients with various medical conditions. There are intrinsic pressure sensors for use for days or weeks, but chronic or permanent implantable pressure sensors are also used. Pressure sensors detect various types of pressure on the body and can detect not only blood pressure and fluid pressure, but also mechanical pressures associated with aneurysms, intracranial pressures and fractures.

  There are several pressure monitors suitable for use in the practice of the present invention. For example, an implantable sensor detects the absolute pressure of bodily fluids and the ambient operating temperature at a selected site by means of leads, sensor modules, sensor circuits (including electrical conductors) and equipment for providing voltage sell. See US Pat. No. 5,535,752. The implantable sensor can be an intracranial pressure monitor that provides an analog data signal that is electronically converted to digital pulses. See US Pat. No. 6,533,733. The implantable sensor can be a barometric sensor that is covered by an air chamber used to derive reference pressure data for use in combination with an implantable medical device such as a pacemaker. See US Pat. No. 6,152,885. The implantable sensor can be adapted for insertion into a body pathway to monitor parameters associated with fluid flow through an intraluminal implant (eg, a stent). See US Pat. No. 5,967,986. The implantable sensor can be an inactive sensor with an inductor capacitor circuit having a resonant frequency adapted for the patient's skull to sense intracranial pressure. See U.S. Patent No. 6,113,553. The implantable sensor can be a self-powered strain sensing system that generates a strain signal in response to stress generated by the bone fixation device. See US Patent No. 6,034,296. The implantable sensor can be a component of a microinjector catheter. The catheter includes a wire electrode and lumen for microinjecting saline around the wire, which are designed for measuring the potential difference across the GI wall and for simultaneous pressure measurements. See US Patent No. 5,551,425. The implantable sensor can be part of a CNS device. For example, an in-cranial pressure sensor attached to the skull at the in-situ monitoring pressure, which transmits pressure from the outside from the skull. See US Patent No. 4,003,141. The implantable sensor can be a component of a left auxiliary artificial heart. For example, a VAD is a blood pump adapted to be incorporated into the blood flow between the left ventricle and the aorta using a controller that can adjust the pump speed based on the response of the sensor and an inflow fluid pressure sensor. sell. See US Pat. No. 6,623,420.

  In accordance with the present invention, pressure and / or stress sensor devices that may benefit from infiltrating the adjacent polymer composition into adjacent tissue also include commercially available products. There are numerous commercially available or experimental pressure and stress sensor devices in the practice of the present invention. Using the figures, some of these devices and implants are described in the next paragraph.

  A device from CardioMEMS (Atlanta, Georgia, @ cardiomems.com, partnership with Georgia Institute of Technology and Cleveland Clinic) is inserted into the aneurysm, monitors the pressure in the pouch, and allows fluid to a level that can rupture. Alert medical professionals when satisfied. Endovascular aneurysm treatment (EVAR) is often performed using a stent graft, which isolates the aneurysm from the circulation. However, if blood leaks persistently into the aneurysm, the pressure increases and as a result there is a risk of rupture. A CardioMEMS device is implanted in an aneurysm after EVAR and monitors the pressure in the isolated bag to detect if the patient is at risk of rupture. The pressure sensor features an inductive capacitor resonance circuit with a variable capacitor. Since the electric capacity depends on the pressure of the environment in which the capacitor is arranged, a change in local pressure can be detected. Data is generated using an external excitation system, which induces an oscillating current in the sensor and detects the oscillating frequency (and is used to calculate the pressure). However, although the circuit is capable of long-term functionality, foreign body reaction and / or graft encapsulation can affect the device's ability to detect accurate pressure levels in an aneurysm (i.e., the device may be micro-environment of the capsule). ) But not the pressure of the entire aneurysm). Sensor implantation may cause or promote infection around the implantation site. Infiltrating the tissue adjacent to the device with the polymer composition of interest allows for accurate detection of pressure levels over a longer period after implantation.

  MicroStrain Inc. (Williston, Vermont, @ microstrain.com) has developed a series of implantable sensors for measuring strain, position and movement in the body. These sensors include, for example, eye tremor, corneal transplant depth, orientation sensor to improve crown preparation, strain on the main ligament, spinal ligament strain, vertebral strain, elbow ligament strain, emg and ekg 3DM-G to measure data, orientation and movement, wrist ligament strain, hip replacement sensor to measure micromotion, graft settlement, knee ligament strain, ankle ligament strain, Achilles tendon Strain, sole bow support strain, and force in the shoe. The company provides artificial knees that can measure compressive forces in vivo and transmit data in real time. U.S. Patent Nos. 6,714,763, 6,625,517, 6,622,567, 6,588,282, 6,529,127, 6,499,368, 6,433,629, 5,887,351, 5,777,467, 5,497,147 And 4,993,428. Patent applications describing this technology and components for producing devices of this technology are as follows: 200440113790, 20040078662, 20030204361, 20030158699, 20030047002, 20020190785, 20020170193, 20020088110, 20020085174, 20010054317 and 20010033187 is included.

  Mesotec (Hannover, Germany, @ mesotec.com) has collaborated with several German institutions (eg Fraunhofer Institute of Microelectronic Circuits and Systems) to develop an implantable intraocular pressure sensor system called MESOGRAPH. I can measure intraocular pressure. This is useful, for example, to confirm the onset of glaucoma. Sensors based on CMOS can be implanted with standard surgery and are inductively linked to an external unit integrated with the frame of the glasses. The glasses are linked to a portable data recording device via a cable. Data is relayed upstream by a modulated RF carrier operating at 13.56 MHz and a switchable load, with power coming downstream from the sensor. By changing the diameter of the polysilicon diaphragm of the micromechanical vacuum gap capacitor on the chip, the pressure range over which the sensor reacts can be adapted between 50kNm-2 and 3.5MNm-2. The device consists of a delicate, collapsible coil for telemetry coupling and a miniature miniature pressure sensor. This sensor is manufactured on a microtechnology basis and provides continuous, long-term reading and monitoring of intraocular pressure. The tip and coil are integrated into a soft modified intraocular lens that is implanted in the patient's eye during today's common surgical procedures. However, foreign body reaction and / or graft encapsulation affects the ability to accurately detect intraocular pressure levels (ie, the device detects the pressure in the microenvironment of the capsule around the implant and not the entire intraocular pressure) So even if the transplant is successful initially, the device will fail later. Sensor implantation may cause or promote infection around the implantation site. Wetting the polymer composition of interest onto the ocular tissue adjacent to the device allows for accurate pressure measurement over a longer period of time after implantation, allowing a reduction in the number of devices that fail.

  For accurate detection of physical and / or physiological properties (such as pressure), regardless of the specific design function of the pressure and / or stress sensor, the device is accurately placed in the tissue and is representative of the overall condition Need to receive. If excessive scar tissue formation or extracellular matrix accumulation occurs around the device, the sensor receives incorrect information that impairs its effectiveness, or the scar tissue does not flow biological information to the sensor. May be blocked. For example, many devices detect pressures that are not applicable by encapsulating the implant (ie, the device detects the pressure in the microenvironment of the coating around the implant, not the pressure of the entire environment) Even if it succeeds, it fails later. Pressure and stress detection devices where the tissue adjacent to the implant is moistened with the polymer composition of interest can improve the efficiency of detection and extend the period during which these devices function clinically. Such pressure and stress detection devices are also effective in releasing therapeutic agents that prevent or reduce infection around the implantation site. In one embodiment, the device includes an implantable sensor device comprising a polymer composition of interest, wherein the polymer composition is an anti-scarring agent moistened to tissue surrounding the site where the device is implanted and / or Or contains anti-infectives. In another aspect, the invention provides a pressure or stress detection device in which the subject polymer composition is wetted by adjacent tissue, the subject polymer composition comprising a therapeutic agent (an anti-scarring agent and / or May contain anti-infectives). A number of polymeric and non-polymeric delivery systems for use in conjunction with pressure and stress detection devices have already been described above.

  The polymer composition comprises: (a) tissue adjacent to the pressure or stress detection device, (b) around the tissue interface of the pressure or stress detection device, (c) the area around the pressure or stress detection device and (d) moistening the periphery of the implanted pressure or stress detection device by applying directly and / or indirectly to and around the tissue around the pressure or stress detection device. it can. Methods of wetting the polymer composition of interest to tissue adjacent to the pressure or stress detection device include delivering the polymer composition to: (a) the surface of the pressure or stress detection device (E.g., as injection material, paste, gel or mesh), (b) Immediately before or during implantation of the pressure or stress detection device graft (eg: injection material, paste, Gel, as a gel or mesh formed in situ), (c) Immediately after implantation of the pressure or stress detection device, the surface of the pressure or stress detection device and / or the implanted pressure or stress detection device (eg injection) (D) Composition into the anatomical space where the pressure or stress detection device is placed on the surface of the substance, paste, gel, gel or mesh formed in situ Topical application of objects (especially useful in this example is the use of a polymeric carrier that releases a fibrosis inhibitor over a period ranging from hours to weeks-liquids, suspensions, emulsions, microemulsions, micross Fairs, pastes, gels, microparticles, sprays, aerosols, solid implants and other formulations that release drugs and can be delivered to the site where the device is inserted), (e) solutions in tissue surrounding pressure or stress detection devices Application by intradermal injection of injections, infusions and sustained release formulations and / or (f) combinations of the methods described above. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the polymer composition of interest can be wetted into the surrounding tissue of the entire device or a portion (device only, sensor only, detector only, and / or combinations thereof).

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the present invention, the subject polymer composition wetted in tissue adjacent to the pressure or stress detection device is one of four general factors for the process of fiber formation (or scarring) including: Or can be adapted to release drugs that inhibit more than one: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) Accumulation and remodeling (fibrotic tissue maturation and organization). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Since pressure or stress detection devices are manufactured in a variety of shapes and sizes, the exact dose administered will also vary depending on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site) and the total administered drug dose can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg. Can be in the range of ~ 2500 mg. Scarring inhibitor dosage (amount) per unit area of the device or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ^{2 to} 10 μg / mm ² or it may be about ^{10 μg / mm 2 ~250 μg /} mm 2 or about ^{250 μg / mm 2 ~1000μg / mm} 2 , or about ^{1000 μg / mm 2 ~2500 μg /} mm 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site) and the total administered drug dose can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (dose) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg. It can range from ˜100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplant or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ^{2 to} 10 μg / mm ² , or it may be about ^{10 μg / mm 2 ~100 μg /} mm 2 or about ^{100 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2,,. Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

(3) Cardiac sensor In one embodiment, the polymer composition of interest can invade tissue adjacent to the heart sensor device. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  In another aspect, the implantable sensor can be a device configured to detect the nature of the heart or myocardial tissue. Cardiac sensors are used to detect parameters that are related to the performance of the heart monitored at some point over time. Cardiac monitoring is usually done to detect changes related to heart disease such as chronic heart failure (CHF). By monitoring patterns related to cardiac function, declines based on hemodynamic changes are detected (parameters such as cardiac output, ejection fraction, pressure, and ventricular wall motion). This constant direct monitoring is important for disease management in patients with CHF. By monitoring the hemodynamic measurements using an implantable sensor, a hemodynamic crisis can be detected and appropriate drugs and medical practices can be performed.

  There are several heart sensors that are suitable for use in the practice of the present invention. For example, an implantable sensor is an activity sensor that includes a magnet and a magnetoresistive sensor and may provide an activation signal as part of a cardiac device. See U.S. Patent Nos. 6,430,440 and 6,411,849. An implantable sensor may send wireless communication to a remote device to monitor ventricular blood pressure. See US Pat. No. 6,409,674. The implantable sensor may be an accelerometer-based heart wall motion sensor that uses electrical signals to convert cardiac tissue enhancement and send it to a cardiac stimulator. See US Pat. No. 5,628,777. An implantable sensor may be implanted in the heart cavity and an additional sensor implanted in the blood vessel to detect pressure and flow within the heart cavity. See U.S. Patent No. 6,277,078.

  In accordance with the present invention, cardiac sensors that may benefit from infiltrating adjacent tissue with the subject polymer composition also include commercially available products. A commercially available cardiac sensor device suitable for carrying out the present invention is the CARDIACAIRBAG ICD SYSTEM manufactured by Biotronik (Biotronik GmbH & Co. (Berlin, Germany), biotronik.com), which has a maximum of three ventricles. It is a rhythm monitoring device that provides emergency shock capability by performing 30 joules of shock treatment for fibrillation. In addition to emergency shock capability, this system can provide bradycardia paging and VT monitoring. PROTOS series pacemakers from Biotronik (see biotronikusa.com) have a paging sensor capability called closed-loop simulation.

  Blood flow and tissue microinfusion monitors can also be used to monitor non-cardiac tissue. Researchers at the Oak Ridge National Laboratory have developed a wireless sensor that monitors blood flow to the transplanted organ for early detection of transplant rejection.

  Medtronic (Minneapolis, Minn., See medtronic.com) has developed its own CHRONICLE implantable product, which uses sensors placed directly in the ventricle to measure pressure, heart rate and Designed to continuously monitor physical activity. The patient periodically downloads this information to a home-based device, and this physiological data is sent securely to the doctor via the Internet.

  For accurate detection of physical and / or physiological properties (pressure, flow rate, etc.), regardless of the specific design function of the heart sensor, the device is accurately placed in the myocardium, ventricle or main blood vessel It is necessary to receive information representative of If excessive scar tissue formation or extracellular matrix accumulation occurs around the sensor device, the sensor receives wrong information that impairs its effectiveness, or the scar tissue is biological to the sensor's detection mechanism May block the flow of information. For example, many cardiac sensors provide an unsuitable level of detection by implant encapsulation (ie, the device detects the condition in the microenvironment of the capsule surrounding the implant, not the pressure of the entire environment) Even if it succeeds, it fails later. Such cardiac sensor devices are also effective in releasing therapeutic agents that prevent or reduce infection around the implantation site. Cardiac sensor devices where the tissue adjacent to the implant is moistened with the polymer composition of interest can improve the efficiency of detection and extend the period during which these devices are clinically functional. In one embodiment, the device is an implantable device comprising a polymer composition of interest, wherein the polymer composition is an anti-scarring agent and / or anti-wetting agent that is moistened to tissue surrounding the site where the device is implanted. Contains infectious agents. In another aspect, the invention provides a cardiac sensor device wherein the subject polymer composition is wetted in adjacent tissue, the subject polymer composition comprising a therapeutic agent (an anti-scarring agent and / or an anti-infection). Medicine). A number of polymeric and non-polymeric delivery systems for use in connection with cardiac sensor devices have already been described above.

  The composition of the polymer comprises: (a) tissue adjacent to the heart sensor device; (b) around the tissue interface of the heart sensor device; (c) the region around the heart sensor device; and (d) the heart sensor device. By applying directly and / or indirectly to and around the surrounding tissue, the periphery of the implanted heart sensor device can be moistened. Methods of wetting the subject polymer composition to tissue adjacent to the heart sensor device include delivering the polymer composition to: (a) against the surface of the heart sensor device ( Example: as injection material, paste, gel or mesh) (b) Implant material, paste, gel, in situ just before or during implantation of heart sensor device graft (eg injection material, paste, gel, in situ) Formed as a gel or mesh) (c) Immediately after implantation of the cardiac sensor device, the surface of the cardiac sensor device and / or the implanted cardiac sensor device (eg, injection material, paste, gel, in situ) (D) topical application of the composition to the anatomical space in which the cardiac sensor device is placed (especially useful in this example for a period ranging from hours to weeks) Is the use of polymer carriers that release fibrosis inhibitors-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and drug releases Other formulations that can be delivered to the site where the device is inserted), (e) by intradermal injection of solutions, infusions, and sustained release formulations into the tissue surrounding the heart sensor device and / or (f) as described above Application by a combination of methods. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the polymer composition of interest can be wetted into the surrounding tissue of the entire device or a portion (device only, sensor only, detector only, and / or combinations thereof).

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the present invention, the subject polymer composition wetted in tissue adjacent to the heart sensor device is one or more of four general elements for the process of fiber formation (or scarring) including: Can be adapted to release drugs that inhibit: new blood vessel formation (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), accumulation of extracellular matrix (ECM) And remodeling (fibrotic tissue maturation and organization). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Since heart sensor devices are manufactured in a variety of shapes and sizes, the exact dose to be administered also depends on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site) and the total administered drug dose can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg. Can be in the range of ~ 2500 mg. Scarring inhibitor dosage (amount) per unit area of the device or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ^{2 to} 10 μg / mm ² or it may be about ^{10 μg / mm 2 ~250 μg /} mm 2 or about ^{250 μg / mm 2 ~1000μg / mm} 2 , or about ^{1000 μg / mm 2 ~2500 μg /} mm 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site) and the total administered drug dose can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (dose) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg. It can range from ˜100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplant or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ^{2 to} 10 μg / mm ² , or it may be about ^{10 μg / mm 2 ~100 μg /} mm 2 or about ^{100 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2,,. Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

(4) Respiration sensor In one embodiment, the polymer composition of interest can infiltrate tissue adjacent to the respiration sensor. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  The implantable sensor can be a device configured to detect the nature of the respiratory system. The respiration sensor can be used to detect changes in the respiration pattern. For example, a respiratory sensor can be used to detect sleep apnea, which is an airway disorder. There are two types of sleep apnea. In one state, the body cannot automatically generate the neuromuscular stimulation necessary to initiate and control the respiratory cycle at the appropriate time. In the other state, the upper airway muscles contract during breathing and the airway is blocked. Apnea causes cardiovascular disorders such as cardiac rhythm disturbances (bradycardia, atrioventricular block, extrasystole) and hemodynamic disturbances (lung seal and systemic hypertension). As a result, the autonomic nervous system is affected by stimulating metabolism and mechanical effects, which may lead to an increase in disease rate. To treat this condition, use an implanted sensor to monitor respiratory function to detect apnea and provide an appropriate response (eg, electrical stimulation of nerves in the upper airway muscles) or other treatment. It is.

  There are several respiration sensors that are suitable for use in the practice of the present invention. For example, an implantable sensor can be a respiratory element implanted in a chest cavity that can generate a respiratory signal as part of a respiratory system for providing gas to a host. See U.S. Patent No. 6,357,438. The implantable sensor includes a sensing element connected to the lead body, can be inserted into the bone (eg, sternum), and communicates with the thoracic cavity that detects respiratory changes. See US Pat. No. 6,572,543.

  Regardless of the specific design function of the respiratory sensor, the device needs to be accurately placed adjacent to the tissue for accurate detection of physical and / or physiological properties. If excessive scar tissue formation or extracellular matrix accumulation occurs around the lung function or airway sensor device, the sensor receives wrong information that impairs its effectiveness, or the scar tissue is a detection mechanism for the sensor May block the flow of biological information to For example, many respiratory sensors (pulmonary function detectors) detect levels that are not applicable by encapsulating the implant (ie, the device detects the condition in the microenvironment of the capsule surrounding the implant, Even if the initial transplant is successful, it fails later. Such a respiratory sensor device is also effective in releasing therapeutic agents that prevent or reduce infection around the implantation site. Respiratory sensor devices that wet the tissue adjacent to the implant with the polymer composition of interest can improve the efficiency of detection and extend the period during which these devices function clinically. In one embodiment, the device includes an implantable sensor device comprising a polymer composition of interest, wherein the polymer composition is an anti-scarring agent moistened to tissue surrounding the site where the device is implanted and / or Or contains anti-infectives. In another aspect, the present invention provides a respiratory sensor device wherein the subject polymer composition is wetted in adjacent tissue, the subject polymer composition comprising a therapeutic agent (an anti-scarring agent and / or an anti-infection). Drugs). A number of polymeric and non-polymeric delivery systems for use in connection with respiratory sensor devices have already been described above.

  The composition of the polymer comprises: (a) tissue adjacent to the respiration sensor device; (b) around the tissue interface of the respiration sensor device; (c) region around the respiration sensor device; and By applying directly and / or indirectly to and around the surrounding tissue, the periphery of the implanted respiratory sensor device can be moistened. Methods of wetting the subject polymer composition to the tissue adjacent to the respiratory sensor device include delivering the polymer composition to: (a) against the surface of the respiratory sensor device ( Example: as injection material, paste, gel or mesh), (b) Implant material, paste, gel, in situ just before or during transplantation of respiratory sensor device graft (eg injection material, paste, gel, in situ) Formed as a gel or mesh) (c) Immediately after implantation of the respiration sensor device, the surface of the respiration sensor device and / or the implanted respiration sensor device (eg infusion material, paste, gel, in situ) (D) topical application of the composition to the anatomical space where the respiratory sensor device is placed (especially useful in this example for a period ranging from hours to weeks) Is the use of polymer carriers that release fibrosis inhibitors-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and drug releases Other formulations that can be delivered to the site where the device is inserted), (e) by intradermal injection of solutions, infusions, and sustained release formulations into the tissue surrounding the respiratory sensor device and / or (f) as described above Application by a combination of methods. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the polymer composition of interest can be wetted into the surrounding tissue of the entire device or a portion (device only, sensor only, detector only, and / or combinations thereof).

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the present invention, the subject polymer composition wetted in tissue adjacent to the respiratory sensor device is one or more of four general elements for the process of fiber formation (or scarring) including: Can be adapted to release drugs that inhibit: new blood vessel formation (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), accumulation of extracellular matrix (ECM) And reformation (maturation and organization of fibrous tissue). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Because respiratory sensor devices are manufactured in a variety of shapes and sizes, the exact dose to be administered also depends on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of dose per unit area (of the treatment site), the total drug dose administered can be measured, and the appropriate surface concentration of the active drug can be determined. The drug is used in the range of several times the concentration normally used in systemic administration applications in chemotherapy to less than 50%, 20%, 10%, 5% or 1%. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg. Can be in the range of ~ 2500 mg. Scarring inhibitor dosage (amount) per unit area of the device or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ^{2 to} 10 μg / mm ² or it may be about ^{10 μg / mm 2 ~250 μg /} mm 2 or about ^{250 μg / mm 2 ~1000μg / mm} 2 , or about ^{1000 μg / mm 2 ~2500 μg /} mm 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site) and the total administered drug dose can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (dose) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg. It can range from ˜100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplant or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ^{2 to} 10 μg / mm ² , or it may be about ^{10 μg / mm 2 ~100 μg /} mm 2 or about ^{100 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2,,. Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

(5) Hearing sensor In one embodiment, the subject polymer composition can invade tissue adjacent to the hearing sensor device. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  The implantable sensor can be a device configured to detect the properties of the auditory system. Hearing sensors are used as part of an implantable auditory system for the purpose of rehabilitation of complete sensorineural hearing loss or a combination of conductive and inner ear hearing loss. The auditory system can include an implantable sensor that delivers an electrical signal. The signal is processed by an implantable processor and delivered to an electromechanical transducer acting on the middle or inner ear. The auditory sensor functions as a microphone for the auditory system, and converts incident sound in the air into an electrical signal.

  For use in the present invention, auditory sensors as part of various auditory systems are suitable. For example, an implantable sensor can generate an electrical audio signal as part of the auditory system in deafness rehabilitation. See US Pat. No. 6,334,072. The implantable sensor may be a capacitive sensor that is mechanically or magnetically coupled to a vibrating auditory element such as a rib (detecting a time-dependent capacitive value caused by vibration). See US Pat. No. 6,190,306. The implantable sensor can be an electromagnetic sensor having permanent magnets and coils and a time-dependent flux chain based on vibrations applied to the output stimulator as a mechanical or electrical stimulus for the cochlea. See US Pat. No. 5,993,376.

  According to the present invention, commercially available products are also included in the hearing sensor that is effective when the target polymer composition is adjacent. Commercially available auditory sensor devices suitable for the practice of the present invention include: HIRES90K Bionic Ear implant, HIRESOLUTION SOUND, CLARION CII Bionic Ear, from Advanced Bionics (Boston Scientific Company, Schilmer, Calif., See advanceddbionics.com) And CLARION 1.2. See also the following US patent numbers: 6,778,858, 6,754,537, 6,735,474, 6,731,986, 6,658,302, 6,636,768, 6,631,296, 6,628,991, 6,498,954, 6,487,453, 6,473,651, 6,415,187, and 6,415,185. NUCLEUS3 population inner ear made by Cochlear (Lanecove, New South Wales, Australia, see cochlear.com). See also: 6,392,386, 6,377,075, 6,301,505, 6,289,246, 6,116,413, 5,720,099, 5,653,742, 5,645,585, and the following US patent application publication numbers: 2004 / 0172102A1 and 2002 / 0138115A1. Med-El (Austria, see medel.com) PULSAR CI 100 and COMBI40 + inner ear. See also US Patent Application Publication No. 20040039245A1 and the following US Patent Numbers: 6,600,955, 6,594,525, 6,556,870, and 5,983,139. ALLHEAR graft from AllHear, Inc. (Aurora, Oregon, see allhear.com). See also patent WO 01/50816, EP 1 245 134. DIGISONICCONVEX, DIGISONIC AUDITORY BRAINSTEM, DIGISONIC MULTI-ARRAY graft from MXM (France, see mxmlab.com). See also the following US patent numbers: 5,123,422, EP 0 219 380, WO 04/002193, EP 1 244 400 A1, US 6,428,484, US20020095194A1, WO 01/50992.

  Regardless of the specific design features of the auditory sensor, the device must be accurately positioned inside the ear to accurately detect speech. If scar tissue grows excessively or accumulates extracellular matrix around the auditory sensor, the sensor receives incorrect information and becomes less effective, or the scar tissue impedes the flow of sound waves to the sensor's detector. Can be blocked. These auditory sensor devices are also effective in releasing therapeutic agents that prevent or reduce infection around the implantation site. Hearing detection devices that include a polymeric object of interest that infiltrate the tissue adjacent to the implant increases the efficiency of voice detection and extends the period during which these devices function clinically. In one embodiment, the device includes an implantable sensor device comprising a polymer composition of interest, wherein the polymer composition is an anti-scarring agent moistened to tissue surrounding the site where the device is implanted and / or Or contains anti-infectives. In another aspect, the invention provides an auditory sensor device comprising a subject polymer composition that infiltrates adjacent tissue, the polymer composition may comprise a therapeutic agent (an anti-scarring agent and / or an anti-infective agent). ). Various polymeric and non-polymeric delivery systems for use with implants of auditory sensor devices have already been described above.

  The polymer compound directly and / or indirectly (a) tissue adjacent to the auditory sensor device, (b) around the interface between the auditory sensor device and the tissue, (c) around the auditory sensor device, (d) hearing When applied within and / or on the tissue surrounding the sensor device, it may infiltrate around the implanted auditory sensor device. Methods of infiltrating the target polymer composition into the tissue adjacent to the auditory sensor device include delivery of the polymer composition: (a) the surface of the auditory sensor device during the implantation process (eg, injection material, paste, gel) Or as a mesh), (b) immediately before or during implantation of the auditory sensor device (eg as an injection material, paste, gel, in situ formed gel or mesh), (c) the auditory sensor device Immediately after the implantation of (d) the hearing sensor device and / or the surface of the tissue surrounding the implanted hearing sensor device (eg injection material, paste, gel, gel or mesh formed in situ) Topical application of the composition to the anatomical space to be placed (especially useful in this example is a polymeric carrier that releases the therapeutic agent over a period ranging from hours to weeks. In use-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and others that can release the drug and be delivered to the site where the device is inserted (E) by application of a combination of the methods described above, (e) by intradermal injection of the solution, injection, and sustained release formulation into the tissue surrounding the auditory sensor device. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the polymer composition of interest can be wetted into the surrounding tissue of the entire device or a portion (device only, sensor only, detector only, and / or combinations thereof).

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the present invention, the subject polymer composition that invades the tissue adjacent to the implant of the auditory sensor device inhibits one or more of the four general factors for the fibrosis (or scarring) process including: Can be adapted to release drugs: new blood vessel formation (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) accumulation, and Remodeling (maturation and organization of fibrous tissue). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Since the auditory sensor device is manufactured in a variety of shapes and sizes, the exact dose to be administered also depends on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of dose per unit area (of the treatment site), the total drug dose administered can be measured, and the appropriate surface concentration of the active drug can be determined. The drug is used in the range of several times the concentration normally used in systemic administration applications in chemotherapy to less than 50%, 20%, 10%, 5% or 1%. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Drug scarring inhibitor dosage per unit area of the device or tissue surface of a subject to be coated (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm, ² or from about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,,.
According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site) and the total drug dose administered can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose (amount) of anti-infective drug per unit area of the device or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² , or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

(6) Electrolytes and metabolite sensors In one embodiment, the polymer composition of interest can infiltrate tissue adjacent to the electrolyte and / or metabolite sensor device. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  In another aspect, implantable sensors can be used to detect electrolytes and metabolites in the blood. For example, an implantable sensor can be a device that monitors the constituents of metabolites or electrolytes in blood by emitting a radiation source toward the blood to interact with multiple detectors that provide an output signal. See Patent No. 6,122,536. The implantable sensor can be an in-vivo sensing transponder consisting of a dye that changes its optical properties in response to environmental changes, a photosensor that detects optical changes, and a transponder that transmits data to a remote reader. See US Pat. No. 5,833,603. The implantable sensor can be a monolithic bioelectronic device for detecting at least one analyte in the animal's body. See US Pat. No. 6,673,596. Sensors for measuring other chemical analytes are described in US Pat. Nos. 6,625,479 and 6,201,980.

  If the scar tissue grows excessively or the extracellular matrix accumulates around the sensor, the sensor will receive incorrect information and become less effective, or the scar tissue will become metabolite or electrolyte to the detection device of the sensor. The flow can be interrupted. For example, many metabolite / electrolyte detection devices fail even if the transplantation is successful first. This is because graft coating results in detection of irrelevant concentrations (ie, the device detects the microenvironment status of the capsule surrounding the graft, not the blood concentration). Detection devices that include polymer structures of interest that infiltrate the tissue adjacent to the graft increase the efficiency of metabolite / electrolyte detection and extend the time period during which these devices function clinically. These electrolyte and / or metabolite sensor devices are also effective in releasing therapeutic agents that prevent or reduce infection around the implantation site. In one embodiment, the device includes an implantable metabolite / electrolyte sensor device comprising a polymer composition of interest, the polymer composition being scarred in tissue surrounding the site where the device is implanted. Contains inhibitors and / or anti-infectives. In another aspect, the present invention provides a metabolite / electrolyte sensor device comprising a subject polymer composition that invades adjacent tissue, the polymer composition may comprise a therapeutic agent (a scarring inhibitor and / or Anti-infectives). Various polymeric and non-polymeric delivery systems for use with metabolite / electrolyte sensor device implants have already been described above.

  The polymer compound directly and / or indirectly (a) tissue adjacent to the metabolite / electrolyte sensor device, (b) around the interface between the metabolite / electrolyte sensor device and the tissue, (c) metabolite / electrolyte When applied to the site around the sensor device, (d) inside and / or on the tissue surrounding the metabolite / electrolyte sensor device, it may infiltrate around the implanted metabolite / electrolyte sensor device. Methods of infiltrating the tissue adjacent to the metabolite / electrolyte sensor device with the polymer composition of interest include delivery of the polymer composition: (a) the surface of the metabolite / electrolyte sensor device (eg, during the implantation process) (B) as a tissue surface (eg, injection material, paste, gel, in situ formed gel or mesh) immediately before or during implantation of the metabolite / electrolyte sensor device ) (C) Immediately after implantation of the metabolite / electrolyte sensor device, the surface of the tissue surrounding the metabolite / electrolyte sensor device and / or the implanted metabolite / electrolyte sensor device (eg injection material, paste, gel, raw material). Gel or mesh formed in position) (d) Topical application of the composition to the anatomical space where the metabolite / electrolyte sensor device is placed (particularly useful in this example) Is the use of polymeric carriers that release therapeutic agents over a period ranging from hours to weeks-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, Solid implants and other formulations that can release the drug and be delivered to the site where the device is inserted), (e) solutions, injections, and controlled release formulations in the tissue surrounding the metabolite / electrolyte sensor device (F) Application by a combination of the methods described above by internal injection. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the polymer composition of interest can be wetted into the surrounding tissue of the entire device or a portion (device only, sensor only, detector only, and / or combinations thereof).

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the invention, the subject polymer composition infiltrating the tissue adjacent to the implant of the metabolite / electrolyte sensor device is one of four general factors for the process of fibrosis (or scarring) comprising: Can be adapted to release drugs that inhibit multiple: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) Accumulation and remodeling (maturation and organization of fibrous tissue). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Since metabolite / electrolyte sensor devices are made in a variety of shapes and sizes, the exact dose administered will also depend on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site) and the total administered drug dose can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Drug scarring inhibitor dosage per unit area of the device or tissue surface of a subject to be coated (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm, ² or from about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site) and the total administered drug dose can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose (amount) of anti-infective drug per unit area of the device or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² , or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

  A number of implantable sensor devices have been described above, all of which have similar design features and cause similar undesirable foreign tissue reactions after implantation, resulting in infection or cause of infection in the implant. There may be. For those skilled in the art, not only the above-mentioned commercially available sensor devices but also the next generation and / or future developed commercially available sensor products are expected and used according to the present invention. It should be clear that it is suitable for. In particular, a detection device, such as a detection element, needs to be positioned very accurately to ensure detection at the correct anatomical position of the body. All or some of the sensor devices may migrate after surgery, or excessive scar tissue growth may occur around the graft, leading to reduced performance of these devices. If a fiber capsule is formed around the sensor, the flow of biological information to the detector may be blocked, or the device may detect a physiologically irrelevant concentration (ie, the physiology outside the appropriate capsule). Detect the concentration inside the coating, not the target concentration). This not only provides incomplete or inaccurate readings, but also risks the physician or patient making inappropriate treatment decisions based on the information transmitted. An implantable sensor comprising a polymer composition of interest that infiltrates tissue adjacent to the sensor-tissue interface can be used to improve efficiency and / or duration of graft activity. For implantable sensor devices, the release of therapeutic agents that prevent or reduce infection around the implantation site is also effective. In one aspect, the present invention provides an implantable sensor device comprising a subject polymer composition to be implanted in adjacent tissue, the polymer composition may comprise a therapeutic agent (an anti-scarring agent and / or an anti-cancer agent). Infectious drugs). In addition to these compositions, one or more fibrosis inhibitors are included to inhibit or reduce overgrowth of granulation tissue, fiber tissue, or neointimal tissue, and / or Inclusion of a plurality of anti-infectives inhibits or prevents infection around the transplant site.

Implantable Drug Delivery Device and Pump In one embodiment, the subject polymer composition can infiltrate the tissue adjacent to the implantable drug delivery device or pump. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  Implantable drug delivery devices and pumps are means of delivering a therapeutic agent to a specific site over time to manage a variety of symptoms. Drug delivery implants and pumps are typically used when the effect of the drug is desired to be applied locally (ie, only on a specific site) or when systemic delivery of the drug is inefficient / ineffective (ie Toxic or severe side effects occur, drugs become inactive before reaching the target tissue, symptoms / disease is poorly managed, and / or become drug dependent). Implantable pumps also help patients maintain systemic drug concentrations for extended periods of time in a fixed or defined manner and prevent “fluctuation” of blood drug concentrations due to intermittent systemic administration. Another advantage of an implantable pump is improved patient cooperation. Many patients forget to take their medication regularly (especially in young people, the elderly, chronically ill and mentally disabled), but these problems are alleviated with an implantable pump . For many patients this is improved symptom management (often titrated according to severity of symptoms), better illness management (especially insulin delivery in diabetes), and reduced need for drugs (especially analgesia). Agent).

  A myriad of drug delivery implants and pumps are used in a variety of clinical applications, including: pre-programmable insulin pumps for the treatment of diabetes, to relieve pain (cancer, low back pain, HIV, postoperative, etc.) Intrathecal (intravertebral) pumps that administer drugs (such as morphine and fentanyl), local or systemic delivery of chemotherapy to treat cancer (such as hepatic artery 5-FU infusion in liver cancer), drugs in heart disease treatment (Such as antiarrhythmic drugs in cardiac rhythm abnormalities), intrathecal delivery of antispastic agents (such as baclofen) during spasticity due to neuropathy (multiple sclerosis, spinal cord injury patients, brain injury patients, cerebral palsy), or Local / local antibiotics for infection prevention (such as osteomyelitis and septic arthritis). Typically, a drug delivery pump is implanted subcutaneously and consists of a pump unit with a drug container and a flexible catheter (delivering the drug to the target tissue). The pump stores a defined amount of drug and releases it locally or systemically through the catheter until a predetermined concentration of the therapeutic drug is achieved (depending on the application). In the center of the pump is a self-sealing access port that is covered by a septum, where a needle can be inserted percutaneously (through both the skin and septum) to refill the pump as needed. There are generally two types of implantable drug delivery pumps. Constant speed pumps are usually driven by gas and are designed to diffuse the drug under pressure (continuously administered at a preprogrammed constant speed). The amount and rate of drug flow is controlled by the length, temperature, and height of the catheter used, and is optimal when fixed drug delivery over a long period of time is required. A rate programmable pump uses a battery-powered pump and a constant pressure vessel to deliver the drug in a programmable cycle by the physician or patient. For programmable infusion devices, small amounts of drug are delivered separately based on a programmed manner (which can vary depending on the individual clinical response).

  In general, delivery pumps are implanted to deliver a defined amount of drug, and in certain applications are used in conjunction with implantable sensors that collect information used to coordinate drug delivery (often “ Called a "closed circuit" system). Implantable drug delivery pumps function in a variety of ways to deliver drugs, including but not limited to: (a) delivering drugs only when changes in the body are detected (eg, : Sensor is stimulated), (b) Continuously delivering drug at a slow rate (eg constant flow rate) (c) Delivering a prescribed amount of drug (eg irregular flow rate), (d) Program Deliver drugs in a controlled manner, (e) Deliver drugs using devices designed for specific anatomical locations (eg, intraocular, intrathecal, intraperitoneal, intraarterial, intracardiac) . Drug delivery pumps are categorized by mechanical delivery techniques in addition to specific methods or delivery of drugs to specific locations (eg, the driving force for drug delivery). For example, methods of delivering drugs include, but are not limited to: osmotic pumps, metering systems, peristaltic (roller) pumps, electronically driven pumps, eye drug delivery pumps and implants, Elastomer pumps, spring contraction pumps, gas driven pumps (e.g. induced by electrolyzer or chemical reaction), hydraulic pumps, piston dependent and piston independent pumps, diffusion chambers, infusion pumps, passive pumps, infusate pumps, And osmotic liquid dispenser.

  The clinical function of an implantable drug delivery device or pump is that the device, especially the catheter or drug diffuser, is anatomically attached to the target tissue (such as the spinal subdural space, arterial lumen, peritoneum, interstitial fluid) Can be effectively maintained, and is affected by factors such as whether scab or occlusion by scar tissue occurs. As mentioned above, unfortunately in many instances, these devices are susceptible to reactions as “foreign” from surrounding host tissues, such as when implanted in the body. For an implantable pump, the drug delivery catheter lumen, catheter tip, drug diffusion, or delivery membrane can become occluded by scar tissue, which can result in complete blockage or interruption of drug flow. Instead, the entire pump, catheter and / or diffusion component is vesicular by the scar (ie, the device is surrounded by fibrous tissue) so that the drug is incompletely diffused into the target tissue (ie, the scar is adequate) Drug transfer and the transfer of implantable pumps to tissues outside the vesicle). In either case, improper or incomplete drug flow is directed to the appropriate target tissue or organ (and clinical benefits are lost), while the vesicles are localized drug accumulation (vesicles). ) And additional clinical complications (such as local drug toxicity, temporary seizure of drugs that cause abrupt and massive “dumping” of drug to surrounding tissues). In addition, the tissue surrounding the implantable pump is inadvertently damaged by an inflammatory foreign body reaction, resulting in loss of function and / or tissue damage (eg, blockage of spinal canal scar tissue or cerebrospinal fluid flow) Can cause Implantation of an implantable drug delivery device or pump can cause or promote infection around the implantation site.

  Implantable drug delivery pumps that release one or more therapeutic agents can reduce scarring at the device-tissue interface, especially in and around drug delivery catheters or drug diffusions. It helps to extend the clinical effect. By preventing fiber formation, it is ensured that the appropriate amount of drug is diffused from the device at the appropriate rate and that potentially toxic drugs are not sequestered within the fiber coating. For devices with electrical or battery components, not only does the device fail to perform best or fail at all due to fiber formation, but also to overcome the electrical resistance imposed by intervening scar tissue. As a result of the demand for increase, battery life may be excessively consumed. Implantable drug delivery devices or pump implants may cause or promote infection around the site of implantation.

  Virtually any implantable pump can benefit from the present invention. In one embodiment, the drug delivery pump releases drug slowly at a constant flow rate continuously. For example, the drug delivery pump can be a passive pump adapted to deliver the drug at a constant flow rate. This is adjusted by changing the constant flow rate to a new constant flow rate in the pressure sensing chamber and the valve chamber. See US Pat. No. 6,589,205. In another aspect, the drug delivery pump delivers a defined dose of drug at an irregular flow rate or pulsatile. For example, drug delivery pumps regularly pump to create a pulsatile liquid drug flow by continuously refilling the chamber and then releasing the valve to obtain a bolus of drug. See US Pat. No. 6,312,409. In another aspect, the drug delivery pump can be programmed to diffuse the drug in a finely defined manner. For example, the drug delivery pump can be a programmable infusate pump consisting of different volumes of infusate chamber, different volume control liquid pressures and displacement containers. The liquid flow is sampled by the microprocessor based on the programmed values and appropriate adjustments are made to maintain the programmed liquid flow. See U.S. Pat. No. 4,443,218.

  In another aspect, drug delivery pumps suitable for use with the present invention are made based on different mechanical technologies (such as motive force) that deliver drugs. For example, a drug delivery pump can be an implant consisting of a piston divided into two chambers (one chamber containing a water-swelling drug and the other containing a leuprolide formulation for delivery). See US Pat. No. 5,728,396. The drug delivery pump can be a non-cylindrical osmotic pump that does not rely on a piston to infuse the drug and is adapted to the anatomical location of the implant. See US Pat. No. 6,464,688. The drug delivery pump can be an osmotic liquid dispenser consisting of a flexible inner bag (including the drug composition and the port through which the composition is delivered). See US Pat. No. 3,987,790. The drug delivery pump may consist of a liquid-absorbing delivery implant consisting of a compartment containing a composition that penetrates the liquid pathway, with an extended rigid sleeve that resists temporary mechanical forces. See U.S. Pat. Nos. 5,234,692 and 5,234,693. The drug delivery pump can consist of a pump that includes a separate hydraulic container, a metering device, a displacement container, a drug storage container, and a drug infusion port (all included in the housing device). See US Pat. No. 6,629,954. The drug delivery pump can consist of a diffusion chamber that includes a diffusion path and a valve that are compressed to allow a one-way flow of drug. See US Pat. No. 6,283,949. The drug delivery pump can be spring-loaded, and the spring controls the pressure differential in various volume drug chambers. See U.S. Pat. No. 4,772,263. Examples of other drug delivery pumps are described in US Pat. Nos. 6,645,176, 6,471,688, 6,283,949, 5,137,727, 5,112,614, and the like.

  In accordance with the present invention, drug delivery devices and pumps that are effective when the subject polymer composition infiltrates adjacent tissue are commercially available products. For example, commercially available osmotic drug delivery pumps are suitable for the practice of the present invention. These osmotic pumps include DUROS grafts and ALZET osmotic pumps from Alza Corporation (Mountain View, CA), which are used to deliver a wide variety of drugs and other therapeutic agents by osmotic pressure ( U.S. Pat. Nos. 6,283,953, 6,270,787, 5,660,847, 5,112,614, 5,030,216, and 4,976,966).

  As discussed above, infiltration of the polymer composition of interest into the tissue adjacent to the drug delivery pump can improve the performance of the device and / or prevent or reduce infection around the implant site. In one embodiment, the present invention provides an implantable drug delivery device and pump comprising a subject polymer composition to be implanted in adjacent tissue, the polymer composition may comprise a therapeutic agent (a scarring inhibitor) And / or anti-infectives). Various polymeric and non-polymeric delivery systems for use with implantable drug delivery devices and pumps have already been described above.

  The polymeric compound directly and / or indirectly in the composition (a) tissue adjacent to the implantable drug delivery device and pump, (b) around the implantable drug delivery device and pump-tissue interface, (c ) Implants around implantable implantable drug delivery devices and pumps when applied on and / or over tissue surrounding implantable drug delivery devices and pumps; There is a case. Methods of infiltrating the tissue adjacent to the implantable drug delivery device and pump with the polymer composition of interest include delivery of the polymer composition: (a) of the implantable drug delivery device or pump during the implantation process On the surface (eg as injection material, paste, gel or mesh), (b) the tissue surface (eg injection material, paste, gel, in situ formed immediately before or during implantation of implantable drug delivery device or pump) Of the tissue surrounding the implantable drug delivery device or pump and / or the implanted implantable drug delivery device or pump immediately after implantation of the implantable drug delivery device or pump. (D) an implantable drug delivery device or pump is placed on the surface (eg injection material, paste, gel, gel or mesh formed in situ) Topical application of the composition to the anatomical space (especially useful in this example is the use of a polymeric carrier that releases the therapeutic agent over a period ranging from hours to weeks-liquid, suspension, milk Suspensions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and other formulations that release drugs and can be delivered to the site where the device is inserted), (e) implantable drugs (F) Application by a combination of the methods described above, by intradermal injection of solutions, infusions and sustained release formulations into the tissue surrounding the delivery device or pump. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the subject polymer composition can be wetted into the surrounding tissue of the entire device or part of the device (device only, pump only, catheter only, drug diffusion region only and / or combinations thereof). Yes.

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the invention, the subject polymer composition infiltrating the tissue adjacent to the implantable drug delivery device and pump is one or more of four general elements for the process of fibrosis (or scarring) comprising: Can be adapted to release drugs that inhibit: new blood vessel formation (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), accumulation of extracellular matrix (ECM) And reformation (maturation and organization of fibrous tissue). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Because implantable drug delivery devices and pumps are made in a variety of shapes and sizes, the exact dose administered will also vary depending on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site) and the total administered drug dose can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Drug scarring inhibitor dosage per unit area of the device or tissue surface of a subject to be coated (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm, ² or from about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site) and the total administered drug dose can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose (amount) of anti-infective drug per unit area of the device or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² , or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

  For those skilled in the art, not only commercially available drug delivery pumps not specifically cited herein but also next generation and / or future developed commercially available drug delivery products are expected to be used in accordance with the present invention, and It must be clear that it is suitable for its use.

Details of some specific drug delivery pumps and treatments are described below.

(1) Implantable insulin pump for diabetes In one embodiment, the subject polymer composition can invade tissue adjacent to the insulin pump. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  Insulin pumps are used for diabetic patients instead of controlling blood glucose levels by routine manual injection of insulin. Accurate dosage titration and timing of insulin administration are important factors in effectively managing diabetes. Glucose levels in blood with too much insulin dose can drop rapidly, causing consciousness to become cloudy or even unconscious. If the insulin dose is too low, blood glucose levels will be too high, resulting in excessive dryness, urine, and changes in metabolism called ketoacidosis. If the timing of insulin administration is not appropriate, blood glucose levels fluctuate between the two extremes. This is a situation believed to be involved in some of the long-term complications of diabetes such as heart disease, renal failure, nerve damage, and blindness. Because these conditions are extremely life-threatening, the exact dose and timing of insulin is most important in preventing the short- and long-term complications of diabetes.

  Implantable pumps automate the administration of insulin and eliminate human error in dosage and timing that can have a long-term health impact. The pump has the function of injecting insulin into the bloodstream, peritoneal cavity, and subcutaneous tissue periodically (small amounts multiple times a day). The pump is supplemented with insulin by injecting it directly into the pump chamber once or twice a month. This reduces the amount of external administration by injection to be performed on the patient, while also allowing various preprogrammed amounts of insulin to be released into the bloodstream at different times. This is a situation that closely resembles the normal functioning of the pancreas and suppresses fluctuations in blood glucose levels. After the patient has taken a drop of blood, subjected it to analysis, and identified the amount of insulin to be delivered, the insulin pump can be triggered by an externally generated signal. However, the most widely practiced application in this technology is the production of closed circuit “artificial pancreas”. This regulates the administration of insulin to diabetic patients by continuously detecting blood glucose levels via the implanted sensor and providing feedback to the implantable pump.

  A variety of insulin pumps are suitable for use in the practice of the present invention. For example, a drug delivery pump may comprise both an implantable sensor and a drug delivery pump because it consists of a large amount of living cells and electrical signals that control the delivery of glucose / glucagon / insulin. See US Pat. No. 5,474,552. The drug delivery pump can consist of a single pathway catheter with a sensor that is implanted into a tube that transfers the blood component to a subcutaneously implanted infusion device and diffuses the drug through the catheter. . See US Pat. No. 5,109,850.

  Insulin pumps that are effective when the polymer composition of interest invades adjacent tissue in accordance with the present invention include commercial products. A commercially available insulin pump device suitable for the practice of the present invention is the MINIIME 2007 implantable insulin pump system from Medtronic Mini Med, Inc. (Northridge, Calif.). In summary, the MINIMED pump delivers insulin to the peritoneal cavity and provides it to the body in the same way as the normal release pancreas (see, eg, US Pat. Nos. 6,558,345 and 6,461,331). The MINIMED2001 Implantable Insulin Pump System (Medtronic Mini Med Inc., Northridge, Calif.) Provides insulin injection into the peritoneum to beat from a negative pressure vessel. Both of these devices are equipped with long catheters that carry insulin from a subcutaneously implanted pump to the peritoneal cavity. As noted above, the peritoneal drug delivery catheter lumen or catheter tip may cause partial or complete occlusion by scar tissue, resulting in slowing or complete blockage of drug flow. Such insulin pump devices are also effective in releasing therapeutic agents that prevent or reduce infection around the catheter and / or implantation site. In one embodiment of the invention, the device comprises a delivery catheter having a polymer composition of interest, the polymer composition inhibiting scarring that is moistened at the site where the delivery catheter is implanted or around the site to be implanted. Agents and / or anti-infectives. This wetting is aimed at maintaining the delivery catheter lumen patent and / or preventing fibrosis of the surrounding tissue and / or preventing or reducing infection around the catheter or implantation site. In another aspect, the invention provides an insulin pump comprising a subject polymer composition that infiltrates adjacent tissue, the polymer composition may comprise a therapeutic agent (an anti-scarring agent and / or an anti-infective agent). . Various polymeric and non-polymeric delivery systems for use with insulin pumps have already been described above.

  Macromolecular compounds directly and / or indirectly (a) tissue adjacent to the insulin pump, (b) around the interface between the insulin pump and tissue, (c) surrounding the insulin pump, (d) surrounding the insulin pump When applied inside and / or on tissue, it may infiltrate around the implanted insulin pump. Methods of infiltrating the tissue adjacent to the insulin pump with the polymer composition of interest include delivery of the polymer composition: (a) the surface of the insulin pump during the implantation process (eg, infusate, paste, gel or mesh) (B) Immediately before or during the implantation of the insulin pump (eg, as an injection material, paste, gel, gel or mesh formed in situ), (c) Immediately after the implantation of the insulin pump (D) the anatomical space where the insulin pump is placed on the surface of the tissue surrounding the insulin pump and / or the implanted insulin pump (eg, infusate, paste, gel, gel or mesh formed in situ) Topical application of the composition to the membrane (especially useful in this example is a polymeric carrier that releases the therapeutic agent over a period ranging from hours to weeks. In use-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and others that can release the drug and be delivered to the site where the device is inserted (E) by application of a combination of the methods described above, (e) by intradermal injection of the solution, infusion, and sustained release formulation into the tissue surrounding the insulin pump. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the polymer composition of interest can wet the surrounding tissue of the entire device or a portion (device only, pump only, catheter only, drug diffusion region only, and / or combinations thereof). ing.

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the invention, the subject polymer composition infiltrating the tissue adjacent to the insulin pump releases an agent that inhibits one or more of the four general factors for the process of fiber formation (or scarring) including: Can be adapted to: new blood vessel formation (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) accumulation, and remodeling (fibers) Sexual maturity and organization). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fibrosis according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Insulin pumps are made in a variety of shapes and sizes, so the exact dose to be administered also depends on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), the total drug dose administered can be measured, and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Drug scarring inhibitor dosage per unit area of the device or tissue surface of a subject to be coated (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm, ² or from about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,,.

  According to another aspect, all of the antiinfectives described above can be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention will depend on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), the total drug dose administered can be measured, and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose (amount) of anti-infective drug per unit area of the device or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² , or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

  For those skilled in the art, not only commercially available drug delivery pumps not specifically cited herein but also next generation and / or future developed commercially available drug delivery products are expected to be used in accordance with the present invention, and It must be clear that it is suitable for its use.

(2) Intrathecal drug delivery pump In one embodiment, the subject polymer composition can infiltrate tissue adjacent to the intrathecal drug delivery pump. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents). An intrathecal drug delivery pump having a polymer composition of interest that can infiltrate the tissue adjacent to the pump can be used to deliver the drug to the spinal cord during pain management or movement disorders.

  Chronic pain is one of the most important clinical problems of all drugs. For example, it is estimated that more than 5 million people in the United States suffer from back pain. The economic cost of chronic back pain is enormous, estimated to cost $ 50 billion to $ 100 billion, losing 100 million work days per year. The cost of treating pain in tumor patients is expected to reach $ 12 billion. Chronic pain powers more people than cancer and heart disease, forcing the American population to pay more than cancer and heart disease combined. In addition to physical effects, chronic pain costs many other things, including job loss, marital discord and prescription drug addiction. Thus, it is clear that reducing the costs associated with morbidity and persistent pain will continue to be an important challenge for healthcare systems.

  Caused by injury, disease, scoliosis, spinal disc degeneration, spinal cord injury, malignant tumor, arachnoiditis, chronic disease, pain syndrome (eg, iatrogenic postoperative instability low back pain, complex local pain syndrome) and other causes The stubborn severe pain that has led to weakening has become a common medical problem. For many patients, continued use of drugs such as analgesics, especially narcotics, is a viable solution because of the potential for tolerance, loss of efficacy, and addiction. To combat this, intrathecal drug delivery devices have been developed and are stubbornly resistant to other traditional treatment therapies such as drug therapy, invasive therapy (surgery) or behavioral / lifestyle changes. Treat pain.

  Intrathecal drug delivery pumps are designed to relieve pain by delivering pain medication directly to cerebrospinal fluid in the intrathecal space surrounding the spinal cord and are used for that purpose. Usually, this treatment can reduce pain with a small amount of analgesic, because the analgesic is delivered locally to pain receptors in the spinal cord that send pain directly to the brain. Morphine and other narcotics (usually fentanyl and safentanil) are the most commonly delivered drugs, and pain is greatly reduced in many patients compared to systemic delivery. Intrathecal drug delivery also allows the administration of analgesics that cannot cross the blood brain barrier (such as Ziconotide, an N-type calcium pathway blocker made by Elan Pharmaceuticals). Only the administration of is effective.

  Intrathecal pumps are also used in the management of neurological and motor disorders. Baclofen (commercially available from Novartis as Lioresal) is an anticonvulsant / muscle relaxant used to treat spasticity and improve motility in patients with multiple sclerosis and cystic fibrosis and spinal cord injury. This drug has proven to be more effective and have fewer side effects when administered to the CSF using an intrathecal drug delivery pump. Administration of drugs that are harmful when delivered systemically or that cannot penetrate the blood-brain barrier into the subarachnoid space leads to sputum, brain tumors, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS) -It is trying to be able to treat Lugueric disease). For example, ALS patients have been tested to administer recombinant brain-derived neurotrophic factor (r-BDNF produced by Amgen) intrathecally.

  The intrathecal drug delivery system consists of an intrathecal drug infusion pump and an intrathecal catheter, both of which are fully implanted. The pump device can be implanted under the skin of the abdomen (slightly above or below the beltline) and refilled by intradermal injection of the drug into the container. The catheter is tunneled under the skin and passes from the pump to the intrathecal space of the spine. In operation, the pump administers a prescribed amount of drug continuously to the cerebrospinal fluid or in a manner that can be controlled by the physician or patient depending on the symptoms.

  In the practice of the present invention, a variety of implantable, but not intramembrane pumps are suitable for use. For example, an implantable pump used to deliver drugs consists of two osmotic pumps with semipermeable membranes configured to deliver up to two drug delivery modes at different rates In addition, a built-in back-up drug delivery system is also provided to allow drug delivery even if the primary delivery system ends its service life or an unexpected failure occurs. See US Pat. No. 6,471,688. The implantable pump consists of a battery-operated pump unit with drug containers, catheters, and electrodes implanted in the patient's epidural space so that liquid analgesics can be delivered from the catheter to the desired location . See U.S. Pat. No. 5,458,631.

  Similar drug delivery pumps also infuse drugs throughout the brain to locally stimulate nerve cells in the treatment of various chronic neurogenic diseases (such as those described above for intrathecal delivery) Has been explained to do. The implantable pump is implanted in the abdomen, and the pump diffuses the drug from the abdominal implantation site through the neck through the neck to all parts of the head through a tunnel-like catheter, and then to a localized treatment site in the brain. Spread. Pumps that deliver drugs to the brain release drugs to a variety of locations, including but not limited to: the anterior thalamus, the thalamus on the ventral side, the inner compartment of the pallidum, and the substantia nigra Reticulated part, hypothalamic nucleus, external division of pallidum and new striatum. For example, a drug delivery pump is a part of an implantable pump that allows a drug to be injected into a pre-defined location in the brain when the sensor detects a condition that it can treat a neurological disorder (such as a stroke). It may be linked to. See US Pat. No. 5,978,702. An implantable pump may be implanted adjacent to a pre-defined brain injection site so that a pre-specified dose of at least one drug can be injected to prevent and / or treat neurodegeneration. is there. See US Pat. No. 5,735,814. An implantable pump may include a container for a therapeutic agent stored between the subject's cap aponeurosis and the skull, where the drug is diffused to the desired location by pumping. See US Pat. No. 6,726,678.

  Intrathecal drug delivery pumps that are effective when the subject polymer composition infiltrates adjacent tissue in accordance with the present invention are commercially available products. There are many commercially available non-implantable intramembrane space drug delivery systems suitable for practicing the present invention. Medtronic, Inc.'s SYNCHROMED EL infusion system is a chronic sub-intravenous baclofen treatment (ITB treatment) (US Pat. Nos. 6,743,204, 6,669,663, 6,635,048, 6,629,954, 6,626,867, 6,102,678, Adapted to 5,978,702, 5,820,589, etc.), SYNCHROMED pumps are programmable battery powered devices that store and deliver drugs based on a programmed mode of administration. Medtronic, Inc. (Minneapolis, MN) also sells an ISOMED constant flow infusion system that delivers morphine sulfate directly into the subarachnoid space as a treatment for chronic pain. Arrow International manufactures Model 3000 infusion pumps that deliver drugs such as morphine and baclofen into the subarachnoid space at a constant flow rate. Tricumed Medizintechnik GmbH (Kiel, Germany) manufactures the Archimedes® constant flow infusion pump (implantable) that delivers analgesics and anticonvulsants into the subarachnoid space. Advanced Neuromodulation Systems (Plano, Texas) manufactures AccuRx® infusion pumps to treat pain and neuromuscular disorders. All of these devices have long catheters that carry the active agent from a subcutaneously implanted pump into the intrathecal space of the spinal cord. As noted above, the drug delivery catheter lumen or catheter tip within the subarachnoid space can cause partial or complete occlusion by scar tissue, which can slow or completely block the drug flow. Another possible complication with intrathecal drug delivery is the formation of fibrous tissue in the subdural space. This can block CSF flow and cause serious complications (eg, head pressure, increased pressure in the subarachnoid space). In this way, it is also effective to release therapeutic agents that prevent or inhibit infection around the catheter and / or implantation site in the intramembrane drug delivery device. In one embodiment of the invention, the device comprises a delivery catheter having a polymer composition of interest, the polymer composition inhibiting scarring that is moistened at the site where the delivery catheter is implanted or around the site to be implanted. Agents and / or anti-infectives. This wetting is aimed at maintaining the delivery catheter lumen patent and / or preventing fibrosis of the surrounding tissue and / or preventing or reducing infection around the catheter or implantation site. In another aspect, the invention provides an intrathecal drug delivery device comprising a subject polymer composition to be implanted in adjacent tissue, the polymer composition may comprise a therapeutic agent (a scarring inhibitor and (Or anti-infectives). Various polymeric and non-polymeric delivery systems for use with intrathecal drug delivery devices have already been described above.

  The polymeric compound directly and / or indirectly in the composition (a) tissue adjacent to the intrathecal drug delivery device, (b) around the intrathecal drug delivery device and tissue interface, (c) the arachnoid membrane When applied to the site surrounding the intrathecal drug delivery device, (d) within and / or on the tissue surrounding the intrathecal drug delivery device, it may infiltrate around the implanted intrathecal drug delivery device. Methods of infiltrating the tissue adjacent to the intrathecal drug delivery device with the polymer composition of interest include delivery of the polymer composition: (a) the surface of the intrathecal drug delivery device during the implantation process ( E.g. as injection material, paste, gel or mesh), (b) tissue surface (e.g. injection material, paste, gel, gel formed in situ) immediately before or during implantation of the intrathecal drug delivery device Or as a mesh) (c) Immediately after implantation of the intrathecal drug delivery device, the surface of the tissue surrounding the intrathecal drug delivery device and / or the implanted intrathecal drug delivery device (eg, infusion material) (D) topical application of the composition to the anatomical space in which the intrathecal drug delivery device is placed (especially useful in this example is a paste, gel, gel or mesh formed in situ) ,A few hours Is the use of polymeric carriers that release therapeutic agents over a period of up to several weeks-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and , Other formulations that can release the drug and be delivered to the site where the device is inserted), (e) by intradermal injection of solutions, injections, and sustained release formulations into the tissue surrounding the intrathecal drug delivery device (F) Application by a combination of the methods described above. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the polymer composition of interest can wet the surrounding tissue of the entire device or a portion (device only, pump only, catheter only, drug diffusion region only, and / or combinations thereof). ing.

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the present invention, the subject polymer composition that invades the tissue adjacent to the intrathecal drug delivery device comprises one or more of four general elements for the process of fiber formation (or scarring) including: Can be adapted to release inhibitory drugs: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), accumulation of extracellular matrix (ECM), And remodeling (maturation and organization of fibrous tissue). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fibrosis according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Because intrathecal drug delivery devices are made in a variety of shapes and sizes, the exact dose administered will also depend on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), the total drug dose administered can be measured, and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Drug scarring inhibitor dosage per unit area of the device or tissue surface of a subject to be coated (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm, ² or from about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention will depend on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), the total drug dose administered can be measured, and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose (amount) of anti-infective drug per unit area of the device or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² , or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

  For those skilled in the art, not only commercially available intrathecal drug delivery pumps not specifically cited herein, but also next generation and / or future developed commercially available drug delivery products may be used in accordance with the present invention. It should be clear that it is expected and suitable for its use.

(3) Implantable drug delivery pump for chemotherapy In one embodiment, the subject polymer composition can infiltrate the tissue adjacent to the chemotherapy drug delivery pump. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  A drug delivery pump can also be a pump that diffuses chemotherapeutic drugs to treat cancer. Pumps that diffuse drugs to treat cancer are used to deliver chemotherapeutic drugs to local areas of the body. While virtually any malignant tumor can be treated in this way (ie, direct injection of drugs into solid tumors or blood vessels that supply the tumor), today's treatments manage liver cancer (liver cancer). It is developing in the center. For example, FUDR (2'-deoxy-5-fluorocytidine) is used for temporary management of adenocarcinoma (colon, breast, stomach) that has metastasized to the liver. In hepatic arterial infusion therapy, the drug is delivered to an artery that supplies blood to the liver via an implantable pump. This allows higher concentrations of the drug to reach the liver (in the blood, the drug is not diluted like intravenous administration) and prevents clearance by the liver (drug is administered intravenously). May disappear quickly from the bloodstream because it is metabolized by the liver). Both effects allow high concentrations of drug to reach the tumor.

  In the practice of the present invention, a variety of implantable pumps are suitable for delivery of chemotherapeutic agents. For example, an implantable pump includes a diffusion chamber with a diffusion path and actuator, a container housing with a receptacle, and a container refill septum. See US Pat. No. 6,283,949. Medtronic, Inc. sells an ISOMED constant flow infusion system used to deliver chronic vascular infusions of floxuridine to treat primary or metastatic cancers at a constant flow rate. Tricumed Medizintechnik GmbH (Kiel, Germany) sells ARCHIMEDES DC implantable infusion pumps adapted to deliver chemotherapy within the vicinity of the tumor at a constant flow rate (US Pat. Nos. 5,908,414 and 5,769,823). Etc.) Arrow International manufactures a Model 3000 infusion pump that delivers chemotherapeutic drugs to the tumor at a constant rate. These devices are equipped with a catheter that carries the chemotherapeutic agent from a subcutaneously implanted pump directly into the tumor or artery supplying the tumor. As noted above, the drug delivery catheter lumen or catheter tip can cause partial or complete occlusion by scar tissue, which can slow or completely block the drug flow. When placed in a blood vessel, the drug delivery catheter lumen or catheter tip can cause partial or complete occlusion by neointimal tissue, resulting in blockage of the drug into the blood vessel. Such chemotherapeutic drug delivery pumps are also effective in releasing therapeutic agents that prevent or inhibit infection around the catheter and / or implantation site. In one embodiment of the invention, the device comprises a delivery catheter having a polymer composition of interest, the polymer composition inhibiting scarring that is moistened at the site where the delivery catheter is implanted or around the site to be implanted. Agents and / or anti-infectives. This wetting is aimed at maintaining the delivery catheter lumen patent and / or preventing fibrosis of the surrounding tissue and / or preventing or reducing infection around the catheter or implantation site. In another aspect, the invention provides a chemotherapeutic drug delivery pump that includes a subject polymer composition that is implanted into adjacent tissue, the polymer composition may include a therapeutic agent (an anti-scarring agent and / or Anti-infectives). Various polymeric and non-polymeric delivery systems for use with chemotherapeutic drug delivery pumps have already been described above.

  The polymeric compound directly and / or indirectly in the composition (a) tissue adjacent to the chemotherapeutic drug delivery pump, (b) around the chemotherapeutic drug delivery pump and tissue interface, (c) chemotherapeutic drug delivery pump When applied to the peripheral site, (d) inside and / or on the tissue surrounding the chemotherapy drug delivery pump, it may infiltrate around the implanted chemotherapy drug delivery pump. Methods of infiltrating the tissue adjacent to the chemotherapeutic drug delivery pump with the polymer composition of interest include delivery of the polymer composition: (a) The surface of the chemotherapeutic drug delivery pump during the implantation process (eg, infusion material) (B) as a paste, gel or mesh), (b) on the tissue surface (eg as an infusion, paste, gel, in situ gel or mesh) immediately before or during implantation of the chemotherapeutic drug delivery pump (c) Immediately after implantation of the chemotherapeutic drug delivery pump, the surface of the tissue surrounding the chemotherapeutic drug delivery pump and / or the transplant chemotherapeutic drug delivery pump (eg, infusate, paste, gel, in situ formed gel or (D) Topical application of the composition to the anatomical space where the chemotherapeutic drug delivery pump is placed (especially useful in this example is a period ranging from hours to weeks) Is the use of polymeric carriers that release therapeutic agents over time-releasing liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and drugs (F) other methods that can be delivered to the site where the device is inserted), (e) intradermal injection of solutions, infusions, and sustained release formulations into the tissue surrounding the chemotherapeutic drug delivery pump; Application by combination. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the polymer composition of interest can wet the surrounding tissue of the entire device or a portion (device only, pump only, catheter only, drug diffusion region only, and / or combinations thereof). ing.

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the invention, a subject polymer composition that infiltrates tissue adjacent to a chemotherapeutic drug delivery pump inhibits one or more of four general factors for the process of fiber formation (or scarring), including: Can be adapted to release drugs: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), accumulation of extracellular matrix (ECM), and regeneration Formation (maturation and organization of fibrous tissue). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fibrosis according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Because chemotherapeutic drug delivery pumps are made in a variety of shapes and sizes, the exact dose administered will also depend on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), the total drug dose administered can be measured, and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Drug scarring inhibitor dosage per unit area of the device or tissue surface of a subject to be coated (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm, ² or from about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention will depend on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), the total drug dose administered can be measured, and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose (amount) of anti-infective drug per unit area of the device or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² , or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

  For those skilled in the art, commercially available chemotherapeutic drug delivery pumps and implants not specifically cited herein, as well as next-generation and / or future developed commercially available chemotherapeutic drug delivery products are also used in accordance with the present invention. It should be clear that it is expected and suitable for its use.

(4) Drug delivery pump for treating heart disease In one embodiment, the subject polymer composition can infiltrate tissue adjacent to a drug delivery pump for treating heart disease. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  A drug delivery pump can be a pump that diffuses drugs to treat heart disease. Pumps that diffuse drugs to treat heart disease are used to treat conditions including, but not limited to, atrial fibrillation and other cardiac rhythm disorders. Atrial fibrillation is a type of heart disease that afflicts millions of people. This is a symptom in which normal regular contraction of the heart is inhibited, mainly due to abnormalities in the heart's atria and loss of control. Normal contractions occur in a controlled order in conjunction with contractions of other chambers of the heart. If the right atrium does not contract, does not contract in order, or does not contract effectively, the flow of blood from the atrium to the bedroom is blocked. Atrial fibrillation can cause weakness, shortness of breath, angina pectoris, lightheadedness, and other symptoms due to decreased ventricular filling and decreased cardiac output. Blood clots form in the atria that do not contract normally, are released and travel to the arteries of the brain through the bloodstream, sticking and blocking the bloodstream, resulting in stroke (brain injury or death) There is also a risk of doing.) Atrial fibrillation is usually treated with medical therapy and electrotherapy (defibrillator), but there are complications that can cause significant pain and life-threatening ventricular arrhythmias There is a case. The pain from electric shock is severe and conscious, and is unbearable for many patients because it warns when the device performs electrotherapy. In medical therapy, an antiarrhythmic drug is injected into a vein, administered by mouth, or locally delivered by a drug delivery pump.

  A variety of implantable pumps have been described for the diffusion of drugs to treat heart disease and are suitable for use in the practice of the present invention. For example, the drug delivery pump can be an implantable cardiac electrode that delivers stimulation energy to diffuse the drug next to the stimulation site. See US Pat. No. 5,496,360. The drug delivery pump has a plurality of septa. This is to facilitate the filling of the drug container in the subcutaneously implanted pump (with the catheter running through the transvenous, delivering the drug via the subclavian vein through the superior vena cava to the right atrium). is there. See US Pat. No. 6,296,630. As noted above, the drug delivery catheter lumen or catheter tip can cause partial or complete occlusion by scar tissue, which can slow or completely block the drug flow. When placed in a blood vessel, the drug delivery catheter lumen or catheter tip may cause partial or complete occlusion by neointimal tissue, resulting in blockage of drug flow to the blood vessel or right atrium. Such drug delivery pumps are also effective in releasing therapeutic agents that prevent or inhibit infection around the catheter and / or implantation site. In one embodiment of the invention, the device comprises a delivery catheter having a polymer composition of interest, the polymer composition inhibiting scarring that is moistened at the site where the delivery catheter is implanted or around the site to be implanted. Agents and / or anti-infectives. This wetting is aimed at maintaining the delivery catheter lumen patent and / or preventing fibrosis of the surrounding tissue and / or preventing or reducing infection around the catheter or implantation site. In another aspect, the present invention provides a drug delivery pump for the treatment of heart disease comprising a subject polymer composition implanted in adjacent tissue, the polymer composition may comprise a therapeutic agent (a scarring inhibitor) And / or anti-infectives). Various polymeric and non-polymeric delivery systems for use with drug delivery pumps for treating heart disease have already been described above.

  The polymeric compound may be used directly and / or indirectly in the composition (a) tissue adjacent to a drug delivery pump for treating heart disease, (b) around the drug delivery pump and tissue interface for treating heart disease, (c ) Peripheral area around the drug delivery pump for heart disease treatment, (d) Infiltration around the implanted drug delivery pump for heart disease treatment when applied inside and / or on the tissue surrounding the drug delivery pump for heart disease treatment There is a case. Methods of infiltrating tissue adjacent to a drug delivery pump for treating heart disease with a polymer composition of interest include delivery of the polymer composition: (a) of a drug delivery pump for treating heart disease during the implantation process On the surface (eg as injection material, paste, gel or mesh), (b) on the tissue surface (eg injection material, paste, gel, in situ) just before or during implantation of the drug delivery pump for heart disease treatment Of the tissue surrounding the drug delivery pump for cardiology and / or the implanted drug delivery pump for cardiology immediately after implantation of the drug delivery pump for cardiology (D) Topical application of the composition to the anatomical space where a drug delivery pump for the treatment of heart disease is placed on the surface (eg injection material, paste, gel, gel or mesh formed in situ) This fruit Particularly useful in the examples is the use of polymeric carriers that release therapeutic agents over a period ranging from hours to weeks-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles Sprays, aerosols, solid implants and other formulations that can release the drug and be delivered to the site where the device is inserted), (e) solutions, infusions into tissue surrounding drug delivery pumps for the treatment of heart disease, And (f) Application by a combination of the methods described above, by intradermal injection of a sustained release formulation. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the polymer composition of interest can wet the surrounding tissue of the entire device or a portion (device only, pump only, catheter only, drug diffusion region only, and / or combinations thereof). ing.

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the invention, the subject polymer composition infiltrating tissue adjacent to a drug delivery pump for treating heart disease is one or more of four general elements for the process of fiber formation (or scarring) comprising: Can be adapted to release drugs that inhibit blood: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), accumulation of extracellular matrix (ECM) And reformation (maturation and organization of fibrous tissue). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fibrosis according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Since drug delivery pumps for the treatment of heart disease are made in a variety of shapes and sizes, the exact dose to be administered also depends on the size, surface area and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), the total drug dose administered can be measured, and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Drug scarring inhibitor dosage per unit area of the device or tissue surface of a subject to be coated (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm, ² or from about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention will depend on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), the total drug dose administered can be measured, and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose (amount) of anti-infective drug per unit area of the device or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² , or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

  For those skilled in the art, not only the commercially available heart disease drug delivery pumps not specifically cited herein but also the next generation and / or future developed commercially available heart disease drug delivery products are used in accordance with the present invention. It should be clear that it is expected and suitable for its use.

(5) Other drug delivery implants In one embodiment, the subject polymer composition can infiltrate the tissue adjacent to the implantable pump for continuous delivery of the medicament. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  Several other implantable pumps useful in the present invention have been developed for the purpose of continuously delivering pharmaceuticals. For example, Debiotech S.A (Switzerland) has developed a MIP device, a piezoelectrically actuated silicon micropump that is implantable for programmable drug delivery applications. This high-performance micropump is based on a MEMS (microelectromechanical) system that allows a low flow rate to be maintained. The Durect Corporation (Cupacino, CA) DUROS sufentanil implant is a titanium cylinder containing a drug container and a piston driven by an osmotic engine. VIADUR (leuprolide acetate) grafts available from AlzaCorporation (Mountain View, Calif.) Use the same DUROS graft technology to deliver leuprolide for 12 months and reduce testosterone levels to treat prostate cancer ( US Pat. Nos. 6,283,953, 6,270,787, 5,660,847, 5,112,614, 5,030,216, 4,976,966, etc.). The fiber coating of the device can be disturbed in several processes including: blocking the semipermeable membrane (impairing the function of the engine by impeding fluid flow to the osmotic engine), outlet Port blocking (inhibiting drug flow out of the device) and / or complete encapsulation (creating a microenvironment that inhibits drug diffusion). Many other drug delivery implants, osmotic pumps, etc. have the same problem (fibrous coating prevents proper release of the drug into the surrounding tissue). Such delivery devices are also effective in releasing therapeutic agents that prevent or inhibit infection around the catheter and / or implantation site. In one embodiment of the present invention, the drug delivery device has a polymer composition of interest, the polymer composition being an anti-scarring agent moistened at the site of implantation of the device or tissue surrounding the site of implantation and / or Or contains anti-infectives. This wetting is intended to prevent or inhibit coating, prevent occlusion of the semipermeable membrane, maintain delivery catheter lumen patents, prevent fibrosis of the surrounding tissue and / or prevent or reduce infection around the catheter or implantation site. In another aspect, the invention provides an implantable pump for continuous delivery of a pharmaceutical comprising a subject polymer composition to be implanted in adjacent tissue, the polymer composition may comprise a therapeutic agent (scarring) Inhibitors and / or anti-infectives). Various polymeric and non-polymeric delivery systems for use with implantable pumps for continuous delivery of pharmaceuticals have already been described above.

  The polymeric compound directly and / or indirectly in the composition (a) tissue adjacent to the implantable pump for continuous delivery of the drug, (b) the implantable pump-tissue interface for continuous delivery of the drug Perimeter, (c) the peripheral area of an implantable pump for continuous delivery of the drug, (d) continuous application of the implanted drug when applied to and / or on the tissue surrounding the implantable pump for continuous delivery of the drug May infiltrate around the implantable pump for delivery. Methods of infiltrating a tissue adjacent to an implantable pump for continuous delivery of a pharmaceutical with a polymer composition of interest include delivery of the polymer composition: (a) For continuous delivery of the pharmaceutical during the implantation process (B) on the surface of an implantable pump (eg as an infusate, paste, gel or mesh), and (b) the tissue surface (eg, infusate, paste, (As a gel, in-situ formed gel or mesh), (c) immediately after implantation of the implantable pump for continuous delivery of the drug, immediately after implantation of the implantable pump for continuous delivery of the drug and / or (D) Implantable pots for continuous delivery of pharmaceuticals on the surface of the tissue surrounding the implantable pump for continuous delivery (eg, infusate, paste, gel, gel or mesh formed in situ) Topical application of the composition to the anatomical space where the amplifier is placed (especially useful in this example is the use of a polymeric carrier that releases the therapeutic agent over a period ranging from hours to weeks-liquid, suspension Suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and other formulations that can release the drug and be delivered to the site where the device is inserted), (e) (F) Application by a combination of the methods described above, by intradermal injection of solutions, infusions and sustained release formulations into the tissue surrounding the implantable pump for continuous delivery of the medicament. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the polymer composition of interest can wet the surrounding tissue of the entire device or a portion (device only, pump only, catheter only, drug diffusion region only, and / or combinations thereof). ing.

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the present invention, the subject polymer composition that infiltrates tissue adjacent to an implantable pump for continuous delivery of a pharmaceutical agent is one of four general factors for the process of fibrosis (or scarring) comprising: Or can be adapted to release drugs that inhibit more than one: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) Accumulation and remodeling (fibrotic tissue maturation and organization). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fibrosis according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Because implantable pumps for continuous delivery of pharmaceutical products are made in a variety of shapes and sizes, the exact dose administered will also vary depending on the size, surface area, and design of the device. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), the total drug dose administered can be measured, and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Drug scarring inhibitor dosage per unit area of the device or tissue surface of a subject to be coated (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm, ² or from about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention will depend on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), the total drug dose administered can be measured, and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the tissue surrounding the device, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose (amount) of anti-infective drug per unit area of the device or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² , or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

  A number of implantable pumps have been described above, all of which have similar design features and are responsible for undesirable similar fiber tissue reactions after transplantation, causing infection or causing infection at the transplant site. There is a case. For those skilled in the art, not only the commercially available sensor devices not specifically cited above, but also the next generation and / or future developed commercially available implantable pump products are expected to be used in accordance with the present invention, and It must be clear that it is suitable for its use. The clinical function of an implantable drug delivery device or pump is that the device, especially the catheter or drug diffuser, is anatomically attached to the target tissue (such as the spinal subdural space, arterial lumen, peritoneum, interstitial fluid) Can be effectively maintained, and is affected by factors such as whether scab or occlusion by scar tissue occurs. For implantable pumps, the drug delivery catheter lumen, catheter tip, drug diffusion, or delivery membrane can become occluded by scar tissue, which can slow or completely block the flow of drug. Instead, the entire pump, catheter and / or diffusion component is vesicular by the scar (ie, the device is surrounded by fibrous tissue) so that the drug is incompletely diffused into the target tissue (ie, the scar is adequate) Drug transfer and the transfer of implantable pumps to tissues outside the vesicle). In either case, improper or incomplete drug flow is directed to the appropriate target tissue or organ (and clinical benefits are lost), while the vesicles are localized drug accumulation (vesicles). ) And additional clinical complications (such as local drug toxicity, temporary seizure of drugs that cause abrupt and massive “dumping” of drug to surrounding tissues). For implantable pumps with electrical or battery components, not only does the device fail to perform best or fail due to fiber formation, but also to overcome the electrical resistance imposed by the intervening scar tissue As a result of the demand for increased energy, battery life may be excessively consumed. Implantable pumps that release therapeutics to reduce scarring at the device-tissue interface have improved efficacy, extended clinical function, and the right amount of drug diffused from the device at the right rate And can be used to reduce the risk of potentially toxic drugs sequestering in the fiber capsule. For implantable sensor devices, the release of therapeutic agents that prevent or reduce infection around the implantation site is also effective. In one embodiment, the present invention provides an implantable pump comprising a subject polymer composition to be implanted in adjacent tissue, the polymer composition may comprise a therapeutic agent (an anti-scarring agent and / or an anti-infection). medicine). In addition to these compositions, one or more fiber formation inhibitors are included to inhibit or reduce granulation tissue or fiber tissue overgrowth, and / or one or more anti-infective agents Inclusions inhibit or prevent infection around the transplant.

Soft Tissue Graft In one embodiment, the subject polymer composition can infiltrate the tissue adjacent to the soft tissue graft. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  There are many types of soft tissue grafts where the occurrence of a fibrous response adversely affects the function or appearance of the graft or surrounding tissue. Normally, fiber coating of a soft tissue graft (or growth of fibrous tissue between the graft and surrounding tissue) can cause fiber contracture and other problems that can lead to suboptimal appearance and patient comfort. You may be invited. Accordingly, the present invention provides a soft tissue graft having a polymer composition of interest, the polymer composition comprising an anti-scarring agent and / or an anti-infective agent that is moistened to surrounding tissue. This wetting aims to minimize scar tissue formation, prevent soft tissue grafting (as well as associated fiber contractures), and prevent or reduce infection around the graft site.

  Soft tissue grafts are used in a variety of cosmetic, plastic, and reconstructive surgery procedures on different body parts including, but not limited to, face, nose, breast, jaw, buttocks, rib cage, lips and cheeks. Can be delivered. Soft tissue grafts are used for reconstruction of tissue cavities made by surgery or trauma, tissue or organ augmentation, tissue contouring, bulk recovery for aged tissue, and soft tissue grooves or rhytides The Soft tissue grafts can be used for cosmetic surgery (aesthetics) or in connection with reconstruction surgery after disease or surgical resection. Representative examples of soft tissue grafts that are effective when the subject polymer composition is moistened into surrounding tissue include, for example, saline augmentation implants, silicone augmentation implants, triglycerides Filled breast implants, jaw / mandibular grafts, nasal grafts, buccal grafts, lip and other facial grafts, pectoral muscle grafts, buccal and subbuccal grafts and buttocks Of grafts.

  Soft tissue grafts are composed of a number of configurations and can be formed from a variety of materials to match the surrounding anatomy and properties. In one embodiment, soft tissue grafts suitable for use in the present invention are formed from polymers such as silicon, poly (tetrafluoroethylene), polyethylene, polyurethane, polymethyl methacrylate, polyester, polyamide and polypropylene. The soft tissue graft may be in the form of a shell (or envelope) filled with a liquid material such as saline.

  In one embodiment, the soft tissue graft contains or is formed from silicon or dimethylsiloxane. Silicone implants are solid but flexible, and are highly durable and stable. They are produced with various durometers (hardness), both soft and extremely hard, and are determined by the degree of polymerization. Short polymer chains result in low-viscosity liquid silicon, while chain elongation produces a gel-type material, resulting in highly tacky silicone rubber with polymer chain crosslinkability. Silicon can also be mixed with water and hydrogel carriers as particles to allow for the implantation of fibrous tissue. These implants are designed to reinforce areas of soft tissue rather than the underlying bone structure. In certain embodiments, a silicon-based graft (eg, a heel graft) can be secured to the underlying bone with one or several titanium screws. Silicone implants can be used to augment tissue at various body sites, including, for example, the chest, nose, heel, cheekbones (eg, cheeks) and chest / muscle. Low-viscosity silicone gels have been used primarily to fill breast augmentation implants, while high-viscosity silicones are used for tissue expanders and breast augmentation implants that are both saline and silicone filled. Used for outer shell. For example, breast augmentation implants are manufactured by both Named Corporation (Santa Barbara, Calif.) And Mentor Corporation (Santa Barbara, Calif.).

  In another embodiment, the soft tissue graft contains or is formed from poly (tetrafluoroethylene) (PTFE). In certain embodiments, the poly (tetrafluoroethylene) is expanded tetrafluoroethylene (ePTFE). PTFE used for soft tissue grafts can be formed of a solid PTFE knotted foam polymer with interconnected thin PTFE fibrils forming a grid pattern, resulting in flexibility and durability A biocompatible material is obtained. Soft tissue grafts made from PTFE are often easily straightened and can be used in sheets that can be stacked to the desired thickness, as well as solid blocks. These implants are porous and can be incorporated into the surrounding tissue to help maintain the implant in an anatomically appropriate location. PTFE grafts are usually not as stiff as silicone grafts. Furthermore, there is less bone resorption under the ePTFE graft compared to the silicon graft. Soft tissue grafts composed of PTFE are used to enhance tissue in various body parts, including, for example, the face, chest, lips, nose, buttocks as well as the lower jaw and cheeks, and wrinkles between the nose lips and eyebrows. It can also be used for treatment. For example, GORE-TEX (W.L. Gore & Associates, Inc., Newark, Del.) Is a synthetic foam PTFE that can be used to form facial implants for augmentation purposes.

  In yet another aspect, the soft tissue graft contains or is formed from polyethylene. Polyethylene grafts are frequently used, for example, to strengthen the jaw. Since polyethylene grafts can be porous and can be incorporated into the surrounding tissue, this provides an alternative to the use of titanium screws for stability. Polyethylene grafts can be utilized as having a variety of biochemical properties, including chemical resistance, tensile strength and hardness. Polyethylene grafts can be used for facial reconstruction, including buccal, chin, nasal and cranial grafts. For example, Porex Surgical Products Group (Newman, GA) manufactures MEDPOR, which is a high density porous polyethylene graft used in facial reconstruction surgery. Porosity allows vascular and soft tissue ingrowth to address the graft.

  In yet another aspect, the soft tissue graft contains or is formed from polypropylene. Polypropylene implants are loosely textured, high density polymers with properties similar to polyethylene. These grafts have legitimate tensile strength and can be used as mesh weaves such as PROLENE (Ethicon, Inc., Somerville, NJ) or MARLEX (C.R .. Bard, Inc., Billerica, Mass.). Polypropylene grafts can be used, for example, as pectoral muscle grafts.

  In yet another aspect, the soft tissue graft contains or is formed from polyamide. Polyamide is a nylon compound that is woven into a mesh that can be implanted for use in facial reconstruction and augmentation surgery. These implants can be easily molded and stitched and are absorbed over time. SUPRAMID and SUPRAMESH (S. Jackson, Inc., Minneapolis, Minn.) Are nylon-based products that can be used for augmentation, but have a limited range of applications due to their absorbent nature.

  In yet another aspect, the soft tissue graft contains or is formed from polyester. Non-biodegradable polyesters such as MERSILENE mesh (Ethicon, Inc.) and DACRON (available from Invista, Wichita, Kansas) for applications that require both tensile strength and stability, such as pectoral muscle, heel and nose enhancement Suitable as a graft.

  In yet another aspect, the soft tissue graft contains or is formed from polymethyl methacrylate. Although these grafts are highly porous, they have a high molecular weight and have compressive strength and rigidity. Polymethylmethacrylates such as Hard Tissue Replacement (HTR) manufactured by US Surgical Corporation (Norwalk, Connecticut) can be used for reconstruction of the skull and rib face as well as heel and cheek enhancement it can.

  In yet another aspect, the soft tissue graft contains or is formed from polyurethane. Polyurethane can be used as a foam covering the breast implant. This polymer promotes tissue ingrowth that leads to a reduction in the contracture rate of breast implants.

  Examples of commercially available polymer soft tissue grafts that are effective when the subject polymer composition is wetted into surrounding tissue in accordance with the present invention include Surgiform Technology, Ltd. (Columbia Station, Ohio), Implant Tech Associates (California). Ventura, Calif.), Named Corporation (Santa Barbara, Calif., See M766A Spectrum Catalog), Mentor Corporation (Santa Barbara, Calif.), And AlliedBiomedical (Ventura, Calif.). Saline filled breast implants are manufactured by both Innamed and Mentor and can benefit from grafts combined with fibrosis inhibitors. Commercially available poly (tetrafluoroethylene) soft tissue grafts suitable for use in combination with fibrosis inhibitors include poly (tetrafluoroethylene) cheek, heel and nose from WL Gore & Associates, Inc. (Newark, Delaware). There is a graft. A commercially available polyethylene soft tissue graft that is effective upon wetting of the polymer composition of interest into the surrounding tissue in accordance with the present invention is Porex Surgical Inc. (Fairburn, Ga.) Sold under the trade name MEDPORBiomaterial. Of polyethylene grafts. MEDPORBiomaterial is composed of a porous high density polyethylene material with an omnidirectional lattice interconnecting the pores, which allows integration into host tissues.

  Depending on the transplantation, excess scar tissue may grow around or around the graft, which can lead to poor performance of these devices (as described above). Soft tissue grafts with targeted polymer composition grafts that infiltrate the tissue surrounding the transplant site will improve appearance, extend life, reduce the need for corrective surgery or repeated treatments, reduce pain cases and other signs , And can be used for improvement of graft clinical function. For soft tissue grafts, it is also effective to release therapeutic agents that prevent or reduce infection around the graft site. Accordingly, in one embodiment, the present invention provides a soft tissue graft comprising a subject polymer composition that is implanted in adjacent tissue, the polymer composition may comprise a therapeutic agent (an anti-scarring agent and / or an anti-cancer agent). Infectious drugs). A number of polymeric and non-polymeric delivery systems have been described above in combination with soft tissue grafts.

  The polymer compound directly and / or indirectly (a) tissue adjacent to the soft tissue graft, (b) around the soft tissue graft-tissue interface, (c) around the soft tissue graft, (d) soft tissue When applied within and / or on the tissue surrounding the graft, it may infiltrate around the transplanted soft tissue graft. Methods of infiltrating the tissue adjacent to the soft tissue graft with the polymer composition of interest include delivery of the polymer composition: (a) the surface of the soft tissue graft during the implantation process (eg, injection material, paste, gel) Or as a mesh), (b) on the tissue surface (eg as injection material, paste, gel, gel or mesh formed in situ) immediately before or during the implantation of the soft tissue graft, (c) soft tissue graft Immediately after implantation of (d) the soft tissue graft and / or the surface of the tissue surrounding the transplanted soft tissue graft (eg injection material, paste, gel, gel or mesh formed in situ) Topical application of the composition to the anatomical space to be placed (especially useful in this example is the use of a polymeric carrier that releases the therapeutic agent over a period ranging from hours to weeks-liquids, suspensions ,milk Liquids, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and other formulations that release drugs and can be delivered to the site where the device is inserted), (e) surround soft tissue implants (F) Application by a combination of the methods described above, by intradermal injection of solutions, infusions, and sustained release formulations into the tissue. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the subject polymer composition can be wetted to the entire implant or to some surrounding tissue.

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the present invention, the subject polymer composition that invades the tissue adjacent to the soft tissue graft comprises an agent that inhibits one or more of the four general factors for the process of fibrosis (or scarring), including: Can be adapted to release: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), accumulation of extracellular matrix (ECM), and remodeling ( Fibrous tissue maturation and organization). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fibrosis according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Soft tissue grafts are formed from a variety of configurations and sizes, and the exact dosage varies depending on the graft size, surface area and design. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), the total drug dose administered can be measured, and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the surrounding tissue, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Drug scarring inhibitor dosage per unit area of the implant or tissue surface of a subject to be coated (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2, or about 1 μg / mm ² ~10 μg / mm ² or about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention will depend on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), the total drug dose administered can be measured, and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the surrounding tissue, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective drug per unit area of the graft or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² , or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

For clarity, some specific soft tissue grafts and treatment details are described below, including breast augmentation implants and other aesthetic grafts.

(1) Breast augmentation implant In one embodiment, the subject polymer composition can infiltrate the tissue adjacent to the breast augmentation implant. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  Placing a breast augmentation implant for breast augmentation or to reconstruct a breast after mastectomy is one of the most frequently performed cosmetic surgeries. For example, in 2002, more than 300,000 women underwent breast augmentation surgery. About 80,000 of these women underwent breast reconstruction surgery after mastectomy with cancer. An increase in the number of breast implants is very likely given the incidence of breast cancer and current trends in cosmetic surgery.

  In general, breast augmentation or reconstruction surgery involves placing a commercially available breast implant, consisting of a coating filled with either saline or silicone, into the tissue under the mammary gland. For breast augmentation, the following four incisions have been used: the axilla (under the armpit), the circumference of the areola (around the areola), the lower breast (the base of the breast intersecting the chest wall) and the umbilical cross ( Around the navel). Tissue is often excised with a small incision using an endoscope (especially for axillary and transumbilical procedures that require drilling from the incision to the chest). Pockets for placing breast augmentation implants are formed either in the subgland or in the subthoracic region. For grafts under the gland, the tissue is incised to create a space between the glandular tissue and the greater pectoral muscle that extends to the heel of the lower breast. For the pectoral muscle graft, the pectoral muscle fibers are carefully excised to create a space between the lower pectoral muscle layer and the surface of the rib cage. Careful hemostasis is essential (because it can contribute to complications such as capsule contractures), and minimally invasive treatment (axillary, transumbilical approach) is more restrictive if bleeding control is inadequate There is a need to change to fewer treatments (eg, areola areola). Depending on the type of surgical approach selected, breast augment implants are often contracted and rolled up for placement in the patient. After being accurately positioned, the implant is filled or expanded to the desired size.

  Although many patients are satisfied with the initial treatment, a high percentage of people suffer from complications that often require repeated treatments for correction. Encapsulation of a breast augmentation prosthesis, which forms a shell (called capsule contracture) around the prosthesis, is the most common complication reported after breast augmentation, accounting for 50% of patients Has reported some dissatisfaction. Calcification can occur within the fibrous coating and increases its hardness further, complicating the interpretation of mammograms. Multiple causes have been identified for capsule contractures including: foreign body reaction, migration of silicone gel molecules throughout the capsule or into tissues, autoimmune disease, genetic predisposition, infection, hematoma, and prosthesis Surface properties. Although the specific etiology has not been identified repeatedly, at the cellular level, the activity of breast fibroblasts stimulated by foreign bodies is a consistent finding. The capsule tissue around the prosthesis contains macrophages and sometimes T and B lymphocytes, suggesting an inflammatory component to the process. The surface of the implant has both smooth and textured areas formed in an attempt to reduce the coating, but none has been demonstrated to produce consistently excellent results. In animal models, it has been suggested that on surfaces with a texture that promotes the ingrowth of fibrous tissue on the surface, there is an increased tendency for increased coating thickness and contracture. Placing the implant in a position below the pectoral muscle appears to reduce the rate of encapsulation in both smooth and open-grained grafts.

  From the patient's point of view, the biological processes described above lead to a series of commonly described complaints. Implant mispositioning, hardness and unfavorable shape are the most frequently cited complications and the biggest factor in causing capsule contractures. When the surrounding scar coating begins to harden and contract, it can cause discomfort, weakening of the shell, asymmetry, skin depression and misplacement. Actual capsule contractures occur in about 10% of patients after breast augmentation and 25-30% in cases of reconstruction surgery, but many patients report dissatisfaction with aesthetic results . Scarring leading to asymmetry occurs in 10% of breast augmentations and 30% of reconstructions and is a major cause of corrective surgery. Skin hatching (due to the skin being pulled in the direction of the graft due to contracture) is a complication reported in 10-20% of patients. When fibrous tissue ingrowth into the diaphragmatic valve (the contact site used to expand the graft) causes the graft to become self-controlling and leaking, scarring is caused by graft contraction (1- 6% of patients, even saline has leaked from the graft, causing the graft to “shrink”). In addition, more than 15% of patients undergoing breast augmentation suffer from chronic pain, and the majority of these ultimately contribute to the formation of scar tissue. Other complications of breast augmentation include late leaks, hematomas (about 1-6% of patients), seromas (2.5%), hypertrophic scars (2-5%) and infections (about cases) 1 to 4%).

  Due to obvious graft infections (occurring in about 1 to 4% of cases) resulting from wound infection, saline contamination in the graft, contamination of breast implants during surgical implantation, and other causes, Excision of the graft is required. Release of anti-infectives into the tissue surrounding the graft reduces the infection of breast implants and is effective in preventing the formation of infection-induced capsule contractures.

  Correction can include graft resection, incision (capsule removal or surgical release), capsule resection (surgical removal of the fiber capsule), or placement of the graft in another location (eg, subgland to chest) Several options may be involved, including submuscular). Ultimately, additional surgery (correction, incision, resection, reimplantation) is needed in more than 20% of breast augmentation patients and more than 40% of reconstruction surgery patients, but scar formation and capsule contractures This is a common cause. Treatment to destroy the scar may not be sufficient, with about 8% for breast augmentation and 25% for reconstructive surgery, eventually with surgical removal of the graft. Minimization of fibrous tissue formation, capsularization, and capsular contracture when the subject polymer composition, including an anti-scarring agent and / or anti-infective agent, infiltrates the breast graft site or the tissue adjacent to the site where the transplant is performed Can be limited and / or prevent or reduce infection around the implantation site. Attempts to administer steroids, for example, either from breast augmentation implants or by immersion in the subject's breast pocket, have caused soft tissue atrophy or malformation. An ideal fiber formation inhibitor targets only the components of the fiber coating and does not damage the surrounding soft tissue. By wetting the polymer composition of interest to the tissue surrounding the breast implant site, fiber contractures that occur in response to breast augmentation implants containing gel or saline placed under the pectoral muscle or under the gland It can be minimized or prevented. Scarring in breast augmentation and reconstruction surgery by wetting the polymer composition of interest into tissue adjacent to the breast implant site, including tissue surrounding the surgical pocket where the breast implant or graft is placed Formation and capsule contracture can be prevented, and infection around the implantation site can be prevented or reduced.

  A number of breast implants are suitable for use in the practice of the present invention and can be used for cosmetic and reconstructive surgery purposes. A breast augmentation implant can be composed of a flexible, soft shell filled with a liquid such as saline, polysiloxane or silicone gel. For example, a breast augmentation implant can be composed of an outer polymeric shell with a cavity filled with a plurality of hollow bodies made of a deformable resilient material containing saline. See US Pat. No. 6,099,565. A breast augmentation implant can be composed of an envelope of vulcanized silicone rubber that contains an aqueous solution of polyethylene glycol and forms a water-impermeable shell that is hermetically sealed. See US Pat. No. 6,312,466. A breast augmentation implant can consist of an envelope made of a flexible non-absorbable material and a filler that is a shortening component (eg, vegetable oil). See US Pat. No. 6,156,066. A breast augmentation implant can be composed of a soft and flexible outer membrane and a partially deformable elastic filler supported by the internal structure of the compartment. See US Pat. No. 5,961,552. A breast augmentation implant can consist of a non-biodegradable conical shell filled with a layer of monofilant yarn formed into a resiliently compressible fiber. See US Pat. No. 6,432,138. Breast augmentation implants can consist of a shell containing a sterile continuous filler made from a continuous yarn of polyolefin or polypropylene. See US Pat. No. 6,544,287. A breast augmentation implant can be composed of an envelope containing a keratin hydrogel. See US Pat. No. 6,371,984. A breast augmentation implant is a hollow, foldable shell formed from a flexible, stretchable material that is elastic, non-deformable, has an enhanced base, and contains a sticky filler inside. Can be configured. See US Pat. No. 5,104,409. Breast augmentation implants can be composed of a smooth, non-porous polymer envelope with a non-woven, porous outer layer made of extruded polycarbonate urethane polymer fibers containing a soft filler. See US Pat. No. 5,376,117. The breast augmentation implant can be configured to be surgically implanted under the pectoral muscle and the second prosthesis implanted between the pectoral muscle and the breast tissue. See US Pat. No. 6,464,726. Breast augmentation implant is a single-structure, homogeneous silicone elastomeric flexible with an internal filler and a rough outer surface with randomly formed open cells to promote tissue ingrowth to prevent capsule contracture It can consist of a shell. See US Pat. No. 5,674,285. The breast augmentation implant may be a plastic implant coated with heparin that is bonded to the surface to prevent or heal capsule formation and / or contraction in the cavity of blood-dried tissue. See U.S. Pat. No. 4,713,073. The breast implant may be a sealed elastic polymer envelope with a microporous structure filled with a sticky / elastic material (eg, chondroitin sulfate salts) to provide a predetermined shape. See US Pat. No. 5,344,451.

  In accordance with the present invention, breast augmentation implants that are effective when the polymer composition of interest infiltrates adjacent tissue also include commercially available products. Commercial breast implants include INAMED Corporation (Santa Barbara, Calif.), Which sells both saline-filled and silicon-filled breast implants. INAMED's saline-filled breast implants include Style68 Saline Matrix and Style 363LF, as well as a variety of models, contours, shapes and sizes. INAMED's silicone-filled breast implants are available in Style 10, Style 20, Style 40, as well as various shapes, contours and sizes. INAMED also sells breast tissue expanders such as the INAMED Style 133V series tissue expanders, which are used to promote rapid tissue fit to maximize expander immobility. . Mentor Corporation (Santa Barbara, Calif.) Has developed a saline-filled Contour Profile Style Breast Implant (available in a variety of models, shapes, contours and sizes) and a simple in-hospital procedure six months after surgery. It sells Spectrum Postoperatively Adjustable Breast Implant, which allows breast size adjustment by adding and removing water. Mentor also manufactures ContourProfile® Gel breast implants in a variety of models, shapes, contours and sizes. These breast augmentation implants can benefit from the release of therapeutic agents and reduce scarring at the graft-tissue interface to minimize the incidence of fiber contractures. These breast augmentation implants are also effective in releasing therapeutic agents that prevent or reduce infection around the implantation site.

As mentioned above, graft misplacement (graft movement or migration after placement) can lead to various complications such as asymmetry and movement under the breast under the breast, causing patient dissatisfaction and corrective surgery. Has become a major cause of. In one embodiment, the breast implant is treated with a fibrosis promoter or composition on the underside (eg, the surface facing the pectoral muscle for a subgland breast implant or the face facing the chest wall for a breast implant under the pectoral muscle) ) Coated with another agent or composition that inhibits fibrosis (for example, the surface facing the pectoral muscle for the subgland augmentation implant, or the chest wall for the subthoracic augmentation implant) The surface is coated. Such coating can be performed directly or by infiltration of the target polymer composition containing the desired drug into the tissue surrounding the desired surface, or a combination thereof. This example promotes fibrosis and colonization at the anatomical site where the breast implant is placed (ie, breast implant) while preventing complications associated with the coating on the surface of the breast implant. To the space below the gland or pectoral muscle to prevent graft migration). Typical examples of drugs that promote fibrosis and are suitable for delivery from the lower (deep) side of breast implants include raw silk, wool, silka, bleomycin, neomycin, talcum powder, metal beryllium, calcium phosphate, calcium sulfate, carbonate Calcium, hydroxyapatite, copper, cytokines (eg, cytokines are bone morphogenetic proteins, desalted bone matrix, TGFb, PDGF, VEGF, bFGF, TNFa, NGF, GM-CSF, IGF-1, IL-1-b, Selected from the group consisting of IL-8, IL-6, and growth hormone), agents that stimulate cell proliferation (eg, agents that stimulate cell proliferation include dexamethasone, isotretinoin, 17-b estradiol, estradiol, 1- a-25-dihydroxyvitamin D _3, diethylstilbestrol, cyclosporin A, N (omega - nitro -L- arginine methyl ester (N (omega - nitro -L- Arginine methyl ester)), and all retinoic acid (ATRA)) as well as their analogs and derivatives, instead of or in addition to coating the lower surface with a composition containing a fibrosis promoter As such, the subject polymer composition containing the fiber inducer can infiltrate the space where the breast implant is juxtaposed to the underlying tissue (the base of the surgically created pocket).

  In one aspect, the invention provides a breast augmentation implant that includes a subject polymer composition that is implanted into adjacent tissue, the polymer composition may include a therapeutic agent (an anti-scarring agent and / or an anti-infection). medicine). Various polymeric and non-polymeric delivery systems for use with breast augmentation implants have already been described above.

  The polymer compound directly and / or indirectly (a) tissue adjacent to the breast implant, (b) around the interface between the breast implant and tissue, (c) around the breast implant, (d) When applied within and / or on the tissue surrounding the breast implant, it may infiltrate around the implanted breast implant. Methods of infiltrating the target polymer composition into the tissue adjacent to the breast implant include delivery of the polymer composition: (a) the surface of the breast implant during the implantation process (eg, injection material, paste, gel) Or as a mesh), (b) immediately before or during implantation of a breast implant, (c) on a tissue surface (eg as injection material, paste, gel, in situ formed gel or mesh), (c) breast implant Immediately after implantation of the breast augmentation implant and / or on the surface of the tissue surrounding the implanted breast augmentation implant (eg, injection material, paste, gel, gel or mesh formed in situ), (d) Topical application of the composition to the anatomical space in which it is placed (especially useful in this example is a polymer carrier that releases the therapeutic agent over a period ranging from hours to weeks. Is the use of the body-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and delivered to the site where the drug is released and the device is inserted (E) application by a combination of the methods described above, (e) by intradermal injection of solutions, infusions, and sustained release formulations into the tissue surrounding the breast implant. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the subject polymer composition can be wetted to the entire implant or to some surrounding tissue.

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the invention, the subject polymer composition infiltrating the tissue adjacent to the breast augmentation implant comprises an agent that inhibits one or more of the four general factors for the process of fibrosis (or scarring) including: Can be adapted to release: new blood vessel formation (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) accumulation, and remodeling ( Fibrous tissue maturation and organization). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fibrosis according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Breast augmentation implants are formed from a variety of configurations and sizes, and the exact dosage will also vary depending on the implant size, surface area and design. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), the total drug dose administered can be measured, and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the surrounding tissue, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Drug scarring inhibitor dosage per unit area of the implant or tissue surface of a subject to be coated (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2, or about 1 μg / mm ² ~10 μg / mm ² or about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention will depend on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), the total drug dose administered can be measured, and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the surrounding tissue, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective drug per unit area of the graft or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² , or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

(2) Facial graft In one embodiment, the subject polymer composition can invade tissue adjacent to the facial graft. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents).

  Soft tissue grafts can be facial grafts and include cheek / medium facial or sub-buccal sites (eg, cheek transplants). Cheek and subbuccal enhancement is often deformed by aging (eg, cheek fossaization and mediofacial soft tissue ptosis), dysplasia of the midface (dish-faced facial malformation), post-traumatic and post-tumor resection And when there is a clear change associated with moderate unilateral facial atrophy. Cheek and subbuccal enhancement can also be performed for cosmetic purposes to dramatically increase or sharpen cheek contours. The placement of the buccal / subbuccal implants often enhances the outcome of fistula excision and nasal surgery by further providing a harmonious balance with the face.

  There are a number of facial implants that can be used for cosmetic and reconstruction purposes. For example, the facial implant may be a tear-shaped thin profile with a wide head and a tapered edge for the mid-face or sub-buccal area of the face to restore softness and softness of the cheeks. See U.S. Pat. No. 4,969,901. Facial implants can usually be constructed from a flexible material having a concave lower surface and a convex upper surface, which is used to augment the subbuccal site. See U.S. Pat. No. 5,421,831. The facial implant may be a modular prosthesis consisting of a thin planar shell and shim that provides the desired contour for the overlapping tissue. See US Pat. No. 5,514,179. The facial implant can be composed of molding silicon with parallel and vertical groove grids on the back side facing the concave bone to promote tissue ingrowth. See US Pat. No. 5,876,447. Facial implants can be constructed of closed cells, cross-linked, foamed polyethylene formed into shells and shapes that closely fit the human face. See U.S. Pat. No. 4,920,580. The facial implant applies laser light to isolate the epidermal layer, thereby exposing the dermis and inserting the dermal plug into the recessed area of the facial skin, and then removing the dermal plug from the donor's skin It is also possible to do it. See US Pat. No. 5,817,090. The facial implant can be composed of a silicone-elastomer with an open cell structure whereby the silicone elastomer is applied to the surface as a solid before the layer is cured. See U.S. Pat. No. 5,007,929. The facial implant may be a hollow or perforated mandibular or maxillary artificial root composed of a transosseous bolt receptor secured to the alveolar ridge with an adjacent strap. See U.S. Pat. No. 4,828,492.

  In accordance with the present invention, facial implants that become effective when the polymer composition of interest infiltrates adjacent tissue include commercially available products. Commercially available facial implants suitable for practicing the present invention include: Tissue Technologies, Inc. (San Francisco, Calif.) Is a soft, easy to mold synthetic e-PTFE used for facial soft tissue augmentation. It sells manufactured UltraSoft-RC Facial Implant. TissueTechnologies, Inc. also sells ULTRASOFT, manufactured from tubular e-PTFE adapted for soft tissue augmentation of the facial area. ImplanTechAssociates offers BINDER SUBMALAR facial implants, BINDER SUBMALAR II FACIAL IMPLANT, TERINOMALAR SHELL, COMBINED SUBMALAR SHELL, FLOWERS TEAR TROUGH implants, Allied Biomedical offers solid silicon facial and cheek implants, WL Gore & Associates , Inc. has a variety of facial implants available, including Subcutaneous Augmentation Material (SAM) made from microporous ePTFE that supports rapid tissue contamination and molded TRIMENSIONAL 3-D Implants.

  These facial grafts can benefit from the release of the therapeutic agent and reduce scarring at the graft-tissue interface to minimize the incidence of fiber contractures. These facial implants are also effective in releasing therapeutic agents that prevent or reduce infection around the implant site. Transplantation of the face that is placed on the face for orthopedic or reconstructive purposes when the subject polymer composition, including an anti-scarring agent and / or anti-infective agent, infiltrates the implant site on the face or tissue adjacent to the implant site Capsular contracture in response to a piece can be reduced or prevented and / or infection around the implantation site can be prevented or reduced. Fibrosis inhibitors reduce the incidence of capsular contracture, asymmetry, skin fold formation, sclerosis, and repetitive surgical procedures (eg, incision, capsulectomy, corrective surgery and resection surgery), and patients with surgery Can improve satisfaction.

Regardless of the specific design function, for a facial implant to be effective in cosmetic or reconstructive surgery, the implant needs to be accurately placed in the body. Facial grafts may migrate after surgery, and it is important that the graft is properly attached to the underlying periosteum and bone tissue. Facial implants are described as having parallel and vertical groove grids on the back side facing the concave bone to promote tissue ingrowth. Facial graft misplacement (movement or migration after graft placement) can lead to asymmetry and is a major cause of patient dissatisfaction and corrective surgery. In one example, the lower surface of the facial implant (eg, the surface facing the periosteum and bone) is coated with a fiber-inducing agent or composition and another surface with an agent or composition that inhibits fiber formation ( Example: Surface facing skin and subcutaneous tissue). Such coating can be performed directly or by infiltration of the target polymer composition containing the desired drug into the tissue surrounding the desired surface, or a combination thereof. This example promotes fibrosis and colonization of the anatomical site where the facial implant is located (ie, facial implantation) while preventing complications associated with the coating on the surface of the implant. The advantage is that the piece is fixed to the underlying bone to prevent migration of the graft). Representative examples of drugs that promote fibrosis and are suitable for delivery from the lower (deep) face of facial implants include silk, wool, silka, bleomycin, neomycin, talcum powder, metal beryllium, calcium phosphate, calcium sulfate, calcium carbonate , Hydroxyapatite, copper, cytokines (eg cytokines are bone morphogenetic proteins, desalted bone matrix, TGFb, PDGF, VEGF, bFGF, TNFa, NGF, GM-CSF, IGF-1, IL-1-b, IL -8, selected from the group consisting of IL-6, and growth hormone), agents that stimulate cell proliferation (eg, agents that stimulate cell proliferation include dexamethasone, isotretinoin, 17-b estradiol, estradiol, 1- a-25 dihydroxyvitamin D ₃ , diethylstilbestrol, cyclosporin A, N (omega-nitro-L-arginine methyl ester (N (omega-nitro-L -Arginine methyl ester) and all retinoic acid (ATRA)) and their analogs and derivatives, instead of covering the lower surface of the facial implant with a composition containing a fibrosis promoter or In addition, the subject polymer composition containing the fiber inducer may infiltrate the tissue adjacent to the surface or space where the facial implant is juxtaposed to the underlying tissue (eg the surface of the periosteum). it can.

  In one embodiment, the present invention provides a facial implant comprising a subject polymer composition to be implanted in adjacent tissue, the polymer composition may comprise a therapeutic agent (a scarring inhibitor and / or an anti-cancer agent). Infectious drugs). Various polymeric and non-polymeric delivery systems for use with facial implants have already been described above.

  The polymeric compound directly and / or indirectly (a) tissue adjacent to the facial graft, (b) around the interface between the facial graft and tissue, (c) around the facial graft, ( d) When applied inside and / or on the tissue surrounding the facial implant, it may infiltrate around the implanted facial implant. Methods of infiltrating the target polymer composition into tissue adjacent to the facial implant include delivery of the polymer composition: (a) the surface of the facial implant during the implantation process (eg, injection material, paste) (B) on the tissue surface (eg injection material, paste, gel, in situ formed gel or mesh) immediately before or during implantation of the facial implant (c) Immediately after implantation of the facial implant, the facial implant and / or the surface of the tissue surrounding the implanted facial implant (eg, injection material, paste, gel, in situ formed gel or mesh), ( d) Topical application of the composition to the anatomical space in which the facial implant is placed (especially useful in this example is the use of a polymeric carrier that releases the therapeutic agent over a period ranging from hours to weeks). Is-liquid, suspension Emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and other formulations that release drugs and can be delivered to the site where the device is inserted), (e) facial implants (F) Application by a combination of the methods described above, by intradermal injection of the solution, infusion, and sustained release formulation into the tissue surrounding the piece. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the subject polymer composition can be wetted to the entire implant or to some surrounding tissue.

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the present invention, the subject polymer composition that invades the tissue adjacent to the facial implant inhibits one or more of the four general factors for the process of fibrosis (or scarring) comprising: Can be adapted to release: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), accumulation of extracellular matrix (ECM), and remodeling (Maturation and organization of fibrous tissue). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fibrosis according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Facial implants are formed from a variety of configurations and sizes, and the exact dosage will also vary depending on the implant size, surface area and design. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), the total drug dose administered can be measured, and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the surrounding tissue, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Drug scarring inhibitor dosage per unit area of the implant or tissue surface of a subject to be coated (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2, or about 1 μg / mm ² ~10 μg / mm ² or about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention will depend on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), the total drug dose administered can be measured, and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the surrounding tissue, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective drug per unit area of the graft or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² , or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

(3) Jaw and mandibular implants In one embodiment, the subject polymer composition can invade tissue adjacent to the jaw or mandible graft. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents). By moistening the polymer composition of interest to the tissue surrounding the implantation site, fiber contractures that occur in response to implantation for orthopedic or regenerative purposes can be minimized or prevented.

  Multiple jaw or mandibular implants can be used for cosmetic and reconstruction purposes. For example, the jaw implant is half-moon shaped, tapered symmetrically to form ends on both sides, and curved protrusions are placed on the outer lower jaw surface to form a natural jaw profile It may be a solid implant that enhances. See U.S. Pat. No. 4,344,191. The jaw implant may be a solid meniscus with a 45 degree axis of symmetry, which has a soft and lower durometer material at the tip of the jaw to stimulate the fat body. See US Pat. No. 5,195,951. The jaw implant may have a raised convex anterior surface with a concave posterior surface to match the irregular bone surface of the lower jaw, enhancing and providing a natural jaw profile. See U.S. Pat. No. 4,990,160. The heel graft may have a porous convex surface made of polytetrafluoroethylene with a void of sufficient size to allow soft tissue ingrowth, while the concave surface made of silicon is a bone tissue. Non-porous to substantially prevent ingrowth. See US Pat. No. 6,277,150.

  In accordance with the present invention, jaw or mandibular implants that are effective when the polymer composition of interest invades adjacent tissue also include commercially available products. Examples of commercially available jaw or mandibular implants include: Implant Tech Associates TELINO EXTENDED ANATOMICAL jaw implants, GLASGOLDWAFER, FLOWERS MANDIBULAR GLOVE, MITTELMAN PRE JOWL-CHIN, GLASGOLD WAFER implants and other models , And a solid silicone jaw implant by AlliedBiomedical.

  Reduction of scarring at the graft-tissue interface when the subject polymer composition, including an anti-scarring agent and / or an anti-infective agent, infiltrates the jaw or mandibular implantation site or the tissue adjacent to the site where the implantation takes place Thus, the occurrence of capsule contractures can be minimized and / or infection around the implantation site can be prevented or reduced. Minimizing fiber contracture that occurs in response to grafts placed on the jaw or mandible for orthopedic or reconstructive purposes by wetting the polymer composition of interest to the tissue surrounding the jaw or mandible implantation site, Can be prevented. Fibrosis inhibitors reduce the incidence of capsular contracture, asymmetry, skin fold formation, sclerosis, and repetitive surgical procedures (eg, incision, capsulectomy, corrective surgery and resection surgery), and patients with surgery Can improve satisfaction.

Regardless of the specific design function, in order for the jaw and mandibular implant to be effective in cosmetic or reconstructive surgery, the implant needs to be accurately placed in the face. Jaw and mandibular grafts may migrate after surgery, and it is important that the graft is properly attached to the underlying periosteum and bone tissue. Misplacement of the jaw and mandibular implants (movement or migration after implant placement) can lead to asymmetry and is a major cause of patient dissatisfaction and corrective surgery. In one embodiment, the lower surface of the jaw or mandibular implant (eg, the surface facing the periosteum and mandible) is coated with a fibrosis promoting agent or composition, separated by an agent or composition that inhibits fibrosis. A coating is applied to the surface (eg, the surface facing the skin and subcutaneous tissue). Such coating can be performed directly or by infiltration of the target polymer composition containing the desired drug into the tissue surrounding the desired surface, or a combination thereof. This example promotes fibrosis and colonization of the underlying jaw of the jaw or mandible while preventing complications associated with the coating on the surface of the graft (ie, graft-based It is fixed to the lower jaw to prevent migration). Representative examples of drugs that promote fibrosis and are suitable for delivery from the lower (deep) surface of the jaw or mandibular implant include silk, wool, silka, bleomycin, neomycin, talcum powder, metal beryllium, calcium phosphate, calcium sulfate, Calcium carbonate, hydroxyapatite, copper, inflammatory cytokines (eg, inflammatory cytokines include bone morphogenetic proteins, desalted bone matrix, TGFb, PDGF, VEGF, bFGF, TNFa, NGF, GM-CSF, IGF-1, IL -1-b, selected from the group consisting of IL-8, IL-6, and growth hormone), agents that stimulate cell proliferation (eg, agents that stimulate cell proliferation include dexamethasone, isotretinoin, 17-b estradiol, estradiol, 1-a-25-dihydroxyvitamin D _3, diethylstilbestrol, cyclosporin A, N (omega - nitro -L- arginine methyl es (Chosen from N (omega-nitro-L-arginine methyl ester) and all retinoic acid (ATRA)) and analogs and derivatives thereof. Jaw or mandible with composition containing fiber inducer As an alternative to or in addition to the coating on the underside of the graft, the target polymer composition containing the fiber inducer is placed around the surface or space (eg, periosteal surface) where the graft is juxtaposed to the underlying tissue Can invade any tissue.

  In one aspect, the present invention provides a jaw or mandibular implant comprising a subject polymer composition to be implanted in adjacent tissue, the polymer composition may include a therapeutic agent (an anti-scarring agent and / or Or antiinfectives). Various polymeric and non-polymeric delivery systems for use with jaw or mandibular implants have already been described above.

  The polymer compound directly and / or indirectly (a) tissue adjacent to the jaw or mandible graft, (b) around the interface between the jaw or mandible graft and tissue, (c) the jaw or mandible When applied to the perigraft site, (d) inside and / or above the tissue surrounding the jaw or mandible graft, it may infiltrate around the transplanted jaw or mandible graft. Methods of infiltrating the subject polymer composition into the tissue adjacent to the jaw or mandibular implant include delivery of the polymer composition: (a) the surface of the jaw or mandible graft during the implantation process (eg: (B) as a tissue surface (eg, injection material, paste, gel, in situ gel or mesh) immediately before or during implantation of the jaw or mandibular implant ) (C) Immediately after transplantation of the jaw or mandible graft, the surface of the tissue surrounding the jaw or mandible graft and / or the transplanted jaw or mandible graft (eg injection material, paste, gel, raw (D) topical application of the composition to the anatomical space where the jaw or mandibular implant is placed (especially useful in this example from hours to weeks) Over a long period Or the use of polymeric carriers that release therapeutic agents-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants, and drug release devices (F) by the intradermal injection of solutions, injections, and sustained release formulations into the tissue surrounding the jaw or mandibular implant, (f) Application by combination. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the subject polymer composition can be wetted to the entire implant or to some surrounding tissue.

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the present invention, a subject polymer composition that infiltrates tissue adjacent to a jaw or mandibular implant inhibits one or more of four general factors for the process of fibrosis (or scarring) including: Can be adapted to release drugs: new blood vessel formation (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), extracellular matrix (ECM) accumulation, and Remodeling (maturation and organization of fibrous tissue). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fibrosis according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Jaw or mandibular implants can be formed from a variety of configurations and sizes, and the exact dosage will also vary depending on the implant size, surface area and design. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), the total drug dose administered can be measured, and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the surrounding tissue, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Drug scarring inhibitor dosage per unit area of the implant or tissue surface of a subject to be coated (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2, or about 1 μg / mm ² ~10 μg / mm ² or about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention will depend on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), the total drug dose administered can be measured, and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the surrounding tissue, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective drug per unit area of the graft or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² , or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

(4) Nasal graft In one embodiment, the subject polymer composition can invade tissue adjacent to the nasal graft. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents). By moistening the polymer composition of interest to the tissue surrounding the implantation site, fiber contractures that occur in response to implantation for orthopedic or regenerative purposes can be minimized or prevented.

  A number of nasal implants are suitable for use in the practice of the present invention and can be used for the purposes of orthopedic and reconstructive surgery. For example, a nasal implant may be stretched and contoured on a concave surface on a selected side to define the end of a nasal muscle support that is adapted for placement on the nasal muscles to enhance the appearance and contour from the front. it can. See US Pat. No. 5,112,353. The nasal implant can be composed of substantially hard silicon, configured in an hourglass shape with soft silicon at the tip. See U.S. Pat. No. 5,030,232. The nasal implant is one selected from the group consisting of a main component that is an allyl acrylic hydrophobic monomer, a remaining material that is a crosslinkable monomer, and, optionally, an ultraviolet light absorbing component and a blue light absorbing component. It can consist essentially of a plurality of additional components. See US Pat. No. 6,528,602. The nasal implant can be composed of a hydrophilic synthetic cartilage material with pores randomly distributed in a size adjusted throughout the material for placement of fibrous tissue. See U.S. Pat. No. 4,912,141.

  In accordance with the present invention, nasal implants that are effective when the polymer composition of interest infiltrates adjacent tissue also include commercially available products. Examples of commercially available nasal grafts suitable for use in the practice of the present invention include Implant Tech Associates FLOWERS DORSAL, RIZZO DORSAL, SHIRAKABE, and DORSAL COLUMELLA nasal grafts and Allied Biomedical solid silicon nasal grafts. .

  These nasal grafts can benefit from the release of therapeutic agents and reduce scarring at the graft-tissue interface to minimize the incidence of fiber contractures. These nasal grafts are also effective in releasing therapeutic agents that prevent or reduce infection around the graft site. Implants placed in the nose for the purpose of shaping or reconstruction when the subject polymer composition comprising an anti-scarring agent and / or an anti-infective agent infiltrates the nasal implant site or tissue adjacent to the site where the transplant is performed Fiber contractures that respond to can be minimized or prevented. Fibrosis inhibitors reduce the incidence of capsular contracture, asymmetry, skin fold formation, sclerosis, and repetitive surgical procedures (eg, incision, capsulectomy, corrective surgery and resection surgery), and patients with surgery Can improve satisfaction.

Regardless of the specific design function, in order for a nasal implant to be effective in cosmetic or reconstructive surgery, the implant must be accurately placed in the face. Nasal grafts may migrate after surgery, and it is important that the graft is properly attached to the underlying cartilage and / or nasal bone tissue. Misplaced nasal grafts (movement or migration after graft placement) can lead to asymmetry, which is a major cause of patient dissatisfaction and corrective surgery. In one embodiment, the underside of the nasal implant (eg, the surface facing the nasal cartilage and / or bone) is coated with a fiber-inducing agent or composition and separated with an agent or composition that inhibits fibrosis. A coating is applied to the surface (eg, the surface facing the skin and subcutaneous tissue). Such coating can be performed directly or by infiltration of the target polymer composition containing the desired drug into the tissue surrounding the desired surface, or a combination thereof. This example promotes fibrosis and establishment of the nasal graft into the underlying nasal cartilage or bone while preventing complications associated with the coating on the surface of the graft (ie, transplantation). It has the advantage of preventing migration by fixing the piece to the underlying nasal cartilage or bone. Representative examples of drugs that promote fibrosis and are suitable for delivery from the lower (deep) surface of nasal implants include silk, wool, silka, bleomycin, neomycin, talcum powder, metal beryllium, calcium phosphate, calcium sulfate, calcium carbonate , Hydroxyapatite, copper, inflammatory cytokines (eg, inflammatory cytokines include bone morphogenetic protein, desalted bone matrix, TGFb, PDGF, VEGF, bFGF, TNFa, NGF, GM-CSF, IGF-1, IL-1 -b, selected from the group consisting of IL-8, IL-6, and growth hormone), agents that stimulate cell proliferation (eg, agents that stimulate cell proliferation include dexamethasone, isotretinoin, 17-b estradiol, Estradiol, 1-a-25 dihydroxyvitamin D ₃ , diethylstilbestrol, cyclosporin A, N (omega-nitro-L-arginine methyl ester (N (ome Ga-nitro-L-arginine methyl ester) and all retinoic acid (ATRA)) and their analogs and derivatives.In the lower surface of the nasal graft with a composition containing a fiber inducer As an alternative to or in addition to the coating, the subject polymer composition containing the fiber inducer is applied to the tissue around the surface or space where the graft is juxtaposed to the underlying tissue (eg, nasal cartilage or bone surface). Can infiltrate.

  In one embodiment, the present invention provides a nasal implant comprising a subject polymer composition to be implanted in adjacent tissue, the polymer composition may include a therapeutic agent (an anti-scarring agent and / or an anti-cancer agent). Infectious drugs). Various polymeric and non-polymeric delivery systems for use with nasal implants have already been described above.

  The polymeric compound directly and / or indirectly (a) tissue adjacent to the nasal graft, (b) around the interface between the nasal graft and tissue, (c) around the nasal graft, ( d) When applied inside and / or on the tissue surrounding the nasal graft, it may infiltrate around the transplanted nasal graft. Methods of infiltrating the polymer composition of interest into the tissue adjacent to the nasal implant include delivery of the polymer composition: (a) the surface of the nasal implant during the implantation process (eg, injection material, paste) (B) on the tissue surface (eg as injection material, paste, gel, gel or mesh formed in situ) immediately before or during implantation of the nasal implant, (c) Immediately after implantation of the nasal implant, on the surface of the nasal implant and / or the tissue surrounding the implanted nasal implant (eg, injection material, paste, gel, gel or mesh formed in situ), ( d) Topical application of the composition to the anatomical space in which the nasal implant is placed (especially useful in this example is the use of a polymeric carrier that releases the therapeutic agent over a period ranging from hours to weeks). -Liquid, suspension, emulsion, my Microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and other formulations that release drugs and can be delivered to the site where the device is inserted), (e) tissue surrounding the nasal implant (F) Application by a combination of the methods described above, by intradermal injection of solutions, infusions, and sustained release formulations. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the subject polymer composition can be wetted to the entire implant or to some surrounding tissue.

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the present invention, the subject polymer composition that invades the tissue adjacent to the nasal graft inhibits one or more of the four general factors for the process of fibrosis (or scarring) comprising: Can be adapted to release: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), accumulation of extracellular matrix (ECM), and remodeling (Maturation and organization of fibrous tissue). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fibrosis according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Nasal implants are formed from a variety of configurations and sizes, and the exact dosage varies depending on the implant size, surface area and design. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), the total drug dose administered can be measured, and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the surrounding tissue, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Drug scarring inhibitor dosage per unit area of the implant or tissue surface of a subject to be coated (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2, or about 1 μg / mm ² ~10 μg / mm ² or about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention will depend on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), the total drug dose administered can be measured, and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the surrounding tissue, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective drug per unit area of the graft or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² , or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

(5) Lip grafts In one embodiment, the subject polymer composition can invade tissue adjacent to the lip graft. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents). By moistening the polymer composition of interest to the tissue surrounding the implantation site, fiber contractures that occur in response to implantation for orthopedic or regenerative purposes can be minimized or prevented.

  There are numerous lip grafts that can be used for cosmetic and reconstruction purposes. For example, lip grafts are non-biodegradable, expanded and fibrillated polytetrafluoro, where the internal cavity expands in the longitudinal direction, resulting in the implantation of fibrous tissue to enhance soft tissue It can be composed of ethylene. See U.S. Pat. Nos. 5,941,910 and 5,607,477. The lip graft can be composed of flexible, malleable, elastic, non-absorbable artificial particles with a rough, irregularly textured surface, which is non-retaining and compatible Dispersed in physiological mediators. See US Pat. No. 5,571,182.

  In accordance with the present invention, lip grafts that are effective when the polymer composition of interest infiltrates adjacent tissue include commercially available products. Commercially available lip grafts suitable for use in the practice of the present invention include SOFTFORM from Tissue Technologies, Inc. (San Francisco, Calif.), A tubular design made of synthetic ePTFE, and Life Cell Corporation (Branchburg, NJ). The ALLODERM sheet (Allograft Dermal Matrix Grafts) sold can also be used as a lip augmentation implant. ALLODERM sheet is very soft and easily strengthens the lips in a diffusing manner. W.L.Gore and Associates (Newark, Delaware) sells secure implantable threads that can also be used for lip grafts.

  When the subject polymer composition, including an anti-scarring agent and / or anti-infective agent, infiltrates the tissue adjacent to the transplantation site of the lip or the site where the transplantation takes place, it reduces the scarring at the graft-tissue interface. The occurrence of capsule contractures can be minimized and / or infection around the implantation site can be prevented or reduced. Minimizing or preventing fiber contracture that occurs in response to a graft placed on the lips for shaping or reconstruction purposes by wetting the targeted polymer composition to the tissue surrounding the graft site Can do. Fibrosis inhibitors can reduce the incidence of asymmetry, skin depression, hardening and repeated treatment, and improve patient satisfaction with the treatment.

Within one embodiment of the present invention, the lip graft is coated with a composition that inhibits fiber formation in one aspect, and in another aspect, a composition that promotes ingrowth of fibrous tissue. The coating is applied with a product or compound. Such coating can be performed directly or by infiltration of the target polymer composition containing the desired drug into the tissue surrounding the desired surface, or a combination thereof. This embodiment has the advantage of facilitating fiber formation and colonization of the lip graft to adjacent tissue while preventing complications associated with fiber coating on the surface of the graft. Representative examples of drugs that promote fibrosis and are suitable for delivery from the lower (deep) surface of lip grafts are silk, wool, silka, bleomycin, neomycin, talcum powder, metal beryllium, calcium phosphate, calcium sulfate, calcium carbonate , Hydroxyapatite, copper, inflammatory cytokines (eg, inflammatory cytokines include bone morphogenetic protein, desalted bone matrix, TGFb, PDGF, VEGF, bFGF, TNFa, NGF, GM-CSF, IGF-1, IL-1 -b, selected from the group consisting of IL-8, IL-6, and growth hormone), agents that stimulate cell proliferation (eg, agents that stimulate cell proliferation include dexamethasone, isotretinoin, 17-b estradiol, Estradiol, 1-a-25 dihydroxyvitamin D ₃ , diethylstilbestrol, cyclosporin A, N (omega-nitro-L-arginine methyl ester (N Ga-nitro-L-arginine methyl ester) and all retinoic acid (ATRA)) and analogs and derivatives thereof.Including lip grafts with subject polymer compositions containing fiber inducers As an alternative to or in addition to the underside coating, the composition containing the fiber inducer can be injected directly into the lips on which the implant is placed.

  In one aspect, the present invention provides a lip graft comprising a subject polymer composition to be implanted in adjacent tissue, the polymer composition may comprise a therapeutic agent (an anti-scarring agent and / or an anti-cancer agent). Infectious drugs). Various polymeric and non-polymeric delivery systems for use with lip grafts have already been described above.

  The polymer compound directly and / or indirectly (a) tissue adjacent to the lip graft, (b) around the interface between the lip graft and tissue, (c) around the lip graft, ( d) When applied inside and / or on the tissue surrounding the lip graft, it may infiltrate around the transplanted lip graft. Methods of infiltrating the targeted polymer composition into the tissue adjacent to the lip graft include delivery of the polymer composition: (a) The surface of the lip graft during the implantation process (eg, injection material, paste) (B) on the tissue surface (eg as injection material, paste, gel, gel or mesh formed in situ) immediately before or during transplantation of the lip graft (c) Immediately after transplantation of the lip graft, the lip graft and / or the surface of the tissue surrounding the transplanted lip graft (eg injection material, paste, gel, gel or mesh formed in situ) ( d) Topical application of the composition to the anatomical space in which the lip graft is placed (especially useful in this example is the use of a polymeric carrier that releases the therapeutic agent over a period ranging from hours to weeks. -Liquid, suspension, emulsion, my Microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and other formulations that release drugs and can be delivered to the site where the device is inserted), (e) tissue surrounding the lip implant (F) Application by a combination of the methods described above, by intradermal injection of solutions, infusions, and sustained release formulations. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the subject polymer composition can be wetted to the entire implant or to some surrounding tissue.

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the invention, the subject polymer composition that infiltrates the tissue adjacent to the lip graft is an agent that inhibits one or more of the four general factors for the process of fibrosis (or scarring) comprising: Can be adapted to release: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), accumulation of extracellular matrix (ECM), and remodeling (Maturation and organization of fibrous tissue). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fibrosis according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Lip implants are formed from a variety of configurations and sizes, and the exact dosage varies depending on the implant size, surface area and design. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), the total drug dose administered can be measured, and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the surrounding tissue, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Drug scarring inhibitor dosage per unit area of the implant or tissue surface of a subject to be coated (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2, or about 1 μg / mm ² ~10 μg / mm ² or about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention will depend on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), the total drug dose administered can be measured, and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the surrounding tissue, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective drug per unit area of the graft or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² , or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

(6) Pectoral muscle graft In one embodiment, the subject polymer composition can invade tissue adjacent to the pectoral muscle graft. The subject polymer compositions may include therapeutic agents (such as anti-scarring agents and / or anti-infective agents). By moistening the polymer composition of interest to the tissue surrounding the implantation site, fiber contractures that occur in response to implantation for orthopedic or regenerative purposes can be minimized or prevented.

  There are a large number of pectoral muscle grafts that can be used for shaping and reconstruction purposes in combination with fibrosis inhibitors. For example, a pectoral muscle implant can be composed of a single square body having a slightly concave cross-section that divides into sections at the end face. See U.S. Pat. No. 5,112,352. The pectoral muscle implant can consist of a hollow shell formed from a flexible elastomeric envelope filled with gel or viscous liquid containing polyacrylamide and polyacrylamide derivatives. See US Pat. No. 5,658,329.

  In accordance with the present invention, pectoral muscle grafts that are effective when the polymer composition of interest infiltrates adjacent tissue also include commercially available products. Commercially available pectoral muscle grafts suitable for use in the present invention include Allied Biomedical's solid silicon grafts. These pectoral muscle grafts can benefit from the release of therapeutic agents and can reduce scarring at the graft-tissue interface to minimize the incidence of fiber contractures. The release of therapeutic agents that prevent or reduce infection around the transplant site is also effective for these pectoral muscle grafts.

As described above, graft placement mistakes (graft movement or migration after placement) can lead to various complications such as asymmetry, which is a major cause of patient dissatisfaction and corrective surgery. In one embodiment, the lower surface of the pectoral muscle graft (eg, the surface facing the chest wall) is coated with a fibrosis promoter or composition and another surface (with an agent or composition that inhibits fibrosis) ( Example: Surface facing the pectoral muscle). Such coating can be performed directly or by infiltration of the target polymer composition containing the desired drug into the tissue surrounding the desired surface, or a combination thereof. This example promotes fibrosis and colonization at the anatomical site where the pectoral muscle graft is placed while preventing complications associated with the coating on the surface of the pectoral muscle graft ( That is, there is an advantage that the pectoral muscle graft is fixed in the space below the pectoral muscle to prevent migration of the graft. Representative examples of drugs that promote fibrosis and are suitable for delivery from the lower (deep) side of the pectoral muscle graft include silk, wool, silka, bleomycin, neomycin, talcum powder, metal beryllium, calcium phosphate, calcium sulfate, carbonate Calcium, hydroxyapatite, copper, cytokines (eg, cytokines are bone morphogenetic proteins, desalted bone matrix, TGFb, PDGF, VEGF, bFGF, TNFa, NGF, GM-CSF, IGF-1, IL-1-b, Selected from the group consisting of IL-8, IL-6, and growth hormone), agents that stimulate cell proliferation (eg, agents that stimulate cell proliferation include dexamethasone, isotretinoin, 17-b estradiol, estradiol, 1 -a-25-dihydroxyvitamin D _3, diethylstilbestrol, cyclosporin a, N (omega - nitro -L- arginine methyl ester) and all records It is selected from Noin acid (ATRA)) as well as analogs and derivatives thereof. As an alternative to or in addition to coating the lower surface with a composition containing a fibrosis promoter, the space in which the subject polymer composition containing the fiber inducer is juxtaposed to the underlying tissue of the pectoral muscle graft Infiltrate the tissue adjacent to the base of the pocket under the pectoral muscle made by surgery.

  In one embodiment, the present invention provides a pectoral muscle graft comprising a subject polymer composition to be implanted in adjacent tissue, the polymer composition may comprise a therapeutic agent (a scarring inhibitor and / or Anti-infectives). Various polymeric and non-polymeric delivery systems for use with pectoral muscle grafts have already been described above.

  Polymeric compounds directly and / or indirectly (a) tissue adjacent to the pectoral muscle graft, (b) around the pectoral muscle graft-tissue interface, (c) around the pectoral muscle graft Site, (d) When applied inside and / or on tissue surrounding the pectoral muscle graft, it may infiltrate around the transplanted pectoral muscle graft. Methods of infiltrating the tissue adjacent to the pectoral muscle graft with the polymer composition of interest include delivery of the polymer composition: (a) The surface of the pectoral muscle graft during the implantation process (eg, injection material) (B) as a paste, gel or mesh), (b) on the tissue surface (eg as injection material, paste, gel, gel or mesh formed in situ) immediately before or during implantation of the pectoral muscle graft (c) Immediately after implantation of the pectoral muscle graft, the surface of the tissue surrounding the pectoral muscle graft and / or the transplanted pectoral muscle graft (eg injection material, paste, gel, gel formed in situ) Or mesh) (d) Topical application of the composition to the anatomical space where the pectoral muscle graft is placed (especially useful in this example is the release of the therapeutic agent over a period ranging from hours to weeks) Is the use of polymeric carriers-liquids, suspensions Emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants and other formulations that release the drug and can be delivered to the site where the device is inserted), (e) pectoral muscle (F) Application by a combination of the methods described above, by intradermal injection of the solution, infusion, and sustained release formulation into the tissue surrounding the implant. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the subject polymer composition can be wetted to the entire implant or to some surrounding tissue.

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one embodiment of the present invention, a subject polymer composition that invades tissue adjacent to a pectoral muscle graft inhibits one or more of four general factors for the process of fibrosis (or scarring), including: Can be adapted to release drugs: formation of new blood vessels (angiogenesis), migration and proliferation of connective tissue cells (such as fibroblasts and smooth muscle cells), accumulation of extracellular matrix (ECM), and regeneration Formation (maturation and organization of fibrous tissue). Suppressing one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) Inosine monophosphate dehydrogenase inhibitors (mycophenolic acid, 1-α-25 dihydroxyvitamin D ₃ etc.), (H) NF κ B inhibitors (Bay11-7082, etc.) ), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives as described above.

  The dosage of drug administered from the composition to prevent or inhibit fibrosis according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. The pectoral muscle implants are formed from a variety of configurations and sizes, and the exact dosage varies depending on the implant size, surface area and design. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), the total drug dose administered can be measured, and the appropriate surface concentration of the active drug can be determined . Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the surrounding tissue, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Drug scarring inhibitor dosage per unit area of the implant or tissue surface of a subject to be coated (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2, or about 1 μg / mm ² ~10 μg / mm ² or about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention will depend on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit area (of the treatment site), the total drug dose administered can be measured, and the appropriate surface concentration of the active drug can be determined . Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the surrounding tissue, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective drug per unit area of the graft or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² , or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

(7) Autologous tissue graft In one embodiment, the subject polymer composition can infiltrate the surrounding tissue of the autologous tissue graft. The subject polymer compositions can include therapeutic agents (such as anti-scarring agents and / or anti-infective agents). Autologous tissue grafts include, but are not limited to, adipose tissue, autologous fat grafts, skin grafts, skin or tissue plugs, muscle tissue flaps, and cell extraction grafts. Adipose tissue grafts are also known as autologous fat grafts, fat grafts, free fat migration / transport, skin fat grafts, liposculptures, lipostructures, lip thickness repair, micro fat injection and fat injection .

  Autologous tissue grafts have been used for many years to augment soft tissue in cosmetic and reconstructive surgery. Autologous tissue grafts, for example, enlarge soft tissue sites (eg breast augmentation or penis enhancement), minimize facial scars (eg acne scars), improve facial size due to disease (eg unilateral facial atrophy) It can also be used to minimize facial aging (eg wrinkles) such as cheek dandruff and facial lines. These injectable autologous tissue grafts are biocompatible, versatile, stable, durable and natural in appearance. For autologous tissue grafts, tissue or cells are removed from one area of the body (eg, excess fat from the chest or thigh) and then reimplanted to another area of the body that needs to be reconstructed or augmented. A simple procedure is involved. The self-organization is soft and has a natural feel. Autologous soft tissue grafts can be composed of a variety of connective tissues including, but not limited to, fat or fat, skin tissue, fibroblasts, muscle tissue or other connective tissue and related cells. Autologous tissue grafts are introduced to correct a variety of defects, are not immunogenic, are readily available, and are inexpensive.

  In one embodiment, the autologous tissue graft can be composed of fat or fat. Extraction and transplantation of adipose tissue involves liposuction from the subcutaneous layer, usually aspiration of chest wall fat by a method called a suction syringe, and then injected into the subcutaneous tissue covering the recess formation. Autologous fat is commonly used as a filler for body surface depressions (eg, physical defects or cosmetic purposes) or to protect other tissues (eg, nerve root protection after surgery) in use. Fat grafts can also be used for body bumps that require soft tissue padding to prevent sensitivity to pressure. In the absence of fat padding, the overlying skin can adhere to the bones, leading to discomfort and even pain, such as ribs or spines at the plantar site of the ribs. Occurs when it occurs (also known as periosteumitis). In this case, the fat graft may be a necessary padding inclusion between the bone and the skin. For example, US Pat. No. 5,681,561 describes an autologous fat graft containing anabolic hormones, amino acids, vitamins and inorganic ions that improve the survival rate of adipocytes once transplanted into the body.

  In another embodiment, the autologous graft consists of a pedunculated flap usually derived from the back (eg, latissimus muscle flap) or abdomen (eg, rectus abdominis muscle flap or TRAM flap) can do. The pedunculated flap may also originate from the buttocks, thighs or groin. These flaps are isolated from the body and then transplanted by reattaching the blood vessels using a microscopic procedure. These muscle tissue flaps are most often used in closure and reconstruction surgery after mastectomy. Some of the other common closure applications for muscle tissue flaps include defects made by covering the defect in the head and neck, especially major head and neck cancers, and further applications include There is a chest wall covering other than deformity due to mastectomy. The latissimus dorsi muscle can also be used as a reverse flap, based on the lumbar penetrating branch, to close a congenital defect of the spine, such as a spina bifida or meningocele. For example, US Pat. No. 5,765,567 describes a method using autologous tissue grafts in the form of tissue flaps with skin islands that can be used for contouring or augmentation for breast tissue reconstruction. The tissue flap may be a free flap or a flap attached via a natural vascular stem.

  In another aspect, the autologous tissue graft may be a suspension of autologous skin fibroblasts that can be used to provide cosmetic enhancement. See U.S. Pat. Nos. 5,858,390, 5,665,372, and 5,591,444. This US patent describes a method for correcting cosmetic and aesthetic skin defects by injection of autologous skin fibroblasts into the dermis or subcutaneous tissue adjacent to the defect. Typical defects that can be corrected by this method include wrinkle resection, striatum, depressed scar, atraumatic skin depression, acne vulgaris, and lip dysplasia. The injected fibroblasts are those that are histocompatible with the subject and expanded by passage through the cell culture system for a period of time in a protein-free medium.

  In another embodiment, the autologous tissue graft is supplied with laser light to isolate the epidermal layer, thereby exposing the dermis and inserting the dermal plug into the facial skin indentation site before providing the donor's The dermal plug collected from the skin may be used. See US Pat. No. 5,817,090. This autologous tissue graft can be used to treat acne scars and facial skin depressions such as wrinkles. Skin grafts can also be used to correct skin depressions where the epidermis has been removed by exfoliation.

  Like other types of synthetic grafts (described above), autologous tissue grafts also tend to migrate, extrude, infect, and can cause painful deformed capsule contractures. Incorporation of the subject polymer composition containing a therapeutic agent (a scarring inhibitor and / or anti-infection) into the adjacent tissue at the site where the autograft is present or transplanted, for cosmetic or reconstructive purposes The fiber contracture in response to the autologous tissue graft placed in can be minimized or prevented, and infection near the transplant site can be prevented or prevented.

  These autologous tissue grafts can benefit from the release of therapeutic agents and reduce scarring at the graft-tissue interface to minimize fiber contracture. These autologous tissue grafts can also benefit from the release of therapeutic agents that prevent or prevent infectivity around the transplant site. In one aspect, the present invention provides an autologous tissue graft that infiltrates a subject polymer composition into adjacent tissues, wherein the subject polymer composition includes a therapeutic agent (an anti-scarring agent and / or an anti-infective agent). Can be included. A number of polymeric or non-polymeric delivery systems have been described above for use in connection with autologous tissue grafts.

  The polymer composition consists of (a) tissue adjacent to the autologous tissue graft, (b) near the interface between the autologous tissue graft and tissue, (c) the peripheral site of the autologous tissue graft, (d) the autologous tissue graft. By applying the composition directly and / or indirectly in and / or on the surrounding tissue, it can infiltrate around the transplanted autologous tissue graft. Methods of infiltrating the subject polymer composition into adjacent tissue of the autologous graft include delivery of the following polymer composition. (a) on the surface of the autologous tissue graft during the transplantation procedure (eg as injection material, paste, gel or mesh), (b) on the tissue surface (eg, injection) just before or during transplantation of the autologous tissue graft Substance, paste, gel, as an in-situ formed gel or mesh), (c) Immediately after transplantation of the autograft, the autograft and / or the tissue surrounding the graft (eg injection material, paste, (D) Topical application of the composition to the anatomical space where the autologous tissue graft is placed (especially useful in this example from a few hours) The use of polymeric carriers that release therapeutic agents over a period of several weeks-liquids, suspensions, emulsions, microemulsions, microspheres, pastes, gels, microparticles, sprays, aerosols, solid implants, and medicine Other formulations that can be delivered to the site where the graft is inserted), (e) by intradermal injection of solutions, infusions, and sustained release formulations into the tissue surrounding the autologous tissue graft (f) Application by a combination of methods. Combination therapy (ie, therapeutic combinations and antithrombotic or antiplatelet drugs) can also be used. In all cases, it is understood that the subject polymer composition can be wetted to the entire implant or to some surrounding tissue.

  According to one embodiment, any of the fiber formation inhibitors and / or anti-infectives described above can be used in the practice of the present invention. In one aspect of the invention, the subject polymer composition infiltrating adjacent tissue of the autologous tissue graft inhibits one or more of four general factors for the process of fiber formation (or scarring), including: Can be adapted to release drugs: formation of new defects (angiogenesis), migration and proliferation of connective tissue cells (fibroblasts and smooth muscle cells), accumulation of extracellular matrix (ECM), and remodeling (Maturation and organization of fibrous tissue). Suppression of one or more of the elements that make up fibrosis (or scarring) can inhibit or reduce granulation tissue overgrowth.

Examples of fiber formation inhibitors used in the present invention include: (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) taxanes (such as paclitaxel, TAXOTERE and docetaxel), (C) pods In addition to cell cycle inhibitors such as phylotoxins (such as etoposide), (D) immunomodulators (such as sirolimus, everolimus, tacrolimus), (E) heat shock protein 90 antagonists (such as geldanamycin), (F) HMGCoA reductase Inhibitors (simvastatin, etc.), (G) inosine monophosphate dehydrogenase inhibitors (such as mykonofemicophenolic acid, 1-α-25 dihydroxyvitamin D ₃ ), (H) NF κ B inhibitors (Bay11 -7082), (I) antifungal agents (such as sulconizole), and (J) p38 MAP kinase inhibitors (SB202190) and analogs and derivatives thereof.

  The dosage of drug administered from the composition to prevent or inhibit fiber formation according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. Autologous tissue grafts are composed of a variety of configurations and sizes, and the exact dosage will also vary depending on the size, surface area and design of the implant. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site) and the total administered drug dose can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are generally used at concentrations ranging from several times the concentration used in single chemotherapeutic systemic applications up to 50%, 20%, 10%, 5%, or even less than 1% Is done. In certain embodiments, the anti-scarring agent is released from an effective concentration of the polymer composition for a period of time that can be measured from the time of infiltration into the surrounding tissue, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

Typical fiber formation inhibitors used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-scarring agent of the composition is about 0.01 μg to 10 μg, or about 10 μg to 10 mg, or about 10 mg to 250 mg, or about 250 mg to 1000 mg, or about 1000 mg to It can be in the range of 2500 mg. Drug transplantation or per unit area scarring inhibitor administration of tissue surface of a subject to be coated (amount) is from about ^{0.01 μg / mm 2 ~1μg / mm} 2 , or about ^{1 μg / mm 2 ~10 μg /} mm 2, or it may be about ^{10 μg / mm 2 ~250μg / mm} 2 or about ^{250 μg / mm 2 ~1000 μg /} mm 2 , or about ^{1000 μg / mm 2 ~2500μg / mm} 2,,.

  According to another aspect, all of the anti-infective agents described above may be used in the practice of the present invention. (A) anthracyclines (such as doxorubicin and mitoxantrone), (B) fluoropyrimidines (such as 5-FU), (C) folic acid antagonists (such as methotrexate), (D) podophyllotoxins (such as etoposide), ( Examples of anti-infectives include E) camptothecin, (F) hydroxyurea, and (G) platinum complexes (such as cisplatin).

  The dosage of drug administered from the composition to prevent or inhibit infection according to the present invention depends on a variety of factors including the type of formulation, the location of the treatment site, and the condition after treatment. However, certain principles can be applied when applying this technique. The drug dose can be calculated as a function of the dose per unit volume (of the treatment site) and the total administered drug dose can be measured and the appropriate surface concentration of the active drug can be determined. Drugs are commonly used at concentrations ranging from several times the concentration used for systemic administration in a single anti-infection to less than 50%, 20%, 10%, 5%, or even 1%. The In certain embodiments, the anti-infective is released from an effective concentration of the polymer composition for a period of time, which can be measured from the time of infiltration into the surrounding tissue, the range extending from less than 1 day to about 180 days. Generally, the release period is less than about 1 day to about 180 days, about 7 days to about 14 days, about 14 days to about 28 days, about 28 days to about 56 days, about 56 days to about 90 days, It ranges from about 90 days to about 180 days.

A typical anti-infective agent used alone or in combination should be administered according to the following administration guidelines. The total amount (administration) of the anti-infective agent of the composition is about 0.01 μg to 1 μg, or about 1 μg to 10 μg, or about 10 μg to 1 mg, or about 1 mg to 10 mg, or about 10 mg to It can range from 100 mg, or from about 100 mg to 250 mg, or from about 250 mg to 1000 mg. The dose of anti-infective agent per unit area of the transplant or tissue surface to which the drug is applied is about 0.01 μg / mm ² to 1 μg / mm ² , or about 1 μg / mm ² to 10 μg / mm ² Or about 10 μg / mm ^{2 to} 100 μg / mm ² , or about 100 μg / mm ² to 250 μg / mm ² , or about 250 μg / mm ^{2 to} 1000 μg / mm ² . Because different polymer compositions release anti-infective agents at different rates, the above dosage parameters are utilized in combination with the rate of drug release from the composition, with a minimum concentration of about 10 ⁻⁸ to 10 ⁻⁷ , Or about 10 ⁻⁷ to 10 ⁻⁶ , or about 10 ⁻⁶ to 10 ⁻⁵ , or about 10 ⁻⁵ to 10 ⁻⁴ of the drug should be maintained on the tissue surface.

  Based on the discussion provided in this document, anthracyclines (eg, doxorubicin or mitoxantrone), fluoropyrimidines (eg, 5-fluorouracil), folic acid antagonists (eg, methotrexate and / or podophyllotoxin (etoposide) are: It should be immediately apparent that it can be used to enhance the antibacterial action of the composition.

  A number of examples of soft tissue grafts have been described above, all of which have similar design features and are responsible for undesirable similar tissue reactions after transplantation and introduce or facilitate infection in the area of the transplant site there is a possibility. For those skilled in the art, not only commercially available soft tissue grafts not specifically cited herein, but also next generation and / or future developed commercially available soft tissue graft products are expected to be used in accordance with the present invention, It must also be clear that it is suitable for its use. The aesthetic implant should be placed with extremely high accuracy to ensure that the augmentation has been performed at the correct anatomical location in the body. These devices may cause all or part of the aesthetic graft to migrate after surgery, excessive scar tissue growth may occur around the graft, and / or infection may occur near the graft site. May lead to performance degradation. Soft tissue grafts that infiltrate the polymer composition of interest within the tissue adjacent to the graft-tissue interface can be used to increase the effectiveness and / or duration of activity of the graft. Soft tissue grafts can also benefit from the release of therapeutic agents that can prevent or prevent infectivity around the transplant site. In one embodiment, the present invention provides a soft tissue graft that infiltrates a subject polymer composition into adjacent tissues, and a therapeutic agent (such as an anti-scarring agent and / or an anti-infective agent) is applied to the subject polymer composition. Can be included. A number of polymeric or non-polymeric delivery systems for use with soft tissue grafts have been described above. These compositions can further include one or more fiber formation inhibitors such that granulation overgrowth or fibrous tissue is inhibited or reduced, and / or infection is inhibited or prevented. One or more anti-infectives can be included.

The present invention, in various aspects and examples, provides the following medical device implantation methods:
1. Medical device In one aspect, the present invention provides a method for implanting a medical device comprising: (a) a medical device comprising: i) a fiber formation inhibitor, ii) an anti-infective agent, iii) a polymer. Iv) a composition comprising a fiber formation inhibitor and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising a fiber formation inhibitor, an anti-infective agent and a polymer. Or tissue infiltration of the transplanted host, and (b) implantation of the medical device into the host.

  Optionally, in another aspect, the following is provided: A method of implanting a medical device comprising: (a) Tissue invasion of a host in which the medical device is implanted or implanted with a fibrosis inhibitor And (b) Medical tissue transplantation into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with an anti-infective agent, and (b) medical tissue transplantation into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a polymer; and (b) medical tissue transplantation into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising a fiber formation inhibitor and a polymer, and (b) medical tissue to the host Transplant. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer, and (b) medical tissue transplantation into the host . A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with a composition comprising a fibrogenesis inhibitor / anti-infective and a polymer; and (b) a host. Medical tissue transplantation.

  For each of the above-described aspects, the invention can be defined with respect to the use of the apparatus according to the inventive method, using one or more (for example, any two) of the following features. The device is an intravascular device. The device is a gastrointestinal stent. The device is a tracheal and bronchial stent. The device is a urogenital stent. The device is an otolaryngeal stent. The device is an ear ventilation device. The device is an intraocular implant. The device is a vascular graft. The device consists of a film or mesh. The device is a glaucoma drainage device. The device is a prosthetic heart valve or a composition thereof. The device is a penile graft. The device is an endotracheal tube or a tracheal cannula. The device is a peritoneal dialysis catheter. The device is a central nervous system shunt or pressure monitoring device. The device is an inferior vena cava filter. The device is a gastrointestinal device. The device is a central venous catheter. The device is an auxiliary artificial heart. The device is a spinal implant. The device is an implantable electrical device. The device is an implantable sensor. The device is an implantable pump. And / or the device is a soft tissue graft.

2. Intravascular device In another aspect, the present invention provides a method for implanting a medical device comprising: (a) a medical device comprising: i) a fibrosis inhibitor; ii) an anti-infective agent; with iii) a polymer, iv) a composition comprising a fiber formation inhibitor and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising a fiber formation inhibitor, an anti-infective agent and a polymer. Tissue infiltration of the transplanted or transplanted host, and (b) implantation of the medical device into the host (where the medical device is an intravascular device).

  Optionally, in another aspect, the following is provided: A method of implanting a medical device comprising: (a) Tissue invasion of a host in which the medical device is implanted or implanted with a fibrosis inhibitor And (b) Medical tissue transplantation into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with an anti-infective agent, and (b) medical tissue transplantation into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a polymer; and (b) medical tissue transplantation into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising a fiber formation inhibitor and a polymer, and (b) medical tissue to the host Transplant. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer, and (b) medical tissue transplantation into the host . A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with a composition comprising a fibrogenesis inhibitor / anti-infective and a polymer; and (b) a host. Medical tissue transplantation.

  For each of the above-described aspects, the invention can be defined with respect to the use of the apparatus according to the inventive method, using one or more (for example, any two) of the following features. The medical device is a catheter. The medical device is a balloon catheter. The medical device is a balloon. The medical device is a stent graft. The medical device is a guide wire. The medical device is a stent. The medical device is an intravascular stent. The medical device is a metal stent. The medical device is a polymer stent. The medical device is a biodegradable stent. The medical device is a non-biodegradable stent. The medical device is a self-expanding stent. The medical device is a balloon expandable stent. The medical device is a coated stent. The medical device is a drug eluting stent. The medical device is a stent made of a radiopaque material. The medical device is a stent made of a sound wave generating material. The medical device is a stent made of an MRI reactive material. The medical device is a connecting device by anastomosis. The medical device is a connecting device using arterial-to-arterial anastomosis. The medical device is a connecting device by venous to arterial anastomosis. The medical device is an arterial-venous anastomosis connecting device. The medical device is an arterial pair synthetic graft anastomosis coupling device. The medical device is a connecting device using synthetic graft versus arterial anastomosis. The medical device is a connecting device by vein-to-synthetic graft anastomosis. The medical device is a connecting device by synthetic graft vs. venous anastomosis. The medical device is a vascular clip. The medical device is a vascular suture. The medical device is a vascular clamp. The medical device is a suturing device. The medical device is an anastomotic coupler. The medical device is an automatic or correction suturing device. The medical device is a connecting device by micromechanical anastomosis. The medical device is an anastomosis coupling device that promotes automatic coupling of a graft or blood vessel to a hole or orifice in a target blood vessel without using sutures or staples. The medical device is an anastomotic coupling device that consists of a tubular graft conduit and can be placed on the side wall of the target vessel so that the tubular graft conduit can extend from the target vessel. The medical device is an anastomotic coupler in the form of a frame. The medical device is a ring-shaped anastomotic coupler. The medical device is a resorbable anastomotic coupling device. The medical device is an anastomotic coupler made of a bioabsorbable elastomeric material. The medical device is an anastomotic coupler adapted to connect a first blood vessel to a second blood vessel with a graft vessel. The medical device is an anastomotic coupler adapted to join a first blood vessel to a second blood vessel without a graft blood vessel. The medical device is an anastomotic coupler that is incorporated into the design of the vascular graft. The medical device is an anastomotic coupler consisting of a graft that incorporates a fixation mechanism. The medical device is an anastomotic coupler consisting of a compressible and expandable fitting for securing the end of the bypass graft to two blood vessels. The medical device is an anastomotic coupler consisting of a pair of connecting disc members for connecting two blood vessels in an end-to-end manner. The medical device is a proximal aortic coupling device. The medical device is a distal coronary artery coupling device. The medical device is a bypass device made of a biocompatible material. The medical device is a bypass device made at least in part of a metal or metal alloy. The medical device is a bypass device made at least in part of a synthetic polymer. The medical device is a bypass device made at least in part of a naturally derived polymer. The medical device is a tubular anastomotic coupler consisting of a tubular structure that can be directly coupled to a proximal blood vessel. The medical device is a tubular anastomotic coupler consisting of a tubular structure that can be directly coupled to a distal blood vessel. The medical device is a tubular anastomotic coupler with a proximal end coupled to the proximal vessel and a distal end coupled to the bypass graft. The medical device is a tubular anastomotic coupler with a proximal end coupled to a graft vessel that secures to a proximal vessel and a distal end coupled to a distal vessel. The medical device is a connecting device by anastomosis adapted to an end-to-end anastomosis procedure. The medical device is an anastomotic stent. The medical device is an anastomosis sleeve. The medical device is an anastomosis connecting device adapted for an end-side anastomosis procedure. The medical device is a single lumen bypass device. The medical device is a multi-lumen bypass device. The medical device is an anastomotic coupling device consisting of a single tubular portion that can be used as a shunt to divert blood from the original vessel to the graft vessel. The medical device is composed of a plurality of tubular portions, at least one of which is an anastomotic coupling device that can be used as a shunt for diverting blood between the original blood vessel and the target blood vessel. The medical device is an anastomosis coupling device that consists of one tubular portion, and one or more ends of the tubular portion can be inserted into the ends or sides of one or more blood vessels. The medical device is a multi-lumen anastomosis coupling device that can couple at least one arm of the device to a graft vessel. The medical device is an anastomotic coupling device that can include three or more tubular arms extending from the junction site. The medical device is a connecting device by multi-lumen anastomosis and is usually T-shaped. The medical device is a connecting device by multi-lumen anastomosis, and is usually Y-shaped. The medical device is an anastomosis coupling device consisting of a tube that bypasses blood flow directly from a portion of the heart to the coronary artery. The medical device is an anastomosis coupling device consisting of interconnected tubular conduit networks. And the medical device is an anastomotic coupling device in which fluid transmission is provided by intersecting lumens in a configuration with two or more terminations where a blood vessel interface is provided without the need for sutures.

3. Gastrointestinal stent In another aspect, the present invention provides a method for implanting a medical device comprising: (a) a medical device comprising: i) a fibrosis inhibitor; ii) an anti-infective agent; with iii) a polymer, iv) a composition comprising a fiber formation inhibitor and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising a fiber formation inhibitor, an anti-infective agent and a polymer. Tissue infiltration of a transplanted or transplanted host, and (b) implantation of a medical device into the host (where the medical device is a gastrointestinal stent).

  Optionally, in another aspect, the following is provided: A method of implanting a medical device comprising: (a) Tissue invasion of a host in which the medical device is implanted or implanted with a fibrosis inhibitor And (b) Medical tissue transplantation into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with an anti-infective agent, and (b) medical tissue transplantation into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a polymer; and (b) medical tissue transplantation into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising a fiber formation inhibitor and a polymer, and (b) medical tissue to the host Transplant. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer, and (b) medical tissue transplantation into the host . A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with a composition comprising a fibrogenesis inhibitor / anti-infective and a polymer; and (b) a host. Medical tissue transplantation.

  For each of the above-described aspects, the invention can be defined with respect to the use of the apparatus according to the inventive method, using one or more (for example, any two) of the following features. The medical device is an esophageal stent. The medical device is a biliary stent. The medical device is a colon stent. The medical device is a spleen stent.

4. Tracheal stent and bronchial stent In another aspect, the present invention provides a method of implanting a medical device comprising: (a) the medical device is i) a fibrosis inhibitor, ii) anti-infection A drug, iii) a polymer, iv) a composition comprising a fiber formation inhibitor and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising a fiber formation inhibitor, an anti-infective agent and a polymer. Tissue infiltration of the host being transplanted or transplanted, and (b) implantation of the medical device into the host (where the medical device is a tracheal stent or bronchial stent).

  Optionally, in another aspect, the following is provided: A method of implanting a medical device comprising: (a) Tissue invasion of a host in which the medical device is implanted or implanted with a fibrosis inhibitor And (b) Medical tissue transplantation into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with an anti-infective agent, and (b) medical tissue transplantation into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a polymer; and (b) medical tissue transplantation into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising a fiber formation inhibitor and a polymer, and (b) medical tissue to the host Transplant. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer, and (b) medical tissue transplantation into the host . A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with a composition comprising a fibrosis inhibitor / anti-infective and a polymer; and (b) a host. Medical device transplantation.

  For each of the above-described aspects, the invention can be defined with respect to the use of the apparatus according to the inventive method, using one or more (for example, any two) of the following features. The medical device is a tracheal stent. The medical device is a bronchial stent. The medical device is a metal tracheal stent. The medical device is a metal bronchial stent. The medical device is a polymer bronchial stent. The medical device is a polymer bronchial stent.

5. Urogenital stent In another aspect, the present invention provides a method of implanting a medical device comprising: (a) a medical device comprising: i) a fibrosis inhibitor; ii) an anti-infective agent; with iii) a polymer, iv) a composition comprising a fiber formation inhibitor and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising a fiber formation inhibitor, an anti-infective agent and a polymer. Tissue infiltration of the transplanted or transplanted host, and (b) implantation of the medical device into the host (where the medical device is a urogenital stent).

  Optionally, in another aspect, the following is provided: a method of implanting a medical device comprising: (a) tissue invasion of a host in which the medical device is implanted or implanted with a fibrosis inhibitor And (b) implantation of a medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with an anti-infective agent, and (b) transplantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a polymer, and (b) implantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising a fiber formation inhibitor and a polymer, and (b) a medical device to the host Transplant. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) implanting the medical device into the host. . A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with a composition comprising a fibrosis inhibitor / anti-infective and a polymer; and (b) a host. Medical device transplantation.

  For each of the above-described aspects, the invention can be defined with respect to the use of the apparatus according to the inventive method, using one or more (for example, any two) of the following features. The medical device is a ureteral stent. The medical device is a urethral stent. The medical device is a fallopian tube stent. The medical device is a prostate stent. The medical device is a metal urogenital stent. The medical device is a polymer urogenital stent.

6. Ear stent and nasal stent In another aspect, the present invention provides a method of implanting a medical device comprising: (a) a medical device comprising: i) a fibrosis inhibitor; ii) anti-infection A drug, iii) a polymer, iv) a composition comprising a fiber formation inhibitor and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising a fiber formation inhibitor, an anti-infective agent and a polymer. Tissue infiltration of the host being transplanted or transplanted, and (b) implantation of the medical device into the host (where the medical device is an ear stent or a nasal stent).

  Optionally, in another aspect, the following is provided: a method of implanting a medical device comprising: (a) tissue invasion of a host in which the medical device is implanted or implanted with a fibrosis inhibitor And (b) implantation of a medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with an anti-infective agent, and (b) transplantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a polymer, and (b) implantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising a fiber formation inhibitor and a polymer, and (b) a medical device to the host Transplant. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) implanting the medical device into the host. . A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with a composition comprising a fibrosis inhibitor / anti-infective and a polymer; and (b) a host. Medical device transplantation.

  For each of the above-described aspects, the invention can be defined with respect to the use of the apparatus according to the inventive method, using one or more (for example, any two) of the following features. The medical device is a lacrimal stent. The medical device is an ear canal stent. The medical device is a nasal stent. The medical device is a sinus stent.

7. Ear ventilation tube In another aspect, the present invention provides a method of implanting a medical device comprising: (a) a medical device comprising: i) a fibrosis inhibitor; ii) an anti-infective agent; with iii) a polymer, iv) a composition comprising a fiber formation inhibitor and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising a fiber formation inhibitor, an anti-infective agent and a polymer. Tissue infiltration of the transplanted or transplanted host, and (b) implantation of the medical device into the host (where the medical device is an ear ventilation tube).

  Optionally, in another aspect, the following is provided: a method of implanting a medical device comprising: (a) tissue invasion of a host in which the medical device is implanted or implanted with a fibrosis inhibitor And (b) implantation of a medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with an anti-infective agent, and (b) transplantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a polymer, and (b) implantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising a fiber formation inhibitor and a polymer, and (b) a medical device to the host Transplant. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) implanting the medical device into the host. . A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with a composition comprising a fibrosis inhibitor / anti-infective and a polymer; and (b) a host. Medical device transplantation.

  For each of the above-described aspects, the invention can be defined with respect to the use of the apparatus according to the inventive method, using one or more (for example, any two) of the following features. The medical device is a grommet tube. The medical device is a T-tube. The medical device is a middle ear cavity ventilation tube. The medical device is a drain tube. The medical device is a tympanic tube. The medical device is an otolaryngological tube. The medical device is a tympanic tube. The medical device is an artificial ear canal. The medical device is an ear canal prosthesis. And the medical device is an ear canal stent.

8. Intraocular graft In another aspect, the present invention provides a method of implanting a medical device comprising: (a) a medical device comprising: i) a fibrosis inhibitor; ii) an anti-infective agent. Iii) a polymer, iv) a composition comprising a fiber formation inhibitor and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising a fiber formation inhibitor, an anti-infective agent and a polymer. And / or (b) implantation of a medical device into the host (where the medical device is an intraocular implant).

  Optionally, in another aspect, the following is provided: a method of implanting a medical device comprising: (a) tissue invasion of a host in which the medical device is implanted or implanted with a fibrosis inhibitor And (b) implantation of a medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with an anti-infective agent, and (b) transplantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a polymer, and (b) implantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising a fiber formation inhibitor and a polymer, and (b) a medical device to the host Transplant. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) implanting the medical device into the host. . A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with a composition comprising a fibrosis inhibitor / anti-infective and a polymer; and (b) a host. Medical device transplantation.

  For each of the above-described aspects, the invention can be defined with respect to the use of the apparatus according to the inventive method, using one or more (for example, any two) of the following features. The medical device is an intraocular lens device for preventing the lens from becoming opaque. The medical device is a polymethyl methacrylate intraocular lens. The medical device is a silicone intraocular lens. The medical device is an achromatic lens. The medical device is a pseudophakic lens. The medical device is a phakic lens. The medical device is an aphakic lens. The medical device is a multifocal intraocular lens. The medical device is a hydrophilic and hydrophobic acrylic intraocular lens. The medical device is an intraocular implant. The medical device is an optical lens. The medical device is a gas permeable hard lens. The medical device is a foldable intraocular lens. The medical device is an intraocular hard lens. The medical device is a graft for correcting vision impairment. The medical device is an intraocular implant adapted for use in conjunction with corneal transplantation. The medical device is also an intraocular implant adapted for use in conjunction with the treatment of secondary cataracts after extracapsular cataract extraction.

9. Medical device for treatment of hypertrophic scars or keloids In another aspect, the present invention provides a method of implanting a medical device comprising: (a) a medical device, i) a fibrosis inhibitor. Ii) an anti-infective agent, iii) a polymer, iv) a composition comprising a fiber formation inhibitor and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) from a fiber formation inhibitor, an anti-infective agent and a polymer A tissue infiltration of a host transplanted or transplanted with the composition, and (b) implantation of a medical device into the host (where the medical device is a medical device for the treatment of hypertrophic scars or keloids) .

  Optionally, in another aspect, the following is provided: a method of implanting a medical device comprising: (a) tissue invasion of a host in which the medical device is implanted or implanted with a fibrosis inhibitor And (b) implantation of a medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with an anti-infective agent, and (b) transplantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a polymer, and (b) implantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising a fiber formation inhibitor and a polymer, and (b) a medical device to the host Transplant. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) implanting the medical device into the host. . A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with a composition comprising a fibrosis inhibitor / anti-infective and a polymer; and (b) a host. Medical device transplantation.

  For each of the above-described aspects, the invention can be defined with respect to the use of the apparatus according to the inventive method, using one or more (for example, any two) of the following features. The medical device is a device for the treatment of hypertrophic scar or keloid consisting of an external tissue expansion device. The medical device is a device for the treatment of hypertrophic scars or keloids consisting of a masking element and a masking element that compresses scar tissue. The medical device is also a device for treating hypertrophic scars or keloids comprising a locking element and a structure for grasping the dermal and epidermal layers of the skin wound so that they can be pressed against each other.

10. Vascular Grafts In another aspect, the present invention provides a method for implanting a medical device comprising: (a) a medical device comprising i) a fibrosis inhibitor, ii) an anti-infective agent, iii Transplanted with a) a polymer, iv) a composition comprising a fiber formation inhibitor and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising a fiber formation inhibitor, an anti-infective agent and a polymer. Tissue infiltration of a host that has been or has been transplanted, and (b) implantation of a medical device into the host (where the medical device is a vascular graft).

  Optionally, in another aspect, the following is provided: a method of implanting a medical device comprising: (a) tissue invasion of a host in which the medical device is implanted or implanted with a fibrosis inhibitor And (b) implantation of a medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with an anti-infective agent, and (b) transplantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a polymer, and (b) implantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising a fiber formation inhibitor and a polymer, and (b) a medical device to the host Transplant. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) implanting the medical device into the host. . A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with a composition comprising a fibrosis inhibitor / anti-infective and a polymer; and (b) a host. Medical device transplantation.

  For each of the above-described aspects, the invention can be defined with respect to the use of the apparatus according to the inventive method, using one or more (for example, any two) of the following features. The medical device is an extravascular graft. The medical device is an endovascular graft. The medical device is a vascular graft adapted to replace blood vessels damaged by an aneurysm. The medical device is a vascular graft adapted to replace blood vessels damaged by intimal hyperplasia. The medical device is a vascular graft adapted to replace blood vessels damaged by thrombus formation. The medical device is a vascular graft adapted to provide access to a blood vessel. The medical device is a vascular graft adapted to provide an alternative conduit for blood flow through venous lesions or diseased areas. The medical device is a vascular graft adapted to provide an alternative conduit for blood flow through an injured or diseased area of an artery. The medical device is a synthetic bypass graft. The medical device is a femoral popliteal bypass graft. The medical device is a thigh bypass graft. The medical device is an axillary femoral bypass graft. The medical device is a vein graft. The medical device is a peripheral vein graft. The medical device is a coronary vein graft. The medical device is an internal thoracic artery graft. The medical device is a branch vessel graft. The medical device is an endoluminal graft. The medical device is a prosthetic vascular graft.

11. Hemodialysis access device In another aspect, the present invention provides a method for implanting a medical device comprising: (a) the medical device is i) a fibrosis inhibitor, ii) an anti-infective agent. Iii) a polymer, iv) a composition comprising a fiber formation inhibitor and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising a fiber formation inhibitor, an anti-infective agent and a polymer. And (b) implantation of a medical device into the host (where the medical device is a hemodialysis access device).

  Optionally, in another aspect, the following is provided: a method of implanting a medical device comprising: (a) tissue invasion of a host in which the medical device is implanted or implanted with a fibrosis inhibitor And (b) implantation of a medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with an anti-infective agent, and (b) transplantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a polymer, and (b) implantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising a fiber formation inhibitor and a polymer, and (b) a medical device to the host Transplant. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) implanting the medical device into the host. . A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with a composition comprising a fibrosis inhibitor / anti-infective and a polymer; and (b) a host. Medical device transplantation.

  For each of the above-described aspects, the invention can be defined with respect to the use of the apparatus according to the inventive method, using one or more (for example, any two) of the following features. The medical device is a pulmonary arteriovenous fistula graft. The medical device is an arteriovenous access graft. The medical device is a venous catheter. The medical device is a vascular graft. The medical device is an implantable port. The medical device is an arteriovenous shunt.

12. Medical device comprising a film or mesh In another aspect, the present invention provides a method for implanting a medical device comprising: (a) the medical device is i) a fibrosis inhibitor, ii) An anti-infective agent, iii) a polymer, iv) a composition comprising a fiber formation inhibitor and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising a fiber formation inhibitor, an anti-infective agent and a polymer And (b) implantation of a medical device into the host (wherein the medical device is a device made of a film or mesh).

  Optionally, in another aspect, the following is provided: a method of implanting a medical device comprising: (a) tissue invasion of a host in which the medical device is implanted or implanted with a fibrosis inhibitor And (b) implantation of a medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with an anti-infective agent, and (b) transplantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a polymer, and (b) implantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising a fiber formation inhibitor and a polymer, and (b) a medical device to the host Transplant. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) implanting the medical device into the host. . A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with a composition comprising a fibrogenesis inhibitor / anti-infective and a polymer; and (b) a host. Medical tissue transplantation.

  For each of the above-described aspects, the invention can be defined with respect to the use of the apparatus according to the inventive method, using one or more (for example, any two) of the following features. The medical device is a surgical barrier. The medical device is a surgical adhesion barrier. The medical device is a surgical sheet. The medical device is a surgical patch. The medical device is a surgical wrap. The medical device is a vascular wrap. The medical device is a perivascular wrap. The medical device is an outer membrane wrap. The medical device is a pericardial wrap. The medical device is an outer membrane sheet. The medical device is a perivascular mesh. The medical device is a bandage. The medical device is a liquid bandage. The medical device is a suture. The medical device is a gauze. The medical device is a fabric. The medical device is a tape. The medical device is a surgical membrane. The medical device is a polymer matrix. The medical device is a tissue cover. The medical device is a surgical substrate. The medical device is an envelope. The medical device is a tissue cover.

13. Glaucoma drainage device In another aspect, the present invention provides a method of implanting a medical device comprising: (a) a medical device comprising: i) a fibrosis inhibitor; ii) an anti-infective agent; with iii) a polymer, iv) a composition comprising a fiber formation inhibitor and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising a fiber formation inhibitor, an anti-infective agent and a polymer. Tissue infiltration of the transplanted or transplanted host, and (b) implantation of the medical device into the host (where the medical device is a glaucoma drainage device).

  Optionally, in another aspect, the following is provided: a method of implanting a medical device comprising: (a) tissue invasion of a host in which the medical device is implanted or implanted with a fibrosis inhibitor And (b) implantation of a medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with an anti-infective agent, and (b) transplantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a polymer, and (b) implantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising a fiber formation inhibitor and a polymer, and (b) a medical device to the host Transplant. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) implanting the medical device into the host. . A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with a composition comprising a fibrosis inhibitor / anti-infective and a polymer; and (b) a host. Medical device transplantation.

  In certain embodiments, the medical device is a glaucoma drainage device consisting of a plate and a tube.

14. Prosthetic heart valve or composition thereof In another aspect, the present invention provides a method of implanting a medical device comprising: (a) a medical device comprising: i) a fibrosis inhibitor; ii ) An anti-infective agent, iii) a polymer, iv) a composition comprising a fiber formation inhibitor and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising a fiber formation inhibitor, an anti-infective agent and a polymer And (b) implantation of a medical device into the host (where the medical device is a prosthetic heart valve or a composition thereof).

  Optionally, in another aspect, the following is provided: a method of implanting a medical device comprising: (a) tissue invasion of a host in which the medical device is implanted or implanted with a fibrosis inhibitor And (b) implantation of a medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with an anti-infective agent, and (b) transplantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a polymer, and (b) implantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising a fiber formation inhibitor and a polymer, and (b) a medical device to the host Transplant. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) implanting the medical device into the host. . A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with a composition comprising a fibrosis inhibitor / anti-infective and a polymer; and (b) a host. Medical device transplantation.

  For each of the above-described aspects, the invention can be defined with respect to the use of the apparatus according to the inventive method, using one or more (for example, any two) of the following features. The medical device is a mechanical prosthetic heart valve. The medical device is a living heart valve. The medical device is an implantable annular ring for receiving a prosthetic heart valve. The medical device is a suture ring with an outer peripheral taper screw for joining a heart valve prosthesis. The medical device is a suture ring for a mechanical heart valve.

15. Penis Grafts In another aspect, the present invention provides a method of implanting a medical device comprising: (a) a medical device comprising: i) a fibrosis inhibitor; ii) an anti-infective agent. Iii) a polymer, iv) a composition comprising a fiber formation inhibitor and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising a fiber formation inhibitor, an anti-infective agent and a polymer. And (b) implantation of a medical device into the host (where the medical device is a penile graft).

  Optionally, in another aspect, the following is provided: a method of implanting a medical device comprising: (a) tissue invasion of a host in which the medical device is implanted or implanted with a fibrosis inhibitor And (b) implantation of a medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with an anti-infective agent, and (b) transplantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a polymer, and (b) implantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising a fiber formation inhibitor and a polymer, and (b) a medical device to the host Transplant. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) implanting the medical device into the host. . A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with a composition comprising a fibrosis inhibitor / anti-infective and a polymer; and (b) a host. Medical device transplantation.

  For each of the above-described aspects, the invention can be defined with respect to the use of the apparatus according to the inventive method, using one or more (for example, any two) of the following features. The medical device is a flexible rod penile implant. The medical device is a hinged rod penile implant. The medical device is a penis implant that can be expanded by a pump.

16. Intratracheal tube or tracheal cannula In another aspect, the present invention provides a method of implanting a medical device comprising: (a) the medical device is i) a fibrosis inhibitor, ii) anti An infectious agent, iii) a polymer, iv) a composition comprising a fiber formation inhibitor and a polymer, v) a composition comprising an antiinfective agent and a polymer, or vi) a composition comprising a fiber formation inhibitor, an antiinfective agent and a polymer, And (b) implantation of the medical device into the host (where the medical device is a tracheal tube or tracheal cannula).

  Optionally, in another aspect, the following is provided: a method of implanting a medical device comprising: (a) tissue invasion of a host in which the medical device is implanted or implanted with a fibrosis inhibitor And (b) implantation of a medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with an anti-infective agent, and (b) transplantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a polymer, and (b) implantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising a fiber formation inhibitor and a polymer, and (b) a medical device to the host Transplant. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) implanting the medical device into the host. . A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with a composition comprising a fibrosis inhibitor / anti-infective and a polymer; and (b) a host. Medical device transplantation.

  For each of the above-described aspects, the invention can be defined with respect to the use of the apparatus according to the inventive method, using one or more (for example, any two) of the following features. The medical device is an endotracheal tube. The medical device is a single lumen endotracheal tube. The medical device is an endotracheal tube with two lumens. The medical device is a tracheal cannula.

17. Peritoneal dialysis catheter In another aspect, the present invention provides a method for implanting a medical device comprising: (a) a medical device comprising: i) a fibrosis inhibitor; ii) an anti-infective agent; with iii) a polymer, iv) a composition comprising a fiber formation inhibitor and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising a fiber formation inhibitor, an anti-infective agent and a polymer. Tissue infiltration of the transplanted or transplanted host, and (b) implantation of the medical device into the host (where the medical device is a peritoneal dialysis catheter).

  Optionally, in another aspect, the following is provided: a method of implanting a medical device comprising: (a) tissue invasion of a host in which the medical device is implanted or implanted with a fibrosis inhibitor And (b) implantation of a medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with an anti-infective agent, and (b) transplantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a polymer, and (b) implantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising a fiber formation inhibitor and a polymer, and (b) a medical device to the host Transplant. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) implanting the medical device into the host. . A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with a composition comprising a fibrosis inhibitor / anti-infective and a polymer; and (b) a host. Medical device transplantation.

  In certain embodiments, the medical device is a peritoneal dialysis catheter adapted to deliver a drug to the peritoneum.

18. Central nervous system shunt or pressure monitoring device In another aspect, the present invention provides a method of implanting a medical device comprising: (a) the medical device is i) a fibrosis inhibitor, ii. ) An anti-infective agent, iii) a polymer, iv) a composition comprising a fiber formation inhibitor and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising a fiber formation inhibitor, an anti-infective agent and a polymer And (b) implantation of the medical device into the host (where the medical device is a central nervous system shunt or pressure monitoring).

  Optionally, in another aspect, the following is provided: a method of implanting a medical device comprising: (a) tissue invasion of a host in which the medical device is implanted or implanted with a fibrosis inhibitor And (b) implantation of a medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with an anti-infective agent, and (b) transplantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a polymer, and (b) implantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising a fiber formation inhibitor and a polymer, and (b) a medical device to the host Transplant. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) implanting the medical device into the host. . A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with a composition comprising a fibrosis inhibitor / anti-infective and a polymer; and (b) a host. Medical device transplantation.

  For each of the above-described aspects, the invention can be defined with respect to the use of the apparatus according to the inventive method, using one or more (for example, any two) of the following features. The medical device is a ventricular pleural shunt. The medical device is a jugular shunt. The medical device is a vena cava shunt. The medical device is a ventricular abdominal cavity shunt. The medical device is a gallbladder shunt. The medical device is a peritoneal shunt. The medical device is an extraventricular drainage device. The medical device is an intracranial pressure monitoring device. The medical device is a dural patch. The medical device is an implant for preventing epidural fibrosis after laminectomy. The medical device is a continuous subarachnoid injection device. The medical device is a drainage shunt that helps drain fluid in the brain. The medical device is a pressure monitoring device.

19. Inferior vena cava filter In certain embodiments, the present invention provides a method of implanting a medical device comprising: (a) the medical device is i) a fibrosis inhibitor, ii) anti-infection A drug, iii) a polymer, iv) a composition comprising a fiber formation inhibitor and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising a fiber formation inhibitor, an anti-infective agent and a polymer. Tissue infiltration of the host being transplanted or transplanted, and (b) implantation of the medical device into the host (where the medical device is an inferior vena cava filter).

  Optionally, in another aspect, the following is provided: a method of implanting a medical device comprising: (a) tissue invasion of a host in which the medical device is implanted or implanted with a fibrosis inhibitor And (b) implantation of a medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with an anti-infective agent, and (b) transplantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a polymer, and (b) implantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising a fiber formation inhibitor and a polymer, and (b) a medical device to the host Transplant. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) implanting the medical device into the host. . A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with a composition comprising a fibrosis inhibitor / anti-infective and a polymer; and (b) a host. Medical device transplantation.

  For each of the above-described aspects, the invention can be defined with respect to the use of the apparatus according to the inventive method, using one or more (for example, any two) of the following features. The medical device is a vascular filter. The medical device is a blood filter. The medical device is a venous filter. The medical device is a vena cava filter. The medical device is a thrombus filter. The medical device is an anti-migration filter. The medical device is a transcutaneous filter system. The medical device is an intravascular trap. The medical device is an intravascular filter. The medical device is a clot filter. The medical device is a venous filter. The medical device is a blood vessel filter.

20. Gastrointestinal device In another aspect, the present invention provides a method for implanting a medical device comprising: (a) a medical device comprising: i) a fibrosis inhibitor; ii) an anti-infective agent; with iii) a polymer, iv) a composition comprising a fiber formation inhibitor and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising a fiber formation inhibitor, an anti-infective agent and a polymer. Tissue infiltration of a transplanted or transplanted host, and (b) implantation of a medical device into the host (where the medical device is a gastrointestinal device).

  Optionally, in another aspect, the following is provided: a method of implanting a medical device comprising: (a) tissue invasion of a host in which the medical device is implanted or implanted with a fibrosis inhibitor And (b) implantation of a medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with an anti-infective agent, and (b) transplantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a polymer, and (b) implantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising a fiber formation inhibitor and a polymer, and (b) a medical device to the host Transplant. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) implanting the medical device into the host. . A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with a composition comprising a fibrosis inhibitor / anti-infective and a polymer; and (b) a host. Medical device transplantation.

  For each of the above-described aspects, the invention can be defined with respect to the use of the apparatus according to the inventive method, using one or more (for example, any two) of the following features. The medical device is a drainage tube. The medical device is a nutrition tube. The medical device is a portal vein vein shunt. The medical device is an ascites shunt. The medical device is a nasal tube or a nasal bowel tube. The medical device is a gastrostomy or transcutaneous feeding tube. The medical device is an endoscope tube for jejunostomy. The medical device is a colostomy device. The medical device is a gallbladder T-tube. The medical device is a biopsy forceps. The medical device is a gallstone removal device. The medical device is a retrograde cholangiopancreatography device using an endoscope. The medical device is an expansion balloon. The medical device is an enteral feeding device. The medical device is a stent. The medical device is a low contractility device. The medical device is a virtual colonoscopy device. The medical device is a capsule endoscope. The medical device is a collection device. The medical device is a gastrointestinal device adapted for examining the interior of the gastrointestinal tract. The medical device is a gastrointestinal device adapted for lavage or aspiration of the gastrointestinal tract. The medical device is a colostomy device. The medical device is a mechanical hemostasis device adapted for gastrointestinal bleeding control. The medical device is a gastrointestinal device adapted to clean the blocked gastrointestinal tract. The medical device is a gastrointestinal device that provides communication between two body systems. The medical device is a portal vein vein shunt. The medical device is an dilatation catheter.

21. Central venous catheter In another aspect, the present invention provides a method for implanting a medical device comprising: (a) a medical device comprising: i) a fibrosis inhibitor; ii) an anti-infective agent; with iii) a polymer, iv) a composition comprising a fiber formation inhibitor and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising a fiber formation inhibitor, an anti-infective agent and a polymer. Tissue infiltration of the transplanted or transplanted host, and (b) implantation of the medical device into the host (where the medical device is a central venous catheter).

  Optionally, in another aspect, the following is provided: a method of implanting a medical device comprising: (a) tissue invasion of a host in which the medical device is implanted or implanted with a fibrosis inhibitor And (b) implantation of a medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with an anti-infective agent, and (b) transplantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a polymer, and (b) implantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising a fiber formation inhibitor and a polymer, and (b) a medical device to the host Transplant. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) implanting the medical device into the host. . A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with a composition comprising a fibrosis inhibitor / anti-infective and a polymer; and (b) a host. Medical device transplantation.

  For each of the above-described aspects, the invention can be defined with respect to the use of the apparatus according to the inventive method, using one or more (for example, any two) of the following features. The medical device is a cuffed central venous catheter. The medical device is a cuffless central venous catheter. The medical device is a flanged central venous catheter. The medical device is a flangeless central venous catheter. The medical device is a central venous catheter adapted to provide access to the circulatory system. The medical device is a central venous catheter adapted to provide multiple conduits for access to the circulatory system. The medical device is a central venous catheter that consists of means to prevent infection as a result of long-term use. The medical device is a central venous catheter that can be adapted for use with a device that provides a means for controlling infection and can be adapted for the collection of body fluids from the central venous catheter. The medical device is a parenteral nutrition catheter. The medical device is a locally inserted central venous catheter. The medical device is a pulmonary artery catheter with a blood flow directional tip balloon. The medical device is also a long-term central venous access catheter.

22. Assisted artificial heart In another aspect, the present invention provides a method for implanting a medical device comprising: (a) a medical device comprising: i) a fibrosis inhibitor; ii) an anti-infective agent; with iii) a polymer, iv) a composition comprising a fiber formation inhibitor and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising a fiber formation inhibitor, an anti-infective agent and a polymer. Tissue infiltration of the transplanted or transplanted host, and (b) transplantation of the medical device to the host (where the medical device is an assistive artificial heart).

  Optionally, in another aspect, the following is provided: a method of implanting a medical device comprising: (a) tissue invasion of a host in which the medical device is implanted or implanted with a fibrosis inhibitor And (b) implantation of a medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with an anti-infective agent, and (b) transplantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a polymer, and (b) implantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising a fiber formation inhibitor and a polymer, and (b) a medical device to the host Transplant. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) implanting the medical device into the host. . A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with a composition comprising a fibrosis inhibitor / anti-infective and a polymer; and (b) a host. Medical device transplantation.

  For each of the above-described aspects, the invention can be defined with respect to the use of the apparatus according to the inventive method, using one or more (for example, any two) of the following features. The medical device is a left ventricular assist device. The medical device is a right ventricular assist device. The medical device is a bi-centric circulatory device. The medical device is an auxiliary artificial heart device. The medical device is a mechanical auxiliary device. The medical device is an auxiliary artificial heart device. The medical device is an implantable cardiac assist system. The medical device is a cardiac assist pump. The medical device is a ventricular assist device.

23. Spine grafts In another aspect, the present invention provides a method of implanting a medical device comprising: (a) a medical device comprising: i) a fibrosis inhibitor; ii) an anti-infective agent. Iii) a polymer, iv) a composition comprising a fiber formation inhibitor and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising a fiber formation inhibitor, an anti-infective agent and a polymer. And (b) implantation of a medical device into the host (where the medical device is a spinal implant).

  Optionally, in another aspect, the following is provided: a method of implanting a medical device comprising: (a) tissue invasion of a host in which the medical device is implanted or implanted with a fibrosis inhibitor And (b) implantation of a medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with an anti-infective agent, and (b) transplantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a polymer, and (b) implantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising a fiber formation inhibitor and a polymer, and (b) a medical device to the host Transplant. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) implanting the medical device into the host. . A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with a composition comprising a fibrosis inhibitor / anti-infective and a polymer; and (b) a host. Medical device transplantation.

  For each of the above-described aspects, the invention can be defined with respect to the use of the apparatus according to the inventive method, using one or more (for example, any two) of the following features. The medical device is a spinal disc. The medical device is a spinal implant. The medical device is an artificial intervertebral disc. The medical device is an intervertebral disc graft. The medical device is a cervical disc implant. The medical device is an intervertebral disc. The medical device is a spinal prosthesis. The medical device is an artificial disc. The medical device is a spinal disc endoprosthesis. The medical device is an intervertebral implant. The medical device is an implantable spinal implant. The medical device is an implantable bone graft. The medical device is an artificial disc. The medical device is a spinal cord nuclear implant. The medical device is an intervertebral disc spacer. The medical device is a fixation cage. The medical device is a fixed basket. The medical device is a fixed cage device. The medical device is an interbody cage. The medical device is an interbody implant. The medical device is a fixing device for a fixing cage. The medical device is a bone fixation device. The medical device is a fixed stabilization chamber. The medical device is a fixed bone plate. The medical device is a bone screw.

24. Electrical device In another aspect, the present invention provides a method of implanting a medical device comprising: (a) a medical device comprising: i) a fibrosis inhibitor, ii) an anti-infective agent, iii Transplanted with a) a polymer, iv) a composition comprising a fiber formation inhibitor and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising a fiber formation inhibitor, an anti-infective agent and a polymer. Tissue infiltration of a host that has been or has been transplanted, and (b) implantation of a medical device into the host (where the medical device is an electrical device).

  Optionally, in another aspect, the following is provided: a method of implanting a medical device comprising: (a) tissue invasion of a host in which the medical device is implanted or implanted with a fibrosis inhibitor And (b) implantation of a medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with an anti-infective agent, and (b) transplantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a polymer, and (b) implantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising a fiber formation inhibitor and a polymer, and (b) a medical device to the host Transplant. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) implanting the medical device into the host. . A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with a composition comprising a fibrosis inhibitor / anti-infective and a polymer; and (b) a host. Medical device transplantation.

  For each of the above-described aspects, the invention can be defined with respect to the use of the apparatus according to the inventive method, using one or more (for example, any two) of the following features. Medical device is nerve stimulation device, medical device is spinal cord stimulation device, medical device is brain stimulation device, medical device is vagus nerve stimulation device, medical device is sacral nerve stimulation device, medical device is Gastric nerve stimulation device, medical device is acoustic nerve stimulation device, medical device delivers stimulation to the organ, medical device delivers stimulation to bone, medical device delivers stimulation to muscle, medical device stimulates A medical device is a continuous subarachnoid injection device, a medical device is an implantable electrode, a medical device is an implantable pulse generator, a medical device is a lead, a medical device The device is a stimulation lead, the medical device is a stimulation catheter lead, the medical device is a transplanted cochlear stimulation device, the medical device is a micro stimulation device, the medical device is battery operated, the medical device is radio frequency formula Some medical devices are both battery powered and radio frequency, medical devices are cardiac rhythm management devices, medical devices are cardiac pacers, medical devices are implantable tachycardia defibrillator systems The medical device is a cardiac lead, the medical device is a pacemaker lead, the medical device is an endocardial lead, the medical device is a cardioverter / defibrillator lead, the medical device is Medical device is an epicardial defibrillator lead, medical device is a patch defibrillator, medical device is a patch defibrillator lead, medical device is an electrical patch The medical device is a transvenous lead wire, the medical device is an active fixed lead wire, the medical device is an inactive fixed lead wire, the medical device is a detection lead wire, the medical device is a defibrillator The medical device is implantable The medical device is a left ventricular assist device, the medical device is a pulse generator, the medical device is a patch lead, the medical device is an electrical patch, the medical device is a heart stimulator The medical device is a sensor capable of electrical device, the medical device is a pump capable of electrical device, the medical device is a dural patch, the medical device is a ventricular peritoneal shunt, the medical device is a ventricular atrial shunt A medical device is an electrical device that is adapted to treat or prevent dural fiber formation after laminectomy, a medical device is an electrical device that is adapted to treat or prevent cardiac rhythm abnormalities A medical device is an electrical device that is adapted to treat or prevent atrial rhythm abnormalities, a medical device is an electrical device that is adapted to treat or prevent conduction abnormalities A medical device is an electrical device adapted to treat or prevent ventricular rhythm abnormalities, a medical device is an electrical device adapted to treat or prevent pain, a medical device treats sputum Or an electrical device adapted to prevent, medical device is an electrical device adapted to treat or prevent Parkinson's disease, medical device adapted to treat or prevent movement disorders A medical device is an electrical device adapted to treat or prevent obesity, a medical device is an electrical device adapted to treat or prevent depression, a medical device is anxious Medical device is an electrical device adapted to treat or prevent hearing loss, medical device is an electrical device adapted to treat or prevent hearing loss, medical device treats ulcer A medical device is an electrical device adapted to treat or prevent deep vein thrombosis, a medical device is adapted to treat or prevent muscle atrophy A medical device is an electrical device adapted to treat or prevent joint stiffness, a medical device is an electrical device adapted to treat or prevent muscle spasm, The medical device is an electrical device adapted to treat or prevent osteoporosis, the medical device is an electrical device adapted to treat or prevent scoliosis, the medical device is a spinal plate A medical device is an electrical device that is adapted to treat or prevent degeneration, a medical device is an electrical device that is adapted to treat or prevent spinal cord injury, a medical device treats urinary dysfunction Is an electrical device adapted to prevent, medical device is an electrical device adapted to treat or prevent gastric paresis, medical device adapted to treat or prevent malignant tumors A medical device is an electrical device adapted to treat or prevent arachnoiditis, a medical device is an electrical device adapted to treat or prevent chronic disease, medical The device is an electrical device that is adapted to treat or prevent migraine, the medical device is an electrical device that is adapted to treat or prevent sleep disorders, the medical device treats or prevents dementia A medical device, which is an electrical device that is adapted for, is an electrical device that is adapted for treating or preventing Alzheimer's disease.

25. Sensor In another aspect, the present invention provides a method of implanting a medical device comprising: (a) the medical device is i) a fibrosis inhibitor, ii) an anti-infective agent, iii) Implanted with a polymer, iv) a composition comprising a fiber formation inhibitor and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising a fiber formation inhibitor, an anti-infective agent and a polymer. Or (b) implantation of a medical device into the host (where the medical device is a sensor).

  Optionally, in another aspect, the following is provided: a method of implanting a medical device comprising: (a) tissue invasion of a host in which the medical device is implanted or implanted with a fibrosis inhibitor And (b) implantation of a medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with an anti-infective agent, and (b) transplantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a polymer, and (b) implantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising a fiber formation inhibitor and a polymer, and (b) a medical device to the host Transplant. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) implanting the medical device into the host. . A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with a composition comprising a fibrosis inhibitor / anti-infective and a polymer; and (b) a host. Medical device transplantation.

  For each of the above-described aspects, the invention can be defined with respect to the use of the apparatus according to the inventive method, using one or more (for example, any two) of the following features. The medical device is a blood or tissue sugar level monitor. The medical device is an electrolyte sensor. The medical device is a blood concentration sensor. The medical device is a temperature sensor. The medical device is a pH sensor. The medical device is an optical sensor. The medical device is a current measuring sensor. The medical device is a pressure sensor. The medical device is a biosensor. The medical device is a detection transponder. The medical device is a strain sensor. The medical device is a magnetoresistive sensor. The medical device is a heart sensor. The medical device is a respiration sensor. The medical device is an auditory sensor. The medical device is a metabolite sensor. A medical device is a sensor that detects mechanical changes. A medical device is a sensor that detects physical changes. Medical devices are sensors that detect electrochemical changes. A medical device is a sensor that detects a magnetic change. A medical device is a sensor that detects accelerated changes. A medical device is a sensor that detects changes in ionizing radiation. A medical device is a sensor that detects changes in sound waves. A medical device is a sensor that detects chemical changes. A medical device is a sensor that detects changes in drug concentration. A medical device is a sensor that detects hormonal changes. A medical device is a sensor that detects changes in atmospheric pressure.

26. In another embodiment of the pump , the present invention provides a method of implanting a medical device comprising: (a) a medical device comprising: i) a fibrosis inhibitor, ii) an anti-infective agent, iii) a polymer, iv) Implanted or implanted with a composition comprising a fibrosis inhibitor and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer. Host tissue infiltration, and (b) implantation of a medical device into the host (where the medical device is a pump).

  Optionally, in another aspect, the following is provided: a method of implanting a medical device comprising: (a) tissue invasion of a host in which the medical device is implanted or implanted with a fibrosis inhibitor And (b) implantation of a medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with an anti-infective agent, and (b) transplantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a polymer, and (b) implantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising a fiber formation inhibitor and a polymer, and (b) a medical device to the host Transplant. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) implanting the medical device into the host. . A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with a composition comprising a fibrosis inhibitor / anti-infective and a polymer; and (b) a host. Medical device transplantation.

  For each of the above-described aspects, the invention can be defined with respect to the use of the apparatus according to the inventive method, using one or more (for example, any two) of the following features. The medical device is a pump that is adapted for the delivery of insulin. The medical device is a pump adapted for the delivery of anesthetics. The medical device is a pump adapted for the delivery of chemotherapeutic drugs. The medical device is a pump that is adapted for the delivery of arrhythmia inhibitors. The medical device is a pump that is adapted for the delivery of anticonvulsants. The medical device is a pump that is adapted for the delivery of antispasmodic agents. The medical device is a pump that is adapted for the delivery of antibiotics. A medical device is a pump that is adapted for drug delivery only when a change in the host is detected. A medical device is a pump that is adapted for delivery by continuous slow delivery of medication. A medical device is a pump that is adapted to deliver a prescribed dose of medication by pulsation. The medical device is a programmable drug delivery pump. A medical device is a pump that is adapted for the delivery of drugs into the eye. The medical device is a pump that is adapted for delivery of the drug into the peritoneum. A medical device is a pump that is adapted for delivery of drugs into an artery. A medical device is a pump that is adapted to deliver drugs into the heart. The medical device is an implantable osmotic pump. The medical device is an ocular drug delivery pump. Medical devices are metered. The medical device is a peristaltic (roller) pump. The medical device is an electronically driven pump. The medical device is an elastomer pump. The medical device is a spring contraction pump. The medical device is a gas driven pump. The medical device is a hydraulic pump. Medical devices are piston-dependent pumps. The medical device is a piston independent pump. The medical device is a dispensing room. The medical device is an infusion pump. The medical device is a passive pump.

27. In another embodiment of a soft tissue graft , the present invention provides a method of implanting a medical device comprising: (a) a medical device comprising: i) a fibrosis inhibitor, ii) an anti-infective agent, iii) a polymer, transplanted with iv) a composition comprising an anti-fibrosis agent and a polymer, v) a composition comprising an anti-infective agent and a polymer, or vi) a composition comprising an anti-infection agent, an anti-infective agent and a polymer, or Tissue infiltration of the transplanted host, and (b) implantation of the medical device into the host (where the medical device is a soft tissue graft).

  Optionally, in another aspect, the following is provided: a method of implanting a medical device comprising: (a) tissue invasion of a host in which the medical device is implanted or implanted with a fibrosis inhibitor And (b) implantation of a medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with an anti-infective agent, and (b) transplantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a polymer, and (b) implantation of the medical device into the host. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising a fiber formation inhibitor and a polymer, and (b) a medical device to the host Transplant. A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) implanting the medical device into the host. . A method of implanting a medical device comprising: (a) tissue infiltration of a host in which the medical device is or is implanted with a composition comprising a fibrosis inhibitor / anti-infective and a polymer; and (b) a host. Medical device transplantation.

  For each of the above-described aspects, the invention can be defined with respect to the use of the apparatus according to the inventive method, using one or more (for example, any two) of the following features. The medical device is an aesthetic implant. The medical device is a transplant for reconstruction. The medical device is breast augmentation. The medical device is a breast augmentation operation made of silicone. The medical device is a breast augmentation operation consisting of saline. The medical device is a facial implant. The medical device is a jaw implant. The medical device is a mandibular implant. The medical device is a lip graft. The medical device is a nasal implant. The medical device is a cheek implant. The medical device is a pectoral muscle graft. The medical device is a hip implant. The medical device is an autologous tissue graft. The medical device is an autologous tissue graft made of adipose tissue. The medical device is an autologous tissue graft made of autologous adipose tissue. The medical device is an autologous tissue graft consisting of a skin graft. The medical device is an autologous tissue graft consisting of a skin plug. The medical device is an autologous tissue graft consisting of a tissue plug. The medical device is an autologous tissue graft made up of muscle tissue valves. The medical device is an autologous tissue graft consisting of a pedicled flap. The medical device is an autologous tissue graft that consists of a pedicled flap that is from the back, abdomen, buttocks, thighs, or groin. The medical device is an autologous tissue graft consisting of a cell extraction graft. The medical device is an autologous tissue graft consisting of a suspension of autologous skin fibroblasts. The medical device is a tissue filler. The medical device is a fat transplant.

The present invention, in various embodiments and examples, provides the following methods for preventing surgical adhesions:
In one embodiment, the present invention comprises delivering a tissue-responsive polymeric composition to a site where coated tissue needs to be provided and delivering a fibrosis inhibitor to the coated tissue. A method for preventing surgical adhesion is provided.

  In another aspect, the present invention provides a method for preventing surgical adhesions comprising delivering a composition that prevents surgical adhesions between a patient's dural sleeve and paravertebral muscle tissue after laminectomy. To do.

  In another aspect, the present invention provides a method for preventing surgical adhesion comprising coating a spinal nerve at a laminectomy site of a patient with a composition that prevents surgical adhesion.

  In another aspect, the present invention provides a method for preventing surgical adhesion comprising infiltrating a tissue surrounding the spinal nerve at a site of a patient's laminectomy with a composition that prevents surgical adhesion.

  In another aspect, the present invention provides a method for preventing surgical adhesion comprising delivering a composition that prevents surgical adhesion to a site of a patient requiring discectomy.

  In another aspect, the present invention provides a method for preventing surgical adhesion comprising delivering a composition that prevents surgical adhesion to a site of a patient in need of a microscopic herniation.

  In another aspect, the present invention provides a method for preventing surgical adhesions comprising delivering a composition that prevents surgical adhesions to a required site of a patient's (brain) neurosurgery.

  In another aspect, the present invention provides a method for preventing surgical adhesion, comprising infiltrating a required site for spinal surgery of a patient with a composition that prevents surgical adhesion.

  In another aspect, the present invention provides a method for preventing surgical adhesion comprising delivering a composition that prevents surgical adhesion to a required site in a patient's epidural tissue.

  In another aspect, the present invention provides a method for preventing surgical adhesion comprising delivering a composition that prevents surgical adhesion to a required site in a patient's dural tissue.

  In another aspect, the present invention provides a method of preventing surgical adhesion comprising delivering a composition that prevents surgical adhesion to a required gynecological site of a patient.

  In another aspect, the present invention provides a method of preventing surgical adhesion comprising delivering a composition that prevents surgical adhesion to a tissue surface of a patient's required pelvic sidewall.

  In another aspect, the present invention provides a method for preventing surgical adhesion comprising delivering a composition that prevents surgical adhesion to a required peritoneal cavity of a patient.

  In another aspect, the present invention provides a method for preventing surgical adhesion comprising delivering a composition that prevents surgical adhesion to a required pelvic cavity of a patient.

  In another aspect, the present invention provides a method for preventing surgical adhesion comprising delivering a composition that prevents surgical adhesion to a required laparotomy site of a patient.

  In another aspect, the present invention provides a method for preventing surgical adhesion comprising delivering a composition that prevents surgical adhesion to a required endoscopic surgical site of a patient.

  In another aspect, the present invention provides a method for preventing surgical adhesion comprising delivering a composition that prevents surgical adhesion to a site in need of hernia repair in a patient.

  In another aspect, the present invention provides a method for preventing surgical adhesion comprising delivering a composition that prevents surgical adhesion to a site of a patient in need of cholecystectomy.

  In another aspect, the present invention provides a method for preventing surgical adhesion comprising delivering a composition that prevents surgical adhesion to a required site of a patient's cardiac surgery.

  In another aspect, the present invention provides a method for preventing surgical adhesions comprising delivering a composition that prevents surgical adhesions to a required site of a patient's heart transplant surgery.

  In another aspect, the present invention provides a method for preventing surgical adhesion comprising delivering a composition that prevents surgical adhesion to a patient in need of cardiovascular repair.

  In another aspect, the present invention provides a method for preventing surgical adhesions comprising delivering a composition that prevents surgical adhesions to a patient's site in need of heart valve replacement.

  In another aspect, the present invention provides a method for preventing surgical pericardial adhesion comprising delivering a composition that prevents surgical adhesion to a patient at a required site for pericardial surgery.

  In another aspect, the present invention provides a method for preventing surgical adhesion comprising delivering a composition that prevents surgical adhesion to a site of a patient requiring orthopedic treatment.

  In another aspect, the present invention provides a method for preventing surgical adhesion comprising delivering a composition that prevents surgical adhesion to a required site of a patient's torn ligament.

  In another aspect, the present invention provides a method for preventing surgical adhesion comprising delivering a composition that prevents surgical adhesion to a site in need of joint damage in a patient.

  In another aspect, the present invention provides a method for preventing surgical adhesion comprising delivering a composition that prevents surgical adhesion to a site in need of a patient's tendon injury.

  In another aspect, the present invention provides a method for preventing surgical adhesion comprising delivering a composition that prevents surgical adhesion to a site in need of cartilage damage in a patient.

  In another aspect, the present invention provides a method of preventing surgical adhesion comprising delivering a composition that prevents surgical adhesion to a site in need of muscle damage in a patient.

  In another aspect, the present invention provides a method for preventing surgical adhesion comprising delivering a composition that prevents surgical adhesion to a site in need of nerve damage in a patient.

  In another aspect, the present invention provides a method for preventing surgical adhesion comprising delivering a composition that prevents surgical adhesion to a required site of a patient's cosmetic surgery.

  In another aspect, the present invention provides a method for preventing surgical adhesion comprising delivering a composition that prevents surgical adhesion to a site of a patient requiring reconstructive surgery.

  In another aspect, the present invention provides a method for preventing surgical adhesion comprising delivering a composition that prevents surgical adhesion to a site of a patient requiring breast augmentation.

  The methods for preventing surgical adhesion described herein can be further defined by one, two, or more of the following features: The composition is delivered with the placement of the medical implant. The composition is delivered with the placement of the medical implant, and the composition is placed in the adjacent tissue of the medical implant. The composition is delivered with the placement of the medical implant, and the composition is placed on the medical implant. The composition is delivered by an endoscope. The composition is delivered from a needle. The composition is delivered from the catheter. The composition is delivered at the time of surgery. The composition is delivered using fluoroscopic guidance.

The present invention also provides, in various aspects and examples, the following methods of treating inflammatory arthritis:
In one embodiment, the present invention provides a method for treating inflammatory arthritis comprising delivering to a patient a composition of a therapeutic agent required by the patient. This composition includes a) a polymer and / or a compound that forms a polymer in situ, and b) a fiber formation inhibitor.

  In another aspect, the present invention provides a method for preventing inflammatory arthritis, comprising delivering to a patient a composition of a therapeutic agent required by the patient. This composition includes a polymer and a fiber formation inhibitor.

  In another aspect, the present invention provides a method for treating osteoarthritis comprising delivering to a patient a composition of a therapeutic agent required by the patient. This composition includes a polymer and a fiber formation inhibitor.

  In another aspect, the present invention provides a method for preventing osteoarthritis comprising delivering to a patient a composition of a therapeutic agent required by the patient. This composition includes a polymer and a fiber formation inhibitor.

  In another aspect, the present invention provides a method for treating primary osteoarthritis comprising delivering to a patient a composition of a therapeutic agent required by the patient. This composition includes a polymer and a fiber formation inhibitor.

  In another aspect, the present invention provides a method for preventing primary osteoarthritis, comprising delivering to a patient a composition of a therapeutic agent required by the patient. This composition includes a polymer and a fiber formation inhibitor.

  In another aspect, the present invention provides a method for treating late osteoarthritis comprising delivering to a patient a composition of a therapeutic agent required by the patient. This composition includes a polymer and a fiber formation inhibitor.

  In another aspect, the present invention provides a method for preventing late osteoarthritis, comprising delivering to a patient a composition of a therapeutic agent required by the patient. This composition includes a polymer and a fiber formation inhibitor.

  In another aspect, the present invention provides a method for treating rheumatoid arthritis comprising delivering to a patient a composition of a therapeutic agent required by the patient. This composition includes a polymer and a fiber formation inhibitor.

  In another aspect, the present invention provides a method for preventing rheumatoid arthritis comprising delivering to a patient a composition of a therapeutic agent required by the patient. This composition includes a polymer and a fiber formation inhibitor.

  The methods of treating inflammatory arthritis described herein can be further defined by one, two, or more of the following characteristics: The composition is delivered by intravenous injection. The composition is delivered by oral administration. The composition is delivered by subcutaneous injection. The composition is delivered by intramuscular injection. The composition is delivered by intra-articular injection.

The present invention, in various embodiments and examples, provides the following methods of treating hypertrophic scars or keloids:
In one embodiment, according to the present invention, a) a fiber formation inhibitor necessary for a patient, or b) a composition comprising: i) a fiber formation inhibitor and ii) a polymer and / or an in situ polymer A method of treating hypertrophic scars comprising delivering a compound that forms a to a patient is provided.

  In another embodiment, according to the present invention, a) a fiber formation inhibitor necessary for a patient, or b) a composition comprising: i) a fiber formation inhibitor and ii) a polymer and / or an in situ polymer A method of treating keloids comprising delivering to a patient a compound that forms.

  In certain embodiments, the agent or composition is injected directly into the scar or keloid. In other specific examples, the agent or composition is generally applied to the scar or keloid.

The present invention also provides, in various aspects and examples, methods for reducing the following cartilage loss:
In one embodiment, according to the present invention, a) a fiber formation inhibitor necessary for a patient, or b) a composition comprising: i) a fiber formation inhibitor and ii) a polymer and / or an in situ polymer A method of reducing cartilage loss after joint injury comprising delivering a compound that forms a to a patient is provided.

  In another embodiment, according to the present invention, a) a fiber formation inhibitor necessary for a patient, or b) a composition comprising: i) a fiber formation inhibitor and ii) a polymer and / or an in situ polymer A method of preventing cartilage loss after joint injury comprising delivering to a patient a compound that forms

  In another embodiment, according to the present invention, a) a fiber formation inhibitor necessary for a patient, or b) a composition comprising: i) a fiber formation inhibitor and ii) a polymer and / or an in situ polymer A method of reducing cartilage loss after cruciate ligament rupture comprising delivering to a patient a compound that forms

  In another embodiment, according to the present invention, a) a fiber formation inhibitor necessary for a patient, or b) a composition comprising: i) a fiber formation inhibitor and ii) a polymer and / or an in situ polymer A method of preventing cartilage loss after cruciate ligament rupture comprising delivering to a patient a compound that forms.

  In another embodiment, according to the present invention, a) a fiber formation inhibitor necessary for a patient, or b) a composition comprising: i) a fiber formation inhibitor and ii) a polymer and / or an in situ polymer A method of reducing cartilage loss after meniscal ligament rupture comprising delivering a compound that forms a to a patient.

  In another embodiment, according to the present invention, a) a fiber formation inhibitor necessary for a patient, or b) a composition comprising: i) a fiber formation inhibitor and ii) a polymer and / or an in situ polymer A method of preventing cartilage loss after rupture of the meniscal ligament, comprising delivering to a patient a compound that forms.

  In certain examples, the agent or composition is delivered by intra-articular injection.

The present invention, in various embodiments and examples, provides the following methods for treating vascular disease:
In one embodiment, according to the present invention, a) a fiber formation inhibitor necessary for a patient, or b) a composition comprising: i) a fiber formation inhibitor and ii) a polymer and / or an in situ polymer A method of treating a vascular disease comprising delivering to a patient a compound that forms In certain embodiments, the drug or composition is delivered around the blood vessel.

  In another embodiment, according to the present invention, a) a fiber formation inhibitor necessary for a patient, or b) a composition comprising: i) a fiber formation inhibitor and ii) a polymer and / or an in situ polymer A method of treating stenosis comprising delivering to a patient a compound that forms In certain embodiments, the drug or composition is delivered around the blood vessel.

  In another embodiment, according to the present invention, a) a fiber formation inhibitor necessary for a patient, or b) a composition comprising: i) a fiber formation inhibitor and ii) a polymer and / or an in situ polymer A method of treating restenosis comprising delivering a compound that forms a to a patient is provided. In certain embodiments, the drug or composition is delivered around the blood vessel.

  In another embodiment, according to the present invention, a) a fiber formation inhibitor necessary for a patient, or b) a composition comprising: i) a fiber formation inhibitor and ii) a polymer and / or an in situ polymer A method of treating atherosclerosis comprising delivering to a patient a compound that forms In certain embodiments, the drug or composition is delivered around the blood vessel.

  The present invention provides, in various embodiments and examples, compositions comprising i) a fiber formation inhibitor, and ii) a polymer or a compound that forms a polymer in situ.

Additional Features for Methods and Compositions Also, in each of the foregoing aspects, one or more of the following (eg, any two, etc.) features further define the invention in terms of fibrosis inhibitors These features can be used in combination with any one or more of the devices described above (eg, certain aspects described above are further defined by the devices described above, and are further described as follows: Defined): Fibrosis inhibitors inhibit cell regeneration. Fibrosis inhibitors inhibit angiogenesis. Fibrosis inhibitors inhibit fibroblast migration. Fibrosis inhibitors inhibit fibroblast proliferation. Fibrosis inhibitors inhibit extracellular matrix deposition. Fibrosis inhibitors inhibit tissue remodeling. Fibrosis inhibitors are angiogenesis inhibitors. Fibrogenesis inhibitors are 5-lipoxygenase inhibitors or antagonists. Fibrosis inhibitors are chemokine receptor antagonists. Fibrosis inhibitors are cell cycle inhibitors. The fiber formation inhibitor is a taxane. Fibrosis inhibitors are microtubule inhibitors. The fibrosis inhibitor is paclitaxel. The fibrosis inhibitor is not paclitaxel. Fibrosis inhibitors are analogs or derivatives of paclitaxel. Fibrosis inhibitors are vinca alkaloids. The fibrosis inhibitor is camptothecin or an analogue or derivative thereof. The fibrosis inhibitor is podophyllotoxin. The fibrosis inhibitor is podophyllotoxin, where the podophyllotoxin is etoposide or an analog or derivative thereof. The fibrosis inhibitor is an anthracycline. The fibrosis inhibitor is an anthracycline, where the anthracycline is doxorubicin or an analogue or derivative thereof. The fibrosis inhibitor is an anthracycline, where the anthracycline is mitoxantrone or an analogue or derivative thereof. The fiber formation inhibitor is a platinum compound. The fiber formation inhibitor is nitrosourea. The fiber formation inhibitor is nitroimidazole. Fibrosis inhibitors are folic acid antagonists. Fibrosis inhibitors are cytidine analogs. Fibrosis inhibitors are fluoropyrimidine analogs. Fibrosis inhibitors are purine analogs. The fiber formation inhibitor is nitrogen mustard or an analogue or derivative thereof. The fiber formation inhibitor is hydroxyurea. The fibrosis inhibitor is mitomycin or an analogue or derivative thereof. The fiber formation inhibitor is an alkyl sulfonate. The fibrosis inhibitor is benzamide or an analogue or derivative thereof. The fibrosis inhibitor is nicotinamide or an analogue or derivative thereof. The fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. Fiber formation inhibitors are DNA alkylating agents. Fibrosis inhibitors are microtubule inhibitors. Fibrosis inhibitors are microtubule inhibitors. Fibrosis inhibitors are topoisomerase inhibitors. Fiber formation inhibitors are DNA cleaving agents. Fibrosis inhibitors are antimetabolites. Fibrosis inhibitors inhibit adenosine deaminase. Fibrosis inhibitors inhibit purine ring synthesis. Fiber formation inhibitors are nucleotide conversion inhibitors. Fibrosis inhibitors inhibit the reduction of hydrofolic acid. Fibrosis inhibitors inhibit thymidine monophosphate. Fibrosis inhibitors cause DNA damage. Fiber formation inhibitors are DNA intercalators. Fiber formation inhibitors are RNA synthesis inhibitors. Fibrogenesis inhibitors are pyrimidine synthesis inhibitors. Fibrosis inhibitors inhibit ribonucleotide synthesis or function. Fibrosis inhibitors inhibit thymidine monophosphate synthesis or function. Fiber formation inhibitors inhibit DNA synthesis. Fiber formation inhibitors cause DNA adduct formation. Fibrosis inhibitors inhibit protein synthesis. Fibrosis inhibitors inhibit microtubule function. Fibrogenesis inhibitors are cyclin dependent protein kinase inhibitors. Fibrosis inhibitors are epidermal growth factor kinase inhibitors. Fibrosis inhibitors are elastase inhibitors. Fibrosis inhibitors are factor Xa inhibitors. Fiber formation inhibitors are farnesyltransferase inhibitors. Fibrogenesis inhibitors are fibrinogen antagonists. Fibrosis inhibitors are guanylate cyclase stimulants. Fibrosis inhibitors are heat shock protein 90 antagonists. The fibrosis inhibitor is a heat shock protein 90 antagonist, where the shock protein 90 antagonist is geldanamycin or an analog or derivative thereof. Fibrosis inhibitors are guanylate cyclase stimulants. Fibrosis inhibitors are HMGCoA reductase inhibitors. The fiber formation inhibitor is an HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analog or derivative thereof. Fibrosis inhibitors are hydroorotic acid dehydrogenase inhibitors. Fibrosis inhibitors are IKK2 inhibitors. Fibrosis inhibitors are IL-1 antagonists. Fibrosis inhibitors are ICE antagonists. Fibrosis inhibitors are IRAK antagonists. Fibrosis inhibitors are IL-4 antagonists. Fibrosis inhibitors are immunomodulators. The fibrosis inhibitor is sirolimus or an analogue or derivative thereof. The fibrosis inhibitor is not sirolimus. The fibrosis inhibitor is everolimus or an analogue or derivative thereof. The fibrosis inhibitor is tacrolimus or an analogue or derivative thereof. The fibrosis inhibitor is not tacrolimus. The fibrosis inhibitor is biolimus or an analogue or derivative thereof. The fibrosis inhibitor is tresperimus or an analogue or derivative thereof. The fibrosis inhibitor is auranofin or an analogue or derivative thereof. The fibrosis inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The fibrosis inhibitor is gusperimus or an analogue or derivative thereof. The fibrosis inhibitor is pimecrolimus or an analogue or derivative thereof. The fibrosis inhibitor is ABT-578 or an analogue or derivative thereof. Fibrosis inhibitors are inosine monophosphate dehydrogenase (IMPDH) inhibitors. The fibrosis inhibitor is an IMPDH inhibitor, where the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof. The fibrosis inhibitor is an IMPDH inhibitor, where the IMPDH inhibitor is 1-α-25 dihydroxyvitamin D ₃ or an analogue or derivative thereof. The fiber formation inhibitor is a leukotriene inhibitor. Fibrosis inhibitors are MCP-1 antagonists. Fibrosis inhibitors are MMP inhibitors. Fibrosis inhibitors are NFκB inhibitors. The fiber formation inhibitor is an NFκB inhibitor, where the NFκB inhibitor is Bay11-7082. Fibrosis inhibitors are NO antagonists. Fibrosis inhibitors are p38 MAP kinase inhibitors. The fibrosis inhibitor is a p38 MAP kinase inhibitor, where the p38 MAP kinase inhibitor is SB 202190. Fibrosis inhibitors are phosphodiesterase inhibitors. Fibrosis inhibitors are TGFβ inhibitors. Fibrosis inhibitors are thromboxane A2 antagonists. Fibrosis inhibitors are TNFα antagonists. Fibrosis inhibitors are TACE inhibitors. Fibrosis inhibitors are tyrosine kinase inhibitors. Fibrogenesis inhibitors are vitronectin inhibitors. Fibrosis inhibitors are fibroblast growth factor inhibitors. Fibrosis inhibitors are protein kinase inhibitors. Fibrosis inhibitors are PDGF receptor kinase inhibitors. Fibrosis inhibitors are endothelial growth factor receptor kinase inhibitors. Fibrosis inhibitors are retinoic acid receptor antagonists. Fibrosis inhibitors are platelet derived growth factor receptor kinase inhibitors. Fibrogenesis inhibitors are fibrinogen antagonists. Fibrosis inhibitors are antifungal agents. The fiber formation inhibitor is an antifungal agent, where the antifungal agent is sulconizole. The fiber formation inhibitor is bisphosphonate. Fibrosis inhibitors are phospholipase A1 inhibitors. Fibrosis inhibitors are histamine H1 / H2 / H3 receptor antagonists. Fibrosis inhibitors are macrolide antibiotics. Fibrosis inhibitors are GPIIb / IIIa receptor antagonists. Fibrosis inhibitors are endothelin receptor antagonists. Fibrosis inhibitors are peroxisome proliferator-responsive receptor antagonists. Fibrosis inhibitors are estrogen receptor drugs. Fibrosis inhibitors are somastatin analogs. Fibrosis inhibitors are neurokinin 1 antagonists. Fibrosis inhibitors are neurokinin 3 antagonists. Fibrosis inhibitors are VLA-4 antagonists. Fibrosis inhibitors are osteoclast inhibitors. The fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. Fibrosis inhibitors are angiotensin II antagonists. The fiber formation inhibitor is an enkephalinase inhibitor. Fibrosis inhibitors are peroxisome proliferator-responsive receptor gamma agonist insulin sensitizers. Fibrosis inhibitors are protein kinase C inhibitors. Fibrosis inhibitors are ROCK (Rho kinase) inhibitors. Fibrosis inhibitors are CXCR3 inhibitors. Fibrosis inhibitors are Itk inhibitors. Fibrosis inhibitors are cytosolic phospholipase A ₂ alpha inhibitors. Fibrosis inhibitors are PPAR agonists. Fibrosis inhibitors are immunosuppressants. Fibrosis inhibitors are Erb inhibitors. Fibrosis inhibitors are apoptosis agonists. Fibrogenesis inhibitors are lipocortin agonists. Fibrosis inhibitors are VCAM-1 antagonists. Fibrosis inhibitors are collagen antagonists. Fibrosis inhibitors are α2 integrin antagonists. Fibrosis inhibitors are TNFα inhibitors. Fibrosis inhibitors are nitric oxide inhibitors. Fibrosis inhibitors are cathepsin inhibitors. Fibrosis inhibitors are not anti-inflammatory drugs. Fibrosis inhibitors are not steroids. Fibrosis inhibitors are not glucocorticosteroids. The fibrosis inhibitor is not dexamethasone. The fibrosis inhibitor is not beclomethasone. The fibrosis inhibitor is not propionic acid. Fibrosis inhibitors are not anti-infectives. Fibrosis inhibitors are not antibiotics. And / or the fibrosis inhibitor is not an antifungal agent.

  Also, in each of the foregoing aspects, one or more of the following features (eg, any two, etc.) can be used to further define the invention with respect to anti-infective agents, and these features can be (Eg, certain embodiments described above are further defined by the devices described above, and are further defined as follows): The anti-infective is an anthracycline . The anti-infective drug is doxorubicin. The antiinfective is mitoxantrone. The anti-infective agent is fluoropyrimidine. The anti-infective agent is 5-fluorouracil (5-FU). Anti-infectives are leaf antagonists. The anti-infective drug is methotrexate. The anti-infective agent is podophyllotoxin. The antiinfective is etoposide. The anti-infective agent is camptothecin. The anti-infective agent is hydroxyurea. The anti-infective agent is a platinum complex. And / or the anti-infective is cisplatin. The composition can further optionally comprise an antithrombotic agent.

  Also, in each aspect described above, one or more of the following features (eg, any two, etc.) can be used to further define the invention with respect to the polymer, and these features can be Can be combined with one or more devices, fibrosis inhibitors and anti-infective agents (e.g., certain embodiments described above are further defined by a particular device and a particular fibrosis inhibitor, and Further defined): The polymer is formed from a reactant consisting of a naturally occurring polymer. Polymers are formed from reactants consisting of proteins. Polymers are formed from reactants consisting of carbohydrates. The polymer is formed from a reactant comprising a biodegradable polymer. The polymer is formed from a reactant comprising a non-biodegradable polymer. The polymer is formed from a reactant consisting of collagen. The polymer is formed from a reactant consisting of methylated collagen. The polymer is formed from a reactant consisting of fibrinogen. The polymer is formed from a reactant consisting of thrombin. The polymer is formed from a reactant consisting of plasma. The polymer is formed from a reactant comprising a calcium salt. The polymer is formed from a reactant consisting of an antifibrinolytic agent. The polymer is formed from a reactant comprising a fibrinogen analog. The polymer is formed from a reactant consisting of albumin. The polymer is formed from a reactant consisting of plasminogen. The polymer is formed from a reactant consisting of von Willebrand factor. The polymer is formed from a reactant consisting of Factor VIII. The polymer is formed from a reactant consisting of hypoallergenic collagen. The polymer is formed from a reactant consisting of atelopeptide collagen. The polymer is formed from a reactant consisting of telopeptide collagen. The polymer is formed from a reactant consisting of cross-linked collagen. The polymer is formed from a reactant consisting of aprotinin. The polymer is formed from a reactant consisting of epsilon amino-n-caproic acid. The polymer is formed from a reactant consisting of gelatin. The polymer is formed from a reactant comprising a protein conjugate. The polymer is formed from a reactant comprising a gelatin conjugate. The polymer is formed from a reactant comprising a synthetic polymer. The polymer is formed from a reactant comprising a synthetic isocyanate-containing compound. The polymer is formed from a reactant comprising a synthetic thiol-containing compound. The polymer is formed from a reactant comprising a synthetic compound containing at least two thiol groups. The polymer is formed from a reactant consisting of a synthetic compound containing at least three thiol groups. The polymer is formed from a reactant consisting of a synthetic compound containing at least four thiol groups. The polymer is formed from a reactant comprising a synthetic amino-containing compound. The polymer is formed from a reactant comprising a synthetic compound containing at least two amino groups. The polymer is formed from a reactant composed of a synthetic compound containing at least three amino groups. The polymer is formed from a reactant composed of a synthetic compound containing at least four amino groups. The polymer is formed from a reactant comprising a synthetic compound containing a carbonyl oxygen succinimidyl group. The polymer is formed from a reactant comprising a synthetic compound containing at least two carbonyl oxygen succinimidyl groups. The polymer is formed from a reactant composed of a synthetic compound containing at least three carbonyl oxygen succinimidyl groups. The polymer is formed from a reactant composed of a synthetic compound containing at least four carbonyl oxygen succinimidyl groups. The polymer is formed from a reactant comprising a synthetic polyalkylene oxide-containing compound. The polymer is formed from a reactant comprising a synthetic compound containing both polyalkylene oxide and biodegradable polyester blocks. The polymer is formed from a reactant comprising a polyalkylene oxide-containing synthetic compound having a reactive amino group. The polymer is formed from a reactant comprising a polyalkylene oxide-containing synthetic compound having a reactive thiol group. The polymer is formed from a reactant comprising a polyalkylene oxide-containing synthetic compound having a reactive carbonyl oxygen succinimidyl group. The polymer is formed from a reactant comprising a synthetic compound containing a block of biodegradable polyester. The polymer is formed from a reactant consisting of a synthetic polymer, wholly or partly formed from lactic acid or lactide. The polymer is formed from a reactant composed of a synthetic polymer formed in whole or in part from glycolic acid or glycolide. The polymer is formed from a reactant composed of polylysine. The polymer is formed from a reactant comprising (a) a protein and (b) a compound containing an oxidized polyalkylene moiety. The polymer is formed from a reactant consisting of (a) a protein and (b) polylysine. The polymer is formed from a reactant comprising (a) a protein and (b) a compound having at least four thiol groups. The polymer is formed from a reactant comprising (a) a protein and (b) a compound having at least four amino groups. The polymer is formed from a reactant comprising (a) a protein and (b) a compound having at least four carbonyl oxygen succinimide groups. The polymer is formed from a reactant comprising (a) a protein and (b) a compound having a biodegradable site formed from a reactant selected from lactic acid, lactide, glycolic acid, glycolide, and e-caprolactone. The polymer is formed from a reactant comprising (a) collagen and (b) a compound containing an oxidized polyalkylene moiety. The polymer is formed from a reactant consisting of (a) collagen and (b) polylysine. The polymer is formed from a reactant comprising (a) collagen and (b) a compound having at least four thiol groups. The polymer is formed from a reactant comprising (a) collagen and (b) a compound having at least four amino groups. The polymer is formed from a reactant comprising (a) collagen and (b) a compound having at least four carbonyl oxygen succinimide groups. The polymer is formed from a reactant comprising (a) collagen and (b) a compound having a biodegradable site formed from a reactant selected from lactic acid, lactide, glycolic acid, glycolide, and e-caprolactone. The polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound containing an oxidized polyalkylene moiety. The polymer is formed from a reactant consisting of (a) methylated collagen and (b) polylysine. The polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having at least four thiol groups. The polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having at least four amino groups. The polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having at least four carbonyl oxygen succinimide groups. The polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having a biodegradable site formed from a reactant selected from lactic acid, lactide, glycolic acid, glycolide, and e-caprolactone. . The polymer is formed from a reactant consisting of hyaluronic acid. The polymer is formed from a reactant comprising a hyaluronic acid derivative. The polymer is formed from a reactant consisting of pentaerythritol poly (ethylene glycol) ether tetrasulfhydryl with an average molecular weight between 3,000 and 30,000. The polymer is formed from a reactant composed of pentaerythritol poly (ethylene glycol) ether tetraamino having an average molecular weight between 3,000 and 30,000. The polymer comprises (a) a synthetic compound with an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene moiety and a polynucleophilic group, and (b) a synthetic compound with an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene moiety and Formed from a reactant comprising a multi-electrophilic group. The composition comprises a colorant. The composition is also sterile.

  The following examples are provided by way of illustration and are not intended to be limiting.

Example 1
Preparation of drug-filled microspheres by spray drying
3.6 grams of methoxypoly (ethylene glycol 5000))-block- (poly (DL-lactide). (65:35 MePEG: PDLLA load distribution ratio) was dissolved in 200 ml of dichloromethane.400 grams of drug (mycophenolic acid ( MPA))), chlorpromazine (CPZ) or paclitaxel (PTX)) were added and the resulting solution was spray dried. Inlet temperature 50 ° C, outlet temperature <39 ° C, suction machine 100%, flow rate 700 l / hr. The collected microspheres were dried overnight at room temperature under vacuum to produce uniform, spherical particles having a size in the range of about 10 microns (usually about 0.5 to about 2 microns) or less.

Example 2
MPA-filled microspheres with w / o / w emulsification (<10 microns)
100 ml of freshly prepared 10% polyvinyl alcohol (PVA) solution and 10 ml of pH 3 acetic acid solution saturated with MPA were added to a 600 ml beaker. The acidified PVA solution was stirred for 30 minutes at a speed of 2000 rpm. Meanwhile, a solution of 400 mg MPA and 800 mg MePEG5000-PDLLA (65:35) in 20 ml dichloromethane was prepared. While stirring with a Fisher Dyna-Mix stirrer at a speed of 2000 rpm, the polymer / dichloromethane solution was added dropwise to the PVA solution. After the addition was complete, the solution was allowed to stir for an additional 45 minutes. The microsphere solution was transferred to several disposable graduated polypropylene conical centrifuge tubes, washed with a pH 3 acetic acid solution saturated with MPA, and centrifuged at 2600 rpm for 10 minutes. The aqueous solution layer was transferred to a decanter and washed, centrifuged, and transferred to the decanter three times. The coalesced and washed microspheres were lyophilized and vacuum dried to remove excess moisture.

Example 3
MPA containing microspheres (50-100 micro) by emulsification
Microspheres with an average size of about 50-100 microns were prepared by the same procedure described in Example 2 using a 1% PVA solution and a stirring speed of 500 rpm.

Example 4
CPZ and PTX containing microspheres by w / o / w emulsification
PTX and CPZ containing microspheres were prepared using the procedure described in Example 2 except that the PVA and wash solutions were not acidified and need not be saturated with drug.

Example 5
Paclitaxel containing micelles
MePEG2000 (41 g) and MePEG2000-PDLLA (60:40) (410 g) were mixed in a container and heated to 75 ° C. with stirring. After the polymer was completely melted and mixed, the temperature was lowered to 55 ° C. Meanwhile, a solution of tetrahydrofuran (46 g / 200 ml) in PTX was prepared and poured into the polymer with constant stirring. Stirring was continued for an additional hour. PTX containing micelles was dried at 50 ° C. under vacuum to remove the solvent, and after cooling, was ground on a 2 mm mesh screen.

Example 6
Tetrafunctional poly (ethylene glycol) succinimidyl glutarate, (PEG-SG4), non-gelling formulation PEG-SG4 (100 mg) (Sunbio, Inc., Olinda, California). 0.25 ml of a 6.3 mM HCl solution (pH 2.1) was weighed into a capped 1 ml syringe (syringe 2). To a capped 1 ml syringe (syringe 3) was weighed 0.25 ml of a buffer of 0.12 M monosodium phosphate and 0.2 M sodium carbonate (pH 9.7). The solid contents of syringe 1 and the acidic solution of syringe 2 were mixed through the mixing connector by repeatedly transferring the contents from one syringe to the other. After mixing was complete, the entire mixture was extruded into one syringe. A syringe containing the mixture was then attached to one inlet of the applicator (Micromedics Air Assisted Spray Applicator (Model SA-6105)). A syringe 3 with a pH 9.7 solution was attached to another inlet of the applicator. The formulation was applied to the tissue surface according to the applicator manufacturer's instructions.

Example 7
Gelled preparation (premixed) I
PEG-SG4 (50 mg) and PEG-SH4 (4-functional poly (ethylene glycol) thiol) (50 mg) (Sunbio, Inc.) (Sunbio, Inc.) Weighed the mixture. 0.25 ml of a 6.3 mM HCl solution (pH 2.1) was weighed into a capped 1 ml syringe (syringe 2). To a capped 1 ml syringe (syringe 3) was weighed 0.25 ml of a buffer of 0.12 M monosodium phosphate and 0.2 M sodium carbonate (pH 9.7). The composition was mixed and applied to the tissue surface according to the procedure described in Example 6.

Example 8
Tetrafunctional poly (ethylene glycol) amine, (PEG-N4) gelled formulation PEG-SG4 (50 mg) and PEG-SH4 (tetrafunctional poly (ethylene glycol)) in a 1 ml syringe (syringe 1) with lualock mixing connector Thiol) (10, 25 or 40 mg) was weighed. 0.25 ml of a 6.3 mM HCl solution (pH 2.1) was weighed into a capped 1 ml syringe (syringe 2). To a capped 1 ml syringe (syringe 3) was weighed 0.25 ml of a buffer of 0.12 M monosodium phosphate and 0.2 M sodium carbonate (pH 9.7). Weigh PEG-N4 (Sunbio, Inc.) (40, 25, or 10 mg) into a 1 ml syringe with luer lock mixing connector (syringe 4) and mix PEG-SH4 (syringe 1) and PEG-N4 (syringe 4) ( A total of 50 mg) was prepared. The contents of syringe 1 and syringe 2 were mixed through a mixing connector by repeatedly transferring the contents from one syringe to the other. After mixing was complete, all the formulation was extruded into one of the syringes, which was then attached to one inlet of the applicator (Micromedics Air Assisted Spray Applicator (Model SA-6105)). With a mixing connector, syringe 4 was attached to syringe 3 containing pH 9.7 solution. After completing the mixing of the contents of Syringe 3 and Syringe 4, the mixture was extruded into one of the syringes, which was subsequently attached to the second inlet of the applicator. The formulation was applied to the tissue surface according to the applicator manufacturer's instructions.

Example 9
Mycophenolic acid and disodium salt of MPA (Na ₂ MPA) in PEG-SG4
Preparation of the disodium salt of MPA (Na ₂ MPA): Na ₂ MPA is prepared by dissolving MPA (1, 10, or 100 g) in IPA (44 ml, 440 ml, or 4.4 L, respectively) A 2 molar equivalent of 1M NaOH (aq) was quickly added to the vigorously stirred solution. The resulting suspension was boiled until it became a clear yellow solution. Stirring was stopped and the solution was cooled to room temperature. The resulting crystal pieces were mechanically moved, filtered, washed with a large amount of IPA and further dried under vacuum to Na ₂ MPA yellowish white highly crystalline fibers (usually 70-80% Yield).

PEG-SG4 (100 mg) was weighed into a 1 ml syringe (syringe 1) with a luer lock mixing connector. 0.25 ml of a 6.3 mM HCl solution (pH 2.1) was weighed into a capped 1 ml syringe (syringe 2). To a capped 1 ml syringe (syringe 3) was weighed 0.25 ml of a buffer of 0.12 M monosodium phosphate and 0.2 M sodium carbonate (pH 9.7). MPA (5 mg) and Na ₂ MPA (95 mg) sieved to less than 100 microns were weighed into a 1 ml syringe with a luer lock mixing connector (syringe 4). The contents of syringe 4 and syringe 2 were mixed through the mixing connector by repeatedly transferring the contents from one syringe to the other. Subsequently, this solution was used to reconstitute the solid in syringe 1. After mixing was complete, all the formulation was extruded into one of the syringes, which was then attached to one inlet of the applicator (Micromedics Air Assisted Spray Applicator (Model SA-6105)). A syringe 3 with a pH 9.7 solution was attached to another inlet of the applicator. The formulation was applied to the tissue surface according to the applicator manufacturer's instructions.

Example 10
A mixture of PEG-SH4 (50 mg), PEG-SG4 (50 mg) and MPA (100 mg, <100 microns) was weighed into a 1 ml syringe (syringe 1) with a mycophenolate lualock mixing connector in the premix. 0.25 ml of a 6.3 mM HCl solution (pH 2.1) was weighed into a capped 1 ml syringe (syringe 2). A capped 1 ml syringe (syringe 3) was weighed with 0.35 ml of 0.24 M monosodium phosphate and 0.4 M sodium carbonate (pH 10.0) buffer. The composition was mixed and applied to the tissue surface according to the procedure described in Example 6.

Example 11
Mycophenolic acid and disodium salt of MPA (Na ₂ MPA) in premix The mixture of PEG-SG4 (50 mg) and PEG-SH4 (50 mg) was weighed into a 1 ml syringe (syringe 1) with a lualock mixing connector. 0.25 ml of a 6.3 mM HCl solution (pH 2.1) was weighed into a capped 1 ml syringe (syringe 2). To a capped 1 ml syringe (syringe 3) was weighed 0.25 ml of a buffer of 0.12 M monosodium phosphate and 0.2 M sodium carbonate (pH 9.7). MPA (5 mg) and Na ₂ MPA (95 mg) sieved to less than 100 microns were weighed into a 1 ml syringe with a luer lock mixing connector (syringe 4). The composition was mixed and applied to the tissue surface according to the procedure described in Example 9.

Example 12
A mixture of PEG-SG4 (50 mg), PEG-SH4 (50 mg) and CPZ (5 or 10 mg) was weighed into a 1 ml syringe (syringe 1) with a chlorpromazine lurolock mixing connector in the premix. 0.25 ml of a 6.3 mM HCl solution (pH 2.1) was weighed into a capped 1 ml syringe (syringe 2). To a capped 1 ml syringe (syringe 3) was weighed 0.25 ml of a buffer of 0.12 M monosodium phosphate and 0.2 M sodium carbonate (pH 9.7). The composition was mixed and applied to the tissue surface according to the procedure described in Example 6.

Example 13
10% prepared by PEG-SG4 (50 mg), PEG-SH4 (50 mg) and spray-dried (0.5 or 0.2 mg) in a 1 ml syringe (syringe 1) with paclitaxel-filled microsphere-aloc mixing connector in premix A mixture of MePEG5000-PDLLA (65:35) microspheres (prepared using the procedure described in Example 17) loaded with PTX was weighed. 0.25 ml of a 6.3 mM HCl solution (pH 2.1) was weighed into a capped 1 ml syringe (syringe 2). To a capped 1 ml syringe (syringe 3) was weighed 0.25 ml of a buffer of 0.12 M monosodium phosphate and 0.2 M sodium carbonate (pH 9.7). The composition was mixed and applied to the tissue surface according to the procedure described in Example 1.

Example 14
10% CPZ prepared by PEG-SG4 (50 mg), PEG-SH4 (50 mg) and spray drying (50 or 100 mg) in a 1 ml syringe (syringe 1) with CPZ-filled microsphere-alloque mixing connector in premix A mixture of MePEG5000-PDLLA (65:35) microspheres (prepared using the procedure described in Example 17) was weighed. 0.25 ml of a 6.3 mM HCl solution (pH 2.1) was weighed into a capped 1 ml syringe (syringe 2). To a capped 1 ml syringe (syringe 3) was weighed 0.25 ml of a buffer of 0.12 M monosodium phosphate and 0.2 M sodium carbonate (pH 9.7). The composition was mixed and applied to the tissue surface according to the procedure described in Example 6.

Example 15
10% MPA prepared by PEG-SG4 (50 mg), PEG-SH4 (50 mg) and spray drying (25 or 75 mg) in a 1 ml syringe (syringe 1) with MPA-filled microsphere-alloque mixing connector in premix A mixture of MePEG5000-PDLLA (65:35) microspheres (prepared using the procedure described in Example 17) was weighed. 0.25 ml of a 6.3 mM HCl solution (pH 2.1) was weighed into a capped 1 ml syringe (syringe 2). 0.35 ml of a buffer of 0.24 M monosodium phosphate and 0.4 M sodium carbonate (pH 10.0) was weighed into a capped 1 ml syringe (syringe 3). The composition was mixed and applied to the tissue surface according to the procedure described in Example 6.

Example 16
Incorporation of PTX-filled micelles into premix A mixture of PEG-SG4 (50 mg) and PEG-SH4 (50 mg) was weighed into a 1 ml syringe (syringe 1) with luer lock mixing connector. 1.5 ml of a 6.3 mM HCl solution (pH 2.1) was weighed into a 2 ml serum vial. A capped 1 ml syringe (syringe 2) was weighed with 0.25 ml of a buffer of 0.12 M monosodium phosphate and 0.2 M sodium carbonate (pH 9.7). A A micelle (2 mg or 8 mg) filled with 10% PTX (prepared as described in Example 21) was weighed into a 2 ml serum vial and reconstituted with 1 ml of pH 2.1 solution. Remove the 0.25 ml micelle solution with a 1 ml syringe, attach the syringe to syringe 1 containing solids PEG-SG4 and PEG-SH4, and its components are transferred from one syringe to the other. By repeated transfer, it was mixed through the mixing connector. After mixing was complete, all the mixture was extruded into one of the syringes, which was then attached to one inlet of the applicator (Micromedics Air Assisted Spray Applicator (Model SA-6105)). A syringe 3 with a pH 9.7 solution was attached to another inlet of the applicator. The formulation was applied to the tissue surface according to the applicator manufacturer's instructions.

Example 17
Tetrafunctional poly (ethylene glycol) succinimidyl glutarate, (PEG-SG4), non-gelling preparation PEG-SG4 (400 mg) contained in a 3 ml syringe (syringe 1) with luer lock mixing connector was weighed. 1.0 ml of a 6.3 mM HCl solution (pH 2.1) was weighed into a capped 3 ml syringe (syringe 2). To a capped 3 ml syringe (syringe 3) was weighed 1 ml of 0.12 M monosodium phosphate and 0.2 M sodium carbonate (pH 9.7) buffer. The composition was mixed and applied to the tissue surface according to the procedure described in Example 6.

Example 18
Gelled preparation (premix) II
A mixture of PEG-SG4 (200 mg) and PEG-SH4 (200 mg) was weighed into a 3 ml syringe with a luer lock mixing connector (syringe 1). 1.0 ml of a 6.3 mM HCl solution (pH 2.1) was weighed into a capped 3 ml syringe (syringe 2). To a capped 3 ml syringe (syringe 3) was weighed 1 ml of a buffer of 0.12 M monosodium phosphate and 0.2 M sodium carbonate (pH 9.7). The composition was mixed and applied to the tissue surface according to the procedure described in Example 6.

Example 19
A mixture of PEG-SG4 (200 mg), PEG-SH4 (200 mg) and MPA (200 mg or 400 mg) was weighed into a 3 ml syringe (syringe 1) with a pre-mixed Luaroque mixing connector filled with MPA. 1 ml of a 6.3 mM HCl solution (pH 2.1) was weighed into a capped 3 ml syringe (syringe 2). To a capped 3 ml syringe (syringe 3) was weighed 1.5 ml of 0.24 M monosodium phosphate and 0.4 M sodium carbonate (pH 10) buffer. The composition was mixed and applied to the tissue surface according to the procedure described in Example 6.

Example 20
Screening test to assess the efficacy of various compounds against nitric oxide produced by macrophages The mouse macrophage cell line RAW 264.7 is trypsinized to remove cells from the flask and placed in individual wells of a 6-well plate did. Approximately 2 × 10 ⁶ cells were placed in 2 ml of medium containing 5% heat-inactivated fetal bovine serum (FBS). RAW 264.7 cells were cultured for 1.5 hours at 37 ° C so that they could adhere to plastic. Mitoxantrone was prepared in DMSO at a concentration of 10 ⁻² M and serially diluted 10-fold to allow for a range of strain concentrations (10 ⁻⁸ M to 10 ⁻² M). The medium was then removed and cultured in 1 ng / ml of recombinant mouse IFNγ and 5 ng / ml of LPS, regardless of the presence of mitoxantrone in fresh medium containing 5% FBS. Mitoxantrone was added to the cells by directly adding the mitoxantrone DMSO strain solution prepared so far to each well at a 1/1000 dilution. Plates containing IFNγ and LPS (with or without mitoxanone) were cultured at 37 ° C. for 24 hours (Chem. Ber. (1879) 12: 426. J. AOAC (1977) 60-594. Ann. Rev. Biochem. ( 1994) 63: 175).

After 24 hours, supernatants were collected from the cells and evaluated for nitrogen production. Divide 50 μL of the supernatant from the 96-well plate in a 96-well plate and add 50 μL Greiss Reagent A (0.5 g sulfanilamide, 1.5 ml H ₃ PO ₄ , 48.5 ml ddH ₂ O) and 50 μL Greiss Reagent B (0.05 Each sample was tested in triplicate by adding g N- (1-naphthyl) -ethylenediamine, 1.5 ml H ₃ PO ₄ , 48.5 ml ddH ₂ O). The optical density on a microplate photometer was measured immediately at 562 nm absorbance. Absorbance for triplicate wells was averaged after subtracting the background to give a nitrite calibration curve (1 μM to 2 mM). The 50% inhibitory concentration (IC ₅₀ ) was determined by comparing the average concentration of nitrite with a control drug (cells stimulated by IFNγ and LPS). On average, n = 4 replicates were used to determine mitoxantrone IC ₅₀ values (see FIG. 2 (IC ₅₀ = 927 mn)). IC ₅₀ values for the following additional compounds were determined using this test method: IC ₅₀ (nM): paclitaxel, 7. CNI-1493, 249. Halofujinone, 12. Geldanamycin, 51. Anisomycin, 68. 17-AAG, 840. Epirubicin hydrochloride, 769.

Example 21
Screening test to evaluate the efficacy of various scar suppressants against TNF-α produced by macrophages
A human macrophage cell line, THP-1, was placed in a 12-well plate so that each well contained 1 × 10 ⁶ cells in 2 ml medium containing 10% FCS. Opsonized zymosan was prepared by resuspending 20 mg zymosan A in 2 ml ddH ₂ O and homogenizing until a uniform suspension was obtained. Homogenized zymosan is pelleted at 250 g, resuspended in 4 mL human serum to a final concentration of 5 mg / ml, and incubated in a 37 ° C water bath for 20 minutes to allow opsonization. It was. The Bay11-7082 concentration 10 ^-2 M was prepared in DMSO, impart a width concentration of strain (10 ^-8 M~10 ^-2 M) to serially diluted in 10-fold for (J.Immunol. (2000) 165 411-418, J. Immunol. (2000) 164: 4804-4811, J. ImmunolMeth. (2000) 235 (1-2): 33-40).

  THP-1 cells were stimulated to produce TNFα by adding 1 mg / ml opsonized zymosan. Bay11-7082 was added to the cells by adding DMSO strain solution prepared so far directly to each well at a 1/1000 dilution. Each drug concentration was tested in triplicate wells. Plates were incubated at 37 ° C for 24 hours.

After stimulation for 24 hours, supernatants were collected to quantify TNFα production. The TNFα concentration of the supernatant was determined by ELISA using recombinant human TNFα to obtain a standard curve. A 96-well MaxiSorb plate was coated with 100 μL μl of anti-human TNFα capture antibody diluted in coating buffer (0.1 M 0.1M sodium carbonate ph 9.5) at 4 ° C. overnight. The dilution of capture antibody used was lot specific and was determined experimentally. The capture antibody was then aspirated and the plate was washed 3 times with wash buffer (PBS, 0.05% Tween-20). Plates were blocked with 200 μL μl / well assay diluent (PBS, 10% FCS pH 7.0) for 1 hour at room temperature. After blocking, the plate was washed 3 times with wash buffer. Standard dilutions and sample dilutions were prepared as follows: (a) the sample supernatant, _^1/8 and _^1/16, (b) recombinant human TNFα is prepared in 500 pg / ml, the calibration curve 7.8 Serial dilutions were made to yield pg / ml to 500 pg / ml. Sample supernatants and calibration curves were measured in triplicate and incubated at room temperature for 2 hours after adding the plate coated with capture antibody. The plate was washed 5 times and incubated with 100 μL of Working Detector (biotinylated anti-human TNFα detection antibody + avidin-HRP) for 1 hour at room temperature. After this culture, the plate was washed 7 times, 100 μL of substrate solution (tetramethylbenzidine, H ₂ O ₂ ) was added to the plate, and incubated at room temperature for 30 minutes. A stop solution (2 NH ₂ SO ₄ ) was then added to the wells and the yellow reaction was measured at 450 nm with a λ correction of 570 nm. The average absorbance was determined based on the data measured three times, and the average background was subtracted. TNFα concentration values were obtained from a calibration curve. The 50% inhibitory concentration (IC ₅₀ ) was determined by comparing the TNFα mean concentration with a control drug (which stimulated THP-1 cells by opsoinized zymosan). On average, n = 4 replicates were used to determine IC ₅₀ values for Bay11-7082 (see Figure 3, IC ₅₀ = 810 nM) and rapamycin (IC ₅₀ = 51 nM, Figure 4) . IC ₅₀ values for the following additional compounds were determined using this test method: IC ₅₀ (nM): Geldanamycin, 14. Mycophenolic acid, 756. Mofetil, 792. Chlorpromazine, 6. CNI-1493, 0.15. SKF 86002, 831. 15-deoxyprostaglandin J2, 742. Fascapricin, 701. Podophyllotoxin, 75. Mitromycin, 570. Daunorubicin, 195. Celastrol, 87. Chromomycin A3, 394. Vinorelbine, 605. Vinblastine, 65.

Example 22
Surgical Adhesive Model for Assessing Fibrosis Inhibitors in Rats To assess the fiber-forming ability of formulations in vivo, the rat cecal sidewall model is used. Anesthetize SD rats (Sprague Dawley rats) with halothane. A midline abdominal incision is made using aseptic pretreatment. The cecum is exposed and removed from the abdominal cavity. Using a # 10 scalpel blade, the dorsal and ventral sides of the cecum are scraped continuously for a total of 45 times to the end of 1.5 cm. Blade angle and pressure are controlled to produce punctate bleeding while avoiding severe tissue damage. The left side of the abdomen is retracted or turned over to expose a portion of the peritoneal wall located adjacent to the cecum. Excise the surface of the muscle (side of the abdomen) in a 1X 2 cm ² area, leaving behind broken fibers from the second layer of muscle (inner oblique). Tampons are inserted into the abraded surface until bleeding stops. The scraped cecum is then positioned over the side wall wound and attached with two sutures. The formulation is applied to both sides of the scraped cecum and the scraped peritoneal sidewall. Two more sutures are placed and the cecum is attached to the damaged side wall with a total of four sutures, and the abdominal incision is closed in two layers. After 7 days, the extent and severity of adhesions are scored for both quantity and quality, and the animals are evaluated postmortem.

Example 23
Surgical Adhesive Model for Assessing Fibrosis Inhibitors in Rabbits To assess the fiber-forming ability of a formulation in vivo, a rabbit uterine horn model is used. Anesthetize a mature New Zealand White (NZW) rabbit. Using aseptic pretreatment, a midline abdominal incision is made in two layers to expose the uterus. Both uterine horns are removed from the abdominal cavity and sized on the French scale of the catheter. Angles between # 8 and # 14 (diameter 2.5 to 4.5 mm) on the French scale are considered suitable for this model. Scratch both the uterine horn and the contralateral peritoneal sidewall with a # 10 scalpel blade at a 45 degree angle to a 2.5 cm long and 0.4 cm wide area until punctate bleeding is observed . Tampons are inserted into the abraded surface until bleeding stops. The individual corners are then placed against the peritoneal sidewall and secured with two sutures over 2 mm from the edge of the rubbed area. The formulation is applied and the abdomen is closed in three layers. After 14 days, the extent and severity of adhesions are scored for both quantity and quality, and animals are evaluated postmortem.

Example 24
Screening test to assess the effects of various compounds on cell proliferation Trypsinize fibroblasts with cell density of 70-90% and replace with 600 cells / well in a 96-well plate medium and adhere overnight Let Mitoxantrone is prepared in DMSO at a concentration of 10 ⁻² M and diluted 10-fold to allow for a range of strain concentrations (10 ⁻⁸ M to 10 ⁻² M). The drug dilution was diluted 1/1000 in the medium and added to the cells so that the total volume was 200 μL / well. Each drug concentration was tested in triplicate wells. Plates containing fibroblasts and mitoxantrone were cultured at 37 ° C for 72 hours (Invitro toxicol. (1990) 3: 219. Biotech. Histochem. (1993) 68:29. Anal. Biochem. (1993) 213: 426.).

To end the test, the medium is removed by light aspiration. A 1/400 dilution of CyQuant 400X GR dye indicator (Molecular Probes, Eugene, OR) was added to 1X cell lysis buffer and 200 μl of the mixture was added to the plate wells. Plates were incubated at room temperature for 3-5 minutes while protected from light. The excitation wavelength was 480 nm or less, the emission maximum was 520 nm or less, and the fluorescence value was measured with a fluorescence microplate measuring instrument. The 50% inhibitory concentration (IC ₅₀ ) is determined by averaging the three sets of assay wells and comparing the average relative fluorescence unit with the DMSO control group. On average, n = 4 replicates were used to determine IC ₅₀ values. IC ₅₀ values for the following compounds were determined using this test method: IC ₅₀ (nM): mitoxantrone, 20 (FIG. 5). Rapamycin, 19 (Figure 6). Paclitaxel, 23 (Figure 7). Mycophenolic acid, 550. Mofetil, 601. GW8510, 98. Simvastatin, 885. Doxorubicin, 84. Geldanamycin, 11. Anisomycin, 435. 17-AAG, 106. Bleomycin, 86. Halofuginone, 36. Gemfibrozil, 164. Cyprofibrate, 503. Bezafibrate, 184. Epirubicin hydrochloride, 57. Topotemai, 81. Fascapricin, 854. Tamoxifen, 13. Etanidazole, 55. Gemcitabine, 7. Puromycin, 254. Mitromycin, 156. Daunorubicin, 51. L (-)-perillyl alcohol, 966. Celastrol, 271. Anashitabain, 225. Oxaliplatin, 380. Chromomycin A3,4. Vinorelbine, 4. Idarbitine, 34. Nogaramicin, 5. 17-DMAG, 5. Epothilone D, 2. Vinblastine, 2. Vincristine, 7. Cytarabine, 137.

Example 25
Evaluation of paclitaxel-containing meshes for the progression of intimal hyperplasia in the rat balloon-injured carotid artery model as an example of evaluating fibrosis inhibitors Paclitaxel with a mesh system for the progression of intimal hyperplasia 14 days after placement A rat balloon injury carotid artery model was used to demonstrate the efficacy of.

Wistar rats weighing 400-500 g were anesthetized with 1.5% halothane in the control group enzyme to expose the left external carotid artery. An A 2 French Fogarty balloon embolectomy catheter (Baxter, Irvine, Calif.) Was advanced by arteriotomy of the external carotid artery under the left common carotid artery of the aorta. The balloon was inflated with sufficient saline to generate mild resistance (about 0.02 ml) and the balloon was pulled into the carotid bifurcation while twisting. The balloon was then deflated and the procedure was repeated two more times. This technique has resulted in dilation of the arterial wall and delamination of the endothelium. After removing the catheter, the external carotid artery was ligated. The right common carotid artery was intact and used as a control group.

Paclitaxel treatment around local blood vessels Immediately after injury to the left common carotid artery, the 1 cm long arterial terminal node was exposed and treated with a 1x1 cm paclitaxel-containing mesh (10:90 PLG mesh, paclitaxel 345 μg in a 50:50 PLG coating) did. The wound was then closed and the animals were allowed to survive for 14 days.

At the time of histology and immunohistochemistry killing, the animals were anesthetized with carbon dioxide and pressure perfused with 10% phosphate buffered formaldehyde 100 mmHg for 15 minutes. Both carotid arteries were harvested and soaked in fixative overnight. Fixed arteries were processed and embedded in paraffin wax. Continuous cross sections were cut to 3 μm in thickness within 2 mm from the outside and outside of the graft site of the damaged left carotid artery and at a corresponding level for the right carotid artery in the control group. Cross sections were stained using Mayer's hematoxin-and-erosion method for cell number and morphometric analysis for evaluation of extracellular matrix composition using the Movat pentachrome staining method.

Results FIGS. 8-10 clearly show that delivery of paclitaxel around the blood vessels using paclitaxel mesh formulation results in a dramatic reduction in intimal hyperplasia.

Example 26
Effects of paclitaxel and other microtubule inhibitors on matrix metalloproteinase production
J. Materials and Methods
1) Introduce a structure containing AP-1-excited CAT reporter gene into chondrocytes that inhibit IL-1-stimulated AP-1 transcriptional activity with paclitaxel and stimulate with IL-1 and IL-1 (50 ng / ml) This was added at various concentrations in the presence or absence of paclitaxel and cultured for 24 hours. Paclitaxel treatment reduced CAT activity in a concentration-dependent manner (mean ± SD). Data with asterisks (*) are significant compared to IL-1-induced CAT activity according to the t-test (P <0.05). The results displayed are representative of three independent experiments.

2) IL-1 induced AP-1 DNA binding activity, effect of paclitaxel on AP-1 DNA Binding activity was tested by radiolabeled human AP-1 array probe and gel mobility shift test. Extracts obtained from chondrocytes were treated with untreated or varying amounts of paclitaxel (10 ⁻⁷ to 10 ⁻⁵ M), followed by IL-1b (20 ng / ml) with excess probe on ice. Incubate for minutes and then perform native gel electrophoresis. The “com” lane contains the unlabeled AP-1 oligonucleotide. The results displayed are representative of three independent experiments.

3) Effect of paclitaxel on IL-1-induced MMP-1 and MMP-3 mRNA expression Treat cells with various concentrations (10 ^-7 to 10 ^-5 M) of paclitaxel for 24 hours and then for another 18 hours of paclitaxel Treatment with IL-1b (20 ng / ml) was performed in the presence. Total RNA was sequestered and MMP-1 mRNA levels were determined by Northern blot analysis. The blot was subsequently stripped and reprobed with ³² P-radiolabeled rat GAPDH cDNA, which was used as a housekeeping gene. The results displayed are representative of 4 independent experiments. Quantification of collagenase-1 and stromelysin-expressed mRNA levels was performed. MMP-1 and MMP-3 expression levels were normalized by GAPDH.

4) Effect of other microtubule inhibitors on collagenase expression A major chondrocyte culture was newly isolated from calf cartilage. Cells were placed at 2.5 × 10 ⁶ / ml in 100 × 20 mm culture dishes and cultured overnight at 37 ° C. in Ham's F12 medium containing 5% FBS. Cells were left overnight in serum-free medium and treated with microtubule inhibitors at various concentrations for 6 hours. IL-1 (20 ng / ml) was then added to each plate and the plates were incubated for an additional 18 hours. Total RNA was isolated by the acidified guanidine isothiocyanate method and electrophoresed on a denaturing gel. A denatured RNA sample (15 μg) was analyzed by gel electrophoresis in a 1% denaturing gel, transferred to a nylon membrane, and crossed with a ³² P-labeled collagenase cDNA probe. ³² P-labeled glyceraldehyde phosphate dehydrase (GAPDH) cDNA as an internal standard to ensure even packing. The exposed film was scanned and analyzed quantitatively with ImageQuant.

K. Result
1) Promoters of the matrix metalloproteinase group FIG. 11A shows that all matrix metalloproteinases included transcription elements AP-1 and PEA-3 (with the exception of gelatinase B). It is already highly established that the expression of matrix metalloproteinases such as collagenase and stromelysin depends on the activation of the transcription factor AP-1. Therefore, AP-1 inhibitors may inhibit the expression of matrix metalloproteinases.

2) Effect of paclitaxel on AP-1 DNA transcriptional activity As shown in FIG. 11B, IL-1 stimulated AP-1 transcriptional activity 5-fold. Pretreatment of transiently introduced chondrocytes with paclitaxel reduced IL-1-induced AP-1 reporter gene CAT activity. Therefore, IL-1-induced AP-1 activity in chondrocytes was reduced by paclitaxel in a concentration-dependent manner (10 ⁻⁷ to 10 ⁻⁵ M). These data demonstrated that paclitaxel is a potent inhibitor of AP-1 activity in chondrocytes.

3) Effect of paclitaxel on AP-1 binding activity
To confirm that paclitaxel inhibition of AP-1 activity is not due to nonspecific effects, the effect of paclitaxel on IL-1-induced AP-1 binding to oligonucleotides using nuclear lysates of chondrocytes Was considered. As shown in FIG. 11C, IL-1-induced binding activity of lysates obtained from chondrocytes pretreated with paclitaxel for 24 hours at concentrations of 10 ⁻⁷ to 10 ⁻⁵ M was reduced. Inhibition of AP-1 transcriptional activity by paclitaxel correlates closely with a decrease in the rate of AP-1 binding to DNA.

4) Effect of paclitaxel on collagenase and stromelysin expression Since paclitaxel is a potent inhibitor of AP-1 activity, the effect of paclitaxel or the expression of IL-1-induced collagenase and stromelysin, two important matrices involved in inflammatory diseases Metalloproteinases were considered. Briefly, as shown in FIG. 11D, IL-1 induction increases chondrocyte collagenase and stromelysin mRNA levels. Collagenase and stromelysin mRNA levels were significantly reduced when chondrocytes were pretreated with paclitaxel for 24 hours. In 10 ^-5 M paclitaxel, complete inhibition occurred. The results show that paclitaxel completely inhibited the expression of two matrix metalloproteinases at concentrations similar to those that inhibit AP-1 activity.

5) Effect of other microtubule inhibitors on collagenase expression FIGS. 12A-H demonstrate that microtubule inhibitors inhibited collagenase expression. Collagenase expression was stimulated by the addition of IL-1, an inflammatory cytokine. Chondrocyte pre-treatment with various microtubule inhibitors, such as LY290181, hexylene glycol, heavy water, glycine ethyl ester, ethylene glycol bis- (succinimidyl succinate), tubercidin, AIF ₃ , and epothilone. All incubations prevented IL-1-induced collagenase expression at concentrations as low as 1 × 10 ⁻⁷ M.

L. Discussion Paclitaxel had the ability to inhibit collagenase and stromelysin expression in vivo at a concentration of 10 ^-6 M. This inhibition can also be explained by inhibition of AP-1 activity, which is a necessary step in the induction of all matrix metalloproteinases (except for gelatinase B), so that paclitaxel has other matrix metalloproteinases with AP-1 dependence. Is expected to inhibit The levels of these matrix metalloproteinases were elevated in all inflammatory diseases and played a major role in substrate degradation, cell migration and proliferation, and angiogenesis. Thus, paclitaxel inhibitors for the expression of matrix metalloproteinases such as collagenase and stromelysin have a beneficial effect in inflammatory diseases.

In addition to the inhibitory effect of paclitaxel on collagenase expression, LY290181, hexylene glycol, heavy water, glycine ethyl ester, AIF ₃ , tubercidin epothilone, and ethylene glycol bis- (succinimidyl succinate) are all IL-1-induced collagenase expression was prevented at concentrations as low as 1 × 10 ⁻⁷ M. Therefore, microtubule inhibitors have the ability to inhibit the AP-1 pathway at different concentrations.

Example 27
Inhibition of angiogenesis by paclitaxel
M. Chick Chorioallantoic Membrane (“CAM”) Test Method Fertilized domestic chick embryos were cultured for 3 days prior to culture without eggshell. In this procedure, the shell around the airspace was removed to empty the contents of the egg. The egg inner membrane was then cut and a hole was made in the opposite edge of the shell to allow the egg contents to flow gently from the blunt edge. The eggs were emptied and placed in a sterilized round bottom glass bowl and covered with a Betri dish cover. They were then placed in an incubator at 90% relative humidity and 3% CO ₂ and incubated for 3 days.

  Paclitaxel (Sigma, St. Louis, MO) was mixed to a concentration of 0.25, 0.5, 1, 5, 10, 30 μg per 10 ml aliquot of 0.5% aqueous methylcellulose. Because paclitaxel is insoluble in water, glass beads were used to produce fine particles. A 10 microliter aliquot of this solution was dried on parafilm for 1 hour to form a 2 mm diameter disk. A dry disc containing paclitaxel was then carefully placed on the growing edge of each CAM on day 6 of culture. At the same time, a methylcellulose disc without paclitaxel was placed in the CAM to obtain a control group. After 2 days of exposure (day 8 of culture), the vasculature was examined with the aid of a stereomicroscope. Liposyn II, an opaque white solution, was injected into the CAM to increase visibility of blood vessel details. The vasculature of unstained live embryos was imaged using a Zeiss stereomicroscope with an interface to a video camera (Dage-MTI Inc., Michigan City, IN). These video signals were displayed at 160x magnification and captured using an image analysis system (Vidas, Kontron, Etching, Germany). Image negatives were then produced on a graphic recorder (Model 3000, Matrix Instruments, Orangeburg, NY).

  In 0.1 M sodium cacodylate buffer, 2% glutaraldehyde was poured into the embryonic membrane without 8 days old eggshell, and the fixative was further injected under the CAM. After 10 minutes in situ, the CAM was removed and placed in fresh fixative for 2 hours at room temperature. The tissue was then washed overnight with cacodylate buffer containing 6% sucrose. The region of interest was perfused with 1% osmium tetroxide for 1.5 hours at 4 ° C. The tissue was then dehydrated with grade series ethanol, the solvent was replaced with propylene oxide and embedded in a spur resin. Thin sections were cut with a diamond knife, placed on an iron grid, stained, and examined with a Joel1200EX electron microscope. Similarly, 0.5 mm sections were cut and stained with toluene blue for light microscopy.

  On the 11th day after development, chick embryos were used in the corrosion casting technique. A 30 gauge hypodermic needle was used to inject Mercox resin (Ted Pella, Inc., Redding, Calif.) Into the CAM vasculature. The casting consisted of 2.5 grams of Mercox CL-2B polymer and 0.05 grams of catalyst (55% benzoyl peroxide) with a polymerization time of 5 minutes. After injection, the plastic was left in place for 1 hour at room temperature and then left in the oven overnight at 65 ° C. CAM was placed in a 50% aqueous solution of sodium hydroxide to digest all organic components. Plastic castings were washed frequently with dilution water, air dried, coated with gold / palladium and observed with a Philips 501B scanning electron microscope.

  The results of the test method are as follows. On day 6 of culture, the germ was centrally located into a radially expanding vascular network and the CAM grew adjacent to the germ. These growing blood vessels are located near the surface and can be easily observed, making this system an ideal model for angiogenesis research. CAM's live unstained capillary network can also be imaged non-invasively with a stereomicroscope.

  The cross section across the CAM consists of a double cell layer, a wider mesoderm layer containing capillaries located adjacent to the ectoderm, an outer membrane cell, and an inner single mesoderm cell layer. Shows germ layers. At the electron microscope level, typical structural details of CAM capillaries are shown. Typically, these blood vessels are located in close association with the inner cell layer of the ectoderm.

  After exposure to paclitaxel at a concentration of 0.25, 0.5, 1, 5, 10, or 30 μg for 48 hours, use a stereomicroscope equipped with a video / computer interface to assess the effects of angiogenesis and I considered each CAM. This image setting is used at 160x magnification, which allows for direct visualization of blood cells in the capillaries and thus allows easy evaluation and recording of blood flow in the region of interest. For the purposes of this study, angiogenesis inhibitors are defined as the CAM region without capillary network and vascular blood flow (measured as 2-6 mm in diameter). Throughout the experiment, the avascular zone was evaluated with an avascular gradient at four points (Table 1). This criterion shows the overall degree of inhibition with a maximum degree of inhibition shown as 3 on the avascular gradient basis. Paclitaxel was highly consistent and induced maximal avascular zone (diameter 6 mm or avascular gradient reference 3) within 48 hours depending on concentration.

Table 2 shows experimental data for the effect of paclitaxel at different concentrations depending on the dosage.

A typical paclitaxel-treated CAM is also shown with a clear methylcellulose disc centered on a 6 mm diameter avascular zone. At a somewhat higher magnification, the periphery of such an avascular zone is clearly clear and frequently repositions the surrounding functional blood vessels away from the source of paclitaxel. No such blood translocation was observed under normal circumstances. Another function of the effect of paclitaxel is the formation of blood islands within the avascular zone meaning blood cell aggregation.

  In summary, this study shows that angiogenesis was inhibited 48 hours after paclitaxel was applied to CAM. Vascular inhibition formed an avascular zone represented by three transitional phases on the effect of paclitaxel. The capillary, divided by the overflowing red blood cells in the middle, contains the most affected avascular zone, indicating the absence of intercellular connections between endothelial cells. Endoderm and ectoderm cells maintain their cell-cell junctions and therefore these germ layers remain intact but are somewhat thicker. The normal vascular area was approximated, and the blood vessel retained the junction complex and therefore retained its original shape. In the vicinity of the paclitaxel-treated area, the blood vessel growth was further inhibited, as evidenced by the typical migration of blood vessels or the “elboeing” effect.

Example 28
Screening test to assess the effect of paclitaxel on smooth muscle cell migration. 16 hours prior to this test, the primary human smooth muscle cells are insulin-containing smooth muscle cell basal medium and human basic fibroblast proliferation. Factor (bFGF) was placed in a serum-free state. In the migration test method, the cells were trypsinized and the cells were removed from the flask, washed with the migration medium, and diluted in the migration medium at a concentration of 2-2.5 × 10 ⁵ cells / ml. The migration medium consists of phenol red-free Dulbecco's Modified Eagle medium (DMEM) containing 0.35% human serum albumin. A 100 μL amount of smooth muscle cells (approximately 20,000-25,000 cells) was added to the top of the Boyden chamber assembly (Chemicon QCM Chemotaxis 96-well migration plate). The chemotaxis drug, recombinant human platelet derived growth factor (rhPDGF-BB) was added to the lower well at a concentration of 10 ng / ml in a total volume of 150 μL. Prepare paclitaxel in DMSO at a concentration of 10 ^-2 M and serially dilute 10-fold to allow for a range of strain concentrations (10 ^-8 to 10 ^-2 M). Paclitaxel was added to the cells by directly adding the paclitaxel DMSO strain solution prepared so far to each well at a 1/1000 dilution. Plates were cultured for 4 hours to allow cell migration.

After 4 hours, the cells in the upper chamber were discarded, and smooth muscle cells attached to the back side of the filter were separated in a cell separation solution (Chemicon) at 37 ° C for 30 minutes. The removed cells were lysed with a lysis buffer containing DNA-bound CyQuant GR dye and incubated at room temperature for 15 minutes. The excitation wavelength was 480 nm or less, the emission maximum was 520 nm or less, and the fluorescence value was measured with a fluorescence microplate measuring instrument. Relative fluorescence units obtained from triplicate wells are averaged by subtracting background fluorescence (control chamber without migration promotion) and the average number of cells migrating from 25,000 cells / well to 98 cells / well Obtained from a calibration curve of serially diluted smooth muscle cells. The 50% inhibitory concentration (IC ₅₀ ) is determined by comparing the average number of cells that migrate in the presence of paclitaxel with a positive control group (smooth muscle cell chemotaxis in response to rhPDGF-BB). See Figure 13 (IC ₅₀ = 0.76 nM). Reference: Biotechniques (2000) 29:81. J. ImmunolMethods (2001) 254: 85.

Example 29
Screening test method to evaluate the efficacy of various compounds against IL-1β produced by macrophages
A human macrophage cell line, THP-1, was placed in a 12-well plate so that each well contained 1 × 10 ⁶ cells in 2 ml medium containing 10% FCS. Opsonized zymosan was prepared by resuspending 20 mg zymosan A in 2 ml ddH ₂ O and homogenizing until a uniform suspension was obtained. Homogenized zymosan is pelleted at 250 g, resuspended in 4 mL human serum to a final concentration of 5 mg / ml, and incubated in a 37 ° C water bath for 20 minutes to allow opsonization. It was. Geldanamycin is prepared in DMSO at a concentration of 10 ⁻² M and serially diluted 10-fold to allow for a range of strain concentrations (10 ⁻⁸ M to 10 ⁻² M).

  THP-1 cells were stimulated to produce IL-1β by adding 1 mg / ml opsonized zymosan. Geldanamycin was added to THP-1 cells by directly adding DMSO strain solution prepared so far to each well at a 1/1000 dilution. Each drug concentration was tested in triplicate wells. Plates were incubated at 37 ° C for 24 hours.

After stimulation for 24 hours, supernatants were collected to quantify IL-1β production. The IL-1β concentration of the supernatant was determined by ELISA using recombinant human IL-1β to obtain a calibration curve. 96 well MaxiSorb plates were coated with 100 μL μl of anti-human IL-1 β 1β capture antibody diluted in coating buffer (0.10.1 M sodium carbonate ph 9.5) at 4 ° CC overnight. The dilution of capture antibody used was lot specific and was determined experimentally. The capture antibody was then aspirated and the plate was washed 3 times with wash buffer (PBS, 0.05% TWEEN-20). Plates were blocked with 200 μL μl / well assay diluent (PBS, 10% FCS pH 7.0) for 1 hour at room temperature. After blocking, the plate was washed 3 times with wash buffer. Standard and sample dilutions were prepared as follows: (a) Sample supernatants were prepared at 1/4 and 1/8, (b) recombinant human IL-1β was prepared at 1000 pg / ml, A standard curve was serially diluted to produce 15.6 pg / ml to 1000 pg / ml. Sample supernatants and calibration curves were measured in triplicate and incubated at room temperature for 2 hours after adding the plate coated with capture antibody. The plate was washed 5 times and incubated with 100 μL μl of Working Detector (biotinylated anti-human IL-1β detection antibody + avidin-HRP) for 1 hour at room temperature. After this culture, the plate was washed 7 times, 100 μL of a substrate solution (tetramethylbenzidine, H ₂ O ₂ ) was added to the plate, and incubated at room temperature for 30 minutes. A stop solution (2 NH ₂ SO ₄ ) was then added to the wells and the yellow reaction was measured at 450 nm with a λ correction of 570 nm. The average absorbance was determined based on the data measured three times, and the average background was subtracted. IL-1 β concentration values were obtained from a calibration curve. The 50% inhibitory concentration (IC ₅₀ ) was determined by comparing the IL-1 β1β mean concentration with a control drug (THP-1 cells were stimulated by opsoinized zymosan). On average, n = 4 replicates were used in determining the IC ₅₀ value for geldanamycin (IC ₅₀ = 20 nM). See FIG. The IC ₅₀ values of the following further compounds were determined using this test method: IC ₅₀ (nM): mycophenolic acid, 2888 nM. Anisomycin, 127. Rapamycin, 0.48. Halofujinone, 919. IDN-6556, 642. Epirubicin hydrochloride, 774. Topotemai, 509. Fascapricin, 425. Daunorubicin, 517. Celastrol, 23. Oxaliplatin, 107. Chromomycin A3, 148.

  Reference: J. Immunol. (2000) 165: 411-418. J. Immunol. (2000) 164: 4804-4811. J. Immunol Meth. (2000) 235 (1-2): 33-40.

Example 30
Screening test method to evaluate the efficacy of various compounds against IL-8 produced by macrophages
A human macrophage cell line, THP-1, was placed in a 12-well plate so that each well contained 1 × 10 ⁶ cells in 2 ml medium containing 10% FCS. Opsonized zymosan was prepared by resuspending 20 mg zymosan A in 2 ml ddH ₂ O and homogenizing until a uniform suspension was obtained. Homogenized zymosan is pelleted at 250 g, resuspended in 4 ml human serum to a final concentration of 5 mg / ml, and incubated in a 37 ° C water bath for 20 minutes to allow opsonization. It was. Geldanamycin is prepared in DMSO at a concentration of 10 ⁻² M and serially diluted 10-fold to allow for a range of strain concentrations (10 ⁻⁸ M to 10 ⁻² M).

  THP-1 cells were stimulated to produce IL-8 by adding 1 mg / ml opsonized zymosan. Geldanamycin was added to THP-1 cells by directly adding DMSO strain solution prepared so far to each well at a 1/1000 dilution. Each drug concentration was tested in triplicate wells. Plates were incubated at 37 ° C for 24 hours.

After stimulation for 24 hours, supernatants were collected to quantify IL-8 production. The IL-8 concentration in the supernatant was determined by ELISA using recombinant human IL-8 to obtain a calibration curve. 96 well MaxiSorb plates were coated with 100 μL μl of anti-human IL-8 capture antibody diluted in coating buffer (0.1 M sodium carbonate ph 9.5) at 4 ° C. overnight. The dilution of capture antibody used was lot specific and was determined experimentally. The capture antibody was then aspirated and the plate was washed 3 times with wash buffer (PBS, 0.05% TWEEN-20). Plates were blocked with 200 μL μl / well assay diluent (PBS, 10% FCS pH 7.0) for 1 hour at room temperature. After blocking, the plate was washed 3 times with wash buffer. Standard dilutions and sample dilutions were prepared as follows: (a) the sample supernatant, _^1/100 and _^1/1000, (b) recombinant human IL-8 were prepared at 200 pg / ml, calibration Lines were serially diluted to yield between 3.1 pg / ml and 200 pg / ml. Sample supernatants and calibration curves were measured in triplicate and incubated at room temperature for 2 hours after adding the plate coated with capture antibody. The plate was washed 5 times and incubated with 100 μL μl of Working Detector (biotinylated anti-human IL-8 detection antibody + avidin-HRP) for 1 hour at room temperature. After this incubation, the plate was washed 7 times, 100 μl of substrate solution (tetramethylbenzidine, H ₂ O ₂ ) was added to the plate and incubated at room temperature for 30 minutes. A stop solution (2 NH ₂ SO ₄ ) was then added to the wells and the yellow reaction was measured at 450 nm with a λ correction of 570 nm. The average absorbance was determined based on the data measured three times, and the average background was subtracted. IL-8 concentration values were obtained from a calibration curve. The 50% inhibitory concentration (IC ₅₀ ) was determined by comparing the IL-8 mean concentration to a control drug (THP-1 cells stimulated by opsoinized zymosan). On average, n = 4 replicates were used in determining the IC ₅₀ value for geldanamycin (IC ₅₀ = 27 nM). See FIG. IC ₅₀ values for the following additional compounds were determined using this test method: IC ₅₀ (nM): 17-AAG, 56. Mycophenolic acid, 549. Resveratrol, 507. Rapamycin, 4.41. SP600125, 344. Halofuginone, 641. D-mannose-6-phosphate, 220. Epirubicin hydrochloride, 654. Topotemai, 257. Mitromycin, 33. Daunorubicin, 421. Celastrol, 490. Chromomycin A3, 36.

  Reference: J. Immunol. (2000) 165: 411-418. J. Immunol. (2000) 164: 4804-4811. J. Immunol Meth. (2000) 235 (1-2): 33-40.

Example 31
Screening test to evaluate the efficacy of various compounds against MCP-1 produced by macrophages
A human macrophage cell line, THP-1, was placed in a 12-well plate so that each well contained 1 × 10 ⁶ cells in 2 ml medium containing 10% FCS. Opsonized zymosan was prepared by resuspending 20 mg zymosan in 2 ml ddH ₂ O and homogenizing until a uniform suspension was obtained. Homogenized zymosan is pelleted at 250 g, resuspended in 4 mL human serum to a final concentration of 5 mg / ml, and incubated in a 37 ° C water bath for 20 minutes to allow opsonization. It was. Geldanamycin is prepared in DMSO at a concentration of 10 ⁻² M and serially diluted 10-fold to allow for a range of strain concentrations (10 ⁻⁸ M to 10 ⁻² M).

  THP-1 cells were stimulated to produce MCP-1 by adding 1 mg / ml opsonized zymosan. Erdanamycin was added to THP-1 cells by directly adding DMSO strain solution prepared so far to each well at a 1/1000 dilution. Each drug concentration was tested in triplicate wells. Plates were incubated at 37 ° C for 24 hours.

After stimulation for 24 hours, supernatants were collected to quantify MCP-1 production. The supernatant MCP-1 concentration was determined by ELISA using recombinant human MCP-1 to obtain a calibration curve. A 96-well MaxiSorb plate was coated with 100 μl of anti-human MCP-1 capture antibody diluted in coating buffer (0.1 M sodium carbonate pH 9.5) at 4 ° C. overnight. The dilution of capture antibody used was lot specific and was determined experimentally. The capture antibody was then aspirated and the plate was washed 3 times with wash buffer (PBS, 0.05% TWEEN-20). Plates were blocked with 200 μL μl / well assay diluent (PBS, 10% FCS pH 7.0) for 1 hour at room temperature. After blocking, the plate was washed 3 times with wash buffer. Standard dilutions and sample dilutions were prepared as follows: (a) the sample supernatant, _^1/100 and _^1/1000, (b) recombinant human MCP-1 was prepared at 500 pg / ml, calibration Lines were serially diluted to yield 7.8 pg / ml to 500 pg / ml. Sample supernatants and calibration curves were measured in triplicate and incubated at room temperature for 2 hours after adding the plate coated with capture antibody. The plate was washed 5 times and incubated with 100 μL μl of Working Detector (biotinylated anti-human MCP-1 detection antibody + avidin-HRP) for 1 hour at room temperature. After this culture, the plate was washed 7 times, 100 μL of a substrate solution (tetramethylbenzidine, H ₂ O ₂ ) was added to the plate, and incubated at room temperature for 30 minutes. A stop solution (2 NH ₂ SO ₄ ) was then added to the wells and the yellow reaction was measured at 450 nm with a λ correction of 570 nm. The average absorbance was determined based on the data measured three times, and the average background was subtracted. MCP-1 concentration values were obtained from a calibration curve. The 50% inhibitory concentration (IC ₅₀ ) was determined by comparing the mean MCP-1 concentration to a control drug (which stimulated THP-1 cells by opsoinized zymosan). On average, n = 4 replicates were used in determining the IC ₅₀ value for geldanamycin (IC ₅₀ = 7 nM). See FIG. IC ₅₀ values for the following additional compounds were determined using this test method: IC ₅₀ (nM): 17-AAG, 135. Anisomycin, 71. Mycophenolic acid, 764. Mofetil, 217. Mitoxantrone, 62. Chlorpromazine, 0.011, 1-α-25 dihydroxyvitamin D ₃ , 1. Bay 58-2667, 216. 15-deoxyprostaglandin J2, 724. Rapamycin, 0.05. CNI-1493, 0.02. BXT-51072, 683. Halofuginone, 9. CYC202, 306. Topotemai, 514. Fascapricin, 215. Podophyllotoxin, 28. Gemcitabine, 50. Puromycin, 161. Mitromycin, 18. Daunorubicin, 570. Celastrol, 421. Chromomycin A3, 37. Vinorelbine, 69. Tubercidin, 56. Vinblastine, 19. Vincristine, 16.

  Reference: J. Immunol. (2000) 165: 411-418. J. Immunol. (2000) 164: 4804-4811. J. Immunol Meth. (2000) 235 (1-2): 33-40.

Example 32
Screening test method to assess the effect of paclitaxel on cell proliferation Trypsinize smooth muscle cells with 70-90% cell density, replace with 600 cells / well in a medium of a 96-well plate and allow to attach overnight. Prepare paclitaxel at a concentration of 10 ⁻² M in DMSO and dilute 10-fold to allow for a range of strain concentrations (10 ⁻⁸ M to 10 ⁻² M). The drug dilution was diluted 1/1000 in the medium and added to the cells so that the total volume was 200 μL / well. Each drug concentration was tested in triplicate wells. Plates containing cells and paclitaxel were incubated at 37 ° C. for 72 hours.

To end the test, the medium is removed by light aspiration. A 1/400 dilution of CyQuant 400X GR dye indicator (Molecular Probes, Eugene, OR) was added to 1X cell lysis buffer and 200 μl of the mixture was added to the plate wells. Plates were incubated at room temperature for 3-5 minutes while protected from light. The excitation wavelength was 480 nm or less, the emission maximum was 520 nm or less, and the fluorescence value was measured with a fluorescence microplate measuring instrument. The 50% inhibitory concentration (IC ₅₀ ) is determined by averaging the three sets of assay wells and comparing the average relative fluorescence unit with the DMSO control group. On average, n = 3 replicates were used to determine IC ₅₀ values. See Figure 17 (IC ₅₀ = 7 nM). The IC ₅₀ values of the following further compounds were determined using this test method: IC ₅₀ (nM): mycophenolic acid, 579. Mofetil, 463. Doxorubicin, 64. Mitoxantrone, 1. Geldanamycin, 5. Anisomycin, 276. 17-AAG, 47. Cytarabine, 85. Halofuginone, 81. Mitomycin C, 53. Etoposide, 320. Cladribine, 137. Lovastatin, 978. Epirubicin hydrochloride, 19. Topotemai, 51. Fascapricin, 510. Podophilotoxin, 21. Cytochalasin A, 221. Gemcitabine, 9. Puromycin, 384. Mitromycin, 19. Daunorubicin, 50. Celastrol, 493. Chromomycin A3, 12. Vinorelbine, 15. Idarbitine, 38. Nogaramicin, 49. Itraconazole, 795. 17-DMAG, 17. Epothilone D, 5. Tubercidin, 30. Vinblastine, 3. Vincristine, 9.

This test method can also be used to evaluate the effect of compounds on the growth of fibroblasts and murine macrophage cell line RAW 264.7. The results of the test method evaluating the effect of paclitaxel on the proliferation of the murine RAW 264.7 macrophage cell line are shown in FIG. 18 (IC ₅₀ = 134 nM).

  Reference: Invitro toxicol. (1990) 3: 219. Biotech. Histochem. (1993) 68:29. Anal. Biochem. (1993) 213: 426.

Example 33
Perivascular administration of paclitaxel to assess inhibition of fibrosis
Anesthetize Wistar rats weighing 250-300 g by intramuscular injection of Innovar (0.33 ml / kg). Once anesthetized, it is then subjected to halothane anesthesia. Once general anesthesia is established, shave the fur on the neck and clamp the skin and disinfect with betadine. A longitudinal incision is made in the left carotid artery and the exposed external carotid artery. Two ligatures are placed around the external carotid artery and a transverse arteriotomy is performed. A # 2 French Fogarty balloon catheter is then placed into the carotid artery, passed through the left carotid artery, and the balloon is inflated with saline. The catheter will move up and down the carotid artery three times. The catheter was then removed and ligated with the left external carotid artery and tied.

  Paclitaxel (33%) in ethylene vinyl acetate (EVA) was then injected in a circle around the common carotid artery of 10 rats. EVA alone was injected around the common carotid artery of 10 other rats. (Paclitaxel can also be coated on EVA film, which is then placed in a circle around the common carotid artery.) 5 rats from each group on day 14 and the last 5 on day 28 Let your eyes die. Rats were observed for weight loss or other signs of systemic disease. After 14 or 28 days, the animals are anesthetized and the left carotid artery is exposed by the method of the first experiment. The carotid artery was isolated and fixed with 10% buffered formaldehyde, and its histology was considered.

  There was a statistically significant decrease in the degree of intimal hyperplasia as measured by standard morphometric analysis. This point suggests that the drug induced a decrease in the fibrotic response.

Example 34
Determination method of MIC by dilution of microtiter broth
A. MIC test method for various Gram negative and positive bacteria
The MIC test method is essentially Loman, V., (ed) Antibioticsin Laboratory Medicine, 4th edition, Amsterdam and D. 1996, "Sensitivity Testing of antimicrobials in liquid Media", Williams and Wilkins (Baltimore, Maryland), Performed as described on pages 52-111. Briefly, various compounds were tested for antibacterial activity. Minimum inhibitory concentration test method under aerobic conditions using P. aeruginosa, K. pneumoniae, E. coli, S. epidermidis, and S. aureus isolates (96-well polystyrene microtiter plates (Falcon 1177)) at MIC , And MuellerHinton broth for 24 hours at 37 ° C (in most studies except C721 (S. pyogenes) using Todd Hewitt broth and Haemophilus influenzae using Haemophilus test medium (HTM)) MHB was used.) The test was performed in triplicate and the results are provided in Table 1 below.

Activity at molarity
Wt = wild type
N = inactive

N. Antibiotic Bacteria MIC
The antimicrobial activity against clinical isolates of methicillin-resistant S. aureus and a-vancomycin-resistant pediocoocus in the MIC study as described above, the following compounds: mitoxantrone, cisplatin, tubercidin, methotoxalate, 5- Various concentrations of fluorouracil, etoposide, 2-mercaptopurine, doxorubicin, 6-mercaptopurine, camptothecin, hydroxyurea, and cytarabine were tested. Compounds that show growth inhibition (MIC value: <1.0 x 10 ^-3 ) include mitoxantrone (both strains), metoxoxalate (vancomycin-resistant pediocox), 5-fluorouracil (both strains), etoposide (both And 2-mercaptopurine (vancomycin-resistant pediocox).

Example 35
Preparation of release buffer
A release buffer is prepared by adding 8.22 g sodium chloride, 0.32 g sodium phosphate monobasic (monohydrate) and 2.60 g phosphate dibasic (anhydrous) to a beaker. Add 1 L HPLC grade water and stir the solution until all salts are dissolved. If necessary, adjust the pH value of the solution to pH 7.4 ± 0.2 using 0.1 N NaOH or 0.1 N phosphoric acid.

Example 36
Release studies to determine the release characteristics of therapeutic agents from polymer compounds The release characteristics of therapeutic agents from polymer compounds can be determined according to the following procedure.

Release and extract samples are placed in 16 x 125 mm screw-capped culture tubes. Add 16 ml release buffer (Example 35) to the culture tube. The sample is placed on a 37 ° C oven rotating wheel (30 rpm). Remove the sample tubes from the oven at various time intervals (2h, 5h, 8h, 24h and daily), place them in the rack and remove the fume hood cap. Remove as much release buffer as possible and place in the second culture tube. Add 16 ml of release medium to the sample contained in the tube using an Oxford pipette bottle. The sample is capped with a new PTFE screw cap. Return all samples to the rotating wheel device of the oven.

  Using a p1000 pipette (PIPETMAN) and a clean pipette tip, remove 1 ml of release medium from each sample and discard. Using an Oxford pipette bottle, add 1 ml of dichloromethane to each sample. Cap each sample tube with its own PTFE screw cap. Shake each sample vigorously by hand for 5 seconds. Place the sample on the test vibration rotator and rotate for 15 minutes. The sample is centrifuged for 10 minutes at a speed of 1500 rpm. Transfer the sample tube to the fume hood and remove the cap. Remove most of the supernatant (aqueous phase) using a Pasteur pipette and vacuum system. Remove the last part of the supernatant with a glass syringe. Transfer the sample tube to the piercing drying system, set the heating block to 1.5 (45 degrees (° c)) and turn on the system. All samples of the piercing drying system are dried with a stream of nitrogen gas (about 45 minutes). Recap the sample tube, place it in a plastic bag, label the bag with the date and time of the sample, and store at -20 ° c (freezer) until analysis.

External standard preparation
Paclitaxel (GMP grade) from Hauser Chemical Research, Inc. is used as a reference standard for this test method. Accurately weigh paclitaxel (100 mg) and transfer quantitatively to a volume of ACN in a 100 ml volumetric flask (1 mg / ml). Using a volumetric pipette, transfer 5 ml of this standard solution to a 100 ml volumetric flask to a volume of ACN (50 μg / ml). Prepare solutions of 25, 12.5, 6.25, 3.13, 1.56, 0.781 and 0.391 μg / ml using serial dilution methods (10 ml in 5 ml qs and ACN), respectively. On the day of HPLC analysis of the samples, aliquots (~ 100 ml) of each standard are placed in individual vials of the autosampler by small volume insertion and transferred to HPLC.

Control and system compatible sample preparation
Paclitaxel and 7 epitaxial from Hauser Chemical Research, Inc. are used as control criteria for this test method. Weigh accurately and transfer an appropriate amount of 25 mg 7-epitaxel to a 25 ml volumetric flask to a volume of ACN (1 mg / ml). Using a volumetric pipette, transfer 5 ml of this standard solution to a 100 ml flask to give a volume of ACN (50 μg / ml 7-epitaxel). A 50/50 mixture of paclitaxel standard (25 μg / ml) and 7-epitaxel standard (25 μg / ml) is used as a control and system compatible sample. Prepare by adding 5 ml of each paclitaxel dissolved in ACN (50 μg / ml paclitaxel) and 7-epitaxel dissolved in ACN (50 μg / ml 7-Epi-epitaxel) to the same culture tube. Cover with a cap and shake. Refrigerate until ready to use. On the day of HPLC analysis of the sample, the Apricot (~ 150 ml) is placed on two separate automatic sampler bails with small volume inserts for HPLC. One sample is used to check the suitability of the system. The other sample is used as a control sample.

Sample Reconstitution Remove the sample to be analyzed from the freezer and place it in a fume hood so that the tube is at room temperature. Remove the cap and add 1 ml of water / acetonitrile (50/50) to each tube with an Oxford pipette. Cap the sample tube again and vortex for 60 seconds. The sample tube is centrifuged at 1500 rpm for 15 minutes. In a fume hood, transfer approximately 500 ml of each sample to a separate HPLC automated sampler vial with a clean Pasteur pipette. Cap each autosampler vial with a cap and transfer to HPLC. Dispose of the sample tube and Pasteur pipette.

HPLC analysis The following chromatographic conditions are used for paclitaxel analysis.

To balance, first inject 5 acetonitrile samples. After the acetonitrile sample, the control sample is injected 5 times, once after the standard curve sample, once every 10 samples through the set of samples, and once at the end of the sample set to confirm system performance. Standard curve samples are color layer analyzed by injecting once at the beginning of each set of samples.

Data analysis
Use HP ChemStation batch mode to integrate the paclitaxel peak areas of all standards, control samples, and release samples and generate a batch report saved in xls format. Evaluate batch report data using Excel. Calculate the standard deviation (Excel: descriptive statistics) and% coefficient of variation (100 x standard deviation / mean) of the peak area of the control sample. Calculate the amount of paclitaxel injected (μg) into each standard curve sample based on the prepared concentration and 10 mL injection. Calculate slope and intercept of standard curve (peak area vs. amount of injected paclitaxel) using Excel: regression analysis. Calculate the amount of paclitaxel for each injected release sample. Use the formula to define the amount of paclitaxel (μg) released per 16 ml sample. The amount of paclitaxel released at a specified time is defined using the amount of paclitaxel per sample and the time the sample was taken.

Example 37
Formulation of drug in medium containing triblock copolymer Paclitaxel is stirred for at least 2 hours at ambient temperature to dissolve paclitaxel in diluent, followed by addition of triblock copolymer and again stirred for at least 2 hours Incorporated into a formulation containing a triblock copolymer and a diluent (described below). A longer time was used to add the higher concentration of the triblock copolymer. For example, the addition of 33% triblock copolymer was achieved by stirring for at least 15 hours (overnight). The diluent was PEG 300 NF or PEG 400 derived by the end of the addition of 90% trimethylene carbonate / glycolide in a ratio of 400: 100. The triblock copolymer is an ABA copolymer.Block A contains polymerized trimethylene carbonate (90%) and glycolide (10%) and has a total molecular weight of about 900 g / mol. Contains PEG 400. Paclitaxel was effectively incorporated into this formulation at concentrations of 0.015 to 0.45 mg / ml. The amount of triblock copolymer in the formulation varied from 2.3 to 50% w / w by using PEG400 as diluent. This product was sterilized by irradiation with about 2.5 kGy of gamma radiation.

Example 38
Formulation of drug in equivalent solvent medium Paclitaxel was incorporated into a formulation consisting of water and PEG 300 NF. Paclitaxel was first dissolved at 90:10 PEG 300 NF mixture: water by stirring for at least 2 hours at ambient temperature. When the drug was dissolved, the composition was incorporated in a 50:50 equivalent part of a PEG 300 NF: water mixture. The final composition was paclitaxel dissolved in a 70:30 mixture of PEG 300 NF: water. Paclitaxel was incorporated at a concentration of 0.45-4.5 mg / ml. The composition was filtered through a 0.22 μm filter to sterilize.

Example 39
Determination of maximum tolerated dose (MTD) of drug after intra-articular injection Male Hartley guinea pigs at least 6 weeks old were anesthetized with 5% isoflurane in an enclosed room. The animal was weighed and transferred to the operating table, where anesthesia was maintained with a nose cone with 2% isoflurane. The hair around the knees of both legs was shaved and the knee width at the femoral head of both knees was measured. The right knee skin was disinfected. A 25G needle was introduced into the synovial cavity using an intermediate approach and 0.1 mL of the test formulation was injected. Three or seven days after injection, the animals were euthanized by 0.7 mL Euthanyl heart injection under deep anesthesia (5% isoflurane). The sample size was N = 3 for each formulation.

  Knee function was assessed by recording changes in walking behavior and signs of tenderness before being euthanized. The animals were weighed immediately after being euthanized. Next, the width of the femoral head of both knees was measured with a caliper. The knee joint was incised by incising the quadriceps tendon laterally, incising through the outer and inner joint capsules and inverting the patella on the tibia. Knee inflammation was assessed by recording signs such as swelling, vascularization, fluid retention, subcutaneous tissue color change and internal joint structure. A photo was taken to document the findings. All data was recorded by an observer who could not see the treatment group.

  The MTD of the drug in the test formulation was determined to be that in which knee inflammation was not observed.

  The MTD of paclitaxel in the triblock gel formulation of Example A was found to be 0.075 mg / ml based on an evaluation at 7 days. Evaluation of this inflammation after 3 days showed that the dose was tolerated up to 0.15 mg / ml. The 0.015 mg / ml dose showed signs of inflammation only after 7 days. The MTD of paclitaxel in an equivalent solvent formulation was found to be 1.5 mg / ml based on a 3 day evaluation.

Example 40
Evaluation of drug distribution in local tissues after intra-articular injection Animals were injected with the MTD dose of paclitaxel specified for each formulation in the knee joint as described in 4.2 above. Three or seven days after injection into the animals, the animals were euthanized by Euthanyl's heart injection. The knee joint was dissected and the synovium, anterior cruciate ligament, fat pad, knee meniscus and cartilage were collected. Each tissue was quickly rinsed in saline, wiped dry, and stored individually at −20 ° C. in scintillation bails until analysis of paclitaxel.

  Paclitaxel was extracted from three animal pooled samples that were homogenized using a Polytron PT2000 homogenizer. The setting of the apparatus was 3 to 9, and the extraction time was 1 minute. The extraction solution was 1 mL of 50/50 acetonitrile (ACN) /0.2 μg / mL of 10-deacetyltaxol (10-DAT) and water containing 0.1% formic acid. The extract was centrifuged for 10 minutes at 3000 rpm using a Beckman J6-HC centrifuge. The supernatant was filtered from an Acrodisc CR (13 mm, 0.45 μ) syringe filter into an LC / MS / MS analytical HPLC vial. Some fat pad samples that did not produce a clear supernatant were again centrifuged for 10 minutes at a speed of 10,000 rpm using an IEC Micromax centrifuge prior to filtration.

  The paclitaxel content of the extract was determined by LC / MS / MS method using internal calibration. The calibration curve ranged from 0.01 to 1 μg / mL for paclitaxel with 0.2 μg / mL 10-DAT. The LC / MS / MS system consists of a Waters 2695 separation module and a Waters Micromass Quatto Microtriple-Quad mass spectrometer. The explanation of LC method and MS / MS method is shown below.

Using this method, measurable levels of paclitaxel have been shown to be recovered from cartilage, knee joint meniscus, ligament, fat and synovium of treated animals. Drug tissue levels were maintained for at least 7 days, and additional studies showed that the dose of paclitaxel administered allowed tissue levels to be maintained for 21-28 days or more. When 0.015 mg / ml paclitaxel was used to deliver more paclitaxel by injection of the formulation of Example A, the tissue concentration in ligament, fat, synovial, and meniscal tissue was 15 mg / ml Paxceed. 6 to 11 times higher than paclitaxel delivered in This is therefore an effective delivery system for the drug.

Example 41
Evaluation of drug distribution in local tissues after intra-articular injection Animals were treated as described in Example 39. Rabbits are evaluated by intra-articular injection of 0.5 ml formulation. Paclitaxel is extracted from individual tissue samples of three animals homogenized using Freezer / Mill, SPEX CertiPrep 6850. The ground sample is extracted with 12 mL solution containing acetic acid (3.4 mM) and LiCl (4-8 μm) with 50/50 ACN / water. Extraction is performed at room temperature for 30 minutes on a Tube Rotator, Labquake Shaker. The extract is filtered from an Acrodisc CR (13 mm, 0.45 μ) syringe filter into an HPLC vial for LC / MS / MS analysis.

  The paclitaxel content of the extract is determined by LC / MS / MS method using external calibration. The calibration curve is in the range of 0.01-1 μg / mL for paclitaxel. The LC / MS / MS system consists of a Waters 2695 separation module and a Waters Micromass QUATTOMICRO triple-Quad mass spectrometer. The explanation of LC method and MS / MS method is shown below.

Using this method, paclitaxel has been shown to be present in cartilage, knee meniscus, ligament, fat and synovium of animals treated with tissue at concentrations up to 3.25 μg / g. The level of drug tissue was maintained for at least 14 days, indicating that depending on the dose of paclitaxel administered, the tissue level could be maintained for 21-28 days or more.

Example 42
Spinal surgical adhesive model to evaluate fibrosis inhibitors in rabbits Extensive scar formation and adhesion often occurs after lumbar surgery related to the spine. The dense, thick fibrous tissue that adheres to the spine and adjacent muscles must be removed by surgery. Unfortunately, fiber bonds generally form after secondary surgery. Adhesion is formed by the proliferation and migration of fibroblasts from the surrounding tissue at the surgical site. These cells are responsible for the healing response after tissue damage. When they are transferred to the wound, proteins such as collagen are produced to repair the damaged tissue. Hyperproliferation and secretion by these cells induces local damage, compression and contraction of the surrounding tissue with side effects.

  The rabbit laminectomy spinal adhesion model described here is used to investigate the prevention of spinal adhesion due to slow local release of fibrosis inhibitors.

  Five to six animals are included in each experimental group to allow meaningful statistical analysis. Formulations with various concentrations of fiber formation inhibitors are tested by the subject animals for assessment of inhibition of adhesion formation.

  Rabbits are anesthetized by IM injection of ketamine / dirazine. An endotracheal tube is inserted to maintain the drug with halothane. The animal is placed on the heating pad of the operating table and the skin on the lower half of the back is shaved and prepared for surgery sterilization. A longitudinal midline skin incision is made on L-1 to L-5 and along the lumbosacral peritoneum. An incision is made in the peritoneum to expose the ends of the spinous processes. An incision is made in the paraspinal muscles and retracted from the L-4 spinous processes and membrane. A laminectomy is performed with L-4 by carefully excising the bilateral thin film and removing the spinous processes. This creates a small 5x10 mm laminectomy defect. Performed with hemostatic gel foam (Gelfoam). The test formulation is applied to the injury site and the wound is closed in layers with bicyclyl suture. Animals are placed in an incubator until they recover from anesthesia and then returned to the cage.

  Two weeks after surgery, the animals are anesthetized according to the procedure described above. Animals are euthanized by Euthanyl. The skin was incised and the laminectomy site was examined in detail by dissection and the amount of adhesion was scored using a scoring system published in the scientific literature for this type of injury.

Example 43
Surgical adhesion model to evaluate tendon fibrosis inhibitors in rabbits This model investigates whether local slow release of drugs known to inhibit fibrosis can prevent tendon adhesion Used to do. The polymer formulation is filled with drug and implanted around the damaged tendon of the rabbit. In animals without a fibrosis inhibitor, adhesion occurs during the period when the tendon is immobilized within 3 weeks of flexor tendon injury. The advantage of a rabbit is that the anatomy of the tendon and the behavior of cells during healing are similar to that of the human body, except that the healing speed of the tendon is much faster in the rabbit.

  The rabbit is anesthetized and the right hind paw skin is shaved and prepared for sterile surgery. Sterilization is performed with the aid of a surgical microscope. A longitudinal midline skin incision is made in the axial plane of the proximal stamen bundle of the second and fourth fingers. Carefully expose the tendon synovial sheath and make a lateral incision to access the deep flexor muscle end to the superficial digital flexor bifurcation. Gently lift the deep flexor flexor with pointed tweezers and incise half of it to injure the tendon. A formulation containing the test drug is applied around the tendon in the sheath of one of two arbitrarily selected fingers. The other finger is left untreated and used as a control. The sheath is then repaired with 6-0 nylon suture. Fixing the 6-0 nylon suture is inserted through the transverse metacarpal ligament into the tendon / sheath complex, fixing the tendon and sheath as a single unit, making it easier for adhesion formation to occur. The wound is closed with 4-0 nodal suture. Bandages are applied around the hind legs to further reinforce finger fixation, ensuring animal comfort and mobility. When the animal recovers, it is returned to the cage.

  Three weeks after surgery, the animals are anesthetized. After incision of the skin, the tissue surface around the synovial sheath is incised and the tendon-sheath complex is removed with a block and transferred to 10% phosphate buffered formaldehyde for histopathological analysis. Euthanize the animal. After embedding in paraffin, a 5-um thick continuous cross section is cut from the sheath-tendon complex every 2 mm. Sections are stained with H & E and Movat stains to assess adhesion growth. Each slide is digitized using a digital microscope camera (Nikon Micropublisher cooling camera) connected to a computer. Next, morphometric analysis is performed using image analysis software (ImagePro). The thickness and area of adhesion, defined as periosteal space occlusive material, is measured and animals treated with the formulation are compared to control animals.

Example 44
Evaluation of Paclitaxel in Inhibiting Cartilage Damage in Hartley Guinea Pig Osteoarthritis Model of ACL Injury The purpose of this study was to prevent or prevent the development of guinea pig knee osteoarthritis when paclitaxel administered in hyaluronic acid It is to judge whether it can be done.

Surgery procedure.
At least 6 weeks old male Hartley guinea pigs were anesthetized with 5% isoflurane in an enclosed room. The animal was weighed and transferred to the operating table, where anesthesia was maintained with a nose cone with 2% isoflurane. The hair around the knees of both legs was shaved and the knee width at the femoral head of both knees was measured. The right knee skin was disinfected. A 20G needle was introduced into the knee joint using an intermediate approach, and the anterior cruciate ligament was cut with the sharp end of the needle. This procedure was performed in a preliminary experiment and showed that the anterior cruciate ligament can be reliably segmented by using this technique.

  Two weeks after the first procedure, the animals were anesthetized with isoflurane (5% induction-2% maintenance) and weighed. The hair around the knees of both legs was shaved and the knee width at the femoral head of both knees was measured. The wounded knee skin was disinfected. A 25G needle was introduced into the synovial cavity using an intermediate approach and 0.1 ml of the test formulation was injected. A total of 5 injections were repeated weekly. Sample size was N = 12 for each formulation. Two doses of paclitaxel and a control formulation were tested.

  Ten weeks after injection, the animals were euthanized by heart injection of 0.7 mL Euthanyl under deep anesthesia (5% isoflurane) and weighed. A final measurement of the knee was performed. The skin in the knee area was removed without damaging the subcutaneous tissue. The knee joints were then collected in blocks and placed in a fixative formaldehyde (37%) / acetic acid solution (5: 1 ratio). Samples were sent to an independent laboratory where histological pretreatment of the joints was performed and a pathologist evaluated for signs of cartilage damage.

  Briefly, knee sections were made, cartilage was examined, and slides were stained with H & E stain. The pathologist scored the slides according to the following scale, using the corresponding knee slices, in a manner that did not see each animal. No cartilage damage, no proteoglycan loss, no cartilage wear, no cartilage loss for water marks, no cartilage loss for bone. A bar graph was created for each group and compared. Treatment of paclitaxel at low dose (dose 1) and medium dose (dose 2) showed a statistical reduction in cartilage damage compared to controls. See Figures 19 and 20.

Example 45
Proteoglycan Loss Index in Carrageenin-Induced and Antigen-Induced Rabbit Models of Arthritis After Treatment with Paclitaxel All microspheres were created using an oil-in-water solvent evaporation method described by Liggins and Burt (2001). The external phase was 100 ml of water containing 1-5% PVA. The internal phase was 10 ml dichloromethane solution containing 5% w / v total solids (polymer and paclitaxel). In order to form microspheres, stirring was performed for 2 hours at room temperature. By changing the stirring speed between 900-2100 rpm, PVA concentrations, various size ranges were generated. The microspheres were separated from the external phase and rinsed with distilled water. Some microspheres were further divided into separate size ranges by sieving the microsphere suspension through sieves with mesh sizes of 38, 53, 75 and 106 μm. The size distribution of the microspheres was measured using a Coulter LS130 particle size analyzer. The microspheres were suspended in water containing a small amount of Tween 80 to prevent aggregation before analyzing the particle size. The particle size range of chitosan was measured with an optical microscope using a 5 μm gradation microscope slide. An optical microscope was used for both dry and wet samples.

  The thermal properties of the microspheres were measured using DuPont Thermal Analysis DSC. About 5 mg of microspheres were placed in an unsealed aluminum pan and a thermogravimetric change record was obtained at a heating rate of 10 ° C / min. Crystal evidence was obtained by X-ray powder diffractometry using a Rigaku X-ray diffractometer. Samples were scanned with a CuKα X-ray source at a rate of 1o2θ / min in steps of 0.02o2θ per step over a range of 5 to 35o2θ.

  The surface morphology of the microspheres was measured using a Hitachi scanning electron microscope. The microspheres were coated with 100 A gold / palladium and visualized at a magnification of 1000 times.

  In vitro release from paclitaxel contents and microspheres was measured using the Liggins & Burt (2001) method. For total content analysis, approximately 5 mg (exactly measured) of microspheres were dissolved in 1 ml dichloromethane after vigorous mixing with 15 ml aqueous solution of acetonitrile: water 60:40. The solvent mixture could be separated into two of almost the same volume. They also had a polymer precipitate between the two. The amount of each of the two paclitaxels was then measured by HPLC using a Waters HPLC system. The mobile phase was 58: 37: 5 acetonitrile: water: methanol flow rate of 1 ml / min. An injection volume of 20 μl, a Novapak C18 column and UV detection at 232 nm was used.

  Arthritis-inducing antigen was reproduced in rabbits using the method described previously (Kim et al., J. Rheumatol 1995: 22: 1714-21). Briefly, female New Zealand white rabbits weighing 2.5 kg to 2.8 kg were used for biocompatibility and efficacy studies. The animals were placed in a hanging basket with free access to food and water. Animals were habituated to the environment for 7 days prior to all experiments. Arthritis was caused in some animals for use as a control group in biocompatibility studies and efficacy studies. All knee joint injections were performed under anesthesia with intramuscular injections of ketamine HCl (40 mg / kg) and xylazine (5 mg / kg). At the end of the live study, animals are euthanized by intravenous injection of T-61. The knee joint is incised immediately after euthanasia and fixed with 10% formalin before histological analysis.

  Arthritis-inducing antigen was achieved by three injections of bovine serum albumin (BSA) with Freund's complete adjuvant (FCA). The first injection consisted of 5 mg BSA emulsified with 1 ml FCA and diluted with 1 ml PBS. Three weeks later, each rabbit received a subcutaneous booster injection of 2.5 mg BSA emulsified with 1 ml FCA and diluted with 1 ml PBS. Four weeks later, each rabbit received a second booster injection of 0.5 mg BSA in 0.3 mL PBS without pyrogen at the knee joint. Five days after the last booster injection, the rabbits were treated with an intra-articular injection of the test substance.

  Carrageenan-induced arthritis was performed on rabbits, which were treated in the same manner as the antigen-induced arthritis model. All rabbits of the carrageenan group were injected with 0.3 ml of 1% carrageenan in PBS without pyrogen on days 1, 3, 8, 16, and 21. Half of the animals were also injected on day 6 with 35 mg of 20% paclitaxel-filled microspheres. All animals were euthanized on day 29 and joints were dissected for histological analysis.

  Periosteal inflammation was assessed after euthanasia in rabbits. The joints were fixed in formalin and decalcified with 10% formic acid with repeated changes. The decalcified joint was embedded in paraffin, and a section containing synovium, cartilage, and bone was prepared. Cross sections were stained with hematoxylin and eosin (H & E) for cytoplasm and safranin O for proteoglycan contents. Periosteal inflammation and cartilage degradation were assessed by tissue evaluation of patella synovium and femoral condylar articular cartilage, respectively. Villous hyperplasia, fibroblast proliferation, fibrosis, angiogenesis, mononuclear cells and polymorphonuclear cell infiltration were graded as indicators of synovial inflammation. Cartilage degradation was graded as surface erosion, proteoglycan content, and chondrocyte necrosis. The grading of cell invasion and swelling was scored on an integer from 0 to 4 based on erythema, swelling, increased cell invasion (0: normal, 4: maximum). If there was some impact, a score of 0.5 was assigned. This was the only non-integer score. Proteoglycan loss was also scored from 0 (normal) to 4 (almost any loss of stained proteoglycan).

  In the treatment of antigen-induced arthritis, the efficacy of paclitaxel-filled polyester microspheres given by intra-articular injection was evaluated using the control group and 20% -filled 10-35 and 35-105 μm PLA microspheres. Groups of 5 rabbits were treated with 40 mg microspheres or the right joint was treated with PBS alone. The left joint received only PBS. The animals were euthanized 14 days after treatment and histologically examined for synovial inflammation and cartilage degradation as described above.

PLA microspheres containing 20% paclitaxel were selected for efficacy testing. Table 1 shows the injection results of 40 mg control drug and paclitaxel filled PLA microspheres in rabbits with antigen-induced arthritis. In rabbits with antigen-induced arthritis, arthritis-untreated rabbits had a joint swelling rating of 3 and 4.9 x 10 ⁷ cells in synovial joint fluid. Paclitaxel filled microspheres in the 10-35 um size range did not reduce antigen-induced arthritis. In fact, in this group, the amount of cell infiltration was higher in arthritic untreated rabbits (Table 1). However, injection of 35-105 μm paclitaxel-filled microspheres significantly reduced both joint swelling and the number of cells in joint fluid (approximately 50% reduction) relative to the control group (Table 1). Proteoglycan loss and cartilage degradation expressed as chondrocyte necrosis were also evaluated in the control group and the paclitaxel-filled 35-105 μm microsphere group. Injection of control PLA microspheres in diseased animals did not affect either proteoglycan loss or chondrocyte necrosis. However, animals treated with paclitaxel filled microspheres had a significant reduction in proteoglycan loss compared to untreated animals (Table 1 and FIGS. 21A-21C). FIG. 21A shows an upper layer of continuous cartilage and a knee with a normal histological appearance without loss of staining indicating normal proteoglycan capacity (score 0). FIG. 21B shows control microsphere arthritis. Proteoglycan loss is seen in the third layer from the bottom of the cross section, which can be called a large loss (score 3). FIG. 21C shows that arthritic knees treated with paclitaxel microspheres show a slight loss of proteoglycan on the surface of the cartilage and the surface is intact (score 1).

  The efficacy of paclitaxel filled microspheres to prevent proteoglycan loss in carrageenan-induced arthritis was not as pronounced in antigen-induced arthritis (FIGS. 21D-F). FIG. 21E shows severe loss of proteoglycan through all layers of cartilage, but the surface layer remains intact (score 4). Treatment of carrageenan-induced knee with paclitaxel microspheres resulted in less staining reduction (Figure 21F, score 2), but did not see the protective effect observed in the antigen-induced model (Figure 21C) .

  In these studies, antigen-induced arthritis was used to measure efficacy. Although this animal model takes some time to develop, it has many aspects of rheumatoid arthritis in the human body, including inflammatory cytokines (such as TNF-a), loss of proteoglycans and leukocyte infiltration into joints with chronic inflammation. Reflects. The results of this model are compared with the results of carrageenan-induced arthritis, which provides a method for inducing a reproducible level of intense (non-chronic) acute arthritis morphology that is rapidly established in rabbits. Since carrageenan-induced arthritis is characterized by severe proteoglycan loss, this model was also used in this study to determine the efficacy of paclitaxel in joints with respect to proteoglycan loss. Efficacy studies, including measurement of joint swelling, cell invasion, proteoglycan loss and chondrocyte necrosis, show that a single injection of 20-mg paclitaxel-filled 35-105 μm microspheres 40 mg significantly increases all aspects of chronic arthritic conditions in rabbits (Table 1 and FIGS. 21A to C). The efficacy of paclitaxel-filled microspheres in preventing proteoglycan loss in the carrageenan-induced arthritis model was not as pronounced as shown in the antigen-induced arthritis model.

  Table 1.Efficacy of 40 mg control group and 20% paclitaxel-filled PLA microspheres in the size range of 10-35 and 35-105 μm was compared to the mean score for swelling, cell infiltration, proteoglycan loss and chondrocyte necrosis (n = Evaluated in 5).

All US patents, US patent application publications, US patent application documents, foreign patents, foreign patent application documents and non-patent publications referred to in the specification and / or listed on the application data sheet are fully referenced It is incorporated into this document as literature.

  [Note: Important matters cannot be incorporated by reference from foreign patents, foreign patent applications or non-patent literature. However, unless the US PTO permits the subject matter to be explicitly added to the specification in a way that corrects it without affecting the filing date. Built-in ability by reference to ADS has not been tested. It is strongly recommended that those references that you wish to incorporate by reference be noted where appropriate in the text.

  In view of the foregoing description, certain embodiments of the invention have been described for purposes of illustration, but it will be understood that various modifications can be made without departing from the spirit and scope of the invention. Accordingly, the invention is not limited except as by the appended claims.

FIG. 1 is a chart showing how cell cycle inhibitors act in one or more procedures in a biological pathway. FIG. 2 is a graph showing the results of a screening test method for evaluating the effect of mitoxantrone on nitric oxide production by THP-1 macrophages. FIG. 3 is a graph showing the results of a screening test method for evaluating the influence of Bay11-7082 on TNF-α production by THP-1 macrophages. FIG. 4 is a graph showing the results of a screening test method for evaluating the influence of rapamycin concentration on TNFα production by THP-1 macrophages. FIG. 5 is a graph showing the results of a screening test method for evaluating the effect of mitoxantrone on cell proliferation of human fibroblasts. FIG. 6 is a graph showing the results of a screening test method for evaluating the effect of rapamycin on cell proliferation of human fibroblasts. FIG. 7 is a graph showing the results of a screening test method for evaluating the effect of paclitaxel on cell proliferation of human fibroblasts. FIG. 8 shows an uninjured carotid artery from a rat balloon injury model. FIG. 9 shows a damaged carotid artery from a rat balloon injury model. FIG. 10 shows a carotid artery treated with paclitaxel / mesh from a rat balloon injury model. FIG. 11A is a schematic depiction of the transcriptional regulation of matrix metalloproteinases. FIG. 11B is a blot illustrating the stimulation of AP-1 transcriptional activity by IL-1. FIG. 11C is a graph showing that IL-1 induced binding activity was decreased in lysates from chondrocytes pretreated with paclitaxel. FIG. 11D is a blot showing that induction by IL-1 increases collagenase and stromelysin RNA levels in chondrocytes, and this induction can be inhibited by pretreatment with paclitaxel. Figures 12A-H are blots showing the effect of various microtubule toxin agents in inhibiting collagenase expression. Figures 12A-H are blots showing the effect of various microtubule toxin agents in inhibiting collagenase expression. Figures 12A-H are blots showing the effect of various microtubule toxin agents in inhibiting collagenase expression. Figures 12A-H are blots showing the effect of various microtubule toxin agents in inhibiting collagenase expression. Figures 12A-H are blots showing the effect of various microtubule toxin agents in inhibiting collagenase expression. Figures 12A-H are blots showing the effect of various microtubule toxin agents in inhibiting collagenase expression. Figures 12A-H are blots showing the effect of various microtubule toxin agents in inhibiting collagenase expression. Figures 12A-H are blots showing the effect of various microtubule toxin agents in inhibiting collagenase expression. FIG. 13 is a graph showing the results of a screening test method for evaluating the effect of paclitaxel on smooth muscle cell migration. FIG. 14 is a graph showing the results of a screening test method for evaluating the influence of geldanamycin on IL-1β production by THP-1 macrophages. FIG. 15 is a graph showing the results of a screening test to evaluate the effect of geldanamycin on IL-8 production by THP-1 macrophages. FIG. 16 is a graph showing the results of a screening test method for evaluating the effects of geldanamycin on MCP-1 production by THP-1 macrophages. FIG. 17 is a graph showing the results of a screening test method for evaluating the effect of paclitaxel on smooth muscle cell proliferation. FIG. 18 is a graph showing the results of a screening test to evaluate the effect of paclitaxel on the proliferation of mouse RAW264.7 macrophage cell lines. FIG. 19 is a graph showing the average rank of joint scores obtained by processing a knee of a Hartley guinea pig with ACL damage with paclitaxel. A decrease in score indicates an improvement in cartilage score. Dose response is statistically important (p <0.02). 20A-C are cross-sectional examples of Hartley guinea pig knees that have undergone paclitaxel treatment. FIG. 20A. Control species showing bone cartilage erosion. FIG. 20B. Paclitaxel dose 1 (small amount) showing cartilage wear. FIG. 20C. Paclitaxel dose 2 (medium amount) showing a minute defect of cartilage. Figures 21A-F are derived from healthy knees (Figures 21A and 21D) and arthritic knees induced by administration of albumin in complete Freund's adjuvant (Figures 21B and 21C) or carrageenan (Figures E21E and 21F). 3 is a slide of the safranin-O stained tissue of each bone fluid tissue. Arthritic knees gained fines (FIGS. 21C and 21F) incorporating control (FIGS. 21B and 21E) or 20% paclitaxel. The data show a decrease in red stained proteoglycans in the control granule in the form of paclitaxel uptake and in arthritic knees treated with proteoglycan protective properties. Figures 21A-F are derived from healthy knees (Figures 21A and 21D) and arthritic knees induced by administration of albumin in complete Freund's adjuvant (Figures 21B and 21C) or carrageenan (Figures E21E and 21F). 3 is a slide of the safranin-O stained tissue of each bone fluid tissue. Arthritic knees gained fines (FIGS. 21C and 21F) incorporating control (FIGS. 21B and 21E) or 20% paclitaxel. The data show a decrease in red stained proteoglycans in the control granule in the form of paclitaxel uptake and in arthritic knees treated with proteoglycan protective properties.

Claims (8822)

Methods of implanting a medical device comprising: (a) a medical device to which the medical device is implanted or transplanted host tissue i) an inhibitor of fiber formation ii) an anti-infective agent iii) a polymer iv) an inhibitor of fiber formation and a polymer V) a composition comprising an anti-infective agent and a polymer or vi) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer, and (b) implanting a medical device into the host. A method of implanting a device with the medical device of claim 1 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a fibrosis inhibitor; and (b) the host. Implant a medical device. A method for implanting a device with the medical device of claim 1 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in an anti-infective agent; and (b) the host is implanted. Implant medical devices. A method of implanting a device with the medical device of claim 1 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a polymer; and (b) the medical device is implanted in the host. Transplant. A method of implanting a device comprising the following with the medical device of claim 1: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising a fibrosis inhibitor and a polymer; And (b) transplant the medical device into the host. A method of implanting a device with the medical device of claim 1 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising an anti-infective and a polymer; and (b) Transplant the medical device into the host. A method of implanting a device comprising the following with the medical device of claim 1: (a) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer in which the medical device is implanted or the host tissue into which it is implanted. And (b) implant the medical device into the host. 8. The method of any of claims 1-7, wherein the device is an intravascular device. 8. The method of any of claims 1-7, wherein the device is a gastrointestinal stent. 8. The method of any of claims 1-7, wherein the device is a tracheal / bronchial stent. 8. The method of any of claims 1-7, wherein the device is a urogenital device. 8. The method of any of claims 1-7, wherein the device is an ear stent and a nasal stent. 8. The method of any of claims 1-7, wherein the device is an ear ventilation device. 8. The method of any of claims 1-7, wherein the device is an intraocular implant. The device of any one of claims 1-7, wherein the graft is a vascular graft. The device of any of claims 1 to 7, wherein the device comprises a film or mesh. 8. The method of any of claims 1-7, wherein the device is a glaucoma drainage device. 8. The method of any of claims 1-7, wherein the device is a prosthetic heart valve or composition thereof. 8. The device of any of claims 1-7, wherein the device is a penile implant. 8. The device of any of claims 1-7, wherein the device is an endotracheal tube or tracheal cannula. 8. The method of any of claims 1-7, wherein the device is a peritoneal dialysis catheter. 8. The method of any of claims 1-7, wherein the device is a central nervous system shunt or pressure monitoring implant. 8. The method of any of claims 1-7, wherein the device is an inferior vena cava filter. 8. The method of any of claims 1-7, wherein the device is a gastrointestinal device. 8. The method of any of claims 1-7, wherein the device is a central venous catheter. 8. The method of any of claims 1-7, wherein the device is an auxiliary artificial heart. 8. The device of any of claims 1-7, wherein the device is a spinal implant. 8. The method of any of claims 1-7, wherein the device is an implantable electrical device. 8. The method of any of claims 1-7, wherein the device is an implantable sensor. 8. The method of any of claims 1-7, wherein the device is an implantable pump. 8. The method of any of claims 1-7, wherein the device is a soft tissue graft. 2. The method of claim 1, wherein cell regeneration is inhibited by a fiber formation inhibitor. 2. The method of claim 1, wherein angiogenesis is inhibited by the fiber formation inhibitor. 2. The method according to claim 1, wherein fibroblast migration is inhibited by the fibrosis inhibitor. 2. The method of claim 1, wherein fibroblast proliferation is inhibited by the fibrosis inhibitor. 2. The method according to claim 1, wherein the extracellular matrix accumulation is inhibited by the fiber formation inhibitor. 2. The method of claim 1, wherein the tissue remodeling is inhibited by the fiber formation inhibitor. 2. The method of claim 1, wherein the fiber formation inhibitor is an angiogenesis inhibitor. 2. The method of claim 1, wherein the fiber formation inhibitor is a 5-lipoxygenase inhibitor or antagonist. 2. The method of claim 1, wherein the fiber formation inhibitor is a chemokine receptor antagonist. 2. The method of claim 1, wherein the fiber formation inhibitor is a cell cycle inhibitor. 2. The method of claim 1, wherein the fiber formation inhibitor is a taxane. 2. The method of claim 1, wherein the fiber formation inhibitor is a microtubule inhibitor. 2. The method of claim 1, wherein the fiber formation inhibitor is paclitaxel. 2. The method of claim 1, wherein the fiber formation inhibitor is not paclitaxel. 2. The method of claim 1, wherein the fiber formation inhibitor is an analogue or derivative of paclitaxel. 2. The method of claim 1, wherein the fiber formation inhibitor is a vinca alkaloid. 2. The method of claim 1, wherein the fibrosis inhibitor is camptothecin or an analogue or derivative thereof. 2. The method of claim 1, wherein the fiber formation inhibitor is podophyllotoxin. 2. The method of claim 1, wherein the fibrosis inhibitor is podophyllotoxin, and the podophyllotoxin is etoposide or an analogue or derivative thereof. 2. The method of claim 1, wherein the fiber formation inhibitor is an anthracycline. 2. The method of claim 1, wherein the fiber formation inhibitor is an anthracycline, and the anthracycline is doxorubicin or an analogue or derivative thereof. 2. The method of claim 1, wherein the fiber formation inhibitor is an anthracycline, and the anthracycline is mitoxantrone or an analogue or derivative thereof. 2. The method according to claim 1, wherein the fiber formation inhibitor is a platinum compound. 2. The method of claim 1, wherein the fiber formation inhibitor is nitrosourea. 2. The method of claim 1, wherein the fiber formation inhibitor is nitroimidazole. 2. The method of claim 1, wherein the fiber formation inhibitor is a folic acid antagonist. 2. The method of claim 1, wherein the fibrosis inhibitor is a cytidine analog. 2. The method of claim 1, wherein the fibrosis inhibitor is a pyrimidine analog. 2. The method of claim 1, wherein the fiber formation inhibitor is a fluoropyrimidine analog. 2. The method of claim 1, wherein the fiber formation inhibitor is a purine analog. 2. The method of claim 1, wherein the fiber formation inhibitor is a nitrogen mustard or an analogue or derivative thereof. 2. The method of claim 1, wherein the fiber formation inhibitor is hydroxyurea. 2. The method of claim 1, wherein the fibrosis inhibitor is mitomycin or an analogue or derivative thereof. 2. The method of claim 1, wherein the fiber formation inhibitor is an alkyl sulfonate. 2. The method of claim 1, wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. 2. The method of claim 1, wherein the fibrosis inhibitor is nicotinamide or an analogue or derivative thereof. 2. The method of claim 1, wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. 2. The method according to claim 1, wherein the fiber formation inhibitor is a DNA alkylating agent. 2. The method of claim 1, wherein the fiber formation inhibitor is a microtubule inhibitor. 2. The method of claim 1, wherein the fiber formation inhibitor is a topoisomerase inhibitor. 2. The method according to claim 1, wherein the fiber formation inhibitor is a DNA cleaving agent. 2. The method of claim 1, wherein the fiber formation inhibitor is an antimetabolite. 2. The method of claim 1, wherein adenosine deaminase is inhibited by a fiber formation inhibitor. 2. The method according to claim 1, wherein the purine ring synthesis is inhibited by the fiber formation inhibitor. 2. The method of claim 1, wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. 2. The method of claim 1, wherein the fiber formation inhibitor inhibits the reduction of dihydrofolate. 2. The method of claim 1, wherein thymidine monophosphate is inhibited by the fiber formation inhibitor. 2. The method of claim 1, wherein the fiber formation inhibitor causes DNA damage. 2. The method according to claim 1, wherein the fiber formation inhibitor is a DNA insertion agent. 2. The method according to claim 1, wherein the fiber formation inhibitor is an RNA synthesis inhibitor. 2. The method of claim 1, wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. 2. The method of claim 1, wherein ribonucleotide synthesis or function is inhibited by the fiber formation inhibitor. 2. The method of claim 1, wherein the fibrosis inhibitor inhibits thymidine monophosphate synthesis or function. 2. The method of claim 1, wherein DNA synthesis is inhibited by the fiber formation inhibitor. 2. The method of claim 1, wherein the formation of DNA adduct is caused by the fiber formation inhibitor. 2. The method of claim 1, wherein protein synthesis is inhibited by the fiber formation inhibitor. 2. The method of claim 1, wherein the microtubule function is inhibited by the fiber formation inhibitor. 2. The method of claim 1, wherein the fibril formation inhibitor is a cyclin dependent protein kinase inhibitor. 2. The method of claim 1, wherein the fibrosis inhibitor is an epidermal growth factor kinase inhibitor. 2. The method of claim 1, wherein the fiber formation inhibitor is an elastase inhibitor. 2. The method of claim 1, wherein the fiber formation inhibitor is a factor Xa inhibitor. 2. The method of claim 1, wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. 2. The method of claim 1, wherein the fibrosis inhibitor is a fibrinogen antagonist. 2. The method of claim 1, wherein the fiber formation inhibitor is a guanylate cyclase stimulant. 2. The method of claim 1, wherein the fibrosis inhibitor is a heat shock protein 90 antagonist. 2. The method of claim 1, wherein the fibrosis inhibitor is a heat shock protein 90 antagonist and the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof. 2. The method of claim 1, wherein the fiber formation inhibitor is a guanylate cyclase stimulant. 2. The method of claim 1, wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. 2. The method of claim 1, wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor, and the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof. 2. The method of claim 1, wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. 2. The method of claim 1, wherein the fiber formation inhibitor is an IKK2 inhibitor. 2. The method of claim 1, wherein the fiber formation inhibitor is an IL-1 antagonist. 2. The method of claim 1, wherein the fiber formation inhibitor is an ICE antagonist. 2. The method of claim 1, wherein the fiber formation inhibitor is an IRAK antagonist. 2. The method of claim 1, wherein the fibrosis inhibitor is an IL-4 agonist. 2. The method of claim 1, wherein the fiber formation inhibitor is an immunomodulator. 2. The method of claim 1, wherein the fibrosis inhibitor is sirolimus or an analogue or derivative thereof. 2. The method of claim 1, wherein the fiber formation inhibitor is not sirolimus. 2. The method of claim 1, wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. 2. The method of claim 1, wherein the fibrosis inhibitor is tacrolimus or an analogue or derivative thereof. 2. The method of claim 1, wherein the fiber formation inhibitor is not tacrolimus. 2. The method of claim 1, wherein the fibrosis inhibitor is biolimus or an analogue or derivative thereof. 2. The method of claim 1, wherein the fibrosis inhibitor is tresperimus or an analogue or derivative thereof. 2. The method of claim 1, wherein the fibrosis inhibitor is auranofin or an analogue or derivative thereof. 2. The method of claim 1, wherein the fibril formation inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. 2. The method of claim 1, wherein the fibrosis inhibitor is gusperimus or an analogue or derivative thereof. 2. The method of claim 1, wherein the fibrosis inhibitor is pimecrolimus or an analogue or derivative thereof. 2. The method of claim 1, wherein the fiber formation inhibitor is ABT-578 or an analogue or derivative thereof. 2. The method of claim 1, wherein the fiber formation inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. 2. The method of claim 1, wherein the fiber formation inhibitor is an IMPDH inhibitor, and the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof. Fiber forming inhibitor is an IMPDH inhibitor, the IMPDH inhibitor is 1-alpha-25-dihydroxyvitamin D ₃ or its analogues or derivatives, A method according to claim 1. 2. The method of claim 1, wherein the fiber formation inhibitor is a leukotriene inhibitor. 2. The method of claim 1, wherein the vascularization inhibitor is an MCP-1 antagonist. 2. The method of claim 1, wherein the fiber formation inhibitor is an MMP inhibitor. 2. The method of claim 1, wherein the fiber formation inhibitor is an NFκB inhibitor. The method according to claim 1, wherein the fiber formation inhibitor is an NFκB inhibitor, and the NFκB inhibitor is Bay11-7082. 2. The method of claim 1, wherein the fiber formation inhibitor is a NO antagonist. 2. The method of claim 1, wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor. 2. The method of claim 1, wherein the fibril formation inhibitor is a p38 MAP kinase inhibitor, and the p38 MAP kinase inhibitor is SB 202190. 2. The method of claim 1, wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. 2. The method of claim 1, wherein the fiber formation inhibitor is a TGFβ inhibitor. 2. The method of claim 1, wherein the fiber formation inhibitor is a thromboxane A2 antagonist. 2. The method of claim 1, wherein the vascularization inhibitor is a TNFα antagonist. 2. The method of claim 1, wherein the fiber formation inhibitor is a TACE inhibitor. 2. The method of claim 1, wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. 2. The method of claim 1, wherein the fiber formation inhibitor is a vitronectin inhibitor. 2. The method of claim 1, wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. 2. The method of claim 1, wherein the fiber formation inhibitor is a protein kinase inhibitor. 2. The method of claim 1, wherein the fibrosis inhibitor is a PDGF receptor kinase inhibitor. 2. The method of claim 1, wherein the fibrosis inhibitor is an endothelial growth factor receptor kinase inhibitor. 2. The method of claim 1, wherein the fiber formation inhibitor is a retinoic acid receptor antagonist. 2. The method of claim 1, wherein the fiber formation inhibitor is a platelet derived growth factor receptor kinase inhibitor. 2. The method of claim 1, wherein the fibrosis inhibitor is a fibrinogen antagonist. 2. The method of claim 1, wherein the fiber formation inhibitor is an antifungal agent. 2. The method of claim 1, wherein the fiber formation inhibitor is an antifungal agent and the antifungal agent is sulconizole. 2. The method of claim 1, wherein the fiber formation inhibitor is a bisphosphonate. 2. The method of claim 1, wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. 2. The method of claim 1, wherein the fibrosis inhibitor is a histamine H1 / H2 / H3 receptor antagonist. 2. The method according to claim 1, wherein the fiber formation inhibitor is a macrolide antibiotic. 2. The method of claim 1, wherein the fiber formation inhibitor is a GPIIb / IIIa receptor antagonist. 2. The method of claim 1, wherein the fiber formation inhibitor is an endothelin receptor antagonist. 2. The method of claim 1, wherein the fibrosis inhibitor is an agonist of a peroxisome proliferator-responsive receptor. 2. The method of claim 1, wherein the fibrosis inhibitor is an estrogen receptor agent. 2. The method of claim 1, wherein the fibrosis inhibitor is a somaststatin analog. 2. The method of claim 1, wherein the fiber formation inhibitor is a neurokinin 1 antagonist. 2. The method of claim 1, wherein the fiber formation inhibitor is a neurokinin 3 antagonist. 2. The method of claim 1, wherein the fibrosis inhibitor is a VLA-4 antagonist. 2. The method of claim 1, wherein the fibrosis inhibitor is an osteoclast inhibitor. 2. The method of claim 1, wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. 2. The method according to claim 1, wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. 2. The method of claim 1, wherein the fiber formation inhibitor is an angiotensin II antagonist. 2. The method of claim 1, wherein the fiber formation inhibitor is an enkephalinase inhibitor. 2. The method of claim 1, wherein the fibrosis inhibitor is a peroxisome proliferator-responsive receptor gamma agonist insulin sensitizer. 2. The method of claim 1, wherein the fiber formation inhibitor is a protein kinase C inhibitor. 2. The method according to claim 1, wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. 2. The method of claim 1, wherein the fiber formation inhibitor is a CXCR3 inhibitor. 2. The method of claim 1, wherein the fiber formation inhibitor is an Itk inhibitor. _2. The method according to claim 1, wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. 2. The method of claim 1, wherein the fibrosis inhibitor is a PPAR agonist. 2. The method of claim 1, wherein the fiber formation inhibitor is an immunosuppressant. 2. The method of claim 1, wherein the fiber formation inhibitor is an Erb inhibitor. 2. The method of claim 1, wherein the fibrosis inhibitor is an apoptosis agonist. 2. The method of claim 1, wherein the fibrosis inhibitor is a lipocortin agonist. 2. The method of claim 1, wherein the fibrosis inhibitor is a VCAM-1 antagonist. 2. The method of claim 1, wherein the fiber formation inhibitor is a collagen antagonist. 2. The method of claim 1, wherein the fiber formation inhibitor is an α2 integrin antagonist. 2. The method of claim 1, wherein the fiber formation inhibitor is a TNFα inhibitor. 2. The method of claim 1, wherein the fiber formation inhibitor is a nitric oxide inhibitor. 2. The method of claim 1, wherein the fiber formation inhibitor is a cathepsin inhibitor. 2. The method of claim 1, wherein the fibrosis inhibitor is not an anti-inflammatory agent. 2. The method of claim 1, wherein the fibrosis inhibitor is not a steroid. 2. The method of claim 1, wherein the fiber formation inhibitor is not a glucocorticosteroid. 2. The method of claim 1, wherein the fiber formation inhibitor is not dexamethasone. 2. The method of claim 1, wherein the fiber formation inhibitor is not beclomethasone. 2. The method of claim 1, wherein the fiber formation inhibitor is not dipropionic acid. 2. The method of claim 1, wherein the fiber formation inhibitor is not an anti-infective agent. 2. The method of claim 1, wherein the fibrosis inhibitor is not an antibiotic. 2. The method of claim 1, wherein the fiber formation inhibitor is not an antifungal agent. 2. The method of claim 1, wherein the anti-infective agent is an anthracycline. 2. The method of claim 1, wherein the anti-infective agent is doxorubicin. 2. The method of claim 1, wherein the anti-infective agent is mitoxantrone. 2. The method of claim 1, wherein the anti-infective agent is fluoropyrimidine. 2. The method of claim 1, wherein the anti-infective agent is 5-fluorouracil (5-FU). 2. The method of claim 1, wherein the anti-infective agent is a folic acid antagonist. 2. The method of claim 1, wherein the anti-infective agent is methotrexate. 2. The method of claim 1, wherein the anti-infective agent is podophyllotoxin. 2. The method of claim 1, wherein the anti-infective agent is etoposide. 2. The method of claim 1, wherein the anti-infective agent is camptothecin. 2. The method according to claim 1, wherein the anti-infective agent is hydroxyurea. 2. The method according to claim 1, wherein the anti-infective agent is a platinum complex. 2. The method of claim 1, wherein the anti-infective agent is cisplatin. 2. The method of claim 1, wherein the composition comprises an antithrombotic agent. The method of claim 1, wherein the polymer is formed from a reactant comprising a naturally occurring polymer. The method of claim 1, wherein the polymer is formed from a reactant comprising a protein. The method of claim 1, wherein the polymer is formed from a reactant comprising a carbohydrate. The method of claim 1, wherein the polymer is formed from a reactant comprising a biodegradable polymer. The method of claim 1, wherein the polymer is formed from a reactant comprising a non-biodegradable polymer. The method of claim 1, wherein the polymer is formed from a reactant comprising collagen. The method of claim 1, wherein the polymer is formed from a reactant comprising methylated collagen. The method of claim 1, wherein the polymer is formed from a reactant comprising fibrinogen. The method of claim 1, wherein the polymer is formed from a reactant comprising thrombin. The method of claim 1, wherein the polymer is formed from a reactant comprising a plasma component. The method of claim 1, wherein the polymer is formed from a reactant comprising a calcium salt. The method of claim 1, wherein the polymer is formed from a reactant comprising a fiber formation inhibitor. The method of claim 1, wherein the polymer is formed from a reactant comprising a fibrinogen analog. The method of claim 1, wherein the polymer is formed from a reactant comprising albumin. The method of claim 1, wherein the polymer is formed from a reactant comprising plasminogen. The method of claim 1, wherein the polymer is formed from a reactant comprising a von Willebrands factor. The method of claim 1, wherein the polymer is formed from a reactant comprising Factor VIII. The method of claim 1, wherein the polymer is formed from a reactant comprising hypoallergenic collagen. The method of claim 1, wherein the polymer is formed from a reactant comprising atelopeptide collagen. The method of claim 1, wherein the polymer is formed from a reactant comprising telopeptide collagen. The method of claim 1, wherein the polymer is formed from a reactant comprising cross-linked collagen. The method of claim 1, wherein the polymer is formed from a reactant comprising aprotinin. The method of claim 1, wherein the polymer is formed from a reactant comprising epsilon amino-n-caproic acid. The method of claim 1, wherein the polymer is formed from a reactant comprising gelatin. The method of claim 1, wherein the polymer is formed from a reactant comprising a protein conjugate. The method of claim 1, wherein the polymer is formed from a reactant comprising a gelatin conjugate. The method of claim 1, wherein the polymer is formed from a reactant comprising a synthetic polymer. The method of claim 1, wherein the polymer is formed from a reactant comprising a compound comprising synthetic isocyanate. The method of claim 1, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic thiol. The method of claim 1, wherein the polymer is formed from a reactant comprising a synthetic compound containing two or more thiol groups. The method of claim 1, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more thiol groups. The method of claim 1, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more thiol groups. The method of claim 1, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic amino. The method of claim 1, wherein the polymer is formed from a reactant comprising a synthetic compound containing two or more amino groups. The method of claim 1, wherein the polymer is formed from a reactant comprising a synthetic compound containing three or more amino groups. The method of claim 1, wherein the polymer is formed from a reactant comprising a synthetic compound containing four or more amino groups. The method of claim 1, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of claim 1, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The method of claim 1, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. The method of claim 1, wherein the polymer is formed from a reactant comprising a synthetic compound containing four or more carbonyl-oxygen-succinimidyl groups. The method of claim 1, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide. The method of claim 1, wherein the polymer is formed from a reactant comprising a synthetic compound comprising both a polyalkylene oxide and a biodegradable polyester block. The method of claim 1, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The method of claim 1, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a thiol reactive group. The method of claim 1, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The method of claim 1, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a biodegradable polyester block. The method of claim 1, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly composed of lactic acid or lactide. The method of claim 1, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly composed of glycolic acid or glycolide. The method of claim 1, wherein the polymer is formed from a reactant comprising polylysine. The method of claim 1, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. 2. The method of claim 1, wherein the polymer is formed from a reactant comprising (a) a protein and (b) polylysine. 2. The method of claim 1, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more thiol groups. 2. The method of claim 1, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more amino groups. The method of claim 1, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more carbonyl-oxygen-succinimidyl groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method according to 1. The method of claim 1, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound comprising an oxidized polyalkylene moiety. 2. The method of claim 1, wherein the polymer is formed from a reactant comprising (a) collagen and (b) polylysine. 2. The method of claim 1, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more thiol groups. The method of claim 1, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more amino groups. The method of claim 1, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method according to 1. 2. The method of claim 1, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound comprising an oxidized polyalkylene moiety. 2. The method of claim 1, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) polylysine. 2. The method of claim 1, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more thiol groups. 2. The method of claim 1, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more amino groups. The method of claim 1, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from a reactant selected from (a) methylated collagen and (b) lactic acid, lactide, glycolic acid, glycolide and epison caprolactone, The method of claim 1. The method of claim 1, wherein the polymer is formed from a reactant comprising hyaluronic acid. The method of claim 1, wherein the polymer is formed from a reactant comprising a hyaluronic acid derivative. 2. The method of claim 1, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. 2. The method of claim 1, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A polymer having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene region. The method of claim 1, wherein the method is formed from a reactant comprising a synthetic compound comprising a plurality of electrophilic groups. The method of claim 1, wherein the composition comprises a colorant. 2. The method of claim 1, wherein the composition is sterile. Methods of implanting a medical device comprising: (a) a medical device to which the medical device is implanted or transplanted host tissue i) an inhibitor of fiber formation ii) an anti-infective agent iii) a polymer iv) an inhibitor of fiber formation and a polymer V) a composition comprising an anti-infective agent and a polymer or vi) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer, and (b) implanting a medical device into a host, and said medical treatment The device is an intravascular device. 278. A method of implanting a device with the medical device of claim 278 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a fibrosis inhibitor; and (b) the host Implant a medical device. A method of implanting a device with the medical device of claim 278 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in an anti-infective agent; and (b) the host is implanted. Implant medical devices. 278. A method of implanting a device with the medical device of claim 278 comprising: (a) the medical device is implanted, or the implanted host tissue is immersed in a polymer, and (b) the medical device in the host Transplant. 278. A method of implanting a device with the medical device of claim 278 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising a fibrosis inhibitor and a polymer; And (b) transplant the medical device into the host. 278. A method of implanting a device with the medical device of claim 278 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) Transplant the medical device into the host. 278. A method of implanting a device with the medical device of claim 278, comprising: (a) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer in which the medical device is implanted or the host tissue into which it is implanted. And (b) implant the medical device into the host. 278. The method of claim 278, wherein the medical device is a catheter. 278. The method of claim 278, wherein the medical device is a balloon catheter. 278. The method of claim 278, wherein the medical device is a balloon. 278. The method of claim 278, wherein the medical device is a stent graft. 278. The method of claim 278, wherein the medical device is a guide wire. 278. The method of claim 278, wherein the medical device is a stent. 278. The method of claim 278, wherein the medical device is an intravascular stent. 278. The method of claim 278, wherein the medical device is a metal stent. 278. The method of claim 278, wherein the medical device is a polymeric stent. 278. The method of claim 278, wherein the medical device is a biodegradable stent. 278. The method of claim 278, wherein the medical device is a non-biodegradable stent. 278. The method of claim 278, wherein the medical device is a self-expanding stent. 278. The method of claim 278, wherein the medical device is a balloon expandable stent. 278. The method of claim 278, wherein the medical device is a coated stent. 278. The method of claim 278, wherein the medical device is a drug eluting stent. 278. The method of claim 278, wherein the medical device is a stent that includes a radiopaque material. 278. The method of claim 278, wherein the medical device comprises a stent that includes an echogenic material. 278. The method of claim 278, wherein the medical device comprises a stent that includes an MRI-responsive material. 278. The method of claim 278, wherein the medical device is an anastomosis coupling device. 278. The method of claim 278, wherein the medical device is an arterial-to-artery connection device. 278. The method of claim 278, wherein the medical device is a venous-arterial connection device. 278. The method of claim 278, wherein the medical device is an arterial and venous anastomosis connection device. 278. The method of claim 278, wherein the medical device is a connecting device by anastomosis between an artery and an artificial blood vessel. 278. The method according to claim 278, wherein the medical device is a connecting device by anastomosis between an artificial blood vessel and an artery. 278. The method of claim 278, wherein the medical device is a connecting device by anastomosis between a vein and an artificial blood vessel. 278. The method of claim 278, wherein the medical device is a connection device by an anastomosis between an artificial blood vessel and a vein. 278. The method of claim 278, wherein the medical device is a vascular clip. 278. The method of claim 278, wherein the medical device is a vascular suture. 278. The method of claim 278, wherein the medical device is a vascular clamp. 278. The method of claim 278, wherein the medical device is a suturing device. 278. The method of claim 278, wherein the medical device is an anastomotic coupler. 278. The method of claim 278, wherein the medical device is an automatic and revision suturing device. 278. The method of claim 278, wherein the medical device is a coupling device by micromechanical anastomosis. 278. The method of claim 278, wherein the medical device is an anastomotic coupling device that facilitates automatic coupling of a blood vessel to a hole or orifice in a target vessel without the use of sutures or staples. 278. The method of claim 278, wherein the medical device is an anastomotic coupling device comprising a tubular graft conduit and can be placed on a side wall of the target vessel such that the tubular graft conduit can be expanded from the target vessel. 278. The method of claim 278, wherein the medical device is an anastomotic coupler in the form of a frame. 278. The method of claim 278, wherein the medical device is an annular anastomosis coupler. 278. The method of claim 278, wherein the medical device is a resorbable anastomotic coupler. 278. The method of claim 278, wherein the medical device is an anastomotic coupler, comprising a bioabsorbable material and an elastomeric material. 278. The method of claim 278, wherein the medical device is an anastomotic coupler adapted to connect the first blood vessel with the graft blood vessel to the second blood vessel. 278. The method of claim 278, wherein the medical device is an anastomotic coupler adapted to connect the first blood vessel to the second blood vessel without using a graft blood vessel. 278. The method of claim 278, wherein the medical device is an anastomotic coupler that is included in the design of the vascular graft. 278. The method of claim 278, wherein the method is an anastomotic coupler that includes a graft that incorporates a fixation mechanism into a medical device. 278. The method of claim 278, wherein the medical device is an anastomotic coupler with a compressible / expandable fitting to secure the bypass graft and the two vessels. 278. The method of claim 278, wherein the medical device is an anastomotic coupler that includes a pair of connecting disc members for connecting two blood vessels in an end-to-end manner. 278. The method of claim 278, wherein the medical device is a proximal aortic coupling device. 278. The method of claim 278, wherein the medical device is a distal coronary artery connection device. 278. The method of claim 278, wherein the medical device is a bypass device made of a biocompatible material. 278. The method of claim 278, wherein the medical device is a bypass device made at least in part of a metal or metal alloy. 278. The method of claim 278, wherein the medical device is a bypass device made at least in part from a synthetic polymer. 278. The method of claim 278, wherein the medical device is a bypass device made at least in part from a naturally occurring polymer. 278. The method of claim 278, wherein the medical device is a tubular anastomotic coupler comprising a tubular structure that can be secured directly to a proximal vessel. 278. The method of claim 278, wherein the medical device is a tubular anastomosis coupler comprising a tubular structure that can be secured directly to a distal vessel. 278. The method of claim 278, wherein the medical device is a tubular anastomotic coupler comprising a proximal end that can be secured to a proximal vessel and a distal end that can be secured to a distal vessel. 278. The method of claim 278, wherein the medical device is a tubular anastomotic coupler that includes a proximal end fixable to a graft vessel secured to a proximal vessel and a distal end capable of being secured to a distal vessel. 278. The method of claim 278, wherein the medical device is an anastomotic connection device adapted for an end-to-end anastomosis connection procedure. 278. The method of claim 278, wherein the medical device is an anastomotic stent. 278. The method of claim 278, wherein the medical device is an anastomosis sleeve. 278. The method of claim 278, wherein the medical device is an anastomotic connection device adapted for an end-to-end anastomosis connection procedure. 278. The method of claim 278, wherein the medical device is a single lumen bypass device. 278. The method of claim 278, wherein the medical device is a multi-lumen bypass device. 278. The method of claim 278, wherein the medical device is an anastomotic coupling device consisting of a single tubular portion that can be used as a shunt to divert blood from the original vessel to the graft vessel. 278. The method of claim 278, wherein the medical device is comprised of one or more tubular portions, wherein at least one tubular portion is an anastomotic coupling device that can be used as a shunt to divert blood from the original vessel to the graft vessel. . 278. The method of claim 278, wherein the medical device is an anastomotic coupling device comprising a tubular portion, wherein one or more tubular portions can be inserted into the end or side of one or more blood vessels. 278. The method of claim 278, wherein the medical device is a multi-lumen anastomotic connection device capable of securing at least one arm of the device to a graft vessel. 278. The method of claim 278, wherein the medical device is an anastomotic coupling device that includes three or more tubular arms extending from the junction site. 278. The method of claim 278, wherein the medical device is a multi-lumen anastomosis coupling device is generally T-shaped. 278. The method of claim 278, wherein the medical device is a multi-lumen anastomosis coupling device is generally Y-shaped. 278. The method of claim 278, wherein the medical device is an anastomotic coupling device including a tube that bypasses blood flow directly from a portion of the heart to the coronary artery. 278. The method of claim 278, wherein the medical device is an anastomotic coupling device that includes interconnected tubular conduit networks. 278. The anastomotic connection device according to claim 278, wherein the medical device is an anastomotic coupling device configured to provide fluid communication with two or three terminations and intersecting lumens where a blood vessel interface is provided without the need for suturing The method described. 278. The method of claim 278, wherein cell regeneration is inhibited by a fiber formation inhibitor. 278. The method of claim 278, wherein angiogenesis is inhibited by a fiber formation inhibitor. 278. The method of claim 278, wherein fibroblast migration is inhibited by a fibrosis inhibitor. 278. The method of claim 278, wherein the fibrosis inhibitor inhibits fibroblast proliferation. 278. The method of claim 278, wherein the fibril formation inhibitor inhibits extracellular matrix accumulation. 278. The method of claim 278, wherein the tissue remodeling is inhibited by the fiber formation inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is an angiogenesis inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is a 5-lipoxygenase inhibitor or antagonist. 278. The method of claim 278, wherein the fiber formation inhibitor is a chemokine receptor antagonist. 278. The method of claim 278, wherein the fiber formation inhibitor is a cell cycle inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is a taxane. 278. The method of claim 278, wherein the fiber formation inhibitor is a microtubule inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is paclitaxel. 278. The method of claim 278, wherein the fiber formation inhibitor is not paclitaxel. 278. The method of claim 278, wherein the fiber formation inhibitor is an analog or derivative of paclitaxel. 278. The method of claim 278, wherein the fiber formation inhibitor is a vinca alkaloid. 278. The method of claim 278, wherein the fiber formation inhibitor is camptothecin or an analog or derivative thereof. 278. The method of claim 278, wherein the fiber formation inhibitor is podophyllotoxin. 278. The method of claim 278, wherein the fiber formation inhibitor is podophyllotoxin, and the podophyllotoxin is etoposide or an analog or derivative thereof. 278. The method of claim 278, wherein the fiber formation inhibitor is an anthracycline. 278. The method of claim 278, wherein the fiber formation inhibitor is an anthracycline, and the anthracycline is doxorubicin or an analogue or derivative thereof. 278. The method of claim 278, wherein the fiber formation inhibitor is an anthracycline, and the anthracycline is mitoxantrone or an analogue or derivative thereof. 278. The method of claim 278, wherein the fiber formation inhibitor is a platinum compound. 278. The method of claim 278, wherein the fiber formation inhibitor is nitrosourea. 278. The method of claim 278, wherein the fiber formation inhibitor is nitroimidazole. 278. The method of claim 278, wherein the fiber formation inhibitor is a folic acid antagonist. 278. The method of claim 278, wherein the fiber formation inhibitor is a cytidine analog. 278. The method of claim 278, wherein the fiber formation inhibitor is a pyrimidine analog. 278. The method of claim 278, wherein the fiber formation inhibitor is a fluoropyrimidine analog. 278. The method of claim 278, wherein the fiber formation inhibitor is a purine analog. The method of claim 278, wherein the fiber formation inhibitor is nitrogen mustard or an analogue or derivative thereof. 278. The method of claim 278, wherein the fiber formation inhibitor is hydroxyurea. 278. The method of claim 278, wherein the fiber formation inhibitor is mitomycin or an analog or derivative thereof. 278. The method of claim 278, wherein the fiber formation inhibitor is an alkyl sulfonate. 278. The method of claim 278, wherein the fiber formation inhibitor is benzamide or an analog or derivative thereof. The method of claim 278, wherein the fiber formation inhibitor is nicotinamide or an analogue or derivative thereof. The method of claim 278, wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. 278. The method of claim 278, wherein the fiber formation inhibitor is a DNA alkylating agent. 278. The method of claim 278, wherein the fiber formation inhibitor is a microtubule inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is a topoisomerase inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is a DNA cleaving agent. 278. The method of claim 278, wherein the fiber formation inhibitor is an antimetabolite. 278. The method of claim 278, wherein adenosine deaminase is inhibited by the fiber formation inhibitor. 278. The method of claim 278, wherein purine ring synthesis is inhibited by the fiber formation inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor inhibits dihydrofolate reduction. 278. The method of claim 278, wherein thymidine monophosphate is inhibited by the fiber formation inhibitor. 278. The method of claim 278, wherein the fibril formation inhibitor causes DNA damage. 278. The method of claim 278, wherein the fiber formation inhibitor is a DNA intercalator. 278. The method of claim 278, wherein the fiber formation inhibitor is an RNA synthesis inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. 278. The method of claim 278, wherein the ribonucleotide synthesis or function is inhibited by the fiber formation inhibitor. 278. The method of claim 278, wherein the fibrosis inhibitor inhibits thymidine monophosphate synthesis or function. The method of claim 278, wherein DNA synthesis is inhibited by the fiber formation inhibitor. 278. The method of claim 278, wherein DNA adduct formation occurs with the fiber formation inhibitor. 278. The method of claim 278, wherein protein synthesis is inhibited by a fiber formation inhibitor. The method of claim 278, wherein the microtubule function is inhibited by the fiber formation inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is a cyclin dependent protein kinase inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is an epidermal growth factor kinase inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is an elastase inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is a factor Xa inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. 278. The method of claim 278, wherein the fibrosis inhibitor is a fibrinogen antagonist. 278. The method of claim 278, wherein the fiber formation inhibitor is a guanylate cyclase stimulant. 278. The method of claim 278, wherein the fiber formation inhibitor is a heat shock protein 90 antagonist. 278. The method of claim 278, wherein the fibrosis inhibitor is a heat shock protein 90 antagonist, and the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof. 278. The method of claim 278, wherein the fiber formation inhibitor is a guanylate cyclase stimulant. 278. The method of claim 278, wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor, and the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof. 278. The method of claim 278, wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is an IKK2 inhibitor. 278. The method of claim 278, wherein the fibrosis inhibitor is an IL-1 antagonist. 278. The method of claim 278, wherein the fiber formation inhibitor is an ICE antagonist. 278. The method of claim 278, wherein the fiber formation inhibitor is an IRAK antagonist. 278. The method of claim 278, wherein the fibrosis inhibitor is an IL-4 agonist. 278. The method of claim 278, wherein the fiber formation inhibitor is an immunomodulator. 278. The method of claim 278, wherein the fibrosis inhibitor is sirolimus or an analogue or derivative thereof. 278. The method of claim 278, wherein the fiber formation inhibitor is not sirolimus. 278. The method of claim 278, wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. 278. The method of claim 278, wherein the fiber formation inhibitor is tacrolimus or an analogue or derivative thereof. 278. The method of claim 278, wherein the fiber formation inhibitor is not tacrolimus. 278. The method of claim 278, wherein the fiber formation inhibitor is biolimus or an analogue or derivative thereof. 278. The method of claim 278, wherein the fiber formation inhibitor is tresperimus or an analogue or derivative thereof. 278. The method of claim 278, wherein the fiber formation inhibitor is auranofin or an analogue or derivative thereof. 278. The method of claim 278, wherein the fiber formation inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. 278. The method of claim 278, wherein the fiber formation inhibitor is gusperimus or an analogue or derivative thereof. 278. The method of claim 278, wherein the fiber formation inhibitor is pimecrolimus or an analogue or derivative thereof. 278. The method of claim 278, wherein the fiber formation inhibitor is ABT-578 or an analogue or derivative thereof. 278. The method of claim 278, wherein the fiber formation inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is an IMPDH inhibitor, and the IMPDH inhibitor is mycophenolic acid or an analog or derivative thereof. Fiber forming inhibitor is an IMPDH inhibitor, the IMPDH inhibitor is 1-alpha-25-dihydroxyvitamin D ₃ or its analogues or derivatives, method of claim 278. 278. The method of claim 278, wherein the fiber formation inhibitor is a leukotriene inhibitor. 278. The method of claim 278, wherein the vascularization inhibitor is an MCP-1 antagonist. 278. The method of claim 278, wherein the fiber formation inhibitor is an MMP inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is an NFκB inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is an NFκB inhibitor and the NFκB inhibitor is Bay11-7082. 278. The method of claim 278, wherein the fiber formation inhibitor is a NO antagonist. 278. The method of claim 278, wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor, and the p38 MAP kinase inhibitor is SB 202190. 278. The method of claim 278, wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is a TGFβ inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is a thromboxane A2 antagonist. 278. The method of claim 278, wherein the vascularization inhibitor is a TNFα antagonist. 278. The method of claim 278, wherein the fiber formation inhibitor is a TACE inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is a vitronectin inhibitor. 278. The method of claim 278, wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is a protein kinase inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is a PDGF receptor kinase inhibitor. 278. The method of claim 278, wherein the fibrosis inhibitor is an endothelial growth factor receptor kinase inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is a retinoic acid receptor antagonist. 278. The method of claim 278, wherein the fiber formation inhibitor is a platelet derived growth factor receptor kinase inhibitor. 278. The method of claim 278, wherein the fibrosis inhibitor is a fibrinogen antagonist. 278. The method of claim 278, wherein the fiber formation inhibitor is an antifungal agent. 278. The method of claim 278, wherein the fiber formation inhibitor is an antifungal agent and the antifungal agent is sulconizole. 278. The method of claim 278, wherein the fiber formation inhibitor is a bisphosphonate. 278. The method of claim 278, wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. 278. The method of claim 278, wherein the fibrosis inhibitor is a histamine H1 / H2 / H3 receptor antagonist. 278. The method of claim 278, wherein the fiber formation inhibitor is a macrolide antibiotic. 278. The method of claim 278, wherein the fiber formation inhibitor is a GPIIb / IIIa receptor antagonist. 278. The method of claim 278, wherein the fiber formation inhibitor is an endothelin receptor antagonist. 278. The method of claim 278, wherein the fibrosis inhibitor is an agonist of a peroxisome proliferator responsive receptor. 278. The method of claim 278, wherein the fibrosis inhibitor is an estrogen receptor agent. 278. The method of claim 278, wherein the fibrosis inhibitor is a somostatin analog. 278. The method of claim 278, wherein the fiber formation inhibitor is a neurokinin 1 antagonist. 278. The method of claim 278, wherein the fiber formation inhibitor is a neurokinin 3 antagonist. 278. The method of claim 278, wherein the fibrosis inhibitor is a VLA-4 antagonist. 278. The method of claim 278, wherein the fiber formation inhibitor is an osteoclast inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is an angiotensin II antagonist. 278. The method of claim 278, wherein the fiber formation inhibitor is an enkephalinase inhibitor. 278. The method of claim 278, wherein the fibrosis inhibitor is a peroxisome proliferator-responsive receptor gamma agonist insulin sensitizer. 278. The method of claim 278, wherein the fiber formation inhibitor is a protein kinase C inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is a CXCR3 inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is an Itk inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. 278. The method of claim 278, wherein the fibrosis inhibitor is a PPAR agonist. 278. The method of claim 278, wherein the fiber formation inhibitor is an immunosuppressant. 278. The method of claim 278, wherein the fiber formation inhibitor is an Erb inhibitor. 278. The method of claim 278, wherein the fibrosis inhibitor is an apoptosis agonist. 278. The method of claim 278, wherein the fibrosis inhibitor is a lipocortin agonist. 278. The method of claim 278, wherein the fiber formation inhibitor is a VCAM-1 antagonist. 278. The method of claim 278, wherein the fiber formation inhibitor is a collagen antagonist. 278. The method of claim 278, wherein the fiber formation inhibitor is an α2 integrin antagonist. 278. The method of claim 278, wherein the fiber formation inhibitor is a TNFα inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is a nitric oxide inhibitor. 278. The method of claim 278, wherein the fiber formation inhibitor is a cathepsin inhibitor. 278. The method of claim 278, wherein the fibrosis inhibitor is not an anti-inflammatory agent. 278. The method of claim 278, wherein the fibrosis inhibitor is not a steroid. 278. The method of claim 278, wherein the fiber formation inhibitor is not a glucocorticosteroid. 278. The method of claim 278, wherein the fiber formation inhibitor is not dexamethasone. 278. The method of claim 278, wherein the fiber formation inhibitor is not beclomethasone. 278. The method of claim 278, wherein the fiber formation inhibitor is not dipropionic acid. 278. The method of claim 278, wherein the fiber formation inhibitor is not an anti-infective agent. 278. The method of claim 278, wherein the fibrosis inhibitor is not an antibiotic. 278. The method of claim 278, wherein the fiber formation inhibitor is not an antifungal agent. 278. The method of claim 278, wherein the anti-infective agent is an anthracycline. 278. The method of claim 278, wherein the anti-infective agent is doxorubicin. 278. The method of claim 278, wherein the anti-infective agent is mitoxantrone. 278. The method of claim 278, wherein the anti-infective agent is a fluoropyrimidine. 278. The method of claim 278, wherein the anti-infective agent is 5-fluorouracil (5-FU). 278. The method of claim 278, wherein the anti-infective agent is a folic acid antagonist. 278. The method of claim 278, wherein the anti-infective agent is methotrexate. 278. The method of claim 278, wherein the anti-infective agent is podophyllotoxin. 278. The method of claim 278, wherein the anti-infective agent is etoposide. 278. The method of claim 278, wherein the anti-infective agent is camptothecin. 278. The method of claim 278, wherein the anti-infective agent is hydroxyurea. 278. The method of claim 278, wherein the anti-infective agent is a platinum complex. 278. The method of claim 278, wherein the anti-infective agent is cisplatin. 278. The method of claim 278, wherein the composition comprises an antithrombotic agent. 278. The method of claim 278, wherein the polymer is formed from a reactant that includes a naturally occurring polymer. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a protein. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a carbohydrate. 278. The method of claim 278, wherein the polymer is formed from a reactant that comprises a biodegradable polymer. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a non-biodegradable polymer. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising collagen. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising methylated collagen. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising fibrinogen. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising thrombin. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a plasma component. 278. The method of claim 278, wherein the polymer is formed from a reactant that includes a calcium salt. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a fiber formation inhibitor. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a fibrinogen analog. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising albumin. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising plasminogen. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a von Willebrand factor. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising Factor VIII. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising hypoallergenic collagen. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising atelopeptide collagen. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising telopeptide collagen. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising cross-linked collagen. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising aprotinin. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising epsilon amino-n-caproic acid. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising gelatin. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a protein conjugate. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a gelatin conjugate. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a synthetic polymer. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a compound comprising synthetic isocyanate. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a compound that includes a synthetic thiol. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a synthetic compound that includes two or more thiol groups. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a synthetic compound that includes three or more thiol groups. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a synthetic compound that includes four or more thiol groups. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a compound that includes a synthetic amino. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a synthetic compound that includes two or more amino groups. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a synthetic compound that includes three or more amino groups. 278. The method of claim 278, wherein the polymer is formed from a reactant consisting of a synthetic compound containing 4 or more amino groups. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a synthetic compound that includes a carbonyl-oxygen-succinimidyl group. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more carbonyl-oxygen-succinimidyl groups. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a synthetic compound comprising both a polyalkylene oxide and a biodegradable polyester block. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having an amino reactive group. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a thiol reactive group. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a synthetic compound that includes a biodegradable polyester block. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly comprised of lactic acid or lactide. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly composed of glycolic acid or glycolide. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising polylysine. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising (a) a protein and (b) polylysine. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more thiol groups. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more amino groups. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more carbonyl-oxygen-succinimidyl groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method according to 278. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound comprising an oxidized polyalkylene moiety. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising (a) collagen and (b) polylysine. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more thiol groups. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more amino groups. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method according to 278. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound comprising an oxidized polyalkylene moiety. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) polylysine. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more thiol groups. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more amino groups. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from a reactant selected from (a) methylated collagen and (b) lactic acid, lactide, glycolic acid, glycolide and epison caprolactone, 278. The method of claim 278. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising hyaluronic acid. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising a hyaluronic acid derivative. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. 278. The method of claim 278, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A polymer having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene region. 278. The method of claim 278, formed from a reactant comprising a synthetic compound comprising a plurality of electrophilic groups. 278. The method of claim 278, wherein the composition includes a colorant. 278. The method of claim 278, wherein the composition is sterile. Methods of implanting a medical device comprising: (a) a medical device to which the medical device is implanted or transplanted host tissue i) an inhibitor of fiber formation ii) an anti-infective agent iii) a polymer iv) an inhibitor of fiber formation and a polymer V) a composition comprising an anti-infective agent and a polymer or vi) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer, and (b) implanting a medical device into a host, and said medical treatment The device is a gastrointestinal stent. 602. A method of implanting a device with the medical device of claim 602 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a fibrosis inhibitor; and (b) the host Implant a medical device. A method of implanting a device with the medical device of claim 602 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in an anti-infective agent; and (b) the host is implanted. Implant medical devices. 602. A method of implanting a device with the medical device of claim 602 comprising: (a) the medical device is implanted, or the implanted host tissue is immersed in a polymer, and (b) the medical device in the host Transplant. 602. A method of implanting a device with the medical device of claim 602 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising a fibrosis inhibitor and a polymer; And (b) transplant the medical device into the host. 602. A method of implanting a device with the medical device of claim 602 comprising: (a) immersing the tissue of the host to which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) Transplant the medical device into the host. 602. A method of implanting a device comprising the medical device of claim 602 comprising: (a) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer in which the medical device is implanted or the host tissue into which it is implanted. And (b) implant the medical device into the host. The method of claim 602, wherein the medical device is an esophageal stent. The method of claim 602, wherein the medical device is a gallbladder stent. The method of claim 602, wherein the medical device is a colonic stent. The method of claim 602, wherein the medical device is a pancreatic stent. The method of claim 602, wherein cell regeneration is inhibited by a fiber formation inhibitor. The method of claim 602, wherein angiogenesis is inhibited by fibrosis inhibitors. 613. The method of claim 602, wherein fibroblast migration is inhibited by a fibrosis inhibitor. The method of claim 602, wherein a fibrosis inhibitor inhibits fibroblast proliferation. 603. The method of claim 602, wherein the formation of extracellular matrix is inhibited by a fiber formation inhibitor. 613. The method of claim 602, wherein tissue remodeling is inhibited by a fiber formation inhibitor. The method of claim 602, wherein the fiber formation inhibitor is an angiogenesis inhibitor. The method of claim 602, wherein the fiber formation inhibitor is a 5- lipoxygenase inhibitor or antagonist. The method of claim 602, wherein the fiber formation inhibitor is a chemokine receptor antagonist. The method of claim 602, wherein the fiber formation inhibitor is a cell cycle inhibitor. The method of claim 602, wherein the fiber formation inhibitor is a taxane. The method of claim 602, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 602, wherein the fiber formation inhibitor is paclitaxel. The method of claim 602, wherein the fiber formation inhibitor is not paclitaxel. The method of claim 602, wherein the fiber formation inhibitor is an analogue or derivative of paclitaxel. 613. The method of claim 602, wherein the fiber formation inhibitor is a vinca alkaloid. The method of claim 602, wherein the fiber formation inhibitor is camptothecin or an analogue or derivative thereof. 613. The method of claim 602, wherein the fiber formation inhibitor is podophyllotoxin. The method of claim 602, wherein the fiber formation inhibitor is podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof. 613. The method of claim 602, wherein the fiber formation inhibitor is an anthracycline. The method of claim 602, wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof. The method of claim 602, wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof. 603. The method of claim 602, wherein the fiber formation inhibitor is a platinum compound. 613. The method of claim 602, wherein the fiber formation inhibitor is nitrosourea. 603. The method of claim 602, wherein the fiber formation inhibitor is nitroimidazole. The method of claim 602, wherein the fiber formation inhibitor is a folic acid antagonist. 613. The method of claim 602, wherein the fiber formation inhibitor is a cytidine analog. The method of claim 602, wherein the fiber formation inhibitor is a pyrimidine analogue. The method of claim 602, wherein the fiber formation inhibitor is a fluoropyrimidine analogue. The method of claim 602, wherein the fiber formation inhibitor is a purine analogue. The method of claim 602, wherein the fiber formation inhibitor is nitrogen mustard or an analogue or derivative thereof. 603. The method of claim 602, wherein the fiber formation inhibitor is hydroxyurea. The method of claim 602, wherein the fiber formation inhibitor is mitomycin or an analogue or derivative thereof. 603. The method of claim 602, wherein the fiber formation inhibitor is an alkyl sulfonate. The method of claim 602, wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The method of claim 602, wherein the fiber formation inhibitor is nicotinamide or an analogue or derivative thereof. The method of claim 602, wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of claim 602, wherein the fiber formation inhibitor is a DNA alkylating agent. The method of claim 602, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 602, wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of claim 602, wherein the fiber formation inhibitor is a DNA cleaving agent. The method of claim 602, wherein the fiber formation inhibitor is an antimetabolite. The method of claim 602, wherein adenosine deaminase is inhibited by a fiber formation inhibitor. 613. The method of claim 602, wherein purine ring synthesis is inhibited by a fiber formation inhibitor. 613. The method of claim 602, wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of claim 602, wherein the fiber formation inhibitor inhibits dihydrofolate reduction. 613. The method of claim 602, wherein thymidine monophosphate is inhibited by the fiber formation inhibitor. The method of claim 602, wherein DNA formation is caused by a fiber formation inhibitor. The method of claim 602, wherein the fiber formation inhibitor is a DNA intercalation agent. 603. The method of claim 602, wherein the fiber formation inhibitor is an RNA synthesis inhibitor. 603. The method of claim 602, wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. 613. The method of claim 602, wherein ribonucleotide synthesis or function is inhibited by a fiber formation inhibitor. The method of claim 602, wherein the fiber formation inhibitor inhibits thymidine monophosphate synthesis or function. The method of claim 602, wherein DNA synthesis is inhibited by a fiber formation inhibitor. 611. The method of claim 602, wherein DNA adduct formation occurs with a fiber formation inhibitor. The method of claim 602, wherein protein synthesis is inhibited by a fiber formation inhibitor. The method of claim 602, wherein the microtubule function is inhibited by the fiber formation inhibitor. The method of claim 602, wherein the fiber formation inhibitor is a cyclin dependent protein kinase inhibitor. The method of claim 602, wherein the fibrosis inhibitor is an epidermal growth factor kinase inhibitor. The method of claim 602, wherein the fiber formation inhibitor is an elastase inhibitor. 613. The method of claim 602, wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of claim 602, wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of claim 602, wherein the fiber formation inhibitor is a fibrinogen antagonist. The method of claim 602, wherein the fiber formation inhibitor is a guanylate cyclase stimulant. 613. The method of claim 602, wherein the fibrosis inhibitor is a heat shock protein 90 antagonist. The method of claim 602, wherein the fibrosis inhibitor is a heat shock protein 90 antagonist, and the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof. The method of claim 602, wherein the fiber formation inhibitor is a guanylate cyclase stimulant. 603. The method of claim 602, wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. 603. The method of claim 602, wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor, and the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof. 613. The method of claim 602, wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. 613. The method of claim 602, wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of claim 602, wherein the fiber formation inhibitor is an IL-1 antagonist. The method of claim 602, wherein the fiber formation inhibitor is an ICE antagonist. The method of claim 602, wherein the fiber formation inhibitor is an IRAK antagonist. 613. The method of claim 602, wherein the fibrosis inhibitor is an IL-4 agonist. The method of claim 602, wherein the fiber formation inhibitor is an immunomodulator. The method of claim 602, wherein the fiber formation inhibitor is sirolimus or an analogue or derivative thereof. The method of claim 602, wherein the fiber formation inhibitor is not sirolimus. The method of claim 602, wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. The method of claim 602, wherein the fiber formation inhibitor is tacrolimus or an analogue or derivative thereof. The method of claim 602, wherein the fiber formation inhibitor is not tacrolimus. The method of claim 602, wherein the fibrosis inhibitor is biolimus or an analogue or derivative thereof. The method of claim 602, wherein the fiber formation inhibitor is tresperimus or an analogue or derivative thereof. The method of claim 602, wherein the fiber formation inhibitor is auranofin or an analogue or derivative thereof. The method of claim 602, wherein the fiber formation inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of claim 602, wherein the fiber formation inhibitor is gusperimus or an analogue or derivative thereof. The method of claim 602, wherein the fibrosis inhibitor is pimecrolimus or an analogue or derivative thereof. The method of claim 602, wherein the fiber formation inhibitor is ABT-578 or an analogue or derivative thereof. 613. The method of claim 602, wherein the fiber formation inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. The method of claim 602, wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof. Fiber forming inhibitor is an IMPDH inhibitor, the IMPDH inhibitor is 1-alpha-25-dihydroxyvitamin D ₃ or its analogues or derivatives, method of claim 602. 613. The method of claim 602, wherein the fiber formation inhibitor is a leukotriene inhibitor. 603. The method of claim 602, wherein the vascularization inhibitor is an MCP-1 antagonist. 603. The method of claim 602, wherein the fiber formation inhibitor is an MMP inhibitor. 613. The method of claim 602, wherein the fiber formation inhibitor is an NFκB inhibitor. 603. The method of claim 602, wherein the fiber formation inhibitor is an NFκB inhibitor and the NFκB inhibitor is Bay11-7082. The method of claim 602, wherein the fiber formation inhibitor is a NO antagonist. The method of claim 602, wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor. 603. The method of claim 602, wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor, and the p38 MAP kinase inhibitor is SB 202190. The method of claim 602, wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. 613. The method of claim 602, wherein the fiber formation inhibitor is a TGFβ inhibitor. The method of claim 602, wherein the fiber formation inhibitor is a thromboxane A2 antagonist. 603. The method of claim 602, wherein the vascularization inhibitor is a TNFα antagonist. 613. The method of claim 602, wherein the fiber formation inhibitor is a TACE inhibitor. 613. The method of claim 602, wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. 613. The method of claim 602, wherein the fiber formation inhibitor is a vitronectin inhibitor. 613. The method of claim 602, wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of claim 602, wherein the fiber formation inhibitor is a protein kinase inhibitor. 613. The method of claim 602, wherein the fiber formation inhibitor is a PDGF receptor kinase inhibitor. The method of claim 602, wherein the fibrosis inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of claim 602, wherein the fiber formation inhibitor is a retinoic acid receptor antagonist. The method of claim 602, wherein the fiber formation inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of claim 602, wherein the fiber formation inhibitor is a fibrinogen antagonist. The method of claim 602, wherein the fiber formation inhibitor is an antifungal agent. The method of claim 602, wherein the fiber formation inhibitor is an antifungal agent, and the antifungal agent is sulconizole. 613. The method of claim 602, wherein the fiber formation inhibitor is a bisphosphonate. The method of claim 602, wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. 603. The method of claim 602, wherein the fiber formation inhibitor is a histamine H1 / H2 / H3 receptor antagonist. 613. The method of claim 602, wherein the fiber formation inhibitor is a macrolide antibiotic. 603. The method of claim 602, wherein the fiber formation inhibitor is a GPIIb / IIIa receptor antagonist. The method of claim 602, wherein the fiber formation inhibitor is an endothelin receptor antagonist. The method of claim 602, wherein the fibrosis inhibitor is an agonist of the peroxisome proliferator-responsive receptor. The method of claim 602, wherein the fibrosis inhibitor is an estrogen receptor agent. 613. The method of claim 602, wherein the fibrosis inhibitor is a somastatin analog. 603. The method of claim 602, wherein the fiber formation inhibitor is a neurokinin 1 antagonist. The method of claim 602, wherein the fiber formation inhibitor is a neurokinin 3 antagonist. 613. The method of claim 602, wherein the fibrosis inhibitor is a VLA-4 antagonist. The method of claim 602, wherein the fiber formation inhibitor is an osteoclast inhibitor. 603. The method of claim 602, wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. 603. The method of claim 602, wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of claim 602, wherein the fiber formation inhibitor is an angiotensin II antagonist. The method of claim 602, wherein the fiber formation inhibitor is an enkephalinase inhibitor. 603. The method of claim 602, wherein the fibrosis inhibitor is a peroxisome proliferator-responsive receptor gamma agonist insulin sensitizer. 613. The method of claim 602, wherein the fiber formation inhibitor is a protein kinase C inhibitor. 603. The method of claim 602, wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. 613. The method of claim 602, wherein the fiber formation inhibitor is a CXCR3 inhibitor. 613. The method of claim 602, wherein the fiber formation inhibitor is an Itk inhibitor. 603. The method of claim 602, wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of claim 602, wherein the fibrosis inhibitor is a PPAR agonist. The method of claim 602, wherein the fiber formation inhibitor is an immunosuppressant. 613. The method of claim 602, wherein the fiber formation inhibitor is an Erb inhibitor. The method of claim 602, wherein the fibrosis inhibitor is an apoptosis agonist. The method of claim 602, wherein the fibrosis inhibitor is a lipocortin agonist. The method of claim 602, wherein the fiber formation inhibitor is a VCAM-1 antagonist. The method of claim 602, wherein the fiber formation inhibitor is a collagen antagonist. 613. The method of claim 602, wherein the fiber formation inhibitor is an α2 integrin antagonist. 603. The method of claim 602, wherein the fiber formation inhibitor is a TNFα inhibitor. 613. The method of claim 602, wherein the fiber formation inhibitor is a nitric oxide inhibitor. 613. The method of claim 602, wherein the fiber formation inhibitor is a cathepsin inhibitor. The method of claim 602, wherein the fibrosis inhibitor is not an anti-inflammatory agent. The method of claim 602, wherein the fibrosis inhibitor is not a steroid. The method of claim 602, wherein the fiber formation inhibitor is not a glucocorticosteroid. The method of claim 602, wherein the fiber formation inhibitor is not dexamethasone. The method of claim 602, wherein the fiber formation inhibitor is not beclomethasone. 613. The method of claim 602, wherein the fiber formation inhibitor is not dipropionic acid. The method of claim 602, wherein the fiber formation inhibitor is not an anti-infective. The method of claim 602, wherein the fiber formation inhibitor is not an antibiotic. The method of claim 602, wherein the fiber formation inhibitor is not an antifungal agent. 613. The method of claim 602, wherein the anti-infective agent is an anthracycline. The method of claim 602, wherein the anti-infective agent is doxorubicin. The method of claim 602, wherein the anti-infective is mitoxantrone. The method of claim 602, wherein the anti-infective is a fluoropyrimidine. 603. The method of claim 602, wherein the anti-infective agent is 5-fluorouracil (5-FU). The method of claim 602, wherein the anti-infective agent is a folic acid antagonist. The method of claim 602, wherein the anti-infective is methotrexate. The method of claim 602, wherein the anti-infective agent is podophyllotoxin. The method of claim 602, wherein the anti-infective is etoposide. 613. The method of claim 602, wherein the anti-infective agent is camptothecin. The method of claim 602, wherein the anti-infective agent is hydroxyurea. The method of claim 602, wherein the anti-infective agent is a platinum complex. The method of claim 602, wherein the anti-infective is cisplatin. The method of claim 602, wherein the composition comprises an antithrombotic agent. 613. The method of claim 602, wherein the polymer is formed from a reactant that includes a naturally occurring polymer. The method of claim 602, wherein the polymer is formed from a reactant comprising protein. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising a carbohydrate. 613. The method of claim 602, wherein the polymer is formed from a reactant that includes a biodegradable polymer. 613. The method of claim 602, wherein the polymer is formed from a reactant that includes a non-biodegradable polymer. The method of claim 602, wherein the polymer is formed from a reactant comprising collagen. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising methylated collagen. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising fibrinogen. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising thrombin. 613. The method of claim 602, wherein the polymer is formed from a reactant that includes a plasma component. 613. The method of claim 602, wherein the polymer is formed from a reactant that includes a calcium salt. The method of claim 602, wherein the polymer is formed from a reactant comprising a fiber formation inhibitor. 613. The method of claim 602, wherein the polymer is formed from a reactant that includes a fibrinogen analog. The method of claim 602, wherein the polymer is formed from a reactant comprising albumin. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising plasminogen. 613. The method of claim 602, wherein the polymer is formed from a reactant that includes a von Willebrand factor. The method of claim 602, wherein the polymer is formed from a reactant comprising Factor VIII. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising hypoallergenic collagen. The method of claim 602, wherein the polymer is formed from a reactant comprising atelopeptide collagen. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising telopeptide collagen. The method of claim 602, wherein the polymer is formed from a reactant comprising cross-linked collagen. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising aprotinin. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising epsilon amino-n-caproic acid. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising gelatin. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising a protein conjugate. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising a gelatin conjugate. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising a synthetic polymer. The method of claim 602, wherein the polymer is formed from a reactant comprising a compound comprising synthetic isocyanate. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising a compound that includes a synthetic thiol. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising a synthetic compound that includes two or more thiol groups. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising a synthetic compound that includes three or more thiol groups. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising a synthetic compound that includes four or more thiol groups. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising a compound that includes a synthetic amino. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising a synthetic compound that includes two or more amino groups. 603. The method of claim 602, wherein the polymer is formed from a reactant comprising a synthetic compound that includes three or more amino groups. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising a synthetic compound that includes four or more amino groups. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising a synthetic compound that includes a carbonyl-oxygen-succinimidyl group. The method of claim 602, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. 603. The method of claim 602, wherein the polymer is formed from a reactant comprising a synthetic compound that includes three or more carbonyl-oxygen-succinimidyl groups. 603. The method of claim 602, wherein the polymer is formed from a reactant comprising a synthetic compound that includes four or more carbonyl-oxygen-succinimidyl groups. The method of claim 602, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide. 603. The method of claim 602, wherein the polymer is formed from a reactant comprising a synthetic compound that includes both a polyalkylene oxide and a biodegradable polyester block. The method of claim 602, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The method of claim 602, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide having a thiol reactive group. 603. The method of claim 602, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising a synthetic compound that includes a biodegradable polyester block. 603. The method of claim 602, wherein the polymer is formed from a reactant comprising a synthetic polymer that is wholly or partly comprised of lactic acid or lactide. 603. The method of claim 602, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly composed of glycolic acid or glycolide. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising polylysine. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising (a) a protein and (b) polylysine. 603. The method of claim 602, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more thiol groups. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more amino groups. 603. The method of claim 602, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method according to 602. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound comprising an oxidized polyalkylene moiety. 603. The method of claim 602, wherein the polymer is formed from a reactant comprising (a) collagen and (b) polylysine. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more thiol groups. 603. The method of claim 602, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more amino groups. 603. The method of claim 602, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method according to 602. The method of claim 602, wherein the polymer is formed from a reactant comprising (a) a methylated collagen and (b) a compound comprising an oxidized polyalkylene moiety. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) polylysine. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more thiol groups. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more amino groups. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from a reactant selected from (a) methylated collagen and (b) lactic acid, lactide, glycolic acid, glycolide and epison caprolactone, 602. The method of claim 602. 613. The method of claim 602, wherein the polymer is formed from a reactant comprising hyaluronic acid. 613. The method of claim 602, wherein the polymer is formed from a reactant that includes a hyaluronic acid derivative. 603. The method of claim 602, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. 603. The method of claim 602, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A polymer having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene region. 613. The method of claim 602, formed from a reactant comprising a synthetic compound comprising a plurality of electrophilic groups. The method of claim 602, wherein the composition comprises a colorant. The method of claim 602, wherein the composition is sterile. Methods of implanting a medical device comprising: (a) a medical device to which the medical device is implanted or transplanted host tissue i) an inhibitor of fiber formation ii) an anti-infective agent iii) a polymer iv) an inhibitor of fiber formation and a polymer V) a composition comprising an anti-infective agent and a polymer or vi) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer, and (b) implanting a medical device into a host, and said medical treatment The device is a tracheal stent or a bronchial stent. The method of implanting a device with the medical device of claim 859, comprising: (a) the medical device is implanted, or the transplanted host tissue is immersed in a fibrosis inhibitor; and (b) the host Implant a medical device. A method of implanting a device with the medical device of claim 859 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in an anti-infective agent; and (b) the host is implanted. Implant medical devices. The method of implanting a device with the medical device of claim 859 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a polymer; and (b) the medical device is in the host. Transplant. The method of implanting a device comprising the following: 8) a medical device according to claim 859, wherein: (a) the medical device is implanted or the implanted host tissue is immersed in a composition comprising a fibrosis inhibitor and a polymer; And (b) transplant the medical device into the host. The method of implanting a device with the medical device of claim 859 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) Transplant the medical device into the host. 86. A method of implanting a device comprising the following with the medical device of claim 859: (a) a composition comprising a fibrosis inhibitor, an anti-infective agent, and a polymer in which the medical device is implanted or the transplanted host tissue And (b) implant the medical device into the host. The method of claim 859 wherein the medical device is a tracheal stent. The method of claim 859 wherein the medical device is a bronchial stent. The method of claim 859 wherein the medical device is a metal tracheal stent. The method of claim 859 wherein the medical device is a metal bronchial stent. The method of claim 859 wherein the medical device is a polymeric tracheal stent. The method of claim 859 wherein the medical device is a polymeric bronchial stent. The method of claim 859, wherein cell regeneration is inhibited by a fiber formation inhibitor. The method of claim 859 wherein angiogenesis is inhibited by a fiber formation inhibitor. The method of claim 859, wherein fibroblast migration is inhibited by a fibrosis inhibitor. The method of claim 859, wherein the fibrosis inhibitor inhibits fibroblast proliferation. The method of claim 859, wherein accumulation of extracellular matrix is inhibited by the fiber formation inhibitor. The method of claim 859, wherein the tissue remodeling is inhibited by the fiber formation inhibitor. The method of claim 859 wherein the fiber formation inhibitor is an angiogenesis inhibitor. The method of claim 859 wherein the fiber formation inhibitor is a 5- lipoxygenase inhibitor or antagonist. The method of claim 859 wherein the fibrosis inhibitor is a chemokine receptor antagonist. The method of claim 859 wherein the fiber formation inhibitor is a cell cycle inhibitor. The method of claim 859, wherein the fiber formation inhibitor is a taxane. The method of claim 859 wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 859 wherein the fiber formation inhibitor is paclitaxel. The method of claim 859 wherein the fiber formation inhibitor is not paclitaxel. The method of claim 859 wherein the fibrosis inhibitor is an analogue or derivative of paclitaxel. The method of claim 859, wherein the fiber formation inhibitor is a vinca alkaloid. The method of claim 859 wherein the fibrosis inhibitor is camptothecin or an analogue or derivative thereof. The method of claim 859 wherein the fiber formation inhibitor is podophyllotoxin. The method of claim 859 wherein the fibrosis inhibitor is podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof. The method of claim 859 wherein the fibrosis inhibitor is an anthracycline. The method of claim 859 wherein the fibrosis inhibitor is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof. The method of claim 859 wherein the fibrosis inhibitor is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof. The method of claim 859, wherein the fiber formation inhibitor is a platinum compound. The method of claim 859, wherein the fiber formation inhibitor is nitrosourea. The method of claim 859, wherein the fiber formation inhibitor is nitroimidazole. The method of claim 859 wherein the fiber formation inhibitor is a folic acid antagonist. The method of claim 859 wherein the fibrosis inhibitor is a cytidine analogue. The method of claim 859 wherein the fibrosis inhibitor is a pyrimidine analogue. The method of claim 859 wherein the fiber formation inhibitor is a fluoropyrimidine analogue. The method of claim 859 wherein the fibrosis inhibitor is a purine analogue. The method of claim 859, wherein the fiber formation inhibitor is nitrogen mustard or an analogue or derivative thereof. The method of claim 859, wherein the fiber formation inhibitor is hydroxyurea. The method of claim 859 wherein the fibrosis inhibitor is mitomycin or an analogue or derivative thereof. The method of claim 859 wherein the fiber formation inhibitor is an alkyl sulfonate. The method of claim 859 wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The method of claim 859 wherein the fibrosis inhibitor is nicotinamide or an analogue or derivative thereof. The method of claim 859 wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of claim 859 wherein the fiber formation inhibitor is a DNA alkylating agent. The method of claim 859 wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 859 wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of claim 859 wherein the fiber formation inhibitor is a DNA cleaving agent. The method of claim 859 wherein the fibrosis inhibitor is an antimetabolite. The method of claim 859, wherein adenosine deaminase is inhibited by a fiber formation inhibitor. The method of claim 859, wherein a purine ring synthesis is inhibited by a fiber formation inhibitor. The method of claim 859 wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of claim 859 wherein the fibrosis inhibitor inhibits dihydrofolate reduction. The method of claim 859, wherein thymidine monophosphate is inhibited by the fiber formation inhibitor. The method of claim 859, wherein DNA damage is caused by a fiber formation inhibitor. The method of claim 859, wherein the fiber formation inhibitor is a DNA intercalation agent. The method of claim 859 wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The method of claim 859 wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The method of claim 859 wherein the fibril formation inhibitor inhibits ribonucleotide synthesis or function. The method of claim 859, wherein the fiber formation inhibitor inhibits thymidine monophosphate synthesis or function. The method of claim 859, wherein DNA synthesis is inhibited by the fiber formation inhibitor. The method of claim 859, wherein DNA adduct formation occurs with the fiber formation inhibitor. The method of claim 859, wherein protein synthesis is inhibited by the fiber formation inhibitor. The method of claim 859, wherein microtubule function is inhibited by the fiber formation inhibitor. The method of claim 859 wherein the fibrosis inhibitor is a cyclin dependent protein kinase inhibitor. The method of claim 859 wherein the fibrosis inhibitor is an epidermal growth factor kinase inhibitor. The method of claim 859, wherein the fiber formation inhibitor is an elastase inhibitor. The method of claim 859 wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of claim 859 wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of claim 859 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 859 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 859 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist. The method of claim 859 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist, and the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof. The method of claim 859 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 859 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The method of claim 859 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof. The method of claim 859 wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. The method of claim 859 wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of claim 859 wherein the fibrosis inhibitor is an IL-1 antagonist. The method of claim 859 wherein the fibrosis inhibitor is an ICE antagonist. The method of claim 859 wherein the fibrosis inhibitor is an IRAK antagonist. The method of claim 859 wherein the fibrosis inhibitor is an IL-4 agonist. The method of claim 859 wherein the fibrosis inhibitor is an immunomodulator. The method of claim 859 wherein the fibrosis inhibitor is sirolimus or an analogue or derivative thereof. The method of claim 859 wherein the fibrosis inhibitor is not sirolimus. The method of claim 859 wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. The method of claim 859 wherein the fibrosis inhibitor is tacrolimus or an analogue or derivative thereof. The method of claim 859 wherein the fibrosis inhibitor is not tacrolimus. The method of claim 859 wherein the fibrosis inhibitor is biolimus or an analogue or derivative thereof. The method of claim 859 wherein the fibrosis inhibitor is tresperimus or an analogue or derivative thereof. The method of claim 859 wherein the fibrosis inhibitor is auranofin or an analogue or derivative thereof. The method of claim 859 wherein the fibrosis inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of claim 859 wherein the fibrosis inhibitor is gusperimus or an analogue or derivative thereof. The method of claim 859 wherein the fibrosis inhibitor is pimecrolimus or an analogue or derivative thereof. The method of claim 859 wherein the fibrosis inhibitor is ABT-578 or an analogue or derivative thereof. The method of claim 859 wherein the fiber formation inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. The method of claim 859, wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof. Fiber forming inhibitor is an IMPDH inhibitor, the IMPDH inhibitor is 1-alpha-25-dihydroxyvitamin D ₃ or its analogues or derivatives, method of claim 859. The method of claim 859 wherein the fiber formation inhibitor is a leukotriene inhibitor. The method of claim 859 wherein the vascularization inhibitor is an MCP-1 antagonist. The method of claim 859 wherein the fiber formation inhibitor is an MMP inhibitor. The method of claim 859 wherein the fiber formation inhibitor is an NFκB inhibitor. The method of claim 859, wherein the fiber formation inhibitor is an NFκB inhibitor, and the NFκB inhibitor is Bay11-7082. The method of claim 859 wherein the fiber formation inhibitor is a NO antagonist. The method of claim 859 wherein the fibrosis inhibitor is a p38 MAP kinase inhibitor. The method of claim 859 wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB 202190. The method of claim 859 wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The method of claim 859 wherein the fiber formation inhibitor is a TGF beta inhibitor. The method of claim 859 wherein the fiber formation inhibitor is a thromboxane A2 antagonist. The method of claim 859 wherein the vascularization inhibitor is a TNFα antagonist. The method of claim 859, wherein the fiber formation inhibitor is a TACE inhibitor. The method of claim 859 wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. The method of claim 859 wherein the fiber formation inhibitor is a vitronectin inhibitor. The method of claim 859 wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of claim 859 wherein the fiber formation inhibitor is a protein kinase inhibitor. The method of claim 859 wherein the fibrosis inhibitor is a PDGF receptor kinase inhibitor. The method of claim 859 wherein the fibrosis inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of claim 859 wherein the fibrosis inhibitor is a retinoic acid receptor antagonist. The method of claim 859 wherein the fibrosis inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of claim 859 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 859 wherein the fibrosis inhibitor is an antifungal agent. The method of claim 859, wherein the fiber formation inhibitor is an antifungal agent, and the antifungal agent is sulconizole. The method of claim 859 wherein the fiber formation inhibitor is a bisphosphonate. The method of claim 859 wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. The method of claim 859 wherein the fibrosis inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The method of claim 859, wherein the fiber formation inhibitor is a macrolide antibiotic. The method of claim 859 wherein the fibrosis inhibitor is a GPIIb / IIIa receptor antagonist. The method of claim 859 wherein the fibrosis inhibitor is an endothelin receptor antagonist. The method of claim 859 wherein the fibrosis inhibitor is an agonist of the peroxisome proliferator-activated receptor. The method of claim 859 wherein the fibrosis inhibitor is an estrogen receptor agent. The method of claim 859 wherein the fibrosis inhibitor is a somostatin analog. The method of claim 859 wherein the fiber formation inhibitor is a neurokinin 1 antagonist. The method of claim 859 wherein the fibrosis inhibitor is a neurokinin 3 antagonist. The method of claim 859 wherein the fibrosis inhibitor is a VLA-4 antagonist. The method of claim 859 wherein the fibrosis inhibitor is an osteoclast inhibitor. The method of claim 859 wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The method of claim 859 wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of claim 859 wherein the fibrosis inhibitor is an angiotensin II antagonist. The method of claim 859 wherein the fiber formation inhibitor is an enkephalinase inhibitor. The method of claim 859 wherein the fibrosis inhibitor is a peroxisome proliferator-responsive receptor gamma agonist insulin sensitizer. The method of claim 859 wherein the fiber formation inhibitor is a protein kinase C inhibitor. The method of claim 859 wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. The method of claim 859 wherein the fiber formation inhibitor is a CXCR3 inhibitor. The method of claim 859 wherein the fiber formation inhibitor is an Itk inhibitor. The method of claim 859 wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of claim 859 wherein the fibrosis inhibitor is a PPAR agonist. The method of claim 859 wherein the fiber formation inhibitor is an immunosuppressant. The method of claim 859 wherein the fiber formation inhibitor is an Erb inhibitor. The method of claim 859 wherein the fibrosis inhibitor is an apoptosis agonist. The method of claim 859 wherein the fibrosis inhibitor is a lipocortin agonist. The method of claim 859 wherein the fibrosis inhibitor is a VCAM-1 antagonist. The method of claim 859, wherein the fiber formation inhibitor is a collagen antagonist. The method of claim 859 wherein the fibrosis inhibitor is an α2 integrin antagonist. The method of claim 859, wherein the fiber formation inhibitor is a TNFα inhibitor. The method of claim 859, wherein the fiber formation inhibitor is a nitric oxide inhibitor. The method of claim 859 wherein the fiber formation inhibitor is a cathepsin inhibitor. The method of claim 859 wherein the fibrosis inhibitor is not an anti-inflammatory agent. The method of claim 859 wherein the fibrosis inhibitor is not a steroid. The method of claim 859 wherein the fibrosis inhibitor is not a glucocorticosteroid. The method of claim 859 wherein the fibrosis inhibitor is not dexamethasone. The method of claim 859 wherein the fiber formation inhibitor is not beclomethasone. The method of claim 859 wherein the fiber formation inhibitor is not dipropionic acid. The method of claim 859 wherein the fibrosis inhibitor is not an anti-infective. The method of claim 859 wherein the fibrosis inhibitor is not an antibiotic. The method of claim 859 wherein the fibrosis inhibitor is not an antifungal agent. The method of claim 859 wherein the anti-infective agent is an anthracycline. The method of claim 859 wherein the anti-infective agent is doxorubicin. The method of claim 859 wherein the anti-infective agent is mitoxantrone. The method of claim 859 wherein the anti-infective agent is fluoropyrimidine. The method of claim 859 wherein the anti-infective is 5-fluorouracil (5-FU). The method of claim 859 wherein the anti-infective agent is a folic acid antagonist. The method of claim 859 wherein the anti-infective agent is methotrexate. The method of claim 859 wherein the anti-infective is podophyllotoxin. The method of claim 859 wherein the anti-infective is etoposide. The method of claim 859 wherein the anti-infective agent is camptothecin. The method of claim 859 wherein the anti-infective agent is hydroxyurea. The method of claim 859 wherein the anti-infective is a platinum complex. The method of claim 859 wherein the anti-infective agent is cisplatin. The method of claim 859, wherein the composition comprises an antithrombotic agent. The method of claim 859, wherein the polymer is formed from a reactant comprising a naturally occurring polymer. The method of claim 859, wherein the polymer is formed from a reactant comprising protein. The method of claim 859, wherein the polymer is formed from a reactant comprising carbohydrate. The method of claim 859, wherein the polymer is formed from a reactant comprising a biodegradable polymer. The method of claim 859, wherein the polymer is formed from a reactant comprising a non-biodegradable polymer. The method of claim 859, wherein the polymer is formed from a reactant comprising collagen. The method of claim 859, wherein the polymer is formed from a reactant comprising methylated collagen. The method of claim 859, wherein the polymer is formed from a reactant comprising fibrinogen. The method of claim 859, wherein the polymer is formed from a reactant comprising thrombin. The method of claim 859, wherein the polymer is formed from a reactant comprising plasma components. The method of claim 859, wherein the polymer is formed from a reactant comprising a calcium salt. The method of claim 859, wherein the polymer is formed from a reactant comprising a fiber formation inhibitor. The method of claim 859, wherein the polymer is formed from a reactant comprising a fibrinogen analog. The method of claim 859, wherein the polymer is formed from a reactant comprising albumin. The method of claim 859, wherein the polymer is formed from a reactant comprising plasminogen. The method of claim 859, wherein the polymer is formed from a reactant comprising von Willebrand factor. The method of claim 859, wherein the polymer is formed from a reactant comprising Factor VIII. The method of claim 859, wherein the polymer is formed from a reactant comprising hypoallergenic collagen. The method of claim 859, wherein the polymer is formed from a reactant comprising atelopeptide collagen. The method of claim 859, wherein the polymer is formed from a reactant comprising telopeptide collagen. The method of claim 859, wherein the polymer is formed from a reactant comprising cross-linked collagen. The method of claim 859, wherein the polymer is formed from a reactant comprising aprotinin. The method of claim 859, wherein the polymer is formed from a reactant comprising epsilon amino-n-caproic acid. The method of claim 859, wherein the polymer is formed from a reactant comprising gelatin. The method of claim 859, wherein the polymer is formed from a reactant comprising a protein conjugate. The method of claim 859, wherein the polymer is formed from a reactant comprising a gelatin conjugate. The method of claim 859, wherein the polymer is formed from a reactant comprising a synthetic polymer. The method of claim 859, wherein the polymer is formed from a reactant comprising a compound comprising synthetic isocyanate. The method of claim 859, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic thiol. The method of claim 859, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more thiol groups. The method of claim 859, wherein the polymer is formed from a reactant comprising a synthetic compound comprising 3 or more thiol groups. The method of claim 859, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more thiol groups. The method of claim 859, wherein the polymer is formed from a reactant comprising a compound comprising synthetic amino. The method of claim 859, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more amino groups. The method of claim 859, wherein the polymer is formed from reactants consisting of a synthetic compound containing three or more amino groups. The method of claim 859, wherein the polymer is formed from a reactant comprising a synthetic compound comprising 4 or more amino groups. The method of claim 859, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of claim 859, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The method of claim 859, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. The method of claim 859, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more carbonyl-oxygen-succinimidyl groups. The method of claim 859, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide. The method of claim 859, wherein the polymer is formed from a reactant comprising a synthetic compound comprising both a polyalkylene oxide and a biodegradable polyester block. The method of claim 859, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide having an amino reactive group. The method of claim 859, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide having a thiol reactive group. The method of claim 859, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The method of claim 859, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a biodegradable polyester block. The method of claim 859, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly comprised of lactic acid or lactide. The method of claim 859, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or in part, consisting of glycolic acid or glycolide. The method of claim 859, wherein the polymer is formed from a reactant comprising polylysine. The method of claim 859, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 859, wherein the polymer is formed from a reactant comprising (a) a protein and (b) polylysine. The method of claim 859, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more thiol groups. The method of claim 859, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more amino groups. The method of claim 859, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. 859. The method according to 859. The method of claim 859, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 859, wherein the polymer is formed from a reactant comprising (a) collagen and (b) polylysine. The method of claim 859, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more thiol groups. The method of claim 859, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more amino groups. The method of claim 859, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. 859. The method according to 859. The method of claim 859 wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 859, wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) polylysine. The method of claim 859, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more thiol groups. The method of claim 859, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more amino groups. The method of claim 859, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone, The method of claim 859. The method of claim 859, wherein the polymer is formed from a reactant comprising hyaluronic acid. The method of claim 859, wherein the polymer is formed from a reactant comprising a hyaluronic acid derivative. The method of claim 859, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The method of claim 859, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A polymer having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene region. The method of claim 859, formed from a reactant consisting of and a synthetic compound comprising a plurality of electrophilic groups. The method of claim 859, wherein the composition comprises a colorant. The method of claim 859, wherein the composition is sterile. Methods of implanting a medical device comprising: (a) a medical device to which the medical device is implanted or transplanted host tissue i) an inhibitor of fiber formation ii) an anti-infective agent iii) a polymer iv) an inhibitor of fiber formation and a polymer V) a composition comprising an anti-infective agent and a polymer or vi) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer, and (b) implanting a medical device into a host, and said medical treatment The device is a urogenital stent. A method of implanting a device with the medical device of claim 1118 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a fibrosis inhibitor; and (b) the host Implant a medical device. A method of implanting a device with the medical device of claim 1118 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in an anti-infective agent; and (b) the host is implanted. Implant medical devices. A method of implanting a device with the medical device of claim 1118 comprising: (a) the medical device is implanted, or the implanted host tissue is immersed in a polymer, and (b) the medical device is in the host. Transplant. A method of implanting a device with the medical device of claim 1118 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising a fibrosis inhibitor and a polymer; And (b) transplant the medical device into the host. A method of implanting a device with the medical device of claim 1118 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising an anti-infective and a polymer; and (b) Transplant the medical device into the host. 120. A method of implanting a device comprising the following with the medical device of claim 1118: (a) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer in which the medical device is implanted or the host tissue into which it is implanted. And (b) implant the medical device into the host. The method of claim 1118 wherein the medical device is a ureteral stent. The method of claim 1118 wherein the medical device is a urethral stent. The method of claim 1118 wherein the medical device is an oviduct stent. The method of claim 1118 wherein the medical device is a prostate stent. The method of claim 1118 wherein the medical device is a metal urogenital stent. The method of claim 1118 wherein the medical device is a polymeric urogenital stent. The method of claim 1118, wherein cell regeneration is inhibited by the fiber formation inhibitor. The method of claim 1118 wherein angiogenesis is inhibited by the fiber formation inhibitor. The method of claim 1118, wherein fibroblast migration is inhibited by a fibrosis inhibitor. The method of claim 1118, wherein the fibrosis inhibitor inhibits fibroblast proliferation. The method of claim 1118, wherein the fiber formation inhibitor inhibits extracellular matrix accumulation. The method of claim 1118, wherein the tissue remodeling is inhibited by the fiber formation inhibitor. The method of claim 1118 wherein the fiber formation inhibitor is an angiogenesis inhibitor. The method of claim 1118 wherein the fiber formation inhibitor is a 5- lipoxygenase inhibitor or antagonist. The method of claim 1118 wherein the fibrosis inhibitor is a chemokine receptor antagonist. The method of claim 1118 wherein the fibrosis inhibitor is a cell cycle inhibitor. The method of claim 1118 wherein the fiber formation inhibitor is a taxane. The method of claim 1118 wherein the fibrosis inhibitor is a microtubule inhibitor. The method of claim 1118 wherein the fiber formation inhibitor is paclitaxel. The method of claim 1118 wherein the fiber formation inhibitor is not paclitaxel. The method of claim 1118 wherein the fibrosis inhibitor is an analogue or derivative of paclitaxel. The method of claim 1118 wherein the fiber formation inhibitor is a vinca alkaloid. The method of claim 1118 wherein the fibrosis inhibitor is camptothecin or an analogue or derivative thereof. The method of claim 1118 wherein the fibrosis inhibitor is podophyllotoxin. The method of claim 1118 wherein the fiber formation inhibitor is podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof. The method of claim 1118 wherein the fibrosis inhibitor is an anthracycline. The method of claim 1118 wherein the fibrosis inhibitor is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof. The method of claim 1118 wherein the fibrosis inhibitor is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof. The method of claim 1118 wherein the fiber formation inhibitor is a platinum compound. The method of claim 1118 wherein the fiber formation inhibitor is nitrosourea. The method of claim 1118 wherein the fiber formation inhibitor is nitroimidazole. The method of claim 1118 wherein the fibrosis inhibitor is a folic acid antagonist. The method of claim 1118 wherein the fibrosis inhibitor is a cytidine analogue. The method of claim 1118 wherein the fibrosis inhibitor is a pyrimidine analogue. The method of claim 1118 wherein the fibrosis inhibitor is a fluoropyrimidine analogue. The method of claim 1118 wherein the fibrosis inhibitor is a purine analogue. The method of claim 1118 wherein the fiber formation inhibitor is nitrogen mustard or an analogue or derivative thereof. The method of claim 1118 wherein the fiber formation inhibitor is hydroxyurea. The method of claim 1118 wherein the fibrosis inhibitor is mitomycin or an analogue or derivative thereof. The method of claim 1118 wherein the fiber formation inhibitor is an alkyl sulfonate. The method of claim 1118 wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The method of claim 1118 wherein the fibrosis inhibitor is nicotinamide or an analogue or derivative thereof. The method of claim 1118 wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of claim 1118 wherein the fiber formation inhibitor is a DNA alkylating agent. The method of claim 1118 wherein the fibrosis inhibitor is a microtubule inhibitor. The method of claim 1118 wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of claim 1118 wherein the fiber formation inhibitor is a DNA cleaving agent. The method of claim 1118 wherein the fibrosis inhibitor is an antimetabolite. The method of claim 1118 wherein adenosine deaminase is inhibited by the fiber formation inhibitor. The method of claim 1118, wherein purine ring synthesis is inhibited by a fiber formation inhibitor. The method of claim 1118 wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of claim 1118 wherein the fiber formation inhibitor inhibits dihydrofolate reduction. The method of claim 1118 wherein thymidine monophosphate is inhibited by the fiber formation inhibitor. The method of claim 1118 wherein the fiber formation inhibitor causes DNA damage. The method of claim 1118 wherein the fiber formation inhibitor is a DNA intercalation agent. The method of claim 1118 wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The method of claim 1118 wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The method of claim 1118 wherein the fiber formation inhibitor inhibits ribonucleotide synthesis or function. The method of claim 1118 wherein the fibrosis inhibitor inhibits thymidine monophosphate synthesis or function. The method of claim 1118, wherein DNA synthesis is inhibited by the fiber formation inhibitor. The method of claim 1118, wherein the fiber formation inhibitor causes DNA adduct formation. The method of claim 1118, wherein protein synthesis is inhibited by the fiber formation inhibitor. The method of claim 1118 wherein the microtubule function is inhibited by the fiber formation inhibitor. The method of claim 1118 wherein the fibrosis inhibitor is a cyclin dependent protein kinase inhibitor. The method of claim 1118 wherein the fibrosis inhibitor is an epidermal growth factor kinase inhibitor. The method of claim 1118 wherein the fiber formation inhibitor is an elastase inhibitor. The method of claim 1118 wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of claim 1118 wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of claim 1118 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 1118 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 1118 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist. The method of claim 1118 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist, and the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof. The method of claim 1118 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 1118 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The method of claim 1118 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof. The method of claim 1118 wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. The method of claim 1118 wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of claim 1118 wherein the fibrosis inhibitor is an IL-1 antagonist. The method of claim 1118 wherein the fibrosis inhibitor is an ICE antagonist. The method of claim 1118 wherein the fibrosis inhibitor is an IRAK antagonist. The method of claim 1118 wherein the fibrosis inhibitor is an IL-4 agonist. The method of claim 1118 wherein the fibrosis inhibitor is an immunomodulator. The method of claim 1118 wherein the fibrosis inhibitor is sirolimus or an analogue or derivative thereof. The method of claim 1118 wherein the fibrosis inhibitor is not sirolimus. The method of claim 1118 wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. The method of claim 1118 wherein the fibrosis inhibitor is tacrolimus or an analogue or derivative thereof. The method of claim 1118 wherein the fibrosis inhibitor is not tacrolimus. The method of claim 1118 wherein the fibrosis inhibitor is biolimus or an analogue or derivative thereof. The method of claim 1118 wherein the fibrosis inhibitor is tresperimus or an analogue or derivative thereof. The method of claim 1118 wherein the fibrosis inhibitor is auranofin or an analogue or derivative thereof. The method of claim 1118 wherein the fibrosis inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of claim 1118 wherein the fibrosis inhibitor is gusperimus or an analogue or derivative thereof. The method of claim 1118 wherein the fibrosis inhibitor is pimecrolimus or an analogue or derivative thereof. The method of claim 1118 wherein the fibrosis inhibitor is ABT-578 or an analogue or derivative thereof. The method of claim 1118 wherein the fiber formation inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. The method of claim 1118 wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof. Fiber forming inhibitor is an IMPDH inhibitor, the IMPDH inhibitor is 1-alpha-25-dihydroxyvitamin D ₃ or its analogues or derivatives, method of claim 1118. The method of claim 1118 wherein the fiber formation inhibitor is a leukotriene inhibitor. The method of claim 1118 wherein the vascularization inhibitor is an MCP-1 antagonist. The method of claim 1118 wherein the fiber formation inhibitor is an MMP inhibitor. The method of claim 1118 wherein the fiber formation inhibitor is an NFκB inhibitor. 1119. The method of claim 1118, wherein the fiber formation inhibitor is an NFκB inhibitor, and the NFκB inhibitor is Bay11-7082. The method of claim 1118 wherein the fibrosis inhibitor is a NO antagonist. The method of claim 1118 wherein the fibrosis inhibitor is a p38 MAP kinase inhibitor. 1119. The method of claim 1118, wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor, and the p38 MAP kinase inhibitor is SB202190. The method of claim 1118 wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The method of claim 1118 wherein the fibrosis inhibitor is a TGF beta inhibitor. The method of claim 1118 wherein the fibrosis inhibitor is a thromboxane A2 antagonist. The method of claim 1118 wherein the vascularization inhibitor is a TNFα antagonist. The method of claim 1118 wherein the fiber formation inhibitor is a TACE inhibitor. The method of claim 1118 wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. The method of claim 1118 wherein the fiber formation inhibitor is a vitronectin inhibitor. The method of claim 1118 wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of claim 1118 wherein the fiber formation inhibitor is a protein kinase inhibitor. The method of claim 1118 wherein the fibrosis inhibitor is a PDGF receptor kinase inhibitor. The method of claim 1118 wherein the fibrosis inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of claim 1118 wherein the fibrosis inhibitor is a retinoic acid receptor antagonist. The method of claim 1118 wherein the fibrosis inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of claim 1118 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 1118 wherein the fibrosis inhibitor is an antifungal agent. The method of claim 1118 wherein the fibrosis inhibitor is an antifungal agent, and the antifungal agent is sulconizole. The method of claim 1118 wherein the fiber formation inhibitor is a bisphosphonate. The method of claim 1118 wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. The method of claim 1118 wherein the fibrosis inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The method of claim 1118 wherein the fiber formation inhibitor is a macrolide antibiotic. The method of claim 1118 wherein the fibrosis inhibitor is a GPIIb / IIIa receptor antagonist. The method of claim 1118 wherein the fibrosis inhibitor is an endothelin receptor antagonist. The method of claim 1118 wherein the fibrosis inhibitor is an agonist of the peroxisome proliferator-responsive receptor. The method of claim 1118 wherein the fibrosis inhibitor is an estrogen receptor agent. The method of claim 1118 wherein the fibrosis inhibitor is a somostatin analog. The method of claim 1118 wherein the fibrosis inhibitor is a neurokinin 1 antagonist. The method of claim 1118 wherein the fibrosis inhibitor is a neurokinin 3 antagonist. The method of claim 1118 wherein the fibrosis inhibitor is a VLA-4 antagonist. The method of claim 1118 wherein the fibrosis inhibitor is an osteoclast inhibitor. The method of claim 1118 wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The method of claim 1118 wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of claim 1118 wherein the fibrosis inhibitor is an angiotensin II antagonist. The method of claim 1118 wherein the fiber formation inhibitor is an enkephalinase inhibitor. The method of claim 1118 wherein the fibrosis inhibitor is a peroxisome proliferator-responsive receptor gamma agonist insulin sensitizer. The method of claim 1118 wherein the fiber formation inhibitor is a protein kinase C inhibitor. The method of claim 1118 wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. The method of claim 1118 wherein the fiber formation inhibitor is a CXCR3 inhibitor. The method of claim 1118 wherein the fiber formation inhibitor is an Itk inhibitor. The method of claim 1118 wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of claim 1118 wherein the fibrosis inhibitor is a PPAR agonist. The method of claim 1118 wherein the fibrosis inhibitor is an immunosuppressant. The method of claim 1118 wherein the fiber formation inhibitor is an Erb inhibitor. The method of claim 1118 wherein the fibrosis inhibitor is an apoptosis agonist. The method of claim 1118 wherein the fibrosis inhibitor is a lipocortin agonist. The method of claim 1118 wherein the fibrosis inhibitor is a VCAM-1 antagonist. The method of claim 1118 wherein the fiber formation inhibitor is a collagen antagonist. The method of claim 1118 wherein the fibrosis inhibitor is an α2 integrin antagonist. The method of claim 1118 wherein the fiber formation inhibitor is a TNFα inhibitor. The method of claim 1118 wherein the fiber formation inhibitor is a nitric oxide inhibitor The method of claim 1118 wherein the fiber formation inhibitor is a cathepsin inhibitor. The method of claim 1118 wherein the fibrosis inhibitor is not an anti-inflammatory agent. The method of claim 1118 wherein the fibrosis inhibitor is not a steroid. The method of claim 1118 wherein the fibrosis inhibitor is not a glucocorticosteroid. The method of claim 1118 wherein the fibrosis inhibitor is not dexamethasone. The method of claim 1118 wherein the fiber formation inhibitor is not beclomethasone. The method of claim 1118 wherein the fiber formation inhibitor is not dipropionic acid. The method of claim 1118 wherein the fibrosis inhibitor is not an anti-infective. The method of claim 1118 wherein the fibrosis inhibitor is not an antibiotic. The method of claim 1118 wherein the fibrosis inhibitor is not an antifungal agent. The method of claim 1118 wherein the anti-infective is an anthracycline. The method of claim 1118 wherein the anti-infective agent is doxorubicin. The method of claim 1118 wherein the anti-infective is mitoxantrone. The method of claim 1118 wherein the anti-infective agent is fluoropyrimidine. The method of claim 1118 wherein the anti-infective is 5-fluorouracil (5-FU). The method of claim 1118 wherein the anti-infective agent is a folic acid antagonist. The method of claim 1118 wherein the anti-infective agent is methotrexate. The method of claim 1118 wherein the anti-infective is podophyllotoxin. The method of claim 1118 wherein the anti-infective is etoposide. The method of claim 1118 wherein the anti-infective agent is camptothecin. The method of claim 1118 wherein the anti-infective is hydroxyurea. The method of claim 1118 wherein the anti-infective is a platinum complex. The method of claim 1118 wherein the anti-infective is cisplatin. The method of claim 1118, wherein the composition comprises an antithrombotic agent. The method of claim 1118, wherein the polymer is formed from a reactant comprising a naturally occurring polymer. The method of claim 1118, wherein the polymer is formed from a reactant comprising protein. The method of claim 1118, wherein the polymer is formed from a reactant comprising carbohydrate. The method of claim 1118, wherein the polymer is formed from a reactant comprising a biodegradable polymer. The method of claim 1118, wherein the polymer is formed from a reactant comprising a non-biodegradable polymer. The method of claim 1118 wherein the polymer is formed from a reactant comprising collagen. The method of claim 1118 wherein the polymer is formed from a reactant comprising methylated collagen. The method of claim 1118, wherein the polymer is formed from a reactant comprising fibrinogen. The method of claim 1118 wherein the polymer is formed from a reactant comprising thrombin. The method of claim 1118 wherein the polymer is formed from reactants comprising plasma components. The method of claim 1118, wherein the polymer is formed from a reactant comprising a calcium salt. The method of claim 1118 wherein the polymer is formed from a reactant comprising a fiber formation inhibitor. The method of claim 1118 wherein the polymer is formed from a reactant comprising a fibrinogen analog. The method of claim 1118 wherein the polymer is formed from a reactant comprising albumin. The method of claim 1118 wherein the polymer is formed from a reactant comprising plasminogen. The method of claim 1118 wherein the polymer is formed from a reactant comprising von Willebrand factor. The method of claim 1118 wherein the polymer is formed from a reactant comprising Factor VIII. The method of claim 1118 wherein the polymer is formed from a reactant comprising hypoallergenic collagen. The method of claim 1118 wherein the polymer is formed from a reactant comprising atelopeptide collagen. The method of claim 1118 wherein the polymer is formed from a reactant comprising telopeptide collagen. The method of claim 1118, wherein the polymer is formed from a reactant comprising cross-linked collagen. The method of claim 1118 wherein the polymer is formed from a reactant comprising aprotinin. The method of claim 1118 wherein the polymer is formed from a reactant comprising epsilon amino-n-caproic acid. The method of claim 1118 wherein the polymer is formed from a reactant comprising gelatin. The method of claim 1118 wherein the polymer is formed from a reactant comprising a protein conjugate. The method of claim 1118 wherein the polymer is formed from a reactant comprising a gelatin conjugate. The method of claim 1118, wherein the polymer is formed from a reactant comprising a synthetic polymer. The method of claim 1118, wherein the polymer is formed from a reactant comprising a compound comprising synthetic isocyanate. The method of claim 1118 wherein the polymer is formed from a reactant comprising a compound comprising a synthetic thiol. The method of claim 1118, wherein the polymer is formed from reactants comprised of synthetic compounds comprising two or more thiol groups. The method of claim 1118 wherein the polymer is formed from a reactant comprised of a synthetic compound comprising 3 or more thiol groups. The method of claim 1118 wherein the polymer is formed from a reactant comprising a synthetic compound comprising 4 or more thiol groups. The method of claim 1118 wherein the polymer is formed from a reactant comprising a compound comprising synthetic amino. The method of claim 1118 wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more amino groups. The method of claim 1118, wherein the polymer is formed from reactants consisting of a synthetic compound containing three or more amino groups. The method of claim 1118 wherein the polymer is formed from a reactant comprising a synthetic compound comprising 4 or more amino groups. The method of claim 1118 wherein the polymer is formed from a reactant comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of claim 1118, wherein the polymer is formed from reactants comprised of synthetic compounds comprising two or more carbonyl-oxygen-succinimidyl groups. 1119. The method of claim 1118, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. 1119. The method of claim 1118, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more carbonyl-oxygen-succinimidyl groups. The method of claim 1118 wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide. 1119. The method of claim 1118, wherein the polymer is formed from a reactant comprising a synthetic compound comprising both a polyalkylene oxide and a biodegradable polyester block. The method of claim 1118 wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The method of claim 1118, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide having a thiol reactive group. The method of claim 1118 wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The method of claim 1118, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a biodegradable polyester block. 1119. The method of claim 1118, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly comprised of lactic acid or lactide. 1119. The method of claim 1118, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly composed of glycolic acid or glycolide. The method of claim 1118 wherein the polymer is formed from a reactant comprising polylysine. The method of claim 1118, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 1118 wherein the polymer is formed from a reactant comprising (a) a protein and (b) polylysine. 1119. The method of claim 1118, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more thiol groups. 1119. The method of claim 1118, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more amino groups. 1119. The method of claim 1118, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. 1118. The method according to 1118. The method of claim 1118, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 1118 wherein the polymer is formed from reactants comprising (a) collagen and (b) polylysine. 1119. The method of claim 1118, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more thiol groups. The method of claim 1118, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more amino groups. 1119. The method of claim 1118, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. 1118. The method according to 1118. 1119. The method of claim 1118, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound comprising an oxidized polyalkylene moiety. 1119. The method of claim 1118, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) polylysine. 1119. The method of claim 1118, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more thiol groups. 1119. The method of claim 1118, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more amino groups. 1119. The method of claim 1118, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone, The method of claim 1118. The method of claim 1118, wherein the polymer is formed from a reactant comprising hyaluronic acid. The method of claim 1118 wherein the polymer is formed from a reactant comprising a hyaluronic acid derivative. The method of claim 1118 wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The method of claim 1118 wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A polymer having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene region. 1119. The method of claim 1118, formed from a reactant comprising a synthetic compound comprising a plurality of electrophilic groups. The method of claim 1118, wherein the composition comprises a colorant. The method of claim 1118 wherein the composition is sterile. Methods of implanting a medical device comprising: (a) a medical device to which the medical device is implanted or transplanted host tissue i) an inhibitor of fiber formation ii) an anti-infective agent iii) a polymer iv) an inhibitor of fiber formation and a polymer V) a composition comprising an anti-infective agent and a polymer or vi) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer, and (b) implanting a medical device into a host, and said medical treatment The device is an ear stent or a nasal stent. A method of implanting a device with the medical device of claim 1377 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a fibrosis inhibitor; and (b) the host Implant a medical device. A method of implanting a device with the medical device of claim 1377 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in an anti-infective agent; and (b) the host is implanted. Implant medical devices. A method of implanting a device with the medical device of claim 1377 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a polymer; and (b) the medical device is implanted in the host. Transplant. A method of implanting a device with the medical device of claim 1377 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising a fibrosis inhibitor and a polymer; And (b) transplant the medical device into the host. A method of implanting a device with the medical device of claim 1377 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) Transplant the medical device into the host. A method of implanting a device comprising the following with the medical device of claim 1377: (a) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer in which the medical device is implanted or the host tissue into which it is implanted And (b) implant the medical device into the host. The method of claim 1377, wherein the medical device is a lacrimal stent. The method of claim 1377, wherein the medical device is an ear canal stent. The method of claim 1377, wherein the medical device is a nasal stent. The method of claim 1377, wherein the medical device is a sinus stent. The method of claim 1377, wherein cell regeneration is inhibited by the fiber formation inhibitor. The method of claim 1377, wherein angiogenesis is inhibited by fibrosis inhibitors. The method of claim 1377, wherein fibroblast migration is inhibited by a fibrosis inhibitor. The method of claim 1377, wherein the fibrosis inhibitor inhibits fibroblast proliferation. The method of claim 1377, wherein the fiber formation inhibitor inhibits extracellular matrix accumulation. The method of claim 1377 wherein the tissue remodeling is inhibited by the fiber formation inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is an angiogenesis inhibitor. The method of claim 1377 wherein the fiber formation inhibitor is a 5- lipoxygenase inhibitor or antagonist. The method of claim 1377, wherein the fiber formation inhibitor is a chemokine receptor antagonist. The method of claim 1377, wherein the fiber formation inhibitor is a cell cycle inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is a taxane. The method of claim 1377, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is paclitaxel. The method of claim 1377, wherein the fiber formation inhibitor is not paclitaxel. The method of claim 1377 wherein the fiber formation inhibitor is an analogue or derivative of paclitaxel. The method of claim 1377, wherein the fiber formation inhibitor is a vinca alkaloid. The method of claim 1377 wherein the fiber formation inhibitor is camptothecin or an analogue or derivative thereof. The method of claim 1377, wherein the fiber formation inhibitor is podophyllotoxin. The method of claim 1377 wherein the fiber formation inhibitor is podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof. The method of claim 1377, wherein the fiber formation inhibitor is an anthracycline. The method of claim 1377 wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof. The method of claim 1377, wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof. The method of claim 1377, wherein the fiber formation inhibitor is a platinum compound. The method of claim 1377, wherein the fiber formation inhibitor is nitrosourea. The method of claim 1377, wherein the fiber formation inhibitor is nitroimidazole. The method of claim 1377, wherein the fiber formation inhibitor is a folic acid antagonist. The method of claim 1377 wherein the fiber formation inhibitor is a cytidine analog. The method of claim 1377 wherein the fiber formation inhibitor is a pyrimidine analogue. The method of claim 1377 wherein the fiber formation inhibitor is a fluoropyrimidine analog. The method of claim 1377, wherein the fiber formation inhibitor is a purine analogue. The method of claim 1377, wherein the fiber formation inhibitor is nitrogen mustard or an analogue or derivative thereof. The method of claim 1377, wherein the fiber formation inhibitor is hydroxyurea. The method of claim 1377 wherein the fiber formation inhibitor is mitomycin or an analogue or derivative thereof. The method of claim 1377, wherein the fiber formation inhibitor is an alkyl sulfonate. The method of claim 1377 wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The method of claim 1377 wherein the fiber formation inhibitor is nicotinamide or an analogue or derivative thereof. The method of claim 1377 wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of claim 1377, wherein the fiber formation inhibitor is a DNA alkylating agent. The method of claim 1377, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is a DNA cleaving agent. The method of claim 1377, wherein the fiber formation inhibitor is an antimetabolite. The method of claim 1377, wherein adenosine deaminase is inhibited by a fiber formation inhibitor. The method of claim 1377, wherein purine ring synthesis is inhibited by a fiber formation inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of claim 1377, wherein the fiber formation inhibitor inhibits dihydrofolate reduction. The method of claim 1377, wherein thymidine monophosphate is inhibited by the fiber formation inhibitor. The method of claim 1377, wherein DNA damage is caused by a fiber formation inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is a DNA intercalation agent. The method of claim 1377, wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The method of claim 1377, wherein the fiber formation inhibitor inhibits ribonucleotide synthesis or function. The method of claim 1377, wherein the fiber formation inhibitor inhibits thymidine monophosphate synthesis or function. The method of claim 1377, wherein DNA synthesis is inhibited by the fiber formation inhibitor. The method of claim 1377, wherein DNA adduct formation occurs with the fiber formation inhibitor. The method of claim 1377, wherein protein synthesis is inhibited by the fiber formation inhibitor. The method of claim 1377, wherein the microtubule function is inhibited by the fiber formation inhibitor. The method of claim 1377 wherein the fiber formation inhibitor is a cyclin dependent protein kinase inhibitor. The method of claim 1377 wherein the fibrosis inhibitor is an epidermal growth factor kinase inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is an elastase inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is a fibrinogen antagonist. The method of claim 1377 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 1377, wherein the fiber formation inhibitor is a heat shock protein 90 antagonist. The method of claim 1377 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist, and the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof. The method of claim 1377 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 1377, wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof. The method of claim 1377, wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of claim 1377 wherein the fibrosis inhibitor is an IL-1 antagonist. The method of claim 1377 wherein the fiber formation inhibitor is an ICE antagonist. The method of claim 1377, wherein the fiber formation inhibitor is an IRAK antagonist. The method of claim 1377 wherein the fibrosis inhibitor is an IL-4 agonist. The method of claim 1377, wherein the fiber formation inhibitor is an immunomodulator. The method of claim 1377 wherein the fibrosis inhibitor is sirolimus or an analogue or derivative thereof. The method of claim 1377, wherein the fiber formation inhibitor is not sirolimus. The method of claim 1377 wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. The method of claim 1377 wherein the fibrosis inhibitor is tacrolimus or an analogue or derivative thereof. The method of claim 1377, wherein the fiber formation inhibitor is not tacrolimus. The method of claim 1377 wherein the fibrosis inhibitor is biolimus or an analogue or derivative thereof. The method of claim 1377 wherein the fibrosis inhibitor is tresperimus or an analogue or derivative thereof. The method of claim 1377 wherein the fiber formation inhibitor is auranofin or an analogue or derivative thereof. The method of claim 1377 wherein the fiber formation inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of claim 1377, wherein the fiber formation inhibitor is gusperimus or an analogue or derivative thereof. The method of claim 1377 wherein the fiber formation inhibitor is pimecrolimus or an analogue or derivative thereof. The method of claim 1377 wherein the fiber formation inhibitor is ABT-578 or an analogue or derivative thereof. The method of claim 1377 wherein the fiber formation inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof. The method of claim 1377 wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1 -α-25 dihydroxy vitamin D ₃ or an analogue or derivative thereof. The method of claim 1377, wherein the fiber formation inhibitor is a leukotriene inhibitor. The method of claim 1377 wherein the vascularization inhibitor is an MCP-1 antagonist. The method of claim 1377, wherein the fiber formation inhibitor is an MMP inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is an NFκB inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is an NFκB inhibitor, and the NFκB inhibitor is Bay11-7082. The method of claim 1377, wherein the fiber formation inhibitor is a NO antagonist. The method of claim 1377 wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor, and the p38 MAP kinase inhibitor is SB202190. The method of claim 1377, wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is a TGF beta inhibitor. The method of claim 1377 wherein the fiber formation inhibitor is a thromboxane A2 antagonist. The method of claim 1377, wherein the vascularization inhibitor is a TNFα antagonist. The method of claim 1377, wherein the fiber formation inhibitor is a TACE inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is a vitronectin inhibitor. The method of claim 1377, wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is a protein kinase inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is a PDGF receptor kinase inhibitor. The method of claim 1377 wherein the fiber formation inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is a retinoic acid receptor antagonist. The method of claim 1377 wherein the fiber formation inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is a fibrinogen antagonist. The method of claim 1377, wherein the fiber formation inhibitor is an antifungal agent. The method of claim 1377, wherein the fiber formation inhibitor is an antifungal agent, and the antifungal agent is sulconizole. The method of claim 1377, wherein the fiber formation inhibitor is a bisphosphonate. The method of claim 1377 wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. The method of claim 1377 wherein the fibrosis inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The method of claim 1377, wherein the fiber formation inhibitor is a macrolide antibiotic. The method of claim 1377, wherein the fiber formation inhibitor is a GPIIb / IIIa receptor antagonist. The method of claim 1377, wherein the fiber formation inhibitor is an endothelin receptor antagonist. The method of claim 1377 wherein the fibrosis inhibitor is an agonist of the peroxisome proliferator-responsive receptor. The method of claim 1377 wherein the fibrosis inhibitor is an estrogen receptor agent. The method of claim 1377 wherein the fibrosis inhibitor is a somostatin analog. The method of claim 1377, wherein the fiber formation inhibitor is a neurokinin 1 antagonist. The method of claim 1377, wherein the fiber formation inhibitor is a neurokinin 3 antagonist. The method of claim 1377 wherein the fibrosis inhibitor is a VLA-4 antagonist. The method of claim 1377, wherein the fiber formation inhibitor is an osteoclast inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of claim 1377 wherein the fiber formation inhibitor is an angiotensin II antagonist. The method of claim 1377, wherein the fiber formation inhibitor is an enkephalinase inhibitor. The method of claim 1377 wherein the fibrosis inhibitor is a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer. The method of claim 1377 wherein the fiber formation inhibitor is a protein kinase C inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is a CXCR3 inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is an Itk inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of claim 1377 wherein the fibrosis inhibitor is a PPAR agonist. The method of claim 1377, wherein the fiber formation inhibitor is an immunosuppressant. The method of claim 1377, wherein the fiber formation inhibitor is an Erb inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is an apoptosis agonist. The method of claim 1377 wherein the fibrosis inhibitor is a lipocortin agonist. The method of claim 1377 wherein the fiber formation inhibitor is a VCAM-1 antagonist. The method of claim 1377, wherein the fiber formation inhibitor is a collagen antagonist. The method of claim 1377, wherein the fiber formation inhibitor is an α2 integrin antagonist. The method of claim 1377, wherein the fiber formation inhibitor is a TNFα inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is a nitric oxide inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is a cathepsin inhibitor. The method of claim 1377, wherein the fiber formation inhibitor is not an anti-inflammatory agent. The method of claim 1377, wherein the fiber formation inhibitor is not a steroid. The method of claim 1377, wherein the fiber formation inhibitor is not a glucocorticosteroid. The method of claim 1377, wherein the fiber formation inhibitor is not dexamethasone. The method of claim 1377, wherein the fiber formation inhibitor is not beclomethasone. The method of claim 1377, wherein the fiber formation inhibitor is not dipropionic acid. The method of claim 1377, wherein the fiber formation inhibitor is not an anti-infective. The method of claim 1377, wherein the fiber formation inhibitor is not an antibiotic. The method of claim 1377, wherein the fiber formation inhibitor is not an antifungal agent. The method of claim 1377 wherein the anti-infective is an anthracycline. The method of claim 1377 wherein the anti-infective is doxorubicin. The method of claim 1377 wherein the anti-infective is mitoxantrone. The method of claim 1377 wherein the anti-infective agent is fluoropyrimidine. The method of claim 1377 wherein the anti-infective is 5-fluorouracil (5-FU). The method of claim 1377 wherein the anti-infective agent is a folic acid antagonist. The method of claim 1377 wherein the anti-infective agent is methotrexate. The method of claim 1377 wherein the anti-infective is podophyllotoxin. The method of claim 1377 wherein the anti-infective is etoposide. The method of claim 1377 wherein the anti-infective agent is camptothecin. The method of claim 1377, wherein the anti-infective is hydroxyurea. The method of claim 1377, wherein the anti-infective is a platinum complex. The method of claim 1377 wherein the anti-infective is cisplatin. The method of claim 1377, wherein the composition comprises an antithrombotic agent. The method of claim 1377, wherein the polymer is formed from a reactant comprising a naturally occurring polymer. The method of claim 1377, wherein the polymer is formed from a reactant comprising protein. The method of claim 1377, wherein the polymer is formed from reactants comprising carbohydrate. The method of claim 1377, wherein the polymer is formed from a reactant comprising a biodegradable polymer. The method of claim 1377, wherein the polymer is formed from a reactant comprising a non-biodegradable polymer. The method of claim 1377, wherein the polymer is formed from a reactant comprising collagen. The method of claim 1377, wherein the polymer is formed from a reactant comprising methylated collagen. The method of claim 1377, wherein the polymer is formed from a reactant comprising fibrinogen. The method of claim 1377, wherein the polymer is formed from a reactant comprising thrombin. The method of claim 1377, wherein the polymer is formed from a reactant comprising a plasma component. The method of claim 1377, wherein the polymer is formed from a reactant comprising a calcium salt. The method of claim 1377, wherein the polymer is formed from a reactant comprising a fiber formation inhibitor. The method of claim 1377, wherein the polymer is formed from a reactant comprising a fibrinogen analog. The method of claim 1377, wherein the polymer is formed from a reactant comprising albumin. The method of claim 1377, wherein the polymer is formed from a reactant comprising plasminogen. The method of claim 1377, wherein the polymer is formed from a reactant comprising von Willebrand factor. The method of claim 1377, wherein the polymer is formed from a reactant comprising Factor VIII. The method of claim 1377, wherein the polymer is formed from a reactant comprising hypoallergenic collagen. The method of claim 1377, wherein the polymer is formed from a reactant comprising atelopeptide collagen. The method of claim 1377, wherein the polymer is formed from a reactant comprising telopeptide collagen. The method of claim 1377, wherein the polymer is formed from a reactant comprising cross-linked collagen. The method of claim 1377, wherein the polymer is formed from a reactant comprising aprotinin. The method of claim 1377, wherein the polymer is formed from a reactant comprising epsilon amino-n-caproic acid. The method of claim 1377, wherein the polymer is formed from a reactant comprising gelatin. The method of claim 1377, wherein the polymer is formed from a reactant comprising a protein conjugate. The method of claim 1377, wherein the polymer is formed from a reactant comprising a gelatin conjugate. The method of claim 1377, wherein the polymer is formed from a reactant comprising a synthetic polymer. The method of claim 1377, wherein the polymer is formed from a reactant comprising a compound comprising synthetic isocyanate. The method of claim 1377, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic thiol. The method of claim 1377, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more thiol groups. The method of claim 1377, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more thiol groups. The method of claim 1377, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more thiol groups. The method of claim 1377, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic amino. The method of claim 1377, wherein the polymer is formed from reactants consisting of a synthetic compound containing two or more amino groups. The method of claim 1377, wherein the polymer is formed from reactants consisting of synthetic compounds containing three or more amino groups. The method of claim 1377, wherein the polymer is formed from reactants consisting of a synthetic compound containing 4 or more amino groups. The method of claim 1377, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of claim 1377, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The method of claim 1377, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. The method of claim 1377, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more carbonyl-oxygen-succinimidyl groups. The method of claim 1377, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide. The method of claim 1377, wherein the polymer is formed from a reactant comprising a synthetic compound comprising both a polyalkylene oxide and a biodegradable polyester block. The method of claim 1377, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The method of claim 1377, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide having a thiol reactive group. The method of claim 1377, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The method of claim 1377, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a biodegradable polyester block. The method of claim 1377, wherein the polymer is formed from reactants comprising a synthetic polymer, wholly or partly comprised of lactic acid or lactide. The method of claim 1377, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or in part, consisting of glycolic acid or glycolide. The method of claim 1377, wherein the polymer is formed from a reactant comprising polylysine. The method of claim 1377, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 1377, wherein the polymer is formed from a reactant comprising (a) a protein and (b) polylysine. The method of claim 1377, wherein the polymer is formed from (a) a reactant and (b) a reactant comprising a compound having four or more thiol groups. The method of claim 1377, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more amino groups. The method of claim 1377, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method of 1377. The method of claim 1377, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 1377, wherein the polymer is formed from reactants comprising (a) collagen and (b) polylysine. The method of claim 1377, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more thiol groups. The method of claim 1377, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more amino groups. The method of claim 1377, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method of 1377. The method of claim 1377, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 1377, wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) polylysine. The method of claim 1377, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more thiol groups. The method of claim 1377, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more amino groups. The method of claim 1377, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone, The method of claim 1377. The method of claim 1377, wherein the polymer is formed from a reactant comprising hyaluronic acid. The method of claim 1377, wherein the polymer is formed from a reactant comprising a hyaluronic acid derivative. The method of claim 1377, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The method of claim 1377, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A polymer having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene region. The method of claim 1377, wherein the method is formed from a reactant comprising a synthetic compound comprising a plurality of electrophilic groups. The method of claim 1377, wherein the composition comprises a colorant. The method of claim 1377, wherein the composition is sterile. Methods of implanting a medical device comprising: (a) a medical device to which the medical device is implanted or transplanted host tissue i) an inhibitor of fiber formation ii) an anti-infective agent iii) a polymer iv) an inhibitor of fiber formation and a polymer V) a composition comprising an anti-infective agent and a polymer or vi) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer, and (b) implanting a medical device into a host, and said medical treatment The device is an ear ventilation tube. A method of implanting a device with the medical device of claim 1634 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a fibrosis inhibitor; and (b) the host Implant a medical device. A method of implanting a device with the medical device of claim 1634 comprising: (a) the medical device is implanted or the transplanted host tissue is immersed in an anti-infective agent; and (b) the host is implanted. Implant medical devices. A method of implanting a device with the medical device of claim 1634 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a polymer; and (b) the medical device is in the host. Transplant. A method of implanting a device with the medical device of claim 1634 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising a fibrosis inhibitor and a polymer; And (b) transplant the medical device into the host. A method of implanting a device with the medical device of claim 1634 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) Transplant the medical device into the host. The method of implanting a device comprising the following with the medical device of claim 1634: (a) a composition comprising a fibrosis inhibitor, an anti-infective agent, and a polymer in which the medical device is implanted or the transplanted host tissue And (b) implant the medical device into the host. The method of claim 1634 wherein the medical device is a grommet shaped tube. The method of claim 1634 wherein the medical device is a T-shaped tube. The method of claim 1634 wherein the medical device is a middle ear cavity ventilation tube. The method of claim 1634, wherein the medical device is a drain tube. The method of claim 1634 wherein the medical device is a tympanic tube. The method of claim 1634 wherein the medical device is an otolaryngological tube. The method of claim 1634 wherein the medical device is a tympanic tube. The method of claim 1634, wherein the medical device is an ear canal. The method of claim 1634 wherein the medical device is an artificial eustachian tube. The method of claim 1634 wherein the medical device is an ear canal stent. The method of claim 1634, wherein cell regeneration is inhibited by a fiber formation inhibitor. The method of claim 1634 wherein angiogenesis is inhibited by the fiber formation inhibitor. The method of claim 1634, wherein fibroblast migration is inhibited by a fibrosis inhibitor. The method of claim 1634, wherein fibroblast proliferation is inhibited by a fibrosis inhibitor. The method of claim 1634, wherein the fiber formation inhibitor inhibits extracellular matrix accumulation. The method of claim 1634, wherein the tissue remodeling is inhibited by the fiber formation inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is an angiogenesis inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is a 5- lipoxygenase inhibitor or antagonist. The method of claim 1634 wherein the fiber formation inhibitor is a chemokine receptor antagonist. The method of claim 1634 wherein the fiber formation inhibitor is a cell cycle inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is a taxane. The method of claim 1634 wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is paclitaxel. The method of claim 1634 wherein the fiber formation inhibitor is not paclitaxel. The method of claim 1634 wherein the fiber formation inhibitor is an analogue or derivative of paclitaxel. The method of claim 1634 wherein the fiber formation inhibitor is a vinca alkaloid. The method of claim 1634 wherein the fibrosis inhibitor is camptothecin or an analogue or derivative thereof. The method of claim 1634 wherein the fiber formation inhibitor is podophyllotoxin. The method of claim 1634 wherein the fibrosis inhibitor is podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof. The method of claim 1634 wherein the fiber formation inhibitor is an anthracycline. The method of claim 1634, wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof. The method of claim 1634 wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof. The method of claim 1634 wherein the fiber formation inhibitor is a platinum compound. The method of claim 1634 wherein the fiber formation inhibitor is nitrosourea. The method of claim 1634 wherein the fiber formation inhibitor is nitroimidazole. The method of claim 1634 wherein the fiber formation inhibitor is a folic acid antagonist. The method of claim 1634 wherein the fibrosis inhibitor is a cytidine analog. The method of claim 1634 wherein the fiber formation inhibitor is a pyrimidine analogue. The method of claim 1634 wherein the fiber formation inhibitor is a fluoropyrimidine analogue. The method of claim 1634 wherein the fiber formation inhibitor is a purine analogue. The method of claim 1634 wherein the fiber formation inhibitor is a nitrogen mustard or an analogue or derivative thereof. The method of claim 1634 wherein the fiber formation inhibitor is hydroxyurea. The method of claim 1634 wherein the fiber formation inhibitor is mitomycin or an analogue or derivative thereof. The method of claim 1634 wherein the fiber formation inhibitor is an alkyl sulfonate. The method of claim 1634 wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The method of claim 1634 wherein the fiber formation inhibitor is nicotinamide or an analogue or derivative thereof. The method of claim 1634 wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of claim 1634 wherein the fiber formation inhibitor is a DNA alkylating agent. The method of claim 1634 wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is a DNA cleaving agent. The method of claim 1634 wherein the fiber formation inhibitor is an antimetabolite. The method of claim 1634 wherein adenosine deaminase is inhibited by a fiber formation inhibitor. The method of claim 1634, wherein purine ring synthesis is inhibited by a fiber formation inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of claim 1634 wherein the fibrosis inhibitor inhibits dihydrofolate reduction. The method of claim 1634 wherein thymidine monophosphate is inhibited by the fiber formation inhibitor. The method of claim 1634, wherein DNA damage is caused by a fiber formation inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is a DNA intercalation agent. The method of claim 1634, wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The method of claim 1634, wherein fibril formation inhibitor inhibits ribonucleotide synthesis or function. The method of claim 1634 wherein the fibrosis inhibitor inhibits thymidine monophosphate synthesis or function. The method of claim 1634, wherein DNA synthesis is inhibited by the fiber formation inhibitor. The method of claim 1634 wherein DNA adduct formation occurs with the fiber formation inhibitor. The method of claim 1634, wherein protein synthesis is inhibited by the fiber formation inhibitor. The method of claim 1634, wherein the microtubule function is inhibited by the fiber formation inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is a cyclin dependent protein kinase inhibitor. The method of claim 1634 wherein the fibrosis inhibitor is an epidermal growth factor kinase inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is an elastase inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of claim 1634 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 1634 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 1634 wherein the fiber formation inhibitor is a heat shock protein 90 antagonist. The method of claim 1634 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist, and the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof. The method of claim 1634 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 1634 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof. The method of claim 1634 wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of claim 1634 wherein the fibrosis inhibitor is an IL-1 antagonist. The method of claim 1634 wherein the fiber formation inhibitor is an ICE antagonist. The method of claim 1634 wherein the fiber formation inhibitor is an IRAK antagonist. The method of claim 1634 wherein the fibrosis inhibitor is an IL-4 agonist. The method of claim 1634 wherein the fiber formation inhibitor is an immunomodulator. The method of claim 1634 wherein the fibrosis inhibitor is sirolimus or an analogue or derivative thereof. The method of claim 1634 wherein the fiber formation inhibitor is not sirolimus. The method of claim 1634 wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. The method of claim 1634 wherein the fibrosis inhibitor is tacrolimus or an analogue or derivative thereof. The method of claim 1634 wherein the fiber formation inhibitor is not tacrolimus. The method of claim 1634 wherein the fibrosis inhibitor is biolimus or an analogue or derivative thereof. The method of claim 1634 wherein the fibrosis inhibitor is tresperimus or an analogue or derivative thereof. The method of claim 1634 wherein the fiber formation inhibitor is auranofin or an analogue or derivative thereof. The method of claim 1634 wherein the fibrosis inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of claim 1634 wherein the fibrosis inhibitor is gusperimus or an analogue or derivative thereof. The method of claim 1634 wherein the fibrosis inhibitor is pimecrolimus or an analogue or derivative thereof. The method of claim 1634 wherein the fiber formation inhibitor is ABT-578 or an analogue or derivative thereof. The method of claim 1634 wherein the fiber formation inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof. A fiber-forming inhibitor is IMPDH inhibitors, the IMPDH inhibitor is 1-alpha-25-dihydroxyvitamin D ₃ or its analogues or derivatives, method of claim 1634. The method of claim 1634 wherein the fiber formation inhibitor is a leukotriene inhibitor. The method of claim 1634 wherein the vascularization inhibitor is an MCP-1 antagonist. The method of claim 1634 wherein the fiber formation inhibitor is an MMP inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is an NFκB inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is an NFκB inhibitor, wherein the NFκB inhibitor is Bay11-7082. The method of claim 1634 wherein the fiber formation inhibitor is a NO antagonist. The method of claim 1634 wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB202190. The method of claim 1634 wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is a TGF beta inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is a thromboxane A2 antagonist. The method of claim 1634 wherein the vascularization inhibitor is a TNFα antagonist. The method of claim 1634 wherein the fiber formation inhibitor is a TACE inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is a vitronectin inhibitor. The method of claim 1634 wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is a protein kinase inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is a PDGF receptor kinase inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is a retinoic acid receptor antagonist. The method of claim 1634 wherein the fiber formation inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of claim 1634 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 1634 wherein the fiber formation inhibitor is an antifungal agent. The method of claim 1634 wherein the fiber formation inhibitor is an antifungal agent, and the antifungal agent is sulconizole. The method of claim 1634 wherein the fiber formation inhibitor is a bisphosphonate. The method of claim 1634 wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. The method of claim 1634 wherein the fibrosis inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The method of claim 1634, wherein the fiber formation inhibitor is a macrolide antibiotic. The method of claim 1634 wherein the fiber formation inhibitor is a GPIIb / IIIa receptor antagonist. The method of claim 1634 wherein the fiber formation inhibitor is an endothelin receptor antagonist. The method of claim 1634 wherein the fibrosis inhibitor is an agonist of the peroxisome proliferator-activated receptor. The method of claim 1634 wherein the fibrosis inhibitor is an estrogen receptor agent. The method of claim 1634 wherein the fibrosis inhibitor is a somostatin analog. The method of claim 1634 wherein the fiber formation inhibitor is a neurokinin 1 antagonist. The method of claim 1634 wherein the fiber formation inhibitor is a neurokinin 3 antagonist. The method of claim 1634 wherein the fibrosis inhibitor is a VLA-4 antagonist. The method of claim 1634 wherein the fiber formation inhibitor is an osteoclast inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is an angiotensin II antagonist. The method of claim 1634 wherein the fiber formation inhibitor is an enkephalinase inhibitor. The method of claim 1634 wherein the fibrosis inhibitor is a peroxisome proliferator-responsive receptor gamma agonist insulin sensitizer. The method of claim 1634 wherein the fiber formation inhibitor is a protein kinase C inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is a CXCR3 inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is an Itk inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of claim 1634 wherein the fibrosis inhibitor is a PPAR agonist. The method of claim 1634 wherein the fiber formation inhibitor is an immunosuppressant. The method of claim 1634 wherein the fiber formation inhibitor is an Erb inhibitor. The method of claim 1634 wherein the fibrosis inhibitor is an apoptosis agonist. The method of claim 1634 wherein the fibrosis inhibitor is a lipocortin agonist. The method of claim 1634 wherein the fiber formation inhibitor is a VCAM-1 antagonist. The method of claim 1634 wherein the fiber formation inhibitor is a collagen antagonist. The method of claim 1634 wherein the fiber formation inhibitor is an α2 integrin antagonist. The method of claim 1634 wherein the fiber formation inhibitor is a TNFα inhibitor. The method of claim 1634 wherein the fiber formation inhibitor is a nitric oxide inhibitor The method of claim 1634 wherein the fiber formation inhibitor is a cathepsin inhibitor. The method of claim 1634 wherein the fibrosis inhibitor is not an anti-inflammatory agent. The method of claim 1634 wherein the fibrosis inhibitor is not a steroid. The method of claim 1634 wherein the fiber formation inhibitor is not a glucocorticosteroid. The method of claim 1634 wherein the fiber formation inhibitor is not dexamethasone. The method of claim 1634 wherein the fiber formation inhibitor is not beclomethasone. The method of claim 1634 wherein the fiber formation inhibitor is not dipropionic acid. The method of claim 1634 wherein the fiber formation inhibitor is not an anti-infective. The method of claim 1634 wherein the fibrosis inhibitor is not an antibiotic. The method of claim 1634 wherein the fiber formation inhibitor is not an antifungal agent. The method of claim 1634 wherein the anti-infective is an anthracycline. The method of claim 1634 wherein the anti-infective is doxorubicin. The method of claim 1634 wherein the anti-infective agent is mitoxantrone. The method of claim 1634 wherein the anti-infective agent is fluoropyrimidine. The method of claim 1634 wherein the anti-infective is 5-fluorouracil (5-FU). The method of claim 1634 wherein the anti-infective agent is a folic acid antagonist. The method of claim 1634 wherein the anti-infective agent is methotrexate. The method of claim 1634 wherein the anti-infective is podophyllotoxin. The method of claim 1634 wherein the anti-infective is etoposide. The method of claim 1634 wherein the anti-infective agent is camptothecin. The method of claim 1634 wherein the anti-infective is hydroxyurea. The method of claim 1634 wherein the anti-infective is a platinum complex. The method of claim 1634 wherein the anti-infective is cisplatin. The method of claim 1634, wherein the composition comprises an antithrombotic agent. The method of claim 1634, wherein the polymer is formed from a reactant comprising a naturally occurring polymer. The method of claim 1634, wherein the polymer is formed from a reactant comprising protein. The method of claim 1634, wherein the polymer is formed from a reactant comprising carbohydrate. The method of claim 1634, wherein the polymer is formed from a reactant comprising a biodegradable polymer. The method of claim 1634, wherein the polymer is formed from a reactant comprising a non-biodegradable polymer. The method of claim 1634, wherein the polymer is formed from a reactant comprising collagen. The method of claim 1634 wherein the polymer is formed from a reactant comprising methylated collagen. The method of claim 1634, wherein the polymer is formed from a reactant comprising fibrinogen. The method of claim 1634, wherein the polymer is formed from a reactant comprising thrombin. The method of claim 1634 wherein the polymer is formed from a reactant comprising a plasma component. The method of claim 1634, wherein the polymer is formed from a reactant comprising a calcium salt. The method of claim 1634, wherein the polymer is formed from a reactant comprising a fiber formation inhibitor. The method of claim 1634 wherein the polymer is formed from a reactant comprising a fibrinogen analog. The method of claim 1634, wherein the polymer is formed from a reactant comprising albumin. The method of claim 1634 wherein the polymer is formed from a reactant comprising plasminogen. The method of claim 1634 wherein the polymer is formed from a reactant comprising von Willebrand factor. The method of claim 1634 wherein the polymer is formed from a reactant comprising Factor VIII. The method of claim 1634 wherein the polymer is formed from a reactant comprising hypoallergenic collagen. The method of claim 1634 wherein the polymer is formed from a reactant comprising atelopeptide collagen. The method of claim 1634 wherein the polymer is formed from a reactant comprising telopeptide collagen. The method of claim 1634 wherein the polymer is formed from a reactant comprising cross-linked collagen. The method of claim 1634 wherein the polymer is formed from a reactant comprising aprotinin. The method of claim 1634 wherein the polymer is formed from a reactant comprising epsilon amino-n-caproic acid. The method of claim 1634, wherein the polymer is formed from a reactant comprising gelatin. The method of claim 1634 wherein the polymer is formed from a reactant comprising a protein conjugate. The method of claim 1634 wherein the polymer is formed from a reactant comprising a gelatin conjugate. The method of claim 1634, wherein the polymer is formed from a reactant comprising a synthetic polymer. The method of claim 1634 wherein the polymer is formed from a reactant comprising a compound comprising synthetic isocyanate. The method of claim 1634 wherein the polymer is formed from a reactant comprising a compound comprising a synthetic thiol. The method of claim 1634, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more thiol groups. The method of claim 1634 wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more thiol groups. The method of claim 1634, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more thiol groups. The method of claim 1634 wherein the polymer is formed from a reactant comprising a compound comprising synthetic amino. The method of claim 1634, wherein the polymer is formed from reactants consisting of a synthetic compound containing two or more amino groups. The method of claim 1634 wherein the polymer is formed from a reactant comprised of a synthetic compound containing 3 or more amino groups. The method of claim 1634 wherein the polymer is formed from a reactant comprised of a synthetic compound containing 4 or more amino groups. The method of claim 1634 wherein the polymer is formed from a reactant comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of claim 1634 wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The method of claim 1634 wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. The method of claim 1634 wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more carbonyl-oxygen-succinimidyl groups. The method of claim 1634 wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide. The method of claim 1634 wherein the polymer is formed from a reactant comprising a synthetic compound comprising both a polyalkylene oxide and a biodegradable polyester block. The method of claim 1634 wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The method of claim 1634 wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide having a thiol reactive group. The method of claim 1634 wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The method of claim 1634 wherein the polymer is formed from a reactant comprising a synthetic compound comprising a biodegradable polyester block. The method of claim 1634, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly comprised of lactic acid or lactide. The method of claim 1634 wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly consisting of glycolic acid or glycolide. The method of claim 1634, wherein the polymer is formed from a reactant comprising polylysine. The method of claim 1634 wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 1634 wherein the polymer is formed from a reactant comprising (a) a protein and (b) polylysine. The method of claim 1634, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more thiol groups. The method of claim 1634, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more amino groups. The method of claim 1634 wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method of 1634. The method of claim 1634 wherein the polymer is formed from a reactant consisting of (a) collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 1634 wherein the polymer is formed from a reactant comprising (a) collagen and (b) polylysine. The method of claim 1634, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more thiol groups. The method of claim 1634 wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more amino groups. The method of claim 1634, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method of 1634. The method of claim 1634 wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 1634, wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) polylysine. The method of claim 1634 wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more thiol groups. The method of claim 1634 wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more amino groups. The method of claim 1634 wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone, The method of claim 1634. The method of claim 1634 wherein the polymer is formed from a reactant comprising hyaluronic acid. The method of claim 1634 wherein the polymer is formed from a reactant comprising a hyaluronic acid derivative. The method of claim 1634 wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The method of claim 1634 wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A polymer having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene region. The method of claim 1634, formed from a reactant comprising a synthetic compound comprising: and a plurality of electrophilic groups. The method of claim 1634, wherein the composition comprises a colorant. The method of claim 1634 wherein the composition is sterile. Methods of implanting a medical device comprising: (a) a medical device to which the medical device is implanted or transplanted host tissue i) an inhibitor of fiber formation ii) an anti-infective agent iii) a polymer iv) an inhibitor of fiber formation and a polymer V) a composition comprising an anti-infective agent and a polymer or vi) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer, and (b) implanting a medical device into a host, and said medical treatment The device is an intraocular implant. A method of implanting a device with the medical device of claim 1897 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a fibrosis inhibitor; and (b) the host Implant a medical device. A method of implanting a device with the medical device of claim 1897 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in an anti-infective agent; and (b) the host is implanted. Implant medical devices. 18. A method of implanting a device with the medical device of claim 1897 comprising: (a) the medical device is implanted, or the transplanted host tissue is immersed in a polymer; and (b) the medical device is in the host. Transplant. 18. A method of implanting a device with the medical device of claim 1897 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising a fibrosis inhibitor and a polymer; And (b) transplant the medical device into the host. 18. A method of implanting a device with the medical device of claim 1897 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) Transplant the medical device into the host. 18. A method of implanting a device comprising the medical device of claim 1897 comprising: (a) a composition comprising a fibrosis inhibitor, an anti-infective agent, and a polymer in which the medical device is implanted or the implanted host tissue. And (b) implant the medical device into the host. The method of claim 1897, wherein the medical device comprises an intraocular lens to prevent lens opacification. The method of claim 1897, wherein the medical device comprises a polymethyl methacrylate intraocular lens. The method of claim 1897, wherein the medical device comprises a silicone intraocular lens. The method of claim 1897, wherein the medical device comprises an achromatic lens. The method of claim 1897 wherein the medical device is pseudophakic. The method of claim 1897, wherein the medical device comprises a phakic lens. The method of claim 1897, wherein the medical device comprises an aphakic lens. The method of claim 1897, wherein the medical device comprises a multifocal intraocular lens. The method of claim 1897, wherein the medical device comprises hydrophilic and hydrophobic acrylic intraocular lenses. The method of claim 1897 wherein the medical device is an intraocular implant. The method of claim 1897, wherein the medical device comprises an optical lens. The method of claim 1897, wherein the medical device comprises a gas permeable hard lens. The method of claim 1897, wherein the medical device comprises a foldable intraocular lens. The method of claim 1897, wherein the medical device comprises a rigid lens. The method of claim 1897, wherein the medical device comprises an implant for correcting vision impairment. The method of claim 1897, wherein the medical device is comprised of an intraocular implant adapted for use in conjunction with corneal transplantation. The method of claim 1897, wherein the medical device comprises an intraocular implant adapted for use in conjunction with treatment of secondary cataract after excision of an extracapsular cataract. The method of claim 1897 wherein cell regeneration is inhibited by a fiber formation inhibitor. The method of claim 1897 wherein angiogenesis is inhibited by a fiber formation inhibitor. The method of claim 1897, wherein fibroblast migration is inhibited by a fibrosis inhibitor. The method of claim 1897 wherein the fibrosis inhibitor inhibits fibroblast proliferation. The method of claim 1897, wherein the fiber formation inhibitor inhibits extracellular matrix accumulation. The method of claim 1897 wherein the tissue remodeling is inhibited by the fiber formation inhibitor. The method of claim 1897, wherein the fiber formation inhibitor is an angiogenesis inhibitor. The method of claim 1897 wherein the fiber formation inhibitor is a 5-lipoxygenase inhibitor or antagonist. The method of claim 1897 wherein the fibrosis inhibitor is a chemokine receptor antagonist. The method of claim 1897, wherein the fiber formation inhibitor is a cell cycle inhibitor. The method of claim 1897, wherein the fiber formation inhibitor is a taxane. The method of claim 1897, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 1897, wherein the fiber formation inhibitor is paclitaxel. The method of claim 1897, wherein the fiber formation inhibitor is not paclitaxel. The method of claim 1897 wherein the fibrosis inhibitor is an analogue or derivative of paclitaxel. The method of claim 1897, wherein the fiber formation inhibitor is a vinca alkaloid. The method of claim 1897 wherein the fibrosis inhibitor is camptothecin or an analogue or derivative thereof. The method of claim 1897 wherein the fibrosis inhibitor is podophyllotoxin. The method of claim 1897, wherein the fiber formation inhibitor is podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof. The method of claim 1897, wherein the fiber formation inhibitor is an anthracycline. The method of claim 1897, wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof. The method of claim 1897, wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof. The method of claim 1897, wherein the fiber formation inhibitor is a platinum compound. The method of claim 1897, wherein the fiber formation inhibitor is nitrosourea. The method of claim 1897, wherein the fiber formation inhibitor is nitroimidazole. The method of claim 1897 wherein the fiber formation inhibitor is a folic acid antagonist. The method of claim 1897 wherein the fibrosis inhibitor is a cytidine analog. The method of claim 1897 wherein the fibrosis inhibitor is a pyrimidine analogue. The method of claim 1897 wherein the fiber formation inhibitor is a fluoropyrimidine analogue. The method of claim 1897 wherein the fibrosis inhibitor is a purine analogue. The method of claim 1897, wherein the fiber formation inhibitor is nitrogen mustard or an analogue or derivative thereof. The method of claim 1897, wherein the fiber formation inhibitor is hydroxyurea. The method of claim 1897 wherein the fibrosis inhibitor is mitomycin or an analogue or derivative thereof. The method of claim 1897, wherein the fiber formation inhibitor is an alkyl sulfonate. The method of claim 1897 wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The method of claim 1897 wherein the fiber formation inhibitor is nicotinamide or an analogue or derivative thereof. The method of claim 1897 wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of claim 1897, wherein the fiber formation inhibitor is a DNA alkylating agent. The method of claim 1897, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 1897, wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of claim 1897, wherein the fiber formation inhibitor is a DNA cleaving agent. The method of claim 1897, wherein the fiber formation inhibitor is an antimetabolite. The method of claim 1897, wherein adenosine deaminase is inhibited by a fiber formation inhibitor. The method of claim 1897, wherein purine ring synthesis is inhibited by a fiber formation inhibitor. The method of claim 1897, wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of claim 1897, wherein the fiber formation inhibitor inhibits dihydrofolate reduction. The method of claim 1897 wherein thymidine monophosphate is inhibited by the fiber formation inhibitor. The method of claim 1897, wherein DNA damage is caused by a fiber formation inhibitor. The method of claim 1897, wherein the fiber formation inhibitor is a DNA intercalation agent. The method of claim 1897, wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The method of claim 1897, wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The method of claim 1897, wherein ribonucleotide synthesis or function is inhibited by the fiber formation inhibitor. The method of claim 1897 wherein the fibrosis inhibitor inhibits thymidine monophosphate synthesis or function. The method of claim 1897, wherein DNA synthesis is inhibited by the fiber formation inhibitor. The method of claim 1897, wherein DNA formation is caused by the fiber formation inhibitor. The method of claim 1897, wherein protein synthesis is inhibited by the fiber formation inhibitor. The method of claim 1897, wherein microtubule function is inhibited by the fiber formation inhibitor. The method of claim 1897 wherein the fiber formation inhibitor is a cyclin dependent protein kinase inhibitor. The method of claim 1897 wherein the fibrosis inhibitor is an epidermal growth factor kinase inhibitor. The method of claim 1897, wherein the fiber formation inhibitor is an elastase inhibitor. The method of claim 1897 wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of claim 1897 wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of claim 1897 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 1897 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 1897 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist. The method of claim 1897 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist, and the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof. The method of claim 1897 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 1897 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The method of claim 1897, wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof. The method of claim 1897, wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. The method of claim 1897 wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of claim 1897 wherein the fibrosis inhibitor is an IL-1 antagonist. The method of claim 1897 wherein the fibrosis inhibitor is an ICE antagonist. The method of claim 1897 wherein the fiber formation inhibitor is an IRAK antagonist. The method of claim 1897 wherein the fibrosis inhibitor is an IL-4 agonist. The method of claim 1897 wherein the fiber formation inhibitor is an immunomodulator. The method of claim 1897 wherein the fibrosis inhibitor is sirolimus or an analogue or derivative thereof. The method of claim 1897, wherein the fiber formation inhibitor is not sirolimus. The method of claim 1897 wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. The method of claim 1897 wherein the fibrosis inhibitor is tacrolimus or an analogue or derivative thereof. The method of claim 1897, wherein the fiber formation inhibitor is not tacrolimus. The method of claim 1897 wherein the fibrosis inhibitor is biolimus or an analogue or derivative thereof. The method of claim 1897 wherein the fibrosis inhibitor is tresperimus or an analogue or derivative thereof. The method of claim 1897 wherein the fibrosis inhibitor is auranofin or an analogue or derivative thereof. The method of claim 1897 wherein the fibrosis inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of claim 1897 wherein the fibrosis inhibitor is gusperimus or an analogue or derivative thereof. The method of claim 1897 wherein the fibrosis inhibitor is pimecrolimus or an analogue or derivative thereof. The method of claim 1897 wherein the fiber formation inhibitor is ABT-578 or an analogue or derivative thereof. The method of claim 1897, wherein the fiber formation inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. The method of claim 1897, wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof. The method of claim 1897, wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-α-25 dihydroxy vitamin D ₃ or an analogue or derivative thereof. The method of claim 1897, wherein the fiber formation inhibitor is a leukotriene inhibitor. The method of claim 1897 wherein the vascularization inhibitor is an MCP-1 antagonist. The method of claim 1897, wherein the fiber formation inhibitor is an MMP inhibitor. The method of claim 1897, wherein the fiber formation inhibitor is an NFκB inhibitor. The method of claim 1897, wherein the fiber formation inhibitor is an NFκB inhibitor, wherein the NFκB inhibitor is Bay11-7082. The method of claim 1897 wherein the fiber formation inhibitor is a NO antagonist. The method of claim 1897 wherein the fibrosis inhibitor is a p38 MAP kinase inhibitor. The method of claim 1897, wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB202190. The method of claim 1897 wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The method of claim 1897, wherein the fiber formation inhibitor is a TGF beta inhibitor. The method of claim 1897 wherein the fiber formation inhibitor is a thromboxane A2 antagonist. The method of claim 1897 wherein the vascularization inhibitor is a TNFα antagonist. The method of claim 1897, wherein the fiber formation inhibitor is a TACE inhibitor. The method of claim 1897 wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. The method of claim 1897 wherein the fiber formation inhibitor is a vitronectin inhibitor. The method of claim 1897 wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of claim 1897, wherein the fiber formation inhibitor is a protein kinase inhibitor. The method of claim 1897 wherein the fibrosis inhibitor is a PDGF receptor kinase inhibitor. The method of claim 1897 wherein the fibrosis inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of claim 1897 wherein the fibrosis inhibitor is a retinoic acid receptor antagonist. The method of claim 1897 wherein the fiber formation inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of claim 1897 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 1897, wherein the fiber formation inhibitor is an antifungal agent. The method of claim 1897, wherein the fiber formation inhibitor is an antifungal agent, and the antifungal agent is sulconizole. The method of claim 1897, wherein the fiber formation inhibitor is a bisphosphonate. The method of claim 1897 wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. The method of claim 1897 wherein the fibrosis inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The method of claim 1897, wherein the fiber formation inhibitor is a macrolide antibiotic. The method of claim 1897 wherein the fibrosis inhibitor is a GPIIb / IIIa receptor antagonist. The method of claim 1897 wherein the fiber formation inhibitor is an endothelin receptor antagonist. The method of claim 1897 wherein the fibrosis inhibitor is an agonist of peroxisome proliferator-activated receptor. The method of claim 1897 wherein the fibrosis inhibitor is an estrogen receptor agent. The method of claim 1897 wherein the fibrosis inhibitor is a somostatin analog. The method of claim 1897 wherein the fiber formation inhibitor is a neurokinin 1 antagonist. The method of claim 1897 wherein the fiber formation inhibitor is a neurokinin 3 antagonist. The method of claim 1897 wherein the fibrosis inhibitor is a VLA-4 antagonist. The method of claim 1897, wherein the fiber formation inhibitor is an osteoclast inhibitor. The method of claim 1897, wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The method of claim 1897, wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of claim 1897 wherein the fibrosis inhibitor is an angiotensin II antagonist. The method of claim 1897, wherein the fiber formation inhibitor is an enkephalinase inhibitor. The method of claim 1897 wherein the fibrosis inhibitor is a peroxisome proliferator-responsive receptor gamma agonist insulin sensitizer. The method of claim 1897 wherein the fiber formation inhibitor is a protein kinase C inhibitor. The method of claim 1897 wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. The method of claim 1897, wherein the fiber formation inhibitor is a CXCR3 inhibitor. The method of claim 1897, wherein the fiber formation inhibitor is an Itk inhibitor. The method of claim 1897 wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of claim 1897 wherein the fibrosis inhibitor is a PPAR agonist. The method of claim 1897, wherein the fiber formation inhibitor is an immunosuppressant. The method of claim 1897, wherein the fiber formation inhibitor is an Erb inhibitor. The method of claim 1897 wherein the fibrosis inhibitor is an apoptosis agonist. The method of claim 1897 wherein the fibrosis inhibitor is a lipocortin agonist. The method of claim 1897 wherein the fibrosis inhibitor is a VCAM-1 antagonist. The method of claim 1897, wherein the fiber formation inhibitor is a collagen antagonist. The method of claim 1897 wherein the fibrosis inhibitor is an α2 integrin antagonist. The method of claim 1897, wherein the fiber formation inhibitor is a TNFα inhibitor. The method of claim 1897, wherein the fiber formation inhibitor is a nitric oxide inhibitor. The method of claim 1897, wherein the fiber formation inhibitor is a cathepsin inhibitor. The method of claim 1897 wherein the fibrosis inhibitor is not an anti-inflammatory agent. The method of claim 1897 wherein the fibrosis inhibitor is not a steroid. The method of claim 1897 wherein the fiber formation inhibitor is not a glucocorticosteroid. The method of claim 1897, wherein the fiber formation inhibitor is not dexamethasone. The method of claim 1897, wherein the fiber formation inhibitor is not beclomethasone. The method of claim 1897, wherein the fiber formation inhibitor is not dipropionic acid. The method of claim 1897, wherein the fiber formation inhibitor is not an anti-infective agent. The method of claim 1897 wherein the fibrosis inhibitor is not an antibiotic. The method of claim 1897, wherein the fiber formation inhibitor is not an antifungal agent. The method of claim 1897 wherein the anti-infective agent is an anthracycline. The method of claim 1897 wherein the anti-infective agent is doxorubicin. The method of claim 1897 wherein the anti-infective agent is mitoxantrone. The method of claim 1897 wherein the anti-infective agent is fluoropyrimidine. The method of claim 1897 wherein the anti-infective agent is 5-fluorouracil (5-FU). The method of claim 1897 wherein the anti-infective agent is a folic acid antagonist. The method of claim 1897 wherein the anti-infective agent is methotrexate. The method of claim 1897 wherein the anti-infective agent is podophyllotoxin. The method of claim 1897 wherein the anti-infective agent is etoposide. The method of claim 1897 wherein the anti-infective agent is camptothecin. The method of claim 1897 wherein the anti-infective agent is hydroxyurea. The method of claim 1897, wherein the anti-infective is a platinum complex. The method of claim 1897 wherein the anti-infective agent is cisplatin. The method of claim 1897, wherein the composition comprises an antithrombotic agent. The method of claim 1897, wherein the polymer is formed from a reactant comprising a naturally occurring polymer. The method of claim 1897, wherein the polymer is formed from a reactant comprising protein. The method of claim 1897, wherein the polymer is formed from a reactant comprising a carbohydrate. The method of claim 1897, wherein the polymer is formed from a reactant comprising a biodegradable polymer. The method of claim 1897, wherein the polymer is formed from a reactant comprising a non-biodegradable polymer. The method of claim 1897, wherein the polymer is formed from a reactant comprising collagen. The method of claim 1897, wherein the polymer is formed from a reactant comprising methylated collagen. The method of claim 1897, wherein the polymer is formed from a reactant comprising fibrinogen. The method of claim 1897, wherein the polymer is formed from a reactant comprising thrombin. The method of claim 1897, wherein the polymer is formed from a reactant comprising a plasma component. The method of claim 1897, wherein the polymer is formed from a reactant comprising a calcium salt. The method of claim 1897, wherein the polymer is formed from a reactant comprising a fiber formation inhibitor. The method of claim 1897, wherein the polymer is formed from a reactant comprising a fibrinogen analog. The method of claim 1897, wherein the polymer is formed from a reactant comprising albumin. The method of claim 1897, wherein the polymer is formed from a reactant comprising plasminogen. The method of claim 1897, wherein the polymer is formed from a reactant comprising von Willebrand factor. The method of claim 1897, wherein the polymer is formed from a reactant comprising Factor VIII. The method of claim 1897, wherein the polymer is formed from a reactant comprising hypoallergenic collagen. The method of claim 1897, wherein the polymer is formed from a reactant comprising atelopeptide collagen. The method of claim 1897, wherein the polymer is formed from a reactant comprising telopeptide collagen. The method of claim 1897, wherein the polymer is formed from a reactant comprising cross-linked collagen. The method of claim 1897, wherein the polymer is formed from a reactant comprising aprotinin. The method of claim 1897, wherein the polymer is formed from a reactant comprising epsilon amino-n-caproic acid. The method of claim 1897, wherein the polymer is formed from a reactant comprising gelatin. The method of claim 1897, wherein the polymer is formed from a reactant comprising a protein conjugate. The method of claim 1897, wherein the polymer is formed from a reactant comprising a gelatin conjugate. The method of claim 1897, wherein the polymer is formed from a reactant comprising a synthetic polymer. The method of claim 1897, wherein the polymer is formed from a reactant comprising a compound comprising synthetic isocyanate. The method of claim 1897, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic thiol. The method of claim 1897, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more thiol groups. The method of claim 1897, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more thiol groups. The method of claim 1897, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more thiol groups. The method of claim 1897, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic amino. The method of claim 1897, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more amino groups. The method of claim 1897, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more amino groups. The method of claim 1897, wherein the polymer is formed from a reactant comprising a synthetic compound comprising 4 or more amino groups. The method of claim 1897, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of claim 1897, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The method of claim 1897, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. The method of claim 1897, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more carbonyl-oxygen-succinimidyl groups. The method of claim 1897, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide. The method of claim 1897, wherein the polymer is formed from a reactant comprising a synthetic compound comprising both a polyalkylene oxide and a biodegradable polyester block. The method of claim 1897, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The method of claim 1897, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a thiol reactive group. The method of claim 1897, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The method of claim 1897, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a biodegradable polyester block. The method of claim 1897, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly comprised of lactic acid or lactide. The method of claim 1897, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly comprised of glycolic acid or glycolide. The method of claim 1897, wherein the polymer is formed from a reactant comprising polylysine. The method of claim 1897, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 1897, wherein the polymer is formed from a reactant comprising (a) a protein and (b) polylysine. The method of claim 1897, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more thiol groups. The method of claim 1897, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more amino groups. The method of claim 1897, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method of 1897. The method of claim 1897, wherein the polymer is formed from a reactant comprising (a) a collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 1897, wherein the polymer is formed from a reactant comprising (a) collagen and (b) polylysine. The method of claim 1897, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more thiol groups. The method of claim 1897, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more amino groups. The method of claim 1897, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method of 1897. The method of claim 1897, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 1897, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) polylysine. The method of claim 1897, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more thiol groups. The method of claim 1897, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more amino groups. The method of claim 1897, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone, The method of claim 1897. The method of claim 1897, wherein the polymer is formed from a reactant comprising hyaluronic acid. The method of claim 1897, wherein the polymer is formed from a reactant comprising a hyaluronic acid derivative. The method of claim 1897, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The method of claim 1897, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A polymer having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene region. The method of claim 1897, formed from a reactant comprising a synthetic compound comprising a plurality of electrophilic groups. The method of claim 1897, wherein the composition comprises a colorant. The method of claim 1897, wherein the composition is sterile. Methods of implanting a medical device comprising: (a) a medical device to which the medical device is implanted or transplanted host tissue i) an inhibitor of fiber formation ii) an anti-infective agent iii) a polymer iv) an inhibitor of fiber formation and a polymer V) a composition comprising an anti-infective agent and a polymer or vi) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer, and (b) implanting a medical device into a host, and said medical treatment The device is a device for treating hypertrophic scars or keloids. A method of implanting a device with the medical device of claim 2167 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a fibrosis inhibitor; and (b) the host Implant a medical device. A method of implanting a device with the medical device of claim 2167 comprising: (a) the medical device is implanted, or the transplanted host tissue is soaked with an anti-infective agent; and (b) the host is implanted. Implant medical devices. A method of implanting a device with the medical device of claim 2167 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a polymer; and (b) the medical device is in the host. Transplant. A method of implanting a device comprising the medical device of claim 2167 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising a fibrosis inhibitor and a polymer; And (b) transplant the medical device into the host. A method of implanting a device with the medical device of claim 2167 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) Transplant the medical device into the host. A method of implanting a device comprising the following with the medical device of claim 2167: (a) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer in which the medical device is implanted or the host tissue into which it is implanted. And (b) implant the medical device into the host. The method of claim 2167, wherein the medical device is a device for treating hypertrophic scars or keloids comprising an external tissue expansion device. The method of claim 2167, wherein the medical device comprises a masking element, wherein the masking element compresses scar tissue with a device for treating hypertrophic scars or keloids. The method of claim 2167, wherein the medical device is a device for treating hypertrophic scars or keloids and has a structure for grasping with the locking element, allowing the dermal and epidermal layers of the skin wound to be pressed together. . The method of claim 2167, wherein cell regeneration is inhibited by a fiber formation inhibitor. The method of claim 2167, wherein angiogenesis is inhibited by the fiber formation inhibitor. The method of claim 2167, wherein fibroblast migration is inhibited by a fibrosis inhibitor. The method of claim 2167, wherein the fibrosis inhibitor inhibits fibroblast proliferation. The method of claim 2167, wherein the fiber formation inhibitor inhibits extracellular matrix accumulation. The method of claim 2167, wherein the tissue remodeling is inhibited by the fiber formation inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is an angiogenesis inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is a 5- lipoxygenase inhibitor or antagonist. The method of claim 2167 wherein the fibrosis inhibitor is a chemokine receptor antagonist. The method of claim 2167, wherein the fiber formation inhibitor is a cell cycle inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is a taxane. The method of claim 2167, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is paclitaxel. The method of claim 2167, wherein the fiber formation inhibitor is not paclitaxel. The method of claim 2167 wherein the fibrosis inhibitor is an analogue or derivative of paclitaxel. The method of claim 2167, wherein the fiber formation inhibitor is a vinca alkaloid. The method of claim 2167 wherein the fibrosis inhibitor is camptothecin or an analogue or derivative thereof. The method of claim 2167, wherein the fiber formation inhibitor is podophyllotoxin. The method of claim 2167, wherein the fiber formation inhibitor is podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof. The method of claim 2167, wherein the fiber formation inhibitor is an anthracycline. The method of claim 2167, wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof. The method of claim 2167, wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof. The method of claim 2167, wherein the fiber formation inhibitor is a platinum compound. The method of claim 2167, wherein the fiber formation inhibitor is nitrosourea. The method of claim 2167, wherein the fiber formation inhibitor is nitroimidazole. The method of claim 2167, wherein the fiber formation inhibitor is a folic acid antagonist. The method of claim 2167 wherein the fibrosis inhibitor is a cytidine analog. The method of claim 2167 wherein the fibrosis inhibitor is a pyrimidine analogue. The method of claim 2167, wherein the fiber formation inhibitor is a fluoropyrimidine analog. The method of claim 2167, wherein the fiber formation inhibitor is a purine analogue. The method of claim 2167, wherein the fiber formation inhibitor is nitrogen mustard or an analogue or derivative thereof. The method of claim 2167, wherein the fiber formation inhibitor is hydroxyurea. The method of claim 2167 wherein the fibrosis inhibitor is mitomycin or an analogue or derivative thereof. The method of claim 2167, wherein the fiber formation inhibitor is an alkyl sulfonate. The method of claim 2167, wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The method of claim 2167 wherein the fibrosis inhibitor is nicotinamide or an analogue or derivative thereof. The method of claim 2167, wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of claim 2167, wherein the fiber formation inhibitor is a DNA alkylating agent. The method of claim 2167, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is a DNA cleaving agent. The method of claim 2167, wherein the fiber formation inhibitor is an antimetabolite. The method of claim 2167, wherein adenosine deaminase is inhibited by a fiber formation inhibitor. The method of claim 2167, wherein purine ring synthesis is inhibited by a fiber formation inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of claim 2167, wherein the fiber formation inhibitor inhibits dihydrofolate reduction. The method of claim 2167, wherein thymidine monophosphate is inhibited by the fiber formation inhibitor. The method of claim 2167, wherein the fiber formation inhibitor causes DNA damage. The method of claim 2167, wherein the fiber formation inhibitor is a DNA intercalation agent. The method of claim 2167, wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The method of claim 2167, wherein the fiber formation inhibitor inhibits ribonucleotide synthesis or function. The method of claim 2167, wherein the fibrosis inhibitor inhibits thymidine monophosphate synthesis or function. The method of claim 2167, wherein DNA synthesis is inhibited by the fiber formation inhibitor. The method of claim 2167, wherein DNA adduct formation occurs with the fiber formation inhibitor. The method of claim 2167, wherein protein synthesis is inhibited by the fiber formation inhibitor. The method of claim 2167, wherein microtubule function is inhibited by the fiber formation inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is a cyclin dependent protein kinase inhibitor. The method of claim 2167 wherein the fibrosis inhibitor is an epidermal growth factor kinase inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is an elastase inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is a fibrinogen antagonist. The method of claim 2167, wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 2167 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist. The method of claim 2167 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist, and the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof. The method of claim 2167, wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 2167, wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof. The method of claim 2167, wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of claim 2167, wherein the fibrosis inhibitor is an IL-1 antagonist. The method of claim 2167, wherein the fiber formation inhibitor is an ICE antagonist. The method of claim 2167, wherein the fiber formation inhibitor is an IRAK antagonist. The method of claim 2167 wherein the fibrosis inhibitor is an IL-4 agonist. The method of claim 2167, wherein the fiber formation inhibitor is an immunomodulator. The method of claim 2167, wherein the fibrosis inhibitor is sirolimus or an analogue or derivative thereof. The method of claim 2167, wherein the fiber formation inhibitor is not sirolimus. The method of claim 2167, wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. The method of claim 2167, wherein the fibrosis inhibitor is tacrolimus or an analogue or derivative thereof. The method of claim 2167, wherein the fiber formation inhibitor is not tacrolimus. The method of claim 2167 wherein the fibrosis inhibitor is biolimus or an analogue or derivative thereof. The method of claim 2167, wherein the fibrosis inhibitor is tresperimus or an analogue or derivative thereof. The method of claim 2167 wherein the fibrosis inhibitor is auranofin or an analogue or derivative thereof. The method of claim 2167, wherein the fiber formation inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of claim 2167 wherein the fibrosis inhibitor is gusperimus or an analogue or derivative thereof. The method of claim 2167 wherein the fibrosis inhibitor is pimecrolimus or an analogue or derivative thereof. The method of claim 2167 wherein the fibrosis inhibitor is ABT-578 or an analogue or derivative thereof. The method of claim 2167, wherein the fiber formation inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof. A fiber-forming inhibitor is IMPDH inhibitors, the IMPDH inhibitor is 1-alpha-25-dihydroxyvitamin D ₃ or its analogues or derivatives, method of claim 2167. The method of claim 2167, wherein the fiber formation inhibitor is a leukotriene inhibitor. The method of claim 2167, wherein the vascularization inhibitor is an MCP-1 antagonist. The method of claim 2167, wherein the fiber formation inhibitor is an MMP inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is an NFκB inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is an NFκB inhibitor, and the NFκB inhibitor is Bay11-7082. The method of claim 2167, wherein the fiber formation inhibitor is a NO antagonist. The method of claim 2167, wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor, and the p38 MAP kinase inhibitor is SB202190. The method of claim 2167, wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is a TGF beta inhibitor. The method of claim 2167 wherein the fibrosis inhibitor is a thromboxane A2 antagonist. The method of claim 2167, wherein the vascularization inhibitor is a TNFα antagonist. The method of claim 2167, wherein the fiber formation inhibitor is a TACE inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is a vitronectin inhibitor. The method of claim 2167, wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is a protein kinase inhibitor. The method of claim 2167 wherein the fibrosis inhibitor is a PDGF receptor kinase inhibitor. The method of claim 2167 wherein the fibrosis inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is a retinoic acid receptor antagonist. The method of claim 2167, wherein the fiber formation inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is a fibrinogen antagonist. The method of claim 2167, wherein the fiber formation inhibitor is an antifungal agent. The method of claim 2167, wherein the fiber formation inhibitor is an antifungal agent, and the antifungal agent is sulconizole. The method of claim 2167, wherein the fiber formation inhibitor is a bisphosphonate. The method of claim 2167, wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. The method of claim 2167 wherein the fibrosis inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The method of claim 2167, wherein the fiber formation inhibitor is a macrolide antibiotic. The method of claim 2167, wherein the fiber formation inhibitor is a GPIIb / IIIa receptor antagonist. The method of claim 2167, wherein the fiber formation inhibitor is an endothelin receptor antagonist. The method of claim 2167 wherein the fibrosis inhibitor is an agonist of the peroxisome proliferator-activated receptor. The method of claim 2167 wherein the fibrosis inhibitor is an estrogen receptor agent. The method of claim 2167 wherein the fibrosis inhibitor is a somostatin analog. The method of claim 2167, wherein the fiber formation inhibitor is a neurokinin 1 antagonist. The method of claim 2167, wherein the fiber formation inhibitor is a neurokinin 3 antagonist. The method of claim 2167 wherein the fibrosis inhibitor is a VLA-4 antagonist. The method of claim 2167, wherein the fiber formation inhibitor is an osteoclast inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is an angiotensin II antagonist. The method of claim 2167, wherein the fiber formation inhibitor is an enkephalinase inhibitor. The method of claim 2167 wherein the fibrosis inhibitor is a peroxisome proliferator-responsive receptor gamma agonist insulin sensitizer. The method of claim 2167, wherein the fiber formation inhibitor is a protein kinase C inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is a CXCR3 inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is an Itk inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of claim 2167 wherein the fibrosis inhibitor is a PPAR agonist. The method of claim 2167, wherein the fiber formation inhibitor is an immunosuppressant. The method of claim 2167, wherein the fiber formation inhibitor is an Erb inhibitor. The method of claim 2167, wherein the fibrosis inhibitor is an apoptosis agonist. The method of claim 2167 wherein the fibrosis inhibitor is a lipocortin agonist. The method of claim 2167 wherein the fibrosis inhibitor is a VCAM-1 antagonist. The method of claim 2167, wherein the fiber formation inhibitor is a collagen antagonist. The method of claim 2167, wherein the fiber formation inhibitor is an α2 integrin antagonist. The method of claim 2167, wherein the fiber formation inhibitor is a TNFα inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is a nitric oxide inhibitor. The method of claim 2167, wherein the fiber formation inhibitor is a cathepsin inhibitor. The method of claim 2167, wherein the fibrosis inhibitor is not an anti-inflammatory agent. The method of claim 2167, wherein the fibrosis inhibitor is not a steroid. The method of claim 2167 wherein the fibrosis inhibitor is not a glucocorticosteroid. The method of claim 2167 wherein the fibrosis inhibitor is not dexamethasone. The method of claim 2167, wherein the fiber formation inhibitor is not beclomethasone. The method of claim 2167, wherein the fiber formation inhibitor is not dipropionic acid. The method of claim 2167, wherein the fiber formation inhibitor is not an anti-infective. The method of claim 2167, wherein the fibrosis inhibitor is not an antibiotic. The method of claim 2167, wherein the fiber formation inhibitor is not an antifungal agent. The method of claim 2167, wherein the anti-infective is an anthracycline. The method of claim 2167, wherein the anti-infective is doxorubicin. The method of claim 2167, wherein the anti-infective is mitoxantrone. The method of claim 2167, wherein the anti-infective is fluoropyrimidine. The method of claim 2167 wherein the anti-infective is 5-fluorouracil (5-FU). The method of claim 2167, wherein the anti-infective agent is a folic acid antagonist. The method of claim 2167, wherein the anti-infective is methotrexate. The method of claim 2167 wherein the anti-infective is podophyllotoxin. The method of claim 2167, wherein the anti-infective is etoposide. The method of claim 2167, wherein the anti-infective is camptothecin. The method of claim 2167, wherein the anti-infective is hydroxyurea. The method of claim 2167, wherein the anti-infective is a platinum complex. The method of claim 2167, wherein the anti-infective is cisplatin. The method of claim 2167, wherein the composition comprises an antithrombotic agent. The method of claim 2167, wherein the polymer is formed from a reactant comprising a naturally occurring polymer. The method of claim 2167, wherein the polymer is formed from a reactant comprising protein. The method of claim 2167, wherein the polymer is formed from reactants comprising carbohydrate. The method of claim 2167, wherein the polymer is formed from a reactant comprising a biodegradable polymer. The method of claim 2167, wherein the polymer is formed from a reactant comprising a non-biodegradable polymer. The method of claim 2167, wherein the polymer is formed from a reactant comprising collagen. The method of claim 2167, wherein the polymer is formed from a reactant comprising methylated collagen. The method of claim 2167, wherein the polymer is formed from a reactant comprising fibrinogen. The method of claim 2167, wherein the polymer is formed from a reactant comprising thrombin. The method of claim 2167, wherein the polymer is formed from a reactant comprising plasma components. The method of claim 2167, wherein the polymer is formed from a reactant comprising a calcium salt. The method of claim 2167, wherein the polymer is formed from a reactant comprising a fiber formation inhibitor. The method of claim 2167, wherein the polymer is formed from a reactant comprising a fibrinogen analog. The method of claim 2167, wherein the polymer is formed from a reactant comprising albumin. The method of claim 2167, wherein the polymer is formed from a reactant comprising plasminogen. The method of claim 2167, wherein the polymer is formed from a reactant comprising von Willebrand factor. The method of claim 2167, wherein the polymer is formed from a reactant comprising Factor VIII. The method of claim 2167, wherein the polymer is formed from reactants comprising hypoallergenic collagen. The method of claim 2167, wherein the polymer is formed from a reactant comprising atelopeptide collagen. The method of claim 2167, wherein the polymer is formed from a reactant comprising telopeptide collagen. The method of claim 2167, wherein the polymer is formed from a reactant comprising cross-linked collagen. The method of claim 2167, wherein the polymer is formed from a reactant comprising aprotinin. The method of claim 2167, wherein the polymer is formed from a reactant comprising epsilon amino-n-caproic acid. The method of claim 2167, wherein the polymer is formed from a reactant comprising gelatin. The method of claim 2167, wherein the polymer is formed from a reactant comprising a protein conjugate. The method of claim 2167, wherein the polymer is formed from a reactant comprising a gelatin conjugate. The method of claim 2167, wherein the polymer is formed from a reactant comprising a synthetic polymer. The method of claim 2167, wherein the polymer is formed from a reactant comprising a compound comprising synthetic isocyanate. The method of claim 2167, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic thiol. The method of claim 2167, wherein the polymer is formed from reactants consisting of a synthetic compound containing two or more thiol groups. The method of claim 2167, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more thiol groups. The method of claim 2167, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more thiol groups. The method of claim 2167, wherein the polymer is formed from a reactant comprising a compound comprising synthetic amino. The method of claim 2167, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more amino groups. The method of claim 2167, wherein the polymer is formed from reactants comprised of synthetic compounds containing three or more amino groups. The method of claim 2167, wherein the polymer is formed from a reactant comprising a synthetic compound comprising 4 or more amino groups. The method of claim 2167, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of claim 2167, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The method of claim 2167, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. The method of claim 2167, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more carbonyl-oxygen-succinimidyl groups. The method of claim 2167, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide. The method of claim 2167, wherein the polymer is formed from a reactant comprising a synthetic compound comprising both a polyalkylene oxide and a biodegradable polyester block. The method of claim 2167, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The method of claim 2167, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide having a thiol reactive group. The method of claim 2167, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The method of claim 2167, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a biodegradable polyester block. The method of claim 2167, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly comprised of lactic acid or lactide. The method of claim 2167, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly consisting of glycolic acid or glycolide. The method of claim 2167, wherein the polymer is formed from a reactant comprising polylysine. The method of claim 2167, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 2167, wherein the polymer is formed from a reactant comprising (a) a protein and (b) polylysine. The method of claim 2167, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more thiol groups. The method of claim 2167, wherein the polymer is formed from (a) a reactant and (b) a reactant comprising a compound having four or more amino groups. The method of claim 2167, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method of 2167. The method of claim 2167, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 2167, wherein the polymer is formed from reactants comprising (a) collagen and (b) polylysine. The method of claim 2167, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more thiol groups. The method of claim 2167, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more amino groups. The method of claim 2167, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method of 2167. The method of claim 2167, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 2167, wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) polylysine. The method of claim 2167, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more thiol groups. The method of claim 2167, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more amino groups. The method of claim 2167, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone, The method of claim 2167. The method of claim 2167, wherein the polymer is formed from a reactant comprising hyaluronic acid. The method of claim 2167, wherein the polymer is formed from a reactant comprising a hyaluronic acid derivative. The method of claim 2167, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The method of claim 2167, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A polymer having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene region. The method of claim 2167, formed from a reactant comprising a synthetic compound comprising a plurality of electrophilic groups. The method of claim 2167, wherein the composition comprises a colorant. The method of claim 2167, wherein the composition is sterile. Methods of implanting a medical device comprising: (a) a medical device to which the medical device is implanted or transplanted host tissue i) an inhibitor of fiber formation ii) an anti-infective agent iii) a polymer iv) an inhibitor of fiber formation and a polymer V) a composition comprising an anti-infective agent and a polymer or vi) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer, and (b) implanting a medical device into a host, and said medical treatment The device is a vascular graft. 24. A method of implanting a device with the medical device of claim 2423 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a fibrosis inhibitor; and (b) the host. Implant a medical device. 24. A method of implanting a device with the medical device of claim 2423 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in an anti-infective agent; and (b) the host is implanted. Implant medical devices. 24. A method of implanting a device with the medical device of claim 2423 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a polymer; and (b) the medical device is in the host. Transplant. 24. A method of implanting a device with the medical device of claim 2423 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising a fibrosis inhibitor and a polymer; And (b) transplant the medical device into the host. 24. A method of implanting a device with the medical device of claim 2423 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising an anti-infective and a polymer; and (b) Transplant the medical device into the host. 24. A method of implanting a device comprising the following with the medical device of claim 2423: (a) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer in which the medical device is implanted or the host tissue into which the medical device is implanted. And (b) implant the medical device into the host. The method of claim 2423 wherein the medical device is an extra vascular graft. The method of claim 2423, wherein the medical device is an endovascular graft. The method of claim 2423, wherein the medical device is a vascular graft for replacing a blood vessel damaged by an aneurysm. The method of claim 2423, wherein the medical device is a vascular graft for replacing blood vessels damaged by intimal hyperplasia. The method of claim 2423, wherein the medical device is a vascular graft for replacing blood vessels damaged by thrombosis. The method of claim 2423, wherein the medical device is a vascular graft adapted to provide access to a blood vessel. The method of claim 2423, wherein the medical device is a vascular graft adapted to provide an alternative conduit for blood flow through a damaged or affected area of a vein. The method of claim 2423, wherein the medical device is a vascular graft adapted to provide an alternative conduit for blood flow through a damaged or affected area of an artery. The method of claim 2423, wherein the medical device is a synthetic bypass graft. The method of claim 2423 wherein the medical device is a femoral and popliteal synthetic bypass graft. The method of claim 2423 wherein the medical device is an inter-thigh synthetic bypass graft. The method of claim 2423 wherein the medical device is an axillary / femoral composite bypass graft. The method of claim 2423 wherein the medical device is a vein graft. The method of claim 2423, wherein the medical device is a peripheral vein graft. The method of claim 2423 wherein the medical device is a coronary vein graft. The method of claim 2423, wherein the medical device is an internal thoracic artery graft. The method of claim 2423, wherein the medical device is a branched vascular graft. The method of claim 2423, wherein the medical device is an endoluminal graft. The method of claim 2423 wherein the medical device is a prosthetic vascular graft. The method of claim 2423, wherein cell regeneration is inhibited by the fiber formation inhibitor. The method of claim 2423, wherein angiogenesis is inhibited by a fiber formation inhibitor. The method of claim 2423, wherein fibroblast migration is inhibited by a fibrosis inhibitor. The method of claim 2423, wherein the fibrosis inhibitor inhibits fibroblast proliferation. The method of claim 2423, wherein the formation of extracellular matrix is inhibited by the fiber formation inhibitor. The method of claim 2423, wherein the tissue remodeling is inhibited by the fiber formation inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is an angiogenesis inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is a 5- lipoxygenase inhibitor or antagonist. The method of claim 2423, wherein the fiber formation inhibitor is a chemokine receptor antagonist. The method of claim 2423, wherein the fiber formation inhibitor is a cell cycle inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is a taxane. The method of claim 2423, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is paclitaxel. The method of claim 2423, wherein the fiber formation inhibitor is not paclitaxel. The method of claim 2423 wherein the fibrosis inhibitor is an analogue or derivative of paclitaxel. The method of claim 2423, wherein the fiber formation inhibitor is a vinca alkaloid. The method of claim 2423 wherein the fibrosis inhibitor is camptothecin or an analogue or derivative thereof. The method of claim 2423, wherein the fiber formation inhibitor is podophyllotoxin. The method of claim 2423, wherein the fiber formation inhibitor is podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof. The method of claim 2423, wherein the fiber formation inhibitor is an anthracycline. The method of claim 2423, wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof. The method of claim 2423, wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof. The method of claim 2423, wherein the fiber formation inhibitor is a platinum compound. The method of claim 2423, wherein the fiber formation inhibitor is nitrosourea. The method of claim 2423, wherein the fiber formation inhibitor is nitroimidazole. The method of claim 2423, wherein the fiber formation inhibitor is a folic acid antagonist. The method of claim 2423 wherein the fibrosis inhibitor is a cytidine analog. The method of claim 2423 wherein the fibrosis inhibitor is a pyrimidine analogue. The method of claim 2423 wherein the fiber formation inhibitor is a fluoropyrimidine analogue. The method of claim 2423 wherein the fibrosis inhibitor is a purine analogue. The method of claim 2423, wherein the fiber formation inhibitor is nitrogen mustard or an analogue or derivative thereof. The method of claim 2423, wherein the fiber formation inhibitor is hydroxyurea. The method of claim 2423 wherein the fibrosis inhibitor is mitomycin or an analogue or derivative thereof. The method of claim 2423, wherein the fiber formation inhibitor is an alkyl sulfonate. The method of claim 2423, wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The method of claim 2423 wherein the fibrosis inhibitor is nicotinamide or an analogue or derivative thereof. The method of claim 2423 wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of claim 2423, wherein the fiber formation inhibitor is a DNA alkylating agent. The method of claim 2423, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is a DNA cleaving agent. The method of claim 2423, wherein the fiber formation inhibitor is an antimetabolite. The method of claim 2423, wherein adenosine deaminase is inhibited by a fiber formation inhibitor. The method of claim 2423, wherein the purine ring synthesis is inhibited by a fiber formation inhibitor. The method of claim 2423 wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of claim 2423, wherein the fiber formation inhibitor inhibits dihydrofolate reduction. The method of claim 2423, wherein the thymidine monophosphate is inhibited by the fiber formation inhibitor. The method of claim 2423, wherein the fiber formation inhibitor causes DNA damage. The method of claim 2423, wherein the fiber formation inhibitor is a DNA intercalation agent. The method of claim 2423, wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The method of claim 2423, wherein the fibril formation inhibitor inhibits ribonucleotide synthesis or function. The method of claim 2423, wherein the fibrosis inhibitor inhibits thymidine monophosphate synthesis or function. The method of claim 2423, wherein DNA synthesis is inhibited by the fiber formation inhibitor. The method of claim 2423, wherein DNA adduct formation occurs with the fiber formation inhibitor. The method of claim 2423, wherein protein synthesis is inhibited by a fiber formation inhibitor. The method of claim 2423, wherein the microtubule function is inhibited by the fiber formation inhibitor. The method of claim 2423 wherein the fiber formation inhibitor is a cyclin dependent protein kinase inhibitor. The method of claim 2423 wherein the fibrosis inhibitor is an epidermal growth factor kinase inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is an elastase inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is a fibrinogen antagonist. The method of claim 2423, wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 2423 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist. The method of claim 2423 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist, and the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof. The method of claim 2423, wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 2423, wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof. The method of claim 2423, wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is an IL-1 antagonist. The method of claim 2423 wherein the fibrosis inhibitor is an ICE antagonist. The method of claim 2423, wherein the fiber formation inhibitor is an IRAK antagonist. The method of claim 2423 wherein the fibrosis inhibitor is an IL-4 agonist. The method of claim 2423, wherein the fiber formation inhibitor is an immunomodulator. The method of claim 2423 wherein the fibrosis inhibitor is sirolimus or an analogue or derivative thereof. The method of claim 2423, wherein the fiber formation inhibitor is not sirolimus. The method of claim 2423 wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. The method of claim 2423 wherein the fibrosis inhibitor is tacrolimus or an analogue or derivative thereof. The method of claim 2423, wherein the fiber formation inhibitor is not tacrolimus. The method of claim 2423 wherein the fibrosis inhibitor is biolimus or an analogue or derivative thereof. The method of claim 2423 wherein the fibrosis inhibitor is tresperimus or an analogue or derivative thereof. The method of claim 2423 wherein the fibrosis inhibitor is auranofin or an analogue or derivative thereof. The method of claim 2423 wherein the fibrosis inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of claim 2423 wherein the fibrosis inhibitor is gusperimus or an analogue or derivative thereof. The method of claim 2423 wherein the fibrosis inhibitor is pimecrolimus or an analogue or derivative thereof. The method of claim 2423, wherein the fiber formation inhibitor is ABT-578 or an analogue or derivative thereof. The method of claim 2423, wherein the fiber formation inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof. The method of claim 2423, wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-α-25 dihydroxy vitamin D ₃ or an analogue or derivative thereof. The method of claim 2423, wherein the fiber formation inhibitor is a leukotriene inhibitor. The method of claim 2423, wherein the vascularization inhibitor is an MCP-1 antagonist. The method of claim 2423, wherein the fiber formation inhibitor is an MMP inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is an NFκB inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is an NFκB inhibitor, wherein the NFκB inhibitor is Bay11-7082. The method of claim 2423, wherein the fiber formation inhibitor is a NO antagonist. The method of claim 2423, wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB202190. The method of claim 2423, wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is a TGF beta inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is a thromboxane A2 antagonist. The method of claim 2423, wherein the vascularization inhibitor is a TNFα antagonist. The method of claim 2423, wherein the fiber formation inhibitor is a TACE inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is a vitronectin inhibitor. The method of claim 2423, wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is a protein kinase inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is a PDGF receptor kinase inhibitor. The method of claim 2423 wherein the fibrosis inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is a retinoic acid receptor antagonist. The method of claim 2423, wherein the fiber formation inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is a fibrinogen antagonist. The method of claim 2423, wherein the fiber formation inhibitor is an antifungal agent. The method of claim 2423, wherein the fiber formation inhibitor is an antifungal agent, and the antifungal agent is sulconizole. The method of claim 2423, wherein the fiber formation inhibitor is a bisphosphonate. The method of claim 2423, wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. The method of claim 2423 wherein the fibrosis inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The method of claim 2423, wherein the fiber formation inhibitor is a macrolide antibiotic. The method of claim 2423, wherein the fiber formation inhibitor is a GPIIb / IIIa receptor antagonist. The method of claim 2423, wherein the fiber formation inhibitor is an endothelin receptor antagonist. The method of claim 2423 wherein the fibrosis inhibitor is an agonist of the peroxisome proliferator-responsive receptor. The method of claim 2423 wherein the fibrosis inhibitor is an estrogen receptor agent. The method of claim 2423 wherein the fibrosis inhibitor is a somostatin analog. The method of claim 2423, wherein the fiber formation inhibitor is a neurokinin 1 antagonist. The method of claim 2423, wherein the fiber formation inhibitor is a neurokinin 3 antagonist. The method of claim 2423 wherein the fibrosis inhibitor is a VLA-4 antagonist. The method of claim 2423, wherein the fiber formation inhibitor is an osteoclast inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is an angiotensin II antagonist. The method of claim 2423, wherein the fiber formation inhibitor is an enkephalinase inhibitor. The method of claim 2423 wherein the fibrosis inhibitor is a peroxisome proliferator-responsive receptor gamma agonist insulin sensitizer. The method of claim 2423, wherein the fiber formation inhibitor is a protein kinase C inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is a CXCR3 inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is an Itk inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of claim 2423 wherein the fibrosis inhibitor is a PPAR agonist. The method of claim 2423, wherein the fiber formation inhibitor is an immunosuppressant. The method of claim 2423, wherein the fiber formation inhibitor is an Erb inhibitor. The method of claim 2423 wherein the fibrosis inhibitor is an apoptosis agonist. The method of claim 2423 wherein the fibrosis inhibitor is a lipocortin agonist. The method of claim 2423 wherein the fibrosis inhibitor is a VCAM-1 antagonist. The method of claim 2423, wherein the fiber formation inhibitor is a collagen antagonist. The method of claim 2423, wherein the fiber formation inhibitor is an α2 integrin antagonist. The method of claim 2423, wherein the fiber formation inhibitor is a TNFα inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is a nitric oxide inhibitor. The method of claim 2423, wherein the fiber formation inhibitor is a cathepsin inhibitor. The method of claim 2423 wherein the fibrosis inhibitor is not an anti-inflammatory agent. The method of claim 2423, wherein the fiber formation inhibitor is not a steroid. The method of claim 2423, wherein the fiber formation inhibitor is not a glucocorticosteroid. The method of claim 2423 wherein the fibrosis inhibitor is not dexamethasone. The method of claim 2423, wherein the fiber formation inhibitor is not beclomethasone. The method of claim 2423, wherein the fiber formation inhibitor is not dipropionic acid. The method of claim 2423, wherein the fiber formation inhibitor is not an anti-infective. The method of claim 2423 wherein the fibrosis inhibitor is not an antibiotic. The method of claim 2423 wherein the fibrosis inhibitor is not an antifungal agent. The method of claim 2423 wherein the anti-infective agent is an anthracycline. The method of claim 2423 wherein the anti-infective agent is doxorubicin. The method of claim 2423, wherein the anti-infective is mitoxantrone. The method of claim 2423 wherein the anti-infective agent is fluoropyrimidine. The method of claim 2423 wherein the anti-infective agent is 5-fluorouracil (5-FU). The method of claim 2423, wherein the anti-infective agent is a folic acid antagonist. The method of claim 2423 wherein the anti-infective agent is methotrexate. The method of claim 2423, wherein the anti-infective is podophyllotoxin. The method of claim 2423 wherein the anti-infective is etoposide. The method of claim 2423, wherein the anti-infective is camptothecin. The method of claim 2423, wherein the anti-infective is hydroxyurea. The method of claim 2423, wherein the anti-infective is a platinum complex. The method of claim 2423 wherein the anti-infective agent is cisplatin. The method of claim 2423, wherein the composition comprises an antithrombotic agent. The method of claim 2423, wherein the polymer is formed from a reactant comprising a naturally occurring polymer. The method of claim 2423, wherein the polymer is formed from a reactant comprising protein. The method of claim 2423, wherein the polymer is formed from a reactant comprising carbohydrate. The method of claim 2423, wherein the polymer is formed from a reactant comprising a biodegradable polymer. The method of claim 2423, wherein the polymer is formed from a reactant comprising a non-biodegradable polymer. The method of claim 2423, wherein the polymer is formed from a reactant comprising collagen. The method of claim 2423, wherein the polymer is formed from a reactant comprising methylated collagen. The method of claim 2423, wherein the polymer is formed from a reactant comprising fibrinogen. The method of claim 2423, wherein the polymer is formed from a reactant comprising thrombin. The method of claim 2423, wherein the polymer is formed from a reactant comprising a plasma component. The method of claim 2423, wherein the polymer is formed from a reactant comprising a calcium salt. The method of claim 2423, wherein the polymer is formed from a reactant comprising a fiber formation inhibitor. The method of claim 2423, wherein the polymer is formed from a reactant comprising a fibrinogen analog. The method of claim 2423, wherein the polymer is formed from a reactant comprising albumin. The method of claim 2423, wherein the polymer is formed from a reactant comprising plasminogen. The method of claim 2423, wherein the polymer is formed from a reactant comprising von Willebrand factor. The method of claim 2423, wherein the polymer is formed from a reactant comprising Factor VIII. The method of claim 2423, wherein the polymer is formed from a reactant comprising hypoallergenic collagen. The method of claim 2423, wherein the polymer is formed from a reactant comprising atelopeptide collagen. The method of claim 2423, wherein the polymer is formed from a reactant comprising telopeptide collagen. The method of claim 2423, wherein the polymer is formed from a reactant comprising cross-linked collagen. The method of claim 2423, wherein the polymer is formed from a reactant comprising aprotinin. The method of claim 2423, wherein the polymer is formed from a reactant comprising epsilon amino-n-caproic acid. The method of claim 2423, wherein the polymer is formed from a reactant comprising gelatin. The method of claim 2423, wherein the polymer is formed from a reactant comprising a protein conjugate. The method of claim 2423, wherein the polymer is formed from a reactant comprising a gelatin conjugate. The method of claim 2423, wherein the polymer is formed from a reactant comprising a synthetic polymer. The method of claim 2423, wherein the polymer is formed from a reactant comprising a compound comprising synthetic isocyanate. The method of claim 2423, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic thiol. The method of claim 2423, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more thiol groups. The method of claim 2423, wherein the polymer is formed from reactants comprising a synthetic compound comprising three or more thiol groups. The method of claim 2423, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more thiol groups. The method of claim 2423, wherein the polymer is formed from a reactant comprising a compound comprising synthetic amino. The method of claim 2423, wherein the polymer is formed from reactants consisting of a synthetic compound containing two or more amino groups. The method of claim 2423, wherein the polymer is formed from reactants comprised of synthetic compounds comprising three or more amino groups. The method of claim 2423, wherein the polymer is formed from reactants comprised of synthetic compounds comprising four or more amino groups. The method of claim 2423, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of claim 2423, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The method of claim 2423, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. The method of claim 2423, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more carbonyl-oxygen-succinimidyl groups. The method of claim 2423, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide. The method of claim 2423, wherein the polymer is formed from a reactant comprising a synthetic compound comprising both a polyalkylene oxide and a biodegradable polyester block. The method of claim 2423, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The method of claim 2423, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide having a thiol reactive group. The method of claim 2423, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The method of claim 2423, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a biodegradable polyester block. The method of claim 2423, wherein the polymer is formed from reactants comprising a synthetic polymer, wholly or partly comprised of lactic acid or lactide. The method of claim 2423, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly comprised of glycolic acid or glycolide. The method of claim 2423, wherein the polymer is formed from a reactant comprising polylysine. The method of claim 2423, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 2423, wherein the polymer is formed from a reactant comprising (a) a protein and (b) polylysine. The method of claim 2423, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more thiol groups. The method of claim 2423, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more amino groups. The method of claim 2423, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method of 2423. The method of claim 2423, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 2423, wherein the polymer is formed from a reactant comprising (a) collagen and (b) polylysine. The method of claim 2423, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more thiol groups. The method of claim 2423, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more amino groups. The method of claim 2423, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method of 2423. The method of claim 2423, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 2423, wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) polylysine. The method of claim 2423, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more thiol groups. The method of claim 2423, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more amino groups. The method of claim 2423, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone, The method of claim 2423. The method of claim 2423, wherein the polymer is formed from a reactant comprising hyaluronic acid. The method of claim 2423, wherein the polymer is formed from a reactant comprising a hyaluronic acid derivative. The method of claim 2423, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The method of claim 2423, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A polymer having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene region. The method of claim 2423, wherein the method is formed from a reactant comprising a synthetic compound comprising a plurality of electrophilic groups. The method of claim 2423, wherein the composition comprises a colorant. The method of claim 2423 wherein the composition is sterile. Methods of implanting a medical device comprising: (a) a medical device to which the medical device is implanted or transplanted host tissue i) an inhibitor of fiber formation ii) an anti-infective agent iii) a polymer iv) an inhibitor of fiber formation and a polymer V) a composition comprising an anti-infective agent and a polymer or vi) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer, and (b) implanting a medical device into a host, and said medical treatment The device is a hemodialysis access device. A method of implanting a device with the medical device of claim 2695 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a fibrosis inhibitor; and (b) the host Implant a medical device. The method of implanting a device with the medical device of claim 2695 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in an anti-infective agent; and (b) the host is implanted. Implant medical devices. The method of implanting a device with the medical device of claim 2695 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a polymer; and (b) the medical device is in the host. Transplant. A method of implanting a device with the medical device of claim 2695 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising a fibrosis inhibitor and a polymer; And (b) transplant the medical device into the host. A method of implanting a device with the medical device of claim 2695 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) Transplant the medical device into the host. The method of implanting a device comprising the medical device of claim 2695 comprising: (a) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer in which the medical device is implanted or the host tissue into which the device is implanted. And (b) implant the medical device into the host. The method of claim 2695 wherein the medical device is an arteriovenous fistula graft. The method of claim 2695 wherein the medical device is an arteriovenous access graft. The method of claim 2695, wherein the medical device is a venous catheter. The method of claim 2695 wherein the medical device is a vascular graft. The method of claim 2695, wherein the medical device is an implantable port. The method of claim 2695, wherein the medical device is an arteriovenous shunt. The method of claim 2695, wherein cell regeneration is inhibited by a fiber formation inhibitor. The method of claim 2695, wherein angiogenesis is inhibited by a fiber formation inhibitor. The method of claim 2695, wherein fibroblast migration is inhibited by a fibrosis inhibitor. The method of claim 2695, wherein the fibrosis inhibitor inhibits fibroblast proliferation. The method of claim 2695, wherein the fiber formation inhibitor inhibits extracellular matrix accumulation. The method of claim 2695, wherein the tissue remodeling is inhibited by the fiber formation inhibitor. The method of claim 2695, wherein the fiber formation inhibitor is an angiogenesis inhibitor. The method of claim 2695 wherein the fiber formation inhibitor is a 5- lipoxygenase inhibitor or antagonist. The method of claim 2695 wherein the fibrosis inhibitor is a chemokine receptor antagonist. The method of claim 2695, wherein the fiber formation inhibitor is a cell cycle inhibitor. The method of claim 2695, wherein the fiber formation inhibitor is a taxane. The method of claim 2695, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 2695, wherein the fiber formation inhibitor is paclitaxel. The method of claim 2695 wherein the fiber formation inhibitor is not paclitaxel. The method of claim 2695 wherein the fibrosis inhibitor is an analogue or derivative of paclitaxel. The method of claim 2695, wherein the fiber formation inhibitor is a vinca alkaloid. The method of claim 2695 wherein the fibrosis inhibitor is camptothecin or an analogue or derivative thereof. The method of claim 2695, wherein the fiber formation inhibitor is podophyllotoxin. The method of claim 2695 wherein the fibrosis inhibitor is podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof. The method of claim 2695, wherein the fiber formation inhibitor is an anthracycline. The method of claim 2695 wherein the fibrosis inhibitor is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof. The method of claim 2695 wherein the fibrosis inhibitor is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof. The method of claim 2695, wherein the fiber formation inhibitor is a platinum compound. The method of claim 2695, wherein the fiber formation inhibitor is nitrosourea. The method of claim 2695, wherein the fiber formation inhibitor is nitroimidazole. The method of claim 2695, wherein the fiber formation inhibitor is a folic acid antagonist. The method of claim 2695 wherein the fibrosis inhibitor is a cytidine analog. The method of claim 2695 wherein the fibrosis inhibitor is a pyrimidine analogue. The method of claim 2695 wherein the fibrosis inhibitor is a fluoropyrimidine analogue. The method of claim 2695 wherein the fibrosis inhibitor is a purine analogue. The method of claim 2695 wherein the fiber formation inhibitor is nitrogen mustard or an analogue or derivative thereof. The method of claim 2695, wherein the fiber formation inhibitor is hydroxyurea. The method of claim 2695 wherein the fibrosis inhibitor is mitomycin or an analogue or derivative thereof. The method of claim 2695 wherein the fiber formation inhibitor is an alkyl sulfonate. The method of claim 2695 wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The method of claim 2695 wherein the fibrosis inhibitor is nicotinamide or an analogue or derivative thereof. The method of claim 2695 wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of claim 2695, wherein the fiber formation inhibitor is a DNA alkylating agent. The method of claim 2695, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 2695, wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of claim 2695, wherein the fiber formation inhibitor is a DNA cleaving agent. The method of claim 2695 wherein the fibrosis inhibitor is an antimetabolite. The method of claim 2695, wherein adenosine deaminase is inhibited by a fiber formation inhibitor. The method of claim 2695, wherein a purine ring synthesis is inhibited by a fiber formation inhibitor. The method of claim 2695 wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of claim 2695, wherein the fiber formation inhibitor inhibits dihydrofolate reduction. The method of claim 2695 wherein thymidine monophosphate is inhibited by the fiber formation inhibitor. The method of claim 2695, wherein DNA damage is caused by a fiber formation inhibitor. The method of claim 2695, wherein the fiber formation inhibitor is a DNA intercalation agent. The method of claim 2695, wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The method of claim 2695, wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The method of claim 2695, wherein ribonucleotide synthesis or function is inhibited by a fiber formation inhibitor. The method of claim 2695, wherein the fiber formation inhibitor inhibits thymidine monophosphate synthesis or function. The method of claim 2695, wherein DNA synthesis is inhibited by the fiber formation inhibitor. The method of claim 2695, wherein DNA formation is caused by the fiber formation inhibitor. The method of claim 2695, wherein protein synthesis is inhibited by the fiber formation inhibitor. The method of claim 2695, wherein the microtubule function is inhibited by the fiber formation inhibitor. The method of claim 2695 wherein the fiber formation inhibitor is a cyclin dependent protein kinase inhibitor. The method of claim 2695 wherein the fibrosis inhibitor is an epidermal growth factor kinase inhibitor. The method of claim 2695, wherein the fiber formation inhibitor is an elastase inhibitor. The method of claim 2695 wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of claim 2695, wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of claim 2695 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 2695 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 2695 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist. The method of claim 2695 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist, and the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof. The method of claim 2695 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 2695, wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The method of claim 2695, wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof. The method of claim 2695 wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. The method of claim 2695 wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of claim 2695 wherein the fibrosis inhibitor is an IL-1 antagonist. The method of claim 2695 wherein the fibrosis inhibitor is an ICE antagonist. The method of claim 2695, wherein the fiber formation inhibitor is an IRAK antagonist. The method of claim 2695 wherein the fibrosis inhibitor is an IL-4 agonist. The method of claim 2695 wherein the fibrosis inhibitor is an immunomodulator. The method of claim 2695 wherein the fibrosis inhibitor is sirolimus or an analogue or derivative thereof. The method of claim 2695, wherein the fiber formation inhibitor is not sirolimus. The method of claim 2695 wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. The method of claim 2695 wherein the fibrosis inhibitor is tacrolimus or an analogue or derivative thereof. The method of claim 2695, wherein the fiber formation inhibitor is not tacrolimus. The method of claim 2695 wherein the fibrosis inhibitor is biolimus or an analogue or derivative thereof. The method of claim 2695 wherein the fibrosis inhibitor is tresperimus or an analogue or derivative thereof. The method of claim 2695 wherein the fibrosis inhibitor is auranofin or an analogue or derivative thereof. The method of claim 2695 wherein the fibrosis inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of claim 2695 wherein the fibrosis inhibitor is gusperimus or an analogue or derivative thereof. The method of claim 2695 wherein the fibrosis inhibitor is pimecrolimus or an analogue or derivative thereof. The method of claim 2695 wherein the fibrosis inhibitor is ABT-578 or an analogue or derivative thereof. The method of claim 2695 wherein the fiber formation inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. The method of claim 2695, wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof. The method of claim 2695 wherein the fibrosis inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-α-25 dihydroxy vitamin D ₃ or an analogue or derivative thereof. The method of claim 2695, wherein the fiber formation inhibitor is a leukotriene inhibitor. The method of claim 2695 wherein the vascularization inhibitor is an MCP-1 antagonist. The method of claim 2695, wherein the fiber formation inhibitor is an MMP inhibitor. The method of claim 2695, wherein the fiber formation inhibitor is an NFκB inhibitor. The method of claim 2695, wherein the fiber formation inhibitor is an NFκB inhibitor, wherein the NFκB inhibitor is Bay11-7082. The method of claim 2695 wherein the fibrosis inhibitor is a NO antagonist. The method of claim 2695 wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor. The method of claim 2695, wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB202190. The method of claim 2695 wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The method of claim 2695, wherein the fiber formation inhibitor is a TGF beta inhibitor. The method of claim 2695 wherein the fibrosis inhibitor is a thromboxane A2 antagonist. The method of claim 2695 wherein the vascularization inhibitor is a TNFα antagonist. The method of claim 2695, wherein the fiber formation inhibitor is a TACE inhibitor. The method of claim 2695 wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. The method of claim 2695, wherein the fiber formation inhibitor is a vitronectin inhibitor. The method of claim 2695, wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of claim 2695 wherein the fiber formation inhibitor is a protein kinase inhibitor. The method of claim 2695 wherein the fibrosis inhibitor is a PDGF receptor kinase inhibitor. The method of claim 2695 wherein the fibrosis inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of claim 2695, wherein the fiber formation inhibitor is a retinoic acid receptor antagonist. The method of claim 2695 wherein the fibrosis inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of claim 2695 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 2695, wherein the fiber formation inhibitor is an antifungal agent. The method of claim 2695, wherein the fiber formation inhibitor is an antifungal agent, wherein the antifungal agent is sulconizole. The method of claim 2695 wherein the fiber formation inhibitor is a bisphosphonate. The method of claim 2695, wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. The method of claim 2695 wherein the fibrosis inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The method of claim 2695, wherein the fiber formation inhibitor is a macrolide antibiotic. The method of claim 2695 wherein the fibrosis inhibitor is a GPIIb / IIIa receptor antagonist. The method of claim 2695 wherein the fibrosis inhibitor is an endothelin receptor antagonist. The method of claim 2695 wherein the fibrosis inhibitor is an agonist of the peroxisome proliferator-responsive receptor. The method of claim 2695 wherein the fibrosis inhibitor is an estrogen receptor agent. The method of claim 2695 wherein the fibrosis inhibitor is a somostatin analog. The method of claim 2695 wherein the fibrosis inhibitor is a neurokinin 1 antagonist. The method of claim 2695 wherein the fibrosis inhibitor is a neurokinin 3 antagonist. The method of claim 2695 wherein the fibrosis inhibitor is a VLA-4 antagonist. The method of claim 2695, wherein the fiber formation inhibitor is an osteoclast inhibitor. The method of claim 2695 wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The method of claim 2695 wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of claim 2695 wherein the fibrosis inhibitor is an angiotensin II antagonist. The method of claim 2695, wherein the fiber formation inhibitor is an enkephalinase inhibitor. The method of claim 2695 wherein the fibrosis inhibitor is a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer. The method of claim 2695 wherein the fiber formation inhibitor is a protein kinase C inhibitor. The method of claim 2695 wherein the fibrosis inhibitor is a ROCK (Rho kinase) inhibitor. The method of claim 2695, wherein the fiber formation inhibitor is a CXCR3 inhibitor. The method of claim 2695, wherein the fiber formation inhibitor is an Itk inhibitor. The method of claim 2695, wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of claim 2695 wherein the fibrosis inhibitor is a PPAR agonist. The method of claim 2695, wherein the fiber formation inhibitor is an immunosuppressant. The method of claim 2695, wherein the fiber formation inhibitor is an Erb inhibitor. The method of claim 2695 wherein the fibrosis inhibitor is an apoptosis agonist. The method of claim 2695 wherein the fibrosis inhibitor is a lipocortin agonist. The method of claim 2695 wherein the fibrosis inhibitor is a VCAM-1 antagonist. The method of claim 2695, wherein the fiber formation inhibitor is a collagen antagonist. The method of claim 2695 wherein the fibrosis inhibitor is an α2 integrin antagonist. The method of claim 2695, wherein the fiber formation inhibitor is a TNFα inhibitor. The method of claim 2695, wherein the fiber formation inhibitor is a nitric oxide inhibitor. The method of claim 2695, wherein the fiber formation inhibitor is a cathepsin inhibitor. The method of claim 2695 wherein the fibrosis inhibitor is not an anti-inflammatory agent. The method of claim 2695 wherein the fibrosis inhibitor is not a steroid. The method of claim 2695 wherein the fibrosis inhibitor is not a glucocorticosteroid. The method of claim 2695 wherein the fibrosis inhibitor is not dexamethasone. The method of claim 2695 wherein the fibrosis inhibitor is not beclomethasone. The method of claim 2695, wherein the fiber formation inhibitor is not dipropionic acid. The method of claim 2695 wherein the fibrosis inhibitor is not an anti-infective. The method of claim 2695 wherein the fibrosis inhibitor is not an antibiotic. The method of claim 2695 wherein the fibrosis inhibitor is not an antifungal agent. The method of claim 2695 wherein the anti-infective is an anthracycline. The method of claim 2695 wherein the anti-infective is doxorubicin. The method of claim 2695 wherein the anti-infective is mitoxantrone. The method of claim 2695 wherein the anti-infective is fluoropyrimidine. The method of claim 2695 wherein the anti-infective is 5-fluorouracil (5-FU). The method of claim 2695 wherein the anti-infective agent is a folic acid antagonist. The method of claim 2695 wherein the anti-infective is methotrexate. The method of claim 2695 wherein the anti-infective is podophyllotoxin. The method of claim 2695 wherein the anti-infective is etoposide. The method of claim 2695 wherein the anti-infective is camptothecin. The method of claim 2695 wherein the anti-infective is hydroxyurea. The method of claim 2695, wherein the anti-infective is a platinum complex. The method of claim 2695, wherein the anti-infective is cisplatin. The method of claim 2695, wherein the composition comprises an antithrombotic agent. The method of claim 2695, wherein the polymer is formed from a reactant comprising a naturally occurring polymer. The method of claim 2695, wherein the polymer is formed from a reactant comprising protein. The method of claim 2695, wherein the polymer is formed from a reactant comprising carbohydrate. The method of claim 2695, wherein the polymer is formed from a reactant comprising a biodegradable polymer. The method of claim 2695, wherein the polymer is formed from a reactant comprising a non-biodegradable polymer. The method of claim 2695, wherein the polymer is formed from a reactant comprising collagen. The method of claim 2695, wherein the polymer is formed from a reactant comprising methylated collagen. The method of claim 2695, wherein the polymer is formed from a reactant comprising fibrinogen. The method of claim 2695, wherein the polymer is formed from a reactant comprising thrombin. The method of claim 2695, wherein the polymer is formed from a reactant comprising a plasma component. The method of claim 2695, wherein the polymer is formed from a reactant comprising a calcium salt. The method of claim 2695, wherein the polymer is formed from a reactant comprising a fiber formation inhibitor. The method of claim 2695, wherein the polymer is formed from a reactant comprising a fibrinogen analog. The method of claim 2695, wherein the polymer is formed from a reactant comprising albumin. The method of claim 2695, wherein the polymer is formed from a reactant comprising plasminogen. The method of claim 2695, wherein the polymer is formed from a reactant comprising von Willebrand factor. The method of claim 2695, wherein the polymer is formed from a reactant comprising Factor VIII. The method of claim 2695, wherein the polymer is formed from a reactant comprising hypoallergenic collagen. The method of claim 2695, wherein the polymer is formed from a reactant comprising atelopeptide collagen. The method of claim 2695, wherein the polymer is formed from a reactant comprising telopeptide collagen. The method of claim 2695, wherein the polymer is formed from a reactant comprising cross-linked collagen. The method of claim 2695, wherein the polymer is formed from a reactant comprising aprotinin. The method of claim 2695, wherein the polymer is formed from a reactant comprising epsilon amino-n-caproic acid. The method of claim 2695, wherein the polymer is formed from a reactant comprising gelatin. The method of claim 2695, wherein the polymer is formed from a reactant comprising a protein conjugate. The method of claim 2695, wherein the polymer is formed from a reactant comprising a gelatin conjugate. The method of claim 2695, wherein the polymer is formed from a reactant comprising a synthetic polymer. The method of claim 2695, wherein the polymer is formed from a reactant comprising a compound comprising synthetic isocyanate. The method of claim 2695, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic thiol. The method of claim 2695, wherein the polymer is formed from a reactant comprised of a synthetic compound comprising two or more thiol groups. The method of claim 2695, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more thiol groups. The method of claim 2695, wherein the polymer is formed from reactants comprised of synthetic compounds comprising four or more thiol groups. The method of claim 2695, wherein the polymer is formed from a reactant comprising a compound comprising synthetic amino. The method of claim 2695, wherein the polymer is formed from reactants consisting of a synthetic compound containing two or more amino groups. The method of claim 2695, wherein the polymer is formed from reactants comprised of synthetic compounds comprising three or more amino groups. The method of claim 2695, wherein the polymer is formed from reactants consisting of synthetic compounds containing four or more amino groups. The method of claim 2695, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of claim 2695, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The method of claim 2695, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. The method of claim 2695, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more carbonyl-oxygen-succinimidyl groups. The method of claim 2695, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide. The method of claim 2695, wherein the polymer is formed from a reactant comprising a synthetic compound comprising both a polyalkylene oxide and a biodegradable polyester block. The method of claim 2695, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The method of claim 2695, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide having a thiol reactive group. The method of claim 2695, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The method of claim 2695, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a biodegradable polyester block. The method of claim 2695, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or in part, consisting of lactic acid or lactide. The method of claim 2695, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or in part, consisting of glycolic acid or glycolide. The method of claim 2695, wherein the polymer is formed from a reactant comprising polylysine. The method of claim 2695, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 2695, wherein the polymer is formed from a reactant comprising (a) a protein and (b) polylysine. The method of claim 2695, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more thiol groups. The method of claim 2695, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more amino groups. The method of claim 2695, wherein the polymer is formed from a reactant comprising: (a) a protein; and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method of 2695. The method of claim 2695, wherein the polymer is formed from a reactant comprising (a) a collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 2695, wherein the polymer is formed from a reactant comprising (a) collagen and (b) polylysine. The method of claim 2695, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more thiol groups. The method of claim 2695, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more amino groups. The method of claim 2695, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method of 2695. The method of claim 2695, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 2695, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) polylysine. The method of claim 2695, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more thiol groups. The method of claim 2695, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more amino groups. The method of claim 2695, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone, The method of claim 2695. The method of claim 2695, wherein the polymer is formed from a reactant comprising hyaluronic acid. The method of claim 2695, wherein the polymer is formed from a reactant comprising a hyaluronic acid derivative. The method of claim 2695, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The method of claim 2695, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A polymer having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene region. The method of claim 2695, formed from a reactant comprising a synthetic compound comprising: and a plurality of electrophilic groups. The method of claim 2695, wherein the composition comprises a colorant. The method of claim 2695, wherein the composition is sterile. Methods of implanting a medical device comprising: (a) a medical device to which the medical device is implanted or transplanted host tissue i) an inhibitor of fiber formation ii) an anti-infective agent iii) a polymer iv) an inhibitor of fiber formation and a polymer V) a composition comprising an anti-infective agent and a polymer or vi) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer, and (b) implanting a medical device into a host and the medical device The device consists of a film or mesh. The method of implanting a device with the medical device of claim 2954, comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a fibrosis inhibitor; and (b) the host Implant a medical device. A method of implanting a device with the medical device of claim 2954 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in an anti-infective agent; and (b) the host is implanted. Implant medical devices. The method of implanting a device with the medical device of claim 2954, comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a polymer; and (b) the medical device is implanted in the host. Transplant. A method of implanting a device with the medical device of claim 2954 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising a fibrosis inhibitor and a polymer; And (b) transplant the medical device into the host. A method of implanting a device with the medical device of claim 2954 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) Transplant the medical device into the host. The method of implanting a device comprising the following: 29) a medical device according to claim 2954: (a) a composition comprising a fibrosis inhibitor, an anti-infective agent, and a polymer in which the medical device is implanted or the transplanted host tissue; And (b) implant the medical device into the host. The method of claim 2954, wherein the medical device is a surgical barrier. The method of claim 2954, wherein the medical device is a surgical adhesion barrier. The method of claim 2954, wherein the medical device is a surgical sheet. The method of claim 2954, wherein the medical device is a surgical patch. The method of claim 2954, wherein the medical device is a surgical wrap. The method of claim 2954, wherein the medical device is a vascular wrap. The method of claim 2954, wherein the medical device is a peri-room wrap. The method of claim 2954, wherein the medical device is an outer membrane wrap. The method of claim 2954, wherein the medical device is a pericardial wrap. The method of claim 2954, wherein the medical device is an outer membrane sheet. The method of claim 2954, wherein the medical device is a peri-room mesh. The method of claim 2954, wherein the medical device is a bandage. The method of claim 2954, wherein the medical device is a liquid bandage. The method of claim 2954, wherein the medical device is a surgical dressing. The method of claim 2954, wherein the medical device is gauze. The method of claim 2954, wherein the medical device is fiber. The method of claim 2954, wherein the medical device is a tape. The method of claim 2954, wherein the medical device is a surgical membrane. The method of claim 2954, wherein the medical device is a polymer matrix. The method of claim 2954, wherein the medical device covers tissue. The method of claim 2954, wherein the medical device is a surgical substrate. The method of claim 2954, wherein the medical device is an envelope. The method of claim 2954, wherein the medical device covers tissue. The method of claim 2954, wherein cell regeneration is inhibited by a fiber formation inhibitor. The method of claim 2954, wherein angiogenesis is inhibited by a fiber formation inhibitor. The method of claim 2954, wherein fibroblast migration is inhibited by a fibrosis inhibitor. The method of claim 2954, wherein the fibrosis inhibitor inhibits fibroblast proliferation. The method of claim 2954, wherein accumulation of extracellular matrix is inhibited by a fiber formation inhibitor. The method of claim 2954, wherein the tissue remodeling is inhibited by the fiber formation inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is an angiogenesis inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is a 5- lipoxygenase inhibitor or antagonist. The method of claim 2954, wherein the fiber formation inhibitor is a chemokine receptor antagonist. The method of claim 2954, wherein the fiber formation inhibitor is a cell cycle inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is a taxane. The method of claim 2954, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is paclitaxel. The method of claim 2954, wherein the fiber formation inhibitor is not paclitaxel. The method of claim 2954, wherein the fiber formation inhibitor is an analogue or derivative of paclitaxel. The method of claim 2954, wherein the fiber formation inhibitor is a vinca alkaloid. The method of claim 2954, wherein the fiber formation inhibitor is camptothecin or an analogue or derivative thereof. The method of claim 2954, wherein the fiber formation inhibitor is podophyllotoxin. The method of claim 2954, wherein the fiber formation inhibitor is podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof. The method of claim 2954, wherein the fiber formation inhibitor is an anthracycline. The method of claim 2954, wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof. The method of claim 2954, wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof. The method of claim 2954, wherein the fiber formation inhibitor is a platinum compound. The method of claim 2954, wherein the fiber formation inhibitor is nitrosourea. The method of claim 2954, wherein the fiber formation inhibitor is nitroimidazole. The method of claim 2954, wherein the fiber formation inhibitor is a folic acid antagonist. The method of claim 2954, wherein the fiber formation inhibitor is a cytidine analogue. The method of claim 2954, wherein the fiber formation inhibitor is a pyrimidine analogue. The method of claim 2954, wherein the fiber formation inhibitor is a fluoropyrimidine analogue. The method of claim 2954, wherein the fiber formation inhibitor is a purine analogue. The method of claim 2954, wherein the fiber formation inhibitor is nitrogen mustard or an analogue or derivative thereof. The method of claim 2954, wherein the fiber formation inhibitor is hydroxyurea. The method of claim 2954, wherein the fiber formation inhibitor is mitomycin or an analogue or derivative thereof. The method of claim 2954, wherein the fiber formation inhibitor is an alkyl sulfonate. The method of claim 2954, wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The method of claim 2954, wherein the fiber formation inhibitor is nicotinamide or an analogue or derivative thereof. The method of claim 2954, wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of claim 2954, wherein the fiber formation inhibitor is a DNA alkylating agent. The method of claim 2954, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is a DNA cleaving agent. The method of claim 2954, wherein the fiber formation inhibitor is an antimetabolite. The method of claim 2954, wherein adenosine deaminase is inhibited by a fiber formation inhibitor. The method of claim 2954, wherein the purine ring synthesis is inhibited by a fiber formation inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of claim 2954, wherein the fiber formation inhibitor inhibits dihydrofolate reduction. The method of claim 2954, wherein thymidine monophosphate is inhibited by a fiber formation inhibitor. The method of claim 2954, wherein DNA damage is caused by a fiber formation inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is a DNA intercalation agent. The method of claim 2954, wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The method of claim 2954, wherein the fiber formation inhibitor inhibits ribonucleotide synthesis or function. The method of claim 2954, wherein the fiber formation inhibitor inhibits thymidine monophosphate synthesis or function. The method of claim 2954, wherein DNA synthesis is inhibited by a fiber formation inhibitor. The method of claim 2954, wherein DNA adduct formation occurs with the fiber formation inhibitor. The method of claim 2954, wherein protein synthesis is inhibited by a fiber formation inhibitor. The method of claim 2954, wherein the microtubule function is inhibited by the fiber formation inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is a cyclin dependent protein kinase inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is an epidermal growth factor kinase inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is an elastase inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is a fibrinogen antagonist. The method of claim 2954, wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 2954, wherein the fiber formation inhibitor is a heat shock protein 90 antagonist. The method of claim 2954, wherein the fiber formation inhibitor is a heat shock protein 90 antagonist, and the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof. The method of claim 2954, wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 2954, wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor, and the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof. The method of claim 2954, wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is an IL-1 antagonist. The method of claim 2954, wherein the fiber formation inhibitor is an ICE antagonist. The method of claim 2954, wherein the fiber formation inhibitor is an IRAK antagonist. The method of claim 2954, wherein the fibrosis inhibitor is an IL-4 agonist. The method of claim 2954, wherein the fiber formation inhibitor is an immunomodulator. The method of claim 2954, wherein the fiber formation inhibitor is sirolimus or an analogue or derivative thereof. The method of claim 2954, wherein the fiber formation inhibitor is not sirolimus. The method of claim 2954, wherein the fiber formation inhibitor is everolimus or an analogue or derivative thereof. The method of claim 2954, wherein the fiber formation inhibitor is tacrolimus or an analogue or derivative thereof. The method of claim 2954, wherein the fiber formation inhibitor is not tacrolimus. The method of claim 2954, wherein the fiber formation inhibitor is biolimus or an analogue or derivative thereof. The method of claim 2954, wherein the fiber formation inhibitor is tresperimus or an analogue or derivative thereof. The method of claim 2954, wherein the fiber formation inhibitor is auranofin or an analogue or derivative thereof. The method of claim 2954, wherein the fiber formation inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of claim 2954, wherein the fiber formation inhibitor is gusperimus or an analogue or derivative thereof. The method of claim 2954, wherein the fiber formation inhibitor is pimecrolimus or an analogue or derivative thereof. The method of claim 2954, wherein the fiber formation inhibitor is ABT-578 or an analogue or derivative thereof. The method of claim 2954, wherein the fiber formation inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof. The method of claim 2954, wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-α-25 dihydroxy vitamin D ₃ or an analogue or derivative thereof. The method of claim 2954, wherein the fiber formation inhibitor is a leukotriene inhibitor. The method of claim 2954, wherein the vascularization inhibitor is an MCP-1 antagonist. The method of claim 2954, wherein the fiber formation inhibitor is an MMP inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is an NFκB inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is an NFκB inhibitor, and the NFκB inhibitor is Bay11-7082. The method of claim 2954, wherein the fiber formation inhibitor is a NO antagonist. The method of claim 2954, wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor, and the p38 MAP kinase inhibitor is SB202190. The method of claim 2954, wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is a TGF beta inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is a thromboxane A2 antagonist. The method of claim 2954, wherein the vascularization inhibitor is a TNFα antagonist. The method of claim 2954, wherein the fiber formation inhibitor is a TACE inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is a vitronectin inhibitor. The method of claim 2954, wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is a protein kinase inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is a PDGF receptor kinase inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is a retinoic acid receptor antagonist. The method of claim 2954, wherein the fiber formation inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is a fibrinogen antagonist. The method of claim 2954, wherein the fiber formation inhibitor is an antifungal agent. The method of claim 2954, wherein the fiber formation inhibitor is an antifungal agent, and the antifungal agent is sulconizole. The method of claim 2954, wherein the fiber formation inhibitor is a bisphosphonate. The method of claim 2954, wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The method of claim 2954, wherein the fiber formation inhibitor is a macrolide antibiotic. The method of claim 2954, wherein the fiber formation inhibitor is a GPIIb / IIIa receptor antagonist. The method of claim 2954, wherein the fiber formation inhibitor is an endothelin receptor antagonist. The method of claim 2954 wherein the fibrosis inhibitor is an agonist of peroxisome proliferator-activated receptor. The method of claim 2954, wherein the fibrosis inhibitor is an estrogen receptor agent. The method of claim 2954, wherein the fiber formation inhibitor is a somostatin analog. The method of claim 2954, wherein the fiber formation inhibitor is a neurokinin 1 antagonist. The method of claim 2954, wherein the fiber formation inhibitor is a neurokinin 3 antagonist. The method of claim 2954 wherein the fibrosis inhibitor is a VLA-4 antagonist. The method of claim 2954, wherein the fiber formation inhibitor is an osteoclast inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is an angiotensin II antagonist. The method of claim 2954, wherein the fiber formation inhibitor is an enkephalinase inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is a peroxisome proliferator-responsive receptor gamma agonist insulin sensitizer. The method of claim 2954, wherein the fiber formation inhibitor is a protein kinase C inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is a CXCR3 inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is an Itk inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of claim 2954, wherein the fibrosis inhibitor is a PPAR agonist. The method of claim 2954, wherein the fiber formation inhibitor is an immunosuppressant. The method of claim 2954, wherein the fiber formation inhibitor is an Erb inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is an apoptosis agonist. The method of claim 2954, wherein the fiber formation inhibitor is a lipocortin agonist. The method of claim 2954, wherein the fiber formation inhibitor is a VCAM-1 antagonist. The method of claim 2954, wherein the fiber formation inhibitor is a collagen antagonist. The method of claim 2954, wherein the fiber formation inhibitor is an α2 integrin antagonist. The method of claim 2954, wherein the fiber formation inhibitor is a TNFα inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is a nitric oxide inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is a cathepsin inhibitor. The method of claim 2954, wherein the fiber formation inhibitor is not an anti-inflammatory agent. The method of claim 2954, wherein the fiber formation inhibitor is not a steroid. The method of claim 2954, wherein the fiber formation inhibitor is not a glucocorticosteroid. The method of claim 2954, wherein the fiber formation inhibitor is not dexamethasone. The method of claim 2954, wherein the fiber formation inhibitor is not beclomethasone. The method of claim 2954, wherein the fiber formation inhibitor is not dipropionic acid. The method of claim 2954, wherein the fiber formation inhibitor is not an anti-infective. The method of claim 2954, wherein the fiber formation inhibitor is not an antibiotic. The method of claim 2954, wherein the fiber formation inhibitor is not an antifungal agent. The method of claim 2954, wherein the anti-infective is an anthracycline. The method of claim 2954, wherein the anti-infective is doxorubicin. The method of claim 2954, wherein the anti-infective is mitoxantrone. The method of claim 2954, wherein the anti-infective agent is fluoropyrimidine. The method of claim 2954, wherein the anti-infective is 5-fluorouracil (5-FU). The method of claim 2954, wherein the anti-infective agent is a folic acid antagonist. The method of claim 2954, wherein the anti-infective is methotrexate. The method of claim 2954, wherein the anti-infective is podophyllotoxin. The method of claim 2954, wherein the anti-infective is etoposide. The method of claim 2954, wherein the anti-infective is camptothecin. The method of claim 2954, wherein the anti-infective is hydroxyurea. The method of claim 2954, wherein the anti-infective is a platinum complex. The method of claim 2954, wherein the anti-infective is cisplatin. The method of claim 2954, wherein the composition comprises an antithrombotic agent. The method of claim 2954, wherein the polymer is formed from a reactant comprising a naturally occurring polymer. The method of claim 2954, wherein the polymer is formed from a reactant comprising protein. The method of claim 2954, wherein the polymer is formed from a reactant comprising carbohydrate. The method of claim 2954, wherein the polymer is formed from a reactant comprising a biodegradable polymer. The method of claim 2954, wherein the polymer is formed from a reactant comprising a non-biodegradable polymer. The method of claim 2954, wherein the polymer is formed from a reactant comprising collagen. The method of claim 2954, wherein the polymer is formed from a reactant comprising methylated collagen. The method of claim 2954, wherein the polymer is formed from a reactant comprising fibrinogen. The method of claim 2954, wherein the polymer is formed from a reactant comprising thrombin. The method of claim 2954, wherein the polymer is formed from a reactant comprising a plasma component. The method of claim 2954, wherein the polymer is formed from a reactant comprising a calcium salt. The method of claim 2954, wherein the polymer is formed from a reactant comprising a fiber formation inhibitor. The method of claim 2954, wherein the polymer is formed from a reactant comprising a fibrinogen analog. The method of claim 2954, wherein the polymer is formed from a reactant comprising albumin. The method of claim 2954, wherein the polymer is formed from a reactant comprising plasminogen. The method of claim 2954, wherein the polymer is formed from a reactant comprising von Willebrand factor. The method of claim 2954, wherein the polymer is formed from a reactant comprising Factor VIII. The method of claim 2954, wherein the polymer is formed from a reactant comprising hypoallergenic collagen. The method of claim 2954, wherein the polymer is formed from a reactant comprising atelopeptide collagen. The method of claim 2954, wherein the polymer is formed from a reactant comprising telopeptide collagen. The method of claim 2954, wherein the polymer is formed from a reactant comprising cross-linked collagen. The method of claim 2954, wherein the polymer is formed from a reactant comprising aprotinin. The method of claim 2954, wherein the polymer is formed from a reactant comprising epsilon amino-n-caproic acid. The method of claim 2954, wherein the polymer is formed from a reactant comprising gelatin. The method of claim 2954, wherein the polymer is formed from a reactant comprising a protein conjugate. The method of claim 2954, wherein the polymer is formed from a reactant comprising a gelatin conjugate. The method of claim 2954, wherein the polymer is formed from a reactant comprising a synthetic polymer. The method of claim 2954, wherein the polymer is formed from a reactant comprising a compound comprising synthetic isocyanate. The method of claim 2954, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic thiol. The method of claim 2954, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more thiol groups. The method of claim 2954, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more thiol groups. The method of claim 2954, wherein the polymer is formed from reactants comprised of synthetic compounds comprising four or more thiol groups. The method of claim 2954, wherein the polymer is formed from a reactant comprising a compound comprising synthetic amino. The method of claim 2954, wherein the polymer is formed from a reactant comprised of a synthetic compound comprising two or more amino groups. The method of claim 2954, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more amino groups. The method of claim 2954, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more amino groups. The method of claim 2954, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of claim 2954, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The method of claim 2954, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. The method of claim 2954, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more carbonyl-oxygen-succinimidyl groups. The method of claim 2954, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide. The method of claim 2954, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a polyalkylene oxide and a biodegradable polyester block. The method of claim 2954, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The method of claim 2954, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide having a thiol reactive group. The method of claim 2954, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The method of claim 2954, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a biodegradable polyester block. The method of claim 2954, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly comprised of lactic acid or lactide. The method of claim 2954, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly comprised of glycolic acid or glycolide. The method of claim 2954, wherein the polymer is formed from a reactant comprising polylysine. The method of claim 2954, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 2954, wherein the polymer is formed from a reactant comprising (a) a protein and (b) polylysine. The method of claim 2954, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more thiol groups. The method of claim 2954, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more amino groups. The method of claim 2954, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method of 2954. The method of claim 2954, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 2954, wherein the polymer is formed from a reactant comprising (a) collagen and (b) polylysine. The method of claim 2954, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more thiol groups. The method of claim 2954, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more amino groups. The method of claim 2954, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method of 2954. The method of claim 2954, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 2954, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) polylysine. The method of claim 2954, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more thiol groups. The method of claim 2954, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more amino groups. The method of claim 2954, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone, The method of claim 2954. The method of claim 2954, wherein the polymer is formed from a reactant comprising hyaluronic acid. The method of claim 2954, wherein the polymer is formed from a reactant comprising a hyaluronic acid derivative. The method of claim 2954, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The method of claim 2954, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A polymer having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene region. The method of claim 2954, wherein the method is formed from a reactant comprising a synthetic compound comprising a plurality of electrophilic groups. The method of claim 2954, wherein the composition comprises a colorant. The method of claim 2954, wherein the composition is sterile. Methods of implanting a medical device comprising: (a) a medical device to which the medical device is implanted or transplanted host tissue i) an inhibitor of fiber formation ii) an anti-infective agent iii) a polymer iv) an inhibitor of fiber formation and a polymer V) a composition comprising an anti-infective agent and a polymer or vi) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer, and (b) implanting a medical device into a host, and said medical treatment The device is a glaucoma drainage device. A method of implanting a device with the medical device of claim 3230 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a fibrosis inhibitor; and (b) the host Implant a medical device. A method of implanting a device with the medical device of claim 3230 comprising: (a) the medical device is implanted, or the transplanted host tissue is immersed in an anti-infective agent; and (b) the host is implanted. Implant medical devices. A method of implanting a device with the medical device of claim 3230 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a polymer; and (b) the medical device is implanted in the host. Transplant. A method of implanting a device with the medical device of claim 3230 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising a fibrosis inhibitor and a polymer; And (b) transplant the medical device into the host. A method of implanting a device with the medical device of claim 3230 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) Transplant the medical device into the host. 34. A method of implanting a device comprising the following with the medical device of claim 3230: (a) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer in which the medical device is implanted or the host tissue into which it is implanted. And (b) implant the medical device into the host. The method of claim 3230, wherein the medical device comprises a glaucoma drainage device including a plate and a tube. The method of claim 3230, wherein cell regeneration is inhibited by a fiber formation inhibitor. The method of claim 3230, wherein angiogenesis is inhibited by a fiber formation inhibitor. The method of claim 3230, wherein fibroblast migration is inhibited by a fibrosis inhibitor. The method of claim 3230, wherein fibroblast proliferation is inhibited by a fibrosis inhibitor. The method of claim 3230, wherein the fiber formation inhibitor inhibits extracellular matrix accumulation. The method of claim 3230, wherein tissue remodeling is inhibited by the fiber formation inhibitor. The method of claim 3230, wherein the fiber formation inhibitor is an angiogenesis inhibitor. The method of claim 3230 wherein the fiber formation inhibitor is a 5- lipoxygenase inhibitor or antagonist. The method of claim 3230 wherein the fibrosis inhibitor is a chemokine receptor antagonist. The method of claim 3230 wherein the fibrosis inhibitor is a cell cycle inhibitor. The method of claim 3230, wherein the fiber formation inhibitor is a taxane. The method of claim 3230 wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 3230, wherein the fiber formation inhibitor is paclitaxel. The method of claim 3230 wherein the fiber formation inhibitor is not paclitaxel. The method of claim 3230 wherein the fibrosis inhibitor is an analogue or derivative of paclitaxel. The method of claim 3230 wherein the fiber formation inhibitor is a vinca alkaloid. The method of claim 3230 wherein the fibrosis inhibitor is camptothecin or an analogue or derivative thereof. The method of claim 3230 wherein the fibrosis inhibitor is podophyllotoxin. The method of claim 3230 wherein the fiber formation inhibitor is podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof. The method of claim 3230 wherein the fibrosis inhibitor is an anthracycline. The method of claim 3230, wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof. The method of claim 3230, wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof. The method of claim 3230, wherein the fiber formation inhibitor is a platinum compound. The method of claim 3230 wherein the fiber formation inhibitor is nitrosourea. The method of claim 3230 wherein the fiber formation inhibitor is nitroimidazole. The method of claim 3230 wherein the fibrosis inhibitor is a folic acid antagonist. The method of claim 3230 wherein the fibrosis inhibitor is a cytidine analog. The method of claim 3230 wherein the fibrosis inhibitor is a pyrimidine analogue. The method of claim 3230 wherein the fiber formation inhibitor is a fluoropyrimidine analog. The method of claim 3230 wherein the fibrosis inhibitor is a purine analogue. The method of claim 3230 wherein the fiber formation inhibitor is a nitrogen mustard or an analogue or derivative thereof. The method of claim 3230 wherein the fiber formation inhibitor is hydroxyurea. The method of claim 3230 wherein the fibrosis inhibitor is mitomycin or an analogue or derivative thereof. The method of claim 3230 wherein the fiber formation inhibitor is an alkyl sulfonate. The method of claim 3230 wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The method of claim 3230 wherein the fibrosis inhibitor is nicotinamide or an analogue or derivative thereof. The method of claim 3230 wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of claim 3230 wherein the fiber formation inhibitor is a DNA alkylating agent. The method of claim 3230 wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 3230 wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of claim 3230 wherein the fiber formation inhibitor is a DNA cleaving agent. The method of claim 3230 wherein the fibrosis inhibitor is an antimetabolite. The method of claim 3230, wherein adenosine deaminase is inhibited by a fiber formation inhibitor. The method of claim 3230, wherein purine ring synthesis is inhibited by the fiber formation inhibitor. The method of claim 3230 wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of claim 3230, wherein the fiber formation inhibitor inhibits dihydrofolate reduction. The method of claim 3230, wherein thymidine monophosphate is inhibited by the fiber formation inhibitor. The method of claim 3230, wherein the fiber formation inhibitor causes DNA damage. The method of claim 3230 wherein the fiber formation inhibitor is a DNA intercalation agent. The method of claim 3230 wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The method of claim 3230 wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The method of claim 3230, wherein the fibril formation inhibitor inhibits ribonucleotide synthesis or function. The method of claim 3230, wherein the fibrosis inhibitor inhibits thymidine monophosphate synthesis or function. The method of claim 3230, wherein DNA synthesis is inhibited by the fiber formation inhibitor. The method of claim 3230, wherein DNA adduct formation occurs with the fiber formation inhibitor. The method of claim 3230, wherein protein synthesis is inhibited by the fiber formation inhibitor. The method of claim 3230, wherein microtubule function is inhibited by the fiber formation inhibitor. The method of claim 3230 wherein the fiber formation inhibitor is a cyclin dependent protein kinase inhibitor. The method of claim 3230 wherein the fibrosis inhibitor is an epidermal growth factor kinase inhibitor. The method of claim 3230 wherein the fiber formation inhibitor is an elastase inhibitor. The method of claim 3230 wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of claim 3230 wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of claim 3230 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 3230 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 3230 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist. The method of claim 3230, wherein the fiber formation inhibitor is a heat shock protein 90 antagonist, wherein the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof. The method of claim 3230 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 3230 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The method of claim 3230 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof. The method of claim 3230 wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. The method of claim 3230 wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of claim 3230 wherein the fibrosis inhibitor is an IL-1 antagonist. The method of claim 3230 wherein the fibrosis inhibitor is an ICE antagonist. The method of claim 3230 wherein the fibrosis inhibitor is an IRAK antagonist. The method of claim 3230 wherein the fibrosis inhibitor is an IL-4 agonist. The method of claim 3230 wherein the fiber formation inhibitor is an immunomodulator. The method of claim 3230 wherein the fibrosis inhibitor is sirolimus or an analogue or derivative thereof. The method of claim 3230 wherein the fibrosis inhibitor is not sirolimus. The method of claim 3230 wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. The method of claim 3230 wherein the fibrosis inhibitor is tacrolimus or an analogue or derivative thereof. The method of claim 3230 wherein the fibrosis inhibitor is not tacrolimus. The method of claim 3230 wherein the fibrosis inhibitor is biolimus or an analogue or derivative thereof. The method of claim 3230 wherein the fibrosis inhibitor is tresperimus or an analogue or derivative thereof. The method of claim 3230 wherein the fibrosis inhibitor is auranofin or an analogue or derivative thereof. The method of claim 3230 wherein the fibrosis inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of claim 3230 wherein the fibrosis inhibitor is gusperimus or an analogue or derivative thereof. The method of claim 3230 wherein the fibrosis inhibitor is pimecrolimus or an analogue or derivative thereof. The method of claim 3230 wherein the fiber formation inhibitor is ABT-578 or an analogue or derivative thereof. The method of claim 3230 wherein the fiber formation inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. The method of claim 3230, wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof. The method of claim 3230, wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-α-25 dihydroxy vitamin D ₃ or an analogue or derivative thereof. The method of claim 3230 wherein the fiber formation inhibitor is a leukotriene inhibitor. The method of claim 3230 wherein the vascularization inhibitor is an MCP-1 antagonist. The method of claim 3230 wherein the fiber formation inhibitor is an MMP inhibitor. The method of claim 3230 wherein the fiber formation inhibitor is an NFκB inhibitor. The method of claim 3230, wherein the fiber formation inhibitor is an NFκB inhibitor, wherein the NFκB inhibitor is Bay11-7082. The method of claim 3230 wherein the fiber formation inhibitor is a NO antagonist. The method of claim 3230 wherein the fibrosis inhibitor is a p38 MAP kinase inhibitor. The method of claim 3230 wherein the fibrosis inhibitor is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB202190. The method of claim 3230 wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The method of claim 3230 wherein the fiber formation inhibitor is a TGF beta inhibitor. The method of claim 3230 wherein the fibrosis inhibitor is a thromboxane A2 antagonist. The method of claim 3230 wherein the fibrosis inhibitor is a TNFα antagonist. The method of claim 3230 wherein the fiber formation inhibitor is a TACE inhibitor. The method of claim 3230 wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. The method of claim 3230 wherein the fiber formation inhibitor is a vitronectin inhibitor. The method of claim 3230 wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of claim 3230 wherein the fiber formation inhibitor is a protein kinase inhibitor. The method of claim 3230 wherein the fibrosis inhibitor is a PDGF receptor kinase inhibitor. The method of claim 3230 wherein the fibrosis inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of claim 3230 wherein the fibrosis inhibitor is a retinoic acid receptor antagonist. The method of claim 3230 wherein the fibrosis inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of claim 3230 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 3230 wherein the fiber formation inhibitor is an antifungal agent. The method of claim 3230, wherein the fiber formation inhibitor is an antifungal agent, wherein the antifungal agent is sulconizole. The method of claim 3230 wherein the fiber formation inhibitor is a bisphosphonate. The method of claim 3230 wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. The method of claim 3230 wherein the fibrosis inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The method of claim 3230, wherein the fiber formation inhibitor is a macrolide antibiotic. The method of claim 3230 wherein the fibrosis inhibitor is a GPIIb / IIIa receptor antagonist. The method of claim 3230 wherein the fibrosis inhibitor is an endothelin receptor antagonist. The method of claim 3230 wherein the fibrosis inhibitor is an agonist of peroxisome proliferator-activated receptor. The method of claim 3230 wherein the fibrosis inhibitor is an estrogen receptor agent. The method of claim 3230 wherein the fibrosis inhibitor is a somaststatin analog. The method of claim 3230 wherein the fibrosis inhibitor is a neurokinin 1 antagonist. The method of claim 3230 wherein the fiber formation inhibitor is a neurokinin 3 antagonist. The method of claim 3230 wherein the fibrosis inhibitor is a VLA-4 antagonist. The method of claim 3230 wherein the fibrosis inhibitor is an osteoclast inhibitor. The method of claim 3230 wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The method of claim 3230 wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of claim 3230 wherein the fibrosis inhibitor is an angiotensin II antagonist. The method of claim 3230 wherein the fiber formation inhibitor is an enkephalinase inhibitor. The method of claim 3230 wherein the fibrosis inhibitor is a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer. The method of claim 3230 wherein the fiber formation inhibitor is a protein kinase C inhibitor. The method of claim 3230 wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. The method of claim 3230 wherein the fiber formation inhibitor is a CXCR3 inhibitor. The method of claim 3230 wherein the fiber formation inhibitor is an Itk inhibitor. The method of claim 3230 wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of claim 3230 wherein the fibrosis inhibitor is a PPAR agonist. The method of claim 3230 wherein the fiber formation inhibitor is an immunosuppressant. The method of claim 3230 wherein the fiber formation inhibitor is an Erb inhibitor. The method of claim 3230 wherein the fibrosis inhibitor is an apoptosis agonist. The method of claim 3230 wherein the fibrosis inhibitor is a lipocortin agonist. The method of claim 3230 wherein the fibrosis inhibitor is a VCAM-1 antagonist. The method of claim 3230, wherein the fiber formation inhibitor is a collagen antagonist. The method of claim 3230 wherein the fiber formation inhibitor is an α2 integrin antagonist. The method of claim 3230, wherein the fiber formation inhibitor is a TNFα inhibitor. The method of claim 3230, wherein the fiber formation inhibitor is a nitric oxide inhibitor. The method of claim 3230, wherein the fiber formation inhibitor is a cathepsin inhibitor. The method of claim 3230 wherein the fibrosis inhibitor is not an anti-inflammatory agent. The method of claim 3230 wherein the fibrosis inhibitor is not a steroid. The method of claim 3230 wherein the fibrosis inhibitor is not a glucocorticosteroid. The method of claim 3230 wherein the fibrosis inhibitor is not dexamethasone. The method of claim 3230 wherein the fibrosis inhibitor is not beclomethasone. The method of claim 3230 wherein the fiber formation inhibitor is not dipropionic acid. The method of claim 3230 wherein the fiber formation inhibitor is not an anti-infective. The method of claim 3230 wherein the fibrosis inhibitor is not an antibiotic. The method of claim 3230 wherein the fibrosis inhibitor is not an antifungal agent. The method of claim 3230 wherein the anti-infective is an anthracycline. The method of claim 3230 wherein the anti-infective agent is doxorubicin. The method of claim 3230 wherein the anti-infective is mitoxantrone. The method of claim 3230 wherein the anti-infective agent is fluoropyrimidine. The method of claim 3230 wherein the anti-infective is 5-fluorouracil (5-FU). The method of claim 3230 wherein the anti-infective agent is a folic acid antagonist. The method of claim 3230 wherein the anti-infective agent is methotrexate. The method of claim 3230 wherein the anti-infective is podophyllotoxin. The method of claim 3230 wherein the anti-infective is etoposide. The method of claim 3230 wherein the anti-infective agent is camptothecin. The method of claim 3230 wherein the anti-infective agent is hydroxyurea. The method of claim 3230 wherein the anti-infective is a platinum complex. The method of claim 3230 wherein the anti-infective is cisplatin. The method of claim 3230, wherein the composition comprises an antithrombotic agent. The method of claim 3230, wherein the polymer is formed from a reactant comprising a naturally occurring polymer. The method of claim 3230, wherein the polymer is formed from a reactant comprising protein. The method of claim 3230, wherein the polymer is formed from a reactant comprising carbohydrate. The method of claim 3230, wherein the polymer is formed from a reactant comprising a biodegradable polymer. The method of claim 3230, wherein the polymer is formed from a reactant comprising a non-biodegradable polymer. The method of claim 3230, wherein the polymer is formed from a reactant comprising collagen. The method of claim 3230, wherein the polymer is formed from a reactant comprising methylated collagen. The method of claim 3230, wherein the polymer is formed from a reactant comprising fibrinogen. The method of claim 3230, wherein the polymer is formed from a reactant comprising thrombin. The method of claim 3230, wherein the polymer is formed from a reactant comprising a plasma component. The method of claim 3230, wherein the polymer is formed from a reactant comprising a calcium salt. The method of claim 3230, wherein the polymer is formed from a reactant comprising a fiber formation inhibitor. The method of claim 3230, wherein the polymer is formed from a reactant comprising a fibrinogen analog. The method of claim 3230, wherein the polymer is formed from a reactant comprising albumin. The method of claim 3230, wherein the polymer is formed from a reactant comprising plasminogen. The method of claim 3230, wherein the polymer is formed from a reactant comprising von Willebrand factor. The method of claim 3230, wherein the polymer is formed from a reactant comprising Factor VIII. The method of claim 3230, wherein the polymer is formed from a reactant comprising hypoallergenic collagen. The method of claim 3230, wherein the polymer is formed from a reactant comprising atelopeptide collagen. The method of claim 3230, wherein the polymer is formed from a reactant comprising telopeptide collagen. The method of claim 3230, wherein the polymer is formed from a reactant comprising cross-linked collagen. The method of claim 3230, wherein the polymer is formed from a reactant comprising aprotinin. The method of claim 3230, wherein the polymer is formed from a reactant comprising epsilon amino-n-caproic acid. The method of claim 3230, wherein the polymer is formed from a reactant comprising gelatin. The method of claim 3230, wherein the polymer is formed from a reactant comprising a protein conjugate. The method of claim 3230, wherein the polymer is formed from a reactant comprising a gelatin conjugate. The method of claim 3230, wherein the polymer is formed from a reactant comprising a synthetic polymer. The method of claim 3230, wherein the polymer is formed from a reactant comprising a compound comprising synthetic isocyanate. The method of claim 3230, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic thiol. The method of claim 3230, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more thiol groups. The method of claim 3230, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more thiol groups. The method of claim 3230, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more thiol groups. The method of claim 3230, wherein the polymer is formed from a reactant comprising a compound comprising synthetic amino. The method of claim 3230, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more amino groups. The method of claim 3230, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more amino groups. The method of claim 3230, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more amino groups. The method of claim 3230, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of claim 3230, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The method of claim 3230, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. The method of claim 3230, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more carbonyl-oxygen-succinimidyl groups. The method of claim 3230, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide. The method of claim 3230, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a polyalkylene oxide and a biodegradable polyester block. The method of claim 3230, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The method of claim 3230, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide having a thiol reactive group. The method of claim 3230, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The method of claim 3230, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a biodegradable polyester block. The method of claim 3230, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly comprised of lactic acid or lactide. The method of claim 3230, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly comprised of glycolic acid or glycolide. The method of claim 3230, wherein the polymer is formed from a reactant comprising polylysine. The method of claim 3230, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 3230, wherein the polymer is formed from a reactant comprising (a) a protein and (b) polylysine. The method of claim 3230, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more thiol groups. The method of claim 3230, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more amino groups. The method of claim 3230, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method according to 3230. The method of claim 3230, wherein the polymer is formed from a reactant comprising (a) a collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 3230, wherein the polymer is formed from a reactant comprising (a) collagen and (b) polylysine. The method of claim 3230, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more thiol groups. The method of claim 3230, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more amino groups. The method of claim 3230, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method according to 3230. The method of claim 3230, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 3230, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) polylysine. The method of claim 3230, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more thiol groups. The method of claim 3230, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more amino groups. The method of claim 3230, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone, The method of claim 3230. The method of claim 3230, wherein the polymer is formed from a reactant comprising hyaluronic acid. The method of claim 3230, wherein the polymer is formed from a reactant comprising a hyaluronic acid derivative. The method of claim 3230, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The method of claim 3230, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A polymer having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene region. The method of claim 3230, wherein the method is formed from a reactant comprising a synthetic compound comprising: The method of claim 3230, wherein the composition comprises a colorant. The method of claim 3230 wherein the composition is sterile. Methods of implanting a medical device comprising: (a) a medical device to which the medical device is implanted or transplanted host tissue i) an inhibitor of fiber formation ii) an anti-infective agent iii) a polymer iv) an inhibitor of fiber formation and a polymer V) a composition comprising an anti-infective agent and a polymer or vi) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer, and (b) implanting a medical device into a host, and said medical treatment The device consists of a prosthetic heart valve or part thereof. A method of implanting a device with the medical device of claim 3484 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a fibrosis inhibitor; and (b) the host Implant a medical device. A method of implanting a device with the medical device of claim 3484 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in an anti-infective agent; and (b) the host is implanted. Implant medical devices. A method of implanting a device with the medical device of claim 3484 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a polymer; and (b) the medical device is in the host. Transplant. A method of implanting a device comprising the following with the medical device of claim 3484: (a) immersing the host tissue into which the medical device is implanted or implanted with a composition comprising a fibrosis inhibitor and a polymer; And (b) transplant the medical device into the host. A method of implanting a device with the medical device of claim 3484 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) Transplant the medical device into the host. 34. A method of implanting a device comprising the following with the medical device of claim 3484: (a) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer in which the medical device is implanted or the host tissue into which it is implanted. And (b) implant the medical device into the host. The method of claim 3484 wherein the medical device is a mechanical prosthetic heart valve. The method of claim 3484, wherein the medical device is a living heart valve. The method of claim 3484 wherein the medical device is an implantable annular ring for receiving a prosthetic heart valve. The method of claim 3484, wherein the medical device has a suture ring with a thread that tapers around to attach the prosthetic heart valve. The method of claim 3484 wherein the medical device is a suture ring for a mechanical prosthetic heart valve. The method of claim 3484, wherein cell regeneration is inhibited by a fiber formation inhibitor. The method of claim 3484, wherein an angiogenesis is inhibited by a fiber formation inhibitor. The method of claim 3484, wherein fibroblast migration is inhibited by a fibrosis inhibitor. The method of claim 3484, wherein the fibrosis inhibitor inhibits fibroblast proliferation. The method of claim 3484, wherein the fiber formation inhibitor inhibits extracellular matrix accumulation. The method of claim 3484, wherein the tissue remodeling is inhibited by the fiber formation inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is an angiogenesis inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is a 5- lipoxygenase inhibitor or antagonist. The method of claim 3484 wherein the fibrosis inhibitor is a chemokine receptor antagonist. The method of claim 3484 wherein the fiber formation inhibitor is a cell cycle inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is a taxane. The method of claim 3484 wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is paclitaxel. The method of claim 3484 wherein the fiber formation inhibitor is not paclitaxel. The method of claim 3484 wherein the fibrosis inhibitor is an analogue or derivative of paclitaxel. The method of claim 3484 wherein the fiber formation inhibitor is a vinca alkaloid. The method of claim 3484 wherein the fibrosis inhibitor is camptothecin or an analogue or derivative thereof. The method of claim 3484 wherein the fibrosis inhibitor is podophyllotoxin. The method of claim 3484 wherein the fibrosis inhibitor is podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof. The method of claim 3484 wherein the fiber formation inhibitor is an anthracycline. The method of claim 3484 wherein the fibrosis inhibitor is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof. The method of claim 3484 wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof. The method of claim 3484, wherein the fiber formation inhibitor is a platinum compound. The method of claim 3484 wherein the fiber formation inhibitor is nitrosourea. The method of claim 3484 wherein the fiber formation inhibitor is nitroimidazole. The method of claim 3484 wherein the fiber formation inhibitor is a folic acid antagonist. The method of claim 3484 wherein the fibrosis inhibitor is a cytidine analog. The method of claim 3484 wherein the fibrosis inhibitor is a pyrimidine analogue. The method of claim 3484 wherein the fiber formation inhibitor is a fluoropyrimidine analogue. The method of claim 3484 wherein the fibrosis inhibitor is a purine analogue. The method of claim 3484 wherein the fiber formation inhibitor is a nitrogen mustard or an analogue or derivative thereof. The method of claim 3484 wherein the fiber formation inhibitor is hydroxyurea. The method of claim 3484 wherein the fiber formation inhibitor is mitomycin or an analogue or derivative thereof. The method of claim 3484 wherein the fiber formation inhibitor is an alkyl sulfonate. The method of claim 3484 wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The method of claim 3484 wherein the fibrosis inhibitor is nicotinamide or an analogue or derivative thereof. The method of claim 3484 wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of claim 3484, wherein the fiber formation inhibitor is a DNA alkylating agent. The method of claim 3484 wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is a DNA cleaving agent. The method of claim 3484 wherein the fiber formation inhibitor is an antimetabolite. The method of claim 3484, wherein adenosine deaminase is inhibited by a fiber formation inhibitor. The method of claim 3484, wherein purine ring synthesis is inhibited by a fiber formation inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of claim 3484, wherein the fiber formation inhibitor inhibits dihydrofolate reduction. The method of claim 3484, wherein the thymidine monophosphate is inhibited by the fiber formation inhibitor. The method of claim 3484, wherein DNA damage is caused by a fiber formation inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is a DNA intercalation agent. The method of claim 3484 wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The method of claim 3484 wherein the fibril formation inhibitor inhibits ribonucleotide synthesis or function. The method of claim 3484, wherein the fibrosis inhibitor inhibits thymidine monophosphate synthesis or function. The method of claim 3484, wherein DNA synthesis is inhibited by the fiber formation inhibitor. The method of claim 3484, wherein the fiber formation inhibitor causes DNA adduct formation. The method of claim 3484, wherein protein synthesis is inhibited by a fiber formation inhibitor. The method of claim 3484, wherein the microtubule function is inhibited by the fiber formation inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is a cyclin dependent protein kinase inhibitor. The method of claim 3484 wherein the fibrosis inhibitor is an epidermal growth factor kinase inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is an elastase inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of claim 3484 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 3484 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 3484 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist. The method of claim 3484 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist, and the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof. The method of claim 3484 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 3484 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof. The method of claim 3484 wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of claim 3484 wherein the fibrosis inhibitor is an IL-1 antagonist. The method of claim 3484 wherein the fibrosis inhibitor is an ICE antagonist. The method of claim 3484 wherein the fiber formation inhibitor is an IRAK antagonist. The method of claim 3484 wherein the fibrosis inhibitor is an IL-4 agonist. The method of claim 3484 wherein the fibrosis inhibitor is an immunomodulator. The method of claim 3484 wherein the fibrosis inhibitor is sirolimus or an analogue or derivative thereof. The method of claim 3484 wherein the fibrosis inhibitor is not sirolimus. The method of claim 3484 wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. The method of claim 3484 wherein the fibrosis inhibitor is tacrolimus or an analogue or derivative thereof. The method of claim 3484 wherein the fiber formation inhibitor is not tacrolimus. The method of claim 3484 wherein the fibrosis inhibitor is biolimus or an analogue or derivative thereof. The method of claim 3484 wherein the fibrosis inhibitor is tresperimus or an analogue or derivative thereof. The method of claim 3484 wherein the fibrosis inhibitor is auranofin or an analogue or derivative thereof. The method of claim 3484 wherein the fibrosis inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of claim 3484 wherein the fibrosis inhibitor is gusperimus or an analogue or derivative thereof. The method of claim 3484 wherein the fibrosis inhibitor is pimecrolimus or an analogue or derivative thereof. The method of claim 3484 wherein the fiber formation inhibitor is ABT-578 or an analogue or derivative thereof. The method of claim 3484 wherein the fiber formation inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof. The method of claim 3484 wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-α-25 dihydroxyvitamin D ₃ or an analogue or derivative thereof. The method of claim 3484 wherein the fiber formation inhibitor is a leukotriene inhibitor. The method of claim 3484 wherein the vascularization inhibitor is an MCP-1 antagonist. The method of claim 3484 wherein the fiber formation inhibitor is an MMP inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is an NFκB inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is an NFκB inhibitor, and the NFκB inhibitor is Bay11-7082. The method of claim 3484 wherein the fiber formation inhibitor is a NO antagonist. The method of claim 3484 wherein the fibrosis inhibitor is a p38 MAP kinase inhibitor. The method of claim 3484 wherein the fibrosis inhibitor is a p38 MAP kinase inhibitor, and the p38 MAP kinase inhibitor is SB202190. The method of claim 3484 wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is a TGF beta inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is a thromboxane A2 antagonist. The method of claim 3484 wherein the vascularization inhibitor is a TNFα antagonist. The method of claim 3484 wherein the fiber formation inhibitor is a TACE inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is a vitronectin inhibitor. The method of claim 3484 wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is a protein kinase inhibitor. The method of claim 3484 wherein the fibrosis inhibitor is a PDGF receptor kinase inhibitor. The method of claim 3484 wherein the fibrosis inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is a retinoic acid receptor antagonist. The method of claim 3484 wherein the fibrosis inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of claim 3484 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 3484 wherein the fibrosis inhibitor is an antifungal agent. The method of claim 3484, wherein the fiber formation inhibitor is an antifungal agent, and the antifungal agent is sulconizole. The method of claim 3484 wherein the fiber formation inhibitor is a bisphosphonate. The method of claim 3484 wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. The method of claim 3484 wherein the fibrosis inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The method of claim 3484 wherein the fiber formation inhibitor is a macrolide antibiotic. The method of claim 3484 wherein the fibrosis inhibitor is a GPIIb / IIIa receptor antagonist. The method of claim 3484 wherein the fibrosis inhibitor is an endothelin receptor antagonist. The method of claim 3484 wherein the fibrosis inhibitor is an agonist of peroxisome proliferator-activated receptor. The method of claim 3484 wherein the fibrosis inhibitor is an estrogen receptor agent. The method of claim 3484 wherein the fibrosis inhibitor is a somostatin analog. The method of claim 3484 wherein the fiber formation inhibitor is a neurokinin 1 antagonist. The method of claim 3484 wherein the fiber formation inhibitor is a neurokinin 3 antagonist. The method of claim 3484 wherein the fibrosis inhibitor is a VLA-4 antagonist. The method of claim 3484 wherein the fibrosis inhibitor is an osteoclast inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is an angiotensin II antagonist. The method of claim 3484 wherein the fiber formation inhibitor is an enkephalinase inhibitor. The method of claim 3484 wherein the fibrosis inhibitor is a peroxisome proliferator-responsive receptor gamma agonist insulin sensitizer. The method of claim 3484 wherein the fiber formation inhibitor is a protein kinase C inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is a CXCR3 inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is an Itk inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of claim 3484 wherein the fibrosis inhibitor is a PPAR agonist. The method of claim 3484 wherein the fiber formation inhibitor is an immunosuppressant. The method of claim 3484 wherein the fiber formation inhibitor is an Erb inhibitor. The method of claim 3484 wherein the fibrosis inhibitor is an apoptosis agonist. The method of claim 3484 wherein the fibrosis inhibitor is a lipocortin agonist. The method of claim 3484 wherein the fibrosis inhibitor is a VCAM-1 antagonist. The method of claim 3484 wherein the fiber formation inhibitor is a collagen antagonist. The method of claim 3484 wherein the fiber formation inhibitor is an α2 integrin antagonist. The method of claim 3484 wherein the fiber formation inhibitor is a TNFα inhibitor. The method of claim 3484 wherein the fiber formation inhibitor is a nitric oxide inhibitor The method of claim 3484 wherein the fiber formation inhibitor is a cathepsin inhibitor. The method of claim 3484 wherein the fibrosis inhibitor is not an anti-inflammatory agent. The method of claim 3484 wherein the fibrosis inhibitor is not a steroid. The method of claim 3484 wherein the fiber formation inhibitor is not a glucocorticosteroid. The method of claim 3484 wherein the fiber formation inhibitor is not dexamethasone. The method of claim 3484 wherein the fiber formation inhibitor is not beclomethasone. The method of claim 3484 wherein the fiber formation inhibitor is not dipropionic acid. The method of claim 3484 wherein the fiber formation inhibitor is not an anti-infective. The method of claim 3484 wherein the fibrosis inhibitor is not an antibiotic. The method of claim 3484 wherein the fibrosis inhibitor is not an antifungal agent. The method of claim 3484 wherein the anti-infective is an anthracycline. The method of claim 3484 wherein the anti-infective agent is doxorubicin. The method of claim 3484 wherein the anti-infective agent is mitoxantrone. The method of claim 3484 wherein the anti-infective is fluoropyrimidine. The method of claim 3484 wherein the anti-infective is 5-fluorouracil (5-FU). The method of claim 3484 wherein the anti-infective agent is a folic acid antagonist. The method of claim 3484 wherein the anti-infective is methotrexate. The method of claim 3484 wherein the anti-infective is podophyllotoxin. The method of claim 3484 wherein the anti-infective is etoposide. The method of claim 3484 wherein the anti-infective is camptothecin. The method of claim 3484 wherein the anti-infective agent is hydroxyurea. The method of claim 3484 wherein the anti-infective agent is a platinum complex. The method of claim 3484 wherein the anti-infective is cisplatin. The method of claim 3484, wherein the composition comprises an antithrombotic agent. The method of claim 3484, wherein the polymer is formed from a reactant comprising a naturally occurring polymer. The method of claim 3484, wherein the polymer is formed from a reactant comprising protein. The method of claim 3484, wherein the polymer is formed from a reactant comprising carbohydrate. The method of claim 3484, wherein the polymer is formed from a reactant comprising a biodegradable polymer. The method of claim 3484, wherein the polymer is formed from a reactant comprising a non-biodegradable polymer. The method of claim 3484, wherein the polymer is formed from a reactant comprising collagen. The method of claim 3484, wherein the polymer is formed from a reactant comprising methylated collagen. The method of claim 3484, wherein the polymer is formed from a reactant comprising fibrinogen. The method of claim 3484, wherein the polymer is formed from a reactant comprising thrombin. The method of claim 3484 wherein the polymer is formed from a reactant comprising a plasma component. The method of claim 3484, wherein the polymer is formed from a reactant comprising a calcium salt. The method of claim 3484, wherein the polymer is formed from a reactant comprising a fiber formation inhibitor. The method of claim 3484, wherein the polymer is formed from a reactant comprising a fibrinogen analog. The method of claim 3484, wherein the polymer is formed from a reactant comprising albumin. The method of claim 3484, wherein the polymer is formed from a reactant comprising plasminogen. The method of claim 3484, wherein the polymer is formed from a reactant comprising von Willebrand factor. The method of claim 3484 wherein the polymer is formed from a reactant comprising Factor VIII. The method of claim 3484 wherein the polymer is formed from a reactant comprising hypoallergenic collagen. The method of claim 3484 wherein the polymer is formed from a reactant comprising atelopeptide collagen. The method of claim 3484 wherein the polymer is formed from a reactant comprising telopeptide collagen. The method of claim 3484, wherein the polymer is formed from a reactant comprising cross-linked collagen. The method of claim 3484 wherein the polymer is formed from a reactant comprising aprotinin. The method of claim 3484 wherein the polymer is formed from a reactant comprising epsilon amino-n-caproic acid. The method of claim 3484, wherein the polymer is formed from a reactant comprising gelatin. The method of claim 3484 wherein the polymer is formed from a reactant comprising a protein conjugate. The method of claim 3484, wherein the polymer is formed from a reactant comprising a gelatin conjugate. The method of claim 3484, wherein the polymer is formed from a reactant comprising a synthetic polymer. The method of claim 3484, wherein the polymer is formed from a reactant comprising a compound comprising synthetic isocyanate. The method of claim 3484, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic thiol. The method of claim 3484, wherein the polymer is formed from a reactant comprised of a synthetic compound comprising two or more thiol groups. The method of claim 3484, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more thiol groups. The method of claim 3484, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more thiol groups. The method of claim 3484, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic amino. The method of claim 3484, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more amino groups. The method of claim 3484, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more amino groups. The method of claim 3484, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more amino groups. The method of claim 3484, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of claim 3484, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The method of claim 3484, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. The method of claim 3484, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more carbonyl-oxygen-succinimidyl groups. The method of claim 3484, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide. The method of claim 3484, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a polyalkylene oxide and a biodegradable polyester block. The method of claim 3484, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The method of claim 3484, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a thiol reactive group. The method of claim 3484, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The method of claim 3484, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a biodegradable polyester block. The method of claim 3484, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly comprised of lactic acid or lactide. The method of claim 3484, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly consisting of glycolic acid or glycolide. The method of claim 3484, wherein the polymer is formed from a reactant comprising polylysine. The method of claim 3484, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 3484, wherein the polymer is formed from a reactant comprising (a) a protein and (b) polylysine. The method of claim 3484, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more thiol groups. The method of claim 3484, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more amino groups. The method of claim 3484, wherein the polymer is formed from a reactant comprising: (a) a protein; and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method of 3484. The method of claim 3484, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 3484, wherein the polymer is formed from a reactant comprising (a) collagen and (b) polylysine. The method of claim 3484, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more thiol groups. The method of claim 3484, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more amino groups. The method of claim 3484, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method of 3484. The method of claim 3484 wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 3484, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) polylysine. The method of claim 3484, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more thiol groups. The method of claim 3484 wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more amino groups. The method of claim 3484, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone, The method of claim 3484. The method of claim 3484, wherein the polymer is formed from a reactant comprising hyaluronic acid. The method of claim 3484, wherein the polymer is formed from a reactant comprising a hyaluronic acid derivative. The method of claim 3484, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The method of claim 3484, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A polymer having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene region. The method of claim 3484, wherein the method is formed from a reactant comprising a synthetic compound comprising a plurality of electrophilic groups. The method of claim 3484, wherein the composition comprises a colorant. The method of claim 3484 wherein the composition is sterile. Methods of implanting a medical device comprising: (a) a medical device to which the medical device is implanted or transplanted host tissue i) an inhibitor of fiber formation ii) an anti-infective agent iii) a polymer iv) an inhibitor of fiber formation V) a composition comprising an anti-infective agent and a polymer or vi) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer, and (b) implanting a medical device into a host, and said medical treatment The device is a penile implant. The method of implanting a device with the medical device of claim 3742 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a fibrosis inhibitor; and (b) the host Implant a medical device. The method of implanting a device with the medical device of claim 3742 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in an anti-infective agent; and (b) the host is implanted. Implant medical devices. The method of implanting a device with the medical device of claim 3742 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a polymer; and (b) the medical device is implanted in the host. Transplant. A method of implanting a device comprising the medical device of claim 3742 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising a fibrosis inhibitor and a polymer; And (b) transplant the medical device into the host. The method of implanting a device with the medical device of claim 3742 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) Transplant the medical device into the host. The method of implanting a device comprising: a) a medical device according to claim 3742 comprising: (a) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer in which the medical device is implanted or the host tissue is implanted; And (b) implant the medical device into the host. The method of claim 3742 wherein the medical device is a flexible rod penis implant. The method of claim 3742 wherein the medical device is a hinged rod penis implant. The method of claim 3742 wherein the medical device is an inflatable penile implant with a pump. The method of claim 3742, wherein cell regeneration is inhibited by a fiber formation inhibitor. The method of claim 3742, wherein an angiogenesis is inhibited by a fiber formation inhibitor. The method of claim 3742, wherein fibroblast migration is inhibited by a fibrosis inhibitor. The method of claim 3742, wherein a fibrosis inhibitor inhibits fibroblast proliferation. The method of claim 3742, wherein the fiber formation inhibitor inhibits extracellular matrix accumulation. The method of claim 3742, wherein the tissue remodeling is inhibited by the fiber formation inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is an angiogenesis inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is a 5- lipoxygenase inhibitor or antagonist. The method of claim 3742, wherein the fiber formation inhibitor is a chemokine receptor antagonist. The method of claim 3742, wherein the fiber formation inhibitor is a cell cycle inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is a taxane. The method of claim 3742, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is paclitaxel. The method of claim 3742, wherein the fiber formation inhibitor is not paclitaxel. The method of claim 3742, wherein the fiber formation inhibitor is an analogue or derivative of paclitaxel. The method of claim 3742, wherein the fiber formation inhibitor is a vinca alkaloid. The method of claim 3742, wherein the fiber formation inhibitor is camptothecin or an analogue or derivative thereof. The method of claim 3742, wherein the fiber formation inhibitor is podophyllotoxin. The method of claim 3742, wherein the fiber formation inhibitor is podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof. The method of claim 3742, wherein the fiber formation inhibitor is an anthracycline. The method of claim 3742, wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof. The method of claim 3742, wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof. The method of claim 3742, wherein the fiber formation inhibitor is a platinum compound. The method of claim 3742, wherein the fiber formation inhibitor is nitrosourea. The method of claim 3742, wherein the fiber formation inhibitor is nitroimidazole. The method of claim 3742, wherein the fiber formation inhibitor is a folic acid antagonist. The method of claim 3742, wherein the fiber formation inhibitor is a cytidine analog. The method of claim 3742, wherein the fiber formation inhibitor is a pyrimidine analogue. The method of claim 3742, wherein the fiber formation inhibitor is a fluoropyrimidine analogue. The method of claim 3742, wherein the fiber formation inhibitor is a purine analogue. The method of claim 3742, wherein the fiber formation inhibitor is nitrogen mustard or an analogue or derivative thereof. The method of claim 3742, wherein the fiber formation inhibitor is hydroxyurea. The method of claim 3742, wherein the fiber formation inhibitor is mitomycin or an analogue or derivative thereof. The method of claim 3742, wherein the fiber formation inhibitor is an alkyl sulfonate. The method of claim 3742, wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The method of claim 3742, wherein the fiber formation inhibitor is nicotinamide or an analogue or derivative thereof. The method of claim 3742, wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of claim 3742, wherein the fiber formation inhibitor is a DNA alkylating agent. The method of claim 3742, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is a DNA cleaving agent. The method of claim 3742, wherein the fiber formation inhibitor is an antimetabolite. The method of claim 3742, wherein adenosine deaminase is inhibited by a fiber formation inhibitor. The method of claim 3742, wherein a purine ring synthesis is inhibited by a fiber formation inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of claim 3742, wherein the fiber formation inhibitor inhibits dihydrofolate reduction. The method of claim 3742, wherein thymidine monophosphate is inhibited by a fiber formation inhibitor. The method of claim 3742, wherein DNA damage is caused by a fiber formation inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is a DNA intercalation agent. The method of claim 3742, wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The method of claim 3742, wherein the fibril formation inhibitor inhibits ribonucleotide synthesis or function. The method of claim 3742, wherein the fiber formation inhibitor inhibits thymidine monophosphate synthesis or function. The method of claim 3742, wherein DNA synthesis is inhibited by a fiber formation inhibitor. The method of claim 3742, wherein a fiber formation inhibitor causes DNA adduct formation. The method of claim 3742, wherein protein synthesis is inhibited by a fiber formation inhibitor. The method of claim 3742, wherein the microtubule function is inhibited by the fiber formation inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is a cyclin dependent protein kinase inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is an epidermal growth factor kinase inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is an elastase inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is a fibrinogen antagonist. The method of claim 3742, wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 3742, wherein the fibrosis inhibitor is a heat shock protein 90 antagonist. The method of claim 3742, wherein the fiber formation inhibitor is a heat shock protein 90 antagonist, and the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof. The method of claim 3742, wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 3742, wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor, and the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof. The method of claim 3742, wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is an IL-1 antagonist. The method of claim 3742, wherein the fiber formation inhibitor is an ICE antagonist. The method of claim 3742, wherein the fiber formation inhibitor is an IRAK antagonist. The method of claim 3742 wherein the fibrosis inhibitor is an IL-4 agonist. The method of claim 3742, wherein the fiber formation inhibitor is an immunomodulator. The method of claim 3742, wherein the fiber formation inhibitor is sirolimus or an analogue or derivative thereof. The method of claim 3742, wherein the fiber formation inhibitor is not sirolimus. The method of claim 3742, wherein the fiber formation inhibitor is everolimus or an analogue or derivative thereof. The method of claim 3742, wherein the fiber formation inhibitor is tacrolimus or an analogue or derivative thereof. The method of claim 3742, wherein the fiber formation inhibitor is not tacrolimus. The method of claim 3742, wherein the fiber formation inhibitor is biolimus or an analogue or derivative thereof. The method of claim 3742, wherein the fibrosis inhibitor is tresperimus or an analogue or derivative thereof. The method of claim 3742, wherein the fiber formation inhibitor is auranofin or an analogue or derivative thereof. The method of claim 3742, wherein the fiber formation inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of claim 3742, wherein the fiber formation inhibitor is gusperimus or an analogue or derivative thereof. The method of claim 3742, wherein the fiber formation inhibitor is pimecrolimus or an analogue or derivative thereof. The method of claim 3742, wherein the fiber formation inhibitor is ABT-578 or an analogue or derivative thereof. The method of claim 3742, wherein the fiber formation inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof. The method of claim 3742, wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-α-25 dihydroxy vitamin D ₃ or an analogue or derivative thereof. The method of claim 3742, wherein the fiber formation inhibitor is a leukotriene inhibitor. The method of claim 3742 wherein the fibrosis inhibitor is an MCP-1 antagonist. The method of claim 3742, wherein the fiber formation inhibitor is an MMP inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is an NFκB inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is an NFκB inhibitor, and the NFκB inhibitor is Bay11-7082. The method of claim 3742, wherein the fiber formation inhibitor is a NO antagonist. The method of claim 3742, wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor, and the p38 MAP kinase inhibitor is SB202190. The method of claim 3742, wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is a TGF beta inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is a thromboxane A2 antagonist. The method of claim 3742, wherein the angiogenesis inhibitor is a TNFα antagonist. The method of claim 3742, wherein the fiber formation inhibitor is a TACE inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is a vitronectin inhibitor. The method of claim 3742, wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is a protein kinase inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is a PDGF receptor kinase inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is a retinoic acid receptor antagonist. The method of claim 3742, wherein the fiber formation inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is a fibrinogen antagonist. The method of claim 3742, wherein the fiber formation inhibitor is an antifungal agent. The method of claim 3742, wherein the fiber formation inhibitor is an antifungal agent, and the antifungal agent is sulconizole. The method of claim 3742, wherein the fiber formation inhibitor is a bisphosphonate. The method of claim 3742, wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The method of claim 3742, wherein the fiber formation inhibitor is a macrolide antibiotic. The method of claim 3742, wherein the fiber formation inhibitor is a GPIIb / IIIa receptor antagonist. The method of claim 3742, wherein the fiber formation inhibitor is an endothelin receptor antagonist. The method of claim 3742 wherein the fibrosis inhibitor is an agonist of peroxisome proliferator-activated receptor. The method of claim 3742 wherein the fibrosis inhibitor is an estrogen receptor agent. The method of claim 3742 wherein the fibrosis inhibitor is a somostatin analog. The method of claim 3742, wherein the fiber formation inhibitor is a neurokinin 1 antagonist. The method of claim 3742, wherein the fiber formation inhibitor is a neurokinin 3 antagonist. The method of claim 3742 wherein the fibrosis inhibitor is a VLA-4 antagonist. The method of claim 3742, wherein the fiber formation inhibitor is an osteoclast inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is an angiotensin II antagonist. The method of claim 3742, wherein the fiber formation inhibitor is an enkephalinase inhibitor. The method of claim 3742, wherein the fibrosis inhibitor is a peroxisome proliferator-responsive receptor gamma agonist insulin sensitizer. The method of claim 3742, wherein the fiber formation inhibitor is a protein kinase C inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is a CXCR3 inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is an Itk inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of claim 3742 wherein the fibrosis inhibitor is a PPAR agonist. The method of claim 3742, wherein the fiber formation inhibitor is an immunosuppressant. The method of claim 3742, wherein the fiber formation inhibitor is an Erb inhibitor. The method of claim 3742, wherein the fibrosis inhibitor is an apoptosis agonist. The method of claim 3742 wherein the fibrosis inhibitor is a lipocortin agonist. The method of claim 3742, wherein the fiber formation inhibitor is a VCAM-1 antagonist. The method of claim 3742, wherein the fiber formation inhibitor is a collagen antagonist. The method of claim 3742, wherein the fiber formation inhibitor is an α2 integrin antagonist. The method of claim 3742, wherein the fiber formation inhibitor is a TNFα inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is a nitric oxide inhibitor. The method of claim 3742, wherein the fiber formation inhibitor is a cathepsin inhibitor. The method of claim 3742 wherein the fibrosis inhibitor is not an anti-inflammatory agent. The method of claim 3742 wherein the fibrosis inhibitor is not a steroid. The method of claim 3742, wherein the fiber formation inhibitor is not a glucocorticosteroid. The method of claim 3742, wherein the fiber formation inhibitor is not dexamethasone. The method of claim 3742, wherein the fiber formation inhibitor is not beclomethasone. The method of claim 3742, wherein the fiber formation inhibitor is not dipropionic acid. The method of claim 3742, wherein the fiber formation inhibitor is not an anti-infective. The method of claim 3742, wherein the fiber formation inhibitor is not an antibiotic. The method of claim 3742, wherein the fiber formation inhibitor is not an antifungal agent. The method of claim 3742 wherein the anti-infective is an anthracycline. The method of claim 3742, wherein the anti-infective is doxorubicin. The method of claim 3742, wherein the anti-infective is mitoxantrone. The method of claim 3742, wherein the anti-infective is a fluoropyrimidine. The method of claim 3742, wherein the anti-infective is 5-fluorouracil (5-FU). The method of claim 3742, wherein the anti-infective is a folic acid antagonist. The method of claim 3742, wherein the anti-infective is methotrexate. The method of claim 3742, wherein the anti-infective is podophyllotoxin. The method of claim 3742, wherein the anti-infective is etoposide. The method of claim 3742, wherein the anti-infective is camptothecin. The method of claim 3742, wherein the anti-infective is hydroxyurea. The method of claim 3742, wherein the anti-infective is a platinum complex. The method of claim 3742, wherein the anti-infective is cisplatin. The method of claim 3742, wherein the composition comprises an antithrombotic agent. The method of claim 3742, wherein the polymer is formed from a reactant comprising a naturally occurring polymer. The method of claim 3742, wherein the polymer is formed from a reactant comprising protein. The method of claim 3742, wherein the polymer is formed from a reactant comprising a carbohydrate. The method of claim 3742, wherein the polymer is formed from a reactant comprising a biodegradable polymer. The method of claim 3742, wherein the polymer is formed from a reactant comprising a non-biodegradable polymer. The method of claim 3742, wherein the polymer is formed from a reactant comprising collagen. The method of claim 3742, wherein the polymer is formed from a reactant comprising methylated collagen. The method of claim 3742, wherein the polymer is formed from a reactant comprising fibrinogen. The method of claim 3742, wherein the polymer is formed from a reactant comprising thrombin. The method of claim 3742, wherein the polymer is formed from a reactant comprising a plasma component. The method of claim 3742, wherein the polymer is formed from a reactant comprising a calcium salt. The method of claim 3742, wherein the polymer is formed from a reactant comprising a fiber formation inhibitor. The method of claim 3742, wherein the polymer is formed from a reactant comprising a fibrinogen analog. The method of claim 3742, wherein the polymer is formed from a reactant comprising albumin. The method of claim 3742, wherein the polymer is formed from a reactant comprising plasminogen. The method of claim 3742, wherein the polymer is formed from a reactant comprising von Willebrand Factor. The method of claim 3742, wherein the polymer is formed from a reactant comprising Factor VIII. The method of claim 3742, wherein the polymer is formed from a reactant comprising hypoallergenic collagen. The method of claim 3742, wherein the polymer is formed from a reactant comprising atelopeptide collagen. The method of claim 3742, wherein the polymer is formed from a reactant comprising telopeptide collagen. The method of claim 3742, wherein the polymer is formed from a reactant comprising cross-linked collagen. The method of claim 3742, wherein the polymer is formed from a reactant comprising aprotinin. The method of claim 3742, wherein the polymer is formed from a reactant comprising epsilon amino-n-caproic acid. The method of claim 3742, wherein the polymer is formed from a reactant comprising gelatin. The method of claim 3742, wherein the polymer is formed from a reactant comprising a protein conjugate. The method of claim 3742, wherein the polymer is formed from a reactant comprising a gelatin conjugate. The method of claim 3742, wherein the polymer is formed from a reactant comprising a synthetic polymer. The method of claim 3742, wherein the polymer is formed from a reactant comprising a compound comprising synthetic isocyanate. The method of claim 3742, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic thiol. The method of claim 3742, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more thiol groups. The method of claim 3742, wherein the polymer is formed from reactants comprised of synthetic compounds comprising three or more thiol groups. The method of claim 3742, wherein the polymer is formed from reactants comprised of synthetic compounds comprising four or more thiol groups. The method of claim 3742, wherein the polymer is formed from a reactant comprising a compound comprising synthetic amino. The method of claim 3742, wherein the polymer is formed from reactants consisting of a synthetic compound containing two or more amino groups. The method of claim 3742, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more amino groups. The method of claim 3742, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more amino groups. The method of claim 3742, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of claim 3742, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The method of claim 3742, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. The method of claim 3742, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more carbonyl-oxygen-succinimidyl groups. The method of claim 3742, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide. The method of claim 3742, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a polyalkylene oxide and a biodegradable polyester block. The method of claim 3742, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The method of claim 3742, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide having a thiol reactive group. The method of claim 3742, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The method of claim 3742, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a biodegradable polyester block. The method of claim 3742, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly comprised of lactic acid or lactide. The method of claim 3742, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or in part, consisting of glycolic acid or glycolide. The method of claim 3742, wherein the polymer is formed from a reactant comprising polylysine. The method of claim 3742, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 3742, wherein the polymer is formed from a reactant comprising (a) a protein and (b) polylysine. The method of claim 3742, wherein the polymer is formed from (a) a reactant and (b) a reactant comprising a compound having four or more thiol groups. The method of claim 3742, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more amino groups. The method of claim 3742, wherein the polymer is formed from a reactant comprising: (a) a protein; and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method of 3742. The method of claim 3742, wherein the polymer is formed from a reactant comprising (a) a collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 3742, wherein the polymer is formed from reactants comprising (a) collagen and (b) polylysine. The method of claim 3742, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more thiol groups. The method of claim 3742, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more amino groups. The method of claim 3742, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method of 3742. The method of claim 3742, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 3742, wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) polylysine. The method of claim 3742, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more thiol groups. The method of claim 3742, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more amino groups. The method of claim 3742, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone, The method of claim 3742. The method of claim 3742, wherein the polymer is formed from a reactant comprising hyaluronic acid. The method of claim 3742, wherein the polymer is formed from a reactant comprising a hyaluronic acid derivative. The method of claim 3742, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The method of claim 3742, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A polymer having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene region. The method of claim 3742, wherein the method is formed from a reactant comprising a synthetic compound comprising a plurality of electrophilic groups. The method of claim 3742, wherein the composition comprises a colorant. The method of claim 3742, wherein the composition is sterile. Methods of implanting a medical device comprising: (a) a medical device to which the medical device is implanted or transplanted host tissue i) an inhibitor of fiber formation ii) an anti-infective agent iii) a polymer iv) an inhibitor of fiber formation V) a composition comprising an anti-infective agent and a polymer or vi) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer, and (b) implanting a medical device into a host, and said medical treatment The device is an endotracheal tube or a tracheal cannula. A method of implanting a device with the medical device of claim 3998 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a fibrosis inhibitor; and (b) the host. Implant a medical device. A method of implanting a device with the medical device of claim 3998 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in an anti-infective agent; and (b) the host is implanted. Implant medical devices. A method of implanting a device with the medical device of claim 3998 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a polymer; and (b) the medical device is implanted in the host. Transplant. A method of implanting a device with the medical device of claim 3998 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising a fibrosis inhibitor and a polymer; And (b) transplant the medical device into the host. A method of implanting a device with the medical device of claim 3998, comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) Transplant the medical device into the host. A method of implanting a device comprising the following with the medical device of claim 3998: (a) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer in which the medical device is implanted or the host tissue into which it is implanted And (b) implant the medical device into the host. The method of claim 3998 wherein the medical device is an endotracheal tube. The method of claim 3998 wherein the medical device is an endotracheal tube with a single lumen. The method of claim 3998 wherein the medical device is an endotracheal tube having two lumens. The method of claim 3998 wherein the medical device is a tracheal cannula. The method of claim 3998, wherein cell regeneration is inhibited by a fiber formation inhibitor. The method of claim 3998, wherein angiogenesis is inhibited by a fiber formation inhibitor. The method of claim 3998, wherein fibroblast migration is inhibited by a fibrosis inhibitor. The method of claim 3998, wherein the fibrosis inhibitor inhibits fibroblast proliferation. The method of claim 3998, wherein accumulation of extracellular matrix is inhibited by a fiber formation inhibitor. The method of claim 3998, wherein the fiber formation inhibitor inhibits tissue remodeling. The method of claim 3998, wherein the fiber formation inhibitor is an angiogenesis inhibitor. The method of claim 3998 wherein the fiber formation inhibitor is a 5- lipoxygenase inhibitor or antagonist. The method of claim 3998 wherein the fibrosis inhibitor is a chemokine receptor antagonist. The method of claim 3998, wherein the fiber formation inhibitor is a cell cycle inhibitor. The method of claim 3998, wherein the fiber formation inhibitor is a taxane. The method of claim 3998 wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 3998 wherein the fiber formation inhibitor is paclitaxel. The method of claim 3998 wherein the fiber formation inhibitor is not paclitaxel. The method of claim 3998 wherein the fibrosis inhibitor is an analogue or derivative of paclitaxel. The method of claim 3998, wherein the fiber formation inhibitor is a vinca alkaloid. The method of claim 3998 wherein the fibrosis inhibitor is camptothecin or an analogue or derivative thereof. The method of claim 3998 wherein the fibrosis inhibitor is podophyllotoxin. The method of claim 3998 wherein the fibrosis inhibitor is podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof. The method of claim 3998, wherein the fiber formation inhibitor is an anthracycline. The method of claim 3998 wherein the fibrosis inhibitor is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof. The method of claim 3998 wherein the fibrosis inhibitor is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof. The method of claim 3998, wherein the fiber formation inhibitor is a platinum compound. The method of claim 3998, wherein the fiber formation inhibitor is nitrosourea. The method of claim 3998, wherein the fiber formation inhibitor is nitroimidazole. The method of claim 3998 wherein the fibrosis inhibitor is a folic acid antagonist. The method of claim 3998 wherein the fibrosis inhibitor is a cytidine analog. The method of claim 3998 wherein the fibrosis inhibitor is a pyrimidine analogue. The method of claim 3998 wherein the fiber formation inhibitor is a fluoropyrimidine analogue. The method of claim 3998 wherein the fibrosis inhibitor is a purine analogue. The method of claim 3998 wherein the fiber formation inhibitor is a nitrogen mustard or an analogue or derivative thereof. The method of claim 3998, wherein the fiber formation inhibitor is hydroxyurea. The method of claim 3998 wherein the fibrosis inhibitor is mitomycin or an analogue or derivative thereof. The method of claim 3998, wherein the fiber formation inhibitor is an alkyl sulfonate. The method of claim 3998 wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The method of claim 3998 wherein the fiber formation inhibitor is nicotinamide or an analogue or derivative thereof. The method of claim 3998 wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of claim 3998, wherein the fiber formation inhibitor is a DNA alkylating agent. The method of claim 3998 wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 3998 wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of claim 3998, wherein the fiber formation inhibitor is a DNA cleaving agent. The method of claim 3998, wherein the fiber formation inhibitor is an antimetabolite. The method of claim 3998, wherein adenosine deaminase is inhibited by a fiber formation inhibitor. The method of claim 3998, wherein purine ring synthesis is inhibited by a fiber formation inhibitor. The method of claim 3998 wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of claim 3998, wherein the fiber formation inhibitor inhibits dihydrofolate reduction. The method of claim 3998, wherein thymidine monophosphate is inhibited by the fiber formation inhibitor. The method of claim 3998, wherein the fiber formation inhibitor causes DNA damage. The method of claim 3998, wherein the fiber formation inhibitor is a DNA intercalation agent. The method of claim 3998, wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The method of claim 3998, wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The method of claim 3998, wherein the fiber formation inhibitor inhibits ribonucleotide synthesis or function. The method of claim 3998, wherein the fibrosis inhibitor inhibits thymidine monophosphate synthesis or function. The method of claim 3998, wherein DNA synthesis is inhibited by the fiber formation inhibitor. The method of claim 3998, wherein DNA adduct formation occurs with the fiber formation inhibitor. The method of claim 3998, wherein protein synthesis is inhibited by the fiber formation inhibitor. The method of claim 3998, wherein the microtubule function is inhibited by the fiber formation inhibitor. The method of claim 3998 wherein the fiber formation inhibitor is a cyclin dependent protein kinase inhibitor. The method of claim 3998 wherein the fibrosis inhibitor is an epidermal growth factor kinase inhibitor. The method of claim 3998 wherein the fiber formation inhibitor is an elastase inhibitor. The method of claim 3998 wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of claim 3998 wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of claim 3998 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 3998 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 3998 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist. The method of claim 3998 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist, and the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof. The method of claim 3998 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 3998 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The method of claim 3998 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof. The method of claim 3998, wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. The method of claim 3998 wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of claim 3998 wherein the fibrosis inhibitor is an IL-1 antagonist. The method of claim 3998 wherein the fibrosis inhibitor is an ICE antagonist. The method of claim 3998 wherein the fibrosis inhibitor is an IRAK antagonist. The method of claim 3998 wherein the fibrosis inhibitor is an IL-4 agonist. The method of claim 3998 wherein the fibrosis inhibitor is an immunomodulator. The method of claim 3998 wherein the fibrosis inhibitor is sirolimus or an analogue or derivative thereof. The method of claim 3998, wherein the fiber formation inhibitor is not sirolimus. The method of claim 3998 wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. The method of claim 3998 wherein the fibrosis inhibitor is tacrolimus or an analogue or derivative thereof. The method of claim 3998, wherein the fiber formation inhibitor is not tacrolimus. The method of claim 3998 wherein the fibrosis inhibitor is biolimus or an analogue or derivative thereof. The method of claim 3998 wherein the fibrosis inhibitor is tresperimus or an analogue or derivative thereof. The method of claim 3998 wherein the fiber formation inhibitor is auranofin or an analogue or derivative thereof. The method of claim 3998 wherein the fibrosis inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of claim 3998 wherein the fibrosis inhibitor is gusperimus or an analogue or derivative thereof. The method of claim 3998 wherein the fibrosis inhibitor is pimecrolimus or an analogue or derivative thereof. The method of claim 3998 wherein the fiber formation inhibitor is ABT-578 or an analogue or derivative thereof. The method of claim 3998 wherein the fiber formation inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. The method of claim 3998, wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof. The method of claim 3998 wherein the fibrosis inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-α-25 dihydroxyvitamin D ₃ or an analogue or derivative thereof. The method of claim 3998, wherein the fiber formation inhibitor is a leukotriene inhibitor. The method of claim 3998 wherein the vascularization inhibitor is an MCP-1 antagonist. The method of claim 3998, wherein the fiber formation inhibitor is an MMP inhibitor. The method of claim 3998, wherein the fiber formation inhibitor is an NFκB inhibitor. The method of claim 3998, wherein the fiber formation inhibitor is an NFκB inhibitor, wherein the NFκB inhibitor is Bay11-7082. The method of claim 3998, wherein the fiber formation inhibitor is a NO antagonist. The method of claim 3998 wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor. The method of claim 3998 wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB202190. The method of claim 3998 wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The method of claim 3998 wherein the fiber formation inhibitor is a TGF beta inhibitor. The method of claim 3998 wherein the fiber formation inhibitor is a thromboxane A2 antagonist. The method of claim 3998 wherein the vascularization inhibitor is a TNFα antagonist. The method of claim 3998, wherein the fiber formation inhibitor is a TACE inhibitor. The method of claim 3998 wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. The method of claim 3998 wherein the fiber formation inhibitor is a vitronectin inhibitor. The method of claim 3998 wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of claim 3998 wherein the fiber formation inhibitor is a protein kinase inhibitor. The method of claim 3998 wherein the fibrosis inhibitor is a PDGF receptor kinase inhibitor. The method of claim 3998 wherein the fibrosis inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of claim 3998 wherein the fibrosis inhibitor is a retinoic acid receptor antagonist. The method of claim 3998 wherein the fibrosis inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of claim 3998 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 3998, wherein the fiber formation inhibitor is an antifungal agent. The method of claim 3998, wherein the fiber formation inhibitor is an antifungal agent, and the antifungal agent is sulconizole. The method of claim 3998 wherein the fiber formation inhibitor is a bisphosphonate. The method of claim 3998 wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. The method of claim 3998 wherein the fibrosis inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The method of claim 3998, wherein the fiber formation inhibitor is a macrolide antibiotic. The method of claim 3998 wherein the fibrosis inhibitor is a GPIIb / IIIa receptor antagonist. The method of claim 3998 wherein the fibrosis inhibitor is an endothelin receptor antagonist. The method of claim 3998 wherein the fibrosis inhibitor is an agonist of peroxisome proliferator-activated receptor. The method of claim 3998 wherein the fibrosis inhibitor is an estrogen receptor agent. The method of claim 3998 wherein the fibrosis inhibitor is a somostatin analog. The method of claim 3998 wherein the fibrosis inhibitor is a neurokinin 1 antagonist. The method of claim 3998 wherein the fibrosis inhibitor is a neurokinin 3 antagonist. The method of claim 3998 wherein the fibrosis inhibitor is a VLA-4 antagonist. The method of claim 3998, wherein the fiber formation inhibitor is an osteoclast inhibitor. The method of claim 3998 wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The method of claim 3998 wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of claim 3998 wherein the fibrosis inhibitor is an angiotensin II antagonist. The method of claim 3998 wherein the fiber formation inhibitor is an enkephalinase inhibitor. The method of claim 3998 wherein the fibrosis inhibitor is a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer. The method of claim 3998 wherein the fiber formation inhibitor is a protein kinase C inhibitor. The method of claim 3998 wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. The method of claim 3998 wherein the fiber formation inhibitor is a CXCR3 inhibitor. The method of claim 3998 wherein the fiber formation inhibitor is an Itk inhibitor. The method of claim 3998 wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of claim 3998 wherein the fibrosis inhibitor is a PPAR agonist. The method of claim 3998, wherein the fiber formation inhibitor is an immunosuppressant. The method of claim 3998 wherein the fiber formation inhibitor is an Erb inhibitor. The method of claim 3998 wherein the fibrosis inhibitor is an apoptosis agonist. The method of claim 3998 wherein the fibrosis inhibitor is a lipocortin agonist. The method of claim 3998 wherein the fibrosis inhibitor is a VCAM-1 antagonist. The method of claim 3998, wherein the fiber formation inhibitor is a collagen antagonist. The method of claim 3998 wherein the fiber formation inhibitor is an α2 integrin antagonist. The method of claim 3998, wherein the fiber formation inhibitor is a TNFα inhibitor. The method of claim 3998, wherein the fiber formation inhibitor is a nitric oxide inhibitor. The method of claim 3998, wherein the fiber formation inhibitor is a cathepsin inhibitor. The method of claim 3998 wherein the fibrosis inhibitor is not an anti-inflammatory agent. The method of claim 3998 wherein the fibrosis inhibitor is not a steroid. The method of claim 3998 wherein the fibrosis inhibitor is not a glucocorticosteroid. The method of claim 3998 wherein the fibrosis inhibitor is not dexamethasone. The method of claim 3998 wherein the fiber formation inhibitor is not beclomethasone. The method of claim 3998, wherein the fiber formation inhibitor is not dipropionic acid. The method of claim 3998 wherein the fibrosis inhibitor is not an anti-infective. The method of claim 3998 wherein the fibrosis inhibitor is not an antibiotic. The method of claim 3998 wherein the fibrosis inhibitor is not an antifungal agent. The method of claim 3998 wherein the anti-infective agent is an anthracycline. The method of claim 3998 wherein the anti-infective agent is doxorubicin. The method of claim 3998 wherein the anti-infective is mitoxantrone. The method of claim 3998 wherein the anti-infective agent is fluoropyrimidine. The method of claim 3998 wherein the anti-infective is 5-fluorouracil (5-FU). The method of claim 3998 wherein the anti-infective agent is a folic acid antagonist. The method of claim 3998 wherein the anti-infective is methotrexate. The method of claim 3998 wherein the anti-infective is podophyllotoxin. The method of claim 3998 wherein the anti-infective is etoposide. The method of claim 3998 wherein the anti-infective agent is camptothecin. The method of claim 3998 wherein the anti-infective is hydroxyurea. The method of claim 3998 wherein the anti-infective is a platinum complex. The method of claim 3998 wherein the anti-infective is cisplatin. The method of claim 3998, wherein the composition comprises an antithrombotic agent. The method of claim 3998, wherein the polymer is formed from a reactant comprising a naturally occurring polymer. The method of claim 3998, wherein the polymer is formed from a reactant comprising protein. The method of claim 3998, wherein the polymer is formed from a reactant comprising a carbohydrate. The method of claim 3998, wherein the polymer is formed from a reactant comprising a biodegradable polymer. The method of claim 3998, wherein the polymer is formed from a reactant comprising a non-biodegradable polymer. The method of claim 3998, wherein the polymer is formed from a reactant comprising collagen. The method of claim 3998, wherein the polymer is formed from a reactant comprising methylated collagen. The method of claim 3998, wherein the polymer is formed from a reactant comprising fibrinogen. The method of claim 3998, wherein the polymer is formed from a reactant comprising thrombin. The method of claim 3998, wherein the polymer is formed from a reactant comprising a plasma component. The method of claim 3998, wherein the polymer is formed from a reactant comprising a calcium salt. The method of claim 3998, wherein the polymer is formed from a reactant comprising a fiber formation inhibitor. The method of claim 3998, wherein the polymer is formed from a reactant comprising a fibrinogen analog. The method of claim 3998, wherein the polymer is formed from a reactant comprising albumin. The method of claim 3998, wherein the polymer is formed from a reactant comprising plasminogen. The method of claim 3998, wherein the polymer is formed from a reactant comprising von Willebrand factor. The method of claim 3998, wherein the polymer is formed from a reactant comprising Factor VIII. The method of claim 3998, wherein the polymer is formed from a reactant comprising hypoallergenic collagen. The method of claim 3998, wherein the polymer is formed from a reactant comprising atelopeptide collagen. The method of claim 3998, wherein the polymer is formed from a reactant comprising telopeptide collagen. The method of claim 3998, wherein the polymer is formed from a reactant comprising cross-linked collagen. The method of claim 3998, wherein the polymer is formed from a reactant comprising aprotinin. The method of claim 3998, wherein the polymer is formed from a reactant comprising epsilon amino-n-caproic acid. The method of claim 3998, wherein the polymer is formed from a reactant comprising gelatin. The method of claim 3998, wherein the polymer is formed from a reactant comprising a protein conjugate. The method of claim 3998, wherein the polymer is formed from a reactant comprising a gelatin conjugate. The method of claim 3998, wherein the polymer is formed from a reactant comprising a synthetic polymer. The method of claim 3998, wherein the polymer is formed from a reactant comprising a compound comprising synthetic isocyanate. The method of claim 3998, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic thiol. The method of claim 3998, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more thiol groups. The method of claim 3998, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more thiol groups. The method of claim 3998, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more thiol groups. The method of claim 3998, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic amino. The method of claim 3998, wherein the polymer is formed from a reactant consisting of a synthetic compound containing two or more amino groups. The method of claim 3998, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more amino groups. The method of claim 3998, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more amino groups. The method of claim 3998, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of claim 3998, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The method of claim 3998, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. The method of claim 3998, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more carbonyl-oxygen-succinimidyl groups. The method of claim 3998, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide. The method of claim 3998, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a polyalkylene oxide and a biodegradable polyester block. The method of claim 3998, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The method of claim 3998, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a thiol reactive group. The method of claim 3998, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The method of claim 3998, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a biodegradable polyester block. The method of claim 3998, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly comprised of lactic acid or lactide. The method of claim 3998, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly comprised of glycolic acid or glycolide. The method of claim 3998, wherein the polymer is formed from a reactant comprising polylysine. The method of claim 3998, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 3998, wherein the polymer is formed from a reactant comprising (a) a protein and (b) polylysine. The method of claim 3998, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more thiol groups. The method of claim 3998, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more amino groups. The method of claim 3998, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method described in 3998. The method of claim 3998, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 3998, wherein the polymer is formed from a reactant comprising (a) collagen and (b) polylysine. The method of claim 3998, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more thiol groups. The method of claim 3998, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more amino groups. The method of claim 3998, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method described in 3998. The method of claim 3998, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 3998, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) polylysine. The method of claim 3998, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more thiol groups. The method of claim 3998, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more amino groups. The method of claim 3998, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone, The method of claim 3998. The method of claim 3998, wherein the polymer is formed from a reactant comprising hyaluronic acid. The method of claim 3998, wherein the polymer is formed from a reactant comprising a hyaluronic acid derivative. The method of claim 3998, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The method of claim 3998, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A polymer having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene region. The method of claim 3998, formed from a reactant consisting of and a synthetic compound comprising a plurality of electrophilic groups. The method of claim 3998, wherein the composition comprises a colorant. The method of claim 3998, wherein the composition is sterile. Methods of implanting a medical device comprising: (a) a medical device to which the medical device is implanted or transplanted host tissue i) an inhibitor of fiber formation ii) an anti-infective agent iii) a polymer iv) an inhibitor of fiber formation and a polymer V) a composition comprising an anti-infective agent and a polymer or vi) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer, and (b) implanting a medical device into a host, and said medical treatment The device is a peritoneal dialysis catheter. A method of implanting a device with the medical device of claim 4255 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a fibrosis inhibitor; and (b) the host Implant a medical device. A method of implanting a device comprising the following with the medical device of claim 4255: (a) the medical device is implanted or the implanted host tissue is immersed in an anti-infective agent; and (b) the host is implanted. Implant medical devices. A method of implanting a device with the medical device of claim 4255 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a polymer; and (b) the medical device is implanted in the host. Transplant. A method of implanting a device comprising the following with the medical device of claim 4255: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising a fibrosis inhibitor and a polymer; And (b) transplant the medical device into the host. A method of implanting a device with the medical device of claim 4255 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising an anti-infective and a polymer; and (b) Transplant the medical device into the host. 40. A method of implanting a device comprising the following with the medical device of claim 4255: (a) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer in which the medical device is implanted or the host tissue into which it is implanted. And (b) implant the medical device into the host. The method of claim 4255, wherein the medical device is a peritoneal dialysis catheter adapted to deliver a drug to the peritoneum. The method of claim 4255, wherein cell regeneration is inhibited by a fiber formation inhibitor. The method of claim 4255, wherein angiogenesis is inhibited by a fiber formation inhibitor. The method of claim 4255, wherein fibroblast migration is inhibited by a fibrosis inhibitor. The method of claim 4255, wherein the fibrosis inhibitor inhibits fibroblast proliferation. The method of claim 4255, wherein the fiber formation inhibitor inhibits extracellular matrix accumulation. The method of claim 4255, wherein the tissue remodeling is inhibited by the fiber formation inhibitor. The method of claim 4255, wherein the fiber formation inhibitor is an angiogenesis inhibitor. The method of claim 4255 wherein the fiber formation inhibitor is a 5- lipoxygenase inhibitor or antagonist. The method of claim 4255, wherein the fiber formation inhibitor is a chemokine receptor antagonist. The method of claim 4255, wherein the fiber formation inhibitor is a cell cycle inhibitor. The method of claim 4255, wherein the fiber formation inhibitor is a taxane. The method of claim 4255, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 4255, wherein the fiber formation inhibitor is paclitaxel. The method of claim 4255, wherein the fiber formation inhibitor is not paclitaxel. The method of claim 4255 wherein the fibrosis inhibitor is an analogue or derivative of paclitaxel. The method of claim 4255, wherein the fiber formation inhibitor is a vinca alkaloid. The method of claim 4255 wherein the fibrosis inhibitor is camptothecin or an analogue or derivative thereof. The method of claim 4255, wherein the fiber formation inhibitor is podophyllotoxin. The method of claim 4255 wherein the fibrosis inhibitor is podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof. The method of claim 4255, wherein the fiber formation inhibitor is an anthracycline. The method of claim 4255 wherein the fibrosis inhibitor is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof. The method of claim 4255, wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof. The method of claim 4255, wherein the fiber formation inhibitor is a platinum compound. The method of claim 4255, wherein the fiber formation inhibitor is nitrosourea. The method of claim 4255, wherein the fiber formation inhibitor is nitroimidazole. The method of claim 4255, wherein the fiber formation inhibitor is a folic acid antagonist. The method of claim 4255 wherein the fibrosis inhibitor is a cytidine analogue. The method of claim 4255 wherein the fibrosis inhibitor is a pyrimidine analogue. The method of claim 4255 wherein the fiber formation inhibitor is a fluoropyrimidine analogue. The method of claim 4255 wherein the fibrosis inhibitor is a purine analogue. The method of claim 4255 wherein the fiber formation inhibitor is a nitrogen mustard or an analogue or derivative thereof. The method of claim 4255, wherein the fiber formation inhibitor is hydroxyurea. The method of claim 4255 wherein the fibrosis inhibitor is mitomycin or an analogue or derivative thereof. The method of claim 4255, wherein the fiber formation inhibitor is an alkyl sulfonate. The method of claim 4255 wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The method of claim 4255 wherein the fibrosis inhibitor is nicotinamide or an analogue or derivative thereof. The method of claim 4255 wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of claim 4255, wherein the fiber formation inhibitor is a DNA alkylating agent. The method of claim 4255, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 4255 wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of claim 4255, wherein the fiber formation inhibitor is a DNA cleaving agent. The method of claim 4255, wherein the fiber formation inhibitor is an antimetabolite. The method of claim 4255, wherein adenosine deaminase is inhibited by a fiber formation inhibitor. The method of claim 4255, wherein purine ring synthesis is inhibited by a fiber formation inhibitor. The method of claim 4255, wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of claim 4255, wherein the fiber formation inhibitor inhibits dihydrofolate reduction. The method of claim 4255, wherein thymidine monophosphate is inhibited by the fiber formation inhibitor. The method of claim 4255, wherein the fiber formation inhibitor causes DNA damage. The method of claim 4255, wherein the fiber formation inhibitor is a DNA intercalation agent. The method of claim 4255, wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The method of claim 4255, wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The method of claim 4255, wherein the fibril formation inhibitor inhibits ribonucleotide synthesis or function. The method of claim 4255, wherein the fibrosis inhibitor inhibits thymidine monophosphate synthesis or function. The method of claim 4255, wherein DNA synthesis is inhibited by the fiber formation inhibitor. The method of claim 4255, wherein the fiber formation inhibitor causes DNA adduct formation. The method of claim 4255, wherein protein synthesis is inhibited by the fiber formation inhibitor. The method of claim 4255, wherein the microtubule function is inhibited by the fiber formation inhibitor. The method of claim 4255 wherein the fibrosis inhibitor is a cyclin dependent protein kinase inhibitor. The method of claim 4255 wherein the fibrosis inhibitor is an epidermal growth factor kinase inhibitor. The method of claim 4255, wherein the fiber formation inhibitor is an elastase inhibitor. The method of claim 4255, wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of claim 4255 wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of claim 4255 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 4255 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 4255 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist. The method of claim 4255 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist, and the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof. The method of claim 4255 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 4255 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The method of claim 4255 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof. The method of claim 4255 wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. The method of claim 4255 wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of claim 4255 wherein the fibrosis inhibitor is an IL-1 antagonist. The method of claim 4255 wherein the fibrosis inhibitor is an ICE antagonist. The method of claim 4255, wherein the fiber formation inhibitor is an IRAK antagonist. The method of claim 4255 wherein the fibrosis inhibitor is an IL-4 agonist. The method of claim 4255, wherein the fiber formation inhibitor is an immunomodulator. The method of claim 4255 wherein the fibrosis inhibitor is sirolimus or an analogue or derivative thereof. The method of claim 4255, wherein the fiber formation inhibitor is not sirolimus. The method of claim 4255 wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. The method of claim 4255 wherein the fibrosis inhibitor is tacrolimus or an analogue or derivative thereof. The method of claim 4255, wherein the fiber formation inhibitor is not tacrolimus. The method of claim 4255 wherein the fibrosis inhibitor is biolimus or an analogue or derivative thereof. The method of claim 4255 wherein the fibrosis inhibitor is tresperimus or an analogue or derivative thereof. The method of claim 4255 wherein the fibrosis inhibitor is auranofin or an analogue or derivative thereof. The method of claim 4255 wherein the fibrosis inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of claim 4255 wherein the fibrosis inhibitor is gusperimus or an analogue or derivative thereof. The method of claim 4255 wherein the fibrosis inhibitor is pimecrolimus or an analogue or derivative thereof. The method of claim 4255 wherein the fibrosis inhibitor is ABT-578 or an analogue or derivative thereof. The method of claim 4255 wherein the fiber formation inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. The method of claim 4255, wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof. The method of claim 4255 wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-α-25 dihydroxy vitamin D ₃ or an analogue or derivative thereof. The method of claim 4255, wherein the fiber formation inhibitor is a leukotriene inhibitor. The method of claim 4255 wherein the vascularization inhibitor is an MCP-1 antagonist. The method of claim 4255, wherein the fiber formation inhibitor is an MMP inhibitor. The method of claim 4255, wherein the fiber formation inhibitor is an NFκB inhibitor. The method of claim 4255, wherein the fiber formation inhibitor is an NFκB inhibitor, wherein the NFκB inhibitor is Bay11-7082. The method of claim 4255, wherein the fiber formation inhibitor is a NO antagonist. The method of claim 4255 wherein the fibrosis inhibitor is a p38 MAP kinase inhibitor. The method of claim 4255, wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor, and the p38 MAP kinase inhibitor is SB202190. The method of claim 4255, wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The method of claim 4255, wherein the fiber formation inhibitor is a TGF beta inhibitor. The method of claim 4255 wherein the fibrosis inhibitor is a thromboxane A2 antagonist. The method of claim 4255 wherein the vascularization inhibitor is a TNFα antagonist. The method of claim 4255, wherein the fiber formation inhibitor is a TACE inhibitor. The method of claim 4255 wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. The method of claim 4255, wherein the fiber formation inhibitor is a vitronectin inhibitor. The method of claim 4255 wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of claim 4255, wherein the fiber formation inhibitor is a protein kinase inhibitor. The method of claim 4255, wherein the fiber formation inhibitor is a PDGF receptor kinase inhibitor. The method of claim 4255 wherein the fibrosis inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of claim 4255, wherein the fiber formation inhibitor is a retinoic acid receptor antagonist. The method of claim 4255 wherein the fibrosis inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of claim 4255 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 4255, wherein the fiber formation inhibitor is an antifungal agent. The method of claim 4255, wherein the fiber formation inhibitor is an antifungal agent, and the antifungal agent is sulconizole. The method of claim 4255, wherein the fiber formation inhibitor is a bisphosphonate. The method of claim 4255, wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. The method of claim 4255 wherein the fibrosis inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The method of claim 4255, wherein the fiber formation inhibitor is a macrolide antibiotic. The method of claim 4255 wherein the fibrosis inhibitor is a GPIIb / IIIa receptor antagonist. The method of claim 4255, wherein the fiber formation inhibitor is an endothelin receptor antagonist. The method of claim 4255 wherein the fibrosis inhibitor is an agonist of the peroxisome proliferator-responsive receptor. The method of claim 4255 wherein the fibrosis inhibitor is an estrogen receptor agent. The method of claim 4255 wherein the fibrosis inhibitor is a somastatin analog. The method of claim 4255, wherein the fiber formation inhibitor is a neurokinin 1 antagonist. The method of claim 4255, wherein the fiber formation inhibitor is a neurokinin 3 antagonist. The method of claim 4255 wherein the fibrosis inhibitor is a VLA-4 antagonist. The method of claim 4255 wherein the fibrosis inhibitor is an osteoclast inhibitor. The method of claim 4255, wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The method of claim 4255 wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of claim 4255 wherein the fibrosis inhibitor is an angiotensin II antagonist. The method of claim 4255, wherein the fiber formation inhibitor is an enkephalinase inhibitor. The method of claim 4255 wherein the fibrosis inhibitor is a peroxisome proliferator-responsive receptor gamma agonist insulin sensitizer. The method of claim 4255, wherein the fiber formation inhibitor is a protein kinase C inhibitor. The method of claim 4255 wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. The method of claim 4255, wherein the fiber formation inhibitor is a CXCR3 inhibitor. The method of claim 4255, wherein the fiber formation inhibitor is an Itk inhibitor. The method of claim 4255 wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of claim 4255 wherein the fibrosis inhibitor is a PPAR agonist. The method of claim 4255, wherein the fiber formation inhibitor is an immunosuppressant. The method of claim 4255, wherein the fiber formation inhibitor is an Erb inhibitor. The method of claim 4255 wherein the fibrosis inhibitor is an apoptosis agonist. The method of claim 4255 wherein the fibrosis inhibitor is a lipocortin agonist. The method of claim 4255 wherein the fibrosis inhibitor is a VCAM-1 antagonist. The method of claim 4255, wherein the fiber formation inhibitor is a collagen antagonist. The method of claim 4255 wherein the fiber formation inhibitor is an α2 integrin antagonist. The method of claim 4255, wherein the fiber formation inhibitor is a TNFα inhibitor. The method of claim 4255, wherein the fiber formation inhibitor is a nitric oxide inhibitor. The method of claim 4255, wherein the fiber formation inhibitor is a cathepsin inhibitor. The method of claim 4255 wherein the fibrosis inhibitor is not an anti-inflammatory agent. The method of claim 4255 wherein the fibrosis inhibitor is not a steroid. The method of claim 4255, wherein the fiber formation inhibitor is not a glucocorticosteroid. The method of claim 4255, wherein the fiber formation inhibitor is not dexamethasone. The method of claim 4255 wherein the fibrosis inhibitor is not beclomethasone. The method of claim 4255, wherein the fiber formation inhibitor is not dipropionic acid. The method of claim 4255, wherein the fiber formation inhibitor is not an anti-infective. The method of claim 4255 wherein the fibrosis inhibitor is not an antibiotic. The method of claim 4255, wherein the fiber formation inhibitor is not an antifungal agent. The method of claim 4255 wherein the anti-infective is an anthracycline. The method of claim 4255 wherein the anti-infective is doxorubicin. The method of claim 4255, wherein the anti-infective is mitoxantrone. The method of claim 4255 wherein the anti-infective is fluoropyrimidine. The method of claim 4255 wherein the anti-infective is 5-fluorouracil (5-FU). The method of claim 4255 wherein the anti-infective agent is a folic acid antagonist. The method of claim 4255 wherein the anti-infective is methotrexate. The method of claim 4255 wherein the anti-infective is podophyllotoxin. The method of claim 4255, wherein the anti-infective is etoposide. The method of claim 4255, wherein the anti-infective is camptothecin. The method of claim 4255, wherein the anti-infective is hydroxyurea. The method of claim 4255, wherein the anti-infective is a platinum complex. The method of claim 4255 wherein the anti-infective is cisplatin. The method of claim 4255, wherein the composition comprises an antithrombotic agent. The method of claim 4255, wherein the polymer is formed from a reactant comprising a naturally occurring polymer. The method of claim 4255, wherein the polymer is formed from a reactant comprising protein. The method of claim 4255, wherein the polymer is formed from reactants comprising carbohydrate. The method of claim 4255, wherein the polymer is formed from a reactant comprising a biodegradable polymer. The method of claim 4255, wherein the polymer is formed from a reactant comprising a non-biodegradable polymer. The method of claim 4255, wherein the polymer is formed from a reactant comprising collagen. The method of claim 4255, wherein the polymer is formed from a reactant comprising methylated collagen. The method of claim 4255, wherein the polymer is formed from a reactant comprising fibrinogen. The method of claim 4255, wherein the polymer is formed from a reactant comprising thrombin. The method of claim 4255, wherein the polymer is formed from reactants comprising plasma components. The method of claim 4255, wherein the polymer is formed from a reactant comprising a calcium salt. The method of claim 4255, wherein the polymer is formed from a reactant comprising a fiber formation inhibitor. The method of claim 4255, wherein the polymer is formed from a reactant comprising a fibrinogen analog. The method of claim 4255, wherein the polymer is formed from a reactant comprising albumin. The method of claim 4255, wherein the polymer is formed from a reactant comprising plasminogen. The method of claim 4255, wherein the polymer is formed from a reactant comprising von Willebrand factor. The method of claim 4255, wherein the polymer is formed from a reactant comprising Factor VIII. The method of claim 4255, wherein the polymer is formed from reactants comprising hypoallergenic collagen. The method of claim 4255, wherein the polymer is formed from a reactant comprising atelopeptide collagen. The method of claim 4255, wherein the polymer is formed from a reactant comprising telopeptide collagen. The method of claim 4255, wherein the polymer is formed from a reactant comprising cross-linked collagen. The method of claim 4255, wherein the polymer is formed from a reactant comprising aprotinin. The method of claim 4255, wherein the polymer is formed from a reactant comprising epsilon amino-n-caproic acid. The method of claim 4255, wherein the polymer is formed from a reactant comprising gelatin. The method of claim 4255, wherein the polymer is formed from a reactant comprising a protein conjugate. The method of claim 4255, wherein the polymer is formed from a reactant comprising a gelatin conjugate. The method of claim 4255, wherein the polymer is formed from a reactant comprising a synthetic polymer. The method of claim 4255, wherein the polymer is formed from a reactant comprising a compound comprising synthetic isocyanate. The method of claim 4255, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic thiol. The method of claim 4255, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more thiol groups. The method of claim 4255, wherein the polymer is formed from reactants comprised of synthetic compounds comprising three or more thiol groups. The method of claim 4255, wherein the polymer is formed from reactants comprised of synthetic compounds comprising four or more thiol groups. The method of claim 4255, wherein the polymer is formed from a reactant comprising a compound comprising synthetic amino. The method of claim 4255, wherein the polymer is formed from reactants consisting of a synthetic compound containing two or more amino groups. The method of claim 4255, wherein the polymer is formed from reactants consisting of synthetic compounds containing three or more amino groups. The method of claim 4255, wherein the polymer is formed from reactants comprised of synthetic compounds comprising four or more amino groups. The method of claim 4255, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of claim 4255, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The method of claim 4255, wherein the polymer is formed from reactants comprised of synthetic compounds comprising three or more carbonyl-oxygen-succinimidyl groups. The method of claim 4255, wherein the polymer is formed from reactants comprised of synthetic compounds comprising four or more carbonyl-oxygen-succinimidyl groups. The method of claim 4255, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide. The method of claim 4255, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a polyalkylene oxide and a biodegradable polyester block. The method of claim 4255, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The method of claim 4255, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide having a thiol reactive group. The method of claim 4255, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The method of claim 4255, wherein the polymer is formed from reactants comprising a synthetic compound comprising a biodegradable polyester block. The method of claim 4255, wherein the polymer is formed from reactants comprising a synthetic polymer, wholly or partly comprised of lactic acid or lactide. The method of claim 4255, wherein the polymer is formed from reactants comprising a synthetic polymer, wholly or partly comprised of glycolic acid or glycolide. The method of claim 4255, wherein the polymer is formed from a reactant comprising polylysine. The method of claim 4255, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 4255, wherein the polymer is formed from reactants comprising (a) a protein and (b) polylysine. The method of claim 4255, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more thiol groups. The method of claim 4255, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more amino groups. The method of claim 4255, wherein the polymer is formed from a reactant comprising: (a) a protein; and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method described in 4255. The method of claim 4255, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 4255, wherein the polymer is formed from reactants comprising (a) collagen and (b) polylysine. The method of claim 4255, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more thiol groups. The method of claim 4255, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more amino groups. The method of claim 4255, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method described in 4255. The method of claim 4255, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 4255, wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) polylysine. The method of claim 4255, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more thiol groups. The method of claim 4255, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more amino groups. The method of claim 4255, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone, The method of claim 4255. The method of claim 4255, wherein the polymer is formed from a reactant comprising hyaluronic acid. The method of claim 4255, wherein the polymer is formed from a reactant comprising a hyaluronic acid derivative. The method of claim 4255, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The method of claim 4255, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A polymer having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene region. The method of claim 4255, wherein the method is formed from a reactant comprising a synthetic compound comprising a plurality of electrophilic groups. The method of claim 4255, wherein the composition comprises a colorant. The method of claim 4255, wherein the composition is sterile. Methods of implanting a medical device comprising: (a) a medical device to which the medical device is implanted or transplanted host tissue i) an inhibitor of fiber formation ii) an anti-infective agent iii) a polymer iv) an inhibitor of fiber formation and a polymer V) a composition comprising an anti-infective and polymer or vi) a composition comprising a fibrosis inhibitor, an anti-infective and a polymer, and (b) implanting a medical device into a host The device is a central nervous system shunt or pressure monitoring. A method of implanting a device with the medical device of claim 4509 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a fibrosis inhibitor; and (b) the host Implant a medical device. A method of implanting a device with the medical device of claim 4509 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in an anti-infective agent; and (b) the host is implanted. Implant medical devices. The method of implanting a device with the medical device of claim 4509 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a polymer; and (b) the medical device is in the host. Transplant. A method of implanting a device comprising the following with the medical device of claim 4509: (a) immersing the host tissue into which the medical device is implanted or implanted with a composition comprising a fibrosis inhibitor and a polymer; And (b) transplant the medical device into the host. A method of implanting a device with the medical device of claim 4509 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) Transplant the medical device into the host. A method of implanting a device comprising the following with the medical device of claim 4509: (a) a composition comprising a fibrosis inhibitor, an anti-infective agent, and a polymer in which the medical device is implanted or the implanted host tissue. And (b) implant the medical device into the host. The method of claim 4509 wherein the medical device is a ventricular thoracic shunt. The method of claim 4509 wherein the medical device is a jugular vein shunt. The method of claim 4509 wherein the medical device is a vena cava shunt. The method of claim 4509 wherein the medical device is a ventricular thoracic shunt. The method of claim 4509 wherein the medical device is a gallbladder shunt. The method of claim 4509 wherein the medical device is a peritoneal shunt. The method of claim 4509 wherein the medical device is an extraventricular drainage device. The method of claim 4509 wherein the medical device is an intracranial pressure monitoring device. The method of claim 4509 wherein the medical device is a dural patch. The method of claim 4509 wherein the medical device is an implant to prevent epidural fibrosis after laminectomy. The method of claim 4509 wherein the medical device is a device for continuous subarachnoid injection. The method of claim 4509 wherein the medical device is a drainage shunt that serves to drain brain fluid. The method of claim 4509, wherein the medical device is a pressure monitoring device. The method of claim 4509, wherein cell regeneration is inhibited by a fiber formation inhibitor. The method of claim 4509 wherein angiogenesis is inhibited by a fiber formation inhibitor. The method of claim 4509, wherein fibrosis inhibitor is inhibited by fibrosis inhibitor. The method of claim 4509 wherein the fibrosis inhibitor inhibits fibroblast proliferation. The method of claim 4509 wherein the fiber formation inhibitor inhibits extracellular matrix accumulation. The method of claim 4509 wherein the tissue remodeling is inhibited by the fiber formation inhibitor. The method of claim 4509 wherein the fibrosis inhibitor is an angiogenesis inhibitor. The method of claim 4509 wherein the fibrosis inhibitor is a 5-lipoxygenase inhibitor or antagonist. The method of claim 4509 wherein the fibrosis inhibitor is a chemokine receptor antagonist. The method of claim 4509 wherein the fibrosis inhibitor is a cell cycle inhibitor. The method of claim 4509 wherein the fiber formation inhibitor is a taxane. The method of claim 4509 wherein the fibrosis inhibitor is a microtubule inhibitor. The method of claim 4509 wherein the fiber formation inhibitor is paclitaxel. The method of claim 4509 wherein the fiber formation inhibitor is not paclitaxel. The method of claim 4509 wherein the fibrosis inhibitor is an analogue or derivative of paclitaxel. The method of claim 4509 wherein the fiber formation inhibitor is a vinca alkaloid. The method of claim 4509 wherein the fibrosis inhibitor is camptothecin or an analogue or derivative thereof. The method of claim 4509 wherein the fibrosis inhibitor is podophyllotoxin. The method of claim 4509 wherein the fibrosis inhibitor is podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof. The method of claim 4509 wherein the fibrosis inhibitor is an anthracycline. The method of claim 4509 wherein the fibrosis inhibitor is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof. The method of claim 4509 wherein the fibrosis inhibitor is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof. The method of claim 4509 wherein the fiber formation inhibitor is a platinum compound. The method of claim 4509 wherein the fiber formation inhibitor is nitrosourea. The method of claim 4509 wherein the fiber formation inhibitor is nitroimidazole. The method of claim 4509 wherein the fibrosis inhibitor is a folic acid antagonist. The method of claim 4509 wherein the fibrosis inhibitor is a cytidine analog. The method of claim 4509 wherein the fibrosis inhibitor is a pyrimidine analogue. The method of claim 4509 wherein the fiber formation inhibitor is a fluoropyrimidine analogue. The method of claim 4509 wherein the fibrosis inhibitor is a purine analogue. The method of claim 4509 wherein the fiber formation inhibitor is nitrogen mustard or an analogue or derivative thereof. The method of claim 4509 wherein the fiber formation inhibitor is hydroxyurea. The method of claim 4509 wherein the fibrosis inhibitor is mitomycin or an analogue or derivative thereof. The method of claim 4509 wherein the fiber formation inhibitor is an alkyl sulfonate. The method of claim 4509 wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The method of claim 4509 wherein the fibrosis inhibitor is nicotinamide or an analogue or derivative thereof. The method of claim 4509 wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of claim 4509 wherein the fiber formation inhibitor is a DNA alkylating agent. The method of claim 4509 wherein the fibrosis inhibitor is a microtubule inhibitor. The method of claim 4509 wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of claim 4509 wherein the fiber formation inhibitor is a DNA cleaving agent. The method of claim 4509 wherein the fibrosis inhibitor is an antimetabolite. The method of claim 4509, wherein adenosine deaminase is inhibited by a fiber formation inhibitor. The method of claim 4509, wherein purine ring synthesis is inhibited by a fiber formation inhibitor. The method of claim 4509 wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of claim 4509 wherein the fibrosis inhibitor inhibits dihydrofolate reduction. The method of claim 4509 wherein thymidine monophosphate is inhibited by the fiber formation inhibitor. The method of claim 4509 wherein the fiber formation inhibitor causes DNA damage. The method of claim 4509 wherein the fiber formation inhibitor is a DNA intercalation agent. The method of claim 4509 wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The method of claim 4509 wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The method of claim 4509 wherein the fibril formation inhibitor inhibits ribonucleotide synthesis or function. The method of claim 4509 wherein the fibrosis inhibitor inhibits thymidine monophosphate synthesis or function. The method of claim 4509, wherein DNA synthesis is inhibited by the fiber formation inhibitor. The method of claim 4509 wherein DNA adduct formation occurs with a fiber formation inhibitor. The method of claim 4509 wherein protein synthesis is inhibited by a fiber formation inhibitor. The method of claim 4509, wherein the microtubule function is inhibited by the fiber formation inhibitor. The method of claim 4509 wherein the fibrosis inhibitor is a cyclin dependent protein kinase inhibitor. The method of claim 4509 wherein the fibrosis inhibitor is an epidermal growth factor kinase inhibitor. The method of claim 4509 wherein the fiber formation inhibitor is an elastase inhibitor. The method of claim 4509 wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of claim 4509 wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of claim 4509 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 4509 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 4509 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist. The method of claim 4509 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist, and the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof. The method of claim 4509 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 4509 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The method of claim 4509 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof. The method of claim 4509 wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. The method of claim 4509 wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of claim 4509 wherein the fibrosis inhibitor is an IL-1 antagonist. The method of claim 4509 wherein the fibrosis inhibitor is an ICE antagonist. The method of claim 4509 wherein the fibrosis inhibitor is an IRAK antagonist. The method of claim 4509 wherein the fibrosis inhibitor is an IL-4 agonist. The method of claim 4509 wherein the fibrosis inhibitor is an immunomodulator. The method of claim 4509 wherein the fibrosis inhibitor is sirolimus or an analogue or derivative thereof. The method of claim 4509 wherein the fibrosis inhibitor is not sirolimus. The method of claim 4509 wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. The method of claim 4509 wherein the fibrosis inhibitor is tacrolimus or an analogue or derivative thereof. The method of claim 4509 wherein the fibrosis inhibitor is not tacrolimus. The method of claim 4509 wherein the fibrosis inhibitor is biolimus or an analogue or derivative thereof. The method of claim 4509 wherein the fibrosis inhibitor is tresperimus or an analogue or derivative thereof. The method of claim 4509 wherein the fibrosis inhibitor is auranofin or an analogue or derivative thereof. The method of claim 4509 wherein the fibrosis inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of claim 4509 wherein the fibrosis inhibitor is gusperimus or an analogue or derivative thereof. The method of claim 4509 wherein the fibrosis inhibitor is pimecrolimus or an analogue or derivative thereof. The method of claim 4509 wherein the fibrosis inhibitor is ABT-578 or an analogue or derivative thereof. The method of claim 4509 wherein the fiber formation inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. The method of claim 4509 wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof. The method of claim 4509 wherein the fibrosis inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-α-25 dihydroxy vitamin D ₃ or an analogue or derivative thereof. The method of claim 4509 wherein the fiber formation inhibitor is a leukotriene inhibitor. The method of claim 4509 wherein the vascularization inhibitor is an MCP-1 antagonist. The method of claim 4509 wherein the fiber formation inhibitor is an MMP inhibitor. The method of claim 4509 wherein the fiber formation inhibitor is an NFκB inhibitor. The method of claim 4509, wherein the fiber formation inhibitor is an NFκB inhibitor, wherein the NFκB inhibitor is Bay11-7082. The method of claim 4509 wherein the fibrosis inhibitor is a NO antagonist. The method of claim 4509 wherein the fibrosis inhibitor is a p38 MAP kinase inhibitor. The method of claim 4509 wherein the fibrosis inhibitor is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB202190. The method of claim 4509 wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The method of claim 4509 wherein the fibrosis inhibitor is a TGF beta inhibitor. The method of claim 4509 wherein the fibrosis inhibitor is a thromboxane A2 antagonist. The method of claim 4509 wherein the vascularization inhibitor is a TNFα antagonist. The method of claim 4509 wherein the fiber formation inhibitor is a TACE inhibitor. The method of claim 4509 wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. The method of claim 4509 wherein the fiber formation inhibitor is a vitronectin inhibitor. The method of claim 4509 wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of claim 4509 wherein the fiber formation inhibitor is a protein kinase inhibitor. The method of claim 4509 wherein the fibrosis inhibitor is a PDGF receptor kinase inhibitor. The method of claim 4509 wherein the fibrosis inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of claim 4509 wherein the fibrosis inhibitor is a retinoic acid receptor antagonist. The method of claim 4509 wherein the fibrosis inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of claim 4509 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 4509 wherein the fibrosis inhibitor is an antifungal agent. The method of claim 4509 wherein the fibrosis inhibitor is an antifungal agent, and the antifungal agent is sulconizole. The method of claim 4509 wherein the fiber formation inhibitor is a bisphosphonate. The method of claim 4509 wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. The method of claim 4509 wherein the fibrosis inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The method of claim 4509 wherein the fiber formation inhibitor is a macrolide antibiotic. The method of claim 4509 wherein the fibrosis inhibitor is a GPIIb / IIIa receptor antagonist. The method of claim 4509 wherein the fibrosis inhibitor is an endothelin receptor antagonist. The method of claim 4509 wherein the fibrosis inhibitor is an agonist of peroxisome proliferator-responsive receptor. The method of claim 4509 wherein the fibrosis inhibitor is an estrogen receptor agent. The method of claim 4509 wherein the fibrosis inhibitor is a somostatin analog. The method of claim 4509 wherein the fibrosis inhibitor is a neurokinin 1 antagonist. The method of claim 4509 wherein the fibrosis inhibitor is a neurokinin 3 antagonist. The method of claim 4509 wherein the fibrosis inhibitor is a VLA-4 antagonist. The method of claim 4509 wherein the fibrosis inhibitor is an osteoclast inhibitor. The method of claim 4509 wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The method of claim 4509 wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of claim 4509 wherein the fibrosis inhibitor is an angiotensin II antagonist. The method of claim 4509 wherein the fiber formation inhibitor is an enkephalinase inhibitor. The method of claim 4509 wherein the fibrosis inhibitor is a peroxisome proliferator-responsive receptor gamma agonist insulin sensitizer. The method of claim 4509 wherein the fiber formation inhibitor is a protein kinase C inhibitor. The method of claim 4509 wherein the fibrosis inhibitor is a ROCK (Rho kinase) inhibitor. The method of claim 4509 wherein the fiber formation inhibitor is a CXCR3 inhibitor. The method of claim 4509 wherein the fiber formation inhibitor is an Itk inhibitor. The method of claim 4509 wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of claim 4509 wherein the fibrosis inhibitor is a PPAR agonist. The method of claim 4509 wherein the fibrosis inhibitor is an immunosuppressant. The method of claim 4509 wherein the fiber formation inhibitor is an Erb inhibitor. The method of claim 4509 wherein the fibrosis inhibitor is an apoptosis agonist. The method of claim 4509 wherein the fibrosis inhibitor is a lipocortin agonist. The method of claim 4509 wherein the fibrosis inhibitor is a VCAM-1 antagonist. The method of claim 4509 wherein the fiber formation inhibitor is a collagen antagonist. The method of claim 4509 wherein the fibrosis inhibitor is an α2 integrin antagonist. The method of claim 4509 wherein the fibrosis inhibitor is a TNFα inhibitor. The method of claim 4509 wherein the fiber formation inhibitor is a nitric oxide inhibitor The method of claim 4509 wherein the fibrosis inhibitor is a cathepsin inhibitor. The method of claim 4509 wherein the fibrosis inhibitor is not an anti-inflammatory agent. The method of claim 4509 wherein the fibrosis inhibitor is not a steroid. The method of claim 4509 wherein the fibrosis inhibitor is not a glucocorticosteroid. The method of claim 4509 wherein the fibrosis inhibitor is not dexamethasone. The method of claim 4509 wherein the fiber formation inhibitor is not beclomethasone. The method of claim 4509 wherein the fiber formation inhibitor is not dipropionic acid. The method of claim 4509 wherein the fibrosis inhibitor is not an anti-infective. The method of claim 4509 wherein the fibrosis inhibitor is not an antibiotic. The method of claim 4509 wherein the fibrosis inhibitor is not an antifungal agent. The method of claim 4509 wherein the anti-infective is an anthracycline. The method of claim 4509 wherein the anti-infective is doxorubicin. The method of claim 4509 wherein the anti-infective is mitoxantrone. The method of claim 4509 wherein the anti-infective agent is a fluoropyrimidine. The method of claim 4509 wherein the anti-infective is 5-fluorouracil (5-FU). The method of claim 4509 wherein the anti-infective agent is a folic acid antagonist. The method of claim 4509 wherein the anti-infective agent is methotrexate. The method of claim 4509 wherein the anti-infective is podophyllotoxin. The method of claim 4509 wherein the anti-infective is etoposide. The method of claim 4509 wherein the anti-infective is camptothecin. The method of claim 4509 wherein the anti-infective is hydroxyurea. The method of claim 4509 wherein the anti-infective is a platinum complex. The method of claim 4509 wherein the anti-infective is cisplatin. The method of claim 4509, wherein the composition comprises an antithrombotic agent. The method of claim 4509, wherein the polymer is formed from a reactant comprising a naturally occurring polymer. The method of claim 4509, wherein the polymer is formed from a reactant comprising protein. The method of claim 4509, wherein the polymer is formed from reactants comprising carbohydrate. The method of claim 4509, wherein the polymer is formed from a reactant comprising a biodegradable polymer. The method of claim 4509 wherein the polymer is formed from a reactant comprising a non-biodegradable polymer. The method of claim 4509, wherein the polymer is formed from a reactant comprising collagen. The method of claim 4509 wherein the polymer is formed from a reactant comprising methylated collagen. The method of claim 4509, wherein the polymer is formed from a reactant comprising fibrinogen. The method of claim 4509 wherein the polymer is formed from a reactant comprising thrombin. The method of claim 4509, wherein the polymer is formed from a reactant comprising a plasma component. The method of claim 4509, wherein the polymer is formed from a reactant comprising a calcium salt. The method of claim 4509 wherein the polymer is formed from a reactant comprising a fiber formation inhibitor. The method of claim 4509 wherein the polymer is formed from a reactant comprising a fibrinogen analog. The method of claim 4509, wherein the polymer is formed from a reactant comprising albumin. The method of claim 4509 wherein the polymer is formed from a reactant comprising plasminogen. The method of claim 4509 wherein the polymer is formed from a reactant comprising von Willebrand factor. The method of claim 4509 wherein the polymer is formed from a reactant comprising Factor VIII. The method of claim 4509 wherein the polymer is formed from a reactant comprising hypoallergenic collagen. The method of claim 4509 wherein the polymer is formed from a reactant comprising atelopeptide collagen. The method of claim 4509 wherein the polymer is formed from a reactant comprising telopeptide collagen. The method of claim 4509 wherein the polymer is formed from a reactant comprising cross-linked collagen. The method of claim 4509 wherein the polymer is formed from a reactant comprising aprotinin. The method of claim 4509 wherein the polymer is formed from a reactant comprising epsilon amino-n-caproic acid. The method of claim 4509, wherein the polymer is formed from a reactant comprising gelatin. The method of claim 4509 wherein the polymer is formed from a reactant comprising a protein conjugate. The method of claim 4509 wherein the polymer is formed from a reactant comprising a gelatin conjugate. The method of claim 4509, wherein the polymer is formed from a reactant comprising a synthetic polymer. The method of claim 4509, wherein the polymer is formed from a reactant comprising a compound comprising synthetic isocyanate. The method of claim 4509, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic thiol. The method of claim 4509 wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more thiol groups. The method of claim 4509 wherein the polymer is formed from a reactant comprising a synthetic compound comprising 3 or more thiol groups. The method of claim 4509 wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more thiol groups. The method of claim 4509, wherein the polymer is formed from a reactant comprising a compound comprising synthetic amino. The method of claim 4509 wherein the polymer is formed from a reactant comprised of a synthetic compound containing two or more amino groups. The method of claim 4509 wherein the polymer is formed from reactants consisting of a synthetic compound containing three or more amino groups. The method of claim 4509 wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more amino groups. The method of claim 4509 wherein the polymer is formed from a reactant comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of claim 4509 wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The method of claim 4509 wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. The method of claim 4509, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more carbonyl-oxygen-succinimidyl groups. The method of claim 4509, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide. The method of claim 4509, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a polyalkylene oxide and a biodegradable polyester block. The method of claim 4509, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The method of claim 4509 wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide having a thiol reactive group. The method of claim 4509, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The method of claim 4509, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a biodegradable polyester block. The method of claim 4509, wherein the polymer is formed from reactants comprising a synthetic polymer, wholly or partly comprised of lactic acid or lactide. The method of claim 4509, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly consisting of glycolic acid or glycolide. The method of claim 4509, wherein the polymer is formed from a reactant comprising polylysine. The method of claim 4509, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 4509, wherein the polymer is formed from a reactant comprising (a) a protein and (b) polylysine. The method of claim 4509, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more thiol groups. The method of claim 4509 wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more amino groups. The method of claim 4509, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method of 4509. The method of claim 4509 wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 4509, wherein the polymer is formed from reactants comprising (a) collagen and (b) polylysine. The method of claim 4509 wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more thiol groups. The method of claim 4509 wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more amino groups. The method of claim 4509 wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method of 4509. The method of claim 4509, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 4509, wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) polylysine. The method of claim 4509 wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more thiol groups. The method of claim 4509 wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more amino groups. The method of claim 4509, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone, The method of claim 4509. The method of claim 4509, wherein the polymer is formed from a reactant comprising hyaluronic acid. The method of claim 4509 wherein the polymer is formed from a reactant comprising a hyaluronic acid derivative. The method of claim 4509 wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The method of claim 4509 wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A polymer having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene region. The method of claim 4509, wherein the method is formed from a reactant comprising a synthetic compound comprising a plurality of electrophilic groups. The method of claim 4509, wherein the composition comprises a colorant. The method of claim 4509 wherein the composition is sterile. Methods of implanting a medical device comprising: (a) a medical device to which the medical device is implanted or transplanted host tissue i) an inhibitor of fiber formation ii) an anti-infective agent iii) a polymer iv) an inhibitor of fiber formation and a polymer V) a composition comprising an anti-infective agent and a polymer or vi) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer, and (b) implanting a medical device into a host, and said medical treatment The device is an inferior vena cava filter. A method of implanting a device with the medical device of claim 4775 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a fibrosis inhibitor; and (b) the host Implant a medical device. A method of implanting a device with the medical device of claim 4775 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in an anti-infective agent; and (b) the host is implanted. Implant medical devices. A method of implanting a device with the medical device of claim 4775 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a polymer; and (b) the medical device is in the host. Transplant. A method of implanting a device comprising the medical device of claim 4775 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising a fibrosis inhibitor and a polymer; And (b) transplant the medical device into the host. A method of implanting a device with the medical device of claim 4775 comprising: (a) immersing the tissue of the host to which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) Transplant the medical device into the host. The method of implanting a device comprising: a) a medical device in which the medical device is implanted or the host tissue into which the device is implanted comprises a fibrosis inhibitor, an anti-infective agent and a polymer; And (b) implant the medical device into the host. The method of claim 4775, wherein the medical device is a vascular filter. The method of claim 4775, wherein the medical device is a blood filter. The method of claim 4775, wherein the medical device is a vena cava filter. The method of claim 4775, wherein the medical device is an aortic filter. The method of claim 4775, wherein the medical device is a thrombus filter. The method of claim 4775, wherein the medical device is a migration inhibition filter. The method of claim 4775, wherein the medical device is a transcutaneous filter system. The method of claim 4775, wherein the medical device is an intravascular trap. The method of claim 4775, wherein the medical device is an intravascular filter. The method of claim 4775, wherein the medical device is a clot filter. The method of claim 4775, wherein the medical device is a venous filter. The method of claim 4775, wherein the medical device is a body vascular filter. The method of claim 4775, wherein cell regeneration is inhibited by the fiber formation inhibitor. The method of claim 4775, wherein angiogenesis is inhibited by the fiber formation inhibitor. The method of claim 4775, wherein fibroblast migration is inhibited by a fibrosis inhibitor. The method of claim 4775, wherein the fibrosis inhibitor inhibits fibroblast proliferation. The method of claim 4775, wherein the fiber formation inhibitor inhibits extracellular matrix accumulation. The method of claim 4775, wherein the tissue remodeling is inhibited by the fiber formation inhibitor. The method of claim 4775, wherein the fiber formation inhibitor is an angiogenesis inhibitor. The method of claim 4775 wherein the fibrosis inhibitor is a 5- lipoxygenase inhibitor or antagonist. The method of claim 4775 wherein the fibrosis inhibitor is a chemokine receptor antagonist. The method of claim 4775, wherein the fiber formation inhibitor is a cell cycle inhibitor. The method of claim 4775, wherein the fiber formation inhibitor is a taxane. The method of claim 4775 wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 4775 wherein the fiber formation inhibitor is paclitaxel. The method of claim 4775 wherein the fiber formation inhibitor is not paclitaxel. The method of claim 4775 wherein the fibrosis inhibitor is an analogue or derivative of paclitaxel. The method of claim 4775, wherein the fiber formation inhibitor is a vinca alkaloid. The method of claim 4775 wherein the fibrosis inhibitor is camptothecin or an analogue or derivative thereof. The method of claim 4775 wherein the fiber formation inhibitor is podophyllotoxin. The method of claim 4775 wherein the fiber formation inhibitor is podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof. The method of claim 4775 wherein the fiber formation inhibitor is an anthracycline. The method of claim 4775 wherein the fibrosis inhibitor is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof. The method of claim 4775 wherein the fibrosis inhibitor is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof. The method of claim 4775, wherein the fiber formation inhibitor is a platinum compound. The method of claim 4775 wherein the fiber formation inhibitor is nitrosourea. The method of claim 4775, wherein the fiber formation inhibitor is nitroimidazole. The method of claim 4775 wherein the fiber formation inhibitor is a folic acid antagonist. The method of claim 4775 wherein the fiber formation inhibitor is a cytidine analog. The method of claim 4775 wherein the fibrosis inhibitor is a pyrimidine analogue. The method of claim 4775 wherein the fiber formation inhibitor is a fluoropyrimidine analog. The method of claim 4775 wherein the fibrosis inhibitor is a purine analogue. The method of claim 4775 wherein the fiber formation inhibitor is nitrogen mustard or an analogue or derivative thereof. The method of claim 4775, wherein the fiber formation inhibitor is hydroxyurea. The method of claim 4775 wherein the fibrosis inhibitor is mitomycin or an analogue or derivative thereof. The method of claim 4775 wherein the fiber formation inhibitor is an alkyl sulfonate. The method of claim 4775 wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The method of claim 4775 wherein the fibrosis inhibitor is nicotinamide or an analogue or derivative thereof. The method of claim 4775 wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of claim 4775, wherein the fiber formation inhibitor is a DNA alkylating agent. The method of claim 4775 wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 4775 wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of claim 4775, wherein the fiber formation inhibitor is a DNA cleaving agent. The method of claim 4775, wherein the fiber formation inhibitor is an antimetabolite. The method of claim 4775, wherein adenosine deaminase is inhibited by the fiber formation inhibitor. The method of claim 4775, wherein a purine ring synthesis is inhibited by a fiber formation inhibitor. The method of claim 4775 wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of claim 4775, wherein the fiber formation inhibitor inhibits dihydrofolate reduction. The method of claim 4775, wherein thymidine monophosphate is inhibited by the fiber formation inhibitor. The method of claim 4775 wherein the fiber formation inhibitor causes DNA damage. The method of claim 4775 wherein the fiber formation inhibitor is a DNA intercalation agent. The method of claim 4775, wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The method of claim 4775, wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The method of claim 4775 wherein the fibril formation inhibitor inhibits ribonucleotide synthesis or function. The method of claim 4775, wherein the fiber formation inhibitor inhibits thymidine monophosphate synthesis or function. The method of claim 4775, wherein DNA synthesis is inhibited by the fiber formation inhibitor. The method of claim 4775, wherein DNA adduct formation occurs with the fiber formation inhibitor. The method of claim 4775, wherein protein synthesis is inhibited by the fiber formation inhibitor. The method of claim 4775, wherein the microtubule function is inhibited by the fiber formation inhibitor. The method of claim 4775 wherein the fiber formation inhibitor is a cyclin dependent protein kinase inhibitor. The method of claim 4775 wherein the fibrosis inhibitor is an epidermal growth factor kinase inhibitor. The method of claim 4775 wherein the fiber formation inhibitor is an elastase inhibitor. The method of claim 4775 wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of claim 4775 wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of claim 4775 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 4775 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 4775 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist. The method of claim 4775 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist, and the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof. The method of claim 4775 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 4775 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The method of claim 4775 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof. The method of claim 4775 wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. The method of claim 4775 wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of claim 4775 wherein the fibrosis inhibitor is an IL-1 antagonist. The method of claim 4775 wherein the fibrosis inhibitor is an ICE antagonist. The method of claim 4775 wherein the fibrosis inhibitor is an IRAK antagonist. The method of claim 4775 wherein the fibrosis inhibitor is an IL-4 agonist. The method of claim 4775 wherein the fiber formation inhibitor is an immunomodulator. The method of claim 4775 wherein the fibrosis inhibitor is sirolimus or an analogue or derivative thereof. The method of claim 4775 wherein the fibrosis inhibitor is not sirolimus. The method of claim 4775 wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. The method of claim 4775 wherein the fibrosis inhibitor is tacrolimus or an analogue or derivative thereof. The method of claim 4775, wherein the fiber formation inhibitor is not tacrolimus. The method of claim 4775 wherein the fibrosis inhibitor is biolimus or an analogue or derivative thereof. The method of claim 4775 wherein the fibrosis inhibitor is tresperimus or an analogue or derivative thereof. The method of claim 4775 wherein the fibrosis inhibitor is auranofin or an analogue or derivative thereof. The method of claim 4775 wherein the fibrosis inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of claim 4775 wherein the fibrosis inhibitor is gusperimus or an analogue or derivative thereof. The method of claim 4775 wherein the fibrosis inhibitor is pimecrolimus or an analogue or derivative thereof. The method of claim 4775 wherein the fiber formation inhibitor is ABT-578 or an analogue or derivative thereof. The method of claim 4775 wherein the fiber formation inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. The method of claim 4775 wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof. The method of claim 4775, wherein the fiber formation inhibitor is an IMPDH inhibitor, and the IMPDH inhibitor is 1-α-25 dihydroxyvitamin D ₃ or an analogue or derivative thereof. The method of claim 4775 wherein the fiber formation inhibitor is a leukotriene inhibitor. The method of claim 4775 wherein the vascularization inhibitor is an MCP-1 antagonist. The method of claim 4775 wherein the fiber formation inhibitor is an MMP inhibitor. The method of claim 4775, wherein the fiber formation inhibitor is an NFκB inhibitor. The method of claim 4775, wherein the fiber formation inhibitor is an NFκB inhibitor, and the NFκB inhibitor is Bay11-7082. The method of claim 4775 wherein the fiber formation inhibitor is a NO antagonist. The method of claim 4775 wherein the fibrosis inhibitor is a p38 MAP kinase inhibitor. The method of claim 4775 wherein the fibrosis inhibitor is a p38 MAP kinase inhibitor, and the p38 MAP kinase inhibitor is SB202190. The method of claim 4775 wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The method of claim 4775 wherein the fiber formation inhibitor is a TGF beta inhibitor. The method of claim 4775 wherein the fiber formation inhibitor is a thromboxane A2 antagonist. The method of claim 4775 wherein the vascularization inhibitor is a TNFα antagonist. The method of claim 4775, wherein the fiber formation inhibitor is a TACE inhibitor. The method of claim 4775 wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. The method of claim 4775 wherein the fiber formation inhibitor is a vitronectin inhibitor. The method of claim 4775 wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of claim 4775 wherein the fiber formation inhibitor is a protein kinase inhibitor. The method of claim 4775 wherein the fibrosis inhibitor is a PDGF receptor kinase inhibitor. The method of claim 4775 wherein the fibrosis inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of claim 4775 wherein the fibrosis inhibitor is a retinoic acid receptor antagonist. The method of claim 4775 wherein the fibrosis inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of claim 4775 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 4775 wherein the fiber formation inhibitor is an antifungal agent. The method of claim 4775 wherein the fibrosis inhibitor is an antifungal agent, and the antifungal agent is sulconizole. The method of claim 4775 wherein the fiber formation inhibitor is a bisphosphonate. The method of claim 4775 wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. The method of claim 4775 wherein the fibrosis inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The method of claim 4775, wherein the fiber formation inhibitor is a macrolide antibiotic. The method of claim 4775 wherein the fibrosis inhibitor is a GPIIb / IIIa receptor antagonist. The method of claim 4775 wherein the fibrosis inhibitor is an endothelin receptor antagonist. The method of claim 4775 wherein the fibrosis inhibitor is an agonist of the peroxisome proliferator-responsive receptor. The method of claim 4775 wherein the fibrosis inhibitor is an estrogen receptor agent. The method of claim 4775 wherein the fibrosis inhibitor is a somostatin analog. The method of claim 4775 wherein the fibrosis inhibitor is a neurokinin 1 antagonist. The method of claim 4775 wherein the fibrosis inhibitor is a neurokinin 3 antagonist. The method of claim 4775 wherein the fibrosis inhibitor is a VLA-4 antagonist. The method of claim 4775 wherein the fibrosis inhibitor is an osteoclast inhibitor. The method of claim 4775 wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The method of claim 4775 wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of claim 4775 wherein the fibrosis inhibitor is an angiotensin II antagonist. The method of claim 4775 wherein the fiber formation inhibitor is an enkephalinase inhibitor. The method of claim 4775 wherein the fibrosis inhibitor is a peroxisome proliferator-responsive receptor gamma agonist insulin sensitizer. The method of claim 4775 wherein the fiber formation inhibitor is a protein kinase C inhibitor. The method of claim 4775, wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. The method of claim 4775 wherein the fiber formation inhibitor is a CXCR3 inhibitor. The method of claim 4775 wherein the fiber formation inhibitor is an Itk inhibitor. The method of claim 4775, wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of claim 4775 wherein the fibrosis inhibitor is a PPAR agonist. The method of claim 4775, wherein the fiber formation inhibitor is an immunosuppressant. The method of claim 4775 wherein the fiber formation inhibitor is an Erb inhibitor. The method of claim 4775 wherein the fibrosis inhibitor is an apoptosis agonist. The method of claim 4775 wherein the fibrosis inhibitor is a lipocortin agonist. The method of claim 4775 wherein the fibrosis inhibitor is a VCAM-1 antagonist. The method of claim 4775, wherein the fiber formation inhibitor is a collagen antagonist. The method of claim 4775 wherein the fiber formation inhibitor is an α2 integrin antagonist. The method of claim 4775, wherein the fiber formation inhibitor is a TNFα inhibitor. The method of claim 4775, wherein the fiber formation inhibitor is a nitric oxide inhibitor. The method of claim 4775 wherein the fiber formation inhibitor is a cathepsin inhibitor. The method of claim 4775 wherein the fibrosis inhibitor is not an anti-inflammatory agent. The method of claim 4775 wherein the fibrosis inhibitor is not a steroid. The method of claim 4775 wherein the fibrosis inhibitor is not a glucocorticosteroid. The method of claim 4775 wherein the fibrosis inhibitor is not dexamethasone. The method of claim 4775 wherein the fiber formation inhibitor is not beclomethasone. The method of claim 4775 wherein the fiber formation inhibitor is not dipropionic acid. The method of claim 4775 wherein the fiber formation inhibitor is not an anti-infective. The method of claim 4775 wherein the fibrosis inhibitor is not an antibiotic. The method of claim 4775 wherein the fiber formation inhibitor is not an antifungal agent. The method of claim 4775 wherein the anti-infective is an anthracycline. The method of claim 4775 wherein the anti-infective is doxorubicin. The method of claim 4775 wherein the anti-infective is mitoxantrone. The method of claim 4775 wherein the anti-infective agent is fluoropyrimidine. The method of claim 4775 wherein the anti-infective is 5-fluorouracil (5-FU). The method of claim 4775 wherein the anti-infective agent is a folic acid antagonist. The method of claim 4775 wherein the anti-infective is methotrexate. The method of claim 4775 wherein the anti-infective is podophyllotoxin. The method of claim 4775 wherein the anti-infective is etoposide. The method of claim 4775 wherein the anti-infective is camptothecin. The method of claim 4775 wherein the anti-infective is hydroxyurea. The method of claim 4775 wherein the anti-infective is a platinum complex. The method of claim 4775 wherein the anti-infective is cisplatin. The method of claim 4775, wherein the composition comprises an antithrombotic agent. The method of claim 4775, wherein the polymer is formed from a reactant comprising a naturally occurring polymer. The method of claim 4775, wherein the polymer is formed from a reactant comprising protein. The method of claim 4775, wherein the polymer is formed from a reactant comprising carbohydrate. The method of claim 4775, wherein the polymer is formed from a reactant comprising a biodegradable polymer. The method of claim 4775, wherein the polymer is formed from a reactant comprising a non-biodegradable polymer. The method of claim 4775, wherein the polymer is formed from a reactant comprising collagen. The method of claim 4775, wherein the polymer is formed from a reactant comprising methylated collagen. The method of claim 4775, wherein the polymer is formed from a reactant comprising fibrinogen. The method of claim 4775, wherein the polymer is formed from a reactant comprising thrombin. The method of claim 4775, wherein the polymer is formed from a reactant comprising a plasma component. The method of claim 4775, wherein the polymer is formed from a reactant comprising a calcium salt. The method of claim 4775, wherein the polymer is formed from a reactant comprising a fiber formation inhibitor. The method of claim 4775, wherein the polymer is formed from a reactant comprising a fibrinogen analog. The method of claim 4775, wherein the polymer is formed from a reactant comprising albumin. The method of claim 4775, wherein the polymer is formed from a reactant comprising plasminogen. The method of claim 4775, wherein the polymer is formed from a reactant comprising von Willebrand factor. The method of claim 4775 wherein the polymer is formed from a reactant comprising Factor VIII. The method of claim 4775, wherein the polymer is formed from a reactant comprising hypoallergenic collagen. The method of claim 4775, wherein the polymer is formed from a reactant comprising atelopeptide collagen. The method of claim 4775, wherein the polymer is formed from a reactant comprising telopeptide collagen. The method of claim 4775, wherein the polymer is formed from a reactant comprising cross-linked collagen. The method of claim 4775, wherein the polymer is formed from a reactant comprising aprotinin. The method of claim 4775, wherein the polymer is formed from a reactant comprising epsilon amino-n-caproic acid. The method of claim 4775, wherein the polymer is formed from a reactant comprising gelatin. The method of claim 4775, wherein the polymer is formed from a reactant comprising a protein conjugate. The method of claim 4775, wherein the polymer is formed from a reactant comprising a gelatin conjugate. The method of claim 4775, wherein the polymer is formed from a reactant comprising a synthetic polymer. The method of claim 4775, wherein the polymer is formed from a reactant comprising a compound comprising synthetic isocyanate. The method of claim 4775, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic thiol. The method of claim 4775, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more thiol groups. The method of claim 4775, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more thiol groups. The method of claim 4775, wherein the polymer is formed from a reactant comprising a synthetic compound comprising 4 or more thiol groups. The method of claim 4775, wherein the polymer is formed from a reactant comprising a compound comprising synthetic amino. The method of claim 4775, wherein the polymer is formed from a reactant consisting of a synthetic compound containing two or more amino groups. The method of claim 4775, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more amino groups. The method of claim 4775, wherein the polymer is formed from a reactant consisting of a synthetic compound containing 4 or more amino groups. The method of claim 4775, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of claim 4775, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The method of claim 4775, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. The method of claim 4775, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more carbonyl-oxygen-succinimidyl groups. The method of claim 4775, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide. The method of claim 4775, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a polyalkylene oxide and a biodegradable polyester block. The method of claim 4775, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The method of claim 4775, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a thiol reactive group. The method of claim 4775, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The method of claim 4775, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a biodegradable polyester block. The method of claim 4775, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly comprised of lactic acid or lactide. The method of claim 4775, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly consisting of glycolic acid or glycolide. The method of claim 4775, wherein the polymer is formed from a reactant comprising polylysine. The method of claim 4775, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 4775, wherein the polymer is formed from a reactant comprising (a) a protein and (b) polylysine. The method of claim 4775, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more thiol groups. The method of claim 4775, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more amino groups. The method of claim 4775, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method described in 4775. The method of claim 4775, wherein the polymer is formed from a reactant comprising (a) a collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 4775, wherein the polymer is formed from a reactant comprising (a) collagen and (b) polylysine. The method of claim 4775, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more thiol groups. The method of claim 4775, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more amino groups. The method of claim 4775, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method described in 4775. The method of claim 4775, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 4775, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) polylysine. The method of claim 4775, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more thiol groups. The method of claim 4775, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more amino groups. The method of claim 4775, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone, The method of claim 4775. The method of claim 4775, wherein the polymer is formed from a reactant comprising hyaluronic acid. The method of claim 4775, wherein the polymer is formed from a reactant comprising a hyaluronic acid derivative. The method of claim 4775, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The method of claim 4775, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A polymer having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene region. The method of claim 4775, wherein the method is formed from a reactant comprising a synthetic compound comprising a plurality of electrophilic groups. The method of claim 4775, wherein the composition comprises a colorant. The method of claim 4775, wherein the composition is sterile. Methods of implanting a medical device comprising: (a) a medical device to which the medical device is implanted or transplanted host tissue i) an inhibitor of fiber formation ii) an anti-infective agent iii) a polymer iv) an inhibitor of fiber formation and a polymer V) a composition comprising an anti-infective agent and a polymer or vi) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer, and (b) implanting a medical device into a host, and said medical treatment The device is a gastrointestinal device. The method of implanting a device with the medical device of claim 5040, comprising: (a) the medical device is implanted, or the transplanted host tissue is immersed in a fibrosis inhibitor; and (b) the host Implant a medical device. A method of implanting a device with the medical device of claim 5040 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in an anti-infective agent; and (b) the host is implanted. Implant medical devices. A method of implanting a device with the medical device of claim 5040 comprising: (a) the medical device is implanted, or the implanted host tissue is immersed in a polymer, and (b) the medical device is in the host. Transplant. A method of implanting a device with the medical device of claim 5040 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising a fibrosis inhibitor and a polymer; And (b) transplant the medical device into the host. A method of implanting a device with the medical device of claim 5040 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising an anti-infective and a polymer; and (b) Transplant the medical device into the host. A method of implanting a device comprising the following with the medical device of claim 5040: (a) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer in which the medical device is implanted or the host tissue into which it is implanted And (b) implant the medical device into the host. The method of claim 5040, wherein the medical device is a drainage officer. The method of claim 5040, wherein the medical device is a nutritional tube. The method of claim 5040, wherein the medical device is a portal vein venous shunt. The method of claim 5040, wherein the medical device is an ascites shunt. The method of claim 5040 wherein the medical device is a nasal gastric tube or a nasal intestinal tube. The method of claim 5040 wherein the medical device is a gastrostomy or transcutaneous feeding tube. The method of claim 5040, wherein the medical device is a jejunostomy endoscopic tube. The method of claim 5040, wherein the medical device is a colostomy device. The method of claim 5040, wherein the medical device is a gallbladder T tube. The method of claim 5040, wherein the medical device is biopsy tweezers. The method of claim 5040, wherein the medical device is a gallstone removal device. The method of claim 5040, wherein the medical device is an endoscopic retrograde cholangiopancreatography (ERCP) device. The method of claim 5040, wherein the medical device is a dilatation balloon. The method of claim 5040, wherein the medical device is an enteral feeding device. The method of claim 5040, wherein the medical device is a stent. The method of claim 5040, wherein the medical device is a low profile instrument. The method of claim 5040, wherein the medical device is a virtual colonoscopy device (VC). The method of claim 5040, wherein the medical device is a capsule endoscope. The method of claim 5040, wherein the medical device is a retrieval device. The method of claim 5040, wherein the medical device is a gastrointestinal device adapted for examining the interior of the gastrointestinal tract. The method of claim 5040, wherein the medical device is a gastrointestinal device adapted for irrigation or aspiration of the gastrointestinal tract. The method of claim 5040, wherein the medical device is a colostomy device. The method of claim 5040, wherein the medical device is a mechanical hemostasis device adapted to control gastrointestinal bleeding. The method of claim 5040, wherein the medical device is a gastrointestinal device adapted to flush a blocked gastrointestinal tract. The method of claim 5040, wherein the medical device is a gastrointestinal device for providing communication between the two physical systems. The method of claim 5040, wherein the medical device is a portal vein vein shunt. The method of claim 5040, wherein the medical device is a dilatation catheter. The method of claim 5040, wherein cell regeneration is inhibited by a fiber formation inhibitor. The method of claim 5040, wherein angiogenesis is inhibited by fibrosis inhibitors. The method of claim 5040, wherein fibroblast migration is inhibited by a fibrosis inhibitor. The method of claim 5040, wherein the fibrosis inhibitor inhibits fibroblast proliferation. The method of claim 5040, wherein extracellular matrix accumulation is inhibited by the fibrosis inhibitor. The method of claim 5040, wherein the tissue remodeling is inhibited by the fiber formation inhibitor. The method of claim 5040, wherein the fiber formation inhibitor is an angiogenesis inhibitor. The method of claim 5040 wherein the fiber formation inhibitor is a 5- lipoxygenase inhibitor or antagonist. The method of claim 5040 wherein the fibrosis inhibitor is a chemokine receptor antagonist. The method of claim 5040, wherein the fiber formation inhibitor is a cell cycle inhibitor. The method of claim 5040, wherein the fiber formation inhibitor is a taxane. The method of claim 5040 wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 5040, wherein the fiber formation inhibitor is paclitaxel. The method of claim 5040, wherein the fiber formation inhibitor is not paclitaxel. The method of claim 5040 wherein the fibrosis inhibitor is an analogue or derivative of paclitaxel. The method of claim 5040, wherein the fiber formation inhibitor is a vinca alkaloid. The method of claim 5040 wherein the fibrosis inhibitor is camptothecin or an analogue or derivative thereof. The method of claim 5040 wherein the fibrosis inhibitor is podophyllotoxin. The method of claim 5040 wherein the fiber formation inhibitor is podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof. The method of claim 5040 wherein the fibrosis inhibitor is an anthracycline. The method of claim 5040 wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof. The method of claim 5040 wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof. The method of claim 5040, wherein the fiber formation inhibitor is a platinum compound. The method of claim 5040, wherein the fiber formation inhibitor is nitrosourea. The method of claim 5040, wherein the fiber formation inhibitor is nitroimidazole. The method of claim 5040, wherein the fiber formation inhibitor is a folic acid antagonist. The method of claim 5040 wherein the fibrosis inhibitor is a cytidine analog. The method of claim 5040 wherein the fibrosis inhibitor is a pyrimidine analogue. The method of claim 5040 wherein the fiber formation inhibitor is a fluoropyrimidine analogue. The method of claim 5040 wherein the fibrosis inhibitor is a purine analogue. The method of claim 5040 wherein the fiber formation inhibitor is nitrogen mustard or an analogue or derivative thereof. The method of claim 5040, wherein the fiber formation inhibitor is hydroxyurea. The method of claim 5040 wherein the fibrosis inhibitor is mitomycin or an analogue or derivative thereof. The method of claim 5040, wherein the fiber formation inhibitor is an alkyl sulfonate. The method of claim 5040 wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The method of claim 5040 wherein the fibrosis inhibitor is nicotinamide or an analogue or derivative thereof. The method of claim 5040 wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of claim 5040, wherein the fiber formation inhibitor is a DNA alkylating agent. The method of claim 5040 wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 5040 wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of claim 5040, wherein the fiber formation inhibitor is a DNA cleaving agent. The method of claim 5040 wherein the fiber formation inhibitor is an antimetabolite. The method of claim 5040, wherein adenosine deaminase is inhibited by a fiber formation inhibitor. The method of claim 5040, wherein purine ring synthesis is inhibited by a fiber formation inhibitor. The method of claim 5040 wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of claim 5040 wherein the fibrosis inhibitor inhibits dihydrofolate reduction. The method of claim 5040, wherein thymidine monophosphate is inhibited by a fiber formation inhibitor. The method of claim 5040, wherein the fiber formation inhibitor causes DNA damage. The method of claim 5040 wherein the fiber formation inhibitor is a DNA intercalation agent. The method of claim 5040, wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The method of claim 5040, wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The method of claim 5040 wherein the fibril formation inhibitor inhibits ribonucleotide synthesis or function. The method of claim 5040 wherein the fibrosis inhibitor inhibits thymidine monophosphate synthesis or function. The method of claim 5040, wherein DNA synthesis is inhibited by the fiber formation inhibitor. The method of claim 5040, wherein DNA adduct formation occurs with the fiber formation inhibitor. The method of claim 5040, wherein protein synthesis is inhibited by a fiber formation inhibitor. The method of claim 5040, wherein the microtubule function is inhibited by the fiber formation inhibitor. The method of claim 5040 wherein the fibrosis inhibitor is a cyclin dependent protein kinase inhibitor. The method of claim 5040 wherein the fibrosis inhibitor is an epidermal growth factor kinase inhibitor. The method of claim 5040, wherein the fiber formation inhibitor is an elastase inhibitor. The method of claim 5040, wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of claim 5040 wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of claim 5040 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 5040 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 5040 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist. The method of claim 5040 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist, and the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof. The method of claim 5040 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 5040 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The method of claim 5040, wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof. The method of claim 5040 wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. The method of claim 5040 wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of claim 5040 wherein the fibrosis inhibitor is an IL-1 antagonist. The method of claim 5040 wherein the fibrosis inhibitor is an ICE antagonist. The method of claim 5040 wherein the fibrosis inhibitor is an IRAK antagonist. The method of claim 5040 wherein the fibrosis inhibitor is an IL-4 agonist. The method of claim 5040, wherein the fiber formation inhibitor is an immunomodulator. The method of claim 5040 wherein the fibrosis inhibitor is sirolimus or an analogue or derivative thereof. The method of claim 5040 wherein the fibrosis inhibitor is not sirolimus. The method of claim 5040 wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. The method of claim 5040 wherein the fibrosis inhibitor is tacrolimus or an analogue or derivative thereof. The method of claim 5040 wherein the fibrosis inhibitor is not tacrolimus. The method of claim 5040 wherein the fibrosis inhibitor is biolimus or an analogue or derivative thereof. The method of claim 5040 wherein the fibrosis inhibitor is tresperimus or an analogue or derivative thereof. The method of claim 5040 wherein the fibrosis inhibitor is auranofin or an analogue or derivative thereof. The method of claim 5040 wherein the fibrosis inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of claim 5040 wherein the fibrosis inhibitor is gusperimus or an analogue or derivative thereof. The method of claim 5040 wherein the fibrosis inhibitor is pimecrolimus or an analogue or derivative thereof. The method of claim 5040 wherein the fiber formation inhibitor is ABT-578 or an analogue or derivative thereof. The method of claim 5040 wherein the fiber formation inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. The method of claim 5040, wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof. Fiber forming inhibitor is an IMPDH inhibitor, the IMPDH inhibitor is 1-alpha-25-dihydroxyvitamin D ₃ or its analogues or derivatives, method of claim 5040. The method of claim 5040, wherein the fiber formation inhibitor is a leukotriene inhibitor. The method of claim 5040 wherein the fibrosis inhibitor is an MCP-1 antagonist. The method of claim 5040, wherein the fiber formation inhibitor is an MMP inhibitor. The method of claim 5040, wherein the fiber formation inhibitor is an NFκB inhibitor. The method of claim 5040, wherein the fiber formation inhibitor is an NFκB inhibitor, wherein the NFκB inhibitor is Bay11-7082. The method of claim 5040 wherein the fiber formation inhibitor is a NO antagonist. The method of claim 5040 wherein the fibrosis inhibitor is a p38 MAP kinase inhibitor. The method of claim 5040 wherein the fibrosis inhibitor is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB202190. The method of claim 5040 wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The method of claim 5040, wherein the fiber formation inhibitor is a TGF beta inhibitor. The method of claim 5040 wherein the fiber formation inhibitor is a thromboxane A2 antagonist. The method of claim 5040 wherein the fibrosis inhibitor is a TNFα antagonist. The method of claim 5040, wherein the fiber formation inhibitor is a TACE inhibitor. The method of claim 5040 wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. The method of claim 5040 wherein the fiber formation inhibitor is a vitronectin inhibitor. The method of claim 5040 wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of claim 5040 wherein the fiber formation inhibitor is a protein kinase inhibitor. The method of claim 5040 wherein the fibrosis inhibitor is a PDGF receptor kinase inhibitor. The method of claim 5040 wherein the fibrosis inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of claim 5040 wherein the fiber formation inhibitor is a retinoic acid receptor antagonist. The method of claim 5040 wherein the fiber formation inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of claim 5040 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 5040 wherein the fiber formation inhibitor is an antifungal agent. The method of claim 5040, wherein the fiber formation inhibitor is an antifungal agent, and the antifungal agent is sulconizole. The method of claim 5040 wherein the fiber formation inhibitor is a bisphosphonate. The method of claim 5040 wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. The method of claim 5040 wherein the fibrosis inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The method of claim 5040, wherein the fiber formation inhibitor is a macrolide antibiotic. The method of claim 5040 wherein the fiber formation inhibitor is a GPIIb / IIIa receptor antagonist. The method of claim 5040, wherein the fiber formation inhibitor is an endothelin receptor antagonist. The method of claim 5040 wherein the fibrosis inhibitor is an agonist of peroxisome proliferator-activated receptor. The method of claim 5040 wherein the fibrosis inhibitor is an estrogen receptor agent. The method of claim 5040 wherein the fibrosis inhibitor is a somostatin analog. The method of claim 5040 wherein the fiber formation inhibitor is a neurokinin 1 antagonist. The method of claim 5040 wherein the fiber formation inhibitor is a neurokinin 3 antagonist. The method of claim 5040 wherein the fibrosis inhibitor is a VLA-4 antagonist. The method of claim 5040 wherein the fibrosis inhibitor is an osteoclast inhibitor. The method of claim 5040 wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The method of claim 5040 wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of claim 5040 wherein the fibrosis inhibitor is an angiotensin II antagonist. The method of claim 5040, wherein the fiber formation inhibitor is an enkephalinase inhibitor. The method of claim 5040 wherein the fibrosis inhibitor is a peroxisome proliferator-responsive receptor gamma agonist insulin sensitizer. The method of claim 5040 wherein the fiber formation inhibitor is a protein kinase C inhibitor. The method of claim 5040 wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. The method of claim 5040, wherein the fiber formation inhibitor is a CXCR3 inhibitor. The method of claim 5040, wherein the fiber formation inhibitor is an Itk inhibitor. The method of claim 5040 wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of claim 5040 wherein the fibrosis inhibitor is a PPAR agonist. The method of claim 5040, wherein the fiber formation inhibitor is an immunosuppressant. The method of claim 5040, wherein the fiber formation inhibitor is an Erb inhibitor. The method of claim 5040 wherein the fibrosis inhibitor is an apoptosis agonist. The method of claim 5040 wherein the fibrosis inhibitor is a lipocortin agonist. The method of claim 5040 wherein the fibrosis inhibitor is a VCAM-1 antagonist. The method of claim 5040, wherein the fiber formation inhibitor is a collagen antagonist. The method of claim 5040 wherein the fiber formation inhibitor is an α2 integrin antagonist. The method of claim 5040, wherein the fiber formation inhibitor is a TNFα inhibitor. The method of claim 5040, wherein the fiber formation inhibitor is a nitric oxide inhibitor. The method of claim 5040, wherein the fiber formation inhibitor is a cathepsin inhibitor. The method of claim 5040 wherein the fibrosis inhibitor is not an anti-inflammatory agent. The method of claim 5040 wherein the fibrosis inhibitor is not a steroid. The method of claim 5040 wherein the fibrosis inhibitor is not a glucocorticosteroid. The method of claim 5040 wherein the fibrosis inhibitor is not dexamethasone. The method of claim 5040 wherein the fiber formation inhibitor is not beclomethasone. The method of claim 5040 wherein the fiber formation inhibitor is not dipropionic acid. The method of claim 5040 wherein the fiber formation inhibitor is not an anti-infective. The method of claim 5040 wherein the fibrosis inhibitor is not an antibiotic. The method of claim 5040 wherein the fiber formation inhibitor is not an antifungal agent. The method of claim 5040 wherein the anti-infective is an anthracycline. The method of claim 5040 wherein the anti-infective agent is doxorubicin. The method of claim 5040 wherein the anti-infective is mitoxantrone. The method of claim 5040 wherein the anti-infective agent is a fluoropyrimidine. The method of claim 5040 wherein the anti-infective is 5-fluorouracil (5-FU). The method of claim 5040 wherein the anti-infective agent is a folic acid antagonist. The method of claim 5040 wherein the anti-infective agent is methotrexate. The method of claim 5040 wherein the anti-infective is podophyllotoxin. The method of claim 5040 wherein the anti-infective is etoposide. The method of claim 5040 wherein the anti-infective agent is camptothecin. The method of claim 5040 wherein the anti-infective is hydroxyurea. The method of claim 5040 wherein the anti-infective is a platinum complex. The method of claim 5040 wherein the anti-infective is cisplatin. The method of claim 5040, wherein the composition comprises an antithrombotic agent. The method of claim 5040, wherein the polymer is formed from a reactant comprising a naturally occurring polymer. The method of claim 5040, wherein the polymer is formed from a reactant comprising protein. The method of claim 5040, wherein the polymer is formed from a reactant comprising carbohydrate. The method of claim 5040, wherein the polymer is formed from a reactant comprising a biodegradable polymer. The method of claim 5040, wherein the polymer is formed from a reactant comprising a non-biodegradable polymer. The method of claim 5040, wherein the polymer is formed from a reactant comprising collagen. The method of claim 5040, wherein the polymer is formed from a reactant comprising methylated collagen. The method of claim 5040, wherein the polymer is formed from a reactant comprising fibrinogen. The method of claim 5040, wherein the polymer is formed from a reactant comprising thrombin. The method of claim 5040, wherein the polymer is formed from a reactant comprising a plasma component. The method of claim 5040, wherein the polymer is formed from a reactant comprising a calcium salt. The method of claim 5040, wherein the polymer is formed from a reactant comprising a fiber formation inhibitor. The method of claim 5040, wherein the polymer is formed from a reactant comprising a fibrinogen analog. The method of claim 5040, wherein the polymer is formed from a reactant comprising albumin. The method of claim 5040, wherein the polymer is formed from a reactant comprising plasminogen. The method of claim 5040, wherein the polymer is formed from a reactant comprising von Willebrand factor. The method of claim 5040, wherein the polymer is formed from a reactant comprising Factor VIII. The method of claim 5040, wherein the polymer is formed from a reactant comprising hypoallergenic collagen. The method of claim 5040 wherein the polymer is formed from a reactant comprising atelopeptide collagen. The method of claim 5040, wherein the polymer is formed from a reactant comprising telopeptide collagen. The method of claim 5040, wherein the polymer is formed from a reactant comprising cross-linked collagen. The method of claim 5040 wherein the polymer is formed from a reactant comprising aprotinin. The method of claim 5040, wherein the polymer is formed from a reactant comprising epsilon amino-n-caproic acid. The method of claim 5040, wherein the polymer is formed from a reactant comprising gelatin. The method of claim 5040, wherein the polymer is formed from a reactant comprising a protein conjugate. The method of claim 5040, wherein the polymer is formed from a reactant comprising a gelatin conjugate. The method of claim 5040, wherein the polymer is formed from a reactant comprising a synthetic polymer. The method of claim 5040, wherein the polymer is formed from a reactant comprising a compound comprising synthetic isocyanate. The method of claim 5040, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic thiol. The method of claim 5040, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more thiol groups. The method of claim 5040, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more thiol groups. The method of claim 5040, wherein the polymer is formed from a reactant comprising a synthetic compound comprising 4 or more thiol groups. The method of claim 5040, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic amino. The method of claim 5040, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more amino groups. The method of claim 5040, wherein the polymer is formed from a reactant comprised of a synthetic compound containing 3 or more amino groups. The method of claim 5040, wherein the polymer is formed from a reactant comprising a synthetic compound comprising 4 or more amino groups. The method of claim 5040, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of claim 5040, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The method of claim 5040, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. The method of claim 5040, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more carbonyl-oxygen-succinimidyl groups. The method of claim 5040, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide. The method of claim 5040, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a polyalkylene oxide and a biodegradable polyester block. The method of claim 5040, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The method of claim 5040, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide having a thiol reactive group. The method of claim 5040, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The method of claim 5040, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a biodegradable polyester block. The method of claim 5040, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly comprised of lactic acid or lactide. The method of claim 5040, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly consisting of glycolic acid or glycolide. The method of claim 5040, wherein the polymer is formed from a reactant comprising polylysine. The method of claim 5040, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 5040, wherein the polymer is formed from a reactant comprising (a) a protein and (b) polylysine. The method of claim 5040, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more thiol groups. The method of claim 5040, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more amino groups. The method of claim 5040 wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method according to 5040. The method of claim 5040, wherein the polymer is formed from a reactant comprising (a) a collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 5040, wherein the polymer is formed from a reactant comprising (a) collagen and (b) polylysine. The method of claim 5040, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more thiol groups. The method of claim 5040, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more amino groups. The method of claim 5040, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method according to 5040. The method of claim 5040, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 5040, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) polylysine. The method of claim 5040, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more thiol groups. The method of claim 5040, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more amino groups. The method of claim 5040, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone, The method of claim 5040. The method of claim 5040, wherein the polymer is formed from a reactant comprising hyaluronic acid. The method of claim 5040, wherein the polymer is formed from a reactant comprising a hyaluronic acid derivative. The method of claim 5040 wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The method of claim 5040 wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A polymer having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene region. The method of claim 5040, wherein the method is formed from a reactant comprising a synthetic compound comprising a plurality of electrophilic groups. The method of claim 5040, wherein the composition comprises a colorant. The method of claim 5040, wherein the composition is sterile. Methods of implanting a medical device comprising: (a) a medical device to which the medical device is implanted or transplanted host tissue i) an inhibitor of fiber formation ii) an anti-infective agent iii) a polymer iv) an inhibitor of fiber formation and a polymer V) a composition comprising an anti-infective agent and a polymer or vi) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer, and (b) implanting a medical device into a host, and said medical treatment The device is a central venous catheter. A method of implanting a device with the medical device of claim 5320 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a fibrosis inhibitor; and (b) the host Implant a medical device. A method of implanting a device with the medical device of claim 5320 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in an anti-infective agent; and (b) the host is implanted. Implant medical devices. A method of implanting a device with the medical device of claim 5320 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a polymer; and (b) the medical device is implanted in the host. Transplant. A method of implanting a device comprising the medical device of claim 5320 comprising: (a) immersing the host tissue into which the medical device is implanted or implanted with a composition comprising a fibrosis inhibitor and a polymer; And (b) transplant the medical device into the host. A method of implanting a device with the medical device of claim 5320 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) Transplant the medical device into the host. The method of implanting a device comprising: 5a a medical device according to claim 5320, comprising: (a) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer in which the medical device is implanted or the implanted host tissue; And (b) implant the medical device into the host. The method of claim 5320, wherein the medical device is a cuffed central venous catheter. The method of claim 5320, wherein the medical device is a cuffless central venous catheter. The method of claim 5320, wherein the medical device is a flanged central venous catheter. The method of claim 5320, wherein the medical device is a flanged central venous catheter. The method of claim 5320, wherein the medical device is a central venous catheter adapted to provide access to the circulatory system. The method of claim 5320, wherein the medical device is a central venous catheter adapted to provide a plurality of conduits for accessing the circulatory system. The method of claim 5320, wherein the medical device is a central venous catheter to prevent infection from prolonged use. The method of claim 5320, wherein the medical device is a central venous catheter adapted for use with an apparatus for controlling infusion and extraction of fluid from the body through the central venous catheter. The method of claim 5320 wherein the medical device is a parenteral nutrition catheter. The method of claim 5320, wherein the medical device is a centrally inserted central venous catheter. The method of claim 5320 wherein the medical device is a pulmonary artery catheter with a blood flow directional tip balloon. The method of claim 5320, wherein the medical device is a long-term central venous access catheter. The method of claim 5320, wherein cell regeneration is inhibited by a fiber formation inhibitor. The method of claim 5320, wherein angiogenesis is inhibited by a fiber formation inhibitor. The method of claim 5320, wherein fibroblast migration is inhibited by a fibrosis inhibitor. The method of claim 5320, wherein fibrosis inhibitor inhibits fibroblast proliferation. The method of claim 5320, wherein the fiber formation inhibitor inhibits extracellular matrix accumulation. The method of claim 5320, wherein the tissue remodeling is inhibited by the fiber formation inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is an angiogenesis inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is a 5- lipoxygenase inhibitor or antagonist. The method of claim 5320 wherein the fiber formation inhibitor is a chemokine receptor antagonist. The method of claim 5320 wherein the fiber formation inhibitor is a cell cycle inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is a taxane. The method of claim 5320 wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is paclitaxel. The method of claim 5320 wherein the fiber formation inhibitor is not paclitaxel. The method of claim 5320 wherein the fibrosis inhibitor is an analogue or derivative of paclitaxel. The method of claim 5320 wherein the fiber formation inhibitor is a vinca alkaloid. The method of claim 5320 wherein the fibrosis inhibitor is camptothecin or an analogue or derivative thereof. The method of claim 5320 wherein the fiber formation inhibitor is podophyllotoxin. The method of claim 5320 wherein the fiber formation inhibitor is podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof. The method of claim 5320 wherein the fiber formation inhibitor is an anthracycline. The method of claim 5320 wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof. The method of claim 5320 wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof. The method of claim 5320 wherein the fiber formation inhibitor is a platinum compound. The method of claim 5320 wherein the fiber formation inhibitor is nitrosourea. The method of claim 5320 wherein the fiber formation inhibitor is nitroimidazole. The method of claim 5320 wherein the fiber formation inhibitor is a folic acid antagonist. The method of claim 5320 wherein the fibrosis inhibitor is a cytidine analogue. The method of claim 5320 wherein the fibrosis inhibitor is a pyrimidine analogue. The method of claim 5320 wherein the fiber formation inhibitor is a fluoropyrimidine analogue. The method of claim 5320 wherein the fibrosis inhibitor is a purine analogue. The method of claim 5320 wherein the fiber formation inhibitor is nitrogen mustard or an analogue or derivative thereof. The method of claim 5320 wherein the fiber formation inhibitor is hydroxyurea. The method of claim 5320 wherein the fiber formation inhibitor is mitomycin or an analogue or derivative thereof. The method of claim 5320 wherein the fiber formation inhibitor is an alkyl sulfonate. The method of claim 5320 wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The method of claim 5320 wherein the fiber formation inhibitor is nicotinamide or an analogue or derivative thereof. The method of claim 5320 wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of claim 5320 wherein the fiber formation inhibitor is a DNA alkylating agent. The method of claim 5320 wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is a DNA cleaving agent. The method of claim 5320 wherein the fiber formation inhibitor is an antimetabolite. The method of claim 5320, wherein adenosine deaminase is inhibited by a fiber formation inhibitor. The method of claim 5320, wherein purine ring synthesis is inhibited by a fiber formation inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of claim 5320, wherein the fiber formation inhibitor inhibits dihydrofolate reduction. The method of claim 5320, wherein thymidine monophosphate is inhibited by a fiber formation inhibitor. The method of claim 5320, wherein the fiber formation inhibitor causes DNA damage. The method of claim 5320 wherein the fiber formation inhibitor is a DNA intercalation agent. The method of claim 5320 wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The method of claim 5320, wherein fibril formation inhibitor inhibits ribonucleotide synthesis or function. The method of claim 5320, wherein the fibrosis inhibitor inhibits thymidine monophosphate synthesis or function. The method of claim 5320, wherein DNA synthesis is inhibited by a fiber formation inhibitor. The method of claim 5320, wherein DNA adduct formation occurs with the fiber formation inhibitor. The method of claim 5320, wherein protein synthesis is inhibited by a fiber formation inhibitor. The method of claim 5320, wherein the microtubule function is inhibited by the fiber formation inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is a cyclin dependent protein kinase inhibitor. The method of claim 5320 wherein the fibrosis inhibitor is an epidermal growth factor kinase inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is an elastase inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of claim 5320 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 5320 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 5320 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist. The method of claim 5320 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist, and the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof. The method of claim 5320 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 5320 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof. The method of claim 5320 wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of claim 5320 wherein the fibrosis inhibitor is an IL-1 antagonist. The method of claim 5320 wherein the fiber formation inhibitor is an ICE antagonist. The method of claim 5320 wherein the fiber formation inhibitor is an IRAK antagonist. The method of claim 5320 wherein the fibrosis inhibitor is an IL-4 agonist. The method of claim 5320 wherein the fiber formation inhibitor is an immunomodulator. The method of claim 5320 wherein the fibrosis inhibitor is sirolimus or an analogue or derivative thereof. The method of claim 5320 wherein the fibrosis inhibitor is not sirolimus. The method of claim 5320 wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. The method of claim 5320 wherein the fibrosis inhibitor is tacrolimus or an analogue or derivative thereof. The method of claim 5320 wherein the fiber formation inhibitor is not tacrolimus. The method of claim 5320 wherein the fibrosis inhibitor is biolimus or an analogue or derivative thereof. The method of claim 5320 wherein the fibrosis inhibitor is tresperimus or an analogue or derivative thereof. The method of claim 5320 wherein the fibrosis inhibitor is auranofin or an analogue or derivative thereof. The method of claim 5320 wherein the fibrosis inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of claim 5320 wherein the fibrosis inhibitor is gusperimus or an analogue or derivative thereof. The method of claim 5320 wherein the fibrosis inhibitor is pimecrolimus or an analogue or derivative thereof. The method of claim 5320 wherein the fiber formation inhibitor is ABT-578 or an analogue or derivative thereof. The method of claim 5320 wherein the fiber formation inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof. The method of claim 5320 wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1 -α-25 dihydroxy vitamin D ₃ or an analogue or derivative thereof. The method of claim 5320 wherein the fiber formation inhibitor is a leukotriene inhibitor. The method of claim 5320 wherein the vascularization inhibitor is an MCP-1 antagonist. The method of claim 5320 wherein the fiber formation inhibitor is an MMP inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is an NFκB inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is an NFκB inhibitor, wherein the NFκB inhibitor is Bay11-7082. The method of claim 5320 wherein the fiber formation inhibitor is a NO antagonist. The method of claim 5320 wherein the fibrosis inhibitor is a p38 MAP kinase inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB202190. The method of claim 5320 wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is a TGF beta inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is a thromboxane A2 antagonist. The method of claim 5320 wherein the vascularization inhibitor is a TNFα antagonist. The method of claim 5320 wherein the fiber formation inhibitor is a TACE inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is a vitronectin inhibitor. The method of claim 5320 wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is a protein kinase inhibitor. The method of claim 5320 wherein the fibrosis inhibitor is a PDGF receptor kinase inhibitor. The method of claim 5320 wherein the fibrosis inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is a retinoic acid receptor antagonist. The method of claim 5320 wherein the fiber formation inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of claim 5320 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 5320 wherein the fiber formation inhibitor is an antifungal agent. The method of claim 5320 wherein the fiber formation inhibitor is an antifungal agent, and the antifungal agent is sulconizole. The method of claim 5320 wherein the fiber formation inhibitor is a bisphosphonate. The method of claim 5320 wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. The method of claim 5320 wherein the fibrosis inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The method of claim 5320 wherein the fiber formation inhibitor is a macrolide antibiotic. The method of claim 5320 wherein the fiber formation inhibitor is a GPIIb / IIIa receptor antagonist. The method of claim 5320 wherein the fiber formation inhibitor is an endothelin receptor antagonist. The method of claim 5320 wherein the fibrosis inhibitor is an agonist of peroxisome proliferator-activated receptor. The method of claim 5320 wherein the fibrosis inhibitor is an estrogen receptor agent. The method of claim 5320 wherein the fibrosis inhibitor is a somostatin analog. The method of claim 5320 wherein the fiber formation inhibitor is a neurokinin 1 antagonist. The method of claim 5320 wherein the fiber formation inhibitor is a neurokinin 3 antagonist. The method of claim 5320 wherein the fibrosis inhibitor is a VLA-4 antagonist. The method of claim 5320 wherein the fiber formation inhibitor is an osteoclast inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is an angiotensin II antagonist. The method of claim 5320 wherein the fiber formation inhibitor is an enkephalinase inhibitor. The method of claim 5320 wherein the fibrosis inhibitor is a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer. The method of claim 5320 wherein the fiber formation inhibitor is a protein kinase C inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is a CXCR3 inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is an Itk inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of claim 5320 wherein the fibrosis inhibitor is a PPAR agonist. The method of claim 5320 wherein the fiber formation inhibitor is an immunosuppressant. The method of claim 5320 wherein the fiber formation inhibitor is an Erb inhibitor. The method of claim 5320 wherein the fibrosis inhibitor is an apoptosis agonist. The method of claim 5320 wherein the fibrosis inhibitor is a lipocortin agonist. The method of claim 5320 wherein the fibrosis inhibitor is a VCAM-1 antagonist. The method of claim 5320 wherein the fiber formation inhibitor is a collagen antagonist. The method of claim 5320 wherein the fiber formation inhibitor is an α2 integrin antagonist. The method of claim 5320 wherein the fiber formation inhibitor is a TNFα inhibitor. The method of claim 5320 wherein the fiber formation inhibitor is a nitric oxide inhibitor The method of claim 5320 wherein the fiber formation inhibitor is a cathepsin inhibitor. The method of claim 5320 wherein the fibrosis inhibitor is not an anti-inflammatory agent. The method of claim 5320 wherein the fibrosis inhibitor is not a steroid. The method of claim 5320 wherein the fiber formation inhibitor is not a glucocorticosteroid. The method of claim 5320 wherein the fibrosis inhibitor is not dexamethasone. The method of claim 5320 wherein the fiber formation inhibitor is not beclomethasone. The method of claim 5320 wherein the fiber formation inhibitor is not dipropionic acid. The method of claim 5320 wherein the fiber formation inhibitor is not an anti-infective. The method of claim 5320 wherein the fibrosis inhibitor is not an antibiotic. The method of claim 5320 wherein the fiber formation inhibitor is not an antifungal agent. The method of claim 5320 wherein the anti-infective is an anthracycline. The method of claim 5320 wherein the anti-infective is doxorubicin. The method of claim 5320 wherein the anti-infective is mitoxantrone. The method of claim 5320 wherein the anti-infective is a fluoropyrimidine. The method of claim 5320 wherein the anti-infective is 5-fluorouracil (5-FU). The method of claim 5320 wherein the anti-infective agent is a folic acid antagonist. The method of claim 5320 wherein the anti-infective is methotrexate. The method of claim 5320 wherein the anti-infective is podophyllotoxin. The method of claim 5320 wherein the anti-infective is etoposide. The method of claim 5320 wherein the anti-infective is camptothecin. The method of claim 5320 wherein the anti-infective is hydroxyurea. The method of claim 5320 wherein the anti-infective is a platinum complex. The method of claim 5320 wherein the anti-infective is cisplatin. The method of claim 5320, wherein the composition comprises an antithrombotic agent. The method of claim 5320, wherein the polymer is formed from a reactant comprising a naturally occurring polymer. The method of claim 5320, wherein the polymer is formed from a reactant comprising protein. The method of claim 5320, wherein the polymer is formed from a reactant comprising a carbohydrate. The method of claim 5320, wherein the polymer is formed from a reactant comprising a biodegradable polymer. The method of claim 5320, wherein the polymer is formed from a reactant comprising a non-biodegradable polymer. The method of claim 5320, wherein the polymer is formed from a reactant comprising collagen. The method of claim 5320, wherein the polymer is formed from a reactant comprising methylated collagen. The method of claim 5320, wherein the polymer is formed from a reactant comprising fibrinogen. The method of claim 5320, wherein the polymer is formed from a reactant comprising thrombin. The method of claim 5320 wherein the polymer is formed from a reactant comprising a plasma component. The method of claim 5320, wherein the polymer is formed from a reactant comprising a calcium salt. The method of claim 5320, wherein the polymer is formed from a reactant comprising a fiber formation inhibitor. The method of claim 5320 wherein the polymer is formed from a reactant comprising a fibrinogen analog. The method of claim 5320, wherein the polymer is formed from a reactant comprising albumin. The method of claim 5320, wherein the polymer is formed from a reactant comprising plasminogen. The method of claim 5320, wherein the polymer is formed from a reactant comprising von Willebrand factor. The method of claim 5320, wherein the polymer is formed from a reactant comprising Factor VIII. The method of claim 5320 wherein the polymer is formed from a reactant comprising hypoallergenic collagen. The method of claim 5320, wherein the polymer is formed from a reactant comprising atelopeptide collagen. The method of claim 5320 wherein the polymer is formed from a reactant comprising telopeptide collagen. The method of claim 5320, wherein the polymer is formed from a reactant comprising cross-linked collagen. The method of claim 5320 wherein the polymer is formed from a reactant comprising aprotinin. The method of claim 5320 wherein the polymer is formed from a reactant comprising epsilon amino-n-caproic acid. The method of claim 5320, wherein the polymer is formed from a reactant comprising gelatin. The method of claim 5320 wherein the polymer is formed from a reactant comprising a protein conjugate. The method of claim 5320, wherein the polymer is formed from a reactant comprising a gelatin conjugate. The method of claim 5320, wherein the polymer is formed from a reactant comprising a synthetic polymer. The method of claim 5320, wherein the polymer is formed from a reactant comprising a compound comprising synthetic isocyanate. The method of claim 5320, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic thiol. The method of claim 5320, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more thiol groups. The method of claim 5320, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more thiol groups. The method of claim 5320, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more thiol groups. The method of claim 5320, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic amino. The method of claim 5320, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more amino groups. The method of claim 5320, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more amino groups. The method of claim 5320, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more amino groups. The method of claim 5320, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of claim 5320, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The method of claim 5320, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. The method of claim 5320, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more carbonyl-oxygen-succinimidyl groups. The method of claim 5320, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide. The method of claim 5320, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a polyalkylene oxide and a biodegradable polyester block. The method of claim 5320, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The method of claim 5320, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide having a thiol reactive group. The method of claim 5320, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The method of claim 5320, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a biodegradable polyester block. The method of claim 5320, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly comprised of lactic acid or lactide. The method of claim 5320, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly comprised of glycolic acid or glycolide. The method of claim 5320, wherein the polymer is formed from a reactant comprising polylysine. The method of claim 5320, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 5320, wherein the polymer is formed from a reactant comprising (a) a protein and (b) polylysine. The method of claim 5320, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more thiol groups. The method of claim 5320, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more amino groups. The method of claim 5320, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method according to 5320. The method of claim 5320, wherein the polymer is formed from a reactant comprising (a) a collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 5320, wherein the polymer is formed from a reactant comprising (a) collagen and (b) polylysine. The method of claim 5320, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more thiol groups. The method of claim 5320, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more amino groups. The method of claim 5320, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method according to 5320. The method of claim 5320, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 5320, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) polylysine. The method of claim 5320, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more thiol groups. The method of claim 5320, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more amino groups. The method of claim 5320, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone, The method of claim 5320. The method of claim 5320, wherein the polymer is formed from a reactant comprising hyaluronic acid. The method of claim 5320, wherein the polymer is formed from a reactant comprising a hyaluronic acid derivative. The method of claim 5320, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The method of claim 5320, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A polymer having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene region. The method of claim 5320, wherein the method is formed from a reactant comprising a synthetic compound comprising a plurality of electrophilic groups. The method of claim 5320, wherein the composition comprises a colorant. The method of claim 5320 wherein the composition is sterile. Methods of implanting a medical device comprising: (a) a medical device to which the medical device is implanted or transplanted host tissue i) an inhibitor of fiber formation ii) an anti-infective agent iii) a polymer iv) an inhibitor of fiber formation and a polymer V) a composition comprising an anti-infective agent and a polymer or vi) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer, and (b) implanting a medical device into a host, and said medical treatment The device is an auxiliary artificial heart. A method of implanting a device with the medical device of claim 5585 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a fibrosis inhibitor; and (b) the host Implant a medical device. A method of implanting a device with the medical device of claim 5585, including: (a) the medical device is implanted or the implanted host tissue is immersed in an anti-infective agent; and (b) the host is implanted. Implant medical devices. A method of implanting a device including the following with the medical device of claim 5585: (a) the medical device is implanted or the implanted host tissue is immersed in a polymer; and (b) the medical device is in the host. Transplant. A method of implanting a device comprising the following with the medical device of claim 5585: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising a fibrosis inhibitor and a polymer; And (b) transplant the medical device into the host. A method of implanting a device with the medical device of claim 5585, comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) Transplant the medical device into the host. A method of implanting a device comprising the following with the medical device of claim 5585: (a) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer into which the medical device is implanted or the host tissue into which the medical device is implanted And (b) implant the medical device into the host. The method of claim 5585 wherein the medical device is a left ventricular assist device. The method of claim 5585 wherein the medical device is a right ventricular assist device. The method of claim 5585 wherein the medical device is a bi-cardiac assisted circulation device. The method of claim 5585 wherein the medical device is an auxiliary heart device. The method of claim 5585 wherein the medical device is a mechanical assisted circulation device. The method of claim 5585 wherein the medical device is an auxiliary artificial heart. The method of claim 5585 wherein the medical device is an implantable assistive heart system. The method of claim 5585 wherein the medical device is an auxiliary heart pump. The method of claim 5585 wherein the medical device is an auxiliary intracardiac device. The method of claim 5585, wherein cell regeneration is inhibited by a fiber formation inhibitor. The method of claim 5585, wherein an angiogenesis is inhibited by a fiber formation inhibitor. The method of claim 5585, wherein fibroblast migration is inhibited by a fibrosis inhibitor. The method of claim 5585, wherein the fibrosis inhibitor inhibits fibroblast proliferation. The method of claim 5585, wherein the fiber formation inhibitor inhibits extracellular matrix accumulation. The method of claim 5585 wherein the tissue remodeling is inhibited by the fiber formation inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is an angiogenesis inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is a 5- lipoxygenase inhibitor or antagonist. The method of claim 5585 wherein the fiber formation inhibitor is a chemokine receptor antagonist. The method of claim 5585 wherein the fiber formation inhibitor is a cell cycle inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is a taxane. The method of claim 5585 wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is paclitaxel. The method of claim 5585 wherein the fiber formation inhibitor is not paclitaxel. The method of claim 5585 wherein the fiber formation inhibitor is an analogue or derivative of paclitaxel. The method of claim 5585 wherein the fiber formation inhibitor is a vinca alkaloid. The method of claim 5585 wherein the fiber formation inhibitor is camptothecin or an analogue or derivative thereof. The method of claim 5585 wherein the fiber formation inhibitor is podophyllotoxin. The method of claim 5585 wherein the fiber formation inhibitor is podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof. The method of claim 5585 wherein the fiber formation inhibitor is an anthracycline. The method of claim 5585 wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof. The method of claim 5585 wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof. The method of claim 5585, wherein the fiber formation inhibitor is a platinum compound. The method of claim 5585 wherein the fiber formation inhibitor is nitrosourea. The method of claim 5585 wherein the fiber formation inhibitor is nitroimidazole. The method of claim 5585 wherein the fiber formation inhibitor is a folic acid antagonist. The method of claim 5585 wherein the fiber formation inhibitor is a cytidine analog. The method of claim 5585 wherein the fiber formation inhibitor is a pyrimidine analogue. The method of claim 5585 wherein the fiber formation inhibitor is a fluoropyrimidine analogue. The method of claim 5585 wherein the fiber formation inhibitor is a purine analogue. The method of claim 5585 wherein the fiber formation inhibitor is a nitrogen mustard or an analogue or derivative thereof. The method of claim 5585 wherein the fiber formation inhibitor is hydroxyurea. The method of claim 5585 wherein the fiber formation inhibitor is mitomycin or an analogue or derivative thereof. The method of claim 5585 wherein the fiber formation inhibitor is an alkyl sulfonate. The method of claim 5585 wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The method of claim 5585 wherein the fiber formation inhibitor is nicotinamide or an analogue or derivative thereof. The method of claim 5585 wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of claim 5585 wherein the fiber formation inhibitor is a DNA alkylating agent. The method of claim 5585 wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is a DNA cleaving agent. The method of claim 5585 wherein the fiber formation inhibitor is an antimetabolite. The method of claim 5585, wherein adenosine deaminase is inhibited by a fiber formation inhibitor. The method of claim 5585, wherein a purine ring synthesis is inhibited by a fiber formation inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of claim 5585, wherein the fiber formation inhibitor inhibits dihydrofolate reduction. The method of claim 5585 wherein thymidine monophosphate is inhibited by the fiber formation inhibitor. The method of claim 5585 wherein DNA damage is caused by a fiber formation inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is a DNA intercalation agent. The method of claim 5585 wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The method of claim 5585 wherein the fibril formation inhibitor inhibits ribonucleotide synthesis or function. The method of claim 5585 wherein the fibrosis inhibitor inhibits thymidine monophosphate synthesis or function. The method of claim 5585, wherein DNA synthesis is inhibited by the fiber formation inhibitor. The method of claim 5585, wherein the fiber formation inhibitor causes DNA adduct formation. The method of claim 5585, wherein protein synthesis is inhibited by a fiber formation inhibitor. The method of claim 5585, wherein the microtubule function is inhibited by the fiber formation inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is a cyclin dependent protein kinase inhibitor. The method of claim 5585 wherein the fibrosis inhibitor is an epidermal growth factor kinase inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is an elastase inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is a fibrinogen antagonist. The method of claim 5585 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 5585 wherein the fiber formation inhibitor is a heat shock protein 90 antagonist. The method of claim 5585 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist, and the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof. The method of claim 5585 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 5585 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof. The method of claim 5585 wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is an IL-1 antagonist. The method of claim 5585 wherein the fiber formation inhibitor is an ICE antagonist. The method of claim 5585 wherein the fiber formation inhibitor is an IRAK antagonist. The method of claim 5585 wherein the fibrosis inhibitor is an IL-4 agonist. The method of claim 5585 wherein the fiber formation inhibitor is an immunomodulator. The method of claim 5585 wherein the fibrosis inhibitor is sirolimus or an analogue or derivative thereof. The method of claim 5585 wherein the fiber formation inhibitor is not sirolimus. The method of claim 5585 wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. The method of claim 5585 wherein the fiber formation inhibitor is tacrolimus or an analogue or derivative thereof. The method of claim 5585 wherein the fiber formation inhibitor is not tacrolimus. The method of claim 5585 wherein the fibrosis inhibitor is biolimus or an analogue or derivative thereof. The method of claim 5585 wherein the fibrosis inhibitor is tresperimus or an analogue or derivative thereof. The method of claim 5585 wherein the fiber formation inhibitor is auranofin or an analogue or derivative thereof. The method of claim 5585 wherein the fiber formation inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of claim 5585 wherein the fiber formation inhibitor is gusperimus or an analogue or derivative thereof. The method of claim 5585 wherein the fibrosis inhibitor is pimecrolimus or an analogue or derivative thereof. The method of claim 5585 wherein the fiber formation inhibitor is ABT-578 or an analogue or derivative thereof. The method of claim 5585 wherein the fiber formation inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof. The method of claim 5585 wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-α-25 dihydroxy vitamin D ₃ or an analogue or derivative thereof. The method of claim 5585 wherein the fiber formation inhibitor is a leukotriene inhibitor. The method of claim 5585 wherein the vascularization inhibitor is an MCP-1 antagonist. The method of claim 5585 wherein the fiber formation inhibitor is an MMP inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is an NFκB inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is an NFκB inhibitor, wherein the NFκB inhibitor is Bay11-7082. The method of claim 5585 wherein the fiber formation inhibitor is a NO antagonist. The method of claim 5585 wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB202190. The method of claim 5585 wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is a TGF beta inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is a thromboxane A2 antagonist. The method of claim 5585 wherein the fibrosis inhibitor is a TNFα antagonist. The method of claim 5585 wherein the fiber formation inhibitor is a TACE inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is a vitronectin inhibitor. The method of claim 5585 wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is a protein kinase inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is a PDGF receptor kinase inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is a retinoic acid receptor antagonist. The method of claim 5585 wherein the fiber formation inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is a fibrinogen antagonist. The method of claim 5585 wherein the fiber formation inhibitor is an antifungal agent. The method of claim 5585 wherein the fiber formation inhibitor is an antifungal agent, and the antifungal agent is sulconizole. The method of claim 5585 wherein the fiber formation inhibitor is a bisphosphonate. The method of claim 5585 wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The method of claim 5585 wherein the fiber formation inhibitor is a macrolide antibiotic. The method of claim 5585 wherein the fiber formation inhibitor is a GPIIb / IIIa receptor antagonist. The method of claim 5585 wherein the fiber formation inhibitor is an endothelin receptor antagonist. The method of claim 5585 wherein the fibrosis inhibitor is an agonist of the peroxisome proliferator-responsive receptor. The method of claim 5585 wherein the fibrosis inhibitor is an estrogen receptor agent. The method of claim 5585 wherein the fibrosis inhibitor is a somostatin analog. The method of claim 5585 wherein the fiber formation inhibitor is a neurokinin 1 antagonist. The method of claim 5585 wherein the fiber formation inhibitor is a neurokinin 3 antagonist. The method of claim 5585 wherein the fibrosis inhibitor is a VLA-4 antagonist. The method of claim 5585 wherein the fiber formation inhibitor is an osteoclast inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is an angiotensin II antagonist. The method of claim 5585 wherein the fiber formation inhibitor is an enkephalinase inhibitor. The method of claim 5585 wherein the fibrosis inhibitor is a peroxisome proliferator-responsive receptor gamma agonist insulin sensitizer. The method of claim 5585 wherein the fiber formation inhibitor is a protein kinase C inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is a CXCR3 inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is an Itk inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of claim 5585 wherein the fibrosis inhibitor is a PPAR agonist. The method of claim 5585 wherein the fiber formation inhibitor is an immunosuppressant. The method of claim 5585 wherein the fiber formation inhibitor is an Erb inhibitor. The method of claim 5585 wherein the fibrosis inhibitor is an apoptosis agonist. The method of claim 5585 wherein the fiber formation inhibitor is a lipocortin agonist. The method of claim 5585 wherein the fiber formation inhibitor is a VCAM-1 antagonist. The method of claim 5585 wherein the fiber formation inhibitor is a collagen antagonist. The method of claim 5585 wherein the fiber formation inhibitor is an α2 integrin antagonist. The method of claim 5585 wherein the fiber formation inhibitor is a TNFα inhibitor. The method of claim 5585 wherein the fiber formation inhibitor is a nitric oxide inhibitor The method of claim 5585 wherein the fiber formation inhibitor is a cathepsin inhibitor. The method of claim 5585 wherein the fibrosis inhibitor is not an anti-inflammatory agent. The method of claim 5585 wherein the fiber formation inhibitor is not a steroid. The method of claim 5585 wherein the fiber formation inhibitor is not a glucocorticosteroid. The method of claim 5585 wherein the fiber formation inhibitor is not dexamethasone. The method of claim 5585 wherein the fiber formation inhibitor is not beclomethasone. The method of claim 5585 wherein the fiber formation inhibitor is not dipropionic acid. The method of claim 5585 wherein the fiber formation inhibitor is not an anti-infective. The method of claim 5585 wherein the fiber formation inhibitor is not an antibiotic. The method of claim 5585 wherein the fiber formation inhibitor is not an antifungal agent. The method of claim 5585 wherein the anti-infective is an anthracycline. The method of claim 5585 wherein the anti-infective is doxorubicin. The method of claim 5585 wherein the anti-infective is mitoxantrone. The method of claim 5585 wherein the anti-infective is fluoropyrimidine. The method of claim 5585 wherein the anti-infective is 5-fluorouracil (5-FU). The method of claim 5585 wherein the anti-infective agent is a folic acid antagonist. The method of claim 5585 wherein the anti-infective is methotrexate. The method of claim 5585 wherein the anti-infective is podophyllotoxin. The method of claim 5585 wherein the anti-infective is etoposide. The method of claim 5585 wherein the anti-infective is camptothecin. The method of claim 5585 wherein the anti-infective is hydroxyurea. The method of claim 5585 wherein the anti-infective is a platinum complex. The method of claim 5585 wherein the anti-infective is cisplatin. The method of claim 5585, wherein the composition comprises an antithrombotic agent. The method of claim 5585, wherein the polymer is formed from a reactant comprising a naturally occurring polymer. The method of claim 5585 wherein the polymer is formed from a reactant comprising protein. The method of claim 5585, wherein the polymer is formed from a reactant comprising carbohydrate. The method of claim 5585, wherein the polymer is formed from a reactant comprising a biodegradable polymer. The method of claim 5585, wherein the polymer is formed from a reactant comprising a non-biodegradable polymer. The method of claim 5585 wherein the polymer is formed from a reactant comprising collagen. The method of claim 5585 wherein the polymer is formed from a reactant comprising methylated collagen. The method of claim 5585 wherein the polymer is formed from a reactant comprising fibrinogen. The method of claim 5585 wherein the polymer is formed from a reactant comprising thrombin. The method of claim 5585 wherein the polymer is formed from a reactant comprising a plasma component. The method of claim 5585, wherein the polymer is formed from a reactant comprising a calcium salt. The method of claim 5585 wherein the polymer is formed from a reactant comprising a fiber formation inhibitor. The method of claim 5585 wherein the polymer is formed from a reactant comprising a fibrinogen analog. The method of claim 5585, wherein the polymer is formed from a reactant comprising albumin. The method of claim 5585, wherein the polymer is formed from a reactant comprising plasminogen. The method of claim 5585 wherein the polymer is formed from a reactant comprising von Willebrand factor. The method of claim 5585 wherein the polymer is formed from a reactant comprising Factor VIII. The method of claim 5585 wherein the polymer is formed from a reactive material comprising hypoallergenic collagen. The method of claim 5585 wherein the polymer is formed from a reactant comprising atelopeptide collagen. The method of claim 5585 wherein the polymer is formed from a reactant comprising telopeptide collagen. The method of claim 5585 wherein the polymer is formed from a reactant comprising cross-linked collagen. The method of claim 5585 wherein the polymer is formed from a reactant comprising aprotinin. The method of claim 5585 wherein the polymer is formed from a reactant comprising epsilon amino-n-caproic acid. The method of claim 5585, wherein the polymer is formed from a reactant comprising gelatin. The method of claim 5585 wherein the polymer is formed from a reactant comprising a protein conjugate. The method of claim 5585 wherein the polymer is formed from a reactant comprising a gelatin conjugate. The method of claim 5585, wherein the polymer is formed from a reactant comprising a synthetic polymer. The method of claim 5585, wherein the polymer is formed from a reactant comprising a compound comprising synthetic isocyanate. The method of claim 5585, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic thiol. The method of claim 5585, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more thiol groups. The method of claim 5585 wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more thiol groups. The method of claim 5585, wherein the polymer is formed from a reactant comprising a synthetic compound comprising 4 or more thiol groups. The method of claim 5585, wherein the polymer is formed from a reactant comprising a compound comprising synthetic amino. The method of claim 5585, wherein the polymer is formed from reactants consisting of a synthetic compound containing two or more amino groups. The method of claim 5585 wherein the polymer is formed from a reactant comprised of a synthetic compound containing 3 or more amino groups. The method of claim 5585 wherein the polymer is formed from a reactant comprising a synthetic compound comprising 4 or more amino groups. The method of claim 5585, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of claim 5585, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The method of claim 5585, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. The method of claim 5585, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more carbonyl-oxygen-succinimidyl groups. The method of claim 5585, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide. The method of claim 5585, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a polyalkylene oxide and a biodegradable polyester block. The method of claim 5585, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The method of claim 5585, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide having a thiol reactive group. The method of claim 5585, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The method of claim 5585, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a biodegradable polyester block. The method of claim 5585, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly comprised of lactic acid or lactide. The method of claim 5585, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly consisting of glycolic acid or glycolide. The method of claim 5585, wherein the polymer is formed from a reactant comprising polylysine. The method of claim 5585, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 5585 wherein the polymer is formed from a reactant comprising (a) a protein and (b) polylysine. The method of claim 5585, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more thiol groups. The method of claim 5585 wherein the polymer is formed from a reactant comprising: (a) a protein; and (b) a compound having four or more amino groups. The method of claim 5585 wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method described in 5585. The method of claim 5585, wherein the polymer is formed from a reactant comprising (a) a collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 5585 wherein the polymer is formed from a reactant comprising (a) collagen and (b) polylysine. The method of claim 5585, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more thiol groups. The method of claim 5585, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more amino groups. The method of claim 5585 wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method described in 5585. The method of claim 5585, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 5585, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) polylysine. The method of claim 5585 wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more thiol groups. The method of claim 5585 wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more amino groups. The method of claim 5585 wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone, The method of claim 5585. The method of claim 5585 wherein the polymer is formed from a reactant comprising hyaluronic acid. The method of claim 5585 wherein the polymer is formed from a reactant comprising a hyaluronic acid derivative. The method of claim 5585 wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The method of claim 5585 wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A polymer having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene region. The method of claim 5585, wherein the method is formed from a reactant comprising a synthetic compound comprising a plurality of electrophilic groups. The method of claim 5585, wherein the composition comprises a colorant. The method of claim 5585 wherein the composition is sterile. Methods of implanting a medical device comprising: (a) a medical device to which the medical device is implanted or transplanted host tissue i) an inhibitor of fiber formation ii) an anti-infective agent iii) a polymer iv) an inhibitor of fiber formation and a polymer V) a composition comprising an anti-infective agent and a polymer or vi) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer, and (b) implanting a medical device into a host, and said medical treatment The device is a spinal implant. The method of implanting a device with the medical device of claim 5847 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a fibrosis inhibitor; and (b) the host Implant a medical device. The method of implanting a device with the medical device of claim 5847 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in an anti-infective agent; and (b) the host is implanted. Implant medical devices. The method of implanting a device with the medical device of claim 5847 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a polymer; and (b) the medical device is in the host. Transplant. A method of implanting a device with the medical device of claim 5847 comprising: (a) immersing a tissue of a host into which the medical device is implanted or implanted with a composition comprising a fibrosis inhibitor and a polymer; And (b) transplant the medical device into the host. A method of implanting a device with the medical device of claim 5847 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) Transplant the medical device into the host. The method of claim 5847, wherein the device comprises: (a) a composition comprising a fibrosis inhibitor, an anti-infective agent, and a polymer in which the medical device is implanted or the host tissue into which the device is implanted. And (b) implant the medical device into the host. The method of claim 5847 wherein the medical device is a spinal disc. The method of claim 5847 wherein the medical device is a spinal transplant. The method of claim 5847 wherein the medical device is an artificial vertebral disc. The method of claim 5847 wherein the medical device is a lumbar disc implant. The method of claim 5847 wherein the medical device is a cervical disc implant. The method of claim 5847 wherein the medical device is an intervertebral disc. The method of claim 5847 wherein the medical device is an artificial spine. The method of claim 5847 wherein the medical device is an artificial disc. The method of claim 5847 wherein the medical device is a spinal circle endoprosthesis. The method of claim 5847 wherein the medical device is an intervertebral implant. The method of claim 5847 wherein the medical device is an implantable spinal implant. The method of claim 5847 wherein the medical device is an implantable bone graft. The method of claim 5847 wherein the medical device is an artificial lumbar disc. The method of claim 5847 wherein the medical device is a spinal nucleus implant. The method of claim 5847 wherein the medical device is an intervertebral disc spacer. The method of claim 5847 wherein the medical device is a fixed cage. The method of claim 5847, wherein the medical device is a stationary basket. The method of claim 5847 wherein the medical device is a fixed cage instrument. The method of claim 5847 wherein the medical device is an interbody cage. The method of claim 5847 wherein the medical device is an interbody implant. The method of claim 5847 wherein the medical device is a fixed cage anchoring device. The method of claim 5847 wherein the medical device is a bone fixation device. The method of claim 5847 wherein the medical device is a fixed stabilization chamber. The method of claim 5847 wherein the medical device is a fixation bone plate. The method of claim 5847 wherein the medical device is a bone screw. The method of claim 5847, wherein cell regeneration is inhibited by a fiber formation inhibitor. The method of claim 5847 wherein angiogenesis is inhibited by a fiber formation inhibitor. The method of claim 5847, wherein fibroblast migration is inhibited by a fibrosis inhibitor. The method of claim 5847 wherein the fibrosis inhibitor inhibits fibroblast proliferation. The method of claim 5847, wherein the fiber formation inhibitor inhibits extracellular matrix accumulation. The method of claim 5847 wherein the fibrosis inhibitor inhibits tissue remodeling. The method of claim 5847 wherein the fiber formation inhibitor is an angiogenesis inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is a 5- lipoxygenase inhibitor or antagonist. The method of claim 5847 wherein the fibrosis inhibitor is a chemokine receptor antagonist. The method of claim 5847 wherein the fiber formation inhibitor is a cell cycle inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is a taxane. The method of claim 5847 wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is paclitaxel. The method of claim 5847 wherein the fiber formation inhibitor is not paclitaxel. The method of claim 5847 wherein the fibrosis inhibitor is an analogue or derivative of paclitaxel. The method of claim 5847 wherein the fiber formation inhibitor is a vinca alkaloid. The method of claim 5847 wherein the fiber formation inhibitor is camptothecin or an analogue or derivative thereof. The method of claim 5847 wherein the fiber formation inhibitor is podophyllotoxin. The method of claim 5847 wherein the fiber formation inhibitor is podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof. The method of claim 5847 wherein the fibrosis inhibitor is an anthracycline. The method of claim 5847 wherein the fibrosis inhibitor is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof. The method of claim 5847 wherein the fibrosis inhibitor is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof. The method of claim 5847, wherein the fiber formation inhibitor is a platinum compound. The method of claim 5847 wherein the fiber formation inhibitor is nitrosourea. The method of claim 5847 wherein the fiber formation inhibitor is nitroimidazole. The method of claim 5847 wherein the fiber formation inhibitor is a folic acid antagonist. The method of claim 5847 wherein the fibrosis inhibitor is a cytidine analog. The method of claim 5847 wherein the fiber formation inhibitor is a pyrimidine analogue. The method of claim 5847 wherein the fiber formation inhibitor is a fluoropyrimidine analog. The method of claim 5847 wherein the fibrosis inhibitor is a purine analogue. The method of claim 5847 wherein the fiber formation inhibitor is nitrogen mustard or an analogue or derivative thereof. The method of claim 5847 wherein the fiber formation inhibitor is hydroxyurea. The method of claim 5847 wherein the fiber formation inhibitor is mitomycin or an analogue or derivative thereof. The method of claim 5847 wherein the fiber formation inhibitor is an alkyl sulfonate. The method of claim 5847 wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The method of claim 5847 wherein the fiber formation inhibitor is nicotinamide or an analogue or derivative thereof. The method of claim 5847 wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of claim 5847 wherein the fiber formation inhibitor is a DNA alkylating agent. The method of claim 5847 wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is a DNA cleaving agent. The method of claim 5847 wherein the fiber formation inhibitor is an antimetabolite. The method of claim 5847 wherein adenosine deaminase is inhibited by a fiber formation inhibitor. The method of claim 5847, wherein purine ring synthesis is inhibited by a fiber formation inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of claim 5847 wherein the fibrosis inhibitor inhibits dihydrofolate reduction. The method of claim 5847 wherein thymidine monophosphate is inhibited by the fiber formation inhibitor. The method of claim 5847 wherein the fiber formation inhibitor causes DNA damage. The method of claim 5847 wherein the fiber formation inhibitor is a DNA intercalation agent. The method of claim 5847 wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The method of claim 5847 wherein the fibril formation inhibitor inhibits ribonucleotide synthesis or function. The method of claim 5847 wherein the fibrosis inhibitor inhibits thymidine monophosphate synthesis or function. The method of claim 5847, wherein DNA synthesis is inhibited by the fiber formation inhibitor. The method of claim 5847, wherein the fiber formation inhibitor causes DNA adduct formation. The method of claim 5847 wherein protein synthesis is inhibited by a fiber formation inhibitor. The method of claim 5847, wherein the microtubule function is inhibited by the fiber formation inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is a cyclin dependent protein kinase inhibitor. The method of claim 5847 wherein the fibrosis inhibitor is an epidermal growth factor kinase inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is an elastase inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of claim 5847 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 5847 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 5847 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist. The method of claim 5847 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist, and the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof. The method of claim 5847 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 5847 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof. The method of claim 5847 wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of claim 5847 wherein the fibrosis inhibitor is an IL-1 antagonist. The method of claim 5847 wherein the fibrosis inhibitor is an ICE antagonist. The method of claim 5847 wherein the fiber formation inhibitor is an IRAK antagonist. The method of claim 5847 wherein the fibrosis inhibitor is an IL-4 agonist. The method of claim 5847 wherein the fiber formation inhibitor is an immunomodulator. The method of claim 5847 wherein the fibrosis inhibitor is sirolimus or an analogue or derivative thereof. The method of claim 5847 wherein the fiber formation inhibitor is not sirolimus. The method of claim 5847 wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. The method of claim 5847 wherein the fibrosis inhibitor is tacrolimus or an analogue or derivative thereof. The method of claim 5847 wherein the fibrosis inhibitor is not tacrolimus. The method of claim 5847 wherein the fibrosis inhibitor is biolimus or an analogue or derivative thereof. The method of claim 5847 wherein the fibrosis inhibitor is tresperimus or an analogue or derivative thereof. The method of claim 5847 wherein the fibrosis inhibitor is auranofin or an analogue or derivative thereof. The method of claim 5847 wherein the fibrosis inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of claim 5847 wherein the fibrosis inhibitor is gusperimus or an analogue or derivative thereof. The method of claim 5847 wherein the fibrosis inhibitor is pimecrolimus or an analogue or derivative thereof. The method of claim 5847 wherein the fiber formation inhibitor is ABT-578 or an analogue or derivative thereof. The method of claim 5847 wherein the fiber formation inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof. The method of claim 5847 wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1 -α-25 dihydroxy vitamin D ₃ or an analogue or derivative thereof. The method of claim 5847 wherein the fiber formation inhibitor is a leukotriene inhibitor. The method of claim 5847 wherein the fibrosis inhibitor is an MCP-1 antagonist. The method of claim 5847 wherein the fiber formation inhibitor is an MMP inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is an NFκB inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is an NFκB inhibitor, wherein the NFκB inhibitor is Bay11-7082. The method of claim 5847 wherein the fiber formation inhibitor is a NO antagonist. The method of claim 5847 wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor. The method of claim 5847 wherein the fibrosis inhibitor is a p38 MAP kinase inhibitor, and the p38 MAP kinase inhibitor is SB202190. The method of claim 5847 wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is a TGF beta inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is a thromboxane A2 antagonist. The method of claim 5847 wherein the fibrosis inhibitor is a TNFα antagonist. The method of claim 5847 wherein the fiber formation inhibitor is a TACE inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is a vitronectin inhibitor. The method of claim 5847 wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is a protein kinase inhibitor. The method of claim 5847 wherein the fibrosis inhibitor is a PDGF receptor kinase inhibitor. The method of claim 5847 wherein the fibrosis inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is a retinoic acid receptor antagonist. The method of claim 5847 wherein the fiber formation inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of claim 5847 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 5847 wherein the fiber formation inhibitor is an antifungal agent. The method of claim 5847 wherein the fiber formation inhibitor is an antifungal agent, and the antifungal agent is sulconizole. The method of claim 5847 wherein the fiber formation inhibitor is a bisphosphonate. The method of claim 5847 wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. The method of claim 5847 wherein the fibrosis inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The method of claim 5847, wherein the fiber formation inhibitor is a macrolide antibiotic. The method of claim 5847 wherein the fibrosis inhibitor is a GPIIb / IIIa receptor antagonist. The method of claim 5847 wherein the fiber formation inhibitor is an endothelin receptor antagonist. The method of claim 5847 wherein the fibrosis inhibitor is an agonist of peroxisome proliferator-activated receptor. The method of claim 5847 wherein the fibrosis inhibitor is an estrogen receptor agent. The method of claim 5847 wherein the fibrosis inhibitor is a somostatin analog. The method of claim 5847 wherein the fiber formation inhibitor is a neurokinin 1 antagonist. The method of claim 5847 wherein the fiber formation inhibitor is a neurokinin 3 antagonist. The method of claim 5847 wherein the fibrosis inhibitor is a VLA-4 antagonist. The method of claim 5847 wherein the fibrosis inhibitor is an osteoclast inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is an angiotensin II antagonist. The method of claim 5847 wherein the fiber formation inhibitor is an enkephalinase inhibitor. The method of claim 5847 wherein the fibrosis inhibitor is a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer. The method of claim 5847 wherein the fiber formation inhibitor is a protein kinase C inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is a CXCR3 inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is an Itk inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of claim 5847 wherein the fibrosis inhibitor is a PPAR agonist. The method of claim 5847 wherein the fiber formation inhibitor is an immunosuppressant. The method of claim 5847 wherein the fiber formation inhibitor is an Erb inhibitor. The method of claim 5847 wherein the fibrosis inhibitor is an apoptosis agonist. The method of claim 5847 wherein the fibrosis inhibitor is a lipocortin agonist. The method of claim 5847 wherein the fibrosis inhibitor is a VCAM-1 antagonist. The method of claim 5847 wherein the fiber formation inhibitor is a collagen antagonist. The method of claim 5847 wherein the fiber formation inhibitor is an α2 integrin antagonist. The method of claim 5847 wherein the fiber formation inhibitor is a TNFα inhibitor. The method of claim 5847 wherein the fiber formation inhibitor is a nitric oxide inhibitor The method of claim 5847 wherein the fiber formation inhibitor is a cathepsin inhibitor. The method of claim 5847 wherein the fibrosis inhibitor is not an anti-inflammatory agent. The method of claim 5847 wherein the fibrosis inhibitor is not a steroid. The method of claim 5847 wherein the fiber formation inhibitor is not a glucocorticosteroid. The method of claim 5847 wherein the fibrosis inhibitor is not dexamethasone. The method of claim 5847 wherein the fibrosis inhibitor is not beclomethasone. The method of claim 5847 wherein the fiber formation inhibitor is not dipropionic acid. The method of claim 5847 wherein the fiber formation inhibitor is not an anti-infective. The method of claim 5847 wherein the fibrosis inhibitor is not an antibiotic. The method of claim 5847 wherein the fibrosis inhibitor is not an antifungal agent. The method of claim 5847 wherein the anti-infective is an anthracycline. The method of claim 5847 wherein the anti-infective agent is doxorubicin. The method of claim 5847 wherein the anti-infective is mitoxantrone. The method of claim 5847 wherein the anti-infective agent is fluoropyrimidine. The method of claim 5847 wherein the anti-infective is 5-fluorouracil (5-FU). The method of claim 5847 wherein the anti-infective agent is a folic acid antagonist. The method of claim 5847 wherein the anti-infective agent is methotrexate. The method of claim 5847 wherein the anti-infective is podophyllotoxin. The method of claim 5847 wherein the anti-infective is etoposide. The method of claim 5847 wherein the anti-infective agent is camptothecin. The method of claim 5847 wherein the anti-infective is hydroxyurea. The method of claim 5847 wherein the anti-infective is a platinum complex. The method of claim 5847 wherein the anti-infective is cisplatin. The method of claim 5847, wherein the composition comprises an antithrombotic agent. The method of claim 5847, wherein the polymer is formed from a reactant comprising a naturally occurring polymer. The method of claim 5847, wherein the polymer is formed from a reactant comprising protein. The method of claim 5847, wherein the polymer is formed from a reactant comprising carbohydrate. The method of claim 5847, wherein the polymer is formed from a reactant comprising a biodegradable polymer. The method of claim 5847, wherein the polymer is formed from a reactant comprising a non-biodegradable polymer. The method of claim 5847, wherein the polymer is formed from a reactant comprising collagen. The method of claim 5847, wherein the polymer is formed from a reactant comprising methylated collagen. The method of claim 5847, wherein the polymer is formed from a reactant comprising fibrinogen. The method of claim 5847, wherein the polymer is formed from a reactant comprising thrombin. The method of claim 5847 wherein the polymer is formed from a reactant comprising a plasma component. The method of claim 5847, wherein the polymer is formed from a reactant comprising a calcium salt. The method of claim 5847 wherein the polymer is formed from a reactant comprising a fiber formation inhibitor. The method of claim 5847, wherein the polymer is formed from a reactant comprising a fibrinogen analog. The method of claim 5847, wherein the polymer is formed from a reactant comprising albumin. The method of claim 5847, wherein the polymer is formed from a reactant comprising plasminogen. The method of claim 5847 wherein the polymer is formed from a reactant comprising von Willebrand factor. The method of claim 5847 wherein the polymer is formed from a reactant comprising Factor VIII. The method of claim 5847 wherein the polymer is formed from a reactant comprising hypoallergenic collagen. The method of claim 5847 wherein the polymer is formed from a reactant comprising atelopeptide collagen. The method of claim 5847 wherein the polymer is formed from a reactant comprising telopeptide collagen. The method of claim 5847, wherein the polymer is formed from a reactant comprising cross-linked collagen. The method of claim 5847, wherein the polymer is formed from a reactant comprising aprotinin. The method of claim 5847 wherein the polymer is formed from a reactant comprising epsilon amino-n-caproic acid. The method of claim 5847, wherein the polymer is formed from a reactant comprising gelatin. The method of claim 5847 wherein the polymer is formed from a reactant comprising a protein conjugate. The method of claim 5847, wherein the polymer is formed from a reactant comprising a gelatin conjugate. The method of claim 5847, wherein the polymer is formed from a reactant comprising a synthetic polymer. The method of claim 5847, wherein the polymer is formed from a reactant comprising a compound comprising synthetic isocyanate. The method of claim 5847, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic thiol. The method of claim 5847, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more thiol groups. The method of claim 5847, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more thiol groups. The method of claim 5847, wherein the polymer is formed from a reactant comprising a synthetic compound comprising 4 or more thiol groups. The method of claim 5847, wherein the polymer is formed from a reactant comprising a compound comprising synthetic amino. The method of claim 5847, wherein the polymer is formed from a reactant comprised of a synthetic compound comprising two or more amino groups. The method of claim 5847, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more amino groups. The method of claim 5847, wherein the polymer is formed from a reactant comprising a synthetic compound comprising 4 or more amino groups. The method of claim 5847, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of claim 5847, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The method of claim 5847, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. The method of claim 5847, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more carbonyl-oxygen-succinimidyl groups. The method of claim 5847, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide. The method of claim 5847, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a polyalkylene oxide and a biodegradable polyester block. The method of claim 5847, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The method of claim 5847, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a thiol reactive group. The method of claim 5847 wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The method of claim 5847, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a biodegradable polyester block. The method of claim 5847, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly comprised of lactic acid or lactide. The method of claim 5847, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly consisting of glycolic acid or glycolide. The method of claim 5847, wherein the polymer is formed from a reactant comprising polylysine. The method of claim 5847, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 5847, wherein the polymer is formed from a reactant comprising (a) a protein and (b) polylysine. The method of claim 5847, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more thiol groups. The method of claim 5847 wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more amino groups. The method of claim 5847 wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer of claim 5847, wherein the polymer is formed from a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide, and epison caprolactone. Method. The method of claim 5847, wherein the polymer is formed from a reactant comprising (a) a collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 5847, wherein the polymer is formed from a reactant comprising (a) collagen and (b) polylysine. The method of claim 5847 wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more thiol groups. The method of claim 5847, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more amino groups. The method of claim 5847 wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method according to 5847. The method of claim 5847, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 5847, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) polylysine. The method of claim 5847, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more thiol groups. The method of claim 5847 wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more amino groups. The method of claim 5847 wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone, The method of claim 5847. The method of claim 5847, wherein the polymer is formed from a reactant comprising hyaluronic acid. The method of claim 5847, wherein the polymer is formed from a reactant comprising a hyaluronic acid derivative. The method of claim 5847, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The method of claim 5847 wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A polymer having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene region. The method of claim 5847, wherein the method is formed from a reactant comprising a synthetic compound comprising a plurality of electrophilic groups. The method of claim 5847, wherein the composition comprises a colorant. The method of claim 5847 wherein the composition is sterile. Methods of implanting a medical device comprising: (a) a medical device to which the medical device is implanted or transplanted host tissue i) an inhibitor of fiber formation ii) an anti-infective agent iii) a polymer iv) an inhibitor of fiber formation and a polymer V) a composition comprising an anti-infective agent and a polymer or vi) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer, and (b) implanting a medical device into a host, and said medical treatment The device is an electrical device. A method of implanting a device with the medical device of claim 6125 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a fibrosis inhibitor; and (b) the host Implant a medical device. A method for implanting a device with the medical device of claim 6125 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in an anti-infective agent; and (b) the host is implanted. Implant medical devices. A method of implanting a device with the medical device of claim 6125 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a polymer; and (b) the medical device is in the host. Transplant. A method of implanting a device comprising the following with a medical device according to claim 6125: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising a fibrosis inhibitor and a polymer; And (b) transplant the medical device into the host. A method of implanting a device with the medical device of claim 6125 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) Transplant the medical device into the host. 64. A method of implanting a device comprising the medical device of claim 6125 comprising: (a) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer in which the medical device is implanted or the host tissue into which the device is implanted. And (b) implant the medical device into the host. The method of claim 6125, wherein the medical device is a neurostimulator. The method of claim 6125, wherein the medical device is a spinal cord stimulator. The method of claim 6125, wherein the medical device is a brain stimulator. The method of claim 6125, wherein the medical device is a vagus nerve stimulator. The method of claim 6125, wherein the medical device is a sacral nerve stimulation device. The method of claim 6125, wherein the medical device is a gastric nerve stimulation device. The method of claim 6125, wherein the medical device is an acoustic nerve stimulator. The method of claim 6125, wherein the medical device stimulates the organ. The method of claim 6125, wherein the medical device stimulates bone. The method of claim 6125, wherein the medical device stimulates muscles. The method of claim 6125, wherein the medical device stimulates the tissue. The method of claim 6125, wherein the medical device is a device for continuous subarachnoid injection. The method of claim 6125, wherein the medical device is an implantable electrode. The method of claim 6125, wherein the medical device is an implantable device. The method of claim 6125, wherein the medical device is a lead. The method of claim 6125, wherein the medical device is a stimulation lead. The method of claim 6125, wherein the medical device is a stimulation catheter lead. The method of claim 6125, wherein the medical device is a transplanted cochlear stimulator. The method of claim 6125, wherein the medical device is a micro stimulator. The method of claim 6125, wherein the medical device is battery powered. The method of claim 6125, wherein the medical device is radio frequency. The method of claim 6125, wherein the medical device is both battery powered and radio frequency. The method of claim 6125, wherein the medical device is a cardiac rhythm management device. The method of claim 6125, wherein the medical device is a cardiac pacemaker. The method of claim 6125, wherein the medical device is an implantable tachycardia defibrillator system. The method of claim 6125, wherein the medical device is a cardiac lead. The method of claim 6125, wherein the medical device is a pacer lead. The method of claim 6125, wherein the medical device is an endocardial lead. The method of claim 6125, wherein the medical device is a cardioverter lead. The method of claim 6125, wherein the medical device is an epicardial lead. The method of claim 6125, wherein the medical device is an epicardial defibrillator lead. The method of claim 6125, wherein the medical device is a patch defibrillator. The method of claim 6125, wherein the medical device is a patch defibrillator lead. The method of claim 6125, wherein the medical device is an electrical patch. The method of claim 6125, wherein the medical device is a transvenous lead. The method of claim 6125, wherein the medical device is an active fixation lead. The method of claim 6125, wherein the medical device is an inactive fixed lead. The method of claim 6125, wherein the medical device is a detection lead. The method of claim 6125, wherein the medical device is a defibrillator. The method of claim 6125, wherein the medical device is an implantable sensor. The method of claim 6125, wherein the medical device is a left ventricular assist device. The method of claim 6125, wherein the medical device is an implantable pulse generator. The method of claim 6125, wherein the medical device is a patch lead. The method of claim 6125, wherein the medical device is an electrical patch. The method of claim 6125, wherein the medical device is a cardiac stimulator. The method of claim 6125, wherein the medical device is an electrical device sensor. The method of claim 6125, wherein the medical device is an electrical device pump. The method of claim 6125, wherein the medical device is a dural patch. The method of claim 6125, wherein the medical device is a ventricular peritoneal shunt. The method of claim 6125, wherein the medical device is a ventricular atrial shunt. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent dural fiber formation following laminectomy. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent cardiac rhythm abnormalities. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent atrial rhythm abnormalities. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent conduction abnormalities. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent ventricular rhythm abnormalities. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent pain. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent epilepsy. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent Parkinson's disease. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent movement disorders. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent obesity. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent depression. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent anxiety. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent hearing loss. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent ulcers. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent deep vein thrombosis. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent muscle atrophy. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent joint stiffness. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent muscle spasm. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent osteoporosis. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent scoliosis. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent spinal disc degeneration. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent spinal cord injury. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent urinary dysfunction. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent gastric paresis. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent malignant tumors. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent arachnoiditis. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent chronic disease. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent migraine. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent sleep disorders. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent dementia. The method of claim 6125, wherein the medical device is an electrical device adapted to treat or prevent Alzheimer's disease. The method of claim 6125, wherein cell regeneration is inhibited by a fiber formation inhibitor. The method of claim 6125, wherein an angiogenesis is inhibited by a fiber formation inhibitor. The method of claim 6125, wherein fibroblast migration is inhibited by a fibrosis inhibitor. The method of claim 6125, wherein the fibrosis inhibitor inhibits fibroblast proliferation. The method of claim 6125, wherein the fiber formation inhibitor inhibits extracellular matrix accumulation. The method of claim 6125, wherein the tissue remodeling is inhibited by the fiber formation inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is an angiogenesis inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is a 5- lipoxygenase inhibitor or antagonist. The method of claim 6125, wherein the fiber formation inhibitor is a chemokine receptor antagonist. The method of claim 6125, wherein the fiber formation inhibitor is a cell cycle inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is a taxane. The method of claim 6125, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is paclitaxel. The method of claim 6125, wherein the fiber formation inhibitor is not paclitaxel. The method of claim 6125 wherein the fibrosis inhibitor is an analogue or derivative of paclitaxel. The method of claim 6125, wherein the fiber formation inhibitor is a vinca alkaloid. The method of claim 6125 wherein the fibrosis inhibitor is camptothecin or an analogue or derivative thereof. The method of claim 6125, wherein the fiber formation inhibitor is podophyllotoxin. The method of claim 6125, wherein the fiber formation inhibitor is podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof. The method of claim 6125, wherein the fiber formation inhibitor is an anthracycline. The method of claim 6125, wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof. The method of claim 6125, wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof. The method of claim 6125, wherein the fiber formation inhibitor is a platinum compound. The method of claim 6125, wherein the fiber formation inhibitor is nitrosourea. The method of claim 6125, wherein the fiber formation inhibitor is nitroimidazole. The method of claim 6125, wherein the fiber formation inhibitor is a folic acid antagonist. The method of claim 6125 wherein the fibrosis inhibitor is a cytidine analogue. The method of claim 6125 wherein the fibrosis inhibitor is a pyrimidine analogue. The method of claim 6125 wherein the fiber formation inhibitor is a fluoropyrimidine analogue. The method of claim 6125, wherein the fiber formation inhibitor is a purine analogue. The method of claim 6125, wherein the fiber formation inhibitor is nitrogen mustard or an analogue or derivative thereof. The method of claim 6125, wherein the fiber formation inhibitor is hydroxyurea. The method of claim 6125 wherein the fibrosis inhibitor is mitomycin or an analogue or derivative thereof. The method of claim 6125, wherein the fiber formation inhibitor is an alkyl sulfonate. The method of claim 6125, wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The method of claim 6125 wherein the fibrosis inhibitor is nicotinamide or an analogue or derivative thereof. The method of claim 6125 wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of claim 6125, wherein the fiber formation inhibitor is a DNA alkylating agent. The method of claim 6125, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is a DNA cleaving agent. The method of claim 6125, wherein the fiber formation inhibitor is an antimetabolite. The method of claim 6125, wherein adenosine deaminase is inhibited by a fiber formation inhibitor. The method of claim 6125, wherein purine ring synthesis is inhibited by a fiber formation inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of claim 6125, wherein the fiber formation inhibitor inhibits dihydrofolate reduction. The method of claim 6125, wherein thymidine monophosphate is inhibited by the fiber formation inhibitor. The method of claim 6125, wherein the fiber formation inhibitor causes DNA damage. The method of claim 6125, wherein the fiber formation inhibitor is a DNA intercalation agent. The method of claim 6125, wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The method of claim 6125, wherein the fibril formation inhibitor inhibits ribonucleotide synthesis or function. The method of claim 6125, wherein the fibrosis inhibitor inhibits thymidine monophosphate synthesis or function. The method of claim 6125, wherein DNA synthesis is inhibited by the fiber formation inhibitor. The method of claim 6125, wherein the fiber formation inhibitor causes DNA adduct formation. The method of claim 6125, wherein protein synthesis is inhibited by the fiber formation inhibitor. The method of claim 6125, wherein the microtubule function is inhibited by the fiber formation inhibitor. The method of claim 6125 wherein the fibrosis inhibitor is a cyclin dependent protein kinase inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is an epidermal growth factor kinase inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is an elastase inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of claim 6125 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 6125, wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 6125 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist. The method of claim 6125 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist, and the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof. The method of claim 6125, wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 6125, wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof. The method of claim 6125, wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is an IL-1 antagonist. The method of claim 6125, wherein the fiber formation inhibitor is an ICE antagonist. The method of claim 6125, wherein the fiber formation inhibitor is an IRAK antagonist. The method of claim 6125 wherein the fibrosis inhibitor is an IL-4 agonist. The method of claim 6125, wherein the fiber formation inhibitor is an immunomodulator. The method of claim 6125 wherein the fibrosis inhibitor is sirolimus or an analogue or derivative thereof. The method of claim 6125, wherein the fiber formation inhibitor is not sirolimus. The method of claim 6125 wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. The method of claim 6125 wherein the fibrosis inhibitor is tacrolimus or an analogue or derivative thereof. The method of claim 6125, wherein the fiber formation inhibitor is not tacrolimus. The method of claim 6125 wherein the fibrosis inhibitor is biolimus or an analogue or derivative thereof. The method of claim 6125 wherein the fibrosis inhibitor is tresperimus or an analogue or derivative thereof. The method of claim 6125 wherein the fibrosis inhibitor is auranofin or an analogue or derivative thereof. The method of claim 6125 wherein the fibrosis inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of claim 6125 wherein the fibrosis inhibitor is gusperimus or an analogue or derivative thereof. The method of claim 6125 wherein the fibrosis inhibitor is pimecrolimus or an analogue or derivative thereof. The method of claim 6125 wherein the fibrosis inhibitor is ABT-578 or an analogue or derivative thereof. The method of claim 6125, wherein the fiber formation inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof. A fiber-forming inhibitor is IMPDH inhibitors, the IMPDH inhibitor is 1-alpha-25-dihydroxyvitamin D ₃ or its analogues or derivatives, method of claim 6125. The method of claim 6125, wherein the fiber formation inhibitor is a leukotriene inhibitor. The method of claim 6125, wherein the vascularization inhibitor is an MCP-1 antagonist. The method of claim 6125, wherein the fiber formation inhibitor is an MMP inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is an NFκB inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is an NFκB inhibitor, and the NFκB inhibitor is Bay11-7082. The method of claim 6125, wherein the fiber formation inhibitor is a NO antagonist. The method of claim 6125, wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor, and the p38 MAP kinase inhibitor is SB202190. The method of claim 6125, wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is a TGF beta inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is a thromboxane A2 antagonist. The method of claim 6125, wherein the vascularization inhibitor is a TNFα antagonist. The method of claim 6125, wherein the fiber formation inhibitor is a TACE inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is a vitronectin inhibitor. The method of claim 6125, wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is a protein kinase inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is a PDGF receptor kinase inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is a retinoic acid receptor antagonist. The method of claim 6125, wherein the fiber formation inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of claim 6125 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 6125, wherein the fiber formation inhibitor is an antifungal agent. The method of claim 6125, wherein the fiber formation inhibitor is an antifungal agent, and the antifungal agent is sulconizole. The method of claim 6125, wherein the fiber formation inhibitor is a bisphosphonate. The method of claim 6125, wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. The method of claim 6125 wherein the fibrosis inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The method of claim 6125, wherein the fiber formation inhibitor is a macrolide antibiotic. The method of claim 6125, wherein the fiber formation inhibitor is a GPIIb / IIIa receptor antagonist. The method of claim 6125, wherein the fiber formation inhibitor is an endothelin receptor antagonist. The method of claim 6125 wherein the fibrosis inhibitor is an agonist of peroxisome proliferator-activated receptor. The method of claim 6125 wherein the fibrosis inhibitor is an estrogen receptor agent. The method of claim 6125 wherein the fibrosis inhibitor is a somostatin analog. The method of claim 6125, wherein the fiber formation inhibitor is a neurokinin 1 antagonist. The method of claim 6125, wherein the fiber formation inhibitor is a neurokinin 3 antagonist. The method of claim 6125 wherein the fibrosis inhibitor is a VLA-4 antagonist. The method of claim 6125, wherein the fiber formation inhibitor is an osteoclast inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is an angiotensin II antagonist. The method of claim 6125, wherein the fiber formation inhibitor is an enkephalinase inhibitor. The method of claim 6125 wherein the fibrosis inhibitor is a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer. The method of claim 6125, wherein the fiber formation inhibitor is a protein kinase C inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is a CXCR3 inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is an Itk inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of claim 6125, wherein the fibrosis inhibitor is a PPAR agonist. The method of claim 6125, wherein the fiber formation inhibitor is an immunosuppressant. The method of claim 6125, wherein the fiber formation inhibitor is an Erb inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is an apoptosis agonist. The method of claim 6125, wherein the fiber formation inhibitor is a lipocortin agonist. The method of claim 6125, wherein the fiber formation inhibitor is a VCAM-1 antagonist. The method of claim 6125, wherein the fiber formation inhibitor is a collagen antagonist. The method of claim 6125, wherein the fiber formation inhibitor is an α2 integrin antagonist. The method of claim 6125, wherein the fiber formation inhibitor is a TNFα inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is a nitric oxide inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is a cathepsin inhibitor. The method of claim 6125, wherein the fiber formation inhibitor is not an anti-inflammatory agent. The method of claim 6125, wherein the fiber formation inhibitor is not a steroid. The method of claim 6125, wherein the fiber formation inhibitor is not a glucocorticosteroid. The method of claim 6125, wherein the fiber formation inhibitor is not dexamethasone. The method of claim 6125, wherein the fiber formation inhibitor is not beclomethasone. The method of claim 6125, wherein the fiber formation inhibitor is not dipropionic acid. The method of claim 6125, wherein the fiber formation inhibitor is not an anti-infective. The method of claim 6125, wherein the fiber formation inhibitor is not an antibiotic. The method of claim 6125, wherein the fiber formation inhibitor is not an antifungal agent. The method of claim 6125, wherein the anti-infective is an anthracycline. The method of claim 6125, wherein the anti-infective is doxorubicin. The method of claim 6125, wherein the anti-infective is mitoxantrone. The method of claim 6125, wherein the anti-infective agent is fluoropyrimidine. The method of claim 6125 wherein the anti-infective is 5-fluorouracil (5-FU). The method of claim 6125, wherein the anti-infective agent is a folic acid antagonist. The method of claim 6125, wherein the anti-infective is methotrexate. The method of claim 6125, wherein the anti-infective is podophyllotoxin. The method of claim 6125, wherein the anti-infective is etoposide. The method of claim 6125, wherein the anti-infective is camptothecin. The method of claim 6125, wherein the anti-infective is hydroxyurea. The method of claim 6125, wherein the anti-infective is a platinum complex. The method of claim 6125, wherein the anti-infective is cisplatin. The method of claim 6125, wherein the composition comprises an antithrombotic agent. The method of claim 6125, wherein the polymer is formed from a reactant comprising a naturally occurring polymer. The method of claim 6125, wherein the polymer is formed from reactants comprising proteins. The method of claim 6125, wherein the polymer is formed from reactants comprising carbohydrate. The method of claim 6125, wherein the polymer is formed from a reactant comprising a biodegradable polymer. The method of claim 6125, wherein the polymer is formed from a reactant comprising a non-biodegradable polymer. The method of claim 6125, wherein the polymer is formed from reactants comprising collagen. The method of claim 6125, wherein the polymer is formed from a reactant comprising methylated collagen. The method of claim 6125, wherein the polymer is formed from a reactant comprising fibrinogen. The method of claim 6125, wherein the polymer is formed from reactants comprising thrombin. The method of claim 6125, wherein the polymer is formed from reactants comprising plasma components. The method of claim 6125, wherein the polymer is formed from a reactant comprising a calcium salt. The method of claim 6125, wherein the polymer is formed from a reactant comprising a fiber formation inhibitor. The method of claim 6125, wherein the polymer is formed from a reactant comprising a fibrinogen analog. The method of claim 6125, wherein the polymer is formed from a reactant comprising albumin. The method of claim 6125, wherein the polymer is formed from a reactant comprising plasminogen. The method of claim 6125, wherein the polymer is formed from a reactant comprising von Willebrand factor. The method of claim 6125, wherein the polymer is formed from a reactant comprising Factor VIII. The method of claim 6125, wherein the polymer is formed from reactants comprising hypoallergenic collagen. The method of claim 6125, wherein the polymer is formed from reactants comprising atelopeptide collagen. The method of claim 6125, wherein the polymer is formed from reactants comprising telopeptide collagen. The method of claim 6125, wherein the polymer is formed from a reactant comprising cross-linked collagen. The method of claim 6125, wherein the polymer is formed from a reactant comprising aprotinin. The method of claim 6125, wherein the polymer is formed from a reactant comprising epsilon amino-n-caproic acid. The method of claim 6125, wherein the polymer is formed from a reactant comprising gelatin. The method of claim 6125, wherein the polymer is formed from a reactant comprising a protein conjugate. The method of claim 6125, wherein the polymer is formed from a reactant comprising a gelatin conjugate. The method of claim 6125, wherein the polymer is formed from a reactant comprising a synthetic polymer. The method of claim 6125, wherein the polymer is formed from a reactant comprising a compound comprising synthetic isocyanate. The method of claim 6125, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic thiol. The method of claim 6125, wherein the polymer is formed from reactants consisting of a synthetic compound containing two or more thiol groups. The method of claim 6125, wherein the polymer is formed from reactants comprised of synthetic compounds comprising three or more thiol groups. The method of claim 6125, wherein the polymer is formed from reactants comprised of synthetic compounds comprising four or more thiol groups. The method of claim 6125, wherein the polymer is formed from a reactant comprising a compound comprising synthetic amino. The method of claim 6125, wherein the polymer is formed from reactants consisting of a synthetic compound containing two or more amino groups. The method of claim 6125, wherein the polymer is formed from reactants comprised of synthetic compounds comprising three or more amino groups. The method of claim 6125, wherein the polymer is formed from reactants comprised of synthetic compounds comprising four or more amino groups. The method of claim 6125, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of claim 6125, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The method of claim 6125, wherein the polymer is formed from reactants comprised of synthetic compounds comprising three or more carbonyl-oxygen-succinimidyl groups. The method of claim 6125, wherein the polymer is formed from reactants comprised of synthetic compounds comprising four or more carbonyl-oxygen-succinimidyl groups. The method of claim 6125, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide. The method of claim 6125, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a polyalkylene oxide and a biodegradable polyester block. The method of claim 6125, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide having an amino reactive group. The method of claim 6125, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide having a thiol reactive group. The method of claim 6125, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The method of claim 6125, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a biodegradable polyester block. The method of claim 6125, wherein the polymer is formed from reactants comprising synthetic polymers, wholly or partly comprised of lactic acid or lactide. The method of claim 6125, wherein the polymer is formed from reactants comprising a synthetic polymer, wholly or partly comprised of glycolic acid or glycolide. The method of claim 6125, wherein the polymer is formed from a reactant comprising polylysine. The method of claim 6125, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 6125, wherein the polymer is formed from a reactant comprising (a) a protein and (b) polylysine. The method of claim 6125, wherein the polymer is formed from (a) a reactant and (b) a reactant comprising a compound having four or more thiol groups. The method of claim 6125, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more amino groups. The method of claim 6125, wherein the polymer is formed from a reactant comprising: (a) a protein; and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method of 6125. The method of claim 6125, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 6125, wherein the polymer is formed from reactants comprising (a) collagen and (b) polylysine. The method of claim 6125, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more thiol groups. The method of claim 6125, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more amino groups. The method of claim 6125, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method of 6125. The method of claim 6125, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 6125, wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) polylysine. The method of claim 6125, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more thiol groups. The method of claim 6125, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more amino groups. The method of claim 6125, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone, The method of claim 6125. The method of claim 6125, wherein the polymer is formed from a reactant comprising hyaluronic acid. The method of claim 6125, wherein the polymer is formed from a reactant comprising a hyaluronic acid derivative. The method of claim 6125, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The method of claim 6125, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A polymer having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene region. The method of claim 6125, formed from a reactant consisting of and a synthetic compound comprising a plurality of electrophilic groups. The method of claim 6125, wherein the composition comprises a colorant. The method of claim 6125, wherein the composition is sterile. Methods of implanting a medical device comprising: (a) a medical device to which the medical device is implanted or transplanted host tissue i) an inhibitor of fiber formation ii) an anti-infective agent iii) a polymer iv) an inhibitor of fiber formation and a polymer V) a composition comprising an anti-infective agent and a polymer or vi) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer, and (b) implanting a medical device into a host, and said medical treatment The device is a sensor. 64. A method of implanting a device with the medical device of claim 6459 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a fibrosis inhibitor; and (b) the host Implant a medical device. 64. A method of implanting a device with the medical device of claim 6459 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in an anti-infective agent; and (b) the host is implanted. Implant medical devices. The method of implanting a device with the medical device of claim 6459, comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a polymer; and (b) the medical device is implanted in the host. Transplant. 64. A method of implanting a device comprising the medical device of claim 6459 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising a fibrosis inhibitor and a polymer; And (b) transplant the medical device into the host. 64. A method of implanting a device with the medical device of claim 6459 comprising: (a) immersing the tissue of the host to which the medical device is implanted or implanted with a composition comprising an anti-infective and a polymer; and (b) Transplant the medical device into the host. 64. A method of implanting a device comprising the medical device of claim 6459, comprising: (a) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer in which the medical device is implanted or the host tissue into which the device is implanted. And (b) implant the medical device into the host. The method of claim 6459, wherein the medical device is a blood / tissue sugar content monitor. The method of claim 6459, wherein the medical device is an electrolyte sensor. The method of claim 6459, wherein the medical device is a blood concentration sensor. The method of claim 6459, wherein the medical device is a temperature sensor. The method of claim 6459, wherein the medical device is a pH sensor. The method of claim 6459, wherein the medical device is an optical sensor. The method of claim 6459, wherein the medical device is an amperometric sensor. The method of claim 6459, wherein the medical device is a pressure sensor. The method of claim 6459, wherein the medical device is a biosensor. The method of claim 6459, wherein the medical device is a detection transponder. The method of claim 6459, wherein the medical device is a strain sensor. The method of claim 6459, wherein the medical device is a magnetoresistive sensor. The method of claim 6459, wherein the medical device is a heart sensor. The method of claim 6459, wherein the medical device is a respiratory sensor. The method of claim 6459, wherein the medical device is an audio sensor. The method of claim 6459, wherein the medical device is a metabolite sensor. The method of claim 6459, wherein the medical device is a sensor that detects a mechanical change. The method of claim 6459, wherein the medical device is a sensor that detects a physical change. The method of claim 6459, wherein the medical device is a sensor that detects an electrochemical change. The method of claim 6459, wherein the medical device is a sensor that detects a change in magnetism. The method of claim 6459, wherein the medical device is a sensor that detects an accelerated change. The method of claim 6459, wherein the medical device is a sensor that detects a change in ionizing radiation. The method of claim 6459, wherein the medical device is a sensor that detects a change in sound waves. The method of claim 6459, wherein the medical device is a sensor that detects a chemical change. The method of claim 6459, wherein the medical device is a sensor that detects a change in drug concentration. The method of claim 6459, wherein the medical device is a sensor that detects hormonal changes. The method of claim 6459, wherein the medical device is a sensor that detects a change in atmospheric pressure. The method of claim 6459, wherein cell regeneration is inhibited by fibrosis inhibitor. The method of claim 6459, wherein angiogenesis is inhibited by fibrosis inhibitors. The method of claim 6459, wherein fibroblast migration is inhibited by a fibrosis inhibitor. The method of claim 6459, wherein the fibrosis inhibitor inhibits fibroblast proliferation. The method of claim 6459, wherein the fiber formation inhibitor inhibits extracellular matrix accumulation. The method of claim 6459, wherein the tissue remodeling is inhibited by the fiber formation inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is an angiogenesis inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is a 5- lipoxygenase inhibitor or antagonist. The method of claim 6459, wherein the fiber formation inhibitor is a chemokine receptor antagonist. The method of claim 6459, wherein the fiber formation inhibitor is a cell cycle inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is a taxane. The method of claim 6459, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is paclitaxel. The method of claim 6459, wherein the fiber formation inhibitor is not paclitaxel. The method of claim 6459 wherein the fibrosis inhibitor is an analogue or derivative of paclitaxel. The method of claim 6459, wherein the fiber formation inhibitor is a vinca alkaloid. The method of claim 6459, wherein the fiber formation inhibitor is camptothecin or an analogue or derivative thereof. The method of claim 6459, wherein the fiber formation inhibitor is podophyllotoxin. The method of claim 6459, wherein the fiber formation inhibitor is podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof. The method of claim 6459, wherein the fiber formation inhibitor is an anthracycline. The method of claim 6459, wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof. The method of claim 6459, wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof. The method of claim 6459, wherein the fiber formation inhibitor is a platinum compound. The method of claim 6459, wherein the fiber formation inhibitor is nitrosourea. The method of claim 6459, wherein the fiber formation inhibitor is nitroimidazole. The method of claim 6459, wherein the fiber formation inhibitor is a folic acid antagonist. The method of claim 6459 wherein the fibrosis inhibitor is a cytidine analogue. The method of claim 6459 wherein the fibrosis inhibitor is a pyrimidine analogue. The method of claim 6459, wherein the fiber formation inhibitor is a fluoropyrimidine analogue. The method of claim 6459 wherein the fibrosis inhibitor is a purine analogue. The method of claim 6459, wherein the fiber formation inhibitor is nitrogen mustard or an analogue or derivative thereof. The method of claim 6459, wherein the fiber formation inhibitor is hydroxyurea. The method of claim 6459 wherein the fibrosis inhibitor is mitomycin or an analogue or derivative thereof. The method of claim 6459, wherein the fiber formation inhibitor is an alkyl sulfonate. The method of claim 6459, wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The method of claim 6459 wherein the fibrosis inhibitor is nicotinamide or an analogue or derivative thereof. The method of claim 6459 wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of claim 6459, wherein the fiber formation inhibitor is a DNA alkylating agent. The method of claim 6459, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is a DNA cleaving agent. The method of claim 6459, wherein the fiber formation inhibitor is an antimetabolite. The method of claim 6459, wherein adenosine deaminase is inhibited by a fiber formation inhibitor. The method of claim 6459, wherein the purine ring synthesis is inhibited by a fiber formation inhibitor. The method of claim 6459 wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of claim 6459, wherein the fiber formation inhibitor inhibits dihydrofolate reduction. The method of claim 6459, wherein the thymidine monophosphate is inhibited by the fiber formation inhibitor. The method of claim 6459, wherein the fiber formation inhibitor causes DNA damage. The method of claim 6459, wherein the fiber formation inhibitor is a DNA intercalation agent. The method of claim 6459, wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The method of claim 6459 wherein the fibril formation inhibitor inhibits ribonucleotide synthesis or function. The method of claim 6459, wherein the fibrosis inhibitor inhibits thymidine monophosphate synthesis or function. The method of claim 6459, wherein DNA synthesis is inhibited by a fiber formation inhibitor. The method of claim 6459, wherein DNA adduct formation occurs with the fiber formation inhibitor. The method of claim 6459, wherein protein synthesis is inhibited by a fiber formation inhibitor. The method of claim 6459, wherein the microtubule function is inhibited by the fiber formation inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is a cyclin dependent protein kinase inhibitor. The method of claim 6459 wherein the fibrosis inhibitor is an epidermal growth factor kinase inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is an elastase inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of claim 6459 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 6459, wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 6459 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist. The method of claim 6459, wherein the fiber formation inhibitor is a heat shock protein 90 antagonist, wherein the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof. The method of claim 6459, wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 6459, wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof. The method of claim 6459, wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of claim 6459 wherein the fibrosis inhibitor is an IL-1 antagonist. The method of claim 6459, wherein the fiber formation inhibitor is an ICE antagonist. The method of claim 6459, wherein the fiber formation inhibitor is an IRAK antagonist. The method of claim 6459 wherein the fibrosis inhibitor is an IL-4 agonist. The method of claim 6459, wherein the fiber formation inhibitor is an immunomodulator. The method of claim 6459, wherein the fibrosis inhibitor is sirolimus or an analogue or derivative thereof. The method of claim 6459, wherein the fiber formation inhibitor is not sirolimus. The method of claim 6459, wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. The method of claim 6459, wherein the fiber formation inhibitor is tacrolimus or an analogue or derivative thereof. The method of claim 6459, wherein the fiber formation inhibitor is not tacrolimus. The method of claim 6459 wherein the fibrosis inhibitor is biolimus or an analogue or derivative thereof. The method of claim 6459 wherein the fibrosis inhibitor is tresperimus or an analogue or derivative thereof. The method of claim 6459 wherein the fibrosis inhibitor is auranofin or an analogue or derivative thereof. The method of claim 6459 wherein the fibrosis inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of claim 6459, wherein the fiber formation inhibitor is gusperimus or an analogue or derivative thereof. The method of claim 6459 wherein the fibrosis inhibitor is pimecrolimus or an analogue or derivative thereof. The method of claim 6459, wherein the fiber formation inhibitor is ABT-578 or an analogue or derivative thereof. The method of claim 6459, wherein the fiber formation inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof. A fiber-forming inhibitor is IMPDH inhibitors, the IMPDH inhibitor is 1-alpha-25-dihydroxyvitamin D ₃ or its analogues or derivatives, method of claim 6459. The method of claim 6459, wherein the fiber formation inhibitor is a leukotriene inhibitor. The method of claim 6459 wherein the vascularization inhibitor is an MCP-1 antagonist. The method of claim 6459, wherein the fiber formation inhibitor is an MMP inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is an NFκB inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is an NFκB inhibitor, and the NFκB inhibitor is Bay11-7082. The method of claim 6459, wherein the fiber formation inhibitor is a NO antagonist. The method of claim 6459 wherein the fibrosis inhibitor is a p38 MAP kinase inhibitor. The method of claim 6459 wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB202190. The method of claim 6459, wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is a TGFβ inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is a thromboxane A2 antagonist. The method of claim 6459 wherein the vascularization inhibitor is a TNFα antagonist. The method of claim 6459, wherein the fiber formation inhibitor is a TACE inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is a vitronectin inhibitor. The method of claim 6459, wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is a protein kinase inhibitor. The method of claim 6459 wherein the fibrosis inhibitor is a PDGF receptor kinase inhibitor. The method of claim 6459 wherein the fibrosis inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is a retinoic acid receptor antagonist. The method of claim 6459 wherein the fibrosis inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of claim 6459 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 6459, wherein the fiber formation inhibitor is an antifungal agent. The method of claim 6459, wherein the fiber formation inhibitor is an antifungal agent, and the antifungal agent is sulconizole. The method of claim 6459, wherein the fiber formation inhibitor is a bisphosphonate. The method of claim 6459, wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. The method of claim 6459 wherein the fibrosis inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The method of claim 6459, wherein the fiber formation inhibitor is a macrolide antibiotic. The method of claim 6459, wherein the fiber formation inhibitor is a GPIIb / IIIa receptor antagonist. The method of claim 6459, wherein the fiber formation inhibitor is an endothelin receptor antagonist. The method of claim 6459 wherein the fibrosis inhibitor is an agonist of peroxisome proliferator-activated receptor. The method of claim 6459 wherein the fibrosis inhibitor is an estrogen receptor agent. The method of claim 6459 wherein the fibrosis inhibitor is a somostatin analog. The method of claim 6459, wherein the fiber formation inhibitor is a neurokinin 1 antagonist. The method of claim 6459, wherein the fiber formation inhibitor is a neurokinin 3 antagonist. The method of claim 6459 wherein the fibrosis inhibitor is a VLA-4 antagonist. The method of claim 6459, wherein the fiber formation inhibitor is an osteoclast inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is an angiotensin II antagonist. The method of claim 6459, wherein the fiber formation inhibitor is an enkephalinase inhibitor. The method of claim 6459 wherein the fibrosis inhibitor is a peroxisome proliferator-responsive receptor gamma agonist insulin sensitizer. The method of claim 6459, wherein the fiber formation inhibitor is a protein kinase C inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is a CXCR3 inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is an Itk inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of claim 6459 wherein the fibrosis inhibitor is a PPAR agonist. The method of claim 6459, wherein the fiber formation inhibitor is an immunosuppressant. The method of claim 6459, wherein the fiber formation inhibitor is an Erb inhibitor. The method of claim 6459 wherein the fibrosis inhibitor is an apoptosis agonist. The method of claim 6459 wherein the fibrosis inhibitor is a lipocortin agonist. The method of claim 6459 wherein the fibrosis inhibitor is a VCAM-1 antagonist. The method of claim 6459, wherein the fiber formation inhibitor is a collagen antagonist. The method of claim 6459, wherein the fiber formation inhibitor is an α2 integrin antagonist. The method of claim 6459, wherein the fiber formation inhibitor is a TNFα inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is a nitric oxide inhibitor. The method of claim 6459, wherein the fiber formation inhibitor is a cathepsin inhibitor. The method of claim 6459 wherein the fibrosis inhibitor is not an anti-inflammatory agent. The method of claim 6459 wherein the fibrosis inhibitor is not a steroid. The method of claim 6459, wherein the fiber formation inhibitor is not a glucocorticosteroid. The method of claim 6459 wherein the fibrosis inhibitor is not dexamethasone. The method of claim 6459, wherein the fiber formation inhibitor is not beclomethasone. The method of claim 6459, wherein the fiber formation inhibitor is not dipropionic acid. The method of claim 6459, wherein the fiber formation inhibitor is not an anti-infective agent. The method of claim 6459 wherein the fibrosis inhibitor is not an antibiotic. The method of claim 6459, wherein the fiber formation inhibitor is not an antifungal agent. The method of claim 6459, wherein the anti-infective is an anthracycline. The method of claim 6459, wherein the anti-infective agent is doxorubicin. The method of claim 6459, wherein the anti-infective agent is mitoxantrone. The method of claim 6459, wherein the anti-infective agent is fluoropyrimidine. The method of claim 6459 wherein the anti-infective agent is 5-fluorouracil (5-FU). The method of claim 6459 wherein the anti-infective agent is a folic acid antagonist. The method of claim 6459 wherein the anti-infective agent is methotrexate. The method of claim 6459, wherein the anti-infective is podophyllotoxin. The method of claim 6459 wherein the anti-infective agent is etoposide. The method of claim 6459 wherein the anti-infective agent is camptothecin. The method of claim 6459 wherein the anti-infective agent is hydroxyurea. The method of claim 6459, wherein the anti-infective is a platinum complex. The method of claim 6459, wherein the anti-infective is cisplatin. The method of claim 6459, wherein the composition comprises an antithrombotic agent. The method of claim 6459, wherein the polymer is formed from a reactant comprising a naturally occurring polymer. The method of claim 6459, wherein the polymer is formed from a reactant comprising protein. The method of claim 6459, wherein the polymer is formed from a reactant comprising a carbohydrate. The method of claim 6459, wherein the polymer is formed from a reactant comprising a biodegradable polymer. The method of claim 6459, wherein the polymer is formed from a reactant comprising a non-biodegradable polymer. The method of claim 6459, wherein the polymer is formed from a reactant comprising collagen. The method of claim 6459, wherein the polymer is formed from a reactant comprising methylated collagen. The method of claim 6459, wherein the polymer is formed from a reactant comprising fibrinogen. The method of claim 6459, wherein the polymer is formed from a reactant comprising thrombin. The method of claim 6459, wherein the polymer is formed from a reactant comprising a plasma component. The method of claim 6459, wherein the polymer is formed from a reactant comprising a calcium salt. The method of claim 6459, wherein the polymer is formed from a reactant comprising a fiber formation inhibitor. The method of claim 6459, wherein the polymer is formed from a reactant comprising a fibrinogen analog. The method of claim 6459, wherein the polymer is formed from a reactant comprising albumin. The method of claim 6459, wherein the polymer is formed from a reactant comprising plasminogen. The method of claim 6459, wherein the polymer is formed from a reactant comprising von Willebrand factor. The method of claim 6459, wherein the polymer is formed from a reactant comprising Factor VIII. The method of claim 6459, wherein the polymer is formed from a reactant comprising hypoallergenic collagen. The method of claim 6459, wherein the polymer is formed from a reactant comprising atelopeptide collagen. The method of claim 6459, wherein the polymer is formed from a reactant comprising telopeptide collagen. The method of claim 6459, wherein the polymer is formed from a reactant comprising cross-linked collagen. The method of claim 6459, wherein the polymer is formed from a reactant comprising aprotinin. The method of claim 6459, wherein the polymer is formed from a reactant comprising epsilon amino-n-caproic acid. The method of claim 6459, wherein the polymer is formed from a reactant comprising gelatin. The method of claim 6459, wherein the polymer is formed from a reactant comprising a protein conjugate. The method of claim 6459, wherein the polymer is formed from a reactant comprising a gelatin conjugate. The method of claim 6459, wherein the polymer is formed from a reactant comprising a synthetic polymer. The method of claim 6459, wherein the polymer is formed from a reactant comprising a compound comprising synthetic isocyanate. The method of claim 6459, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic thiol. The method of claim 6459, wherein the polymer is formed from a reactant comprised of a synthetic compound comprising two or more thiol groups. The method of claim 6459, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more thiol groups. The method of claim 6459, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more thiol groups. The method of claim 6459, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic amino. The method of claim 6459, wherein the polymer is formed from a reactant comprised of a synthetic compound comprising two or more amino groups. The method of claim 6459, wherein the polymer is formed from reactants comprised of synthetic compounds comprising three or more amino groups. The method of claim 6459, wherein the polymer is formed from reactants comprised of synthetic compounds comprising four or more amino groups. The method of claim 6459, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of claim 6459, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The method of claim 6459, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. The method of claim 6459, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more carbonyl-oxygen-succinimidyl groups. The method of claim 6459, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide. The method of claim 6459, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a polyalkylene oxide and a biodegradable polyester block. The method of claim 6459, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The method of claim 6459, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide having a thiol reactive group. The method of claim 6459, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The method of claim 6459, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a biodegradable polyester block. The method of claim 6459, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly comprised of lactic acid or lactide. The method of claim 6459, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly consisting of glycolic acid or glycolide. The method of claim 6459, wherein the polymer is formed from a reactant comprising polylysine. The method of claim 6459, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 6459, wherein the polymer is formed from a reactant comprising (a) a protein and (b) polylysine. The method of claim 6459, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more thiol groups. The method of claim 6459, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more amino groups. The method of claim 6459, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method according to 6459. The method of claim 6459, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 6459, wherein the polymer is formed from a reactant comprising (a) collagen and (b) polylysine. The method of claim 6459, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more thiol groups. The method of claim 6459, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more amino groups. The method of claim 6459, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method according to 6459. The method of claim 6459, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 6459, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) polylysine. The method of claim 6459, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more thiol groups. The method of claim 6459, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more amino groups. The method of claim 6459, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone, The method of claim 6459. The method of claim 6459, wherein the polymer is formed from a reactant comprising hyaluronic acid. The method of claim 6459, wherein the polymer is formed from a reactant comprising a hyaluronic acid derivative. The method of claim 6459, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The method of claim 6459, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A polymer having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene region. The method of claim 6459, formed from a reactant consisting of and a synthetic compound comprising a plurality of electrophilic groups. The method of claim 6459, wherein the composition comprises a colorant. The method of claim 6459, wherein the composition is sterile. Methods of implanting a medical device comprising: (a) a medical device to which the medical device is implanted or transplanted host tissue i) an inhibitor of fiber formation ii) an anti-infective agent iii) a polymer iv) an inhibitor of fiber formation and a polymer V) a composition comprising an anti-infective agent and a polymer or vi) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer, and (b) implanting a medical device into a host, and said medical treatment The device is a pump. 72. A method of implanting a device with the medical device of claim 6739 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a fibrosis inhibitor; and (b) the host Implant a medical device. A method of implanting a device with the medical device of claim 6739 comprising: (a) the medical device is implanted, or the transplanted host tissue is immersed in an anti-infective agent; and (b) the host is implanted. Implant medical devices. A method of implanting a device with the medical device of claim 6739 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in a polymer; and (b) the medical device is implanted in the host. Transplant. A method of implanting a device comprising the following with a medical device according to claim 6739: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising a fibrosis inhibitor and a polymer; And (b) transplant the medical device into the host. A method of implanting a device with the medical device of claim 6739 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising an anti-infective and a polymer; and (b) Transplant the medical device into the host. 68. A method of implanting a device comprising: 67) a medical device according to claim 6739, comprising: (a) a composition comprising a fibrosis inhibitor, an anti-infective agent, and a polymer in which the medical device is implanted or the host tissue to which it is implanted; And (b) implant the medical device into the host. The method of claim 6739 wherein the medical device is a pump adapted to deliver insulin. The method of claim 6739 wherein the medical device is a pump adapted to deliver narcotics. The method of claim 6739 wherein the medical device is a pump adapted to deliver a chemotherapeutic agent. The method of claim 6739 wherein the medical device is a pump adapted to deliver an arrhythmia suppressing drug. The method of claim 6739 wherein the medical device is a pump adapted to deliver seizure arrest medication. The method of claim 6739 wherein the medical device is a pump adapted to deliver a seizure inhibiting drug. The method of claim 6739 wherein the medical device is a pump adapted to deliver antibiotics. The method of claim 6739, wherein the medical device is a pump adapted to deliver a drug only when a change is detected in the host. The method of claim 6739 wherein the medical device is a pump adapted for continuous slow release of drug. The method of claim 6739 wherein the medical device is a pump adapted to pulse a drug at a prescribed dosage. The method of claim 6739, wherein the medical device is a programmable drug delivery pump. The method of claim 6739 wherein the medical device is a pump adapted to deliver a drug into the eye. The method of claim 6739 wherein the medical device is a pump adapted to deliver a drug subarachnoidally. The method of claim 6739 wherein the medical device is a pump adapted to deliver a drug into the abdominal cavity. The method of claim 6739 wherein the medical device is a pump adapted to deliver a drug into the artery. The method of claim 6739, wherein the medical device is a pump adapted to deliver a drug into the heart. The method of claim 6739, wherein the medical device is an implantable osmotic pump. The method of claim 6739 wherein the medical device is an ophthalmic drug delivery pump. The method of claim 6739, wherein the medical device is metered. The method of claim 6739 wherein the medical device is a peristaltic (roller) pump. The method of claim 6739, wherein the medical device is an electronically driven pump. The method of claim 6739, wherein the medical device is an error stoma pump. The method of claim 6739, wherein the medical device is a spring retractable pump. The method of claim 6739, wherein the medical device is a gas driven pump. The method of claim 6739, wherein the medical device is a hydraulic pump. The method of claim 6739 wherein the medical device is a piston dependent pump. The method of claim 6739, wherein the medical device is a piston independent pump. The method of claim 6739, wherein the medical device is a dispensing cavity. The method of claim 6739, wherein the medical device is an infusion pump. The method of claim 6739, wherein the medical device is a passive pump. The method of claim 6739 wherein cell regeneration is inhibited by a fiber formation inhibitor. The method of claim 6739 wherein angiogenesis is inhibited by a fiber formation inhibitor. The method of claim 6739, wherein fibroblast migration is inhibited by a fibrosis inhibitor. The method of claim 6739 wherein the fibrosis inhibitor inhibits fibroblast proliferation. The method of claim 6739, wherein extracellular matrix accumulation is inhibited by the fiber formation inhibitor. The method of claim 6739 wherein the tissue remodeling is inhibited by the fiber formation inhibitor. The method of claim 6739, wherein the fiber formation inhibitor is an angiogenesis inhibitor. The method of claim 6739 wherein the fiber formation inhibitor is a 5-lipoxygenase inhibitor or antagonist. The method of claim 6739 wherein the fibrosis inhibitor is a chemokine receptor antagonist. The method of claim 6739 wherein the fibrosis inhibitor is a cell cycle inhibitor. The method of claim 6739, wherein the fiber formation inhibitor is a taxane. The method of claim 6739 wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 6739 wherein the fiber formation inhibitor is paclitaxel. The method of claim 6739 wherein the fiber formation inhibitor is not paclitaxel. The method of claim 6739 wherein the fibrosis inhibitor is an analogue or derivative of paclitaxel. The method of claim 6739 wherein the fiber formation inhibitor is a vinca alkaloid. The method of claim 6739 wherein the fibrosis inhibitor is camptothecin or an analogue or derivative thereof. The method of claim 6739 wherein the fiber formation inhibitor is podophyllotoxin. The method of claim 6739 wherein the fibrosis inhibitor is podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof. The method of claim 6739 wherein the fibrosis inhibitor is an anthracycline. The method of claim 6739, wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof. The method of claim 6739, wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof. The method of claim 6739, wherein the fiber formation inhibitor is a platinum compound. The method of claim 6739, wherein the fiber formation inhibitor is nitrosourea. The method of claim 6739, wherein the fiber formation inhibitor is nitroimidazole. The method of claim 6739 wherein the fibrosis inhibitor is a folic acid antagonist. The method of claim 6739 wherein the fibrosis inhibitor is a cytidine analog. The method of claim 6739 wherein the fibrosis inhibitor is a pyrimidine analogue. The method of claim 6739 wherein the fiber formation inhibitor is a fluoropyrimidine analogue. The method of claim 6739 wherein the fibrosis inhibitor is a purine analogue. The method of claim 6739 wherein the fiber formation inhibitor is nitrogen mustard or an analogue or derivative thereof. The method of claim 6739, wherein the fiber formation inhibitor is hydroxyurea. The method of claim 6739 wherein the fibrosis inhibitor is mitomycin or an analogue or derivative thereof. The method of claim 6739 wherein the fiber formation inhibitor is an alkyl sulfonate. The method of claim 6739 wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The method of claim 6739 wherein the fibrosis inhibitor is nicotinamide or an analogue or derivative thereof. The method of claim 6739 wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of claim 6739 wherein the fiber formation inhibitor is a DNA alkylating agent. The method of claim 6739 wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 6739 wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of claim 6739 wherein the fiber formation inhibitor is a DNA cleaving agent. The method of claim 6739 wherein the fiber formation inhibitor is an antimetabolite. The method of claim 6739, wherein adenosine deaminase is inhibited by a fiber formation inhibitor. The method of claim 6739, wherein purine ring synthesis is inhibited by a fiber formation inhibitor. The method of claim 6739 wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of claim 6739 wherein the fiber formation inhibitor inhibits dihydrofolate reduction. The method of claim 6739 wherein thymidine monophosphate is inhibited by the fiber formation inhibitor. The method of claim 6739 wherein DNA damage is caused by a fiber formation inhibitor. The method of claim 6739 wherein the fiber formation inhibitor is a DNA intercalation agent. The method of claim 6739 wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The method of claim 6739, wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The method of claim 6739 wherein the fiber formation inhibitor inhibits ribonucleotide synthesis or function. The method of claim 6739 wherein the fibrosis inhibitor inhibits thymidine monophosphate synthesis or function. The method of claim 6739, wherein DNA synthesis is inhibited by the fiber formation inhibitor. The method of claim 6739 wherein DNA adduct formation occurs with the fiber formation inhibitor. The method of claim 6739 wherein protein synthesis is inhibited by a fiber formation inhibitor. The method of claim 6739 wherein microtubule function is inhibited by the fiber formation inhibitor. The method of claim 6739 wherein the fiber formation inhibitor is a cyclin dependent protein kinase inhibitor. The method of claim 6739 wherein the fibrosis inhibitor is an epidermal growth factor kinase inhibitor. The method of claim 6739 wherein the fiber formation inhibitor is an elastase inhibitor. The method of claim 6739 wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of claim 6739 wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of claim 6739 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 6739 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 6739 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist. The method of claim 6739 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist, and the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof. The method of claim 6739 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 6739 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The method of claim 6739 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof. The method of claim 6739 wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. The method of claim 6739 wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of claim 6739 wherein the fibrosis inhibitor is an IL-1 antagonist. The method of claim 6739 wherein the fibrosis inhibitor is an ICE antagonist. The method of claim 6739 wherein the fibrosis inhibitor is an IRAK antagonist. The method of claim 6739 wherein the fibrosis inhibitor is an IL-4 agonist. The method of claim 6739 wherein the fibrosis inhibitor is an immunomodulator. The method of claim 6739 wherein the fibrosis inhibitor is sirolimus or an analogue or derivative thereof. The method of claim 6739 wherein the fibrosis inhibitor is not sirolimus. The method of claim 6739 wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. The method of claim 6739 wherein the fibrosis inhibitor is tacrolimus or an analogue or derivative thereof. The method of claim 6739 wherein the fibrosis inhibitor is not tacrolimus. The method of claim 6739 wherein the fibrosis inhibitor is biolimus or an analogue or derivative thereof. The method of claim 6739 wherein the fibrosis inhibitor is tresperimus or an analogue or derivative thereof. The method of claim 6739 wherein the fibrosis inhibitor is auranofin or an analogue or derivative thereof. The method of claim 6739 wherein the fibrosis inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of claim 6739 wherein the fibrosis inhibitor is gusperimus or an analogue or derivative thereof. The method of claim 6739 wherein the fibrosis inhibitor is pimecrolimus or an analogue or derivative thereof. The method of claim 6739 wherein the fiber formation inhibitor is ABT-578 or an analogue or derivative thereof. The method of claim 6739 wherein the fiber formation inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. The method of claim 6739, wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof. The method of claim 6739, wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-α-25 dihydroxy vitamin D ₃ or an analogue or derivative thereof. The method of claim 6739 wherein the fiber formation inhibitor is a leukotriene inhibitor. The method of claim 6739 wherein the vascularization inhibitor is an MCP-1 antagonist. The method of claim 6739 wherein the fiber formation inhibitor is an MMP inhibitor. The method of claim 6739 wherein the fiber formation inhibitor is an NFκB inhibitor. The method of claim 6739, wherein the fiber formation inhibitor is an NFκB inhibitor, and the NFκB inhibitor is Bay11-7082. The method of claim 6739 wherein the fiber formation inhibitor is a NO antagonist. The method of claim 6739 wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor. The method of claim 6739, wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor, and the p38 MAP kinase inhibitor is SB202190. The method of claim 6739 wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The method of claim 6739, wherein the fiber formation inhibitor is a TGFβ inhibitor. The method of claim 6739 wherein the fiber formation inhibitor is a thromboxane A2 antagonist. The method of claim 6739 wherein the fibrosis inhibitor is a TNFα antagonist. The method of claim 6739 wherein the fiber formation inhibitor is a TACE inhibitor. The method of claim 6739 wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. The method of claim 6739 wherein the fiber formation inhibitor is a vitronectin inhibitor. The method of claim 6739 wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of claim 6739 wherein the fiber formation inhibitor is a protein kinase inhibitor. The method of claim 6739 wherein the fibrosis inhibitor is a PDGF receptor kinase inhibitor. The method of claim 6739 wherein the fibrosis inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of claim 6739 wherein the fiber formation inhibitor is a retinoic acid receptor antagonist. The method of claim 6739 wherein the fiber formation inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of claim 6739 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 6739 wherein the fiber formation inhibitor is an antifungal agent. The method of claim 6739 wherein the fiber formation inhibitor is an antifungal agent, and the antifungal agent is sulconizole. The method of claim 6739 wherein the fiber formation inhibitor is a bisphosphonate. The method of claim 6739 wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. The method of claim 6739 wherein the fibrosis inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The method of claim 6739, wherein the fiber formation inhibitor is a macrolide antibiotic. The method of claim 6739 wherein the fiber formation inhibitor is a GPIIb / IIIa receptor antagonist. The method of claim 6739 wherein the fibrosis inhibitor is an endothelin receptor antagonist. The method of claim 6739 wherein the fibrosis inhibitor is an agonist of the peroxisome proliferator-responsive receptor. The method of claim 6739 wherein the fibrosis inhibitor is an estrogen receptor agent. The method of claim 6739 wherein the fibrosis inhibitor is a somostatin analog. The method of claim 6739 wherein the fiber formation inhibitor is a neurokinin 1 antagonist. The method of claim 6739 wherein the fiber formation inhibitor is a neurokinin 3 antagonist. The method of 6739 wherein the fibrosis inhibitor is a VLA-4 antagonist. The method of claim 6739 wherein the fibrosis inhibitor is an osteoclast inhibitor. The method of claim 6739 wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The method of claim 6739 wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of claim 6739 wherein the fiber formation inhibitor is an angiotensin II antagonist. The method of claim 6739 wherein the fiber formation inhibitor is an enkephalinase inhibitor. The method of claim 6739 wherein the fibrosis inhibitor is a peroxisome proliferator-responsive receptor gamma agonist insulin sensitizer. The method of claim 6739 wherein the fiber formation inhibitor is a protein kinase C inhibitor. The method of claim 6739 wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. The method of claim 6739 wherein the fiber formation inhibitor is a CXCR3 inhibitor. The method of claim 6739 wherein the fiber formation inhibitor is an Itk inhibitor. The method of claim 6739 wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of claim 6739 wherein the fibrosis inhibitor is a PPAR agonist. The method of claim 6739 wherein the fiber formation inhibitor is an immunosuppressant. The method of claim 6739 wherein the fiber formation inhibitor is an Erb inhibitor. The method of claim 6739 wherein the fibrosis inhibitor is an apoptosis agonist. The method of claim 6739 wherein the fibrosis inhibitor is a lipocortin agonist. The method of claim 6739 wherein the fibrosis inhibitor is a VCAM-1 antagonist. The method of claim 6739, wherein the fiber formation inhibitor is a collagen antagonist. The method of claim 6739 wherein the fiber formation inhibitor is an α2 integrin antagonist. The method of claim 6739 wherein the fiber formation inhibitor is a TNFα inhibitor. The method of claim 6739, wherein the fiber formation inhibitor is a nitric oxide inhibitor. The method of claim 6739 wherein the fiber formation inhibitor is a cathepsin inhibitor. The method of claim 6739 wherein the fibrosis inhibitor is not an anti-inflammatory agent. The method of claim 6739 wherein the fibrosis inhibitor is not a steroid. The method of claim 6739 wherein the fibrosis inhibitor is not a glucocorticosteroid. The method of claim 6739 wherein the fibrosis inhibitor is not dexamethasone. The method of claim 6739 wherein the fiber formation inhibitor is not beclomethasone. The method of claim 6739 wherein the fiber formation inhibitor is not dipropionic acid. The method of claim 6739 wherein the fibrosis inhibitor is not an anti-infective. The method of claim 6739 wherein the fibrosis inhibitor is not an antibiotic. The method of claim 6739 wherein the fibrosis inhibitor is not an antifungal agent. The method of claim 6739 wherein the anti-infective agent is an anthracycline. The method of claim 6739 wherein the anti-infective agent is doxorubicin. The method of claim 6739 wherein the anti-infective agent is mitoxantrone. The method of claim 6739 wherein the anti-infective agent is fluoropyrimidine. The method of claim 6739 wherein the anti-infective is 5-fluorouracil (5-FU). The method of claim 6739 wherein the anti-infective agent is a folic acid antagonist. The method of claim 6739 wherein the anti-infective agent is methotrexate. The method of claim 6739 wherein the anti-infective agent is podophyllotoxin. The method of claim 6739 wherein the anti-infective agent is etoposide. The method of claim 6739 wherein the anti-infective agent is camptothecin. The method of claim 6739 wherein the anti-infective agent is hydroxyurea. The method of claim 6739 wherein the anti-infective agent is a platinum complex. The method of claim 6739 wherein the anti-infective agent is cisplatin. The method of claim 6739, wherein the composition comprises an antithrombotic agent. The method of claim 6739, wherein the polymer is formed from a reactant comprising a naturally occurring polymer. The method of claim 6739, wherein the polymer is formed from a reactant comprising protein. The method of claim 6739, wherein the polymer is formed from a reactant comprising a carbohydrate. The method of claim 6739, wherein the polymer is formed from a reactant comprising a biodegradable polymer. The method of claim 6739, wherein the polymer is formed from a reactant comprising a non-biodegradable polymer. The method of claim 6739, wherein the polymer is formed from a reactant comprising collagen. The method of claim 6739, wherein the polymer is formed from a reactant comprising methylated collagen. The method of claim 6739, wherein the polymer is formed from a reactant comprising fibrinogen. The method of claim 6739, wherein the polymer is formed from a reactant comprising thrombin. The method of claim 6739, wherein the polymer is formed from a reactant comprising a plasma component. The method of claim 6739, wherein the polymer is formed from a reactant comprising a calcium salt. The method of claim 6739 wherein the polymer is formed from a reactant comprising a fiber formation inhibitor. The method of claim 6739, wherein the polymer is formed from a reactant comprising a fibrinogen analog. The method of claim 6739, wherein the polymer is formed from a reactant comprising albumin. The method of claim 6739, wherein the polymer is formed from a reactant comprising plasminogen. The method of claim 6739 wherein the polymer is formed from a reactant comprising von Willebrand factor. The method of claim 6739 wherein the polymer is formed from a reactant comprising Factor VIII. The method of claim 6739 wherein the polymer is formed from a reactant comprising hypoallergenic collagen. The method of claim 6739 wherein the polymer is formed from a reactant comprising atelopeptide collagen. The method of claim 6739 wherein the polymer is formed from a reactant comprising telopeptide collagen. The method of claim 6739, wherein the polymer is formed from a reactant comprising cross-linked collagen. The method of claim 6739, wherein the polymer is formed from a reactant comprising aprotinin. The method of claim 6739 wherein the polymer is formed from a reactant comprising epsilon amino-n-caproic acid. The method of claim 6739, wherein the polymer is formed from a reactant comprising gelatin. The method of claim 6739 wherein the polymer is formed from a reactant comprising a protein conjugate. The method of claim 6739, wherein the polymer is formed from a reactant comprising a gelatin conjugate. The method of claim 6739, wherein the polymer is formed from a reactant comprising a synthetic polymer. The method of claim 6739, wherein the polymer is formed from a reactant comprising a compound comprising synthetic isocyanate. The method of claim 6739, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic thiol. The method of claim 6739 wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more thiol groups. The method of claim 6739, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more thiol groups. The method of claim 6739, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more thiol groups. The method of claim 6739, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic amino. The method of claim 6739, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more amino groups. The method of claim 6739, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more amino groups. The method of claim 6739, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more amino groups. The method of claim 6739, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of claim 6739, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The method of claim 6739, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. The method of claim 6739, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more carbonyl-oxygen-succinimidyl groups. The method of claim 6739, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide. The method of claim 6739, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a polyalkylene oxide and a biodegradable polyester block. The method of claim 6739, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The method of claim 6739, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a thiol reactive group. The method of claim 6739, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The method of claim 6739, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a biodegradable polyester block. The method of claim 6739, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly comprised of lactic acid or lactide. The method of claim 6739, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly comprised of glycolic acid or glycolide. The method of claim 6739, wherein the polymer is formed from a reactant comprising polylysine. The method of claim 6739, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 6739, wherein the polymer is formed from a reactant comprising (a) a protein and (b) polylysine. The method of claim 6739, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more thiol groups. The method of claim 6739, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more amino groups. The method of claim 6739, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method of 6739. The method of claim 6739, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 6739, wherein the polymer is formed from a reactant comprising (a) collagen and (b) polylysine. The method of claim 6739, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more thiol groups. The method of claim 6739 wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more amino groups. The method of claim 6739, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method of 6739. The method of claim 6739, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 6739, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) polylysine. The method of claim 6739, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more thiol groups. The method of claim 6739, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more amino groups. The method of claim 6739, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone, The method of claim 6739. The method of claim 6739, wherein the polymer is formed from a reactant comprising hyaluronic acid. The method of claim 6739, wherein the polymer is formed from a reactant comprising a hyaluronic acid derivative. The method of claim 6739, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The method of claim 6739, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A polymer having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene region. The method of claim 6739, wherein the method is formed from a reactant comprising a synthetic compound comprising a plurality of electrophilic groups. The method of claim 6739, wherein the composition comprises a colorant. The method of claim 6739, wherein the composition is sterile. Methods of implanting a medical device comprising: (a) a medical device to which the medical device is implanted or transplanted host tissue i) an inhibitor of fiber formation ii) an anti-infective agent iii) a polymer iv) an inhibitor of fiber formation and a polymer V) a composition comprising an anti-infective agent and a polymer or vi) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer, and (b) implanting a medical device into a host, and said medical treatment The device is a soft tissue graft. The method of implanting a device with the medical device of claim 7022 comprising: (a) the medical device is implanted or the transplanted host tissue is immersed in a fibrosis inhibitor; and (b) the host Implant a medical device. The method of implanting a device with the medical device of claim 7022 comprising: (a) the medical device is implanted or the implanted host tissue is immersed in an anti-infective agent; and (b) the host is implanted. Implant medical devices. 70. A method of implanting a device with the medical device of claim 7022 comprising: (a) the medical device is implanted, or the implanted host tissue is immersed in a polymer, and (b) the medical device in the host. Transplant. A method of implanting a device comprising the following with the medical device of claim 7022: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising a fibrosis inhibitor and a polymer; And (b) transplant the medical device into the host. A method of implanting a device with the medical device of claim 7022 comprising: (a) immersing the tissue of the host into which the medical device is implanted or implanted with a composition comprising an anti-infective agent and a polymer; and (b) Transplant the medical device into the host. 70. A method of implanting a device including the following with the medical device of claim 7022: (a) a composition comprising a fibrosis inhibitor, an anti-infective agent and a polymer in which the medical device is implanted or the host tissue into which it is implanted And (b) implant the medical device into the host. The method of claim 7022, wherein the medical device is a cosmetic implant. The method of claim 7022, wherein the medical device is a reconstruction implant. The method of claim 7022, wherein the medical device is breast augmentation surgery. The method of claim 7022, wherein the medical device is a breast augmentation comprising silicone. The method of claim 7022, wherein the medical device is a breast augmentation procedure that includes saline. The method of claim 7022 wherein the medical device is a facial implant. The method of claim 7022, wherein the medical device is an implantation of candy. The method of claim 7022, wherein the medical device is a mandibular implant. The method of claim 7022, wherein the medical device is a lip transplant. The method of claim 7022 wherein the medical device is a nasal implant. The method of claim 7022 wherein the medical device is a buccal implant. The method of claim 7022 wherein the medical device is a pectoral muscle transplant. The method of claim 7022, wherein the medical device is a hip implant. The method of claim 7022, wherein the medical device is an autologous tissue graft. The method of claim 7022, wherein the medical device is an autologous tissue graft that includes adipose tissue. The method of claim 7022, wherein the medical device is an autologous tissue graft that includes an autologous fat graft. The method of claim 7022, wherein the medical device is an autologous tissue graft that includes a skin graft. The method of claim 7022, wherein the medical device is an autologous tissue graft that includes a skin plug. The method of claim 7022, wherein the medical device is an autologous tissue graft that includes a tissue obturator. The method of claim 7022, wherein the medical device is an autologous tissue graft that includes a muscle tissue valve. The method of claim 7022, wherein the medical device is an autologous tissue graft that includes a pedicled flap. The device of claim 7022, wherein the medical device is an autologous tissue graft that includes a pedicled flap, wherein the pedunculated flap is from the back, abdomen, buttocks, thigh, or groin. The method of claim 7022, wherein the medical device is an autologous tissue graft that comprises a cell extraction transplant. The method of claim 7022, wherein the medical device is an autologous tissue graft consisting of a suspension of autologous skin fibroblasts. The method of claim 7022, wherein the medical device is a tissue filler. The method of claim 7022 wherein the medical device is a fat graft. The method of claim 7022, wherein cell regeneration is inhibited by a fiber formation inhibitor. The method of claim 7022 wherein angiogenesis is inhibited by a fiber formation inhibitor. The method of claim 7022, wherein fibroblast migration is inhibited by a fibrosis inhibitor. The method of claim 7022, wherein the fibrosis inhibitor inhibits fibroblast proliferation. The method of claim 7022, wherein the fiber formation inhibitor inhibits extracellular matrix accumulation. The method of claim 7022 wherein the tissue remodeling is inhibited by the fiber formation inhibitor. The method of claim 7022 wherein the fibrosis inhibitor is an angiogenesis inhibitor. The method of claim 7022 wherein the fiber formation inhibitor is a 5- lipoxygenase inhibitor or antagonist. The method of claim 7022 wherein the fibrosis inhibitor is a chemokine receptor antagonist. The method of claim 7022 wherein the fibrosis inhibitor is a cell cycle inhibitor. The method of claim 7022, wherein the fiber formation inhibitor is a taxane. The method of claim 7022 wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 7022, wherein the fiber formation inhibitor is paclitaxel. The method of claim 7022 wherein the fiber formation inhibitor is not paclitaxel. The method of claim 7022 wherein the fibrosis inhibitor is an analogue or derivative of paclitaxel. The method of claim 7022, wherein the fiber formation inhibitor is a vinca alkaloid. The method of claim 7022 wherein the fibrosis inhibitor is camptothecin or an analogue or derivative thereof. The method of claim 7022 wherein the fibrosis inhibitor is podophyllotoxin. The method of claim 7022 wherein the fibrosis inhibitor is podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof. The method of claim 7022 wherein the fibrosis inhibitor is an anthracycline. The method of claim 7022 wherein the fibrosis inhibitor is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof. The method of claim 7022, wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof. The method of claim 7022, wherein the fiber formation inhibitor is a platinum compound. The method of claim 7022, wherein the fiber formation inhibitor is nitrosourea. The method of claim 7022, wherein the fiber formation inhibitor is nitroimidazole. The method of claim 7022 wherein the fibrosis inhibitor is a folic acid antagonist. The method of claim 7022 wherein the fibrosis inhibitor is a cytidine analogue. The method of claim 7022 wherein the fibrosis inhibitor is a pyrimidine analogue. The method of claim 7022 wherein the fiber formation inhibitor is a fluoropyrimidine analogue. The method of claim 7022 wherein the fibrosis inhibitor is a purine analogue. The method of claim 7022 wherein the fiber formation inhibitor is nitrogen mustard or an analogue or derivative thereof. The method of claim 7022, wherein the fiber formation inhibitor is hydroxyurea. The method of claim 7022 wherein the fibrosis inhibitor is mitomycin or an analogue or derivative thereof. The method of claim 7022, wherein the fiber formation inhibitor is an alkyl sulfonate. The method of claim 7022 wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The method of claim 7022 wherein the fibrosis inhibitor is nicotinamide or an analogue or derivative thereof. The method of claim 7022 wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of claim 7022 wherein the fiber formation inhibitor is a DNA alkylating agent. The method of claim 7022 wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 7022 wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of claim 7022 wherein the fiber formation inhibitor is a DNA cleaving agent. The method of claim 7022 wherein the fibrosis inhibitor is an antimetabolite. The method of claim 7022 wherein adenosine deaminase is inhibited by a fiber formation inhibitor. The method of claim 7022, wherein purine ring synthesis is inhibited by a fiber formation inhibitor. The method of claim 7022 wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of claim 7022 wherein the fiber formation inhibitor inhibits dihydrofolate reduction. The method of claim 7022 wherein thymidine monophosphate is inhibited by a fiber formation inhibitor. The method of claim 7022 wherein the fiber formation inhibitor causes DNA damage. The method of claim 7022 wherein the fiber formation inhibitor is a DNA intercalation agent. The method of claim 7022 wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The method of claim 7022 wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The method of claim 7022 wherein the fibril formation inhibitor inhibits ribonucleotide synthesis or function. The method of claim 7022 wherein the fibrosis inhibitor inhibits thymidine monophosphate synthesis or function. The method of claim 7022, wherein DNA synthesis is inhibited by a fiber formation inhibitor. The method of claim 7022 wherein the fiber formation inhibitor causes DNA adduct formation. The method of claim 7022, wherein protein synthesis is inhibited by a fiber formation inhibitor. The method of claim 7022, wherein the microtubule function is inhibited by the fiber formation inhibitor. The method of claim 7022 wherein the fibrosis inhibitor is a cyclin dependent protein kinase inhibitor. The method of claim 7022 wherein the fibrosis inhibitor is an epidermal growth factor kinase inhibitor. The method of claim 7022 wherein the fiber formation inhibitor is an elastase inhibitor. The method of claim 7022 wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of claim 7022 wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of claim 7022 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 7022 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 7022 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist. The method of claim 7022 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist, and the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof. The method of claim 7022 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 7022 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The method of claim 7022 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof. The method of claim 7022 wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. The method of claim 7022 wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of claim 7022 wherein the fibrosis inhibitor is an IL-1 antagonist. The method of claim 7022 wherein the fibrosis inhibitor is an ICE antagonist. The method of claim 7022 wherein the fibrosis inhibitor is an IRAK antagonist. The method of claim 7022 wherein the fibrosis inhibitor is an IL-4 agonist. The method of claim 7022 wherein the fibrosis inhibitor is an immunomodulator. The method of claim 7022 wherein the fibrosis inhibitor is sirolimus or an analogue or derivative thereof. The method of claim 7022 wherein the fibrosis inhibitor is not sirolimus. The method of claim 7022 wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. The method of claim 7022 wherein the fibrosis inhibitor is tacrolimus or an analogue or derivative thereof. The method of claim 7022, wherein the fiber formation inhibitor is not tacrolimus. The method of claim 7022 wherein the fibrosis inhibitor is biolimus or an analogue or derivative thereof. The method of claim 7022 wherein the fibrosis inhibitor is tresperimus or an analogue or derivative thereof. The method of claim 7022 wherein the fibrosis inhibitor is auranofin or an analogue or derivative thereof. The method of claim 7022 wherein the fibrosis inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of claim 7022 wherein the fibrosis inhibitor is gusperimus or an analogue or derivative thereof. The method of claim 7022 wherein the fibrosis inhibitor is pimecrolimus or an analogue or derivative thereof. The method of claim 7022 wherein the fibrosis inhibitor is ABT-578 or an analogue or derivative thereof. The method of claim 7022 wherein the fiber formation inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. The method of claim 7022 wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof. The method of claim 7022 wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1 -α-25 dihydroxy vitamin D ₃ or an analogue or derivative thereof. The method of claim 7022 wherein the fiber formation inhibitor is a leukotriene inhibitor. The method of claim 7022 wherein the vascularization inhibitor is an MCP-1 antagonist. The method of claim 7022 wherein the fiber formation inhibitor is an MMP inhibitor. The method of claim 7022 wherein the fiber formation inhibitor is an NFκB inhibitor. The method of claim 7022 wherein the fiber formation inhibitor is an NFκB inhibitor, wherein the NFκB inhibitor is Bay11-7082. The method of claim 7022 wherein the fiber formation inhibitor is a NO antagonist. The method of claim 7022 wherein the fibrosis inhibitor is a p38 MAP kinase inhibitor. The method of claim 7022 wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB202190. The method of claim 7022 wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The method of claim 7022 wherein the fibrosis inhibitor is a TGFβ inhibitor. The method of claim 7022 wherein the fiber formation inhibitor is a thromboxane A2 antagonist. The method of claim 7022 wherein the vascularization inhibitor is a TNFα antagonist. The method of claim 7022, wherein the fiber formation inhibitor is a TACE inhibitor. The method of claim 7022 wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. The method of claim 7022 wherein the fiber formation inhibitor is a vitronectin inhibitor. The method of claim 7022 wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of claim 7022 wherein the fibrosis inhibitor is a protein kinase inhibitor. The method of claim 7022 wherein the fibrosis inhibitor is a PDGF receptor kinase inhibitor. The method of claim 7022 wherein the fibrosis inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of claim 7022 wherein the fibrosis inhibitor is a retinoic acid receptor antagonist. The method of claim 7022 wherein the fibrosis inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of claim 7022 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 7022 wherein the fibrosis inhibitor is an antifungal agent. The method of claim 7022 wherein the fibrosis inhibitor is an antifungal agent, and the antifungal agent is sulconizole. The method of claim 7022, wherein the fiber formation inhibitor is a bisphosphonate. The method of claim 7022 wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. The method of claim 7022 wherein the fibrosis inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The method of claim 7022, wherein the fiber formation inhibitor is a macrolide antibiotic. The method of claim 7022 wherein the fibrosis inhibitor is a GPIIb / IIIa receptor antagonist. The method of claim 7022 wherein the fibrosis inhibitor is an endothelin receptor antagonist. The method of claim 7022 wherein the fibrosis inhibitor is an agonist of peroxisome proliferator-activated receptor. The method of claim 7022 wherein the fibrosis inhibitor is an estrogen receptor agent. The method of claim 7022 wherein the fibrosis inhibitor is a somostatin analog. The method of claim 7022 wherein the fibrosis inhibitor is a neurokinin 1 antagonist. The method of claim 7022 wherein the fibrosis inhibitor is a neurokinin 3 antagonist. The method of claim 7022 wherein the fibrosis inhibitor is a VLA-4 antagonist. The method of claim 7022 wherein the fibrosis inhibitor is an osteoclast inhibitor. The method of claim 7022 wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The method of claim 7022 wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of claim 7022 wherein the fibrosis inhibitor is an angiotensin II antagonist. The method of claim 7022 wherein the fiber formation inhibitor is an enkephalinase inhibitor. The method of claim 7022 wherein the fibrosis inhibitor is a peroxisome proliferator-responsive receptor gamma agonist insulin sensitizer. The method of claim 7022 wherein the fiber formation inhibitor is a protein kinase C inhibitor. The method of claim 7022 wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. The method of claim 7022 wherein the fiber formation inhibitor is a CXCR3 inhibitor. The method of claim 7022, wherein the fiber formation inhibitor is an Itk inhibitor. The method of claim 7022 wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of claim 7022 wherein the fibrosis inhibitor is a PPAR agonist. The method of claim 7022 wherein the fiber formation inhibitor is an immunosuppressant. The method of claim 7022 wherein the fiber formation inhibitor is an Erb inhibitor. The method of claim 7022 wherein the fibrosis inhibitor is an apoptosis agonist. The method of claim 7022 wherein the fibrosis inhibitor is a lipocortin agonist. The method of claim 7022 wherein the fibrosis inhibitor is a VCAM-1 antagonist. The method of claim 7022 wherein the fiber formation inhibitor is a collagen antagonist. The method of claim 7022 wherein the fibrosis inhibitor is an α2 integrin antagonist. The method of claim 7022 wherein the fibrosis inhibitor is a TNFα inhibitor. The method of claim 7022 wherein the fiber formation inhibitor is a nitric oxide inhibitor The method of claim 7022 wherein the fiber formation inhibitor is a cathepsin inhibitor. The method of claim 7022 wherein the fibrosis inhibitor is not an anti-inflammatory agent. The method of claim 7022 wherein the fibrosis inhibitor is not a steroid. The method of claim 7022 wherein the fibrosis inhibitor is not a glucocorticosteroid. The method of claim 7022 wherein the fibrosis inhibitor is not dexamethasone. The method of claim 7022 wherein the fibrosis inhibitor is not beclomethasone. The method of claim 7022 wherein the fiber formation inhibitor is not dipropionic acid. The method of claim 7022 wherein the fibrosis inhibitor is not an anti-infective. The method of claim 7022 wherein the fibrosis inhibitor is not an antibiotic. The method of claim 7022 wherein the fibrosis inhibitor is not an antifungal agent. The method of claim 7022 wherein the anti-infective is an anthracycline. The method of claim 7022 wherein the anti-infective is doxorubicin. The method of claim 7022 wherein the anti-infective is mitoxantrone. The method of claim 7022 wherein the anti-infective is fluoropyrimidine. The method of claim 7022 wherein the anti-infective is 5-fluorouracil (5-FU). The method of claim 7022 wherein the anti-infective agent is a folic acid antagonist. The method of claim 7022 wherein the anti-infective is methotrexate. The method of claim 7022 wherein the anti-infective is podophyllotoxin. The method of claim 7022 wherein the anti-infective is etoposide. The method of claim 7022 wherein the anti-infective is camptothecin. The method of claim 7022 wherein the anti-infective is hydroxyurea. The method of claim 7022, wherein the anti-infective is a platinum complex. The method of claim 7022, wherein the anti-infective is cisplatin. The method of claim 7022, wherein the composition comprises an antithrombotic agent. The method of claim 7022, wherein the polymer is formed from a reactant comprising a naturally occurring polymer. The method of claim 7022, wherein the polymer is formed from a reactant comprising protein. The method of claim 7022, wherein the polymer is formed from a reactant comprising a carbohydrate. The method of claim 7022, wherein the polymer is formed from a reactant comprising a biodegradable polymer. The method of claim 7022, wherein the polymer is formed from a reactant comprising a non-biodegradable polymer. The method of claim 7022, wherein the polymer is formed from a reactant comprising collagen. The method of claim 7022, wherein the polymer is formed from a reactant comprising methylated collagen. The method of claim 7022, wherein the polymer is formed from a reactant comprising fibrinogen. The method of claim 7022, wherein the polymer is formed from a reactant comprising thrombin. The method of claim 7022, wherein the polymer is formed from a reactant comprising a plasma component. The method of claim 7022, wherein the polymer is formed from a reactant comprising a calcium salt. The method of claim 7022, wherein the polymer is formed from a reactant comprising a fiber formation inhibitor. The method of claim 7022, wherein the polymer is formed from a reactant comprising a fibrinogen analog. The method of claim 7022, wherein the polymer is formed from a reactant comprising albumin. The method of claim 7022, wherein the polymer is formed from a reactant comprising plasminogen. The method of claim 7022, wherein the polymer is formed from a reactant comprising von Willebrand factor. The method of claim 7022, wherein the polymer is formed from a reactant comprising Factor VIII. The method of claim 7022, wherein the polymer is formed from a reactant comprising hypoallergenic collagen. The method of claim 7022, wherein the polymer is formed from a reactant comprising atelopeptide collagen. The method of claim 7022, wherein the polymer is formed from a reactant comprising telopeptide collagen. The method of claim 7022, wherein the polymer is formed from a reactant comprising cross-linked collagen. The method of claim 7022, wherein the polymer is formed from a reactant comprising aprotinin. The method of claim 7022, wherein the polymer is formed from a reactant comprising epsilon amino-n-caproic acid. The method of claim 7022, wherein the polymer is formed from a reactant comprising gelatin. The method of claim 7022, wherein the polymer is formed from a reactant comprising a protein conjugate. The method of claim 7022, wherein the polymer is formed from a reactant comprising a gelatin conjugate. The method of claim 7022, wherein the polymer is formed from a reactant comprising a synthetic polymer. The method of claim 7022, wherein the polymer is formed from a reactant comprising a compound comprising synthetic isocyanate. The method of claim 7022, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic thiol. The method of claim 7022, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more thiol groups. The method of claim 7022, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more thiol groups. The method of claim 7022, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more thiol groups. The method of claim 7022, wherein the polymer is formed from a reactant comprising a compound comprising synthetic amino. The method of claim 7022, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more amino groups. The method of claim 7022, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more amino groups. The method of claim 7022, wherein the polymer is formed from reactants comprised of synthetic compounds comprising four or more amino groups. The method of claim 7022, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of claim 7022, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The method of claim 7022, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. The method of claim 7022, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more carbonyl-oxygen-succinimidyl groups. The method of claim 7022, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide. The method of claim 7022, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a polyalkylene oxide and a biodegradable polyester block. The method of claim 7022, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The method of claim 7022, wherein the polymer is formed from a reactant comprising a compound comprising synthetic polyalkylene oxide having a thiol reactive group. The method of claim 7022, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The method of claim 7022, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a biodegradable polyester block. The method of claim 7022, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly comprised of lactic acid or lactide. The method of claim 7022, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or in part, consisting of glycolic acid or glycolide. The method of claim 7022, wherein the polymer is formed from a reactant comprising polylysine. The method of claim 7022, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 7022, wherein the polymer is formed from a reactant comprising (a) a protein and (b) polylysine. The method of claim 7022, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more thiol groups. The method of claim 7022, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more amino groups. The method of claim 7022, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method according to 7022. The method of claim 7022, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 7022, wherein the polymer is formed from a reactant comprising (a) collagen and (b) polylysine. The method of claim 7022, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more thiol groups. The method of claim 7022, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more amino groups. The method of claim 7022, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. The method according to 7022. The method of claim 7022, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 7022, wherein the polymer is formed from reactants comprising (a) methylated collagen and (b) polylysine. The method of claim 7022, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more thiol groups. The method of claim 7022, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more amino groups. The method of claim 7022, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone, The method of claim 7022. The method of claim 7022, wherein the polymer is formed from a reactant comprising hyaluronic acid. The method of claim 7022, wherein the polymer is formed from a reactant comprising a hyaluronic acid derivative. The method of claim 7022, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The method of claim 7022, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A polymer having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene region. The method of claim 7022, wherein the method is formed from a reactant comprising a synthetic compound comprising a plurality of electrophilic groups. The method of claim 7022, wherein the composition comprises a colorant. The method of claim 7022, wherein the composition is sterile. Delivering a tissue-responsive polymeric compound to a required site in a manner that prevents the formation of a surgical bond, providing a tissue coated at the site, and providing a fiber to the coated tissue A method of delivering a formation inhibitor. A method of delivering a composition between a dura mater sleeve and a paraspinal muscle after a patient's laminectomy, wherein the composition prevents surgical adhesions in a manner that prevents the formation of surgical adhesions. A method of preventing the formation of a surgical bond, comprising covering a spinal nerve at a site after laminectomy for a patient in need thereof, wherein the composition prevents the formation of a surgical bond. A method of preventing the formation of a surgical bond by immersing the composition in tissue surrounding the spinal nerve at a site after laminectomy for a patient in need, wherein the composition prevents the formation of a surgical bond . A method of preventing the formation of a surgical bond comprising delivering the composition to a surgical site of an intervertebral disc for a patient in need thereof, wherein the composition prevents the formation of a surgical bond. A method of preventing the formation of a surgical bond comprising delivering the composition to the site of a microscopic herniectomy for a patient in need thereof, wherein the composition prevents the formation of a surgical bond. A method of preventing the formation of a surgical bond comprising delivering the composition to a site of neurosurgical (brain) surgery for a patient in need, wherein the composition prevents the formation of a surgical bond. A method of preventing the formation of a surgical bond comprising immersing a site of spinal surgery on a patient in need thereof, wherein the composition prevents the formation of a surgical bond. A method of preventing the formation of a surgical bond, comprising delivering the composition to the epidural tissue of a patient in need thereof, wherein the composition prevents the formation of a surgical bond. A method of preventing the formation of a surgical bond comprising delivering the composition to the dural tissue of a patient in need thereof, wherein the composition prevents the formation of a surgical bond. A method of preventing the formation of a surgical bond comprising delivering the composition to a gynecological site of a patient in need thereof, wherein the composition prevents the formation of a surgical bond. A method of preventing the formation of a surgical bond comprising delivering the composition to a tissue surface within the pelvic sidewall of a patient in need thereof, wherein the composition prevents the formation of a surgical bond. A method of preventing the formation of a surgical bond comprising delivering the composition to the peritoneal cavity of a patient in need thereof, wherein the composition prevents the formation of a surgical bond. A method of preventing the formation of a surgical bond comprising delivering the composition to a pelvic cavity of a patient in need thereof, wherein the composition prevents the formation of a surgical bond. A method of preventing the formation of a surgical bond comprising delivering the composition to a site of an abdominal wall incision for a patient in need thereof, wherein the composition prevents the formation of a surgical bond. A method of preventing the formation of a surgical bond comprising delivering the composition to a site of endoscopic treatment for a patient in need thereof, wherein the composition prevents the formation of a surgical bond. A method of preventing the formation of a surgical bond comprising delivering the composition to a site of hernia repair for a patient in need thereof, wherein the composition prevents the formation of a surgical bond. A method of preventing the formation of a surgical bond, comprising delivering the composition to a site of a required patient's cholecystectomy, wherein the composition prevents the formation of a surgical bond. A method of preventing the formation of a surgical bond, comprising delivering the composition to a site of cardiac treatment for a patient in need thereof, wherein the composition prevents the formation of a surgical bond. A method of preventing the formation of a surgical bond comprising delivering the composition to a site of cardiac transplant surgery for a patient in need thereof, wherein the composition prevents the formation of a surgical bond. A method of preventing the formation of a surgical bond comprising delivering the composition to a site of cardiovascular repair for a patient in need thereof, wherein the composition prevents the formation of a surgical bond. A method of preventing the formation of a surgical bond comprising delivering the composition to a site of heart valve replacement for a patient in need thereof, wherein the composition prevents the formation of a surgical bond. A method of preventing the formation of a surgical bond comprising delivering the composition to a site of pericardial surgery in a patient in need thereof, wherein the composition prevents the formation of a surgical bond. A method of preventing the formation of a surgical bond comprising delivering the composition to a site of an orthopedic surgical procedure for a patient in need thereof, wherein the composition prevents the formation of a surgical bond. A method of preventing the formation of a surgical bond comprising delivering the composition to a site of ligament failure for a patient in need thereof, wherein the composition prevents the formation of a surgical bond. A method of preventing the formation of a surgical bond comprising delivering the composition to a site of joint damage to a patient in need thereof, wherein the composition prevents the formation of a surgical bond. A method of preventing the formation of a surgical bond comprising delivering the composition to a site of tendon injury to a patient in need thereof, wherein the composition prevents the formation of a surgical bond. A method of preventing the formation of a surgical bond comprising delivering the composition to a site of cartilage damage to a patient in need thereof, wherein the composition prevents the formation of a surgical bond. A method of preventing the formation of a surgical bond comprising delivering the composition to a site of muscle damage to a patient in need thereof, wherein the composition prevents the formation of a surgical bond. A method of preventing the formation of a surgical bond comprising delivering the composition to a site of nerve injury to a patient in need thereof, wherein the composition prevents the formation of a surgical bond. A method of preventing the formation of a surgical bond comprising delivering the composition to a site of a cosmetic surgery procedure for a patient in need thereof, wherein the composition prevents the formation of a surgical bond. A method of preventing the formation of a surgical bond, comprising delivering the composition to a site of a reconstructive surgical procedure for a patient in need thereof, wherein the composition prevents the formation of a surgical bond. A method of preventing the formation of a surgical bond comprising delivering the composition to a site of breast augmentation for a patient in need thereof, wherein the composition prevents the formation of a surgical bond. The method of any of claims 7301-7733 wherein the composition is delivered with a medical implant placement. The method of any of claims 7301 to 7333, wherein the composition is delivered with a medical implant placement and the composition is placed in tissue adjacent to the medical implant. The method of any of claims 7301 to 7333 wherein the composition is delivered with a medical implant placement and the composition is placed on the medical implant. The method of any of claims 7301-7733 wherein the composition is delivered via endoscopy. The method of any of claims 7301-7333 wherein the composition is delivered via a needle. The method of any of claims 7301-7333 wherein the composition is delivered via a catheter. The method of any of claims 7301-7333 wherein the composition is delivered at the time of surgery. The method of any of claims 7301-7733 wherein the composition is delivered using fluoroscopic guidance. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor inhibits cell regeneration. The method of any of claims 7301-7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor inhibits angiogenesis. The method of any of claims 7301 to 7333, wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor inhibits fibroblast migration. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor inhibits fibroblast proliferation. The method of any of claims 7301 to 7333, wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor inhibits extracellular matrix accumulation. The method of any of claims 7301 to 7333, wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor inhibits tissue remodeling. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is an angiogenesis inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a 5-lipoxygenase inhibitor or antagonist. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a chemokine receptor antagonist. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a cell cycle inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a taxane. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a microtubule inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is paclitaxel. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is not paclitaxel. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is an analogue or derivative of paclitaxel. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a vinca alkaloid. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is camptothecin or an analogue or derivative thereof. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is podophyllotoxin. The composition comprises a fiber formation inhibitor, the fiber formation inhibitor is a podophyllotoxin, the composition comprises a fiber formation inhibitor, and the podophyllotoxin is etoposide or an analog or derivative thereof. Any method of paragraphs 7301-7733. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is an anthracycline. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is doxorubicin or an analogue or derivative thereof. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is mitoxantrone or an analogue or derivative thereof. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a platinum compound. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is nitrosourea. The method of any of claims 7301-7733 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is nitroimidazole. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a folic acid antagonist. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a cytidine analog. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a pyrimidine analogue. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a fluoropyrimidine analog. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a purine analog. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is nitrogen mustard or an analogue or derivative thereof. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is hydroxyurea. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is mitomycin or an analogue or derivative thereof. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is an alkyl sulfonate. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is nicotinamide or an analogue or derivative thereof. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a DNA alkylating agent. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a microtubule inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a DNA cleaving agent. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is an antimetabolite. The method of any of claims 7301-7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor inhibits adenosine deaminase. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor inhibits purine ring synthesis. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor inhibits hydrofolate reduction. The method of any of claims 7301 to 7333, wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor inhibits thymidine monophosphate. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor causes DNA damage. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a DNA intercalation agent. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor inhibits ribonucleotide synthesis or function. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor inhibits thymidine monophosphate synthesis or function. The method of any of claims 7301-7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor inhibits DNA synthesis. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor causes DNA adduct formation. The method of any of claims 7301-7733 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor inhibits protein synthesis. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor inhibits microtubule function. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a cyclin dependent protein kinase inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is an epidermal growth factor kinase inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is an elastase inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a heat shock protein 90 antagonist. The composition comprises a fibrosis inhibitor, the fibrosis inhibitor is a heat shock protein 90 antagonist, the composition comprises a fibrosis inhibitor, and the heat shock protein 90 antagonist is geldanamycin or an analog thereof or The method of any of claims 7301-7733 which is a derivative. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is simvastatin or an analogue or derivative thereof. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a hydroorotic acid dehydrogenase inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is an IL-1 antagonist. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is an ICE antagonist. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is an IRAK antagonist. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is an IL-4 agonist. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is an immunomodulator. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is sirolimus or an analogue or derivative thereof. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is not sirolimus. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is tacrolimus or an analogue or derivative thereof. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is not tacrolimus. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is biolimus or an analogue or derivative thereof. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is tresperimus or an analogue or derivative thereof. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is auranofin or an analogue or derivative thereof. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is gusperimus or an analogue or derivative thereof. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is pimecrolimus or an analogue or derivative thereof. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is ABT-578 or an analogue or derivative thereof. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is mycophenolic acid or an analogue or derivative thereof. The composition of claim 7301-7333, wherein the composition comprises a fibrosis inhibitor, the fibrosis inhibitor is an IMPDH inhibitor, and the IMPDH inhibitor is 1-α-25 dihydroxyvitamin D3 or an analogue or derivative thereof. Any way out. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a leukotriene inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is an MCP-1 antagonist. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is an MMP inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is an NFκB inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, the fiber formation inhibitor is an NFκB inhibitor, and the NFκB inhibitor is Bay11-7082. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a NO antagonist. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a p38 MAP kinase inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, the fibrosis inhibitor is a p38 MAP kinase inhibitor, and the p38 MAP kinase inhibitor is SB 202190. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a TGFβ inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a thromboxane A2 antagonist. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a TNFα antagonist. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a TACE inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a tyrosine kinase inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a vitronectin inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of any of claims 7301-7733 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a protein kinase inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a PDGF receptor kinase inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a retinoic acid receptor antagonist. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is an antifungal agent. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, the fiber formation inhibitor is an antifungal agent, and the antifungal agent is sulconizol. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a bisphosphonate. The method of any of claims 7301-7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a phospholipase A1 inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a macrolide antibiotic. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a GPIIb / IIIa receptor antagonist. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is an endothelin receptor antagonist. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is an agonist of a peroxisome proliferator-responsive receptor. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is an estrogen receptor agent. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a somostatin analog. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a neurokinin 1 antagonist. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a neurokinin 3 antagonist. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a VLA-4 antagonist. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is an osteoclast inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is an angiotensin II antagonist. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is an enkephalinase inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a peroxisome proliferator-responsive receptor gamma agonist insulin sensitizer. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a protein kinase C inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a ROCK (Rho kinase) inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a CXCR3 inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is an Itk inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a PPAR agonist. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is an immunosuppressant. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is an Erb inhibitor. The method of any of claims 7301-7733 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is an apoptosis agonist. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a lipocortin agonist. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is a VCAM-1 antagonist. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a collagen antagonist. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is an α 2 integrin antagonist. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a TNFα inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a nitric oxide inhibitor. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is a cathepsin inhibitor. The method of any of claims 7301-7733 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is not an anti-inflammatory agent. The method of any of claims 7301-7733 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is not a steroid. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is not a glucocorticosteroid. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is not dexamethasone. The method of any of claims 7301 to 7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is not beclomethasone. The method of any of claims 7301-7333 wherein the composition comprises a fiber formation inhibitor, wherein the fiber formation inhibitor is not dipropionic acid. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is not an anti-infective agent. The method of any of claims 7301-7733 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is not an antibiotic. The method of any of claims 7301 to 7333 wherein the composition comprises a fibrosis inhibitor, wherein the fibrosis inhibitor is not an antifungal agent. The method of any of claims 7301-7333, wherein the composition comprises an antithrombotic agent. The method of any of claims 7301-7733 wherein the composition comprises a naturally occurring polymer. The method of any of 7301-7733, wherein the composition comprises a protein. The method of any of claims 7301-7333 wherein the composition comprises a carbohydrate. The method of any of claims 7301-7733 wherein the composition comprises a biodegradable polymer. The method of any of claims 7301-7733, wherein the composition comprises a non-biodegradable polymer. The method of any of 7301-7733, wherein the composition comprises collagen. The method of any of claims 7301-7733 wherein the composition comprises methylated collagen. The method of any of claims 7301-7733 wherein the composition comprises fibrinogen. The method of any of claims 7301 to 7333, wherein the composition comprises thrombin. The method of any of claims 7301-7733 wherein the composition comprises a plasma component. The method of any of claims 7301-7333 wherein the composition comprises a calcium salt. The method of any of claims 7301-7333, wherein the composition comprises a fiber formation inhibitor. The method of any of claims 7301-7733 wherein the composition comprises a fibrinogen analog. The method of any of 7301-7733 wherein the composition comprises albumin. The method of any one of claims 7301 to 7333 wherein the composition comprises plasminogen. The method of any of claims 7301-7733, wherein the composition comprises a von Willebrand factor. The method of any of claims 7301 to 7333, wherein the composition comprises Factor VIII. The method of any of claims 7301 to 7333, wherein the composition comprises hypoallergenic collagen. The method of any of claims 7301 to 7333 wherein the composition comprises atelopeptide collagen. The method of any of claims 7301 to 7333, wherein the composition comprises telopeptide collagen. The method of any of claims 7301-7333 wherein the composition comprises cross-linked collagen. The method of any of claims 7301 to 7333 wherein the composition comprises aprotinin. The method of any of claims 7301-7733 wherein the composition comprises epsilon amino-n-caproic acid. The method of any of claims 7301 to 7333, wherein the composition comprises gelatin. The method of any of claims 7301-7733 wherein the composition comprises a protein conjugate. The method of any of claims 7301-7733 wherein the composition comprises a gelatin conjugate. The method of any of claims 7301-7733 wherein the composition comprises a synthetic polymer. The method of any of claims 7301 to 7333, wherein the composition comprises a compound comprising synthetic isocyanate. The method of any of claims 7301 to 7333, wherein the composition comprises a compound comprising a synthetic thiol. The method of any of claims 7301 to 7333, wherein the composition comprises a synthetic compound having two or more thiol groups. The method of any of claims 7301 to 7333, wherein the composition comprises a synthetic compound having three or more thiol groups. The method of any of claims 7301 to 7333, wherein the composition comprises a synthetic compound having four or more thiol groups. The method of any of claims 7301 to 7333, wherein the composition comprises a compound comprising synthetic amino. The method of any of claims 7301 to 7333, wherein the composition comprises a synthetic compound having two or more amino groups. The method of any of claims 7301 to 7333, wherein the composition comprises a synthetic compound having three or more amino groups. The method of any of claims 7301 to 7333, wherein the composition comprises a synthetic compound having four or more amino groups. The method of any of claims 7301-7733 wherein the composition comprises a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of any of claims 7301 to 7333, wherein the composition comprises a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The method of any of claims 7301 to 7333 wherein the composition comprises a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. The method of any of claims 7301 to 7333 wherein the composition comprises a synthetic compound comprising four or more carbonyl-oxygen-succinimidyl groups. The method of any of claims 7301 to 7333, wherein the composition comprises a compound comprising a synthetic polyalkylene oxide. The method of any of claims 7301-7333 wherein the composition comprises a synthetic compound comprising both a polyalkylene oxide and a biodegradable polyester block. The method of any of claims 7301 to 7333, wherein the composition comprises a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The method of any of claims 7301 to 7333, wherein the composition comprises a compound comprising a synthetic polyalkylene oxide having a thiol reactive group. The method of any of claims 7301 to 7333, wherein the composition comprises a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The method of any of claims 7301-7333 wherein the composition comprises a synthetic compound comprising a biodegradable polyester block. The method of any of claims 7301 to 7333, wherein the composition is formed from a synthetic polymer, wholly or partly comprised of lactic acid or lactide. The method of any of claims 7301 to 7333, wherein the composition is formed from a synthetic polymer, wholly or partly consisting of glycolic acid or glycolide. The method of any of claims 7301-7333 wherein the composition comprises polylysine. The method of any of claims 7301 to 7333 wherein the composition is formed from (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The method of any of claims 7301 to 7333, wherein the composition comprises (a) a protein and (b) polylysine. The method of any of claims 7301 to 7333 wherein the composition is formed from (a) a protein and (b) a compound comprising 4 or more thiol groups. The method of any of claims 7301-7733 wherein the composition comprises (a) a protein and (b) 4 or more amino groups. The method of any of claims 7301 to 7333, wherein the composition comprises (a) a protein and (b) four or more carbonyl-oxygen-succinimide groups. The composition is formed from a reactant comprising a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. Any method of paragraphs 7301-7733. The method of any of claims 7301 to 7333, wherein the composition is formed from (a) collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of any of claims 7301 to 7333, wherein the composition comprises (a) collagen and (b) polylysine. The method of any of claims 7301 to 7333 wherein the composition is formed from (a) collagen and (b) a compound comprising 4 or more thiol groups. The method of any of claims 7301 to 7333, wherein the composition is formed from (a) collagen and (b) a compound comprising 4 or more amino groups. The method of any of claims 7301 to 7333, wherein the composition is formed from (a) collagen and (b) a compound comprising four or more carbonyl-oxygen-succinimide groups. The composition is formed from a reactant comprising a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. Any method of paragraphs 7301-7733. The method of any of claims 7301 to 7333 wherein the composition is formed from a compound comprising (a) methylated collagen and (b) an oxidized polyalkylene moiety. The method of any of claims 7301 to 7333, wherein the composition comprises (a) methylated collagen and (b) polylysine. The method of any of claims 7301 to 7333, wherein the composition is formed from (a) methylated collagen and (b) a compound comprising 4 or more thiol groups. The method of any of claims 7301 to 7333, wherein the composition is formed from (a) methylated collagen and (b) a compound comprising 4 or more amino groups. The method of any of claims 7301 to 7333 wherein the composition comprises (a) methylated collagen and (b) four or more carbonyl-oxygen-succinimide groups. The composition is formed from a reactant comprising a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone Any method of claims 7301-7733. The method of any of claims 7301-7733 wherein the composition comprises hyaluronic acid. The method of any of claims 7301-7733 wherein the composition comprises a hyaluronic acid analog. The method of any of claims 7301 to 7333 wherein the composition is formed from pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The method of any of claims 7301 to 7333 wherein the composition is formed from pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A composition having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000, The method of any of claims 7301 to 7333, formed from a synthetic compound comprising a region and a plurality of electrophilic groups. The method of any of claims 7301 to 7333, wherein the composition comprises a colorant. The method of any of claims 7301-7333 wherein the composition is sterile. A method for treating inflammatory arthritis, delivering a therapeutic composition to a patient in need thereof, the composition comprising a) a polymer and / or an in situ polymer forming compound, and b) a fiber Contains a formation inhibitor. In a method for preventing inflammatory arthritis, a composition of a therapeutic agent is delivered to a patient in need, the composition comprising a polymer and a fibrosis inhibitor. In a method for treating osteoarthritis, a therapeutic composition is delivered to a patient in need, the composition comprising a polymer and a fibrosis inhibitor. A method for preventing osteoarthritis delivers a composition of a therapeutic agent to a patient in need, the composition comprising a polymer and a fibrosis inhibitor. A method for treating primary osteoarthritis delivers a composition of a therapeutic agent to a patient in need, the composition comprising a polymer and a fibrosis inhibitor. A method for preventing primary osteoarthritis delivers a composition of a therapeutic agent to a patient in need, the composition comprising a polymer and a fibrosis inhibitor. In a method for treating secondary osteoarthritis, a composition of a therapeutic agent is delivered to a patient in need, the composition comprising a polymer and a fibrosis inhibitor. In a method for preventing secondary osteoarthritis, a composition of a therapeutic agent is delivered to a patient in need, the composition comprising a polymer and a fibrosis inhibitor. In a method for treating rheumatoid arthritis, a therapeutic composition is delivered to a patient in need, the composition comprising a polymer and a fibrosis inhibitor. A method for inhibiting rheumatoid arthritis delivers a composition of a therapeutic agent to a patient in need, the composition comprising a polymer and a fibrosis inhibitor. The method of any of claims 7575-7484, wherein the composition is delivered by infusion. The method of any of claims 7575-7484, wherein the composition is delivered orally. The method of any of claims 7575-7484, wherein the composition is delivered by subcutaneous injection. The method of any of claims 7575-7484, wherein the composition is delivered by intramuscular injection. The method of any of claims 7575-7484, wherein the composition is delivered by arterial injection. The method of any of claims 7575-7854, wherein cell regeneration is inhibited by a fiber formation inhibitor. The method of any one of claims 7575-7758, wherein angiogenesis is inhibited by a fiber formation inhibitor. The method of any one of claims 7575-7854, wherein fibroblast migration is inhibited by a fibrosis inhibitor. The method of any of claims 7575-7484, wherein fibroblast growth is inhibited by a fibrosis inhibitor. The method of any of claims 7575-7484, wherein accumulation of extracellular matrix is inhibited by a fiber formation inhibitor. The method of any one of claims 7575-7854, wherein the tissue remodeling is inhibited by the fiber formation inhibitor. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is an angiogenesis inhibitor. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is a 5- lipoxygenase inhibitor or antagonist. The method of any of claims 7575-7484, wherein the fibrosis inhibitor is a chemokine receptor antagonist. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is a cell cycle inhibitor. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is a taxane. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is paclitaxel. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is not paclitaxel. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is paclitaxel or an analogue or derivative thereof. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is a vinca alkaloid. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is camptothecin or an analogue or derivative thereof. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is podophyllotoxin. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is etoposide or an analogue or derivative thereof. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is an anthracycline. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is doxorubicin or an analogue or derivative thereof. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is mitoxantrone or an analogue or derivative thereof. The method of any of claims 7575-7758, wherein the fiber formation inhibitor is a platinum compound. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is nitrosourea. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is nitroimidazole. The method of any of claims 7575-7484, wherein the fibrosis inhibitor is a folic acid antagonist. The method of any of claims 7575-7484, wherein the fibrosis inhibitor is a cytidine analogue. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is a pyrimidine analogue. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is a fluoropyrimidine analogue. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is a purine analogue. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is nitrogen mustard or an analogue or derivative thereof. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is hydroxyurea. The method of any of claims 7575-7854 wherein the fibrosis inhibitor is mitomycin or an analogue or derivative thereof. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is an alkyl sulfonate. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The method of any of claims 7575-7854 wherein the fibrosis inhibitor is nicotinamide or an analogue or derivative thereof. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is a DNA alkylating agent. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of any of claims 7575-7758, wherein the fiber formation inhibitor is a DNA cleaving agent. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is an antimetabolite. The method of any of claims 7575-7484, wherein adenosine deaminase is inhibited by a fiber formation inhibitor. The method of any of claims 7575-7854, wherein the fiber formation inhibitor inhibits purine ring synthesis. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of any of claims 7575-7854, wherein a reduction in dihydrofolic acid is inhibited by a fiber formation inhibitor. The method of any of claims 7575-7484, wherein the fiber formation inhibitor inhibits thymidine monophosphate. The method of any of claims 7575-7484, wherein the fiber formation inhibitor causes DNA damage. The method of any of claims 7575-7758, wherein the fiber formation inhibitor is a DNA intercalation agent. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The method of any of claims 7575-7854, wherein the fiber formation inhibitor inhibits ribonucleotide synthesis or function. The method of any of claims 7575-7854, wherein the fiber formation inhibitor inhibits thymidine monophosphate synthesis or function. The method of any of claims 7575-7484, wherein the fiber formation inhibitor inhibits DNA synthesis. The method of any of claims 7575-7484, wherein the fiber formation inhibitor results in DNA adduct formation. The method of any of claims 7575-7484, wherein the fiber formation inhibitor inhibits protein synthesis. The method of any of claims 7575-7484, wherein microtubule function is inhibited by the fiber formation inhibitor. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is a cyclin dependent protein kinase inhibitor. The method of any of claims 7575-7484, wherein the fibrosis inhibitor is an epidermal growth factor kinase inhibitor. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is an elastase inhibitor. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of any of claims 7575-7484, wherein the fibrosis inhibitor is a heat shock protein 90 antagonist. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is geldanamycin or an analogue or derivative thereof. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is simvastatin or an analogue or derivative thereof. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is an IL-1 antagonist. The method of any of claims 7575-7484, wherein the fibrosis inhibitor is an ICE antagonist. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is an IRAK antagonist. The method of any of claims 7575-7484, wherein the fibrosis inhibitor is an IL-4 agonist. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is an immunomodulator. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is sirolimus or an analogue or derivative thereof. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is not sirolimus. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is tacrolimus or an analogue or derivative thereof. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is not tacrolimus. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is biolimus or an analogue or derivative thereof. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is tresperimus or an analogue or derivative thereof. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is auranofin or an analogue or derivative thereof. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is gusperimus or an analogue or derivative thereof. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is pimecrolimus or an analogue or derivative thereof. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is ABT-578 or an analogue or derivative thereof. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is an inosine monophosphate dehydrogenase (IMPDH) inhibitor. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is mycophenolic acid or an analogue or derivative thereof. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1 -α-25 dihydroxy vitamin D3 or an analogue or derivative thereof. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is a leukotriene inhibitor. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is an MCP-1 antagonist. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is an MMP inhibitor. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is an NFκB inhibitor. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is an NFκB inhibitor, and the NFκB inhibitor is Bay 11-7082. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is a NO antagonist. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor, and the p38 MAP kinase inhibitor is SB202190. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is a TGF beta inhibitor. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is a thromboxane A2 antagonist. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is a TNF alpha antagonist. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is a TACE inhibitor. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is a vitronectin inhibitor. The method of any of claims 7575-7484, wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is a protein kinase inhibitor. The method of any of claims 7575-7484, wherein the fibrosis inhibitor is a PDGF receptor kinase inhibitor. The method of any of claims 7575-7484, wherein the fibrosis inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is a retinoic acid receptor antagonist. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is an antifungal agent. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is an antifungal agent, wherein the antifungal agent is sulconizole. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is a bisphosphonate. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is a macrolide antibiotic. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is a GPIIb / IIIa receptor antagonist. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is an endothelin receptor antagonist. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is an agonist of the peroxisome proliferator-responsive receptor. The method of any of claims 7575-7484, wherein the fibrosis inhibitor is an estrogen receptor agent. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is a somostatin analog. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is a neurokinin 1 antagonist. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is a neurokinin 3 antagonist. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is a VLA-4 antagonist. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is an osteoclast inhibitor. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is an angiotensin II antagonist. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is an enkephalinase inhibitor. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is a peroxisome proliferator-responsive receptor gamma agonist insulin sensitizer. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is a protein kinase C inhibitor. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is a CXCR3 inhibitor. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is an Itk inhibitor. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of any of claims 7575-7484, wherein the fibrosis inhibitor is a PPAR agonist. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is an immunosuppressant. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is an Erb inhibitor. The method of any of claims 7575-7484, wherein the fibrosis inhibitor is an apoptosis agonist. The method of any of claims 7575-7484, wherein the fibrosis inhibitor is a lipocortin agonist. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is a VCAM-1 antagonist. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is a collagen antagonist. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is an α2 integrin antagonist. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is a TNF alpha inhibitor. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is a nitric oxide inhibitor. The method of any of claims 7575-7854, wherein the fiber formation inhibitor is a cathepsin inhibitor. The method of any of claims 7575-7484, wherein the fibrosis inhibitor is not an anti-inflammatory agent. The method of any of claims 7575-7854, wherein the fibrosis inhibitor is not a steroid. The method of any of claims 7575-7484, wherein the fibrosis inhibitor is not a glucocorticosteroid. The method of any of claims 7575-7484, wherein the fibrosis inhibitor is not dexamethasone. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is not beclomethasone. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is not dipropionic acid. The method of any of claims 7575-7484, wherein the fibrosis inhibitor is not an anti-infective. The method of any of claims 7575-7484, wherein the fibrosis inhibitor is not an antibiotic. The method of any of claims 7575-7484, wherein the fiber formation inhibitor is not an antifungal agent. The method of any of claims 7575-7484, wherein the composition comprises an antithrombotic agent. The method of any of claims 7575-7758, wherein the composition comprises a naturally occurring polymer. The method of any of claims 7575-7484, wherein the composition comprises a protein. The method of any of claims 7575-7484, wherein the composition comprises a carbohydrate. The method of any of claims 7575-7758, wherein the composition comprises a biodegradable polymer. The method of any of claims 7575-7758, wherein the composition comprises a non-biodegradable polymer. The method of any of claims 7575-7484, wherein the composition comprises collagen. The method of any one of claims 7575-7758, wherein the composition comprises methylated collagen. The method of any of claims 7575-7758, wherein the composition comprises fibrinogen. The method of any of claims 7575-7484, wherein the composition comprises thrombin. The method of any of claims 7575-7484, wherein the composition comprises a plasma component. The method of any of claims 7575-7484, wherein the composition comprises a calcium salt. The method of any of claims 7575-75843, wherein the composition comprises a fiber formation inhibitor. The method of any of claims 7575-7854, wherein the composition comprises a fibrinogen analog. The method of any of 7575-7758, wherein the composition comprises albumin. The method of any of claims 7575-7484, wherein the composition comprises plasminogen. The method of any of claims 7575-7854, wherein the composition comprises a von Willebrand factor. The method of any of claims 7575-7484, wherein the composition comprises Factor VIII. The method of any of 7575-7758, wherein the composition comprises hypoallergenic collagen. The method of any of claims 7575-7854, wherein the composition comprises atelopeptide collagen. The method of any of claims 7575-7484, wherein the composition comprises telopeptide collagen. The method of any of claims 7575-7854, wherein the composition comprises cross-linked collagen. The method of any of claims 7575-7484, wherein the composition comprises aprotinin. The method of any of claims 7575-7854, wherein the composition comprises epsilon amino-n-caproic acid. The method of any of claims 7575-7484, wherein the composition comprises gelatin. The method of any of claims 7575-7758, wherein the composition comprises a protein conjugate. The method of any of claims 7575-7484, wherein the composition comprises a gelatin conjugate. The method of any of claims 7575-7484, wherein the composition comprises a synthetic polymer. The method of any of claims 7575-7854, wherein the composition comprises a compound comprising synthetic isocyanate. The method of any of claims 7575-7854, wherein the composition comprises a compound comprising a synthetic thiol. The method of any of claims 7575-7854, wherein the composition comprises a synthetic compound having two or more thiol groups. The method of any of claims 7575-7484, wherein the composition comprises a synthetic compound having three or more thiol groups. The method of any of claims 7575-7484, wherein the composition comprises a synthetic compound having four or more thiol groups. The method of any of claims 7575-7854, wherein the composition comprises a compound comprising synthetic amino. The method of any of claims 7575-7484, wherein the composition comprises a synthetic compound having two or more amino groups. The method of any of claims 7575-7484, wherein the composition comprises a synthetic compound having three or more amino groups. The method of any of claims 7575-7484, wherein the composition comprises a synthetic compound having four or more amino groups. The method of any of claims 7575-7854, wherein the composition comprises a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of any of claims 7575-7484, wherein the composition comprises a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The method of any of claims 7575-7854, wherein the composition comprises a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. The method of any of claims 7575-7854, wherein the composition comprises a synthetic compound comprising four or more carbonyl-oxygen-succinimidyl groups. The method of any of claims 7575-7854, wherein the composition comprises a compound comprising synthetic polyalkylene oxide. The method of any of claims 7575-7854, wherein the composition comprises a synthetic compound comprising both a polyalkylene oxide and a biodegradable polyester block. The method of any of claims 7575-7854, wherein the composition comprises a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The method of any of claims 7575-7854, wherein the composition comprises a compound comprising a synthetic polyalkylene oxide having a thiol reactive group. The method of any of claims 7575-7854, wherein the composition comprises a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The method of any of claims 7575-7854, wherein the composition comprises a synthetic compound comprising a biodegradable polyester block. The method of any of claims 7575-7854, wherein the composition is formed from a synthetic polymer, wholly or in part, consisting of lactic acid or lactide. The method of any of claims 7575-7854, wherein the composition is formed from a synthetic polymer, wholly or in part, consisting of glycolic acid or glycolide. The method of any of claims 7575-7484, wherein the composition comprises polylysine. The method of any of claims 7575-7854, wherein the composition is formed from (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The method of any one of claims 7575-7854, wherein the composition comprises (a) a protein and (b) polylysine. The method of any of claims 7575-7854, wherein the composition is formed from (a) a protein and (b) a compound comprising 4 or more thiol groups. The method of any of claims 7575-7484, wherein the composition comprises (a) a protein and (b) 4 or more amino groups. The method of any of claims 7575-7484, wherein the composition comprises (a) a protein and (b) four or more carbonyl-oxygen-succinimide groups. The composition is formed from a reactant comprising a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. Any method of paragraphs 7575-7758. The method of any of claims 7575-7854, wherein the composition is formed from (a) a collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of any one of claims 7575-7854, wherein the composition comprises (a) collagen and (b) polylysine. The method of any of claims 7575-7854, wherein the composition is formed from (a) collagen and (b) a compound comprising 4 or more thiol groups. The method of any of claims 7575-7854, wherein the composition is formed from (a) collagen and (b) a compound comprising 4 or more amino groups. The method of any of claims 7575-7854, wherein the composition is formed from (a) collagen and (b) a compound comprising four or more carbonyl-oxygen-succinimide groups. The composition is formed from a reactant comprising a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. Any method of paragraphs 7575-7758. The method of any of claims 7575-7854, wherein the composition is formed from a compound comprising (a) methylated collagen and (b) an oxidized polyalkylene moiety. The method of any one of claims 7575-7854, wherein the composition comprises (a) methylated collagen and (b) polylysine. The method of any of claims 7575-7854, wherein the composition is formed from (a) methylated collagen and (b) a compound comprising 4 or more thiol groups. The method of any of claims 7575-7854, wherein the composition is formed from (a) methylated collagen and (b) a compound comprising 4 or more amino groups. The method of any of claims 7575-7484, wherein the composition comprises (a) methylated collagen and (b) four or more carbonyl-oxygen-succinimide groups. The composition is formed from a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and episoncaprolactone. Any method of ~ 7584. The method of any of claims 7575-7758, wherein the composition comprises hyaluronic acid. The method of any of claims 7575-7854, wherein the composition comprises a hyaluronic acid analog. The method of any of claims 7575-7484, wherein the composition is formed from pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The method of any of claims 7575-7854, wherein the composition is formed from pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A composition having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000, The method of any of claims 7575-7484 formed from a synthetic compound comprising a region and a plurality of electrophilic groups. The method of any of claims 7575-7854, wherein the composition comprises a colorant. The method of any of claims 7575-7484, wherein the composition is sterile. For patients in need, form a) a fibrosis inhibitor or b) i) a fibrosis inhibitor and ii) a polymer and / or an in situ polymer in a method for treating hypertrophic scars A method of delivering a composition comprising a compound. In a method for treating keloids for a patient in need, the patient is provided with a) a fiber formation inhibitor or b) i) a fiber formation inhibitor and ii) a polymer and / or a compound that forms an in situ polymer A method of delivering a composition comprising. The method of claim 7823 or 7824 wherein the agent or composition is injected directly into a scar or keloid. The method of claim 7823 or 7824, wherein the agent or the composition is applied topically to the scar or keloid. The method of claim 7823 or 7824, wherein cell regeneration is inhibited by a fiber formation inhibitor. The method of claim 7823 or 7824, wherein angiogenesis is inhibited by fibrosis inhibitors. The method of claim 7823 or 7824, wherein fibroblast migration is inhibited by a fibrosis inhibitor. The method of claim 7823 or 7824, wherein fibroblast proliferation is inhibited by a fibrosis inhibitor. The method of claim 7823 or 7824, wherein the fiber formation inhibitor inhibits extracellular matrix accumulation. The method of claim 7823 or 7824, wherein the tissue remodeling is inhibited by the fiber formation inhibitor. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is an angiogenesis inhibitor. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a 5- lipoxygenase inhibitor or antagonist. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is a chemokine receptor antagonist. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a cell cycle inhibitor. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a taxane. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is paclitaxel. The method of claim 7823 or 7824 wherein the fiber formation inhibitor is not paclitaxel. The method of claim 7823 or 7824, wherein the fibrosis inhibitor is an analogue or derivative of paclitaxel. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a vinca alkaloid. The method of claim 7823 or 7824, wherein the fibrosis inhibitor is camptothecin or an analogue or derivative thereof. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is podophyllotoxin. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is etoposide or an analogue or derivative thereof. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is an anthracycline. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is doxorubicin or an analogue or derivative thereof. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is mitoxantrone or an analogue or derivative thereof. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a platinum compound. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is nitrosourea. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is nitroimidazole. The method of any of 7823 or 7824, wherein the fibrosis inhibitor is a folic acid antagonist. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is a cytidine analogue. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is a pyrimidine analogue. The method of claim 7823 or 7824 wherein the fiber formation inhibitor is a fluoropyrimidine analogue. The method of claim 7823 or 7824, wherein the fibrosis inhibitor is a purine analogue. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is nitrogen mustard or an analogue or derivative thereof. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is hydroxyurea. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is mitomycin or an analogue or derivative thereof. The method of claim 7823 or 7824 wherein the fiber formation inhibitor is an alkyl sulfonate. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is benzamide or an analogue or derivative thereof. The method of claim 7823 or 7824 wherein the fiber formation inhibitor is nicotinamide or an analogue or derivative thereof. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a DNA alkylating agent. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a DNA cleaving agent. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is an antimetabolite. The method of claim 7823 or 7824, wherein adenosine deaminase is inhibited by a fiber formation inhibitor. The method of claim 7823 or 7824, wherein a purine ring synthesis is inhibited by a fiber formation inhibitor. The method of claim 7823 or 7824 wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of claim 7823 or 7824, wherein a decrease in dihydrofolic acid is inhibited by a fiber formation inhibitor. The method of claim 7823 or 7824, wherein thymidine monophosphate is inhibited by a fiber formation inhibitor. The method of claim 7823 or 7824, wherein DNA damage is caused by a fiber formation inhibitor. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a DNA intercalation agent. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The method of claim 7823 or 7824, wherein ribonucleotide synthesis or function is inhibited by a fiber formation inhibitor. The method of claim 7823 or 7824, wherein the fibrosis inhibitor inhibits thymidine monophosphate synthesis or function. The method of claim 7823 or 7824, wherein DNA synthesis is inhibited by a fiber formation inhibitor. The method of claim 7823 or 7824, wherein DNA adduct formation occurs with the fiber formation inhibitor. The method of claim 7823 or 7824, wherein protein synthesis is inhibited by a fiber formation inhibitor. The method of claim 7823 or 7824, wherein microtubule function is inhibited by a fiber formation inhibitor. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a cyclin-dependent protein kinase inhibitor. The method of claim 7823 or 7824, wherein the fibrosis inhibitor is an epidermal growth factor kinase inhibitor. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is an elastase inhibitor. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 7823 or 7824 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is geldanamycin or an analogue or derivative thereof. The method of claim 7823 or 7824 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is simvastatin or an analogue or derivative thereof. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is an IL-1 antagonist. The method of any of 7823 or 7824, wherein the fibrosis inhibitor is an ICE antagonist. The method of any of 7823 or 7824, wherein the fibrosis inhibitor is an IRAK antagonist. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is an IL-4 agonist. The method of claim 7823 or 7824, wherein the fibrosis inhibitor is an immunomodulator. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is sirolimus or an analogue or derivative thereof. The method of claim 7823 or 7824, wherein the fibrosis inhibitor is not sirolimus. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is tacrolimus or an analogue or derivative thereof. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is not tacrolimus. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is biolimus or an analogue or derivative thereof. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is tresperimus or an analogue or derivative thereof. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is auranofin or an analogue or derivative thereof. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is gusperimus or an analogue or derivative thereof. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is pimecrolimus or an analogue or derivative thereof. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is ABT-578 or an analogue or derivative thereof. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. The method of any of 7823 or 7824 wherein the fiber formation inhibitor is mycophenolic acid or an analogue or derivative thereof. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-α-25 dihydroxy vitamin D ₃ or an analogue or derivative thereof. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a leukotriene inhibitor. The method of any of 7823 or 7824, wherein the fibrosis inhibitor is an MCP-1 antagonist. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is an MMP inhibitor. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is an NFκB inhibitor. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is an NFκB inhibitor, and the NFκB inhibitor is Bay11-7082. The method of any of 7823 or 7824, wherein the fibrosis inhibitor is a NO antagonist. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is a p38 MAP kinase inhibitor. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB202190. The method of claim 7823 or 7824 wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a TGF beta inhibitor. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is a thromboxane A2 antagonist. The method of claim 7823 or 7824, wherein the method is a fibrosis inhibitor TNFα antagonist. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a TACE inhibitor. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a vitronectin inhibitor. The method of claim 7823 or 7824, wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a protein kinase inhibitor. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is a PDGF receptor kinase inhibitor. The method of claim 7823 or 7824, wherein the fibrosis inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is a retinoic acid receptor antagonist. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is an antifungal agent. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is an antifungal agent, and the antifungal agent is sulconizole. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a bisphosphonate. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a macrolide antibiotic. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a GPIIb / IIIa receptor antagonist. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is an endothelin receptor antagonist. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is an agonist of peroxisome proliferator-activated receptor. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is an estrogen receptor antagonist. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is a somostatin analog. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is a neurokinin 1 antagonist. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is a neurokinin 3 antagonist. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is a VLA-4 antagonist. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is an osteoclast inhibitor. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of any of 7823 or 7824 wherein the fibrosis inhibitor is an angiotensin II antagonist. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is an enkephalinase inhibitor. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is a peroxisome proliferator-activated receptor gamma agonist insulin sensitizer. The method of claim 7823 or 7824 wherein the fiber formation inhibitor is a protein kinase C inhibitor. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a CXCR3 inhibitor. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is an Itk inhibitor. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is a PPAR agonist. The method of claim 7823 or 7824, wherein the fibrosis inhibitor is an immunosuppressant. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is an Erb inhibitor. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is an apoptosis agonist. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is a lipocortin agonist. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is a VCAM-1 antagonist. The method of any of 7823 or 7824, wherein the fibrosis inhibitor is a collagen antagonist. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is an α2 integrin antagonist. The method of claim 7823 or 7824, wherein the method is a fibrosis inhibitor TNFα inhibitor. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a nitric oxide inhibitor. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is a cathepsin inhibitor. The method of claim 7823 or 7824, wherein the fibrosis inhibitor is not an anti-inflammatory agent. The method of claim 7823 or 7824, wherein the fibrosis inhibitor is not a steroid. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is not a glucocorticosteroid. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is not dexamethasone. The method of claim 7823 or 7824 wherein the fibrosis inhibitor is not beclomethasone. The method of claim 7823 or 7824 wherein the fiber formation inhibitor is not dipropionic acid. The method of claim 7823 or 7824, wherein the fibrosis inhibitor is not an anti-infective. The method of claim 7823 or 7824, wherein the fibrosis inhibitor is not an antibiotic. The method of claim 7823 or 7824, wherein the fiber formation inhibitor is not an antifungal agent. The method of claim 7823 or 7824, wherein the composition comprises an antithrombotic agent. The method of claim 7823 or 7824, wherein the composition comprises a naturally occurring polymer. The method of claim 7823 or 7824, wherein the composition comprises a protein. The method of claim 7823 or 7824, wherein the composition comprises a carbohydrate. The method of claim 7823 or 7824, wherein the composition comprises a biodegradable polymer. The method of claim 7823 or 7824, wherein the composition comprises a non-biodegradable polymer. The method of claim 7823 or 7824, wherein the composition comprises collagen. The method of claim 7823 or 7824, wherein the composition comprises methylated collagen. The method of claim 7823 or 7824, wherein the composition comprises fibrinogen. The method of claim 7823 or 7824, wherein the composition comprises thrombin. The method of claim 7823 or 7824, wherein the composition comprises a plasma component. The method of claim 7823 or 7824, wherein the composition comprises a calcium salt. The method of claim 7823 or 7824, wherein the composition comprises a fiber formation inhibitor. The method of claim 7823 or 7824, wherein the composition comprises a fibrinogen analog. The method of claim 7823 or 7824, wherein the composition comprises albumin. The method of claim 7823 or 7824, wherein the composition comprises plasminogen. The method of claim 7823 or 7824, wherein the composition comprises a von Willebrand factor. The method of claim 7823 or 7824, wherein the composition comprises Factor VIII. The method of claim 7823 or 7824, wherein the composition comprises a mild allergen. The method of claim 7823 or 7824, wherein the composition comprises atelopeptide collagen. The method of claim 7823 or 7824, wherein the composition comprises telopeptide collagen. The method of claim 7823 or 7824, wherein the composition comprises cross-linked collagen. The method of claim 7823 or 7824, wherein the composition comprises aprotinin. The method of claim 7823 or 7824, wherein the composition comprises epsilon amino-n-caproic acid. The method of claim 7823 or 7824, wherein the composition comprises gelatin. The method of claim 7823 or 7824, wherein the composition comprises a protein conjugate. The method of claim 7823 or 7824, wherein the composition comprises a gelatin conjugate. The method of claim 7823 or 7824, wherein the composition comprises a synthetic polymer. The method of claim 7823 or 7824, wherein the composition comprises a compound comprising synthetic isocyanate. The method of claim 7823 or 7824, wherein the composition comprises a compound comprising a synthetic thiol. The method of claim 7823 or 7824, wherein the composition comprises a synthetic compound having two or more thiol groups. The method of claim 7823 or 7824, wherein the composition comprises a synthetic compound having three or more thiol groups. The method of claim 7823 or 7824, wherein the composition comprises a synthetic compound having four or more thiol groups. The method of claim 7823 or 7824, wherein the composition comprises a compound comprising synthetic amino. The method of claim 7823 or 7824, wherein the composition comprises a synthetic compound having two or more amino groups. The method of claim 7823 or 7824, wherein the composition comprises a synthetic compound having three or more amino groups. The method of claim 7823 or 7824, wherein the composition comprises a synthetic compound having four or more amino groups. The method of claim 7823 or 7824, wherein the composition comprises a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of claim 7823 or 7824, wherein the composition comprises a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The method of claim 7823 or 7824, wherein the composition comprises a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. The method of claim 7823 or 7824, wherein the composition comprises a synthetic compound comprising four or more carbonyl-oxygen-succinimidyl groups. The method of claim 7823 or 7824, wherein the composition comprises a compound comprising a synthetic polyalkylene oxide. The method of claim 7823 or 7824, wherein the composition comprises a synthetic compound comprising both a polyalkylene oxide and a biodegradable polyester block. The method of claim 7823 or 7824, wherein the composition comprises a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The method of claim 7823 or 7824, wherein the composition comprises a compound comprising a synthetic polyalkylene oxide having a thiol reactive group. The method of claim 7823 or 7824, wherein the composition comprises a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl group. The method of claim 7823 or 7824, wherein the composition comprises a synthetic compound comprising a biodegradable polyester block. The method of claim 7823 or 7824, wherein the composition is formed from a synthetic polymer, wholly or partly consisting of lactic acid or lactide. The method of claim 7823 or 7824, wherein the composition is formed in whole or in part from a synthetic polymer consisting of glycolic acid or glycolide. The method of claim 7823 or 7824, wherein the composition comprises polylysine. The method of claim 7823 or 7824, wherein the composition is formed from (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 7823 or 7824, wherein the composition comprises (a) a protein and (b) polylysine. The method of claim 7823 or 7824, wherein the composition comprises (a) a protein and (b) four or more thiol groups. The method of claim 7823 or 7824, wherein the composition comprises (a) a protein and (b) 4 or more amino groups. The method of claim 7823 or 7824, wherein the composition comprises (a) a protein and (b) four or more carbonyl-oxygen-succinimide groups. The composition is formed from a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. the method of. The method of claim 7823 or 7824, wherein the composition is formed from (a) a collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of claim 7823 or 7824, wherein the composition comprises (a) collagen and (b) polylysine. The method of claim 7823 or 7824, wherein the composition comprises (a) collagen and (b) four or more thiol groups. The method of claim 7823 or 7824, wherein the composition comprises (a) collagen and (b) four or more amino groups. The method of claim 7823 or 7824, wherein the composition comprises (a) collagen and (b) four or more carbonyl-oxygen-succinimide groups. The composition is formed from a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. the method of. The method of claim 7823 or 7824 wherein the composition is formed from a compound comprising (a) methylated collagen and (b) an oxidized polyalkylene moiety. The method of claim 7823 or 7824, wherein the composition comprises (a) methylated collagen and (b) polylysine. The method of claim 7823 or 7824, wherein the composition comprises (a) methylated collagen and (b) four or more thiol groups. The method of claim 7823 or 7824, wherein the composition comprises (a) methylated collagen and (b) four or more amino groups. The method of claim 7823 or 7824, wherein the composition comprises (a) methylated collagen and (b) four or more carbonyl-oxygen-succinimide groups. The composition is formed from a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and episoncaprolactone. Or 7824 way. The method of claim 7823 or 7824, wherein the composition comprises hyaluronic acid. The method of claim 7823 or 7824, wherein the composition comprises a hyaluronic acid derivative. The method of claim 7823 or 7824, wherein the composition is formed from pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The method of claim 7823 or 7824, wherein the composition is formed from pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A composition having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000, The method of claim 7823 or 7824, formed from a synthetic compound comprising a region and a plurality of electrophilic groups. The method of claim 7823 or 7824, wherein the composition comprises a colorant. The method of claim 7823 or 7824, wherein the composition is sterile. In a method to reduce cartilage loss following joint damage to a patient in need of a) a) a fibrosis inhibitor or b) i) a fibrosis inhibitor and ii) a polymer and / or in situ A method of delivering a composition comprising a compound that forms a polymer. In a method to prevent cartilage loss following joint damage for patients in need: a) a fibrosis inhibitor or b) i) a fibrosis inhibitor and ii) a polymer and / or in situ A method of delivering a composition comprising a compound that forms a polymer. For patients in need, a method to reduce cartilage loss following cruciate ligament failure in a patient with a) a fiber formation inhibitor or b) i) a fiber formation inhibitor and ii) a polymer and / or in situ A method of delivering a composition comprising a compound that forms a polymer in For patients in need, in a way to prevent cartilage loss following cruciate ligament failure, the patient can be a) a fibrosis inhibitor or b) i) a fibrosis inhibitor and ii) a polymer and / or in situ. A method of delivering a composition comprising a compound that forms a polymer in For patients in need, a method to reduce cartilage loss following meniscal breakage in a patient with a) a fibrosis inhibitor or b) i) a fibrosis inhibitor and ii) a polymer and / or in situ A method of delivering a composition comprising a compound that forms a polymer in In a method to prevent cartilage loss following meniscal breakage for a patient in need: a) a fibrosis inhibitor or b) i) a fibrosis inhibitor and ii) a polymer and / or in situ A method of delivering a composition comprising a compound that forms a polymer in The method of any of claims 8060-8065, wherein the agent or composition is delivered by arterial injection. The method of any one of claims 8060-8065, wherein cell regeneration is inhibited by a fiber formation inhibitor. The method of any one of claims 8060-8065, wherein angiogenesis is inhibited by a fiber formation inhibitor. The method of any of claims 8060-8065, wherein fibroblast migration is inhibited by a fibrosis inhibitor. The method of any one of claims 8060-8065, wherein fibroblast proliferation is inhibited by a fibrosis inhibitor. The method of any of claims 8060-8065, wherein accumulation of extracellular matrix is inhibited by a fiber formation inhibitor. The method of any one of claims 8060-8065, wherein the tissue remodeling is inhibited by the fiber formation inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is an angiogenesis inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a 5-lipoxygenase inhibitor or antagonist. The method of any of claims 8060-8065, wherein the fibrosis inhibitor is a chemokine receptor antagonist. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a cell cycle inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a taxane. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is paclitaxel. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is not paclitaxel. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is paclitaxel or an analogue or derivative thereof. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a vinca alkaloid. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is camptothecin or an analogue or derivative thereof. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is podophyllotoxin. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is etoposide or an analogue or derivative thereof. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is an anthracycline. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is doxorubicin or an analogue or derivative thereof. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is mitoxantrone or an analogue or derivative thereof. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a platinum compound. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is nitrosourea. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is nitroimidazole. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a folic acid antagonist. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a cytidine analog. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a pyrimidine analog. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a fluoropyrimidine analog. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a purine analogue. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is nitrogen mustard or an analogue or derivative thereof. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is hydroxyurea. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is mitomycin or an analogue or derivative thereof. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is an alkyl sulfonate. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is nicotinamide or an analogue or derivative thereof. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a DNA alkylating agent. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a DNA cleaving agent. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is an antimetabolite. The method of any of claims 8060-8065, wherein adenosine deaminase is inhibited by a fiber formation inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor inhibits purine ring synthesis. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor inhibits dihydrofolate reduction. The method of any of claims 8060-8065, wherein the fiber formation inhibitor inhibits thymidine monophosphate. The method of any of claims 8060-8065, wherein the fiber formation inhibitor causes DNA damage. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a DNA intercalation agent. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor inhibits ribonucleotide synthesis or function. The method of any of claims 8060-8065, wherein the fiber formation inhibitor inhibits thymidine monophosphate synthesis or function. The method of any of claims 8060-8065, wherein the fiber formation inhibitor inhibits DNA synthesis. The method of any of claims 8060-8065, wherein the fiber formation inhibitor results in DNA adduct formation. The method of any of claims 8060-8065, wherein the fiber formation inhibitor inhibits protein synthesis. The method of any of claims 8060-8065, wherein microtubule function is inhibited by the fiber formation inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a cyclin dependent protein kinase inhibitor. The method of any of claims 8060-8065, wherein the fibrosis inhibitor is an epidermal growth factor kinase inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is an elastase inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of any of claims 8060-8065, wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a heat shock protein 90 antagonist. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is geldanamycin or an analogue or derivative thereof. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The method of any of claims 8060-8065, wherein the fibrosis inhibitor is simvastatin or an analogue or derivative thereof. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is an IL-1 antagonist. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is an ICE antagonist. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is an IRAK antagonist. The method of any of claims 8060-8065, wherein the fibrosis inhibitor is an IL-4 agonist. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is an immunomodulator. The method of any of claims 8060-8065, wherein the fibrosis inhibitor is sirolimus or an analogue or derivative thereof. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is not sirolimus. The method of any of claims 8060-8065, wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. The method of any of claims 8060-8065, wherein the fibrosis inhibitor is tacrolimus or an analogue or derivative thereof. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is not tacrolimus. The method of any of claims 8060-8065, wherein the fibrosis inhibitor is biolimus or an analogue or derivative thereof. The method of any of claims 8060-8065, wherein the fibrosis inhibitor is tresperimus or an analogue or derivative thereof. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is auranofin or an analogue or derivative thereof. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is gusperimus or an analogue or derivative thereof. The method of any of claims 8060-8065, wherein the fibrosis inhibitor is pimecrolimus or an analogue or derivative thereof. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is ABT-578 or an analogue or derivative thereof. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is an inosine monophosphate dehydrogenase (IMPDH) inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is mycophenolic acid or an analogue or derivative thereof. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1-α-25 dihydroxyvitamin D3 or an analogue or derivative thereof. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a leukotriene inhibitor. The method of any of claims 8060-8065, wherein the fibrosis inhibitor is an MCP-1 antagonist. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is an MMP inhibitor. The method of any one of claims 8060-8065, wherein the fiber formation inhibitor is an NFκB inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is an NFκB inhibitor, wherein the NFκB inhibitor is Bay11-7082. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a NO antagonist. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor, wherein the p38 MAP kinase inhibitor is SB202190. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a TGF beta inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a thromboxane A2 antagonist. The method of any one of claims 8060-8065, wherein the fibrosis inhibitor is a TNFα antagonist. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a TACE inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a vitronectin inhibitor. The method of any of claims 8060-8065, wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a protein kinase inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a PDGF receptor kinase inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a retinoic acid receptor antagonist. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of any of claims 8060-8065, wherein the fibrosis inhibitor is a fibrinogen antagonist. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is an antifungal agent. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is an antifungal agent, and the antifungal agent is sulconizole. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a bisphosphonate. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. The method of any of claims 8060-8065, wherein the fibrosis inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a macrolide antibiotic. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a GPIIb / IIIa receptor antagonist. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is an endothelin receptor antagonist. The method of any of claims 8060-8065, wherein the fibrosis inhibitor is an agonist of a peroxisome proliferator-responsive receptor. The method of any of claims 8060-8065, wherein the fibrosis inhibitor is an estrogen receptor agent. The method of any of claims 8060-8065, wherein the fibrosis inhibitor is a somostatin analog. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a neurokinin 1 antagonist. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a neurokinin 3 antagonist. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a VLA-4 antagonist. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is an osteoclast inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is an angiotensin II antagonist. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is an enkephalinase inhibitor. The method of any of claims 8060-8065, wherein the fibrosis inhibitor is a peroxisome proliferator-responsive receptor gamma agonist insulin sensitizer. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a protein kinase C inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a CXCR3 inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is an Itk inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of any of claims 8060-8065, wherein the fibrosis inhibitor is a PPAR agonist. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is an immunosuppressant. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is an Erb inhibitor. The method of any of claims 8060-8065, wherein the fibrosis inhibitor is an apoptosis agonist. The method of any of claims 8060-8065, wherein the fibrosis inhibitor is a lipocortin agonist. The method of any of claims 8060-8065, wherein the fibrosis inhibitor is a VCAM-1 antagonist. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a collagen antagonist. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is an α2 integrin antagonist. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a TNF alpha inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a nitric oxide inhibitor. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is a cathepsin inhibitor. The method of any of claims 8060-8065, wherein the fibrosis inhibitor is not an anti-inflammatory agent. The method of any of claims 8060-8065, wherein the fibrosis inhibitor is not a steroid. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is not a glucocorticosteroid. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is not dexamethasone. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is not beclomethasone. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is not dipropionic acid. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is not an anti-infective. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is not an antibiotic. The method of any of claims 8060-8065, wherein the fiber formation inhibitor is not an antifungal agent. The method of any of claims 8060-8065, wherein the composition comprises an antithrombotic agent. The method of any of claims 8060-8065, wherein the composition comprises a naturally occurring polymer. The method of any of claims 8060-8065, wherein the composition comprises a protein. The method of any of claims 8060-8065, wherein the composition comprises a carbohydrate. The method of any of claims 8060-8065, wherein the composition comprises a biodegradable polymer. The method of any of claims 8060-8065, wherein the composition comprises a non-biodegradable polymer. The method of any of claims 8060-8065, wherein the composition comprises collagen. The method of any of claims 8060-8065, wherein the composition comprises methylated collagen. The method of any of claims 8060-8065, wherein the composition comprises fibrinogen. The method of any of claims 8060-8065, wherein the composition comprises thrombin. The method of any of claims 8060-8065, wherein the composition comprises a plasma component. The method of any of claims 8060-8065, wherein the composition comprises a calcium salt. The method of any of claims 8060-8065, wherein the composition comprises a fiber formation inhibitor. The method of any of claims 8060-8065, wherein the composition comprises a fibrinogen analog. The method of any of claims 8060-8065, wherein the composition comprises albumin. The method of any of claims 8060-8065, wherein the composition comprises plasminogen. The method of any of claims 8060-8065, wherein the composition comprises a von Willebrand factor. The method of any of claims 8060-8065, wherein the composition comprises Factor VIII. The method of any of claims 8060-8065, wherein the composition comprises hypoallergenic collagen. The method of any of claims 8060-8065, wherein the composition comprises atelopeptide collagen. The method of any of claims 8060-8065, wherein the composition comprises telopeptide collagen. The method of any of claims 8060-8065, wherein the composition comprises cross-linked collagen. The method of any of claims 8060-8065, wherein the composition comprises aprotinin. The method of any of claims 8060-8065, wherein the composition comprises epsilon amino-n-caproic acid. The method of any of claims 8060-8065, wherein the composition comprises gelatin. The method of any of claims 8060-8065, wherein the composition comprises a protein conjugate. The method of any of claims 8060-8065, wherein the composition comprises a gelatin conjugate. The method of any of claims 8060-8065, wherein the composition comprises a synthetic polymer. The method of any of claims 8060-8065, wherein the composition comprises a compound comprising synthetic isocyanate. The method of any of claims 8060-8065, wherein the composition comprises a compound comprising a synthetic thiol. The method of any of claims 8060-8065, wherein the composition comprises a synthetic compound having two or more thiol groups. The method of any of claims 8060-8065, wherein the composition comprises a synthetic compound having three or more thiol groups. The method of any of claims 8060-8065, wherein the composition comprises a synthetic compound having four or more thiol groups. The method of any of claims 8060-8065, wherein the composition comprises a compound comprising synthetic amino. The method of any of claims 8060-8065, wherein the composition comprises a synthetic compound having two or more amino groups. The method of any of claims 8060-8065, wherein the composition comprises a synthetic compound having three or more amino groups. The method of any of claims 8060-8065, wherein the composition comprises a synthetic compound having four or more amino groups. The method of any of claims 8060-8065, wherein the composition comprises a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of any of claims 8060-8065, wherein the composition comprises a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The method of any of claims 8060-8065, wherein the composition comprises a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. The method of any of claims 8060-8065, wherein the composition comprises a synthetic compound comprising four or more carbonyl-oxygen-succinimidyl groups. The method of any of claims 8060-8065, wherein the composition comprises a compound comprising a synthetic polyalkylene oxide. The method of any of claims 8060-8065, wherein the composition comprises a synthetic compound comprising both a polyalkylene oxide and a biodegradable polyester block. The method of any of claims 8060-8065, wherein the composition comprises a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The method of any of claims 8060-8065, wherein the composition comprises a compound comprising a synthetic polyalkylene oxide having a thiol reactive group. The method of any of claims 8060-8065, wherein the composition comprises a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The method of any of claims 8060-8065, wherein the composition comprises a synthetic compound comprising a biodegradable polyester block. The method of any of claims 8060-8065, wherein the composition is formed from a synthetic polymer, wholly or partly comprised of lactic acid or lactide. The method of any of claims 8060-8065, wherein the composition is formed from a synthetic polymer, wholly or partly consisting of glycolic acid or glycolide. The method of any of claims 8060-8065, wherein the composition comprises polylysine. The method of any of claims 8060-8065, wherein the composition is formed from (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The method of any of claims 8060-8065, wherein the composition comprises (a) a protein and (b) polylysine. The method of any of claims 8060-8065, wherein the composition is formed from (a) a protein and (b) a compound comprising 4 or more thiol groups. The method of any of claims 8060-8065, wherein the composition comprises (a) a protein and (b) four or more amino groups. The method of any of claims 8060-8065, wherein the composition comprises (a) a protein and (b) four or more carbonyl-oxygen-succinimide groups. The composition is formed from a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. 8060-8065 Any way out. The method of any of claims 8060-8065, wherein the composition is formed from (a) a collagen and (b) a compound comprising an oxidized polyalkylene moiety. The method of any of claims 8060-8065, wherein the composition comprises (a) collagen and (b) polylysine. The method of any of claims 8060-8065, wherein the composition is formed from (a) collagen and (b) a compound comprising 4 or more thiol groups. The method of any of claims 8060-8065, wherein the composition is formed from (a) collagen and (b) a compound comprising 4 or more amino groups. The method of any of claims 8060-8065, wherein the composition is formed from (a) collagen and (b) a compound comprising four or more carbonyl-oxygen-succinimide groups. The composition is formed from a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. 8060-8065 Any way out. The method of any of claims 8060-8065, wherein the composition is formed from a compound comprising (a) methylated collagen and (b) an oxidized polyalkylene moiety. The method of any of claims 8060-8065, wherein the composition comprises (a) methylated collagen and (b) polylysine. The method of any of claims 8060-8065, wherein the composition is formed from (a) methylated collagen and (b) a compound comprising 4 or more thiol groups. The method of any of claims 8060-8065, wherein the composition is formed from (a) methylated collagen and (b) a compound comprising 4 or more amino groups. The method of any of claims 8060-8065, wherein the composition comprises (a) methylated collagen and (b) four or more carbonyl-oxygen-succinimide groups. The composition is formed from a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. 8060 Any method of ~ 8065. The method of any of claims 8060-8065, wherein the composition comprises hyaluronic acid. The method of any of claims 8060-8065, wherein the composition comprises a hyaluronic acid analog. The method of any of claims 8060-8065, wherein the composition is formed from pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The method of any of claims 8060-8065, wherein the composition is formed from pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A composition having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000, The method of any of claims 8060-8065, formed from a synthetic compound comprising a region and a plurality of electrophilic groups. The method of any of claims 8060-8065, wherein the composition comprises a colorant. The method of any of claims 8060-8065, wherein the composition is sterile. In a method for treating vascular disease for a patient in need, the patient is formed with a) a fiber formation inhibitor or b) i) a fiber formation inhibitor and ii) a polymer and / or an in situ polymer. A method of delivering a composition comprising a compound. The method of claim 8300, wherein the agent or composition is delivered around the blood vessel. In a method for treating stenosis for a patient in need, the patient is treated with a) a fibrosis inhibitor or b) i) a fibrosis inhibitor and ii) a polymer and / or a compound that forms a polymer in situ. A method of delivering a composition comprising. The method of claim 8303 wherein the agent or composition is delivered around the blood vessel. A compound that forms a) a fibrosis inhibitor or b) i) a fibrosis inhibitor and ii) a polymer and / or an in situ polymer in a method for treating restenosis for a patient in need A method of delivering a composition comprising: The method of claim 8305 wherein the agent or composition is delivered around the blood vessel. In a method for treating atherosclerosis for patients in need, a patient is formed with a) a fibrosis inhibitor or b) i) a fibrosis inhibitor and ii) a polymer and / or an in situ polymer A method of delivering a composition comprising a compound. The method of claim 8307 wherein the agent or composition is delivered around the blood vessel. The method of any one of claims 8300-8307, wherein cell regeneration is inhibited by a fiber formation inhibitor. The method of any one of claims 8300-8307, wherein angiogenesis is inhibited by a fiber formation inhibitor. The method of any one of claims 8300-8307, wherein fibroblast migration is inhibited by a fibrosis inhibitor. The method of any one of claims 8300-8307, wherein fibroblast proliferation is inhibited by a fibrosis inhibitor. The method of any one of claims 8300-8307, wherein accumulation of extracellular matrix is inhibited by a fiber formation inhibitor. The method of any one of claims 8300-8307, wherein tissue remodeling is inhibited by the fiber formation inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an angiogenesis inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a 5-lipoxygenase inhibitor or antagonist. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a chemokine receptor antagonist. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a cell cycle inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a taxane. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is paclitaxel. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is not paclitaxel. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is paclitaxel or an analogue or derivative thereof. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a vinca alkaloid. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is camptothecin or an analogue or derivative thereof. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is podophyllotoxin. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is etoposide or an analogue or derivative thereof. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an anthracycline. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is doxorubicin or an analogue or derivative thereof. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is mitoxantrone or an analogue or derivative thereof. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a platinum compound. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is nitrosourea. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is nitroimidazole. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a folic acid antagonist. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a cytidine analog. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a pyrimidine analogue. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a fluoropyrimidine analogue. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a purine analogue. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is nitrogen mustard or an analogue or derivative thereof. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is hydroxyurea. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is mitomycin or an analogue or derivative thereof. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an alkyl sulfonate. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is nicotinamide or an analogue or derivative thereof. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a DNA alkylating agent. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a microtubule inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a topoisomerase inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a DNA cleaving agent. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an antimetabolite. The method of any one of claims 8300-8307, wherein adenosine deaminase is inhibited by the fiber formation inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor inhibits purine ring synthesis. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor inhibits dihydrofolate reduction. The method of any of claims 8300-8307, wherein the fiber formation inhibitor inhibits thymidine monophosphate. The method of any of claims 8300-8307, wherein the fiber formation inhibitor causes DNA damage. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a DNA intercalation agent. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor inhibits ribonucleotide synthesis or function. The method of any of claims 8300-8307, wherein the fiber formation inhibitor inhibits thymidine monophosphate synthesis or function. The method of any of claims 8300-8307, wherein the fiber formation inhibitor inhibits DNA synthesis. The method of any of claims 8300-8307, wherein the fiber formation inhibitor results in DNA adduct formation. The method of any of claims 8300-8307, wherein the fiber formation inhibitor inhibits protein synthesis. The method of any one of claims 8300-8307, wherein the microtubule function is inhibited by the fiber formation inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a cyclin dependent protein kinase inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an epidermal growth factor kinase inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an elastase inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a factor Xa inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a fibrinogen antagonist. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a heat shock protein 90 antagonist. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is geldanamycin or an analogue or derivative thereof. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is simvastatin or an analogue or derivative thereof. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an IKK2 inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an IL-1 antagonist. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an ICE antagonist. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an IRAK antagonist. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an IL-4 agonist. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an immunomodulator. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is sirolimus or an analogue or derivative thereof. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is not sirolimus. The method of any of claims 8300-8307, wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is tacrolimus or an analogue or derivative thereof. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is not tacrolimus. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is biolimus or an analogue or derivative thereof. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is tresperimus or an analogue or derivative thereof. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is auranofin or an analogue or derivative thereof. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is gusperimus or an analogue or derivative thereof. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is pimecrolimus or an analogue or derivative thereof. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is ABT-578 or an analogue or derivative thereof. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an inosine monophosphate dehydrogenase (IMPDH) inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is mycophenolic acid or an analogue or derivative thereof. Fiber forming inhibitor is an IMPDH inhibitor, the IMPDH inhibitor is 1-alpha-25-dihydroxyvitamin D ₃ or its analogues or derivatives, any method of claims 8300-8307. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a leukotriene inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an MCP-1 antagonist. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an MMP inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an NFκB inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an NFκB inhibitor, and the NFκB inhibitor is Bay11-7082. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a NO antagonist. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor, and the p38 MAP kinase inhibitor is SB202190. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a TGF beta inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a thromboxane A2 antagonist. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a TNFα antagonist. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a TACE inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a vitronectin inhibitor. The method of any of claims 8300-8307, wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a protein kinase inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a PDGF receptor kinase inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an endothelial growth factor receptor kinase inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a retinoic acid receptor antagonist. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a platelet derived growth factor receptor kinase inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a fibrinogen antagonist. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an antifungal agent. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an antifungal agent, and the antifungal agent is sulconizole. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a bisphosphonate. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a macrolide antibiotic. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a GPIIb / IIIa receptor antagonist. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an endothelin receptor antagonist. The method of any of claims 8300-8307, wherein the fibrosis inhibitor is an agonist of a peroxisome proliferator-responsive receptor. The method of any of claims 8300-8307, wherein the fibrosis inhibitor is an estrogen receptor agent. The method of any of claims 8300-8307, wherein the fibrosis inhibitor is a somostatin analog. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a neurokinin 1 antagonist. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a neurokinin 3 antagonist. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a VLA-4 antagonist. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an osteoclast inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an angiotensin II antagonist. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an enkephalinase inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a peroxisome proliferator-responsive receptor gamma agonist insulin sensitizer. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a protein kinase C inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a CXCR3 inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an Itk inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a PPAR agonist. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an immunosuppressant. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an Erb inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an apoptosis agonist. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a lipocortin agonist. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a VCAM-1 antagonist. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a collagen antagonist. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is an α2 integrin antagonist. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a TNFα inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a nitric oxide inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is a cathepsin inhibitor. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is not an anti-inflammatory agent. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is not a steroid. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is not a glucocorticosteroid. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is not dexamethasone. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is not beclomethasone. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is not dipropionic acid. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is not an anti-infective. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is not an antibiotic. The method of any of claims 8300-8307, wherein the fiber formation inhibitor is not an antifungal agent. The method of any of claims 8300-8307, wherein the composition comprises an antithrombotic agent. The method of any of claims 8300-8307, wherein the composition comprises a naturally occurring polymer. The method of any of claims 8300-8307, wherein the composition comprises a protein. The method of any of claims 8300-8307, wherein the composition comprises a carbohydrate. The method of any of claims 8300-8307, wherein the composition comprises a biodegradable polymer. The method of any of claims 8300-8307, wherein the composition comprises a non-biodegradable polymer. The method of any of claims 8300-8307, wherein the composition comprises collagen. The method of any of claims 8300-8307, wherein the composition comprises methylated collagen. The method of any of claims 8300-8307, wherein the composition comprises fibrinogen. The method of any of claims 8300-8307, wherein the composition comprises thrombin. The method of any of claims 8300-8307, wherein the composition comprises a plasma component. The method of any of claims 8300-8307, wherein the composition comprises a calcium salt. The method of any of claims 8300-8307, wherein the composition comprises a fiber formation inhibitor. The method of any of claims 8300-8307, wherein the composition comprises a fibrinogen analog. The method of any of claims 8300-8307, wherein the composition comprises albumin. The method of any of claims 8300-8307, wherein the composition comprises plasminogen. The method of any of claims 8300-8307, wherein the composition comprises von Willebrand factor. The method of any of claims 8300-8307, wherein the composition comprises Factor VIII. The method of any of claims 8300-8307, wherein the composition comprises hypoallergenic collagen. The method of any of claims 8300-8307, wherein the composition comprises atelopeptide collagen. The method of any of claims 8300-8307, wherein the composition comprises telopeptide collagen. The method of any of claims 8300-8307, wherein the composition comprises cross-linked collagen. The method of any of claims 8300-8307, wherein the composition comprises aprotinin. The method of any of claims 8300-8307, wherein the composition comprises epsilon amino-n-caproic acid. The method of any of claims 8300-8307, wherein the composition comprises gelatin. The method of any of claims 8300-8307, wherein the composition comprises a protein conjugate. The method of any of claims 8300-8307, wherein the composition comprises a gelatin conjugate. The method of any of claims 8300-8307, wherein the composition comprises a synthetic polymer. The method of any of claims 8300-8307, wherein the composition comprises a compound comprising synthetic isocyanate. The method of any of claims 8300-8307, wherein the composition comprises a compound comprising a synthetic thiol. The method of any of claims 8300-8307, wherein the composition comprises a synthetic compound with two or more thiol groups. The method of any of claims 8300-8307, wherein the composition comprises a synthetic compound having three or more thiol groups. The method of any of claims 8300-8307, wherein the composition comprises a synthetic compound having four or more thiol groups. The method of any of claims 8300-8307, wherein the composition comprises a compound comprising synthetic amino. The method of any of claims 8300-8307, wherein the composition comprises a synthetic compound with two or more amino groups. The method of any of claims 8300-8307, wherein the composition comprises a synthetic compound with three or more amino groups. The method of any of claims 8300-8307, wherein the composition comprises a synthetic compound having four or more amino groups. The method of any of claims 8300-8307, wherein the composition comprises a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The method of any of claims 8300-8307, wherein the composition comprises a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The method of any of claims 8300-8307, wherein the composition comprises a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. The method of any of claims 8300-8307, wherein the composition comprises a synthetic compound comprising four or more carbonyl-oxygen-succinimidyl groups. The method of any of claims 8300-8307, wherein the composition comprises a compound comprising a synthetic polyalkylene oxide. The method of any of claims 8300-8307, wherein the composition comprises a synthetic compound comprising both a polyalkylene oxide and a biodegradable polyester block. The method of any of claims 8300-8307, wherein the composition comprises a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The method of any of claims 8300-8307, wherein the composition comprises a compound comprising a synthetic polyalkylene oxide having a thiol reactive group. The method of any of claims 8300-8307, wherein the composition comprises a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The method of any of claims 8300-8307, wherein the composition comprises a synthetic compound comprising a biodegradable polyester block. The method of any of claims 8300-8307, wherein the composition is formed in whole or in part from a synthetic polymer consisting of lactic acid or lactide. The method of any of claims 8300-8307, wherein the composition is formed from a synthetic polymer, wholly or partly consisting of glycolic acid or glycolide. The method of any of claims 8300-8307, wherein the composition comprises polylysine. The method of any of claims 8300-8307, wherein the composition is formed from (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The method of any of claims 8300-8307, wherein the composition comprises (a) a protein and (b) polylysine. The method of any of claims 8300-8307, wherein the composition is formed from (a) a protein and (b) a compound comprising 4 or more thiol groups. The method of any of claims 8300-8307, wherein the composition comprises (a) a protein and (b) four or more amino groups. The method of any of claims 8300-8307, wherein the composition comprises (a) a protein and (b) four or more carbonyl-oxygen-succinimide groups. The composition is formed from a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. Any way out. The method of any of claims 8300-8307, wherein the composition is formed from a compound comprising (a) collagen and (b) an oxidized polyalkylene moiety. The method of any of claims 8300-8307, wherein the composition comprises (a) collagen and (b) polylysine. The method of any of claims 8300-8307, wherein the composition is formed from (a) collagen and (b) a compound comprising 4 or more thiol groups. The method of any of claims 8300-8307, wherein the composition is formed from (a) collagen and (b) a compound comprising 4 or more amino groups. The method of any of claims 8300-8307, wherein the composition is formed from (a) collagen and (b) a compound comprising four or more carbonyl-oxygen-succinimide groups. The composition is formed from a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. Any way out. The method of any of claims 8300-8307, wherein the composition is formed from a compound comprising (a) methylated collagen and (b) an oxidized polyalkylene moiety. The method of any of claims 8300-8307, wherein the composition comprises (a) methylated collagen and (b) polylysine. The method of any of claims 8300-8307, wherein the composition is formed from (a) methylated collagen and (b) a compound comprising 4 or more thiol groups. The method of any of claims 8300-8307, wherein the composition is formed from (a) methylated collagen and (b) a compound comprising 4 or more amino groups. The method of any of claims 8300-8307, wherein the composition comprises (a) methylated collagen and (b) four or more carbonyl-oxygen-succinimide groups. The composition is formed from a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. Any method of ~ 8307. The method of any of claims 8300-8307, wherein the composition comprises hyaluronic acid. The method of any of claims 8300-8307, wherein the composition comprises a hyaluronic acid analog. The method of any of claims 8300-8307, wherein the composition is formed from pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The method of any of claims 8300-8307, wherein the composition is formed from pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A composition having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000 The method of any of claims 8300-8307, formed from a synthetic compound comprising a region and a plurality of electrophilic groups. The method of any of claims 8300-8307, wherein the composition includes a colorant. The method of any of claims 8300-8307, wherein the composition is sterile. A composition comprising i) a fiber formation inhibitor and ii) a polymer or a compound that forms a polymer in situ. The composition of claim 8541, wherein cell regeneration is inhibited by a fiber formation inhibitor. The composition of claim 8541 wherein angiogenesis is inhibited by a fiber formation inhibitor. The composition of claim 8541, wherein fibroblast migration is inhibited by a fibrosis inhibitor. The composition of claim 8541, wherein fibroblast proliferation is inhibited by a fibrosis inhibitor. The composition of claim 8541, wherein the fiber formation inhibitor inhibits extracellular matrix accumulation. The composition of claim 8541 wherein the fiber formation inhibitor inhibits tissue remodeling. The composition of claim 8541 wherein the fiber formation inhibitor is an angiogenesis inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is a 5- lipoxygenase inhibitor or antagonist. The composition of claim 8541 wherein the fiber formation inhibitor is a chemokine receptor antagonist. The composition of claim 8541 wherein the fiber formation inhibitor is a cell cycle inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is a taxane. The composition of claim 8541 wherein the fiber formation inhibitor is a microtubule inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is paclitaxel. The composition of claim 8541 wherein the fiber formation inhibitor is not paclitaxel. The composition of claim 8541 wherein the fiber formation inhibitor is an analogue or derivative of paclitaxel. The composition of claim 8541 wherein the fiber formation inhibitor is a vinca alkaloid. The composition of claim 8541 wherein the fibrosis inhibitor is camptothecin or an analogue or derivative thereof. The composition of claim 8541 wherein the fiber formation inhibitor is podophyllotoxin. The composition of claim 8541 wherein the fiber formation inhibitor is podophyllotoxin, wherein the podophyllotoxin is etoposide or an analogue or derivative thereof. The composition of claim 8541 wherein the fiber formation inhibitor is an anthracycline. The composition of claim 8541 wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is doxorubicin or an analogue or derivative thereof. The composition of claim 8541 wherein the fiber formation inhibitor is an anthracycline, wherein the anthracycline is mitoxantrone or an analogue or derivative thereof. The composition of claim 8541 wherein the fiber formation inhibitor is a platinum compound. The composition of claim 8541 wherein the fiber formation inhibitor is nitrosourea. The composition of claim 8541 wherein the fiber formation inhibitor is nitroimidazole. The composition of claim 8541 wherein the fiber formation inhibitor is a folic acid antagonist. The composition of claim 8541 wherein the fiber formation inhibitor is a cytidine analogue. The composition of claim 8541 wherein the fiber formation inhibitor is a pyrimidine analogue. The composition of claim 8541 wherein the fiber formation inhibitor is a fluoropyrimidine analogue. The composition of claim 8541 wherein the fiber formation inhibitor is a purine analogue. The composition of claim 8541 wherein the fiber formation inhibitor is nitrogen mustard or an analogue or derivative thereof. The composition of claim 8541 wherein the fiber formation inhibitor is hydroxyurea. The composition of claim 8541 wherein the fibrosis inhibitor is mitomycin or an analogue or derivative thereof. The composition of claim 8541 wherein the fiber formation inhibitor is an alkyl sulfonate. The composition of claim 8541 wherein the fiber formation inhibitor is benzamide or an analogue or derivative thereof. The composition of claim 8541 wherein the fiber formation inhibitor is nicotinamide or an analogue or derivative thereof. The composition of claim 8541 wherein the fiber formation inhibitor is a halogenated sugar or an analogue or derivative thereof. The composition of claim 8541 wherein the fiber formation inhibitor is a DNA alkylating agent. The composition of claim 8541 wherein the fiber formation inhibitor is a microtubule inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is a topoisomerase inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is a DNA cleaving agent. The composition of claim 8541 wherein the fiber formation inhibitor is an antimetabolite. The composition of claim 8541 wherein adenosine deaminase is inhibited by a fiber formation inhibitor. The composition of claim 8541, wherein purine ring synthesis is inhibited by a fiber formation inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is a nucleotide exchange inhibitor. The composition of claim 8541 wherein the formation of dihydrofolic acid is inhibited by a fiber formation inhibitor. The composition of claim 8541 wherein thymidine monophosphate is inhibited by a fiber formation inhibitor. The composition of claim 8541, wherein DNA damage is caused by a fiber formation inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is a DNA intercalation agent. The composition of claim 8541 wherein the fiber formation inhibitor is an RNA synthesis inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is a pyrimidine synthesis inhibitor. The composition of claim 8541 wherein ribonucleotide synthesis or function is inhibited by a fiber formation inhibitor. The composition of claim 8541 wherein the fibrosis inhibitor inhibits thymidine monophosphate synthesis or function. The composition of claim 8541, wherein DNA synthesis is inhibited by a fiber formation inhibitor. The composition of claim 8541, wherein DNA adduct formation occurs with the fiber formation inhibitor. The composition of claim 8541, wherein protein synthesis is inhibited by a fiber formation inhibitor. The composition of claim 8541 wherein microtubule function is inhibited by a fiber formation inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is a cyclin dependent protein kinase inhibitor. The composition of claim 8541 wherein the fibrosis inhibitor is an epidermal growth factor kinase inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is an elastase inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is a factor Xa inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is a farnesyl transferase inhibitor. The composition of claim 8541 wherein the fibrosis inhibitor is a fibrinogen antagonist. The composition of claim 8541 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The composition of claim 8541 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist. The composition of claim 8541 wherein the fibrosis inhibitor is a heat shock protein 90 antagonist, and the heat shock protein 90 antagonist is geldanamycin or an analogue or derivative thereof. The composition of claim 8541 wherein the fiber formation inhibitor is a guanylate cyclase stimulant. The composition of claim 8541 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is a HMGCoA reductase inhibitor, wherein the HMGCoA reductase inhibitor is simvastatin or an analogue or derivative thereof. The composition of claim 8541 wherein the fiber formation inhibitor is a hydroorotic acid dehydrogenase inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is an IKK2 inhibitor. The composition of claim 8541 wherein the fibrosis inhibitor is an IL-1 antagonist. The composition of claim 8541 wherein the fiber formation inhibitor is an ICE antagonist. The composition of claim 8541 wherein the fiber formation inhibitor is an IRAK antagonist. The composition of claim 8541 wherein the fibrosis inhibitor is an IL-4 agonist. The composition of claim 8541 wherein the fiber formation inhibitor is an immunomodulator. The composition of claim 8541 wherein the fibrosis inhibitor is sirolimus or an analogue or derivative thereof. The composition of claim 8541 wherein the fiber formation inhibitor is not sirolimus. The composition of claim 8541 wherein the fibrosis inhibitor is everolimus or an analogue or derivative thereof. The composition of claim 8541 wherein the fibrosis inhibitor is tacrolimus or an analogue or derivative thereof. The composition of claim 8541 wherein the fiber formation inhibitor is not tacrolimus. The composition of claim 8541 wherein the fibrosis inhibitor is biolimus or an analogue or derivative thereof. The composition of claim 8541 wherein the fibrosis inhibitor is tresperimus or an analogue or derivative thereof. The composition of claim 8541 wherein the fibrosis inhibitor is auranofin or an analogue or derivative thereof. The composition of claim 8541 wherein the fibrosis inhibitor is 27-0-demethylrapamycin or an analogue or derivative thereof. The composition of claim 8541 wherein the fibrosis inhibitor is gusperimus or an analogue or derivative thereof. The composition of claim 8541 wherein the fibrosis inhibitor is pimecrolimus or an analogue or derivative thereof. The composition of claim 8541 wherein the fiber formation inhibitor is ABT-578 or an analogue or derivative thereof. The composition of claim 8541 wherein the fiber formation inhibitor is an IMP dehydrogenase (IMPDH) inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is mycophenolic acid or an analogue or derivative thereof. The composition of claim 8541 wherein the fiber formation inhibitor is an IMPDH inhibitor, wherein the IMPDH inhibitor is 1 -α-25 dihydroxy vitamin D ₃ or an analogue or derivative thereof. The composition of claim 8541 wherein the fiber formation inhibitor is a leukotriene inhibitor. The composition of claim 8541 which is a fiber formation inhibitor MCP-1 antagonist. The composition of claim 8541 wherein the fiber formation inhibitor is an MMP inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is an NFκB inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is an NFκB inhibitor, wherein the NFκB inhibitor is Bay11-7082. The composition of claim 8541 wherein the fiber formation inhibitor is a NO antagonist. The composition of claim 8541 wherein the fiber formation inhibitor is a p38 MAP kinase inhibitor. The composition of claim 8541 wherein the fibrosis inhibitor is a p38 MAP kinase inhibitor, and the p38 MAP kinase inhibitor is SB202190. The composition of claim 8541 wherein the fiber formation inhibitor is a phosphodiesterase inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is a TGF beta inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is a thromboxane A2 antagonist. The composition of claim 8541 which is a fibrosis inhibitor TNFα antagonist. The composition of claim 8541 wherein the fiber formation inhibitor is a TACE inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is a tyrosine kinase inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is a vitronectin inhibitor. The composition of claim 8541 wherein the fibrosis inhibitor is a fibroblast growth factor inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is a protein kinase inhibitor. The composition of claim 8541 wherein the fibrosis inhibitor is a PDGF receptor kinase inhibitor. The composition of claim 8541 wherein the fibrosis inhibitor is an endothelial growth factor receptor kinase inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is a retinoic acid receptor antagonist. The composition of claim 8541 wherein the fibrosis inhibitor is a platelet derived growth factor receptor kinase inhibitor. The composition of claim 8541 wherein the fibrosis inhibitor is a fibrinogen antagonist. The composition of claim 8541 wherein the fiber formation inhibitor is an antifungal agent. The composition of claim 8541 wherein the fiber formation inhibitor is an antifungal agent, and the antifungal agent is sulconizole. The composition of claim 8541 wherein the fiber formation inhibitor is a bisphosphonate. The composition of claim 8541 wherein the fiber formation inhibitor is a phospholipase A1 inhibitor. The composition of claim 8541 wherein the fibrosis inhibitor is a histamine H1 / H2 / H3 receptor antagonist. The composition of claim 8541 wherein the fiber formation inhibitor is a macrolide antibiotic. The composition of claim 8541 wherein the fibrosis inhibitor is a GPIIb / IIIa receptor antagonist. The composition of claim 8541 wherein the fiber formation inhibitor is an endothelin receptor antagonist. The composition of claim 8541 wherein the fibrosis inhibitor is an agonist of peroxisome proliferator-activated receptor. The composition of claim 8541 wherein the fibrosis inhibitor is an estrogen receptor agent. The composition of claim 8541 wherein the fibrosis inhibitor is a somostatin analog. The composition of claim 8541 wherein the fiber formation inhibitor is a neurokinin 1 antagonist. The method of claim 8541 wherein the fiber formation inhibitor is a neurokinin 3 antagonist. The method of claim 8541 wherein the fibrosis inhibitor is a VLA-4 antagonist. The composition of claim 8541 wherein the fibrosis inhibitor is an osteoclast inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is a DNA topoisomerase ATP hydrolysis inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is an angiotensin I converting enzyme inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is an angiotensin II antagonist. The composition of claim 8541 wherein the fiber formation inhibitor is an enkephalinase inhibitor. The composition of claim 8541 wherein the fibrosis inhibitor is a peroxisome proliferator-activated receptor γ agonist insulin sensitizer. The composition of claim 8541 wherein the fiber formation inhibitor is a protein kinase C inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is a ROCK (Rho kinase) inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is a CXCR3 inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is an Itk inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is a cytoplasmic phospholipase A ₂ -α inhibitor. The composition of claim 8541 wherein the fibrosis inhibitor is a PPAR agonist. The composition of claim 8541 wherein the fiber formation inhibitor is an immunosuppressant. The composition of claim 8541 wherein the fiber formation inhibitor is an Erb inhibitor. The composition of claim 8541 wherein the fibrosis inhibitor is an apoptosis agonist. The composition of claim 8541 wherein the fibrosis inhibitor is a lipocortin agonist. The composition of claim 8541 which is a fibrosis inhibitor VCAM-1 antagonist. The composition of claim 8541 wherein the fiber formation inhibitor is a collagen antagonist. The composition of claim 8541 wherein the fiber formation inhibitor is an α2 integrin antagonist. The composition of claim 8541 which is a fiber formation inhibitor TNFα inhibitor. The composition of claim 8541 wherein the fiber formation inhibitor is a nitric oxide inhibitor The composition of claim 8541 wherein the fiber formation inhibitor is a cathepsin inhibitor. The composition of claim 8541 wherein the fibrosis inhibitor is an anti-inflammatory agent. The composition of claim 8541 wherein the fibrosis inhibitor is not a steroid. The composition of claim 8541 wherein the fiber formation inhibitor is not a glucocorticosteroid. The composition of claim 8541 wherein the fiber formation inhibitor is not dexamethasone. The composition of claim 8541 wherein the fiber formation inhibitor is not beclomethasone. The composition of claim 8541 wherein the fiber formation inhibitor is not dipropionic acid. The composition of claim 8541 wherein the fiber formation inhibitor is an anti-infective agent. The composition of claim 8541 wherein the fibrosis inhibitor is not an antibiotic. The composition of claim 8541 wherein the fiber formation inhibitor is not an antifungal agent. The composition of any of 8541-8699, wherein the polymer is crosslinked. The composition of any of 8541-8699, wherein the polymer reacts with mammalian tissue. The composition of any of claims 8541-8699 wherein the polymer is a naturally occurring polymer. The composition of any of 8541-8699 wherein the polymer is a protein. The composition of any of 8541-8699, wherein the polymer is a carbohydrate. The composition of any of claims 8541-8699 wherein the polymer is a biodegradable polymer. The composition of any of 8541-8699, wherein the polymer is crosslinked and biodegradable. The composition of any of claims 8541-8699 wherein the polymer is a non-biodegradable polymer. The composition of any of 8541-8699 wherein the polymer is collagen. The composition of any of 8541-8699 wherein the polymer is methylated collagen. The composition of any of 8541-8699, comprising fibrinogen. The composition of any of 8541-8699, comprising thrombin. The composition of any of 8541-8699, wherein a calcium salt is included. The composition of any of claims 8541-8699, comprising a fiber formation inhibitor. The composition of any one of claims 8541-8699 comprising a fibrinogen analog. The composition of any one of claims 8541-8699, comprising albumin. The composition of any of claims 8541-8699, comprising plasminogen. The composition of any of claims 8541-8699, comprising the von Willebrands factor. The composition of any of claims 8541-8699, comprising Factor VIII The composition of any of claims 8541-8699, comprising hypoallergenic collagen. The composition of any one of claims 8541-8699, comprising atelopeptide collagen. The composition of any one of claims 8541-8699, comprising telopeptide collagen. The composition of any one of claims 8541-8699, comprising cross-linked collagen. The composition of any of 8541-8699, comprising aprotinin. The composition of any of 8541-8699, comprising epsilon amino-n-caproic acid. The composition of any of 8541-8699, comprising gelatin. The composition of any of 8541-8699, comprising a protein conjugate. The composition of any of 8541-8699, wherein a gelatin conjugate is included. The composition of any of 8541-8699, comprising hyaluronic acid. The composition of any of 8541-8699, wherein a hyaluronic acid derivative is included. The composition of any of 8541-8699, comprising a synthetic polymer. The composition of any of claims 8541-8699, wherein the polymer is formed from a reactant comprising a compound comprising synthetic isocyanate. The composition of any of 8541-8699, comprising a compound comprising synthetic isocyanate. The composition of any of claims 8541-8699, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic thiol. The composition of any of 8541-8699, comprising a compound comprising a synthetic thiol. The composition of any of claims 8541-8699, wherein the polymer is formed from a reactant comprised of a synthetic compound containing two or more thiol groups. The composition of any of 8541-8699, comprising a synthetic compound having two or more thiol groups. The composition of any of claims 8541-8699, wherein the polymer is formed from a reactant that comprises a synthetic compound that includes three or more thiol groups. The composition of any of 8541-8699, comprising a synthetic compound having three or more thiol groups. The composition of any of claims 8541-8699, wherein the polymer is formed from a reactant that comprises a synthetic compound that includes four or more thiol groups. The composition of any of 8541-8699, comprising a synthetic compound having 4 or more thiol groups. The composition of any of claims 8541-8699, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic amino. The composition of any of 8541-8699, comprising a compound comprising a synthetic amino. The composition of any of claims 8541-8699, wherein the polymer is formed from a reactant comprising a synthetic compound containing two or more amino groups. The composition of any of 8541-8699, comprising a synthetic compound having two or more amino groups. The composition of any of claims 8541-8699, wherein the polymer is formed from a reactant comprising a synthetic compound containing three or more amino groups. The composition of any of 8541-8699, comprising a synthetic compound having three or more amino groups. The composition of any of claims 8541-8699, wherein the polymer is formed from a reactant comprised of a synthetic compound containing 4 or more amino groups. The composition of any of 8541-8699, comprising a synthetic compound having 4 or more amino groups. The composition of any of claims 8541-8699, wherein the polymer is formed from a reactant comprising a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The composition of any of claims 8541-8699 wherein there is a synthetic compound comprising a carbonyl-oxygen-succinimidyl group. The composition of any of 8541-8699, wherein the polymer is formed from a reactant comprising a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The composition of any of claims 8541-8699, wherein there is a synthetic compound comprising two or more carbonyl-oxygen-succinimidyl groups. The composition of any of claims 8541-8699, wherein the polymer is formed from a reactant comprising a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. The composition of any of claims 8541-8699 wherein there is a synthetic compound comprising three or more carbonyl-oxygen-succinimidyl groups. The composition of any of 8541-8699, wherein the polymer is formed from a reactant comprising a synthetic compound comprising four or more carbonyl-oxygen-succinimidyl groups. The composition of any of claims 8541-8699 wherein there is a synthetic compound containing 4 or more carbonyl-oxygen-succinimidyl groups. The composition of any of claims 8541-8699, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide. The composition of any of 8541-8699, comprising a compound comprising synthetic polyalkylene oxide. The composition of any of claims 8541-8699, wherein the polymer is formed from a synthetic reactant comprising a compound comprising a polyalkylene oxide and a biodegradable polyester block. The composition of any of claims 8541-8699 comprising a synthetic compound comprising both a polyalkylene oxide and a biodegradable polyester block. The composition of any of claims 8541-8699, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The composition of any of 8541-8699, comprising a compound comprising a synthetic polyalkylene oxide having an amino reactive group. The composition of any of claims 8541-8699, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a thiol reactive group. The composition of any of 8541-8699, comprising a compound comprising a synthetic polyalkylene oxide having a thiol reactive group. The composition of any of claims 8541-8699, wherein the polymer is formed from a reactant comprising a compound comprising a synthetic polyalkylene oxide having a sulfonyl-oxygen-succinimidyl reactive group. The composition of any of claims 8541-8699, comprising a compound comprising a synthetic polyalkylene oxide having a carbonyl-oxygen-succinimidyl reactive group. The composition of any of claims 8541-8699, wherein the polymer is formed from a synthetic reactant comprising a compound comprising a biodegradable polyester block. The composition of any of 8541-8699, comprising a synthetic compound comprising a biodegradable polyester block. The composition of any of claims 8541-8699, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly comprised of lactic acid or lactide. The composition of any of claims 8541-8699, formed in whole or in part from a synthetic polymer consisting of lactic acid or lactide. The composition of any of claims 8541-8699, wherein the polymer is formed from a reactant comprising a synthetic polymer, wholly or partly comprised of glycolic acid or glycolide. The composition of any of claims 8541-8699, formed in whole or in part from a synthetic polymer consisting of glycolic acid or glycolide. The composition of any of 8541-8699, wherein the polymer is formed from a reactant comprising polylysine. The composition of any of 8541-8699, comprising polylysine. The composition of any of 8541-8699, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The composition of any of 8541-8699 formed from (a) a protein and (b) a compound comprising an oxidized polyalkylene moiety. The composition of any of 8541-8699, wherein the polymer is formed from a reactant comprising (a) a protein and (b) polylysine. The composition of any of 8541-8699, comprising (a) a protein and (b) polylysine. The composition of any of 8541-8699, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more thiol groups. The composition of any of 8541-8699, comprising (a) a protein and (b) four or more thiol groups. The composition of any of claims 8541-8699, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more amino groups. The composition of any of claims 8541-8699 comprising (a) a protein and (b) four or more amino groups. The composition of any of claims 8541-8699, wherein the polymer is formed from a reactant comprising (a) a protein and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The composition of any of 8541-8699 comprising (a) a protein and (b) four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a reactant comprising a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. Any composition of ~ 8699. Any of the claims 8541-8699 formed from a compound with a biodegradable region formed from (a) a protein and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epsilon caprolactone. Composition. The composition of any of 8541-8699, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound comprising an oxidized polyalkylene moiety. The composition of any of 8541-8699 formed from (a) collagen and (b) a compound comprising an oxidized polyalkylene moiety. The composition of any of claims 8541-8699, wherein the polymer is formed from a reactant comprising (a) collagen and (b) polylysine. The composition of any of claims 8541-8699, comprising (a) collagen and (b) polylysine. The composition of any of claims 8541-8699, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more thiol groups. The composition of any of claims 8541-8699 comprising (a) collagen and (b) four or more thiol groups. The composition of any of claims 8541-8699, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more amino groups. The composition of any of claims 8541-8699 comprising (a) collagen and (b) four or more amino groups. The composition of any of claims 8541-8699, wherein the polymer is formed from a reactant comprising (a) collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The composition of any of 8541-8699 comprising (a) collagen and (b) four or more carbonyl-oxygen-succinimide groups. The polymer of claim 8541-8699, wherein the polymer is formed from a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. Any composition. Any of the claims 8541-8699 formed from a compound with a biodegradable region formed from (a) collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epsilon caprolactone. Composition. The composition of any of 8541-8699, wherein the polymer is formed from a reactant consisting of (a) methylated collagen and (b) a compound comprising an oxidized polyalkylene moiety. The composition of any of claims 8541-8699, formed from (a) methylated collagen and (b) a compound comprising an oxidized polyalkylene moiety. The composition of any of 8541-8699, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) polylysine. The composition of any of 8541-8699, comprising (a) methylated collagen and (b) polylysine. The composition of any of 8541-8699, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more thiol groups. The composition of any of 8541-8699 comprising (a) methylated collagen and (b) four or more thiol groups. The composition of any of 8541-8699, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more amino groups. The composition of any one of claims 8541-8699 comprising (a) methylated collagen and (b) four or more amino groups. The composition of any of claims 8541-8699, wherein the polymer is formed from a reactant comprising (a) methylated collagen and (b) a compound having four or more carbonyl-oxygen-succinimide groups. The composition of any of claims 8541-8699 comprising (a) methylated collagen and (b) four or more carbonyl-oxygen-succinimide groups. The polymer is formed from a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epison caprolactone. Any composition of 8699. The method of claim 8541-8699, formed from a compound with a biodegradable region formed from (a) methylated collagen and (b) a reactant selected from lactic acid, lactide, glycolic acid, glycolide and epsilon caprolactone. Any composition. The composition of any of 8541-8699, wherein the polymer is formed from a reactant comprising hyaluronic acid. The composition of any of claims 8541-8699, comprising hyaluronic acid. The composition of any of claims 8541-8699, wherein the polymer is formed from a reactant comprising a hyaluronic acid derivative. The composition of any one of claims 8541-8699, comprising a hyaluronic acid derivative. The composition of any of claims 8541-8699, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The composition of any of claims 8541-8699 formed from pentaerythritol poly (ethylene glycol) ether tetra-sulfhydryl having an average molecular weight between 3,000 and 30,000. The composition of any one of claims 8541-8699, wherein the polymer is formed from a reactant comprising pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. The composition of any of 8541-8699 formed from pentaerythritol poly (ethylene glycol) ether tetra-amino having an average molecular weight between 3,000 and 30,000. A polymer having (a) an average molecular weight between 3,000 and 30,000, a synthetic compound comprising an oxidized polyalkylene region and a plurality of nucleophilic groups, and (b) an average molecular weight between 3,000 and 30,000 and an oxidized polyalkylene region. The composition of any of claims 8541-8699, formed from a reactant comprising a synthetic compound comprising: and a plurality of electrophilic groups. (a) a synthetic compound having an average molecular weight of between 3,000 and 30,000, comprising a polyalkylene oxide region and a plurality of nucleophilic groups, and (b) an average molecular weight of between 3,000 and 30,000, having a polyalkylene oxide region and a plurality of The composition of any of 8541-8699 formed from a synthetic compound containing an electrophilic group. The composition of any of 8541-8699, wherein the composition includes a colorant. The composition of any of 8541-8699, wherein the composition is sterile.