WO2013079476A1 - Drug-coated medical device and method for the production thereof - Google Patents

Drug-coated medical device and method for the production thereof Download PDF

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Publication number
WO2013079476A1
WO2013079476A1 PCT/EP2012/073711 EP2012073711W WO2013079476A1 WO 2013079476 A1 WO2013079476 A1 WO 2013079476A1 EP 2012073711 W EP2012073711 W EP 2012073711W WO 2013079476 A1 WO2013079476 A1 WO 2013079476A1
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WIPO (PCT)
Prior art keywords
medical device
characterized
paclitaxel
coating
polymer
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Application number
PCT/EP2012/073711
Other languages
German (de)
French (fr)
Inventor
Jürgen Köcher
Klaus-Peter Schmitz
Katrin Sternberg
Svea Petersen
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Bayer Materialscience Ag
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Priority to EP11191315 priority Critical
Priority to EP11191315.8 priority
Application filed by Bayer Materialscience Ag filed Critical Bayer Materialscience Ag
Publication of WO2013079476A1 publication Critical patent/WO2013079476A1/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L29/00Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/08Materials for coatings
    • A61L29/085Macromolecular materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L29/00Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
    • A61L29/14Materials characterised by their function or physical properties, e.g. lubricating compositions
    • A61L29/16Biologically active materials, e.g. therapeutic substances
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/08Materials for coatings
    • A61L31/10Macromolecular materials
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L31/00Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
    • A61L31/14Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L31/16Biologically active materials, e.g. therapeutic substances
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/40Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
    • A61L2300/416Anti-neoplastic or anti-proliferative or anti-restenosis or anti-angiogenic agents, e.g. paclitaxel, sirolimus
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2300/00Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
    • A61L2300/60Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
    • A61L2300/606Coatings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61LMETHODS 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
    • A61L2420/00Materials or methods for coatings medical devices
    • A61L2420/02Methods for coating medical devices

Abstract

The invention relates to a method for providing a medical device that is intended for insertion into human or animal bodies, with a coating that contains at least one pharmacologically active ingredient, wherein the method comprises the following steps: - coating at least one part of the surface of the medical device with a polymer containing cross-linkable groups, - impregnating the polymer with the pharmacologically active ingredient and - post-cross-linking the polymer, which contains cross-linkable groups, on the surface of the medical device by radiation. The invention further relates to a medical device, which can be obtained using the method according to the invention.

Description

Ar / neimitlelheschichtetes medical device and method for its production

The present invention relates to a method for providing a medical device, which is provided around imports into the human or animal body /, coating with a loading which contains at least one pharmacologically active agent in particular for the local treatment of diseased tissues. The invention further relates to a medical

Device which can be produced by this process, wherein the medical device is specifically designed as a balloon catheter.

It is known that blood vessel constriction, a frequently encountered cause door morbidity and mortality. Local constrictions or occlusions of larger vessels can expand back to its original lumen in many cases by means of the expandable balloon catheters. In this technique, however, very high pressures are applied, which lead to cracks in the vessel wall or other injuries, such as bruising and displacement into surrounding tissue can.

In many cases, stents are implanted in addition in these procedures. Here is tubular perforated metal supports that are inserted into the narrowed blood vessel site and will keep the blood vessel open. Recent generations of such stents contain a coating with a drug that is delivered continuously over several months to the vessel wall to support the healing process. Nevertheless, in many cases, the thus treated blood vessel walls respond within a few months with a reinforced growth in thickness, which is comparable to a scarring. This can again lead to vasoconstriction, a so-called restenosis in a short time. In individual cases, subsequent thrombosis have been observed in drug eluting stents, which present a very serious complication. Thus, there remains a need for gentle methods for local treatment of vascular constrictions.

As an alternative to the above methods of treatment of vascular constrictions drug-eluting balloons have been developed in recent years. Such medical devices are, for example, in WO 2002/076509, WO 2004/028582 and WO 2009/018816 and in the publication by B. Kelsch et al., Investigative Radiology 46 (4), 201 1, discloses 255-263. These balloons whose surface is coated with a drug. In use, the balloon is first guided to the desired location in the body and expanded with compressed air, whereby these take the form of a rigid cylinder, WEL rather to the vessel wall fits tightly. By the contact pressure, not only the vasoconstriction is expanded, but also the outside applied to the Ballonoberfiäche active ingredient transferred to the inner vessel wall. this is again contracted by releasing the pressure and removed to remove the balloon. Of the inner vessel wall überira- gene active substance is to prevent an excessive scarring and thus restenosis or at least reduced to a minimum. The advantage over a medikamentenab- imaging stent is the fact that no foreign matter such as the stent in the bloodstream may cause remaining as clotting or inflammation !, the reactions of the blood.

In the commonly employed for the aforementioned purpose drug is paclitaxel. However, according to WO 2010/121840, a coated exclusively with paclitaxel balloon is unsuitable. It is therefore proposed in this document to provide the balloon surface with a mixture of paclitaxel and an additional component, so that the balloon after dilation shows therapeutic efficacy.

The ineffectiveness of pure paclitaxel is due to the fact that this medication has ment lipophilic properties, resulting in a high adhesion to the commercial Ballonoberfiächen, so it can not be transferred to the vessel wall by pressure. Therefore, the paclitaxel specific additives are added, so that can be transferred under pressure to the vessel wall of this. In this case, the additive must be chosen so that a transfer of the paclitaxel is carried on the vessel wall within about 60 seconds. A longer Dilatationszeit is not possible as it is a very high risk for the patient, because during the expansion of the balloon catheter, the vessel to be treated is closed through the catheter.

For this reason, the use as contrast agents iopromide known as an additive for the mixture with paclitaxel in WO 2002/076509 and WO 2004/028582. In WO 2010/121840 is shellac, 2009/051615 surfactant in WO 2009/051614 and WO

Additives proposed. On the Transcatheter Cardiovascular Therapeutics 2010 conference a coated balloon IN.PACT was still presented Medtronic. This is provided with a Medikamentenb chichtung of paclitaxel and urea. This system is also described in B. Kelsch et al., Investigative Radiology 46 (4), 2011, 255-263 described. More hydrophilic additives are described in WO 2009/018816. Although the use of these additives mentioned improves the transfer of paclitaxel to the vessel wall. However, these additives also lead to the fact that during manipulation of the folded balloon through the blood vessels to the stenotic site a significant proportion of paclitaxel is either settled or resolved and is no longer at its final location for Verfü- supply. This effect is reinforced by the commonly used hydrophilic additives. This applies particularly when the additives are water soluble, whereby the stability of the coating during the travel of the balloon through the blood vessels to the stenotic site is greatly impaired. This adverse circumstance is, for example, in the publications as elsch et al, Investigative Radiology 46 (4), 2011, 255-263 and A. De Labriolle et al, Catheterization and Cardiovascular Interventions 73, 2009 643 - mentioned 652nd.. However, the concentration of the active ingredient on the Baiionoberfläche at the site of dilation is not only much lower than the originally coated amount, but is not reproducible or controllable, above all, which can reduce significantly the success of therapy. Several approaches are described in the literature to deal with the principal problem of the current developments described. 2011/0054396 so are the US in a coating on the balloon, which breaks upon dilation of the balloon into small pieces and transferred to the surrounding body tissue. However, there is a risk that the resulting particles of the original coating transferred not only to the body tissue, but also be entered into the bloodstream. Any development of particles in the blood stream is undesirable because of possible side effects. So all interventional devices are checked to see in the medical device industry generally that a limit on concentrations of particulate matter is not exceeded (USP788).

Another approach is described in WO 2010/133557, in which the use of micro- ropartikeln is proposed in a balloon coating. These microparticles containing an active substance which releases the active substance contained under pressure. This method is very complicated, since the micro-particles must be prepared with the active ingredient in a separate step and then incorporated into a coating.

Hydrogels have long been used for drug delivery products as a matrix. It is these polymers are hydrophilic three-dimensional networks, which are insoluble, due to their cross-linking in solvents or water. The use of such hydrogels to coat balloon upper surfaces is therefore not possible and the coating of medical device surfaces was thus tur hardly used. Therefore, it is proposed in EP 1364664, a stent surface first with an adhesion promoter layer and then with a polysaccharide or Hy Alur ons CDCR it to provide chicht, which is then reacted to completion by chemical induced cross-linking to form a hydrogel. I this layer can be stored a pharmacological agent. Such a process is very complex, because usually an adhesive layer must be applied first. In addition, the cross-linking is carried out with chemical reagents. However, it can not be avoided with this method is that a part of these reagents does not react with the polymer and thus remains as a component in the elutable hydrogel. This means an increased toxicological risk, which can only be reduced by very carefully removing possible remaining low molecular weight materials or eliminated. The execution of such cleaning and analytical validation of the complete separation represents a high technical effort.

The object of the present invention to provide an improved process for coating-medical devices, the coatings obtainable thereby the one hand enables a reliable transfer of data contained in the coating pharmakologis ch active ingredients, however, while the during the transfer through the body of the patient stenotic site showing the least possible loss of active substance.

This object is solved by a method / for providing a medical device, which is intended to be inserted into the human or animal body /, having a coating containing at least one pharmacologically active agent, the method comprising the steps of:

• coating at least a portion of the surface of the medical device with a cross-linkable group-containing polymer, · impregnate the polymer with the active agent and pharmakologis ch

"Post-crosslinking of the crosslinkable group-containing polymer on the surface of the medical device by the action of radiation.

The medical device can thus be partially or completely coated. In this case, preferably the surface of the medical device is completely coated, which comes into contact in use with the vessel wall. This is usually the exterior of the medical device, such as that of a balloon catheter.

The invention also relates to a medical device, in particular a balloon catheter, which is obtainable by this process.

5 In the process according to the invention it can be provided that the impregnation with the ph armakologis ch active agent prior to the post-crosslinking of the crosslinkable group-containing polymer is carried out. Here, however, the radiation source used for the post-crosslinking or the energy of the radiation used in terms of stability of the active ingredient should be adjusted down so that not too great a t Wirki) amount of fuel is decomposed by the radiation. This can for example be checked by means of the spectroscopic absorption behavior of the active substance or in the simplest case of an impregnated with the active substance under test, which is subjected in the time required for the post-crosslinking power density and exposure time of the corresponding radiation.

15 However, it is preferred in the context of the inventive method, the post-crosslinking of the crosslinkable group-containing polymer before the impregnation of the polymer with the active agent pharmakologis ch perform. In this way, the above problems can be circumvented. However, all described in the following embodiments of the method can be applied to both process orders easily. 0 Surprisingly, it has been found that by the use of a post-crosslinking a strahlungsinduzier- th P olymerb chichtung it on the surface of the medical device can be produced in which a ph armakologis ch active agent can be embedded. The active agent depot produced thereby on the surface of the medical device is capable of transmitting high amounts in the active substance 5 by pressing it against the wall of a vessel in the body of the patient. At the same time, however, only a comparatively small loss of the drug is observed during the transport through the vessel to the desired location. This is not only a larger amount of active ingredient when it reaches the desired location is available, but the amount of drug is also more predictable. Overall, this leads to a more reproducible applicability of the medical device and to an improved healing success 0 at the same time reducing the risk of complications. The use of radiation for crosslinking, for example in the form of ultraviolet light, is particularly advantageous, since no chemical reagents are used in this cross-linking method that may remain in the coating. Is already starting from high-polymeric compounds which do not contain low molecular weight components, only additional bonds between the polymeric chains are formed by the irradiation. For toxicological reasons, this method is therefore particularly advantageous. Under a high-polymer compound is a polymer having crosslinkable groups is meant having a number average molecular weight of 200,000 g / mol or more in this connection. in development of the method according to the invention, the medical device is an implant, particularly a stent, a catheter or a balloon catheter.

The medical device to be coated may have any surface, in principle, that come into consideration for such devices. So may comprise a metal, glass or plastic surface (before coating), the device, or also from these materials, in particular of magnesium or a magnesium alloy, titanium or a titanium alloy, stainless steel, palladium, platinum, gold, rubber. Latex, PVC, silicones, polyether

P olyester amides, polyamides, polyurethanes, polycarbonates, polyethylenes, polypropylenes, and mixtures or copolymers of these.

In a further embodiment of the inventive method, the medical device is configured expandable, wherein the coating with the cross-linkable group-containing polymer, and, optionally, also the post-crosslinking and / or impregnation, in the expanded state of the medical device occurs. For this particular device come from the aforementioned polymeric materials are suitable. This approach is advantageous because a better anchoring of the polymer layer is achieved, so that not to tear the polymer layer in the expansion of the medical device inside the body or even delaminated teilwei- se. In this way, the risk of particle entry is further reduced.

As part of the process of the invention all polymers can be used, which can be induced by radiation post-crosslink in principle. For this purpose, the crosslinkable group-containing polymer can be selected from the group consisting of polyvinylpyrrolidone, acrylate polymers, polyurethanes, polyureas, polyesters, polyethers, polyols, polyvinyl lyetherpolyole, ester polyols, polyester polyols, polyether polyols, polycarbonate polyols, Polyestercar- bonatpolyole, polyether carbonate polyols, poly lactones, poly-lactides, poly-glycolides, or mixtures or copolymers of these.

Of the above polymers, polyvinyl pyrrolidone is especially preferred. Polyvinylpyrrolidone (PVP) is a hydrophilic polymer which is soluble in organic solvents or in water and can be over here applied to the surface of the device. As a permanent coating of a balloon catheter is used only by the inventively provided post-crosslinking, as it would washed in nichtvemetzten state because of its good water solubility during contact with the blood stream in a short time from the balloon surface. It has now surprisingly been found that polyvinylpyrrolidone can be converted into a stable hydrogel after coating on the balloon membrane by irradiating with UV light, which can be incorporate with active ingredients such as paclitaxel then. The active ingredient remains in front of the dilation at the site of the stenosis in the matrix of the polymer, can then be by dilation but very rapidly transferred to the surrounding tissue. This was surprising insofar as that even hydrophobic drugs in this very hydrophilic

can store stable hydrogel of polyvinylpyrrolidone. If appropriate, auxiliaries in the UV-cured P olyvinylpyrr olidon- S can chicht besides the active ingredient impregnated to modulate the release kinetics of the drug. These will later be explained in more detail. In a further advantageous embodiment of the method, the eriindungsgemäßen having crosslinkable groups polymer has a number average weight of at least 10,000 g / mol, in particular at least 50,000 g / mol, preferably at least 100,000 g; mol, more preferably at least 200,000 g / mol, more preferably at least 250,000 g / mol or even at least 300,000 g / mol. Even more preferred is a number-average mass of wenigs- least 360,000 g / mol, especially in the use of polyvinylpyrrolidone.

In the coating of the medical device which can Vernet / bare group-containing polymer, for example, in a layer thickness of 0.5 μιη be applied μιτι to 100, especially from 1 μιη to 50 μ m. These layer thicknesses are advantageous because they on the one hand be a sufficient residual function of the pharmacologically active agent and at the same time influence the mechanical properties of the medical device only a little. Also show polymer layers in these thicknesses is less tendency for delamination during expansion of the device, such as a balloon catheter.

Another advantage of the method is based on the fact that no primer layer has to be applied to the surface of the medical device. A corresponding embodiment therefore provides that the crosslinkable group-containing polymer is applied directly to the surface of the medical device and that before any particular adhesive layer is formed on the medical device.

According to a further variant of the inventive method, the coating at least a portion of the surface of the medical device is with the cross-linkable group-containing polymer carried out several times, with either a single coating run, the polymer is post-crosslinked or carried out the post-crosslinking of the polymer after the last coating run , I lierdurch can also be produced a greater layer thickness. In this case, can be used for the individual layers the same or different polymers. The crosslinkable group-containing polymer can be applied in any suitable manner to the surface of the medical device. This can for example be made from a solution of the polymer in an appropriate solvent or a melt of the polymer. The contract may in particular brushes, printing. Trans ferb it chichten, carried out spin coating, knife coating, spraying, or dipping. After applying a drying step may be provided before the post-crosslinking expediently.

As the solvent for the cross-linkable group-containing polymer is a variety of solvents into consideration, for example, water, ethanol or other alcohols and other organic solvents such as chloroform, acetone or the like. Mixtures of these solvents may be used. The suitable concentration of the polymer solution depends on the desired method of application, on the molecular weight of the polymer and on the nature of the polymer. A suitable concentration can be determined in a few experiments.

The radiation-induced post-crosslinking can be done by all types of radiation that are suitable for this purpose, such as electron, alpha, beta, gamma and / or UV radiation. As for the pharmacologically active agent, the latter is preferably used for local

suitable treatment of diseased tissues.

Specific examples of pharmacologically active agents include in particular a thrombore- sistente (non-thrombogenic) agents and other agents for the suppression of acute thrombosis, stenosis or late restenosis of the arteries. These are, for example, heparin, streptokinase, urokinase, tissue plasminogen activator, anti-thromboxane B2-agent; Anti-B-Thromoboglobulin, prostaglandin E, aspirin, dipyridimole, anti-thromboxane A2 agents, murine monoclonal antibody 7E3, triazolopyrimidine, ciprostene, hirudin, ticlopidine. Nicorandil, etc. A growth factor can also be used as a pharmacologically active ingredient to suppress subintimal fibromuscular hyperplasia of the arterial stenosis, or it can be any other inhibitor of cell growth at the stenosis site can be used.

The pharmakologis ch active ingredient may also consist of a vasodilator to act Va sospasmus contrary. This may for example asmus medium to a Antisp act like papaverine. The pharmacological agent may be a vasoactive agent per se such as calcium antagonists, or alpha and beta-adrenergic agonists or antagonists. Additionally, the pharmacological agent can be a biological adhesive such as cyanoacrylate medical grade or fibrin. As pharmacologically active agent is an antineoplastic agent such as 5-fluorouracil can be used further, preferably with a controlled releasing vehicle door, the means, eg for the use of an ongoing controlled-release anti-neoplastic agent to a tumor site.

The active ingredient may pharmakologis ch an antibiotic, preferably in combination with a controlled release carrier for the continued release from the coating loading a medical article to a localized infection within the body, be. Similar to the pharmakologis surface active agent may contain steroids for the purpose of suppressing inflammation in localized tissue, or for other reasons.

Specific examples of suitable pharmacologically active agents include: (a) heparin, heparin sulfate, hirudin, hyaluronic acid, chondroitin sulfate, dermatan sulfate, keratan sulfate, lytic agents, including urokinase and streptokinase, their homologs, analogs, fragments, derivatives and pharmaceutical salts thereof;

(B) antibiotic agents such as penicillins, cephalosporins, Vacomycine, aminoglycosides, quinolones, polymyxins, erythromycins; Tetracyclines, chloramphenicols, clindamycins, Lin- comycine, sulfonamides, their homologs, analogs, derivatives, pharmaceutical salts and mixtures thereof;

(C) paclitaxel, docetaxel, immunosuppressants such as sirolimus or sirolimus related limus derivatives, such as everolimus, biolimus A9, zotarolimus, tacrolimus or, alkylating agents including mechlorethamine, chlorambucil, cyclophosphamide, ifosfamide and Melpha- lan; Antimetabolites including methotrexate, 6-mercaptopurine, 5-fluorouracil and cytarabine; Pflanzenalkoide including vinblastine; Vincristine and Etopo- sid; Antibiotics including doxorubicin, daunomycin, bleomycin and mitomycin; Nitro Surea including carmustine and lomustine; inorganic ions including cisplatin; biological response including interferon; angiostatins and ene dostatinische means; Enzymes including asparaginase; and hormones including tamoxifen and flutamide, their homologs, analogs, fragments, derivatives, pharmaceutical salts and mixtures thereof;

(D) antivrale agents such as amantadine, rimantadine. Rabavirin, idoxuridine, vidarabine, Trif- luridin, acyclovir, Ganciclorir, zidovudine, Phosphonoformate, interferons, their homologs,

Analogs, fragments, derivatives, pharmaceutical salts and mixtures thereof; and

(E) anti-inflammatory agents such as ibuprofen, dexamethasone or metal thylprednisolon.

Of the above-mentioned pharmacologically active substances are paclitaxel, docetaxel, immunosuppressant such as sirolimus or sirolimus related limus derivatives, and combinations thereof are particularly preferred.

According to a preferred variant of the inventive method, the impregnation with the pharmacologically active agent from a solution of this active ingredient in a suitable solvent, whereby the impregnation in particular brushing, printing. Transfer coating, spin coating, knife coating, spraying or dipping is performed. The impregnation can also be repeated at least once. The coated and impregnated device is suitably dried and is then ready for use.

Suitable solvents for the pharmacologically active agent is a plurality of I ö- sungsmitteln into consideration, in particular water, ethanol or other alcohols and other organic solvents such as chloroform, acetone or the like. Mixtures of these solvents may be used wherein a mixture of water and ethanol is particularly preferred. The mixing ratio of ethanol to water may, for example 1: 1 to 10: 1 parts by volume, in particular 2: 1 to 5: 1. If the impregnation carried out on a not postcrosslinked polymer, care should be taken that the deposited polymer layer not by the solvent used for the solution of active substance separates.

The concentration of the active ingredient solution can vary widely and depends inter alia on the medically appropriate loading of the equipment top surface with the particular drug from. In a paclitaxel concentration of 0.1 wt% provides up to 25% by weight of, preferably from 0.5 to 10 wt%. As the solvent, a water / ethanol mixture of the aforementioned kind is particularly suitable.

Of the above specified coating facility that is particularly preferred, wherein the polymer is provided with the medical device is dipped into the solution of the pharmacologically active agent, because in this case the impregnated amount of active ingredient can be controlled by the residence time in the solution. Thus, the residence time may preferably be at least be 30 minutes, in particular is at least 1 hour, preferably at least 2 hours, more preferably at least 4 hours or at least 6 hours.

According to a particularly preferred embodiment of the method the medical device provided with the polymer is impregnated with an adjuvant. As

Excipients may be mentioned, for example: contrast media, matrix and gel-forming additives such. B. lipids or in common use in pharmacy polymers. Sugar. Sugar derivatives, dextrins, low molecular weight P oly ethylene glycol (PEG), organic or inorganic salts, benzoates, urea, citric CDCR eester, salicylates, such polymers. For example, starch, gelatine ne, PEG, albumin, chitosan, beta-cyclodextrins, hydroxy cellulose, as well as lipids, linoleic acid, linolenic acid, oleic acid, stearic acid, phenyl salicylate, Vitamin E, tocotrienols, tocopherols, B is ethyl hexyl ebacat, diisododecyl phthalate, N-methylpyrrolidone, butylhydroxyanisole, butylhydroxytoluene, phosphorylcholine, oils, fatty acids, fatty acid ester, contrast media derivatives, amino acids, peptides, vitamins, neutral and charged amphiphilic substances, salts, polyvinyl lyethylenglycolester, fatty acid ester of sugars, polyglyceryl-6-fatty acid ester, polyglyceryl fatty acid esters 10, Sucrosemonopalmitate, surfactants with lipid chains, surfactants, organic acids and esters and salts.

The surfactants or surface-active substances are from the group of anionic, nonionic, zwitterionic or cationic surfactants.

Suitable anionic surfactants are in principle all suitable for use on the human pERSonal via suitable anionic whether he surfactants. These are characterized by a water solubilizing anionic group such. Example, a carboxylate, sulfate, sulfonate or phosphate group and a lipophilic alkyl group having approximately 8 to 30 carbon -atoms. In addition, glycol or P olyglykolether-Grupp s, ester, ether and amide groups and also hydroxyl groups may be contained in the molecule. Examples of suitable anionic surfactants, each in the form of sodium, potassium and ammonium salts and the mono-, di- and Trialka- nolammoniumsalze having 2 to 4 carbon atoms in the alkanol group: linear and branched fatty acids having 8 to 30 C -atoms,

- ether carboxylic acids of the formula R 14 -0- (CH2-CH20) x-CH2-COOH, in which R 14 is a linear alkyl group having 8 to 30 carbon atoms and x = 0 or 1 to 16, - acyl sarcosides having 8 to 24 C-atoms in the Acyigruppe,

Acyl taurides having 8 to 24 C atoms in the Acyigruppe,

Acyl isethionates containing 8 to 24 carbon atoms in the Acyigruppe,

Sulfosuccinic acid mono- and dialkyl esters containing 8 to 24 carbon atoms in the alkyl group and sulfosuccinic acid monoalkyl polyoxyethyl esters containing 8 to 24 carbon atoms in the alkyl group and 1 to 6 oxyethyl groups, linear alkane sulfonates having 8 to 24 C atoms, linear alpha olefin sulfonates having 8 to 24 carbon atoms, alpha-sulfofatty acid methyl esters of fatty acids having 8 to 30 carbon -atoms.

Alkyl sulfates and alkyl polyglycol ether sulfates of formula R "- () (CII: -C l I-ÖK-OSO] is I. in which R 'is a preferably linear Aikylgruppe having 8 to 30 carbon atoms and x = 0 or 1 to 12,

Mixtures of surface-active hydroxy sulfonates, sulfated hydroxyalkylpolyethylene and / or hydroxyalkylene propylene glycol ethers,

Sulfonates of unsaturated fatty acids having 8 to 24 carbon atoms and 1 to 6 double bonds,

Esters and / or be of tartaric acid and citric acid with alcohols, in particular triethyl citrate, adducts of about 2 1 5 molecules of ethylene oxide propylene oxide with fatty alcohols having 8 to 22 carbon atoms,

Alkyl and / or alkenyl ether of the formula (El-I),

O

II

R 16 (OCH 2 CH 2) h - O - p OR (E 1 -I)

OX wherein R i6 is preferably an aliphatic hydrocarbon radical having 8 to 30 carbon atoms, R 17 represents hydrogen, a (CH 2 CH 2 0) "R 18 or X, h is a number of 1 to 10 and X is hydrogen, an alkali - or alkaline earth metal or NR 9 R 20 R 21 R 22, where R 19 to R 21 independently of one another, are hydrogen or a Cl to C4 - hydrocarbon radical, sulfated Fettsäurealkylenglykolester of formula (El -II) R 22 CO (AlkO) h S0 3 M (El -II) 22 CO- is a linear or branched, aliphatic, saturated and / or unsaturated acyl group containing 6 to 22 carbon atoms, Alk is CH 2 CH 2, (Ί 1 (in which R 1 Ι Ί I · and / or CH2CHCH3, h is a number of 0.5 to 5, and M is a cation,

Monoglyceride sulfates and monoglyceride of formula (El -III) CH 2 0 (CH 2 CH 2 0) x - COR

CHO (CH 2 CH 2 0) y H

Figure imgf000016_0001
in which R 23 CO is a linear or branched acyl group containing 6 to 22 carbon atoms, x, y and i 2 to 10, and X together stand for 0 or for numbers of 1 to 30, preferably an alkali metal or alkaline earth metal. Typical examples for the purposes of the inven- tion suitable monoglyceride (ether) sulfates are the reaction products of lauric acid monoglyceride, coconut f ETTs CDCR emonogly cerid, P almitins CDCR emonogly cerid, stearic monoglyceride, oleic acid monoglyceride and tallow fatty as well as their ethyl enoxidaddukte with sulfur trioxide or chlorosulfonic acid in the form of their sodium salts. Preferably, monoglyceride sulfates of the formula (El-III) are employed in which R 23 CO is a linear acyl group containing 8 to 18 carbon atoms,

Amide-ether carb ons CDCR s,

Condensation products of Cs - C30 - fatty alcohols with protein hydrolysates and / or amino acids and their derivatives, which are known in the art as albumen s fat CDCR ekondens at e, such as Lamepon ® - types Gluadin ® - types Hostapon ® KCG or Amisoft ® - types.

Preferred anionic surfactants are alkyl sulfates, alkyl polyglycol ether sulfates and ether carboxylic acids having 10 to 18 carbon atoms in the alkyl group and up to 12 glycol ether groups in the molecule, sulfosuccinic acid mono- and dialkyl esters containing 8 to 18 carbon atoms in the alkyl group and Sulfob serious one CDCR emono- alkylp olyoxy ethyl ester having 8 to 18 carbon atoms in the alkyl group and 1 to 6 oxyethyl groups, Monoglycerdisulfate, alkyl and Alkenyletherpho- sphate and egg pointing s fat CDCR ekondens at e.

cationic surfactants may also be used.

According to the invention cationic surfactants of the quaternary ammonium compounds, esterquats and the amidoamines are. Preferred quaternary compounds Ammoniumver- are ammonium halides, in particular chlorides and bromides. as alkyltrimethylammonium methyl ammonium chloride, dialkyldimethylammonium chloride and Trialkylmethylammonium-, for example cetyltrimethylammonium chloride, stearyltrimethylammonium chloride, Distea- ryldimethylammoniumchlorid, lauryl, Lauryldimethylbenzylammo- niumchlorid and tricetyl methyl ammonium chloride, as well as those known under the I CI designations Quaternium-27 and Quaternium-83 imidazolium compounds. The long alkyl chains of the above surfactants preferably have 10 to 18 carbon atoms. Ester quats are known substances which contain both at least one Esterfunktion and at least one quaternary ammonium group as structural element. Preferred esterquats are quaternized Estersalze of fatty acids with triethanolamine, quaternized Estersalze of fatty acids with diethanol alkylamines and quaternized Estersalzen of fatty acids with 1, 2-dihydroxypropyl. Such products are marketed under the trademarks Stepantex®, Dehyquart® and Armocare®. The products Armo- care® VG! 1-70. an N, N-bis (2-palmitoyloxyethyl) dimethylammonium chloride, and Dehyquart® F-75, C-Dehyquart® 4046 Dehyquart® L80 and Dehyquart® AU-35 are examples of such esterquats.

The Alkylamidoamine are usually prepared by amidation of natural or synthetic fatty acids and fatty acid cuts with dialkylaminoamines. An inventively particularly suitable compound from this group of substances under the name Tegoamid® S 18 commercial stearamidopropyl dimethylamine is.

In addition to or instead of the cationic surfactants, the compositions may contain other surfactants or emulators, with both anionic and ampholytic and nonionic surfactants and all types of known emulsifiers are suitable. The group of ampholytic or amphoteric surfactants includes zwitterionic surfactants and ampholytes. The surfactants can already have an emulsifying effect.

Zwitterionic surfactants are, whether it denotes surface active compounds containing at least one quaternary ammonium group and at least one -COO H in the molecule - wear S03 H group - or. Particularly suitable zwitterionic surfactants are the betaines such as N-alkyl-N, N-dimethylammonium glycinates, for example cocoalkyl dimethylammonium, N-acyl-aminopropyl-N, N-dimethylammonium glycinates, for example cocoacylaminopropyl dimethyl ammonium, and 2 alkyl-3-hydroxyethyl-imidazolines -carboxymethyl- 3 each having 8 to 18 carbon atoms in the alkyl or acyl group as well as the Kokosacylaminoethylhydroxyethylcarboxymethylglycinat. A preferred zwitte- - Ka nonisches surfactant is known under the INCI name Cocamidopropyl Betaine fatty acid amide derivative.

Ampholytes are surface-active compounds which, in addition to a C - are alkyl or acyl group in the molecule at least one free amino group and at least one -COOH or -SOJ I group and are capable of forming inner salts, examples of suitable - C2 ampholytes are N-alkyl glycines, N-alkyl propionic acids, N-alkylaminobutyric acids, N-alkyliminodipropionic acids, N-hydroxyethyl-N-alkylamidopro- pylglycine, N-alkyltaurines, N-alkylsarcosines, 2-alkylaminopropionic acids and alkylamino acetic acids with in each case about 8 to 24 C -atoms in the alkyl group, particularly preferred ampholytes are N-cocoalkylaminopropionate, cocoacylaminoethyl aminopropionate and C12 - cis - acylsarcosine,

Non-ionic surfactants contain as hydrophilic group, for example, a polyol group, a polyalkylene lenglykolethergruppe or a combination of polyol and polyglycol ether. Such compounds are, for example, - addition products of 2 to 50 mol ethylene oxide and / or 1 to 5 mol propylene oxide onto linear and branched fatty alcohols having 8 to 30 carbon -atoms, onto fatty acids having 8 to 30 carbon -atoms and with alkylphenols having 8 to 15 C -atoms in the alkyl group. with a methyl or C2 - Ce - End-capped alkyl adducts of 2 to 50 mol ethylene oxide and / or 1 to 5 mol propylene oxide onto linear and branched fatty alcohols having 8 to 30 carbon -atoms, onto fatty acids having 8 to 30 carbon -atoms and alkylphenols having 8 to 15 carbon -atoms in the alkyl group, such as those available under the trade names Dehydol ® LS, LT Dehydol ® types (Cognis),

C 2 -C 3 o-fatty acid mono- and diesters of addition products of from I to 30 mol ethylene oxide with glycerol, - addition products of 5 to 60 mol ethylene oxide onto castor oil and hydrogenated castor oil,

Polyol fatty acid esters, such as the commercial product Hydagen ® I ISP (Cognis) or Sovermol - types (Cognis), alkoxylated triglycerides, alkoxylated fatty acid alkyl esters of formula (E4-I)

R 24 CO (OCH 2 CHR 25) w OR 26 (E4-I) in which R 24 CO is a linear or branched, saturated and / or unsaturated acyl radical having 6 to 22 carbon atoms, R 25 represents hydrogen or methyl, R 26 is linear or branched alkyl radicals having 1 to 4 carbon atoms, and w tur numbers from 1 to 20,

Amine oxides,

Hydraulic oxymis chether,

S orbitanfetts CDCR eester and Anlagerungeprodukie of ethylene oxide with S orbitanfetts CDCR eester such as the polysorbates,

Zuckerfettsäureester and adducts of ethylene oxide with Zuckerfettsäureester,

Adducts of ethylene oxide with F ett s CDCR ealkanolamide and fatty amines,

Zuckert enside of the alkyl and alkenyl oligoglycosides corresponding to formula (E4-II),

R 27 0- [G] p (E4-II) in which R 27 is an alkyl or alkenyl radical having 4 to 22 carbon atoms, G is a sugar radical having 5 or 6 carbon atoms and p is a number 1 to 10 They can be obtained by the relevant methods of präparai iven organic chemistry.

The alkyl and alkenyl oligoglycosides may be derived from aldoses or ketoses containing 5 or 6 carbon atoms, preferably from glucose derived. The preferred alkyl and / or alkenyl oligoglycosides are therefore alkyl and / or alkenyl oligoglucosides. The index p in the general formula (E4-II) indicates the degree of oligomerization (DP), ie the distribution of mono- and oligoglycosides, and stands for a number between 1 and 10. While p in the individual molecule must always be an integer and, above especially p may assume the values ​​1 to 6, the value p for a certain alkyl oligoglycoside is an analytically determined calculated quantity which is mostly a broken number. Preferably, alkyl and / or alkenyl oligoglycosides having an average degree of oligomerization p of 1, used 1 to 3.0. From anwendungstechnis rather view of such alkyl and / or alkenyl are preferred whose degree of oligomerization is less than 1, 7 and in particular between 1, 2 and 1; 4. The alkyl or alkenyl R 27 may be derived from primary alcohols containing 4 to 1 1, preferably 8 to 10 carbon atoms. Typical examples are butanol, caproic alcohol, caprylic alcohol, capric alcohol and undecyl alcohol and the technical mixtures such as are obtained, for example, in the hydrogenation of technical F ETTs CDCR emethylestern or in the hydrogenation of aldehydes from the oxo synthesis Roeien'schen. Alkyloli- are preferred oligoglucosides of chain length Cs-C io (DP = 1 to 3), which are obtained as first runnings in the separation of technical Cs-Cis-coconut fatty alcohol with a content of less than 6 wt .-% C 12 alcohol can also alkyl oligoglucosides based on technical C / n-oxo alcohols (DP = 1 to 3). The alkyl or alkenyl R 27 may also be derived from primary alcohols having 12 to 22, preferably 1 2 to 14 carbon atoms. Typical examples are lauryl alcohol, myristyl alcohol, cetyl alcohol, palmoleyl, stearyl, isostearyl, oleyl, elaidyl, petroselinyl, arachyl, gadoleyl, behenyl, erucyl, brassidyl and technical mixtures thereof, which may be obtained as described above. Alkyl oligoglucosides based on hydrogenated Ci2 / i4 coconut alcohol with a DP of 1 to 3

Zuckert enside the type of fatty acid N-alkylpolyhydroxyalkylamides, a nonionic

Surfactant of the formula (E4-III),

R 29

!

R 28 CO-N- [Z] (Ε4-ΠΙ) in which R 28 CO is an aliphatic acyl radical having 6 to 22 carbon atoms, R 29 represents hydrogen, an alkyl or hydroxyalkyl having 1 to 4 carbon atoms and [Z] is a linear or branched polyhydroxyalkyl radical containing 3 to 12 carbon atoms and 3 to 10 hydroxyl groups. In the F ETTs CDCR eN -alkylp olyhydroxy alkylamides are known substances which are usually obtained echlorid by reductive amination of a reducing sugar with ammonia, an alkylamine or an alkanolamine and subsequent acylation with a fatty acid, a F ETTs CDCR ealkylester or Fettsäur can be. Preferably, the fat CDCR eN- alkylpolyhydroxyalkylamides of reducing sugars having 5 or 6 carbon atoms are derived, in particular from glucose. The preferred fatty acid-N-alkyl polyhydroxyalkylamides are fatty acid N-alkyl glucamides, as they are represented by the formula (E4-IV):

R 30 CO-NR 31 -CH 2 (CHOH) 4 CH 2 OH (E4-IV)

Preferably of formula (E4-IV) are used as F ETTs CDCR eN-alkylp olyhydr oxyalkylamide glucamides in which R! is hydrogen or an alkyl group and R 30 CO represents the acyl residue of caproic acid, caprylic acid, capric acid, lauric acid, myristic acid,

Palmitic acid, palmitoleic acid, stearic acid, isostearic acid, oleic acid, elaidic acid, Pe- troselinsäure, is linoleic acid, linolenic acid, arachidic acid, gadoleic acid, behenic acid or erucic acid or technical mixtures of these acids. Particularly preferred are fatty acid-N-alkyl glucamides (E4-IV), by reductive Amini augmentation of glucose with methylamine and subsequent acylation with lauric acid or C12 / 14-

Coconut fatty acid or a corresponding derivative is obtained. The polyhydroxyalkylamides also from maltose and palatinose can be derived.

Preferred nonionic surfactants are the alkylene oxide adducts have proved to saturated linear fatty alcohols and fatty acids each having 2 to 30 moles of ethylene oxide per mole of fatty alcohol or fatty acid. Preparations with excellent properties are also obtained when they contain as nonionic surfactants Fettsäureestei "of ethoxylated glycerol rin.

These compounds are characterized by the following parameters. The alkyl group contains 6 to 22 carbon atoms and may be both linear and branched. primary linear and methyl-branched in the 2-position, aliphatic radicals are preferred. Such alkyl radicals are, for example, 1-octyl, 1 decyl, 1-lauryl, 1-myristyl, 1 -Cetyl and 1-stearyl. Particularly preferred are 1-octyl, decyl i, 1 lauryl, 1-myristyl. Where so-called "oxo alcohols" as starting materials, compounds with an odd number of carbon atoms in the alkyl chain. Furthermore, the sugar surfactants may be contained as nonionic surfactants.

When used as surfactants, compounds having alkyl groups may be single compounds. However, it is generally preferred to proceed in the preparation of these substances from native vegetable or animal raw materials so that one substance mixtures obtained sub with different alkyl chain lengths dependent upon the particular raw material.

The surfactants which are addition products of ethylene and / or propylene oxide with fatty alcohols or derivatives of these Aiilagerungsprodukte, both products having a "normal" H omologenverteilung as well as such can be used with a narrow homolog distribution. "Normal" homologue distribution are mixtures of homologues are understood to be obtained as catalysts in the reaction of fatty alcohol and alkylene oxide using alkali metals, alkali metal hydroxides or alkali. Narrowed homolog distributions are obtained, however, if hydrotalcite, alkaline earth salts of ether carboxylic acids, alkaline earth metal oxides - hydroxides or alcoholates are used as catalysts. The use of products with a narrow homolog distribution may be preferred.

The agents may further comprise at least one emulsifier. Usable in the invention are, for example Emuigatoren

Addition products of 4 to 100 mol of ethylene oxide and / or 1 to 5 mol propylene oxide onto linear fatty alcohols having 8 to 22 carbon -atoms, onto fatty acids having 12 to 22 carbon atoms and onto alkylphenols having 8 to 15 carbon atoms in the alkyl group,

Ci2-C22 fatty acid mono- and diesters of addition products of 1 to 30 mol ethylene oxide onto polyols containing 3 to 6 carbon atoms, in particular glycerol,

Ethylene oxide and polyglycerol addition products with methyl glucoside fatty acid ester-, F ett s CDCR ealkanolamide and F ETTs CDCR egluc amide,

C8-C22-alkyl mono- and oligoglycosides and ethoxylated analogs thereof, wherein olive gomerisierungsgrade from 1.1 to 5, in particular 1.2 to 2.0, and preferably glucose as the sugar component, mixtures of alkyl (oligo) glucosides and fatty alcohols as the country in one! product available Montanov® * 68

Aniagerungsprodukte from 5 to 60 mol ethylene oxide onto castor oil and hydrogenated castor oil, - partial esters of polyols having 3-6 carbon atoms with saturated fatty acids having from 8 to

22 C -atoms,

Sterols. Sterols are a group of steroids is understood that bear on C atom 3 of the steroid skeleton is hydroxy and both from animal tissue (Zooste- rine) and from vegetable fats (phytosterols) are isolated. Examples of Zooste- rine are cholesterol and lanosterol. Examples of suitable phytosterols are gosterin Er, stigmasterol and sitosterol. Also from fungi and lefen I are sterols, the so-called mycosterols isolated.

Phospholipids. These are understood especially the glucose phospholipids, which are, for example, as lecithins or phosphatidylcholines for example from egg yolk or plant seeds (eg, soybeans) gained overall, understood.

Fatty acid ester of sugars and sugar alcohols such as sorbitol,

Polyglycerols and polyglycerol derivatives such as Polyglycerinpoly- 12-hy- droxystearat (Dehymuls ® PGPH commercial product), linear and branched fatty acids having 8 to 30 C - atoms and their Na, K, environmentally ammonium, Ca, Mg and to - salts.

Particularly preferred is the use of albumin as lactalbumin, ovalbumin, bovine albumin. S chweinealbumin or combinations thereof. Here, the I mprägnierung upstream or with the adjuvant of the impregnation with the pharmacologically active agent be downstream. Preferably, the impregnation is carried out at the same time. This can be accomplished dadurcli for example, that the impregnation of the polymer provided with the medical device is carried out with a mixture of pharmacologically active agent and the excipient. Notwithstanding the impregnation sequence has surprisingly been found that when using albumins a significantly higher amount of active ingredient can be transmitted through Druckanawendung on a vessel wall as an adjuvant. particularly pronounced this effect to the use of paclitaxel as an active ingredient. Even a lesser loss of pharmakologis can be observed ch active ingredient during the manipulation of the medium zinischen device within the body.

The concentration of albumin in the impregnation solution may vary over wide ranges. Especially advantageous is a concentration of 0.001 wt% to 15 wt%, preferably from 0.01 wt% to 8 wt%. This is especially true in combination with paclitaxel as the active ingredient. As discussed above, the present invention also relates to a medical device, which is obtainable by the inventive method. The medical device may in particular be provided for expanding vascular constrictions, preferably for Au widening vascular constrictions in the human or animal body.

In an advantageous embodiment of the medical device according to the invention, this is designed expansionary dierbar, especially as a balloon catheter. From this expandable medical device is at least 5 when expanded for one minute and subsequent contraction in a vessel of a human or animal body transfer wt .-% of the pharmacologically active substance on the inner wall of the vessel, in particular at least 8 wt .-%, each on the total amount of the active ingredient. In a particularly preferred disclosed embodiment of the medical device of the present invention are of this when brought into contact with a physiological solution such as blood or a phosphate-buffered physiological saline solution, within a period of 10 minutes at 37 ° C less than 10 wt .-% of the pharmacologically active agent in leave the solution, in particular less than 8 wt .-%, each based on the total amount of the active ingredient.

The present invention will be described below with reference to several examples. methods:

H PI method:

Column: Chromolith RP18e FastGradient 50-2 mm (Knauer Scientific apparatus GmbH, Berlin, Germany) Mobile phase: acetonitrile / 'phosphate buffer (0.005 M, pH 3.5) in the ratio 50:

50, isocratic procedure

Flow rate 0.3 ml / min

UV detection at 230 nm

Sample volume 20 μΐ range between 0.1 to 20 mg / L detection limit of approximately 0.01 mg / L

UV lamp: 3UV, P / N 95-0343-02, 3UV-38, 8 watts, the company Ultraviolet Products Ltd., Upland, United States

At a wavelength of 254 nm and a distance of two inches 1670 .mu.W / cm 2 energy on the irradiated surface are dispensed.

Substances used:

Balloon used: PTA catheter, 4.0 x 40 mm. 0.035er wire FI ersteller Bavaria Medi / domestic technology chloroform 99% (Mallinckrodt Baker Chemicals, Griesheim, Germany)

Bovine serum albumin (BSA, Serva Electrophoresis GmbH, Heidelberg, Germany)

Polyvinylpyrrolidone (PVP K, number average molecular weight of 90 360 000 Da, Carl Roth GMBl 1 and Co. KG, Karlsruhe, Germany) Dulbecco's phosphate buffered saline (PBS, PAA Laboratories, Cölbe, Germany)

Tween 20 (Sigma Aldrich, Taufkirchen, Germany) paclitaxel (Cfm Oskar Tropitzsch, Marktredwitz, Germany) ethanol absolute (Central Pharmacy University of Rostock)

Methanol (HPLC grade, Carl Roth GmbH & Co. KG, Karlsruhe, Germany)

Example 1 Coating of a catheter balloon surface with PVP, cross-linking the PVP by means of UV coating and impregnation of the crosslinked PVP coating with paclitaxel (Invention)

The surface of a balloon was coated with a spray process, which is described in WO 2011/082946 in Example 8, with polyvinylpyrrolidone (PVP). The balloons are in this case in the expanded condition by being dilated bar with a pump with air to about 2 prior to the coating process. In order to keep the pressure during the spraying process, a valve has been placed at the end of the catheter, which was sealed after the dilatation. The balloon was clamped at the top and on both catheters and / moved vertically to spray as well as rotating about its own axis, in order to ensure homogeneous coating of the entire surface of the balloon.

A total of 2000 ug polyvinylpyrrolidone were sprayed from a 0.25 wt% solution in chloroform on the balloon surface. Before further processing, the balloon surfaces were dried for 24 h at room temperature.

The crosslinking of the dried vinylpyrrolidone polymer layer was at by irradiation with UV-light from 254th Each balloon side was irradiated at room temperature for 15 min with the above-mentioned power density. The distance between the lamp and the balloon to be irradiated side was 1 cm. The balloon was also during this process step in the expanded state.

Subsequently, the layer thickness of the applied polymer layer by means of laser Meas- ring microscope (LEXT OLS3 100, Olympus) was determined. For this purpose, a coated Bai- ion was embedded in EpoThin by the company Buchler. In the course of the following processing, the sample was along sanded and polished. The surface structure obtained has a slight depression because of the nature of the material at the location of the coating. The layer thickness was then determined via the trench across 6 different positions, each of the measurements was washed twice (as well as at two different locations) is performed. An exemplary micrograph of the sample is shown in Fig. I, in which the positions of the S chichtdickenb ROVISIONS are marked with the digits 1 to 6. It identifies the layer thicknesses:

Measuring film thickness [μηι]

1 6.9747

2 8.4965

3 7.6088

4 8.1 161

5 7.8624

6 10.3987 The average layer thickness was accordingly μιη at about 8.2.

The expanded balloon with the cross-linked polyvinyl pyrrolidone coating was then / water for 16 h at room temperature in 900 μΐ a paclitaxel solution having a concentration of 15 mg ml in ethanol (8: 2) immersed. The impregnated with paclitaxel crosslinked PVP coating was 24 h at room temperature dried. A balloon surface was obtained with a paclitaxel concentration of 0.37 μ ^ 'ητπι 2 With the so-coated balloon surface investigations were carried out for drug delivery.

Eluting in aqueous medium

The elution of paclitaxel from the B allonb it chichtung by immersing the balloons in watery buffer simulates the premature loss of paclitaxel during the transfer of the balloon through the blood vessels to the stenotic site. For this purpose, the networked with! PVP and paclitaxel coated and manually re-folded after pumping out the air balloon 1 min at room temperature phosphate in 20 ml Dulbecco's buffered saline (PBS, pl I 7.2 At 0.06 wt% Tween 20) immersed. To determine the paclitaxel concentration by HPLC chromatography the sample was diluted with methanol to half of the initial concentration.

Dilatation of the balloon in a silicone tube

The manually folded balloon (2.7 mm AUSS endur chmes he s 4, 1 mm. Inside diameter) dictated in a second step, 1 minute at 8 bar konschlauch in a silicone. The silicone tube here to simulate a vessel in the human or animal body. This balloon dilatation in the silicone tube was carried out in 20 ml PBS / 0.06% Tween. For HPLC analysis, the sample was diluted with methanol to half of the initial concentration. Extraction of the silicone tube and the balloon after dilatation

Both the silicone tube and the balloon were extracted after the balloon dilation in methanol, m to determine the transferred amount of paclitaxel on the silicone tube and the remaining amount on the balloon surface. The silicone tube was this extracted I hour at 37 ° C in 3 ml of methanol, the balloon in 20 ml of methanol also I hour at 37 ° C.

The total loading of paclitaxel was determined by calculation from the sum of the measured Pa stranded wire axel-4 levels in the solutions. The amount of transmitted on the silicone tube paclitaxel was obtained by adding the amount in the aqueous medium after dilatation, and the amount of S after extraction ilikons chlauchs. Results

Total loading of paclitaxel on the balloon: 0.37 ug / mm 2

Eluted Paclitaxel 0.02 ug / mm 2 (5 wt .-% of total loading)

Transmitted on silicone tube Paclitaxel 0.08 ug / mm 2 (20 wt .-% of total loading)

By the cross-linked PVP coating premature elution of paclitaxel is significantly reduced before the balloon dilatation. Only 5 wt .-% of the total load to be lost by a pure elution process. A fifth of the total Paclitaxelmenge can be transferred to the silicone tube as a model of a blood vessel. Example 2: Coating of a balloon catheter surface with polyvinyl pyrrolidone, the crosslinking Polyvinyipyrrolidon-Besehiehtung by UV and impregnation with paclitaxel with the addition of bovine serum albumin (BSA) (invention)

The experiment I was repeated, with the modification that no pure paclitaxel solution is impregnated into the cross-linked UV-PW-coating, but a mixture of paclitaxel and bovine serum albumin (BSA). To 900 μΐ a paclitaxel solution having a concentration of 15 mg ml in ethanol / water (8: 2), 100 μΐ of an aqueous BSA solution was added (15 mg / mL). With this mixture, the balloon surface was impregnated as described in Example 1. The tests for the elution of paclitaxel and paclitaxel on the transfer of a silicone tube were carried out as described in Example. 1 The following results were obtained:

Total loading of paclitaxel on the balloon: 0.44 g / mm 2

Eluted Paclitaxel 0.04 ug / mm 2 (5 wt .-% of total loading) transmitted on silicone tube Paclitaxel 0.16 ug / mm 2 (37 wt .-% of total loading)

By the addition of bovine serum albumin, the transmission of paclitaxel on the silicone tube as compared to experiment 1 (pure paclitaxel) is significantly increased. The premature loss of paclitaxel by pure elution processes is very low as the experiment first

Example 3: Beschichtun a Ballonkatheterobertläche with polyvinylpyrrolidone, comparable shortened cross-linking of polyvinylpyrrolidone Bcsehiehtung by UV light and impregnation with paclitaxel with the addition of bovine serum albumin (BSA) (invention)

Run 2 was repeated with the change that the B polyvinylpyrrolidone not chichtung 15 min, but 5.5 min was irradiated at 254 nm from both sides balloon. Paclitaxel and BSA was not carried out as for Example 1 and 2, it is incorporated chichtung by immersing the balloon in the solution of paclitaxel and BSA in ethanol / water in the polyvinyl nylpyrr olidon-B, but by pipetting on the crosslinked polyvinyl ly vinylpyrr olidon-B is applied chichtung. In contrast to Example 2, a coating solution was loading of paclitaxel at the concentration of 10 mg / mL paclitaxel and 1 mg / mL BSA in ethanol / water (8/2) was used. There were 450 μΐ this paclitaxel / B SA pipetted solution.

The tests for the elution of paclitaxel and paclitaxel on the transfer of a silicone tube were carried out as described in Example I. The following results were obtained:

Total loading of paclitaxel on the balloon: 3.51 g / mm 2

Eluted paclitaxel: 0.074 μ ^ ιηιιι 2 (2 wt .-% of total loading)

Transmitted on silicone tube paclitaxel: 2.195 μ ^ ιηιη 2 (62 wt .-% of total loading) Compared with Experiments 1 and 2 were obtained with this experimental set-up substantially higher loadings of paclitaxel on the coating.

Example 4: Simultaneous coating of a Glasdeckgiäscfaens with a mixture of paclitaxel and polyvinylpyrrolidone, and UV cross-linking (Inventive) For comparison with the two-stage process (coating with polyvinylpyrrolidone and UV-

Crosslinking, then incorporation of paclitaxel) is a mixture of polyvinylpyrrolidone and paclitaxel was simultaneously coated on a cover slip and then crosslinking the polyvinylpyrrolidone by UV irradiation for 12 min at 254 nm. ! Ii he / u was a mixture of 100 μΐ a polyvinylpyrrolidone solution (5 wt% in chloroform) and 10 see μΐ an ethanolic solution of paclitaxel (1.5 mg / ml) on a small coverslips (15 mm thickness) by spin coating (130 revolutions s door 1 min) and was dried for 24 h at room temperature.

The coated coverslips were stored I h at 37 ° C in methanol to extract paclitaxel. The methanol solution was analyzed directly by HPLC and the extracted Paclitaxelmenge determined.

Total loading of paclitaxel on the cover glass 15 ug

Eluted Paclitaxel 0.46 ug (3 wt .-% of total loading) Simultaneous coating of polyvinylpyrrolidone and paclitaxel with subsequent crosslinking of the PVP by UV light is unsuitable as this particular agent is decomposed by the action of irradiation. For UV stable active ingredients, however, this approach is feasible. Example 5: Simultaneous coating of a balloon catheter with a mixture of paclitaxel and polyvinylpyrrolidone without UV cross-linking (comparative)

A balloon was dictated μΐ 30 seconds in 900 at room temperature. immersing an ethanolic solution containing paclitaxel at a concentration of 15 mg ml and polyvinylpyrrolidone in a concentration of 30 mg ml. After the T it auchb chichtungspr s ozes the balloon was dried for 24 h at room temperature.

The obtained coated balloon was tested as described without crosslinking with UV light as in Example. 1 the eluted amounts were determined in the buffer, and after dilation and mechanical contact transmitted with the silicone tube Paclitaxelmengen.

The following results were obtained: total loading paclitaxel on the balloon: 1.18 g / mm 2

Eluted paclitaxel: 0.57 ng / mm 2 (48 wt .-% of total loading)

Transmitted on silicone tube Paclitaxel 0.26 ug / mm 2 (22 wt .-% of total loading)

Compared to Example 1, almost half of paclitaxel is lost by elution in this experiment. Without crosslinking by irradiation with UV light, the coating is processing so unstable that it comes to very large early loss of paclitaxel.

Example 6: Simultaneous coating of a balloon catheter with a mixture of paclitaxel and polyvinylpyrrolidone without UV etworking with the addition of BSA (comparative)

a balloon by dipping as described in Example 5 coated. In contrast to Example 5, the T consisted here auchb it chichtung from 900 μΕ an ethanolic solution dipped, which contains paclitaxel in a concentration of 15 mg ml and polyvinylpyrrolidone in a concentration of 30 mg ml and 100 ul · an aqueous B SA solution with a concentration of 15 mg mL. Further processing and investigation was carried out as described in Example 4. FIG.

The following results were obtained:

Total loading of paclitaxel on the balloon: 1.04 ug / mm 2 Eluted Paclitaxel 0.59 ug / mm 2 (57 wt .-% of total loading)

Transmitted on silicone tube Paclitaxel 0.07 ug / mm 2 (7 wt .-% of total loading)

Compared to Example 1, more than half of paclitaxel eluting lost in this experiment. Only a small part of the total loading of paclitaxel is transmitted by mechanical pressure on the silicone tube. Without Networking by irradiation with UV light, the coating is so unstable that it comes to very large early loss of paclitaxel. As in Example 2, the addition of BSA results in a greater release of paclitaxel. In Example 2 is repeated using crosslinked em Polyvinylpyrro- lidon However the greater part as aimed by mechanical pressure applied to the silicone tube. In this example, without cross-linking of polyvinylpyrrolidone majority is lost by elution advance.

Example 7: Coating of a balloon catheter with paclitaxel and polyvinylpyrrolidone as a two-layer structure (V COMPARISON)

A balloon surface was first coated with paclitaxel by the dilated balloon was immersed at room temperature door 30 seconds in 900 μΕ a paclitaxel solution in ethanol at a concentration of 15 mg / mL. The coating was at 24 hours

Room temperature dried.

Then, a polyvinylpyrrolidone layer using the spraying technique described in Example 1 was applied over the dried chicht P aclitaxels. It was sprayed with a 00:25 wt .-% strength polyvinylpyrrolidone solution in chloroform, and a layer of 500 μ / cm 2 is applied.

The study of leaching and mechanical Trans he paclitaxel was carried out as described in Example I. The following results were obtained:

Total loading of paclitaxel on the balloon: 1.2 μ ^ 2 παη

Eluted paclitaxel: 0.01 μ mm 2 (1 wt .-% of total loading)

transmitted on silicone tube paclitaxel: 0.003 mm ji (1 wt .-% of total loading) The result shows that with this two-ply layer structure and paclitaxel as the lowest

Layer no significant elution and no significant transfer can be achieved by mechanical pressure. This experiment confirmed the information given in the literature that directly coated on the balloon surface paclitaxel adheres so well that it can not be eluted or transferred.

Example 8: Coating of a balloon catheter with paclitaxel and polyvinylpyrrolidone / BSA as a two-layer structure (V COMPARISON)

This experiment was run 7 performed. However, it was not coated pure paclitaxel, but a mixture of paclitaxel and BSA. For this purpose, a mixture of 900 of a paclitaxel solution in ethanol at a concentration of 15 mg / mL and 100 μΐ, an aqueous BSA solution having a concentration of 15 mg / mL was prepared as described in Example 7 coated and dried. Then, as described in Example 7, a polyvinyl pyrrolidone-position as described in Example 7 was sprayed over paclitaxel layer and dried for 24 hours at room temperature. The study of leaching and mechanical transfer of paclitaxel was carried out as described in Example. 1

The following results were obtained:

Total loading of paclitaxel on the balloon: 1.28 ug / mm 2

Eluted paclitaxel: 0.64 | ig mm '(50 wt .-% of total loading) transmitted on silicone tube Paclitaxel 0.13 ug / mm 2 (10 wt .-% of total loading) by the addition of BSA to paclitaxel can be the the Ballonoberfiäche paclitaxel coated again easily elute from the balloon surface. but the premature loss during elution is very high and therefore unacceptable. In mechanical transfer a small fraction of paclitaxel used is only transferred in the desired manner on the tube wall.

Example 9: Evaluation of the balloon according to the invention in an in vitro Gefaümodell

Balloons were coated with 2,000 ug polyvinylpyrrolidone as described in Example. 1 The coatings was 5.5 minutes per side balloon at 254 nm irradiated. The distance of the lamp to the balloon membrane was I cm. After drying the crosslinked by irradiation coatings (24 h at room temperature) paclitaxel and BSA was incorporated in this coating. For this purpose, 450 were μΐ of a 10 mg / ml paclitaxel solution, and 1 mg / ml BSA in ethanol / water (8: 2) applied to the P oly vinylpyrr olidon-B it chichtung.

After 24 h of drying the coating at room temperature the balloon was manually gefal- tet by the introduced Lu t removed via the pump to open the valve (see also Example 1).

The operation of the coated balloons according to this invention was tested with an in vitro model vessel, which was described in the paper by W. Schmidt et al., Cathete- rization and Cardiovascular Interventions 73, 350-360 (2009). The investigations were carried out with the gap 5 in Fig. 3 on page 352 of said publication in a water bath at a temperature of 37 ° C. Each balloon was in a guiding catheter (Cordis Vista brite tip 5F, 100 cm, 1, 4 mm diameter) on a guidewire (Biotronik Cruiser Hydro 0.014 ") attached. Distance into the distal end of the test, a 80 mm long silicone tube was inserted. This tube is used as a model for a stenotic region in which the balloon is dictated chichtete medikamentenb it.

A hemostatic rotary valve was connected to the proximal end of the guidewire. By this valve, the experiment was rinsed stretch wt .-% saline solution before each test with 0.9. In order to position the balloon at the distal end of the test track in the silicone hose (model stenotic site), the proximal end of the guide wire was inserted into the distal end of the guide catheter lumen. The hemostatic rotary valve was opened and out of the balloon catheter manually through the guide catheter through the vascular model to the silicone tube. The entire length of the vessel model with the guide wire has been replaced it chichtung rinsed several times with a total of 27 ml of a 0.9 wt .-% saline solution to capture paclitaxel, which allonb prematurely from B during the Einfuhrens of the balloon catheter through the vessel model in the silicone tube (Elutionslö- solution 1). In positioning of the balloon in the silicone tube, the balloon expands to 7 listed bar and held 30 seconds so on. In that time, the Baiionoberfläche pressed against the silicone tube and transmits the active ingredient to the S ilikonob he area. After expansion of the balloon, the solution was recovered in the silicone tube and 27 ml of 0.9 wt .-% saline solution filled (solution 1 after dilatation). I lier included shares of paclitaxel, which have been eluted by balloon dilation in the silicone tube into the saline. These amounts found were analyzed.

The silicone tube was removed from the vessel model. The tubing was extracted with methanol in order to determine the still adhering amount of paclitaxel. This corresponds to amounts of paclitaxel, which are to be transmitted by the pressing of the balloon to the vessel wall in a desired manner on the stenotic site (solution 2 after dilatation, see below under paclitaxel analysis).

After removing the balloon, the entire test distance of the vessel model was extracted once with 27 ml of methanol. Thereby remaining amounts of paclitaxel were collected in the model that have been lost in an undesirable manner before the balloon dilatation of the stenotic site by elution processes (elution 2). The balloon after dilatation has been cut, and (see below under Paclitaxelanalyse), extracted with methanol to determine the residual on the balloon amounts of paclitaxel (solution balloon residual loading).

Paclitaxel analysis

Both the chopped balloon and the silicone tubing were extracted for 30 min at room temperature with 20 ml as methanol. The extracts were diluted once more with methanol to the tenth part and then the paclitaxel concentration as described in Example 1 by HPLC analysis determined.

The collected sodium chloride solution (eluting solution I and solution 1 after dilatation) and the methanolic elution solution 2 were also diluted with methanol to the tenth part and determined by HPLC, the paclitaxel concentration.

Results of the HPLC determination: a) prematurely lost by elution amount of paclitaxel:

Eluting 1: 270.3 ug, 0.54 ug / mm 2 (15.4 wt .-% of total Paclitaxelmenge)

Eluent 2: 295.1 ug, 0.59 ug / ml (16.8 wt .-% of total Paclitaxelmenge) b) during balloon dilation emitted Paclitaxelmenge:

Solution 1 after dilation: 13.0 micrograms, 0.026 μ ^ 'ηιπι 2, 0.7 wt .-% of total Paclitaxelmenge)

Solution 2 after dilation: 353.6 ^ μ, 0.70 μ ^ ιηπι 2, 20.2 wt .-% of total Paclitaxelmenge c) on balloon remaining amount of paclitaxel:

Solution balloon residual loading: 822.2 ug, 1, 64 μ ^ 'ΐΏΐη 2, 46.9 wt .-% of total Paclitaxelmenge

The balloon of the invention exhibits in total a loss of 32% of the total load-Paclitaxei- in the model. 21% of the total charge were given, however, during the Dilata- tion.

Example 10: Evaluation of Comparative balloon in an in vitro model of vessel

a commercially available, coated with paclitaxel balloon (IN.PACT Falcon paclitaxel-releasing PTCA balloon, 20 x 4 mm) as described in Example 9 evaluated in the above vessel model. A total of five of these balloons were examined. The analysis of the various solutions was also carried out as described in Example 9th The values ​​given are the average of five attempts. Results of the HPLC determination: a) prematurely lost by elution amount of paclitaxel:

Eluting 1: 437.9 micrograms (standard deviation 160.7), 1.7425 (ig itnr (standard deviation 0.6395), 44.3 wt .-% (of total Paclitaxelmenge standard deviation 14.1) eluting 2: 217.9 ug (standard deviation 73.8), 0.8670 g / ml (standard deviation

.2938), 22.5 wt .-% (of total Paclitaxelmenge standard deviation 7.9) b) during balloon dilation emitted Paclitaxelmenge:

Solution 1 after dilation: 33.4 ug (standard deviation 27.8), 0.133 micrograms / mm 2 (standard deviation 0.1106), 3.2 wt .-% of total Paclitaxelmenge (standard deviation 2.5) Solution 2 after dilation: 89 , 6 ug (standard deviation 32.5), 0.3567 g / mm 2 (standard deviation 0.1294), 9.0 wt .-% of the total Paclitaxelmenge (standard deviation 2.9) c) on balloon remaining amount of paclitaxel:

Solution balloon residual loading: 205.3 micrograms (standard deviation 82.9), 0.8169 g / mm 2 (standard deviation 0.3301), 21.0 wt .-% of total Paclitaxelmenge (standard deviation 9.4).

The comparison balloon loses more paclitaxel elution by undesirable than the inventive

Coating and transmits less paclitaxel in the desired manner on the blood vessel as the inventive coating.

Claims

claims:
1. A method for providing a medical device, which is provided for insertion into the human or animal body, with a coating which contains a pharmacologically active agent at least, said method comprising the steps of;
* Coating at least a portion of the surface of the medical device with a cross-linkable group-containing polymer,
* Impregnate the polymer with the pharmacologically active agent and
"Post-crosslinking of the crosslinkable group-containing polymer on the surface of the medical device by the action of radiation.
2. The method according to claim 1, characterized in that the post-crosslinking of the crosslinkable group-containing polymer is carried out with the pharmacologically active agent prior to impregnation of the polymer.
3. The method of claim 1 or 2, characterized in that the medical device is an implant, particularly a stent, a catheter or a balloon catheter.
4. The method according to any one of the preceding claims, characterized in that the medical device is configured expandable, wherein the coating with the cross-linkable group-containing polymer, and, optionally, also the post-crosslinking of the polymer and / or the impregnation with the pharmacologically active agent in the expanded carried state of the medical device.
5. The method according to any one of the preceding claims, characterized in that the cross-linkable group-containing polymer has a number average weight of at least 10,000 g / mol, in particular at least 50,000 g / mol, preferably at least 100,000 g / mol, more preferably at least 200,000 g / mol , more preferably at least 250,000 g / mol or even at least 300,000 g / mol.
6. The method according to any one of the preceding claims, characterized in that the cross-linkable group-containing polymer is applied μηι in a layer thickness of 0.5 μ m to 100, in particular from 1 to 50 μιη μηι.
7. The method according to any one of the preceding claims, characterized in that the cross-linkable group-containing polymer is applied directly to the surface of the medical device and that before any particular adhesive layer is formed on the medical device. 8. The method according to any one of the preceding claims, characterized in that the
Coating a portion of the surface of the medical device with the cross-linkable group-containing polymer with either a single coating run, the polymer is post-crosslinked or there is the post-crosslinking of the polymer after the last B chichtungsdur chlauf is performed several times at least. 9. The method according to any one of the preceding claims, characterized in that the cross-linkable group-containing polymer is applied from a solution in a suitable solvent or as a melt, in particular by brushing, printing. Trans ferb it chichten, spin coating, knife coating, spraying or dipping.
10. The method according to any one of the preceding claims, characterized in that the post-crosslinking, alpha- by electron beam, beta, gamma and / or UV radiation.
1. 1 Method according to one of the preceding claims, characterized in that the pharmakologis ch suitable active ingredient for topical treatment of diseased tissues and in particular is selected from the group consisting of immunosuppressants, anti-cancer drugs, analgesics, anticoagulants, blutverflüssigende agents, thrombotic boresistente means and other means to suppression of acute thrombosis, stenosis or late restenosis of arteries, growth factors, vasodilators, anti-neoplastic agents, antibiotics, preferably free in combination with a controlling set / forming a support for the continued release from the coating egg nes medical article to a localized infection within the body,
Steroids for the purpose of suppressing inflammation in localized tissue antivrale agents, anti-inflammatory agents, and combinations thereof.
Method according to one of the preceding claims, characterized in that the pharmacologically active agent is selected from paclitaxel, docetaxel, immunosuppression such as sirolimus or sirolimus related limus derivatives, and combinations thereof,
13. The method according to any one of the preceding claims, characterized in that the impregnation is carried out with the pharmacologically active agent from a solution of this active ingredient in a suitable solvent, wherein the impregnation is effected in particular in such a way that the medical device provided with the polymer in the solution of the pharmacologically active agent is immersed, wherein the residence time is least 30 minutes, preferably at least 1 hour, preferably at least 2 hours, more preferably at least 4 hours or at least 6 hours.
14. A method according to any one of the preceding claims, characterized in that the impregnation is repeated at least once.
15. The method according to any one of the preceding claims, characterized in that the medical device provided with the polymer impregnation with at least one adjuvant is defined, which is in particular selected from contrast agents, contrast media derivatives, matrix and gel-forming excipients sugar. Sugar vaten deri dextrins, .beta.-cyclodextrins, organic or inorganic salts, benzoates, salicylates, polymers. Albumins, chitosan, hydroxy cellulose, lipids. Linolenic acid, oleic acid, stearic acid, phenyl salicylate, Vitamin E, tocotrienols, tocopherols, Bisethylhe- xylsebacat, ododecylphthalat Diis, N-methyl, butyl, Butylhyd- roxytoluol, phosphorylcholine, äureestern oils, fatty acids, fatty acids, amino acids, peptides. Vitamins, neutral and charged amphiphilic substances Lestern Polyethylenglyco-, polyglyceryl-6-fatty acid ester, polyglyceryl fatty acid ester 10, nopalmitaten Sucrosemo- whether he ren surfactants with lipid chains, surfactants, organic pillars and esters thereof as well as combinations, wherein the albumin is preferably selected from lactalbumin, ovalbumin, bovine albumin. S chweinealbumin or combinations thereof.
16. The method according to claim 15, characterized in that the impregnation of the polymer provided with the medical device from a mixture of pharmacologically active agent and adjuvant is effected. A medical device obtainable by a process according to any one of claims 1 to 16, wherein the medical device is in particular provided for expanding vascular constrictions, preferably for expanding vascular constrictions in the human or animal body.
Medical device according to claim 17, characterized in that the medical device is configured expandable, in particular as a balloon catheter, and that wt .-% of the pharmacologically active by the latter before expansion for one minute and subsequent contraction in a vessel of a human or animal body at least 5 active substance is transferred to the inner wall of the vessel, in particular at least 8 wt .-%, each based on the total amount of the active ingredient.
Medical device according to one of claims 17 or 18, characterized in that, when contacting the medical device with a physiological solution such as blood or a phosphate-buffered physiological saline solution, within a period of 10 minutes at 37 ° C less than 10 wt .-% of pharmakologis be issued ch active agent in the solution, in particular less than 8% by weight, based in each case on the total amount of the active ingredient.
PCT/EP2012/073711 2011-11-30 2012-11-27 Drug-coated medical device and method for the production thereof WO2013079476A1 (en)

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