EP1333869A2 - Composition de remplissage permettant l'augmentation de volume des tissus mous - Google Patents

Composition de remplissage permettant l'augmentation de volume des tissus mous

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Publication number
EP1333869A2
EP1333869A2 EP01996399A EP01996399A EP1333869A2 EP 1333869 A2 EP1333869 A2 EP 1333869A2 EP 01996399 A EP01996399 A EP 01996399A EP 01996399 A EP01996399 A EP 01996399A EP 1333869 A2 EP1333869 A2 EP 1333869A2
Authority
EP
European Patent Office
Prior art keywords
composition
salt
chitosan
phosphate
solution
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01996399A
Other languages
German (de)
English (en)
Inventor
Eric André DESROSIERS
Abdellatif Chenite
Cyril Chaput
Matthew Shive
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biosyntech Canada Inc
Original Assignee
Biosyntech Canada Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Biosyntech Canada Inc filed Critical Biosyntech Canada Inc
Publication of EP1333869A2 publication Critical patent/EP1333869A2/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/52—Hydrogels or hydrocolloids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/60—Sugars; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
    • A61K8/65—Collagen; Gelatin; Keratin; Derivatives or degradation products thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
    • A61K8/73—Polysaccharides
    • A61K8/736—Chitin; Chitosan; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
    • A61L24/04—Surgical adhesives or cements; Adhesives for colostomy devices containing macromolecular materials
    • A61L24/08—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L26/00—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form
    • A61L26/0009—Chemical aspects of, or use of materials for, wound dressings or bandages in liquid, gel or powder form containing macromolecular materials
    • A61L26/0023—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/20—Polysaccharides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/14—Macromolecular materials
    • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
    • A61L27/24—Collagen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
    • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/91—Injection

Definitions

  • the invention relates to a cosmetic composition for use as filler for soft tissue augmentation and reconstructive surgery, (b) Description of Prior Art
  • injectable materials have been used to fill out lines and creases caused by ageing, gravity and sun exposure.
  • Those materials for soft tissue augmentation can be categorized in relation to their origin: synthetic, xenogeneic, homogeneic and autogeneic, and subdivided according to their longevity in the patient as, temporary, undefined or permanent.
  • the oldest filler on the market, and still the most widely used filler is xenogeneic collagen (e.g. Zyderm & Zyplast, of bovine origin, from Collagen Corp. or the porcine Fibrel, from Mentor Corp.).
  • the effect of this filler is temporary. It disappears within a few months, depending on the patient and site of injection.
  • Microdispersions solid particles in a liquid have been proposed as injectables for soft-tissue repair and augmentation (Scopelianos et al. US5,599,852). They proposed a bioabsorbable microdispersion consisting of a liquid polymer comprising lactone units with a particulate component made of synthetic homopolymers. Soft-tissue repair and augmentation in animals was again described by Scopelianos et al. (US5, 824,333) who inject an injectable bioabsorbable liquid copolymer, generally copolymer of lactones such caprolactone, trimethyl carbonate, etc.
  • Soft-tissue augmentation of mammals can be augmented by injecting keratin into the soft-tissue such as the bladder or urethral tissue (Smith, US5.712,252).
  • Biocompatible ceramic microspheres in a lubricious gel carrier were also proposed by Hubbard (US5,922,025).
  • Other biodegradable and injectable microspheres were proposed as injectable for soft-tissues (WO99/11196).
  • One aim of the present invention is to provide an injectable filler composition that could provide a durable correction or augmentation, especially if it provides a substantial mechanical support or volume or thickness increase to the surrounding soft tissues.
  • Another aim of the present invention is to provide a method for filling out lines and creases caused by ageing, gravity and sun exposure.
  • a polysaccharide-based gel which comprises: a) 0.1 to 5.0% by weight of chitosan, collagen or a derivative thereof; and b) 1.0 to 20% by weight of a salt of polyol or sugar selected from the group consisting of mono- phosphate dibasic salt, mono-sulfate salt and a mono-carboxylic acid salt of polyol or sugar; wherein said solution is stable and turns into a gel within a temperature range from 20 to 70°C, said gel having a cosmetically acceptable consistency for providing a mechanical support to surrounding soft tissues once injected therein.
  • the salt may be any of the following or in any of the following combination: a) a mono-phosphate dibasic salt selected from the group consisting of glycerol, comprising glycerol-2-phosphate, sn-glycerol 3- phosphate and L-glycerol-3-phosphate salts; b) a mono-phosphate dibasic salt and said polyol is selected from the group consisting of histidinol, acetol, diethylstilbestrol, indole-glycerol, sorbitol, ribitol, xylitol, arabinitol, erythritol, inositol, mannitol, glucitol and a mixture thereof; c) a mono- phosphate dibasic salt and said sugar is selected from the group consisting of fructose, galactose, ribose, glucose, xylose, rhamnulose, sorbose
  • a preferred gel in accordance with one embodiment of the present invention is selected from the group consisting of chitosan- ⁇ - glycerophosphate, chitosan- ⁇ -glycerophosphate, chitosan-glucose-1 - glycerophosphate, and chitosan-fructose-6-glycerophosphate.
  • Solid particulates or water-soluble additives may be incorporated within said polysaccharide-based gel prior to the gelation.
  • Drugs, polypeptides or non-living pharmaceutical agents may be incorporated within said polysaccharide-based gel prior to the gelation.
  • Living microorganisms, plant cells, animal cells or human cells may be encapsulated within said polysaccharide-based gel prior to the gelation.
  • the gel may be formed in situ subcutaneously, intra-peritoneally, intramuscularly or within the substances of biological connective tissues, organ walls or parts, body conduits or cavities, eye cul-de-sac,etc.
  • a method for producing the composition described above which comprises the steps of: a) dissolving a chitosan, collagen or a derivative thereof within an aqueous acidic solution of a pH from about 2.0 to about 5.0 to obtain an aqueous solution having a concentration of 0.1 to 5.0% by weight of a chitosan, collagen of a derivative thereof; b) dissolving 1.0 to 20% by weight of a salt of polyol or sugar into the aqueous solution of step a) to obtain an injectable thermogelling solution, wherein said salt is selected from the group consisting of mono-phosphate dibasic salt, mono-sulfate salt and a mono-carboxylic acid salt, wherein said an injectable thermogelling solution has a concentration of 0.1 to 5.0% by weight of a chitosan, collagen or a derivative thereof, and a concentration of 1.0 to 20% by weight of a salt of a polyol or sugar, and has a pH from
  • This method may further comprises a step c) after step b), of heating said polysaccharide-based gel solution at a solidifying temperature ranging from about 20°C to about 80°C until formation of a polysaccharide gel.
  • a pharmaceutical agent may be added to the polysaccharide gel solution of step b).
  • the method may further comprises a step i) after step b), of dispensing for gelation the polysaccharide-based gel solution into a desired receiver, either in a mold or within a tissue, an organ or a body cavity.
  • the aqueous acidic solution may be prepared from at least one organic or inorganic acid selected from the group consisting of acetic acid, ascorbic acid, salicylic acid, phosphoric acid, hydrochloric acid, propionic acid, and formic acid.
  • the gelling point of the polysaccharide-based gel solution may be adjusted such that the polysaccharide-based gel solution may be kept in a stable ungelled liquid form at a temperature ranging from about 0°C to about 20°C.
  • the solidifying temperature is preferably ranging from about 20°C to about 60°C, more preferably about 37°C.
  • the molecular weight of chitosan is preferably ranging from about 10,000 to 2,000,000.
  • Solid particulate additives may be added to the polysaccharide- based gel solution of step b).
  • the polysaccharide-based gel solution may be introduced within an animal or human body by injection or endoscopic administration, and gelled in situ at a temperature of about 37°C.
  • the polysaccharide-based gel for producing biocompatible degradable materials used in cosmetics, pharmacology, medicine and/or surgery.
  • the gel may be incorporated as a whole, or as a component, into implantable devices or implants for repair, reconstruction and/or replacement of tissues and/or organs, either in animals or humans.
  • the gel may be used as a whole, or as a component of, implantable, transdermal or dermatological drug delivery systems.
  • the gel may be used as a whole, or as a component of implants or drug delivery systems.
  • the cosmetic or surgical composition defined above as filler for soft tissue augmentation and reconstructive surgery, or for producing biocompatible degradable materials.
  • the complementary polymer is a non-ionic water-soluble polysaccharide, a methylcellulose, a hydroxyalkyl cellulose, a poly(alkylene oxide) or a poly(alkylene glycol), or a derivative or a copolymer thereof.
  • polysaccharide-based gel solution is intended to mean a polysaccharide solution in a stable ungelled liquid form at a temperature ranging from about 0°C to about 15°C which can be gelled or changed to a gel state when heated at the gelling temperature.
  • gelling temperature is intended to mean any temperature ranging from about 20°C to about 80°C, preferably between 37°C to about 60°C, and more preferably at about the physiological temperature or 37°C.
  • salts of polvols or sugars is intended to mean mono-phosphate di-basic salts, mono-sulfate salts and mono-carboxylic acid salts of polyols or sugars.
  • the present invention include method of forming different gelled materials, those materials being either molded (customized shapes, tubes, membranes, films%) or formed in situ within biological environments (filling of tissue substances).
  • the chitosan/organo-phosphate aqueous solution has a pH above the pKa of chitosan and turn into solid gel upon thermal stimulation.
  • This polysaccharide gel can be used as a carrier for drugs or as a non-living therapeutics delivery systems, as substituting materials for tissues and organs and as encapsulants for living cells or microorganisms.
  • Chitosan/organo-phosphate gel matrices are rapidly formed at temperatures between 30 to 60°C.
  • Chitosan/organo- phosphate aqueous systems are used as injectable filling materials, injected and gelled in situ for filling and repairing tissue substances.
  • Glycerol-2-phosphate, glycerol-3-phosphate and glucose-1- phosphate based salts are the preferred disclosed salts in accordance with the present invention.
  • Chitosan/polyol- or sugar-phosphate and chitosan/polyol- or sugar-sulfate gels can be applied also to surgical reconstructive and regeneration uses and drug delivery purposes. They provide thermally reversible or irreversible bioerodible polymeric gels with biologically well- known and compatible components for a broad range of medical/biotechnological applications.
  • the composition comprises at least one fatty acid, that is selected preferably in a group consisting of palmitate, stearate, myristate, palmitoleate, oleate, vaccenate, linoleate, and the like, and their acyclic, cyclic, heterocyclic, aromatic ester derivatives containing at least one moiety selected from the group consisting of hydroxy, acyloxy, aryloxy, amino, sulfhydryl, sulfonate, sulfate, phosphonate, phosphate, bis-, tris- and poly- phosphonates and phosphates, phosphatidyl, nucleosides, oligosaccharides, polysaccharides, polyols, and the like.
  • the fatty acid is mixed with an appropriate metabolically absorbable liquid vehicle to reduce viscosity and allow injectability at room temperature.
  • the fatty acid solution may comprise a metabolically absorbable liquid vehicle selected in a group consisting of water, alcoholic solvent, alkylene glycol, poly-alcohol, and the like.
  • the metabolically absorbable liquid vehicle is preferably selected in a group consisting of ethanol, isopropyl alcohol, ethylene glycol, glycerol, and the like.
  • the solution comprises oleoate and palmitate.
  • the solution may be under gel or solid form at low to room temperatures, e.g. 20 degrees Celsius and below, but may become more or less viscous liquids at higher temperatures, e.g. above 35-40 degrees
  • Fig. 1 illustrates the tissue-bulking effect of a chitosan hydrogel filler formulation of the present invention, 6 months after sub-cutaneous injection in a human;
  • Fig. 2 illustrates the tissue-bulking effect of a fatty acid filler formulation of the present invention, 28 days after sub-cutaneous injection in a rat;
  • Figs. 3A to 3D illustrate histopathology images from BST- InPodTM injections in rats (Saffranin-O/Fast Green staining) from day 2 at 4X and 40X, (Figs. 3A and 3B, respectively), and from day 5 at 4X and 40X (Figs. 3C and 3D, respectively).
  • thermoforming chitosan-based and fatty acid-based solutions and uses thereof. Both compositions are easily injectable, gels in situ and provide substantial mechanical support to the surrounding soft tissues. The solution remains liquid during injection and gels after injection as it reaches body temperature.
  • thermo-gelling chitosan-based solution can be adjusted to be resistant to biodegradation so as to be effective for a long-term, or even permanent, correction, as desired.
  • This combination of characteristics makes possible the long-lasting smoothing of small wrinkles or the correction of pronounced defects.
  • the possibilities of this material fulfill the more demanding needs of reconstructive surgery, bridging the gap to a field that usually require surgically implanted polymeric forms.
  • thermo-gelling chitosan-based solution forms a gel that has mechanical properties compatible with the needs of both cosmetic and reconstructive surgery, if required, sufficiently soft for use in cosmetic surgery for correction of fine skin defects or sufficiently rigid for correction of large defects or use in reconstructive surgery.
  • Chitosan is dissolved in acidic aqueous solutions so as to obtain clear aqueous chitosan solutions having pH levels within the range 4.3 to 5.6.
  • the chitosan solutions can be sterilized through filtering or steam- autoclaving, and stored at low positive temperature (4°C).
  • the organo- phosphate component is added to the chitosan solution, preferably at low positive temperature (4°C), then the aqueous chitosan/organo-phosphate mixture is gelated thermally, through an endothermal mechanism, within the temperature range from 30 to 60°C. Once formed the resulting chitosan/organo-phosphate gels are thermally stable upon heating even up to 180°C (in autoclave), particularly in cell culture medium.
  • Bioencapsulation within chitosan/organo-phosphate gels is obtained by incorporating the living cells within the ungelated aqueous chitosan/organo-phosphate solution at a low temperature (4°C). Then the temperature of the resulting mixture chitosan/organo-phosphate/cells is raised to and maintained at 37°C where the gelation occurs in ⁇ 1 hour, organo-sulfates or mono-carboxylic acid salt of polyols or sugars play a similar role than organo-phosphates.
  • Chitosan and its derivatives are relatively inexpensive and commercially available materials and represent an attractive group of biocompatible and degradable polymers. They have solid or solution properties that can be modified by changing their chemical composition and/or physico-chemical characteristics. The deacetylation degree and molecular weight have been shown to greatly influence the solution properties, enzymatic degradability and biological activity. Chemical modifications, for instance, have been proposed to neutralize or modify chitosan chains by incorporating carboxylic acid, acetate, glutamic acid, carboxymethyl or sulfate groups. Chemical cross-linking (anhydride, glutaraldehyde, glutamate succinimide-PEG%) of chitosan macromolecules induces covalent bonds to create branched or grafted networks.
  • chitosan and its derivatives can be obtained through different techniques: a) neutralization (NaOH, KOH, NH 4 OH...) which induces hydrogen bonding between chitosan chains; b) ionic complexation with divalent anions (borate, molybdate, polyphosphate, sulfate salts and sulphated macromolecules.%) which induces pure electrostatic interactions; and c) complexation with anionic surfactants (sodium alkyl sulfate%), which induces electrostatic interactions and surfactant-surfactant hydrophobic interactions.
  • neutralization NaOH, KOH, NH 4 OH
  • divalent anions borate, molybdate, polyphosphate, sulfate salts and sulphated macromolecules.
  • anionic surfactants sodium alkyl sulfate
  • Polyols are frequently added to compositions for improving gel properties. Sorbitol and mannitol are currently used as tonicity enhancing agents. Glycerol and polyethylene glycol are proposed as plasticizers. Polyols (-ol: glycerol, sorbitol%) and sugars (-ose: fructose, glucose, galactose%) were used as thermal stabilizing agents for proteins in solutions. Depending on the selected molecules, they were found to make or break structuring of water, create hydrogen bonding, electrostatic or hydrophobic interacting, and present endothermic transitions (. Polyols and sugars stabilize proteins to heat denaturation through their structuring effect on water and the strengthen of hydrophobic interactions.
  • Beta-glycerophosphate disodium or calcium salt, or glycerol-2- phosphate disodium or calcium salt is a well studied molecule in biological sciences. It is considered as a substrate for alkaline phosphatase (AL).
  • glycerophosphate is widely used as a cell culture medium supplement for culturing cells isolated from musculo-skeletal tissues, and has been shown to induce or maintain the synthesis of specific matrix components when delivered to bone/cartilage cells in culture. Gelation of chitosan will occur with any grade or purity glycerophosphate while encapsulation of living biologicals would require cell culture tested glycerophosphate.
  • Alpha- glycerophosphate disodium or calcium salt, or glycerol-3-phosphate disodium or calcium salt is also an organic salt of biological importance.
  • Glycerophosphate salts are precipitated from glycerophosphoric acids that are obtained through the hydrolysis of lecithin, a well-know biological molecule and phosphatides of eggs, soybean and fishes.
  • Glycerophosphoric acids are present under two isomeric structures, the alpha and beta, wherein the beta-glycerophosphoric acid is optically inactive and the alpha-glycerophosphoric acid is optically active.
  • Glycerophosphoric acid is physiologically active compound, being involves in the catabolism of carbohydrates.
  • Glycerophosphoric acid is currently available under disodium, calcium, magnesium, dipotassium, strontium and barium salts, having a relatively strong basic character. Both alpha- and beta-glycerophosphate salts are inexpensive readily available sources of organic mono-phosphate dibasic salts among the polyol or sugar phosphate salts.
  • Solubilization of chitosan in aqueous solutions requires the protonation of the amine groups of the chitosan chains, which is reached within acidic aqueous solutions having a pH ranging from 3.0 to 5.0. When solubilized, chitosan remains soluble until a pH about 6.2. Neutralization of acidic chitosan solutions by alkali results in a pH increase as well as a de- protonation of the amine groups.
  • This neo-neutral chitosan/organo-phosphate aqueous solutions (pH 6.5-7.2) will gel when stimulated by an adequate temperature.
  • the time of gelation is controlled by the temperature. For example, a chitosan/organo-phosphate solution that gelates in about 30 minutes at 37°C, needs only about 2 minutes at 60°C to form a gel.
  • the mechanism of gelation as well as the gel characteristics has been expected to be similar for all chitosan/organo-phosphate systems.
  • the gelation of chitosan/ ⁇ -glycerophosphate solutions which has been investigated in more details, can be considered as typical example.
  • Another important characteristic is related to the injectability and in vivo gelation of chitosan/ ⁇ -glycerophosphate solutions.
  • organo-phosphate anions contribute to the cross-linking of chitosan macromolecule chains, but not in the same way as the pure ionic cross-linking that takes place during the gelation of chitosan by inorganic divalent anions, such as sulfate, oxalate, phosphate or polyphosphate (pyrophosphates, metaphosphates or tripolyphosphates).
  • inorganic divalent anions such as sulfate, oxalate, phosphate or polyphosphate (pyrophosphates, metaphosphates or tripolyphosphates).
  • a chitosan aqueous solution turns into gel instantaneously in presence of inorganic divalent anions and independently of the solution pH value. Furthermore, the elevation of temperature constitutes an unfavorable factor for the gelation of this kind of systems.
  • the gelation of chitosan/organo-phosphate solution depends on both, the final pH of chitosan/organo-phosphate solution and the temperature. Every solution of chitosan/organo-phosphate can not be gelled, at any temperature, as long as its pH remains below 6.45, and every solution of chitosan/organo-phosphate with pH above 6.45 can be prepared at 20°C, without immediate gellation and can be stored for long time at 4°C without turning to gel. At 37°C only the chitosan/organo-phosphate solutions with pH above 6.9 can be gelled more or less rapidly.
  • organo-phosphate molecules in chitosan solutions directly affects electrostatic interactions, hydrophobic interactions and hydrogen bonds of chitosan chains.
  • the main interactions involved in the formation of chitosan/organo-phosphate gels become essentially: 1) chitosan/chitosan interchain hydrogen bonding; 2) chitosan/organo-phosphate electrostatic attractions between the ammonium groups of macromolecule chains and the phosphate group of organo-phosphate molecules; 3) chitosan-chitosan hydrophobic interactions induced through the structuring action of the polyol or sugar parts on water molecules.
  • the structuring action of the polyol parts on water reduces the chitosan-water interactions and therefore enhances the chitosan-chitosan interactions.
  • the nontrivial aspect of such a gelation originates essentially from the later polyol-water induced chitosan hydrophobic attractions, which are enhanced upon increasing temperature (temperature-controlled gelation).
  • chitosan-water strong interactions protect the hydrated chitosan macromolecules against aggregations. Removal upon heating of the sheath of water molecules favors and strengthens chitosan- chitosan interactions, and hence induces the macromolecules association.
  • the gelation would never occur if the two first attractions are fully unoperational within the chitosan/organo-phosphate solution. This explains the pH-dependence that still governs the temperature-controlled gelation of chitosan/organo-phosphate systems. Although such electrostatic attractions are present, the phosphate groups can not be the unique cross- linker agent of chitosan chains due to non-compatible stearic hindrance. This significantly differentiates this gelation mechanism from the pure ionic gelation of chitosan by phosphates or polyphosphates divalent anions. A pure ionic cross-linking would not be temperature-controlled or stimulated.
  • This type of temperature-controlled pH-dependant gelation is specifically induced by organic mono-phosphate dibasic salt in chitosan solution, however it may be induced as well by other organic salts such as mono-sulfate salts of polyols or sugars, such as polyol-sulfate or sugar- sulfate, or mono-carboxylic acid salts of polyols or sugars.
  • organic mono-phosphate dibasic salt in chitosan solution may be induced as well by other organic salts such as mono-sulfate salts of polyols or sugars, such as polyol-sulfate or sugar- sulfate, or mono-carboxylic acid salts of polyols or sugars.
  • a chitosan/glucose-1 -sulfate solution is expected to gel so as a chitosan/glucose-1 -phosphate solution does.
  • aqueous chitosan/organo-phosphate solution that can be formed and stored at low temperature (4°C) and transformed at physiological temperatures into three-dimensional stable chitosan/organo-phosphate gel. It includes nontoxic biocompatible components for mammalian or human environments with both components and processes having low toxicity effects towards living biologicals and preserving the cellular viability.
  • the gel also provides good mechanical/ handling performances for long periods of time at the physiological temperature and in physiological aqueous media containing amino-acid, ions and proteins.
  • Chitosan derivatives may be selected as well as to process chitosan/organo- phosphate gels, and comprise N,O-substituents of chitosan.
  • organo-phosphates (salt) refers herein, without limitation, to mono-phosphate dibasic salts of polyols or sugars, such as polyol-phosphate dibasic salts or sugar-phosphate dibasic salts.
  • Organo- sulfates (salt) also refer herein to mono-sulfate salts of polyols or sugars, such as polyol-sulfate salts or sugar-sulfate salts.
  • the preferred organo- phosphate salts may be selected from mono-phosphate dibasic salts of glycerol, including glycerol-2-phosphate, sn-glycerol 3-phosphate and I- glycerol-3-phosphate salts (alpha-glycerophosphate or beta- glycerophosphate), mono-phosphate dibasic salts of histidinol, acetol, d iethylstil bestrol , indoleglycerol, sorbitol, ribitol, xylitol, arabinitol, erythritol, inositol, mannitol, glucitol, palmitoyl-glycerol, linoleoyl-glycerol, oleoyl- glycerol or arachidonoyl-glycerol, and mono-phosphate dibasic salts of fructose, galactose,
  • glycophosphate or glycerophosphate refers herein to both alpha-glycerophosphate and beta-glycerophosphate isomers.
  • Alpha-glycerophosphate is indistinctively referred for glycerol-3- phosphate (all optical eniantomers) while beta-glycerophosphate is similarly referred for glycerol-2-phosphate.
  • three-dimensional refers herein to the fact that the polymeric solution is simultaneously gelated and shaped by the mold wherein the solution was initially poured. Gels can be produced in glass or plastic bechers, dishes, tubes or between two plates so as to obtain any expected shapes.
  • in situ gelation refers herein to the formation of chitosan/organo-phosphate gels by injecting the liquid chitosan/glycerophosphate solution within specific sites of mammalian or human environments, e.g. any tissues (muscles, bone, ligaments, cartilages) and organs. Gelation in situ allows complete and precise filling of tissue defects or body cavities. The gelation of the chitosan/organo- phosphate mixture is induced by the physiological temperature. Gelling and gelation are used herein without any distinction.
  • endothermal gelation refers herein to the thermal mechanism of the chitosan/organo-phosphate solution that enables the solution to gelate upon standing at the desired temperature. Induction of sol to gel transitions of chitosan/organo-phosphate systems requires energy via, for example, the temperature.
  • cells or cellular matters refers herein to living biologicals, such as isolated cells, cellular dispersion, cell aggregates, cell spheroids or cells adhered to solid microspheres particles, that are encapsulated within the chitosan/organo-phosphate gels.
  • in situ forming refers herein to the procedure of administrating the ungelated chitosan/organo-phosphate liquid solution to a body site (e.g. connective tissues, body conduits, articular cavities, fractures, bone defects)., and inducing and ensuring within the body site at the physiological temperature a complete gelation of the polysaccharide solution into a gel.
  • the selected organo-phosphate salt was herein glycerophosphate, but similar results were reached with other mono- phosphate dibasic salts of polyols or Sugars.
  • Chitosan in powder form is dissolved in an aqueous acidic solution until the occurrence of a clear solution is obtained.
  • the proportion of chitosan varies from 0.5 to 5.0% w/v, preferentially from 1.0 to 3.0% w/v.
  • the pH of the aqueous chitosan solution ranges from 4.5 to 5.5.
  • Aqueous chitosan solutions can be sterilized either by filtration with in-line sterile filters (0.22 micrometer) or by steam-autoclaving (120°C).
  • Sterilization of the chitosan/glycerophosphate gels can not be filtered due to the viscosity or steam-autoclaved due to the thermal sensitivity, but can be performed by gamma-irradiation or reached through strictly sterile procedures.
  • Freshly-prepared aqueous chitosan solutions are stored preferably at low positive temperature (4°C).
  • Glycerophosphate felt in fine powder form is added to, and dissolved within, the aqueous chitosan solution at a temperatures ranging from 4 to 15°C, preferentially 10°C.
  • the chitosan/glycerophosphate solutions are expected to lead either to thermally reversible or irreversible gel.
  • Reversible gels arise from chitosan/glycerophosphate solutions having a pH comprising between 6.5 and 6.9, while the irreversible gels originate from chitosan/glycerophosphate solutions having a pH above 6.9.
  • the nature of the acid that is used for the acidic chitosan solutions does not influence fundamentally the sol to gel transition of the chitosan/glycerophosphate system.
  • the final pH within a chitosan/ glycerophosphate solution is dependent upon the pH of the water/acid solution as well as the chitosan and glycerophosphate concentrations.
  • chitosan and glycerophosphate are two alkaline components, they tend to increase the pH of the acidic solution wherein they are dissolved. Concentrations in chitosan and glycerophosphate can be balanced to reach the appropriate pH of the chitosan/glycerophosphate solution, while taking into consideration the solubility limit of both components, and particularly the one of chitosan.
  • the selected organo-phosphate salt was herein glycerophosphate, but similar results were reached with other mono- phosphate dibasic salts, monosulfate salts or monocarboxylate salts of polyols or sugars.
  • the receiver or mold filled with chitosan/ glycerophosphate solution is heated at a temperature ranging from 30 to 60°C, preferentially 37°C.
  • the gelation of chitosan/glycerophosphate solution at 37°C can be performed within a common cell culture incubator.
  • the solution is maintained at the desired temperature until it turns into a gel after a period that ranges from some days to a week (at 30°C) to few minutes (at 60°C).
  • the gelation of chitosan/glycerophosphate solution occurs in 1 hour approximately. Once a three-dimensional chitosan/glycerophosphate gel is formed, the said gel is demolded and washed in distilled water. Chitosan/glycerophosphate gels remain stable and keep their three-dimensional shape even at high temperature, 120°C (in autoclave).
  • Chitosan/glycerophosphate based compositions may also comprise additional water-soluble ingredients.
  • the said Chitosan/glycerophosphate solution may comprise an additional polymer selected in a group consisting of cellulose, methyl cellulose and derivatives, hydroxyalkyl cellulose and derivatives, water-soluble vinyl polymers, poly(alkylene glycol) and copolymers, poly(alkylene oxide) and copolymers, mono-functional poly(ethylene glycol), and any mixture thereof.
  • This novel polymer component may significantly change some composition properties, but does not alter its "gel forming capacity".
  • compositions may comprise additionally a water-soluble chemical agent having a pKa between 6.0 and 8.2 such as a water soluble inorganic salts, and preferably dibasic salts, and for example water-soluble dibasic phosphate, sulfate or carbonate salts. It may also be a biological buffer such as a organic salt or an amino-acid, or a sequence of amino- acids. In situ formation of gels
  • the selected organo-phosphate salt was herein glycerophosphate, but similar results were reached with other mono- phosphate dibasic salts, monosulfate salts or monocarboxylate salts of polyols or sugars.
  • In situ gelation of the chitosan/glycerophosphate solution can be conducted by dispensing the solution from a hypodermic syringe. If needed, the solution may be pre-gelated (initiate the thermal gelation) by keeping the syringe and chitosan/glycerophosphate solution at desired temperature, ideally 37°C, until the first signs of gelation appear.
  • the ready-to-gel chitosan/glycerophosphate mixture is then administrated so as to fill tissue defects or cavities and complete in situ the gelation process (at 37°C). Injection of chitosan/glycerophosphate solutions is however limited by the viscosity of the solutions, which controls the injectability, or extrudability of the solutions.
  • the filler composition may be composed of a fatty acid mixtures.
  • the said composition comprises one or more natural or unnatural saturated and mono- or poly- unsaturated fatty acids, that are selected preferably in a group comprising palmitate, stearate, myristate, palmitoleate, oleate, vaccenate, linoleate, and the like, and their acyclic, cyclic, heterocyclic, aromatic ester derivatives containing one or more groups such as hydroxy, acyloxy, aryloxy, amino, sulfhydryl, sulfonate, sulfate, phosphonate, phosphate, bis- , tris- and poly- phosphonates and phosphates, phosphatidyl, nucleosides, oligo-saccharides, polysaccharides, polyols, and the like, and a mixture thereof.
  • the said fatty acid component is mixed with an appropriate metabolically absorbable liquid vehicle to reduce viscosity and allow injectability at room temperature.
  • the fatty acid solution may comprise a metabolically absorbable liquid vehicle selected in a group comprising water, alcoholic solvents, alkylene glycols, poly-alcohols, and the like.
  • the metabolically absorbable liquid vehicle is preferably selected in a group comprising ethanol, isopropyl alcohol, ethylene glycol, glycerol, and the like, and any mixture thereof.
  • the said solution comprises oleoate and palmitate.
  • the said solution may be under gel or solid form at low to room temperatures, e.g. 20 degrees Celsius and below, but may become more or less viscous liquids at higher temperatures, e.g. above 35-40 degrees Celsius.
  • a method of treating urinary incontinence comprising the step of injecting the said filler composition into the area of the urethral sphincter, said composition having a bulking action into said sphincter.
  • a method of breast augmentation comprises the step of injecting the said filler composition into the breast, said composition being use to increase the tissue volume.
  • a method of cosmetic treatment of wrinkles comprises the step of injecting the said filler composition into the soft tissue in or around the face, said composition having a cosmetically acceptable consistency for providing a mechanical support or a volume or thickness increase to surrounding soft tissues.
  • a method of load bearing tissue augmentation comprises the step of injecting the said filler composition between said load bearing tissue and a load-exerting medium.
  • a method of treating acne scars or viral pock marks comprises the step of injecting the said filler composition into the soft tissue underlying said scar or pock mark.
  • a method of changing the contours of a nose comprises the step of injecting the said filler composition into the soft tissue of the nose.
  • a method of augmenting the volume or thickness of soft-tissues comprising the step of injecting the said filler composition into the soft tissue substance.
  • a method of operating plastic corrections can comprise the step of injecting the said filler composition into soft tissue substances or tissue cavities to create plastic corrections.
  • a method of operating reconstructive or restorative surgeries can comprise the step of injecting the said filler composition into soft tissue substances, body cavities or conduits, organ walls or parts to create a reconstructive or restorative action.
  • the filler compositions is generally injected through an orifice of gauge number above 13, more preferably a gauge number above 22. They are injected through a needle, catheter or trocar. Such compositions can be injected during the course of an endoscopic procedure, or percutaneously.
  • the filler compositions can be composition is prepared by preheating at a temperature between 20 and 45°C before injection.
  • the filler compositions can be stored and supplied in a sealed vial or bottle, or in a closed hypodermic syringe. These compositions can be a part of, or incorporated in, a soft- tissue augmentation kit devoted to healthcare professionals.
  • the filler compositions can be stored under specific conditions, such as at a temperature below 5°C before being used, and even solid frozen before being used.
  • specific conditions such as at a temperature below 5°C before being used, and even solid frozen before being used.
  • Typical experiment was carried out by dissolving 0.2 g of chitosan in 10 ml of aqueous acetic acid solution (0.1M).
  • the pH of the acetic acid solution has been beforehand adjusted to 4.0 by adding droplets of potassium hydroxide solution (1 M).
  • the 2% (w/v) chitosan solution so obtained had a pH of about 5.6.
  • 0.800 g of glycerophosphate disodium salt pentahydrate were added to and dissolved in the chitosan solution at 10°C.
  • the pH of the resulting homogeneous liquid mixture becomes 7. This mixture was disposed in a glass scintillation vial in the incubator at 37°C for 2 hours, enough time to achieve bulk- gelation process.
  • the resulting bulk gel was immersed in renewed baths of distilled water in order to remove the excess of glycerophosphate salt.
  • a homogenized chitosan/glycerophosphate solution was prepared as in Experiment 1 and disposed in a dual gel caster having a glass plates gel sandwich with a 1.6 mm interspaces, and the system was kept in an oven at 37°C. The formation of a gel membrane was reached within 2 hours and the membrane was unmolded from the gel caster.
  • Experiment 3 A homogenized chitosan/glycerophosphate solution was prepared as in Experiment 1 and disposed in a dual gel caster having a glass plates gel sandwich with a 1.6 mm interspaces, and the system was kept in an oven at 37°C. The formation of a gel membrane was reached within 2 hours and the membrane was unmolded from the gel caster.
  • a 0.110 g of fumed silica under solid particle form was dispersed within a solution prepared by dissolving 0.200 g of chitosan in 10 ml of aqueous acetic acid solution. .
  • a 0.800 g of glycerophosphate disodium salt pentahydrate was added to the chitosan-silica dispersion.
  • the resulting composition was disposed in a glass scintillation vial in water bath kept at 37°C.
  • the gelation of the chitosan/glycerophosphate component was observed within 2 hours, and the chitosan/glycerophosphate gel includes dispersed solid silica particles.
  • a 0.200 g of chitosan was dissolved in acetic acid solution as in Experiment 1.
  • a 1.239 g of glucose-1 -phosphate disodium salt tetrahydrate was added and dissolved so as to reach a clear chitosan/glucose-1 -phosphate solution.
  • This chitosan/glucose-1 -phosphate solution placed in a glass scintillation vial was maintained at 37°C.
  • the Sol to Gel transition occurs at 37°C within 3 hours.
  • the resulting bulk gel was immersed in renewed baths of distilled water in order to remove the excess of glucose-phosphate salt.
  • a mother acidic solution made of a Water/Acetic acid was prepared for all experiments.
  • the pH of this mother acidic solution was adjusted to 4.0.
  • High molecular weight (M.w. 2,000,000) Chitosan powder was added and dissolved in a volume of the mother acidic solution so as to produce Chitosan solutions having Chitosan proportions ranging from 0.5 to 2.0% w/v (Table 1 ).
  • Table 1 reports the measured pH for the different samples.
  • Glycerophosphate was added to the chitosan solutions and induces a pH increase.
  • Table 2 shows the effect of glycerophosphate concentration on different chitosan solution. The concentration of glycerophosphate ranges from 0.065 to 0.300 mol/L.
  • the chitosan/glycerophosphate solutions in glass vials were maintained at 60 and 37°C, and bulk and uniform gelation was noted within 30 minutes at 60°C and 6 hours at 37°C (Table 2).
  • Chitosan and beta-glycerophosphate components individually influence the pH increase within the aqueous solutions, and consequently influence the Sol to Gel transition. As well as the dissolved materials, the initial pH of the mother water/acetic acid solution would also influence the Sol to Gel transition, but this potential effect seems to be limited by the counter-action of the chitosan solubility, which depends on the pH of the solution.
  • thermoforming gel system The biological properties of chitosan have historically been very well characterized through multiple medical applications. However, the novelty of this thermoforming gel system and its in-situ gelling capabilities called for new biocompatibility studies.
  • test article was found to cause negligible irritation response in an Intracutanous Reactivity Test in rabbits, a response similar to the one caused by the blank extract.
  • gel in cottonseed oil extract and in saline extract was found to be non-sensitizing in a Skin Sensitization test in Guinea Pigs (aka Maximization test).
  • the chitosan thermogel has been administered by sub-cutaneous injections into rats and dogs. Single-dose tests and multiple-dose weekly injections tests were used in both species. In all cases, after 14 weeks, the implants could be retrieved during the necropsy at the site of implantation, without obvious signs of degradation. In another, long term study, the chitosan-gel implants could still be retrieved after 14 months of subcutaneous implantation in rats. At least 80% of the material could be retrieved at this time-point, illustrating the long resilience and effective life of the product.
  • a filler formulation can be made of a mixture of fatty acids, such as 84% w/w oleic acid and 14%w/w palmitic acid.
  • the fatty acids are weighed, combined in a container, warmed to melt the components, and mixed.
  • the solution can be sterilized by an appropriate method, preferably by filtering the warm solution through 0.2 ⁇ mm filter.
  • This product stored at or below room temperature, can be used by first warming it up slightly above the melting point of the mixture (35°-39°C), using warm tap water or another moderate source of warmth. The liquefied solution is then drawn from the vial with a syringe fitted with a fine needle (26G).
  • the 5 day implants resembled the 2 day samples, except that there was an obvious proliferation of fibroblasts and endothelial cells. Some collagen formation was noted, as was neovascularization. The fatty acids implant showed some degeneration on the ends, but appeared stable (See Figs. 3C and 3D.

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Abstract

La présente invention concerne une composition de remplissage permettant l'augmentation de volume des tissus mous et la chirurgie reconstructive, comprenant une quantité efficace d'une solution thermo-gélifiante injectable comprenant 0,1 à 0,5 % en poids de chitosane ou collagène ou d'un dérivé correspondant; et 1,0 à 20 % en poids d'un sel de polyol ou sucre choisi parmi le groupe comprenant le sel dibasique de monophosphate, le sel de monosulfate et un sel d'acide monocarboxylique de polyol ou de sucre. La solution est stable et se gélifie à une température allant de 20 à 70 °C. le gel a une consistance acceptable du point de vue cosmétique et peut servir de support mécanique aux tissus mous périphériques une fois injecté à l'intérieur de ceux-ci. La composition peut ainsi être utilisé en tant qu'agent de remplissage permettant l'augmentation de volume des tissus mous et la chirurgie reconstructive.
EP01996399A 2000-11-15 2001-11-15 Composition de remplissage permettant l'augmentation de volume des tissus mous Withdrawn EP1333869A2 (fr)

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EP1534215A1 (fr) * 2002-07-02 2005-06-01 Procyte Corporation Compositions renfermant des complexes peptide-cuivre et des charges de tissus mous
CA2543148A1 (fr) * 2003-10-21 2005-04-28 Netech Inc. Composition d'humeur de gonflement de membrane muqueuse comprenant un derive de chitosane contenant une chaine de saccharides prevues pour etre utilisee en chirurgie condoscopique
GB0403938D0 (en) * 2004-02-21 2004-03-24 West Pharm Serv Drug Res Ltd Chitosan containing solution
FR2867073B1 (fr) * 2004-03-08 2006-05-05 Europlak Utilisation cosmetique de chitosane pour le traitement et le comblement des rides
FR2897775B1 (fr) * 2006-02-24 2013-05-03 Elisabeth Laugier Biomateriau, implant injectable le comprenant, son procede de preparation et ses utilisations
US7776840B2 (en) 2007-02-21 2010-08-17 Cutanea Life Sciences, Inc. Methods of use of biomaterial and injectable implant containing biomaterial
JP5860406B2 (ja) * 2010-10-15 2016-02-16 国立大学法人京都大学 徐放性医薬組成物
US9226797B2 (en) 2012-11-04 2016-01-05 Miba Medical Inc. Computer aided implantation of body implants
WO2014100837A1 (fr) * 2012-12-17 2014-06-26 Bui The Duy Implantation assistée par ordinateur d'implants corporels
EP2964184B1 (fr) 2013-03-04 2018-05-09 Dermelle, Llc D/b/a Eternogen, LLC Composition de collagène polymérisable in situ injectable
US9192574B2 (en) 2013-10-24 2015-11-24 Medtronic Xomed, Inc. Chitosan paste wound dressing
US9192692B2 (en) 2013-10-24 2015-11-24 Medtronic Xomed, Inc. Chitosan stenting paste

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