EP2461842A1 - Utilisation de compositions pour revêtir des ballonnets de cathéter et ballonnets de cathéter ainsi revêtus - Google Patents

Utilisation de compositions pour revêtir des ballonnets de cathéter et ballonnets de cathéter ainsi revêtus

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Publication number
EP2461842A1
EP2461842A1 EP10781810A EP10781810A EP2461842A1 EP 2461842 A1 EP2461842 A1 EP 2461842A1 EP 10781810 A EP10781810 A EP 10781810A EP 10781810 A EP10781810 A EP 10781810A EP 2461842 A1 EP2461842 A1 EP 2461842A1
Authority
EP
European Patent Office
Prior art keywords
balloon
transport
coating
transport mediator
mixture
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Withdrawn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
EP10781810A
Other languages
German (de)
English (en)
Inventor
Michael Hoffmann
Erika Hoffmann
Roland Horres
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.)
Hemoteq AG
Original Assignee
Hemoteq AG
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 Hemoteq AG filed Critical Hemoteq AG
Publication of EP2461842A1 publication Critical patent/EP2461842A1/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Withdrawn legal-status Critical Current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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08—Materials for coatings
    • A61L29/085—Macromolecular materials
    • 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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • 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
    • A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16—Biologically active materials, e.g. therapeutic substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M25/00—Catheters; Hollow probes
    • A61M25/10—Balloon catheters
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/41—Anti-inflammatory agents, e.g. NSAIDs
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416—Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/42—Anti-thrombotic agents, anticoagulants, anti-platelet agents
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606—Coatings
    • 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
    • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/80—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special chemical form
    • A61L2300/802—Additives, excipients, e.g. cyclodextrins, fatty acids, surfactants

Definitions

  • the present invention relates briefly to dilated medical devices in contact with the organism, such as, for example, balloon catheters coated with at least one layer of at least one antiproliferative, immunosuppressive, antiangiogenic, antiinflammatory, fungicidal and / or antithrombotic active ingredient and a transport mediator or a mixture of transport mediators, Process for coating these coated dilatable medical devices and the use of compositions for this coating.
  • the narrowed site is flared for a short time of 1-3 minutes using the inflatable balloon at the end of the catheter, repeated more than twice if necessary.
  • the vessel walls must be overstretched so that the constriction is repaired. This procedure results in microcracks in the vessel walls, which reach into the adventitia.
  • the injured vessel is left to itself, so that the healing process, depending on the added injury, resulting from the period of overexpansion, the overstretching and the degree of overstretching results, more or less high-grade services are required. This is reflected in the high rate of reclosure after PTCA.
  • the balloon catheter is used as a transport and implantation aid, so that overstretching of the vessel wall also occurs here, but in this case, this overstretching is required only for the period of stent dilatation. If the stent is stuck firmly in place, the balloon is deflated and removed. Thus, the duration of the overstretching is shortened and unique.
  • the reduction in the rate of restenosis shows that this reduced overexpansion time and also the reduced degree of stent in the stent, despite introduction of the foreign material into the organism already leads to a reduced rate in the aftertreatment.
  • the next goal in the history of the stent is the 100% prevention of reocclusion.
  • the search for the combination of ideal drug and ideal as biodegradable as possible stent has begun.
  • the suppression of cellular reactions in the first days and weeks is achieved primarily with the aid of preferably antiproliferative, immunosuppressive and / or anti-inflammatory agents such as derivatives / analogs and metabolites acting equally.
  • the active ingredients and / or combinations of active ingredients are used in a meaningful manner to assist wound healing or the wound healing process.
  • the improvements that have been made to balloon catheters in the past have related primarily to their ability to accurately and safely place a stent.
  • the PTCA as a stand-alone method was largely superseded by stent implantation, especially in the coronary area.
  • EP 0 383 429 A discloses a balloon catheter with tiny holes through which a heparin solution is delivered to the vessel wall during dilatation.
  • a drug-eluting balloon catheter offers an alternative to the stent (CardioNews Letter 21.04.2006).
  • This is a balloon catheter immersed in a solution of paclitaxel and X-ray contrast media, which, according to the results of the now one-year clinical trial, has achieved a 40% to 9% reduction in restenosis rate compared to the uncoated balloon catheter.
  • Such a balloon catheter is disclosed, for example, in WO2004028582A1.
  • the optical traceability achieved by the application of the contrast agent is advantageous, but the amount of active substance which can actually be used and taken up at the site after PTCA remains individual and uncontrolled, since even during the introduction of the balloon catheter in the bloodstream, starting from the groin to the first Heart dissolves an unquantifiable part of the coating from the balloon. In addition, during the dilatation of the balloon further pieces of the coating crumble and become off the surface in the bloodstream carried away. As a result, a portion of the drug content delivered to the balloon catheter does not reach the diseased site, but can only be considered ineffective, intravenous administration. The amount of lost portion is not controllable and is therefore not available for optimal care at the diseased site and in calculable dosage.
  • the object of the present invention is to provide compositions for the coatings of catheter balloons, which ensure sufficient adhesion of the drug to the balloon surface during the introduction of the catheter balloon and on the other hand optimal drug transfer to the vessel wall during dilatation.
  • a further object of the present invention is to provide drug-eluting balloon catheters and similar medical devices which can be used at short notice in the body and which, even with a short contact time, have a controlled and optimum Ensure drug transfer to and into the vessel wall, so that the healing process takes a positive course.
  • the active substance is not already rinsed prematurely by body fluid from the medical device on the way to the destination site or, at the latest, crumbles when expanding and only an undefined or insufficient amount of active ingredient reaches the target.
  • the very limited contact time must be sufficient so that the drug can be transferred in the appropriate dosage from the balloon catheter on or in the vessel wall.
  • a problem is solved by special coating methods for catheter balloons, which coat the catheter balloon with a defined amount of a pharmacologically active substance, wherein the coating method uses a coating device with a volume measuring device for delivering a measurable amount of a coating solution by means of a dispensing device targeted to the surface of the catheter balloon.
  • volume measuring device Any device capable of providing a measured amount of coating solution or measuring or indicating the amount of coating solution dispensed may serve as the volume measuring device.
  • Volume gauges are therefore in the simplest case scales, scaled pipettes, scaled burettes, scaled containers, scaled wells, as well as pumps, valves, syringes or other piston-shaped containers capable of providing or delivering or dispensing a measured amount of coating solution.
  • the volume measuring device only serves to either supply or dispense a certain amount of a coating solution or to measure and / or display a dispensed amount of coating solution.
  • the volume measuring device thus serves to determine or measure the amount of coating solution transferred from the delivery device to the catheter balloon surface and thus to active substance.
  • transport mediator is used below to refer both to a single transport mediator and to a mixture of transport mediators
  • the dispensing device which can be a nozzle, a multiplicity of nozzles, a thread, a network of filaments, a piece of textile , Leather, sponge, ball, syringe, needle, cannula, capillary, etc.
  • the associated method is referred to herein as a rolling process and the associated apparatus has a ball head with a supply line for a coating solution on the ball head.
  • a controller preferably optical control
  • the ball head is placed on the surface of the catheter balloon.
  • the coating solution flows out of a cavity or a volume measuring device and flows onto the ball head.
  • the ball head is rolled over the surface of the catheter balloon and thus travels the surface of the catheter balloon, wherein the coating solution applied to the ball head is transferred from the ball head to the surface of the catheter balloon.
  • catheter balloons can be completely or even partially coated in the deflated or inflated state.
  • a catheter balloon in the area of the widened folds can be targeted and coated, wherein the coating lies within the folds after deflation (ie, folding), so that a targeted coating of the folds can be achieved in this way ,
  • the ball head the balloon or the balloon material not it is preferably made of a rubbery material such as rubber or of at least one other polymer suitable for this purpose.
  • the present invention relates in particular to coated catheter balloons which have an active substance-releasing coating.
  • catheter balloons As catheter balloons, the conventional catheter balloons, bifurcation balloons as well as fold balloons or special balloons can be used.
  • catheter balloons or "conventional catheter balloons” refers to those dilatable catheter balloons which generally serve to place a stent by means of dilatation. Further, non-dilatable catheter balloons are also referred to for stent placement, which are suitable for self-expanding stents and carry a removable protective cover over the stent to prevent premature stent expansion.
  • expandable and recompressible catheter balloons with a protective sheath such as the non-dilatable catheter balloons for self-expanding stents are typically used without a stent to protect the coating on the catheter balloon from premature detachment.
  • Bifurcation balloons refer to catheter balloons for treating a branch of a vessel, in particular a blood vessel. Such balloons may have two arms or consist of two interconnected or two separate balloons which are used simultaneously or sequentially to treat a vascular fissure or to place a stent or two stents in a vascular fissure or in close proximity to a vascular fissure.
  • Balloons are referred to as "fold balloons", as described, for example, in EP 1189553 B1, EP 0519063 B1, WO 03/059430 A1 and WO 94/23787 A1 and which have "wrinkles" in the compressed state of the balloon that occur during expansion at least partially open the balloon.
  • each angioplasty balloon can also be referred to as a fold balloon, since all such balloons are in the deflated state in folds.
  • balloons are called balloons with pores, especially with micropores, which allow the passage of liquids and solutions in the expansion or the application of pressure.
  • a balloon with micro-openings is disclosed in EP 0 383 429 A.
  • special balloon is also used to refer to balloons with a specially designed surface, such as the catheter balloon with microneedles described in WO 02/043796 A2 or the catheter balloon disclosed in WO 03/026718 A1 with a micronous or nanorod surface for incorporating active substances with or without vehicles.
  • the term “balloon” or “catheter balloon” basically refers to any expandable and re-compressible, as well as temporarily implantable, medical device typically used in conjunction with a catheter.
  • coated balloons according to the invention can be used without a stent or with a crimped stent. Their use is not limited to initial treatment of stenotic vessels, they are also particularly well suited to successfully combat re-stenosis (e.g., stent restenosis) and prevent recurrent constriction.
  • re-stenosis e.g., stent restenosis
  • the catheter balloon may consist of the usual materials, in particular polymers, as described below, and in particular of polyamide, such as e.g. PA 12, polyester, polyurethane, polyacrylates, polyethers etc ..
  • polyamide such as e.g. PA 12, polyester, polyurethane, polyacrylates, polyethers etc ..
  • the stent may also be made from common materials such as medical grade stainless steel, titanium, chromium, vanadium, tungsten, molybdenum, gold, iron, nitinol, magnesium, iron, alloys of the foregoing metals, as well as polymeric material and preferably absorbable polymeric material such as e.g. Chitosan and its derivatives, polyamino acids, polypeptides, polyhydroxybutyrates (PHB), polyvinylpyrrolidone, polyvinyl alcohols, polyglycerides, polylactides and the block and copolymers of the aforementioned substances.
  • common materials such as medical grade stainless steel, titanium, chromium, vanadium, tungsten, molybdenum, gold, iron, nitinol, magnesium, iron, alloys of the foregoing metals, as well as polymeric material and preferably absorbable polymeric material such as e.g. Chitosan and its derivatives, polyamino acids, polypeptides
  • the coated catheter balloons of the present invention are used without an attached stent, however, use with a crimped stent is also possible. If, in addition to the coated balloon, a stented crimped stent is used, the stent may be uncoated (bare stent) or likewise coated, wherein the stent may have a different coating and also a different active substance than the coating of the catheter balloon.
  • coating is intended to encompass not only a coating of the surface of the catheter balloon but also a filling or coating of wrinkles, cavities, pores, microneedles or other fillable spaces on or between or in the balloon material.
  • the coating can be applied in one or more steps, be monolayer or multilayer, wherein the coating solution contains a suitable solvent or solvent mixture, one or more pharmacological agents and a transport agent or a mixture of transport mediators.
  • the coating solution preferably consists only of the three aforementioned constituents.
  • Suitable active substances or combinations of active substances are antiinflammatory, cytostatic, cytotoxic, antiproliferative, antimicrobubuli, antiangiogenic, antirestenotic (anti-restenosis), antifungicidal, antineoplastic, antimigrative, athrombogenic and antithrombogenic substances.
  • vasodilators sirolimus (rapamycin), somatostatin, tacrolimus, roxithromycin, dunaimycin, ascomycin, bafilomycin, Erythromycin, midecamycin, josamycin, concanamycin, clarithromycin, troleandomycin, folimycin, cerivastatin, simvastatin, lovastatin, fluvastatin, rosuvastatin, atorvastatin, pravastatin, pitavastatin, vinblastine, vincristine, vindesine, vinorelbine, etoboside, teniposide, nimustine, carmustine, lomustine, cyclophosphamide, 4-Hyvasodilators, sirolimus (rapamycin), somatostatin, tacrolimus, roxithromycin, dunaimycin, ascomycin, bafilomycin, Erythromycin, midecamycin, josamycin, concanamycin, clarithro
  • any desired active ingredients as well as active ingredient combinations, paclitaxel and paclitaxel derivatives, taxanes, docetaxel and rapamycin and rapamycin derivatives such as Biolimus A9, pimecrolimus, everolimus, zotarolimus, tacrolimus, fasudil and epothilones being preferred, and paclitaxel being particularly preferred and rapamycin.
  • Paclitaxel is available under the arkennamen Taxol ® and the chemical name [2aR- [2a, 4,4a, 6,9 (R *, S *), 11, 12, 12a, 12b]] - (benzoylamino) - hydroxybenzolpropionklare- 6, 12b-bis- (acetyloxy) -12- (benzoyloxy) -2a-3, 4, 4a, 5, 6, 9, 10, 11, 12, 12a, 12b-dodecahydro-4,11-dihydroxy-4a, 8 , 13,13-tetramethyl-5-oxo-7,1-methano-1H-cyclodeca [3,4] benz [1,2-b] oxet-9-yl-ester).
  • Rapamycin is also available under Rapamun or the International Nonproprietary Name (INN) Sirolimus and the lUPAC name [3S- [3R * [E (1S *, 3S *, 4S *)], 4S * , 5R * , 8S * , 9E , 12R *, 14R *, 15S *, 16R *, 18S *, 19S * , 26aR *]] - 5,6,8,1,12,13,14,15,16,17,18,19,24 , 25,26,26a-hexadeca-hydro-5,19-dihydroxy-3- [2- (4-hydroxy-3-methoxycyclohexyl) -1-methyl-ethenyl] -14,16-dimethoxy-4,10,12,18 - tetramethyl-8- (2-propenyl) -15,19-epoxy-3H-pyrido [2,1-c] [1,4] -oxaazacyclo-tricosin-1, 7, 20,
  • produgs is meant a precursor of the pharmacologically active compound which is converted to the active compound under physiological conditions.
  • active ingredients or combinations of active substances preferably reach the site of action via a transport mediator or as their own transport mediator in a sufficient concentration during the limited contact time of the short-term implant.
  • a major problem with the embodiments of the prior art is that with a single dilatation time of a maximum of 1 minute and possibly several repetitions of the dilation after a certain break and preferably a maximum of 45 seconds and more preferably of a maximum of 30 seconds, sufficient active ingredient To transfer the stenotic or re-stenotic or thrombotic vessel section, so that even in a dilation without a stent to set, a re-narrowing or reclosure of the vessel portion is prevented. Since at higher contact times, i.
  • coating solutions which comprise the active substance together with at least one transport mediator in a suitable solvent which can be removed again after coating.
  • transport mediators or transport accelerators are preferably used.
  • These substances may additionally possess active substance properties themselves or also act as a suitable carrier material for an active substance.
  • active substance properties themselves or also act as a suitable carrier material for an active substance.
  • embodiments according to the invention which contain chemical compounds as transport mediators which accelerate or facilitate the uptake of active substances into the vessel wall, so that the active substance or the active ingredient combination is controlled during the short-term contact and in the intended dosage through the cell membrane can be channeled into the cell interior.
  • transport mediators per se is not the subject of the present invention but the selection of very preferred transport mediators, which are particularly effective in connection with catheter balloons and with the special requirements for the short-term drug release, i.
  • the transfer of the active substance to the vessel wall or the introduction of active ingredient into the tissue is particularly effective. promote the stenosed tissue.
  • Common to all transport intermediates is the ability to ideally alter the thermodynamic state of the drug to increase the concentration gradient and enhance diffusion into the cells.
  • the transport accelerator can also act as a carrier.
  • the binding between active ingredient and carrier is already present and is dissolved after entry into the cell or it is formed on the outside of the membrane for the duration of the membrane passage and then dissolved again or carrier and drug form a unit that also exists inside the cell, but without the effectiveness of the drug negative affect.
  • Such properties are possessed by substances which either interact directly with the lipid bilayer of the cell membrane, interact with receptors on the cell membrane, enter the interior of the cell via membrane transport proteins which act as carriers or as channels (ion pump), where they have the membrane potential and thus the membrane permeability of the membrane Change cells. This facilitates or accelerates the uptake of an active substance into the cells.
  • oleic acid may affect the interaction with the lipid bilayer lipids while cyclomoterpenes such as D-limonene or menthol interact with the lipid bilayer hydrocarbons.
  • the hydration of the polar head groups of the lipid bilayer is altered by urea or propylene glycol. Also, the elimination of hydrogen bonds causes accelerated drug uptake (e.g., dimethylsulfoxide, dimethylformamide, or dimethylacetamide). An increase in moisture in the cell wall by moisture-binding substances such. Pyrrolidone also enhances diffusion into the cell.
  • polarity of the molecule is also important.
  • polar and non-polar groups can be combined in a molecule similar to the phosphatidylcholine present in all cells as a membrane constituent.
  • Another possibility consists in the mixture of two substances, each of which brings one of the properties and act in combination as membrane-permeable mixture.
  • vasodilators include endogenous substances such as the kinins, e.g. Bradykinin, kallidin, histamine, and NOS synthase, which releases the vasodilating NO from L-arginine.
  • kinins e.g. Bradykinin, kallidin, histamine, and NOS synthase
  • Substances of plant origin such as the proven vasodilator extract of gingko biloba, DMSO, xanthones, flavonoids, terpenoids, vegetable and animal dyes, food colors, NO-releasing substances such.
  • Pentaerythrityl tetranitrate (PETN), carbon monoxide (CO), contrast agents and contrast agent analogues also belong to this category.
  • the transport accelerator or mediator causes an immediate limited by the contact time with the medical device transfer of the active ingredients in the
  • the transport accelerator or mediator adheres to the removal of the medical device in combination with the active ingredient and possibly with a support supporting the carrier (or reservoir) on the cell walls. As a result, the diffusion of active ingredient into the cells can be retarded and controlled in a dose-controlled manner.
  • Transport mediator, drug or drug combination as well as a possible matrix can be applied adhesively and / or covalently, partially or over the whole area on the medical device:
  • Transport agent and drug adhere adhesively and / or covalently on the medical device or on an adhesive or covalently applied to the medical device matrix.
  • Transport mediator and drug are covalently bonded to each other and adhere adhesively on the medical device or on a matrix which is applied adhesively or covalently on the medical device.
  • Transport mediator and drug are covalently bonded to each other and adhere covalently on the medical device or on a matrix which is applied adhesively or covalently on the medical device.
  • the effect of these substances is not limited to the transport properties, but they also have a positive healing effect.
  • nitric oxide produced by the cell itself not only acts as a vasodilator, but also has an anti-proliferative effect.
  • all NO donors simultaneously act as antiproliferativa and as vasodilators.
  • Combinations with other antiproliferative, cytotoxic and cytostatic, antiinflammatory and also antithrombotic agents can be used here to potentiate or supplement the accompanying ability to act.
  • the medical balloon catheters according to the invention, with or without a stent are used to prevent or reduce restenosis, in particular also in-stent restenosis.
  • the temporary short-term implants are particularly suitable for the treatment and prophylaxis of vascular diseases, which arise due to a decrease in wall shear stress or possibly simultaneous strain-induced increase in leukocyte adhesion and immigration. Such processes often occur at vascular branches.
  • the vascular implants of the invention are capable of increasing wall shear stress and of strengthening or activating smooth muscle cells (SMC) or vascular endothelium, thereby reducing platelet adhesion and diapathesis of leukocytes present in the bloodstream Measure be reduced. This counteracts inflammatory processes and avoids, for example, chronic inflammatory bowel disease, especially Crohn's disease as well as arteriosclerosis, stenosis or restenosis.
  • Transport agent and active substance are identical
  • Transport mediator and active substance are not identical, support each other in their effect
  • the substance should not be so volatile that the substance is no longer or only diminished on the balloon in a short time. This is because the product properties would be changed in such a way that a no longer defined and controllable ratio of transport mediator to active ingredient would be created, which would severely question or render impossible the usability of such a medical device. Not least must also be given a mandatory minimum storage capacity. Under these conditions, substances that have a boiling point below 100 ° C can no longer be used because the guarantee of a stable, defined product is no longer guaranteed. Therefore, substances which are suitable as transport intermediates and which have a boiling point above 150 ° C. and thus have suitable temperature stability are particularly preferred.
  • hydrophobic or predominantly lipophilic molecules such as the phospholipids provided with a hydrophilic head and a long hydrophobic tail of fatty acids, can be used here.
  • phospholipids and sphingolipids, cetimides and cetyl alcohols are very suitable, since these are membrane components, so that membrane components are to be regarded as natural penetration enhancers, since they strive for the membrane dressing.
  • the above statements show that a person skilled in a variety of very different compounds can select and use as transport agents, as many substance classes could theoretically act as a transport agent and just because of the large number of possible substances, the expert can not recognize which work really well and which substance groups the Others are really superior because the requirements placed on the transport mediator, especially with the balloon catheters are much more special than, for example, in some transdermal formulations.
  • the present invention pertains to a selection of particular transport agents and therefore may be referred to as a selection invention, and should be evaluated in this way also in terms of novelty and inventive step.
  • a composition is used for the coating of catheter balloons which contains at least one solvent, at least one pharmacologically active substance and a transport mediator or a mixture of transport mediators, the transport mediator or the mixture of transport mediators having a boiling point of at least 150 ° C., the transport mediator or the mixture of transport mediator has an oily or solid consistency at 20 ° C., does not trigger an immune reaction and the transport mediator or the mixture of transport mediators is used for coating a catheter balloon for vessel dilation, wherein the transport mediator or mixture of transport mediators is not Contrast agent acts.
  • the transport mediator or the mixture of transport mediators to the pharmacological active ingredient in a molar ratio of 1: 100 to 10: 1 and preferably from 1:50 to 2: 1 and more preferably from 1:10 to 1: 1 in the composition is contained and thus in the balloon invention a molar ratio of transport mediator to active ingredient of 1 mol: 100 mol, preferably from 1 mol: 50 mol to 2 mol: 1 mol and more preferably from 1 mol: 10 mol to 1 mol : 1 mol yields.
  • the transport mediator or mixture of transport mediator should have a boiling point of at least 150 ° C, preferably of at least 170 ° C, more preferably of at least 190 ° C, even more preferably of at least 210 ° C and most preferably of at least 230 ° C.
  • the transport mediator is not a polymer and the mixture of transport mediators contains no polymer as transport mediator.
  • transport promoters are preferred which have at least 6 carbon atoms or at least two oxygen atoms or at least one nitrogen atom, and mixtures of such transport mediators. It is also preferred if the transport mediator or the mixture of transport mediators has a vapor pressure at 20 ° C. of less than 100 pascals, preferably less than 65 pascals, more preferably less than 25 pascals and especially preferably less than 6 pascals. For comparison, some vapor pressures are given below:
  • a transport mediator having a molecular weight of from 100 g / mol to 1000 g / mol, more preferably from 200 g / mol to 900 g / mol, even more preferred from 300 g / mol to 800 g / mol, even more preferably from 400 g / mol to 700 g / mol, and more preferably from 500 g / mol to 600 g / mol.
  • Transport mediators which are lipophilic and are hydrophilically esterified in such a way that they have a distribution coefficient between butanol and water of ⁇ 0.5 can also be referred to as preferred.
  • a transport mediator or a mixture of transport mediators which has a pH of 5 ⁇ pH ⁇ 7 in aqueous solution.
  • transport mediators or mixtures of transport mediators are not preferred, which form micelles and in particular hydrophilic micelles to the outside.
  • a transport mediator capable of forming hydrogen bonds may be referred to as preferred.
  • transport mediators and mixtures of transport mediators which can interact with the lipids of the lipid bilayer and / or with the hydrocarbons of the lipid bilayer are preferred. Also preferred are transport mediators which are hydrophilic and are so hydrophobic esterified that they have a distribution coefficient between butanol and water of> 0.5.
  • transport mediators or mixtures of transport mediators are preferred which have an aqueous solution of 9> pH> 7.
  • transport mediators or mixtures of transport mediators which are capable of altering the diffusion potential in such a way that the uptake of the active substance of the cell or the diffusion into the cell is accelerated.
  • a transport mediator is preferred which is capable of abrogating the hydrogen bonds in the cell wall.
  • transport mediator subgroups which are distinguished from the large group of possible transport mediators by a particular suitability for the use according to the invention.
  • These are in particular: amides, phenols, phenol esters, phenol ethers, aromatic alcohols, aromatic acids, sulfoxides, organic boron compounds, polyhydric alcohols having 2 to 6 carbon atoms, monoglycerides of fatty acids and alcohols, fatty acid ethers, terpene hydrocarbons, alcohols having at least 8 carbon atoms, heterocyclic compounds , Alkaloids, nanoparticles, enzymes and quaternary ammonium salts.
  • Amides and amines such as urea, DMF, DMA, cyclophosphamide, alkanolamides e.g. 1,2,3-propanetriol homopolymer (Z) -9-octadecenoate, decyloxy and octyloxy-polyoxyethylene-polyoxypropylene, 2-hydroxyethylethylenediaminetriacetic acid, 1,5-pentamethylene glycol, aspartame;
  • alkanolamides e.g. 1,2,3-propanetriol homopolymer (Z) -9-octadecenoate, decyloxy and octyloxy-polyoxyethylene-polyoxypropylene, 2-hydroxyethylethylenediaminetriacetic acid, 1,5-pentamethylene glycol, aspartame;
  • Phenols phenol esters, phenol ethers such as anisole, ⁇ -anethole, thymol, carvacrol, chlorocresol, octylphenol ethoxylates; in particular vanillin, coniferyl alcohol and coniferin
  • Aromatic alcohols and acids such as salicylic acid, salicyl alcohol, phenylethanol, cinnamyl alcohol, adrenaline, dopamine, amphetamine; in particular ferulic acid, curcumin and caffeic acid
  • Sulfoxides such as all biocompatible sulfoxides, diethyl sulfoxide and acesulfame K;
  • Organic boron compounds all biocompatible boric acid esters, phenyl borates and metaborates; in particular phenylboronic acid
  • Polyhydric alcohols with C2 to C6 such as lactitol, mannitol, dulcitol, isomalt, sucrose, xylitol, 2-ethyl-1,3-hexanediol, especially alitame and maltitol onoglycerides of fatty acids and alcohols such as glycerol monooleate, glycerol monolinoleate, glycerol monolaurate, maltol, meglumine and, in general, acylglycerides,
  • Glycol ethers ethylene glycol monoethers, ethylene glycol diethers, propylene glycol monoethers, especially propylene glycol diethers
  • Fatty acid ethers and carboxylic acid ethers having at least 8 carbon atoms such as
  • Polyoxyethylene lauryl ether polyethylene glycol monolauryl carboxymethyl ether, in particular diethylene glycol lauryl ether,
  • High boiling hydrocarbons containing at least 8 hydrocarbons and mixtures thereof such as
  • Bicycles Terpene (caran-pinane, bornane group): oc-pinene, 3-carene,
  • Monocyclic sesquiterpenes bisabolene and farnesol
  • carotenoids such as carotene, lycopene, zeaxanthin, lutein and lutein in combination with zinc oxide, crocetine, generally lipochromes
  • Corticoids cortisol (INN, cortisone), aldosterone (INN), triamcinolone (INN).
  • Alcohols containing at least 8 hydrocarbon atoms such as alkanols, meristyl alcohol, stearyl alcohol, sterols, alkyl 2- (N, N-disubstituted amino) alkanoates and alkyl 2- (N, N-disubstituted amino) alkanol alkanoates, 1, 2,3 Butanediol, 1, 2,4-butanetriol, 1, 2-butanediol, 1, 3-butanediol, 1, 4-butanediol, 1, 2,3,4-butanetetraol, glycerol, glycol, wool wax alcohols such as lanolin;
  • Heterocyclic compounds such as N-methylpyrrolidone, bilirubin, biotin, sulfamethoxazole (INN), in particular ascorbic acid ethers and hydrophobically esterified ascorbic acids, such as ascorbyl palmitate
  • Nanoparticles such as fullerene-based peptides; Enzymes such as hyalurodinase, streptodornase, chymotrypsin, bromelain, papain, deoxyribonuclease, collagenase, serine proteases,
  • Quaternary ammonium salts such as 2,3-epoxypropyltrimethylammonium chlorides (QUAB 151), 3-chloro-2-hydroxypropyltrimethylammonium chlorides (QUAB 181), dodecyl, hexadecyl, tetradecyltrimethylammonium halide, glycidyltrimethylammonium halide, 3-chloro-2-hydroxypropyltrimethylammonium halide, benzethonium halide, wherein halide denotes : Fluoride, chloride, bromide, iodide;
  • Fumarates such as sodium stearyl fumarate, fumaric acid, fumaric acid ethers;
  • Phosphates such as alkyl (polyoxyethyl) phosphate
  • Polysaccharides such as carrageenan, sorbitol, sorbitol ether sucrose, hydrophobically esterified or etherified xylitol or glucose, maltatol, mannitol, meglumine.
  • tartrates and tartaric acid esters of the following formula:
  • R 1 , R 2 , R 3 and R 4 independently of one another are hydrogen, -CH 3 , -C 2 H 5 , -C 3 H 7 , -CH (CH 3 ) 2 , -C (CH 3 ) 3 , -C 4H 9, -CH 2 -CH (CH 3 ) 2, -CH (CH 3 ) -C 2 H 5 , -C 5 Hn, -C 6 H 13 , -C 7 Hi 5 , -C 8 H 17 , -cyclo-C 3 H 5 , -cyclo-C 4 H 7 , -cyclo-C 5 H 9 , -cyclo-C 6 Hn, or a linear or branched, saturated or unsaturated, substituted with at least one functional group or unsubstituted alkyl radical, arylalkyl radical or cycloalkyl radical ,
  • tartrates are tetramethyl tartrate, tetraethyl tartrate, tetrapropyl tartrate, tetra butyl tartrate.
  • a transport mediator having a molecular weight of from 150 g / mol to 390 g / mol, more preferably from 170 g / mol to 370 g / mol, even more preferably from 190 g / mol to 350 g / mol, even more preferably from 200 g / mol to 330 g / mol, and more preferably from 230 g / mol to 310 g / mol.
  • the coating of transport mediator and active substance according to the invention may have a polymer coating or base coating on the catheter balloon.
  • biocompatible substances can be used which, as a minimum requirement, do not adversely affect the properties and use of the implant compared to the uncoated implant.
  • biocompatible biodegradable and / or biostable polymers can preferably be used for the coating of the catheter balloon:
  • polyacrylic acid and polyacrylates such as polymethylmethacrylate
  • biodegradable or absorbable polymers which can be used are: polyvalerolactones, ⁇ - ⁇ -decalactones, polylactides, polyglycolides, copolymers of polylactides and polyglycolides, poly-s-caprolactone, polyhydroxybutyric acid, polyhydroxybutyrates, polyhydroxyvalerates,
  • Polyhydroxybutyrate-co-valerates poly (1,4-dioxane-2,3-diones), poly (1,3-dioxan-2-ones), poly-para-dioxanones, polyanhydrides such as polymaleic anhydrides, polyhydroxymethacrylates, fibrin, polycyanoacrylates, Polycaprolactone dimethyl acrylates, poly-b-maleic acid polycaprolactone butyl acrylates, multiblock polymers such as from oligocaprolactone diols and oligodioxanonediols, polyetherester multiblock polymers such as e.g.
  • Polyhydroxypentanoic acid Polyanhydrides, polyethylene oxide-propylene oxide, soft polyurethanes, polyurethanes with amino acid residues in the backbone, polyether esters such as polyethylene oxide, Polyalkenoxalate, Polyorthoester and their copolymers, carrageenans, fibrinogen, starch, collagen, protein-based polymers, polyamino acids, synthetic polyamino acids, zein , modified zein, polyhydroxyalkanoates, pectinic acid, actinic acid, modified and unmodified fibrin and casein, carboxymethylsulfate, albumin, further hyaluronic acid, heparan sulfate, heparin, chondroitin sulfate, dextran, b-cyclodextrins, and copolymers with PEG and polypropylene glycol, gum arabic, guar, gelatin, Collagen-N-hydroxysuccinimide collagen, modifications and copolymers and
  • Particularly preferred polymers for the matrix are polysulfones, polyethersulfones, silicones, chitosan, polyacrylates, polyamides, polyetheramides, polyurethanes, polylactides, polyglycolides, copolymers of polylactides and polyglycolides, polyhydroxybutyric acid, polyhydroxybutyrates, polyhydroxyvalerates, polyhydroxybutyrate-co-valerates, poly (1,4 dioxane-2,3-diones), poly (1,3-dioxan-2-ones), poly-para-dioxanones, polyanhydrides, polyesters, PEG, hyaluronic acid, heparan sulfate, heparin, chondroitin sulfate, dextran and beta-cyclodextrins. Balloon with crimped stent
  • Another preferred embodiment of the present invention comprises a crimped stent catheter balloon according to the invention.
  • this embodiment in particular, there are 4 variants, which can be selected and used depending on the vasoconstriction to be treated.
  • Variant [A] represents a catheter balloon with a crimped nonabsorbable and uncoated stent.
  • the non-resorbable stent is coated with a drug-releasing carrier system.
  • Variant [C] comprises a resorbable uncoated stent and variant [D] is a catheter balloon with a resorbable drug-eluting stent.
  • the variant [A] offers an ideal system a severely narrowed body passage such as biliary tract, esophagus, urinary tract, Pancreas, kidney, pulmonary, trachea, small intestine and colon, and in particular to keep blood vessels open with a permanent stent, which has no coating, but still need not be dispensed with an active ingredient application.
  • the catheter balloon according to variant [A] is coated with a pure drug layer or a carrier containing an active ingredient and dilation on the one hand the stent set and on the other at least over the entire length of the stent and advantageously even moreover an active ingredient applied, the ensures controlled ingrowth and prevention of overgrowth of the stent with mostly smooth muscle cells.
  • active substance or active substance mixture the above-mentioned active substances and in particular Paclitaxel and / or Rapamycin can be used.
  • the catheter balloon is coated with drug with or without a carrier system such that the balloon coating extends beyond both stent ends and preferably extends beyond 10-20% of the total length of the stent beyond an end of the stent.
  • the active agent is also transferred to the vascular area at both ends of the stent, where the stent is no longer sufficient and it becomes Transfer active substance over the entire surface of the vessel wall, which lies between the widening or expanded stent struts.
  • This embodiment has the advantage that the stent surface has no active substance which inhibits or kills the cells, in particular the smooth muscle cells, which directly communicate with the stent surface.
  • enough active substance is applied to the interstices between the stent struts, so that it is precisely the too rapid overgrowth of the stent which begins in the interstices of the stent struts and continues into the interior of the stent and leads to in-stent restenosis a controlled amount is reduced.
  • a drug-coated stent emits the active substance only from its surface and not from the interstices of the stent struts or at the ends of the stent or the region beyond, and moreover to the adjacent tissue, which is not intended to be inhibited or killed, according to the variant [A] the active ingredient applied there as widely as possible, where it is needed.
  • the drug coverage of the vessel wall be a few millimeters beyond the end of the stent to adequately accompany the end portions of the stent within the vessel Supply active ingredient.
  • the drug coverage of the vessel wall be a few millimeters beyond the end of the stent to adequately accompany the end portions of the stent within the vessel Supply active ingredient.
  • the catheter balloon is coated according to the invention and then an uncoated stent is crimped onto the balloon.
  • variant [B] can be obtained by crimping a nonabsorbable stent onto a balloon as in variant [A] and then coating the stent and balloon with an active ingredient according to the invention.
  • non-resorbable means that the stent is a permanent implant that is not or only slowly dissolves under physiological conditions
  • stents are, for example, medical grade stainless steel, titanium, chromium, vanadium, tungsten, molybdenum, gold, nitinol, magnesium , Zinc, iron, alloys of the aforementioned metals and ceramics or biostable polymers.
  • a catheter balloon with a crimped stent is coated at the same time, it is preferable to use a solution of the active substance and of the at least one transport mediator in a solvent which acts as little as possible on the catheter balloon, but is preferably wetting and is also thin enough to move between the struts of the crimped stent to flow in the compressed state.
  • This embodiment is suitable for spontaneous release of relatively much drug because the interstices of the stent struts and the interstices between the inner surface of the stent and the surface of the catheter balloon serve as a drug reservoir.
  • the difference to the variant [A] consists mainly in the administrable amount of active ingredient, as can be applied to the stent and catheter balloon according to the previously described method, a significantly larger amount of an active ingredient or drug mixture.
  • hydrophobic drugs such as e.g. Paclitaxel solutions of e.g. Dimethylsulfoxide (DMSO), chloroform, ethanol, acetone, methyl acetate and hexane and their mixtures or e.g. Rapamycin in Essigklareethyiester, methanol / ethanol mixtures, ethanol / water mixtures or in ethanol.
  • DMSO Dimethylsulfoxide
  • Rapamycin in Essigklastedreethyiester e.g. Rapamycin in Essigklastedreethyiester
  • methanol / ethanol mixtures ethanol / water mixtures or in ethanol
  • other active ingredients in suitable solvents or mixtures can be used.
  • non-polymeric carriers such as contrast agents or contrast agent analogs
  • biocompatible organics that improve coating properties and increase drug uptake into the vessel, such as amino acids, sugars, vitamins, saccharides, 2 Pyrrolidone, acetyltributyl and triethyl citrate, tributyl and triethyl citrate, benzyl benzoate, triethyl and dimethyl phthalate, fatty acid esters such as isopropyl myristate and palmitate, fatty acid ethers and the like.
  • the balloon is preferably coated beyond the surface covered by the stent.
  • the coated area of the balloon beyond the end of the stent is not more than 20% of the total length of the stent, preferably not more than 15% and most preferably not more than 10% of the total length of the stent.
  • a full-area coating is advantageous, i. the catheter balloon according to variant [A] or stent and catheter balloon according to variant [B] are provided over the entire surface with a coating.
  • Variants [A] and [B] can also be designed so that the coating with active ingredient is not uniform, but one uses a gradient, i. E. produces a concentration gradient of drug on the balloon or balloon and stent surface. For example, in the center of the catheter balloon, a greater concentration of drug may be applied or at one or both ends of the catheter balloon or in the middle and at one or both ends.
  • a higher concentration of active compound can be applied than on the remaining surface.
  • the stent must receive special attention, especially in the early phase after implantation, as these transitional areas are more risky. Any variations are conceivable here.
  • a hemocompatible layer can be adhesively or preferably covalently applied to the uncoated surface of the medical device or crosslinked, e.g. immobilize with glutaraldehyde on the surface of the medical device.
  • a layer of this type which does not activate blood coagulation makes sense, since it increases the hemocompatibility of the medical device surface and reduces the danger of thrombosis.
  • This coating step is particularly useful especially if the short-term implant is to be only partially coated.
  • the non-drug-coated area thus advantageously has a non-coagulating non-activating, athrombogenic surface and thus ensures a significantly higher safety during and after contact of the medical device with the blood.
  • a preferably hemocompatible layer can be applied to the stent as a permanent implant, which is produced from the following preferred substances: heparin of native origin as well as regioselectively prepared derivatives of different degrees of sulfation and degrees of acetylation in the molecular weight range of that responsible for the antithrombotic effect Pentasaccharides up to the standard molecular weight of the commercially available heparin of about 13 kD, heparan sulfates and its derivatives, oligosaccharides and polysaccharides of erythrocyte glycolide, oligosaccharides, polysaccharides, completely desulfated and N-reacetylated heparin, desulfated and N-reacetylated heparin, N-carboxymethylated and / or partially N-acetylated chitosan, polyacrylic acid, polyetheretherketones, polyvinylpyrrolidone, and / or
  • Another aspect of the present invention is directed to methods for coating balloon catheters comprising the following steps:
  • a) providing a composition comprising at least one solvent, at least one pharmacologically active substance and a transport mediator or a mixture of transport mediators, wherein the transport mediator or the mixture of transport mediators has a boiling point of at least 150 ° C, the transport mediator or the mixture of transport mediators at 20 ° C has an oily or solid consistency, does not trigger an immune reaction, and the transport mediator or admixture of transport mediators is used to coat a catheter balloon for vascular dilation, wherein the transport mediator or mixture of transport mediators are not contrast agents;
  • the present invention relates to balloon catheters which can be obtained by any of the methods disclosed herein.
  • the coating methods such as e.g. Injection method, pipetting method, capillary method, wrinkle spraying method, drag method, thread drag method or rolling method will be described in detail below.
  • the catheter balloons can be coated with or without a stent.
  • the balloon catheter according to the invention contain, own or comprise a catheter balloon with a dried oily or solid coating of at least one pharmacologically active agent and a transport agent or a mixture of transport mediators, wherein the transport mediator or the mixture of transport mediators has a boiling point of at least 150 ° C, the Transport mediator or the mixture of transport mediators at 20 ° C has an oily or solid consistency, does not trigger an immune reaction and the transport mediator or the mixture of transport mediators, is used for coating a catheter balloon for vascular dilation, wherein it is the transport mediator or the mixture of transport mediators not about contrast media.
  • Such coated balloon catheter are ideal for expanding and keeping open body passages, especially of blood vessels and especially in the cardiovascular area and thus for the prophylaxis and treatment of stenosis and re-stenosis.
  • the catheter balloon is wholly or partly or completely or partially or in combination with a matrix either with a solution of the substances to be applied including the active ingredient or the active ingredient mixture by spraying, dipping, brushing, spraying, dragging, rolling or pipetting methods or electrospinning coated.
  • volatile organic compounds are used such as dichloromethane, chloroform, ethanol, acetone, heptane, n-hexane, DMF, DMSO, methanol, propanol, tetrahydrofuran (THF), methylene chloride, ether, petroleum ether, acetonitrile, ethyl acetate and methyl ester, cyclohexane and corresponding mixtures.
  • the coating material eg hydrogels or water-soluble active ingredients
  • the presence of water may also be desirable.
  • the catheter balloon can be coated, partially or fully coated, either in the expanded or folded state, selectively coated under the folds, or coated together with an attached (crimped) stent.
  • the coating can be carried out in the spray, dip, brush, syringe, drag, roll and / or pipetting method.
  • the pipetting, dragging, rolling or spraying method is particularly suitable for use on a folded catheter balloon or a folded balloon, since this method can specifically bring the active ingredient solution or the mixture of substances to be applied into the folds or under the folds , It is important that no impairment of functionality is connected by this partial coating.
  • the folds may not stick together during expansion and thus expand counteract.
  • the nominal pressure on the balloon should not be increased above the maximum value to counteract adhesion forces of the coating in the pleats. Uneven expansion is also to be avoided.
  • the coating must not negatively affect the expansion properties of the balloon catheter.
  • the catheter balloon can be coated together with a crimped stent, or an uncoated stent and an already coated stent can be crimped onto the coated catheter balloon to form a system of, for example, a drug released rapidly from the catheter balloon and slowly deployed Obtain the coating of the stent released drug.
  • a drug-eluting balloon catheter is particularly advantageous in the early stages of the healing process, since only in this way the full-surface contact with the site to be treated is achieved and active ingredient in the entire area Diseased vessel wall passes.
  • the entire diseased area is provided with drug on contact with the balloon catheter surface, while the stent with a surface as small as possible covers only a small vessel wall surface.
  • a catheter balloon which can deliver drug in the peripheral areas of the stent, ensures optimal supply of the vessel to the problem areas of a stent.
  • the catheter balloons with a specially designed surface are preferably coated by spraying or pipetting.
  • the catheter balloon is suspended in a rotating manner and the application of a slight vacuum stabilizes the balloon catheter form.
  • a slight vacuum stabilizes the balloon catheter form.
  • the balloon catheter is briefly sprayed several times, during which time it dries.
  • an outer protective layer or barrier layer is also preferably applied by spraying.
  • pure active substance transport enhancer layers containing, for example, paclitaxel or rapamycin, which are likewise preferably applied by spraying.
  • the pipetting method is particularly well suited for coating a balloon catheter.
  • the rotatably fixed balloon catheter (with or without stent) is coated by means of a fine nozzle, which is extended with a capillary and through which the coating solution exits in the longitudinal direction of the balloon catheter.
  • a fine nozzle or cannula is pushed under the fold and the mixture to be introduced is injected into the fold, preferably moving the nozzle or cannula along the fold or, in the case of a stationary nozzle or cannula, the fold balloon is moved in the longitudinal direction of the fold.
  • This method allows a very precise and accurate coating of each individual fold or the entire folding balloon. Any solvent used evaporates or is removed in vacuo.
  • the fold balloon is stored horizontally with a fold or preferably inclined at 5 to 25 degrees so that the syringe or nozzle contacts the lower end of the fold balloon the fold opening can be applied and the mixture flows into the fold independently and fills it completely.
  • the fold balloon is rotated and the next fold is filled until usually all the folds of the balloon are filled.
  • Fold balloons are preferably coated in the compressed state, with some specific embodiments of fold balloons also being able to be coated in the expanded state.
  • Such a coating process comprises the steps
  • the present invention further relates to a method for keeping closed blood vessel passages, in particular of cardiovascular vessels, by means of short-term dilatation.
  • a catheter balloon without stent expands and compressed again to a diameter smaller than 1.5 times the initial diameter in the compressed state, during this process, the vessel is only overstretched to a maximum of 10% of its diameter in the unconstricted state and at least 20% of the active substance contained per mm 2 balloon surface and transferred largely to the vessel wall.
  • the transfer of the active ingredient preferably does not take place in pure form, but in a matrix of transport mediator, which preferably acts as a drug reservoir at least within one hour after dilatation and releases further active ingredient to the vessel wall before it has been released or degraded.
  • This method is characterized by the fact that in the shortest possible time the largest possible amount of active substance locally and selectively transferred to the vessel wall of a narrowed vascular site and within the following 30 to 60 minutes up to max. 3 days to provide for a local drug reservoir, which is then dissolved or degraded.
  • active substances which combine anti-inflammatory and antiproliferative properties have proven to be particularly suitable for this process (see list of active substances p. 6-9).
  • active substances which combine anti-inflammatory and antiproliferative properties have proven to be particularly suitable for this process (see list of active substances p. 6-9).
  • active substances which combine anti-inflammatory and antiproliferative properties have proven to be particularly suitable for this process (see list of active substances p. 6-9).
  • active substances which combine anti-inflammatory and antiproliferative properties have proven to be particularly suitable for this process (see list of active substances p. 6-9).
  • active substances which combine anti-inflammatory and antiproliferative properties have proven to be particularly suitable for this process.
  • active substances include, for example, colchicine, angiopeptin, but especially rapamycin and its derivatives, in addition, further hydrophobic drugs, especially paclitaxel and paclitaxel derivatives are very suitable.
  • the wrinkle coating methods or wrinkle filling methods according to the invention are the pipetting method also referred to as
  • a syringe delivering a continuous flow of a drug-containing composition is moved along the fold relative to the catheter fold balloon;
  • a plurality of in-line dispensing openings are pushed under the fold of the fold balloon and at the same time from the plurality of dispensing openings a drug-containing composition is delivered into the fold.
  • these coating or filling methods are preferably carried out in the compressed or deflated state or a maximum of 10% inflated state of the catheter balloon.
  • 10% inflated state is meant that the catheter balloon accounts for 10% of the inflation, i. dilation up to the maximum extent planned during dilatation. If the expansion provided for in the dilation is designated 100% and the deflated condition is set at 0%, the result is a 10% inflation according to the following formula:
  • the inventive method several or all folds can be coated or filled at the same time and the coating or filling can be targeted.
  • Targeted filling of the wrinkles or targeted coating of the wrinkles should mean that only the wrinkles are filled or coated and the surface of the catheter wrinkle balloon is not coated outside the wrinkles.
  • a preferred composition of active ingredient, solvent and transport promoter has the consistency of a paste, gel, viscous mass or a viscous dispersion or emulsion or a tough pulp.
  • This composition has the advantage of maintaining its consistency during the coating process.
  • This paste or (high) viscous mass or viscous slurry is introduced into the folds under pressure by means of a spray device, preferably a nozzle. If necessary, the nozzle can widen the balloon folds and specifically fill the cavities formed by the folds.
  • the fold balloons usually have four or more folds, which are individually filled.
  • the composition dries in the wrinkles either at atmospheric pressure or under reduced pressure. Drying or curing of the composition is accomplished by removal of the at least one solvent by evaporation.
  • the dried composition has a porous consistency and dissolves very easily from the balloon surface during dilatation.
  • the solvent was removed to the usual residues and the contrast agent forms a porous matrix for the drug and is also able to release the drug after dilatation of the fold balloon the drug quickly and in high concentration.
  • the inventive method has the advantage of working very gentle to the material, since only the wrinkles are coated or filled and thus no drug is on the outer balloon surface, which is lost in the introduction of the catheter.
  • This procedure includes the following steps:
  • step f) for the drying can follow:
  • This method specifically coats or fills the wrinkles and should be carried out with any coating solution which is still so viscous that it is pulled into the fold within 5 minutes, preferably 2 minutes due to capillary forces or additionally by gravity, and the fold is substantially complete filled.
  • coating solution is understood to mean the composition used according to the invention containing at least one solvent, at least one pharmacologically active substance and a transport mediator or a mixture of transport mediators, wherein the substance classes of transport mediators described herein are preferably used as transport mediators.
  • This procedure includes the following steps:
  • step f) for the drying can follow:
  • This method selectively coats or fills the wrinkles and should be carried out with any coating solution which is still so viscous that it can be filled into the fold by means of small nozzles or small outlet openings.
  • Spraying method or wrinkle spraying method :
  • This procedure includes the following steps:
  • step f) for the drying can follow:
  • This method selectively coats or fills the wrinkles and should be carried out with any coating solution which is still so viscous that it can be filled into the fold by means of small nozzles or small outlet openings.
  • This procedure includes the following steps:
  • This elegant and particularly gentle method for the catheter balloon uses a drop of the coating solution which, without the dispenser touching the balloon surface, is moved or pulled across the balloon surface by moving the dispenser and thus the droplets and balloon surface relative to one another.
  • the coating solution is replenished in such a way that the drop substantially retains its size and the connection between the dispenser and Maintains balloon surface.
  • the amount of coating solution dispensed can be precisely determined after coating, and thus the amount of active substance present on the balloon.
  • This procedure includes the following steps:
  • This also very elegant method is also very gentle on the balloon surface, since the dispensing device touches the surface of the balloon but is designed such that it can not damage the balloon surface.
  • the dispenser is pulled or dragged across the balloon surface by relative movement of the balloon to the dispenser, dispensing a certain amount of coating solution.
  • a volume measuring device it can be determined exactly after coating how much coating solution has been transferred to the balloon surface, resulting in the exact amount of active ingredient on the balloon surface.
  • This procedure includes the following steps:
  • the dispenser rolls over the balloon surface due to relative movement of the catheter balloon to the dispenser, thereby dispensing an amount of coating solution, determinable by means of a volume measuring device, onto the balloon surface via a ball head.
  • This method employs a pipette or syringe or other device capable of point-donating the drug-containing composition.
  • active substance-containing composition or "coating solution” as used herein is understood to mean the mixture of active ingredient, transport mediator and solvent and optionally additives, ie an actual solution, dispersion, suspension or emulsion of an active substance or an active substance mixture, a transport mediator or transport mediator mixture and at least one solvent.
  • solution should also clarify that it is a liquid mixture, which, however, may also be gelatinous, viscous or pasty (viscous or highly viscous).
  • the pipette or syringe or outlet or other device capable of point delivery of the drug-containing composition is filled with the composition and its outlet is preferably applied at the proximal or distal end of a fold.
  • the exiting composition is drawn into the fold and along the fold due to capillary forces until the opposite end of the fold is reached.
  • the catheter balloon is in the compressed, ie deflated state. Even a partial or minor inflation of the catheter balloon is usually not required to open the wrinkles a little. Nevertheless, the filling of the wrinkles can be carried out with a slight inflation of the catheter balloon of a maximum of 10% of the diameter provided during the dilation.
  • the filling of the folds can also be done with a slight expansion of the folds by 100 kPa (1 bar) overpressure, Preferably, 50 kPa (0.5 bar) pressure applied to slightly widen the wrinkles.
  • compositions are solutions of an active substance or mixture of active substances and transport mediator or transport mediator mixture in an alcohol or alcohol mixture.
  • the capillary forces should be strong enough to completely fill a 10 mm length fold within 5 to 80 seconds, preferably within 15 to 60 seconds, and most preferably within 25 to 45 seconds. If the composition or solution is too viscous, it may also be advantageous to tilt the catheter balloon with the fold to be filled upwards out of the horizontal position by a maximum of 45 °, preferably a maximum of 30 °, and thereby also utilize gravity. As a rule, the filling of a fold by means of capillary forces, however, takes place in the horizontal state of the catheter balloon with the fold to be filled upwards.
  • the syringe or pipette or other device capable of point delivery of the drug-containing composition is preferably pointed at the proximal or distal end of the fold in the direction of the fold at an angle of 10 ° to 65 °, more preferably 20 ° to 55 °, more preferably an angle of 27 ° to 50 ° and particularly preferably at an angle of 35 ° to 45 ° measured from the horizontal to the fold.
  • the filling of the fold then takes place from the higher end of a fold, so that the coating solution finds a gradient and in addition to the capillary action and the gravity is utilized.
  • the syringe or pipette or the other device capable of point delivery of the active substance-containing composition in the middle of the folds or at any other point lying between the distal and proximal ends, so that the fold is due to capillary forces simultaneously filled in the direction of the proximal and the distal end, but the starting points at the end of the fold have been found to be preferred.
  • the flow of substance usually stops spontaneously and the syringe or pipette or the other device capable of point delivery of the active ingredient-containing composition can be removed.
  • the syringe or pipette or the other device capable of delivering the punctiform delivery of the active ingredient-containing composition it has proven advantageous to remove the syringe or pipette or the other delivery device before the active ingredient-containing composition is completely removed has reached the other end of the fold.
  • the remaining active ingredient-containing composition remaining at the point where the syringe or the pipette or the other dispenser approaches is pulled into the fold so that no coating composition or better filling composition remains outside the fold.
  • the syringe or pipette or other dispenser is removed when about 90% of the fold is filled with drug-containing composition.
  • the optimal time to remove the syringe or pipette or the other dispenser can be accurately determined by a few experiments and is also reproducible.
  • another device capable of point delivery of the drug-containing composition is meant a device which, like a pipette, is capable of providing a uniform and continuous flow of drug-containing composition, including a pump, micropump or other reservoir which ensures this uniform and continuous delivery of active ingredient-containing composition.
  • the catheter balloon After filling a fold, the catheter balloon is rotated so that the next fold to be coated is up and preferably horizontal. The wrinkle filling process is now repeated.
  • the drying is preferably carried out by evaporation of the solvent.
  • the pipetting method is suitable for the simultaneous filling of several or all folds of a catheter balloon.
  • the catheter balloon can be stored horizontally or preferably vertically and the dispensing devices are set from above to the ends of the wrinkles preferably at an angle of 10 to 70 degrees, so that the drug-containing composition can flow into the folds.
  • the dilation preferably lasts for a maximum of 60 seconds and particularly preferably for a maximum of 30 seconds.
  • the drying of the last wrinkles i. the content of the last fold preferably without vacuum under atmospheric pressure by evaporation of the solvent.
  • This predrying can be followed by final drying, which according to the invention is carried out with a rotating catheter balloon. If required or desired, vacuum can also be applied during the rotation. This particular drying process is described in more detail following the coating process of the invention.
  • a fine syringe, syringe-shaped opening, syringe-shaped outlet or needle or nozzle is attached to the proximal or distal end of a fold and this dispenser moves in the form of a syringe, needle or nozzle along the longitudinal direction of the fold relative to the fold and per distance traveled delivered a certain amount of an active ingredient-containing composition or a defined flow of coating solution. It is irrelevant whether the catheter balloon is fixed and the dispenser moves along the fold or the dispenser is fixed and moves relative to the catheter balloon or even catheter balloon and dispenser both move relative to each other. Should the catheter balloon and dispenser move relative to one another, then movement on a straight line in the opposite direction is preferred.
  • a medium to thick viscous active ingredient-containing composition is preferably delivered in the form of a paste or a gel or an oil in the interior of the fold.
  • the viscosities of preferred solutions are between 10 1 to 10 6 mPa ⁇ s, preferably between 10 2 to 10 5 mPa ⁇ s and particularly preferably between 10 3 to 10 4 mPa ⁇ s.
  • compositions containing active compounds are, in particular, those with the abovementioned oily transport promoters, for example the polyols, phenols, glycerides or alcohols having at least 8 hydrocarbon atoms.
  • the tip of the syringe, nozzle or needle extends to about the middle of the inside of the wrinkle, that is, to about the middle of the fold, i. the nozzle or the outlet is located relatively centrally in the cavity formed by the fold.
  • a continuous flow of the drug-containing composition is delivered such that delivery rate and delivery rate relative to the relative velocity of movement of delivery device and catheter balloon are appropriate, the fold at least 50% by volume, preferably at least 70% by volume. and particularly preferably to fill at least 85 vol .-% with the active ingredient-containing composition.
  • the filling of a fold takes about 5 to 80 seconds, preferably about 15 to 60 seconds and more preferably about 25 to 45 seconds with a pleat length of 10 mm.
  • the catheter balloon is in the process of filling the folds in the compressed, i. deflated condition. Even a partial or minor inflation of the catheter balloon is usually not required to open the folds a little. Nevertheless, the filling of the wrinkles can occur with a slight inflation of the catheter balloon of a maximum of 10% of the diameter provided during the dilatation.
  • the filling of the pleats can also be done with a slight expansion of the pleats by applying 100 kPa (1 bar) overpressure, preferably 50 kPa (0.5 bar) overpressure, to slightly widen the pleats.
  • this coating process can also be carried out with low-viscosity active substance-containing compositions, but is more suitable for oily compositions as well as for highly concentrated salt solutions.
  • this method also has the advantage that more than one fold and in particular all folds can be coated or filled at the same time.
  • an annular arrangement of dispensing devices is arranged according to the number of folds such that a dispensing device is available per fold.
  • the tips of the dispensers are inserted into the folds and placed approximately centrally in the interior of the fold.
  • all pleats can be filled simultaneously with a continuous and uniform flow of drug-containing composition.
  • the catheter balloon When coating or filling one or all folds, the catheter balloon may be in a vertical or horizontal position or an oblique position.
  • the rotation or rotation of the catheter balloon in the direction of the fold openings can also serve to distribute the compositions located in the folds or under the folds uniformly in the respective fold.
  • This rotation of the fold balloon may be particularly advantageous in the use of oily or pasty drug-containing compositions to ensure a uniform distribution of the drug-containing composition in the folds as well as on the inner surface of the folds.
  • the term “coating” also primarily refers to the coating of the inner wrinkles surfaces, wherein the entire interior of the wrinkle is usually not filled with drug-containing composition or after drying with the remaining composition.
  • the term “filling” rather the complete filling of the wrinkle interior with drug-containing composition.
  • additives substances with high boiling points, such as oils, are used as additives, a more or less complete filling of the wrinkles is possible, provided that no appreciable amounts of volatile substances are present in the active substance-containing composition.
  • additives is optional.
  • This spraying method or syringe method is particularly suitable for introducing active ingredient-containing compositions into the folds of catheter fold balloons, which can not be applied to a catheter balloon, let alone inserted into the folds, by means of conventional dipping or spraying methods.
  • the oily and paste-like coatings and fillings have the advantage that these active substance-containing compositions do not completely dry, but largely retain their consistency. Therefore, it is preferable to use coating solutions which do not become completely hard in air or under a protective gas atmosphere at normal pressure, i.
  • coating solutions which after removal of the solvent or solvent mixture optionally used have a melting point or solidification point less than 20 ° C preferably less than 30 ° C and also have a thick viscous, oily or paste-like consistency, so that even when storing the coated catheter balloon over several months For up to a year, the coating does not run out of the folds.
  • a solvent to be removed is not mandatory, so that a physiologically acceptable solvent can be used, such as polyethylene glycol, glycerol, propylene glycol or the like, which is not removed and remains in the coating and the coating in the wrinkles for the duration the shelf life of coated medical devices is oily or pasty.
  • a physiologically acceptable solvent such as polyethylene glycol, glycerol, propylene glycol or the like, which is not removed and remains in the coating and the coating in the wrinkles for the duration the shelf life of coated medical devices is oily or pasty.
  • this oily or paste-like composition is at least partially generally transferred to the vessel wall and serves as a drug reservoir for a delayed release of active substance from several hours to days to the surrounding tissue and has
  • the positive property of dissolving plaque or counteracting the deposition of plaque is itself biodegraded thereafter, without releasing physiologically harmful degradation products.
  • This system perfectly solves the problem of firstly applying a coating to a catheter balloon so securely that it is not washed away by the bloodstream or transferred to it by touching the vessel wall during insertion, and secondly, at the site of action during dilatation a relatively short time, ie enough drug is transferred to the vessel wall within 30 to 300 seconds, ie as little as possible coating remains on the catheter balloon and as much as possible, ie at least 50% of the coating is transferred to the vessel wall to effectively counteract the formation of restenosis ,
  • Such systems according to the invention can be prepared not only by the spraying method but also by the other coating methods described herein.
  • a plurality of dispensing openings in series are pushed or brought under the fold of the fold balloon and at the same time an active ingredient-containing composition is dispensed from the plurality of dispensing openings into the respective fold.
  • the dispenser preferably consists of 2 to 10 nozzles or dispensing openings, which are arranged at preferably uniform intervals along the longitudinal direction of the folds.
  • This dispenser is then inserted under the fold of the catheter balloon and the respective fold is filled or coated by simultaneous delivery of the drug-containing composition from the nozzles or other delivery ports.
  • the filling of a fold takes about 5 to 80 seconds, preferably about 15 to 60 seconds and more preferably about 25 to 45 seconds with a pleat length of 10 mm and the use of 4 dispensing openings.
  • the discharge openings are preferably also located substantially in the middle of the cavity under the folds.
  • it is not necessary that the dispensing device is moved in the fold of the catheter balloon relative to the fold longitudinal direction.
  • the catheter balloon and dispenser are fixed during filling or coating, but movement along the longitudinal direction of the fold is possible. If a relative movement is provided, the distance for the movement is preferably not greater than the distance between two nozzles or discharge openings of the dispenser.
  • the dispensing device comprises or consists of at least 2 and a maximum of 10 dispensing openings or nozzles or the like and preferably from 3 to 6 and more preferably from 4 or 5 dispensing openings or nozzles or the like, which are preferably evenly distributed over a distance of 10 mm.
  • the dispenser has 2 to 10 nozzles or similar openings which are capable of uniformly dispensing or evenly spraying the active ingredient-containing composition into the fold.
  • the catheter balloon is in compressed, i. deflated condition. Even a partial or minor inflation of the catheter balloon is usually not required to open the folds a little. Nevertheless, the filling of the wrinkles can occur with a slight inflation of the catheter balloon of a maximum of 10% of the diameter provided during the dilatation.
  • the filling of the pleats can also be done with a slight expansion of the pleats by applying 100 kPa (1 bar) overpressure, preferably 50 kPa (0.5 bar) overpressure, to slightly widen the pleats.
  • the catheter balloon is rotated, so that the next fold to be coated preferably lies upwards and preferably horizontally. The wrinkle filling or folding coating process is now repeated.
  • the drying is preferably carried out by evaporation of the solvent.
  • this method it is also possible to simultaneously fill or coat two, more than two or all of the folds of a catheter balloon, if the consistency of the drug-containing composition permits this, i. the consistency is not so thin that the composition leaks out of the non-horizontal folds.
  • a corresponding circular array of dispensers corresponding to the number of folds is provided around the preferably vertically disposed catheter balloon, and by rotation the dispensing openings are passed under the folds, where concurrent delivery of the drug-containing composition occurs.
  • the final drying takes place.
  • it is of course not necessary that all folds of the catheter fold balloon be filled, but the filling of all wrinkles is the common and preferred embodiment, since during dilation in the shortest possible time a maximum amount of drug to be transferred to the vessel wall.
  • the drying of the last wrinkles i. the content of the last fold preferably without vacuum under atmospheric pressure by evaporation of the solvent.
  • This predrying can be followed by final drying, which according to the invention is carried out with a rotating catheter balloon. If required or desired, vacuum can also be applied during the rotation. This particular drying process is described in more detail following the coating process of the invention.
  • a particularly preferred method for the entire surface coating as well as for the targeted coating or filling of the folds is the so-called dragging process or droplet dragging process.
  • This method makes it possible to coat a catheter balloon in the folded state with a liquid drug-containing composition over its entire circumference inside and outside the fold.
  • the balloon is approximated and then a volume of the drug-containing composition is metered to form a drop at the tip of the delivery device that is in contact with both the metering device and the balloon.
  • the metering device may preferably be lengthened with a thin wire, thread or sponge-like aid at the outlet end, so that the liquid contact between the metering device and the balloon is made and maintained via this aid when approaching.
  • a dispensing needle with a side opening or a fork-shaped extension.
  • the droplet By lateral movement of the dosing device along the longitudinal direction of the balloon relative to the rotating balloon, the droplet is entrained and, per distance traveled, a certain amount of the drug-containing composition dries as a thin film on the swept area.
  • the droplet size is maintained by adding the drug-containing composition until the target dosage is reached. The movement is maintained until the entire target area is coated and no fluid is left on the balloon surface.
  • the balloon can be pre-wetted with suitable solvent, since the folds are already filled with liquid and the capillary effect does not fill the drop sucks or possibly the better adhesion of the filling material on the balloon material may meet.
  • a particularly preferred embodiment is therein, at the tip of the dispenser or to guide or fasten, by the dispenser or at least through the terminal opening of the dispenser, a thread or wire which then serves to contact the balloon surface without the tip of the dispenser contacting the balloon.
  • This thread or wire is made of a material that can not damage the balloon material.
  • a thread or wire may also be a sponge or sponge-like container, a piece of textile or a correspondingly thin-sized piece of leather or a bundle of hair or bristles are used.
  • these means consist of materials which do not damage the catheter balloon, ie are neither sharp nor angular or emit corrosive, basic, acidic or sticky substances or chemicals which dissolve, dissolve, decompose, stiffen, scratch, the polymer of the catheter balloon or can cut.
  • the tip of the dispenser can be kept at a certain distance from the balloon surface and yet controlled via the contact device in the form of thread, wire, sponge, leather strip, bristle or textile piece of the drops and the movement of the drop relative to the balloon surface and can be controlled.
  • a preferred embodiment consists of a horizontally located and rotating balloon with a top-mounted and moving along the longitudinal axis of the balloon dispenser. In this embodiment, a spiral coating of the entire surface of the catheter balloon takes place.
  • the movement of the catheter balloon in a horizontal position takes place at intervals. With the balloon in place, the dispenser will move along the longitudinal direction of the catheter balloon in an approximately straight line from one end to the other and back again, rotating the balloon a few degrees as the dispenser reaches the distal or proximal end of the catheter balloon. This embodiment results in a linear coating of the entire balloon surface.
  • This method also has the great advantage that the tip of the dispensing device, which is usually made of hard material, does not touch the balloon material, as in the case of the drag-drag method, and therefore there is no damage to the catheter balloon.
  • the suture is pulled horizontally across the balloon surface along the longitudinal direction of the balloon axis, delivering a rapidly drying trace of drug-containing solution.
  • this method is not limited to an embodiment with a thread, but it can also simultaneously several threads are moved across the balloon surface, in which case the balloon is preferably arranged vertically.
  • the threads can also be connected to each other or form a network. In this case, the threads are connected to at least one dispensing device, which continuously supplies the threads or the net with a solution containing active ingredient.
  • This method is thus suitable for complete and partial coating of the balloon surface. If, on the other hand, only the wrinkles are to be filled or coated, it is possible to insert a thread into the fold at least partially or to insert it into the fold during folding of the balloon and to allow the active ingredient-containing solution to flow into the fold via this thread, wherein after filling the Fold the thread is preferably removed again.
  • the targeted filling of the wrinkles is also particularly a combination of pipetting and thread drag method, wherein the dispenser over the thread such a large amount of drug-containing solution is delivered at the proximal or distal end in the unfilled fold of an inflated catheter balloon, that the capillary effect Pull the solution into the fold.
  • the drip drag method as well as the thread drag method both elegantly solve the problem of coating or filling the balloon surface as well as the targeted folds of the balloon with a defined amount of active ingredient without damaging the balloon material.
  • the dispensing device can have a measuring device which records or indicates the dispensed amount of active ingredient-containing solution.
  • these methods are particularly suitable for coating and / or filling the folds of a balloon in the deflated (folded) state, which is particularly demanding since the balloon surface of a collapsed balloon is not uniform and the usual uniform body coating techniques have only corresponding problems can be applied.
  • differences in distance between the surface of the balloon and the dispensing device are elegantly compensated in the drag dragging and dragging process by the contact device in the form of thread, wire, sponge, leather strip, bristle or textile piece.
  • a preferred variation of the droplet drag process is to use a coating head which is spherical.
  • the ball has a diameter so that it just can not fall out of the outlet opening of the coating container. It closes the vessel completely so that no coating solution can escape between the sphere and the vessel wall. If pressure is exerted on this ball by the contact with the object to be coated, the ball pushes into the container according to the variably exerted pressure and the coating solution can escape between the ball and the vessel wall of the coating container. With simultaneous movement of either the coating container or the object to be coated and the desired angle to each other, the ball rolls on the surface and ensures a particularly uniform coating of the surface.
  • the various objects can be faithfully coated because the ball can roll over the function of the adjustable pressure and angle, the surface as a sensor and thus offers particularly high variability in terms of.
  • This type of coating is very well applicable, especially with catheter balloons, since each catheter balloon has a different surface design, is uneven and does not resemble a balloon surface of the other.
  • a preferably optically controlled ballpoint pen coating process offers the possibility to uniformly coat arbitrarily different and uneven and uneven surfaces.
  • the ball head for the transfer of the coating solution has the advantage that it does not damage the catheter balloon surface and the ball head or ball can be made of a soft or rubbery material such as rubber, silicone or polymers of similar consistency which is even more gentle on the balloon surface is compared to a metal ball.
  • the coating device can be configured such that a three-dimensional movement is possible, so that the entire catheter balloon can be coated without even settling or restoring the ball head once. After a serpentine descending of the balloon surface to be coated, the ball head of the coating device again reaches the starting point, meanwhile the initially coated webs have dried and another can be applied to the first coating layer, whereby coating and drying operations can be carried out without interrupting the entire coating process.
  • the coated or filled catheter balloons may be dried in the rotating state after filling or coating each fold or after coating or filling all folds or pleats to be coated, unless all pleats are to be coated or filled , This is usually indicated in the inventive method as step f).
  • the active ingredient-containing composition is thereby dried and moreover distributed evenly in the folds as well as on the surface within the folds.
  • Rotary drying is particularly suitable for oily or viscous active ingredient-containing composition to achieve a uniform distribution of the composition in the respective fold, these coatings are not dry, but retain their viscous, oily, gelatinous or pasty consistency, which also desired and is very preferred.
  • vacuum can be applied during the rotation of the catheter balloon in order to achieve intensive drying of the active substance-containing composition.
  • the direction of rotation is decisive.
  • the direction of rotation is in the direction of the fold openings, when viewed from inside the fold.
  • the catheter balloon is rotated as a paddle wheel of a bucket wheel excavator, so that the drug-containing composition is pressed into the interior of the fold due to the rotational force.
  • the pleated balloon is rotated at a rotational speed of 50 to 500, preferably 150 to 300 revolutions per minute.
  • the suitable coating method according to the invention can be selected.
  • All coating methods according to the invention which specifically allow the coating or the filling of the folds, are suitable, optionally together with the rotary drying method, to allow a non-solid but oily, gel-like, pasty or viscous coating or filling of the folds.
  • the wrinkle spraying method is preferably suitable for thin-viscose to medium-viscosity active substance-containing compositions, while the pipetting method is preferably suitable for slightly viscous, medium-viscosity to slightly viscous compositions and the spraying process is particularly suitable for medium-viscosity, viscous to highly viscous compositions.
  • viscosity refers to the dynamic viscosity [ ⁇ ]:
  • the spraying method can preferably be used with thick-viscosity compositions. Preference is given to viscosities at room temperature in the range of oils (olive oil: 10 2 mPa s), honey (10 3 mPa s), glycerol (1480 mPa s) or syrup (10 5 mPa s). Of course, this method also works with thin-viscous solutions with ⁇ 10 2 mPa s.
  • the pipetting method may preferably be used with medium-viscosity compositions.
  • room temperature viscosities are in the range of preferably 0.5 mPa s to 5000 mPa s, more preferably in the range of 0.7 mPa s to 1000 mPa s, even more preferably in the range of 0.9 mPa s to 200 mPa s and particularly preferably in the range of 1, 0 mPa s to 100 mPa s.
  • This viscosity range are compositions of oils, contrast agents and / or salts, which are diluted with conventional solvents, in particular alcohols.
  • the pipetting method can be used over a very wide viscosity range.
  • the wrinkle spray method may preferably be used on thin-viscous compositions. Preference is given to viscosities at room temperature in the range of preferably 0.1 mPa s to 400 mPa s, more preferably in the range of 0.2 mPa s to 100 mPa s and particularly preferably in the range of 0.3 mPa s to 50 mPa s (water : 1, 0 mPa s, petroleum: 0.65 mPa s, pentane: 0.22 mPa s, hexane: 0.32 mPa s, heptane: 0.41 mPa s, octane: 0.54 mPa s, nonane: 0 , 71 mPa s, chloroform: 0.56 mPa s, ethanol 1, 2 mPa s, propanol 2.3 mPa s, isopropanol: 2.43 mPa s
  • catheter balloons can be coated without a stent and sometimes also with a stent, so that the present invention relates to coated catheter balloons which can be obtained according to the methods described herein.
  • a particularly preferred embodiment uses a crimped stent catheter balloon.
  • the stent may be an uncoated (bare) stent, or preferably a stent coated only with a hemocompatible layer.
  • hemocompatible coating in particular, the heparin derivatives or chitosan derivatives disclosed herein are preferred and primarily defulfated and reacetylated or re-propionylated heparin.
  • Any solvent that may be used may be removed under reduced pressure and the crumpled mixture thereby dried.
  • the wrinkles or bulge or bulge outward thereby giving their contents to the vessel wall.
  • the methods according to the invention are suitable not only for coating catheter balloons but also for coating guidewires, spirals, catheters, cannulas, tubes and generally tubular implants or parts of the abovementioned medical devices, if a structural element comparable to a stent is contained in such a medical device coated or filled.
  • vascular supports and in particular stents such as, for example, coronary stents, vascular stents, tracheal stents, bronchial stents, urethral stents, esophageal stents, biliary stents, renal stents, small intestinal stents, colon stents.
  • stents such as, for example, coronary stents, vascular stents, tracheal stents, bronchial stents, urethral stents, esophageal stents, biliary stents, renal stents, small intestinal stents, colon stents.
  • the coated medical devices are used in particular for keeping open all gait-like structures, such as urinary tract, esophagus, trachea, biliary tract, kidney, blood vessels throughout the body including the brain, duodenum, pilorus, small and large intestine but also to keep open artificial outputs, as they are for the Intestine or used for the trachea.
  • coated medical devices are useful for preventing, reducing or treating stenosis, restenosis, arteriosclerosis, atherosclerosis, and all other forms of vascular occlusion or vessel narrowing of passageways or exits.
  • the catheter balloons without stents coated according to the invention are particularly suitable for the treatment of in-stent restenosis, i. for treating a new vasoconstriction within an already implanted stent, which is preferably not bioresorbable.
  • in-stent restenosis setting another stent within an already-existing stent is particularly problematic since the vessel usually can not be expanded sufficiently by the second stent.
  • the drug application by means of balloon dilatation offers an ideal treatment option, since this treatment can be repeated several times, if necessary, and can achieve the same or significantly better therapeutic results than the re-stent implantation.
  • the catheter balloons coated according to the invention without a crimped stent are particularly suitable for treating small vessels, preferably small blood vessels.
  • small vessels are those with a vessel diameter less than 2.5 mm, preferably less than 2.2 mm.
  • additives and auxiliaries such as their mixtures and combinations, preferably have at least one of the following properties for the successful local application of one or more active substances: 1) the contact time of the short-term implant is sufficient to transfer a suitable amount of therapeutic agent into the cells,
  • the active substance-containing coating present on the short-term implant has a higher affinity for the vessel wall than for the implant surface, so that an optimal transfer of the active substance to the destination can take place. This is done very well for all pasty, gel or oily coatings.
  • a coated or uncoated stent can form a system with the balloon catheter depending on the individual case of need.
  • the other aids such. the imaging agents zusetzbar if necessary.
  • the contact time is already sufficient to apply a therapeutic amount of the paclitaxel deposited by the spray technique in amorphous form to and into the cell wall together with the at least one transport mediator.
  • a stent made hemocompatible with the semisynthetic oligosaccharide and likewise coated with paclitaxel serves here as a reservoir for elution of further amounts of active compound provided over a relatively long period of time.
  • paclitaxel Due to the amorphous consistency of paclitaxel on the stent and catheter balloon, obtained by the special spraying method, paclitaxel is not flushed or washed away from the surface of the balloon during insertion of the catheter so that the desired amount of drug arrives at the target site and here via dilatation is delivered to the vessel wall. Due to the simultaneous coating of the stent and catheter balloon is also a complete vascular coverage with active ingredient.
  • the catheter balloon is also coated with paclitaxel in the area beyond the stent ends, so that a vascular supply with paclitaxel (or instead of paclitaxel also with any other active substances) also in the area of the stent ends and 1 to 3 mm in the proximal and distal direction beyond.
  • a vascular supply with paclitaxel or instead of paclitaxel also with any other active substances
  • the amorphous structure is of particular importance, since only so the surface of the drug layer is increased in such a way that an optimal amount of the drug adhere to the cell wall and can get into the cell wall or the cells.
  • a directly acting on the cell wall vasodilator or slightly membraneben carrier eg DMSO, PETN, lecithin
  • the inclusion in the Cells during the cumulative contact time preferably 30 to 300 seconds significantly increase.
  • the active ingredient is mixed with a longer-chain fatty acid ester, e.g. Glycerol monooleate dissolved in a suitable solvent and applied to the balloon catheter surface.
  • a longer-chain fatty acid ester e.g. Glycerol monooleate dissolved in a suitable solvent
  • All coating methods described below are suitable for coating.
  • the addition of the glycerol ester allows the transfer of coating material from the catheter surface to the vessel wall, with the amount of the drug-eluting coating transferred sufficient to provide the drug in sufficient concentration as well as preventing the immediate rinsing of the coating in the bloodstream.
  • Another particularly preferred embodiment consists in the use of a taurine to the cell wall mixture of the polysaccharide carrageenan, phosphatidylcholine, one of the main components of cell membranes, membrane permeable substance and glycerol, due to the very good adhesion property delayed drug release of up to 12 hours after dilation of Vessel allows. All coating methods are suitable for this embodiment, with particular preference being given to the methods of pipetting, thread dragging and the ballpoint pen method described herein.
  • FIG. 1 shows a coating device according to the ballpoint pen method, wherein the coating solution is located in the interior of the coating device, which is dispensed via a rotatable ball onto the surface to be coated.
  • Curcumin and paclitaxel are dissolved in chloroform. The procedure is as in 1A.
  • Fosfestrol is an antineoplastic agent and at the same time a transport mediator. Therefore, Fosfestrol can be used without further addition.
  • Fosfestrol as a transsort mediator is to achieve a combination of active ingredient effects.
  • the procedure is as in Example A1.
  • Example A1 Solvent is methanol.
  • R. tibolone and paclitaxel The procedure is as in Example 1 A.
  • 0.5 mg of ascorbic acid ether is dissolved in 0.5 .mu.l of chloroform and combined with a solution of 19.5 mg of rapamycin in 0.5 .mu.l of chloroform.
  • Example 2 Coating of a balloon in two steps with coniferyl alcohol and rapamycin in the ratio 9: 1 (wt%) and 5: 5 according to Example 1Aa and c)
  • the thin-viscous mixture from example 1Ac is first applied by means of a dipping process to a catheter balloon in compressed form.
  • the balloon is introduced vertically into the dipping solution and slowly (v ⁇ 1 mm / s) pulled out of the solution again vertically that a uniform bubble-free film can form on the surface of the catheter.
  • the wrinkles are refilled by means of a pipetting method for 30 minutes.
  • the coated balloon catheter is mounted on a rotary motor with a tilt angle of 25 ° such that the balloon catheter can not kink.
  • the dosing syringe which terminates in a blunt cannula, is positioned so as to be inserted from the raised fold end into the fold and deliver a defined amount of the coating solution into the fold.
  • After filling the fold of the balloon catheter is rotated after a waiting time of up to 30 sec. About its longitudinal axis, so that the next fold can be filled.
  • Example 3a The tilt angle allows the capillary action and gravity to be used to fill the fold completely or partially depending on the desired dosage.
  • the coating cannula is positioned so that during movement from the proximal to the distal end of the fold, and vice versa, it grasps such that only the portion of the pleated material which simultaneously fills with coating solution during movement of the cannula along the fold rises.
  • the speed with which the cannula moves horizontally along the fold and the depth of penetration into the fold are adjusted so that the fold closes evenly after the filling step.
  • the drying of the balloon catheters coated in this way takes place by means of rotary drying at room temperature.
  • a catheter balloon is coated with a biostable cellulose nitrate coating by drop dragging.
  • the catheter is fixed in such a way in the adapter of the rotary motor that it is fixed in a horizontal position, without kinking or sagging is possible.
  • the dispensing device is fixed over the balloon so that the distance of the pipette from which the coating solution emerges is just so great that the exiting droplet makes contact with the surface of the balloon without it having detached itself from the pipette tip.
  • the rate at which the coating solution exits is set so that the droplet can not break during the longitudinal movement of the catheter balloon. If in this way the upper surface of the balloon is completely coated, the balloon is turned so far that the neighboring area can be coated in the same longitudinal direction. The process is repeated until the balloon catheter completes
  • a coating solution according to Example A-V or even a mixture of such coating solutions can be applied to the balloon on this layer.
  • the paclitaxel drug layer may be provided with a barrier layer of polylactides, polyglycolides, polyanhydrides, polyphosphazenes, polyorthoesters, polysaccharides, polynucleotides, polypeptides, polyolefins, vinyl chloride polymers, fluorine-containing polymers, teflon, polyvinyl acetates, polyvinyl alcohols, polyvinyl acetals, polyacrylates, polymethacrylates, polystyrene, Polyamides, polyimides, polyacetals, polycarbonates, polyesters, polyurethanes, polyisocyanates, polysilicones and copolymers and mixtures of these polymers are coated.
  • the balloon catheter is coated over the entire surface with an alcoholic solution of a meristyl alcohol and paclitaxel (or another active substance or combination of active substances) by means of a thread-drag method.
  • a 2% (Meristylalkohol examples is prepared in which so much paclitaxel is dissolved that a 30% (wt%) drug solution is obtained.
  • the balloon is completely coated and then dried with slow rotation about the longitudinal axis for at least three hours at room temperature. This process is repeated at least once.
  • the balloon catheter coated in this way can be treated with a 1% PVA solution, for example with a top coat, in the same way or with another suitable method, such as e.g. the rolling process are coated.
  • the expanded to nominal pressure pleated balloon is immersed in a 1% paclitaxel / chloroform dip solution for 5-10 s and then dried with rotation about the longitudinal axis to the extent that most of the chloroform has volatilized. Before complete drying, the balloon is deflated again in the air stream.
  • the Paclitaxel solution can optionally be supplied to a transport mediator.
  • each wrinkle with a honey to syrupy viscous (viscosities of 10 2 to 10 5 mPa-s) containing active as well as optional transport mediator-containing solution (eg from Example 17) with a slowly from the wrinkle beginning to wrinkle end performed Teflon cannula as an extension of a Needle syringe filled.
  • a honey to syrupy viscous viscosities of 10 2 to 10 5 mPa-s
  • optional transport mediator-containing solution eg from Example 17
  • Teflon cannula is guided to the middle of the cavity formed by the fold and during the movement of the horizontally fixed catheter in its longitudinal direction is a defined amount of highly viscous solution in the Wrinkle cavity discharged (syringe method).
  • the amount of filled material is limited so that the fold does not lift off the balloon body after filling and varies according to the different balloon dimensions and manufacturer.
  • Example 5a drug-loaded and again deflated balloon such as in Example 5b partially drug-loaded fold balloon
  • a polymeric outer layer as a barrier
  • the concentration of the polymeric spray solution must be kept so low that the polymer layer obtained after drying does not hinder the uniform development.
  • a 0.5% PVP solution is already suitable here.
  • the polymer solution is optionally added a transport agent according to the list on page 22.
  • a catheter balloon is coated with a drug layer of Paclitaxel and Transportvermitler.
  • the catheter balloon is provided with a protective sheath such as is used in self-expanding nitinol stents.
  • the protective cover can be removed in vivo immediately before dilatation.
  • a solution of desulfated heparin in a methanol-ethanol mixture is prepared and acidified with acetic acid to give a pH of 3 to 5. Paclitaxel is added to this solution.
  • a catheter balloon is coated with this solution, followed by a slight cross-linking of the dried coating on the balloon by means of glutaraldehyde.
  • Paclitaxel is dissolved in DMSO, which contains about 10% by volume of water. Potassium oxalate, sodium chloride, glutamic acid and oxalic acid are added to this solution and the catheter balloon is floated several times with this solution using the thread drag method and dried after each brushing operation. Thereafter, the coated catheter balloon is provided with a biodegradable layer of a lactam.
  • a transport broker according to p. 22 can be included in both layers or in one or the other.
  • Paclitaxel is mixed with magnesium sulfate, potassium chloride, lithium chloride and sodium acetate and made into a paste by adding an alcoholic solvent and a transporting agent which is then filled into a syringe and injected under the folds of a pleated balloon. During coating, the tip of the spray nozzle moves along the fold and places a layer of the paste in the fold along the pleated longitudinal direction.
  • a low-viscosity ethanol solution of paclitaxel is applied, which is so thin-viscous that this solution draws itself into the folds of a fold balloon due to capillary forces.
  • the alcoholic paclitaxel solution is allowed to flow into the fold until the wrinkle interior has completely filled up due to capillary forces. Allow the fold contents to dry, turn the balloon and fill the next fold. Each fold is filled only once.
  • 100 pg of benzethonium chloride are used as transport mediator per ml of ethanol.
  • a mixture of 70% linseed oil and 30% olive oil is produced. This mixture is dissolved in chloroform at a mixing ratio of 1: 1 and, after addition of paclitaxel (25% by weight) and ocime (2% by volume), applied to the uniformly rotating balloon catheter by means of a rolling process. After evaporation of the chloroform in a gentle stream of air, the balloon catheter is stored in a drying oven at 70 ° C, so that an already adhering to the surface but soft, highly viscous and thus not disabling the expansion of the balloon surface is provided.
  • a cobalt-chrome stent is crimped onto a polyamide catheter balloon.
  • a solution of paclitaxel and transport mediator in DMSO is applied to the stent by means of a syringe.
  • the solution is so thin viscous that it runs between the closely fitting stent struts and fills the spaces between the balloon surface and stent inner side and between the individual stent struts.
  • the solvent evaporates and the pure drug deposits as a solid on the catheter balloon under the stent, in the stent spaces and on the stent and balloon surface.
  • the catheter balloon is coated at both ends of the stent about 2 to 3mm beyond the stent end with the drug.
  • a solution of rapamycin in ethanol is prepared and this solution is sprayed several times onto a catheter balloon without a stent and the catheter balloon is occasionally dried by allowing the solvent to evaporate.
  • Example 14 After repeating the spray coating three times, with the transporting agent Linaool being present in the spray solution in the last step of the spray coating, the catheter balloon is dried for the last time and an uncoated metal stent is crimped onto the balloon.
  • Example 14 After repeating the spray coating three times, with the transporting agent Linaool being present in the spray solution in the last step of the spray coating, the catheter balloon is dried for the last time and an uncoated metal stent is crimped onto the balloon.
  • a commercially available catheter balloon is coated with an amount of 3 pg paclitaxel per mm 2 balloon surface.
  • the coating is carried out by pipetting using a solution of paclitaxel in acetone and a transport agent according to the selection on page 22. , An uncoated cobalt-chromium metal stent is then crimped onto the coated catheter balloon.
  • a catheter balloon is coated with crimped uncoated metal stent with a solution of paclitaxel and papain in DMSO using the drop drag process.
  • the coating process is repeated three to four times until it is clear that the interstices between the balloon surface and the stent inner side as well as the interstices between the individual stent struts are filled with active substance.
  • a protective layer of, for example, a polylactide may now be applied to the active substance layer with paclitaxel.
  • a commercially available catheter balloon is coated with a dispersion of paclitaxel and maltitol in ethyl acetate with 5% by volume of acetic acid to give an amount of 2-3 pg of paclitaxel and 0.1 pg of 0.2 pg of maltitol per mm 2 of balloon surface.
  • a bioresorbable stent of polyhydroxybutyrate is crimped onto the coated balloon surface.
  • a catheter balloon coated in the folds by capillary paclitaxel method and having an amount of 1-2 pg paclitaxel per mm 2 fold is crimped with a titanium stent coated with a polymeric carrier system of a polyethersulfone containing the active ingredient paclitaxel in a preferably cytostatic dose is.
  • the titanium stent was previously coated by pipetting with a solution of paclitaxel and the polyethersulfone in methylene chloride. On the titanium stent are about 0.5 pg paclitaxel per mm 2 stent surface.
  • a catheter balloon coated with rapamycin transport mediator A bioresorbable stent made of polylactide, which is coated with a coating of polylactide containing paclitaxel in an amount of approximately 1.0 ⁇ g paclitaxel per mm 2 stent surface, is then crimped onto this catheter balloon.
  • a non-dilated fold balloon is coated over the entire surface with an active ingredient and an excipient as carrier with the aid of the described pipetting method.
  • the sheath balloon coated according to Example 19 is introduced into a silicone tube filled with PBS and expanded therein to a nominal pressure of 60 sec. Subsequently, the sirolimus content remaining on the balloon catheter, the proportion dissolved in the PBS buffer and the active substance content adhering to the inner wall of the tube are determined by HPLC measurement after extraction with acetonitrile:
  • sirolimus 100 mg are dissolved in 3.5 ml of acetone and mixed with a solution of 2 mg acesulfame K in 500 ⁇ l ethanol.
  • Example 24 The cleaned or covalently coated stents are crimped onto the balloon catheter and coated together with the active substance-containing spray solution according to Example 1A-V by means of thread dragging method.
  • Example 24
  • Coating solution Polylactide RG502 / Taxol solution is made up of 145.2 mg of polylactide and 48.4 mg of taxol to 22 g with chloroform.
  • Base coat 19.8 mg of linseed oil and 6.6 mg of taxol are made up to 3 g with chloroform
  • Topcoat 8.8 mg of taxol are made up to 2 g with chloroform.
  • the balloon catheter with crimped stent is coated with the base coat using the drop drag method. As soon as this base coat becomes a highly viscous film due to the evaporation of the solvent on the system surface, the second pure active substance layer can be sprayed on.
  • the transport mediator carrageenan, phosphatidylcholine and glycerol (1: 2: 2) are dissolved in ethanol-water (1: 1, v: v)). 200 ml of Biolimus A9 are subsequently dissolved in 10 ml of this solution.
  • Thread dragging method
  • a solution of rapamycin in ethanol is prepared and this solution is sprayed onto a catheter balloon without a stent twice and the catheter balloon is occasionally dried by allowing the solvent to evaporate.
  • the solution P from Example 1 is used in the third step, with the transport mediator Fosferol as a spray solution and the catheter balloon is dried for the last time and an uncoated metal stent is crimped onto the balloon.
  • the ratio of rapamycin to fosferol is 10: 1.
  • a low-viscosity ethanolic solution of paclitaxel and vanillin in a ratio of 2: 1 is applied, which is so thin-viscous that this solution draws itself into the folds of a fold balloon due to capillary forces.
  • the alcoholic paclitaxel solution is allowed to flow into the fold until the wrinkle interior has completely filled up due to capillary forces. Allow the fold contents to dry, turn the balloon and fill the next fold. Each fold is filled only once.
  • a nominal balloon expanded balloon is immersed in a 1% paclitaxel / chloroform dipping solution containing maltol (0.5% by weight) for 5-10 seconds and Then, while being rotated about the longitudinal axis, it has dried to such an extent that the major part of the chloroform has volatilized. Before complete drying, the balloon is deflated again in the air stream.
  • the paclitaxel solution can optionally be fed to another transport mediator.
  • each fold is filled with a honey syrup to syrupy (viscosities of 10 2 to 10 5 mPa-s) solution of rapamycin in THF with diethylene glycol dauryl ether with a slowly from the beginning of wrinkles to the wrinkle end Teflon cannula performed as an extension of a needle syringe.
  • honey syrup to syrupy viscosities of 10 2 to 10 5 mPa-s
  • Teflon cannula is guided to the middle of the cavity formed by the fold and during the movement of the horizontally fixed catheter in its longitudinal direction, a defined amount of highly viscous solution in the corrugated cavity is discharged (syringe method).
  • the amount of filled material is limited so that the fold does not lift off the balloon body after filling and varies according to the different balloon dimensions and manufacturer.
  • a commercially available catheter balloon is coated with an amount of 3 g paclitaxel per mm 2 balloon surface.
  • the coating is carried out by pipetting using a solution of paclitaxel in acetone and ferulic acid (solution F of Example 1).
  • An uncoated cobalt-chromium metal stent is then crimped onto the coated catheter balloon.
  • Paclitaxel is dissolved in DMSO, which contains about 10% by volume of water. Potassium oxalate, sodium chloride, glutamic acid, oxalic acid and the transport mediator Octylphenylethoxylates are added to this solution and the catheter balloon is repeatedly coated with this solution using the thread-tow method and dried after each brushing operation. Thereafter, the coated catheter balloon is provided with a biodegradable layer of a lactam.
  • a non-dilated fold balloon is coated over the entire surface with an active ingredient and a transport mediator using the described pipetting method.
  • paclitaxel 160 mg are dissolved in 5 ml of methanol and mixed with a solution of 200 .mu.g of 1, 2,3 butanetriol in 400 .mu.l ethanol. After application of the solution of the fold balloon is dried overnight in a drying oven at 70 ° C.
  • the balloon catheter is attached via an adapter to the drive shaft of the rotation smotors and fixed so that it comes to rest in the horizontal without kinking. After a slight vacuum has been drawn on the balloon, the balloon is coated with the solution and the set number of 4 balloon sweeps. Through the dispensing needle and the welded towing wire, a drop of coating solution is dragged over the rotating balloon until the solvent has evaporated so far that a solid coating has formed. The catheter is then removed from the machine and dried overnight at room temperature and further rotation.
  • the transport mediators stearyl alcohol and 1, 2,4 butanetriol (1: 1, w / w) are dissolved in ethanol / water (3: 1, v: v)). In 10 ml of this solution, 400 pg of paclitaxel are then dissolved.
  • a commercially available balloon catheter with an expandable polyamide balloon is provided.
  • Paclitaxel was dissolved in acetone together with benzethonium fluoride in the concentration of 50 mg paclitaxel and 100 pg benzethonium halide per ml acetone.
  • This coating solution is applied to the catheter balloon by the ballpoint pen method according to the invention.
  • the resulting coating is dried overnight at room temperature and sterilized with ethylene oxide.
  • Paclitaxel is mixed with magnesium sulfate and sodium acetate and made into a paste by the addition of methanol and lanolin, which is then filled into a syringe and injected under the folds of a pleated balloon. During coating, the tip of the spray nozzle moves along the fold and places a layer of the paste in the fold along the pleated longitudinal direction. This results in a coating with an amount of 3 pg paclitaxel per mm 2 balloon surface.
  • a commercially available catheter balloon is coated with an amount of 2.5 pg picrolimus per mm 2 balloon surface.
  • the coating is carried out by means of pipetting methods according to the invention using a solution of picrolimus and tetradecyltrimethylammonium chloride in acetone.
  • a balloon balloon expanded to nominal pressure is immersed in a 2% paclitaxel / methanol dipping solution with laurocapram (0.2%) for 10 to 15 seconds and then dried with rotation about the longitudinal axis until the major part of the methanol has volatilized. Before complete drying, the balloon is deflated again in the air stream.
  • a non-dilated fold balloon is coated over the entire surface with an active ingredient and a transport mediator using the described pipetting method.
  • paclitaxel and 10 mg of phenolboronic acid are dissolved in 1 ml of methanol. After application of the solution, the fold balloon is dried overnight at room temperature. Thereafter, the coated catheter balloon is provided with a biodegradable layer of a lactam.
  • a catheter balloon with three folds is fixed in a horizontal position on a rotatable axis, so that the fold to be filled always comes to rest on the upper side.
  • step by step each wrinkle with a honey to syrup-like viscous (viscosities of 10 2 to 10 5 mPa-s) 2.5% solution of everolimus in acetone with 1 volume percent QUAB 151 with a slowly from the beginning of wrinkle wrinkle end Teflon cannula performed filled as an extension of a needle syringe.
  • the Teflon cannula is guided to the middle of the cavity formed by the fold and during the movement of the horizontally fixed catheter in its longitudinal direction, a defined amount of highly viscous solution in the corrugated cavity is discharged (syringe method).
  • the amount of filled material is limited so that the fold does not lift off the balloon body after filling and varies according to the different balloon dimensions and manufacturer.
  • An uncoated cobalt-chromium metal stent is then crimped onto the coated catheter balloon.
  • Base coat 19.8 mg of linseed oil, 0.3 mg of alkyl (polyoxyethyl) phosphate and 6.6 mg of taxol are made up to 3 g with chloroform
  • Topcoat 8.8 mg of taxol and 0.5 mg of alkyl (polyoxyethyl) phosphate are made up to 2 g with chloroform.
  • the balloon catheter with crimped stent is coated with the base coat using the drop drag method.
  • this basecoat becomes a highly viscous film as a result of the evaporation of the solvent on the system surface, the second active ingredient layer can be sprayed on by means of the method according to the invention.
  • a commercially available catheter balloon is coated with an amount of 2.5 pg paclitaxel per mm 2 balloon surface.
  • the coating is carried out by means of pipetting methods according to the invention using a solution of 0.5 mg / ml paclitaxel in squalene.
  • a solution of paclitaxel in methanol is prepared and this solution is sprayed onto a catheter balloon without a stent three times and the catheter balloon is occasionally dried by allowing the solvent to evaporate.
  • the paclitaxel solution is used, with the transport mediator diethyl sulfoxide as the spray solution and the catheter balloon is last dried and an uncoated metal stent is crimped onto the balloon.
  • the ratio of paclitaxel to diethyl sulfoxide is 1: 1.
  • paclitaxel 42.7 mg (0.05 mmol) of paclitaxel are dissolved in 5 ml of chloroform and admixed with 9.5 mg (0.03 mmol) of tetrapropyl tartrate.

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Abstract

L'invention concerne des produits médicaux expansibles, mis en contact temporairement avec l'organisme, comme, par exemple, des cathéters à ballonnet, qui sont revêtus d'une couche comportant au moins un agent antiprolifératif, immunosuppresseur, anti-angiogène, anti-inflammatoire, fongicide et/ou antithrombotique et un agent de transport ou un mélange d'agents de transport. L'invention porte également sur des procédés de revêtement de ces produits médicaux expansibles et sur l'utilisation de compositions pour ce revêtement.
EP10781810A 2009-10-16 2010-10-16 Utilisation de compositions pour revêtir des ballonnets de cathéter et ballonnets de cathéter ainsi revêtus Withdrawn EP2461842A1 (fr)

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PCT/DE2010/001220 WO2011044889A1 (fr) 2009-10-16 2010-10-16 Utilisation de compositions pour revêtir des ballonnets de cathéter et ballonnets de cathéter ainsi revêtus

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WO2011044889A1 (fr) 2011-04-21
AU2010306251A1 (en) 2012-05-03
JP2013507204A (ja) 2013-03-04
US20120316496A1 (en) 2012-12-13
CN102573946A (zh) 2012-07-11
IN2012DN02419A (fr) 2015-08-21
IL219165A0 (en) 2012-06-28
MX2012004410A (es) 2012-08-23
KR20120098624A (ko) 2012-09-05
RU2012120089A (ru) 2013-11-27
BR112012006925A2 (pt) 2016-06-07
DE112010004061A5 (de) 2013-02-28
CA2777254A1 (fr) 2011-04-21

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