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

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

 Semi-coated medical device and method of making the same

The present invention relates to a method for providing a medical device intended for imports into the human or animal body, with a coating containing 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 method, wherein the medical device is designed specifically as a balloon catheter.

As is known, blood vessel constrictions are a common cause of morbidity and also mortality. Local stenoses or occlusions of larger vessels can in many cases be expanded back to their original lumen with the help of expandable balloon catheters. However, this technique uses very high pressures which can cause cracks in the vessel wall or other injuries such as bruising and displacement into surrounding tissue.

In many cases additional stents are implanted in these procedures. These are tubular perforated metal supports that are inserted into the narrowed blood vessel site and are intended to hold the blood vessel open. Recent generations of such stents still contain a coating of a drug that is continuously delivered over several months to the vessel wall to aid the healing process. Nevertheless, in many cases, the blood vessel walls treated in this way react within a few months with increased thickness growth, which is comparable to scarring. As a result, a vasoconstriction, a so-called restenosis, can occur again in a short time. In isolated cases, drug-coated stents have also been associated with subsequent thrombosis, which is a very serious complication. Thus, there is still a need for gentle methods for the local treatment of vascular constrictions.

As an alternative to the aforementioned vascular constriction treatments, drug-coated balloons have been developed in recent years. Such medical devices are disclosed, 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, 255-263. In these balloons, the surface is coated with a drug. In use, the balloons are first led to the desired location in the body and expanded with compressed air, whereby they take the form of a rigid cylinder, wel rather close to the vessel wall. By the contact pressure not only the vasoconstriction is expanded, but also transferred to the outside of the balloon Oberon surface applied drug on the vessel inner wall. To remove the balloon this is again contracted by removing the pressure and removed. The active ingredient, which is transferred to the inner wall of the vessel, is intended to prevent excessive scar formation and thus restenosis or at least to reduce it to a minimum. The advantage over a drug-eluting stent is the fact that no foreign matter such as the stent remains in the bloodstream, which can trigger blood reactions such as coagulation or inflammation.

The medicament usually used for the aforementioned purpose is paclitaxel. However, according to WO 2010/121840, a balloon coated exclusively with paclitaxel is unsuitable. Therefore, it is proposed in this document to provide the balloon surface with a mixture of paclitaxel and an additional component, so that the balloon shows a therapeutic efficacy after dilation.

The ineffectiveness of pure paclitaxel is due to the fact that this drug has lipophilic properties, which leads to a high adhesion to the commercial balloon surfaces, so that it can not be transferred to the vessel wall by pressure. Therefore special additives are added to paclitaxel so that it can be transferred under pressure to the vessel wall. In this case, the additive must be selected so that a transfer of paclitaxel on the vessel wall takes place within about 60 seconds. A longer dilatation time is not possible because it poses a very high risk to the patient, because during the expansion of the balloon catheter, the vessel to be treated is closed by the catheter.

For this reason, WO 2002/076509 and WO 2004/028582 use the lopromide known as a contrast agent as an additive for mixing with paclitaxel. In WO 2010/121840 shellac, in WO 2009/051614 and WO 2009/051615 surface-active

Additives proposed. At the Transcatheter Cardiovascular Therapeutics 2010 conference, a coated balloon IN.PACT from Medtronic was unveiled. This is provided with a medicament coating of paclitaxel and urea. This system is also described in B. Kelsch et al., Investigative Radiology 46 (4), 2011, 255-263. Further hydrophilic additives are described in WO 2009/018816. Although the use of these additives improves the transfer of paclitaxel to the vessel wall. However, these additives also cause a significant portion of the paclitaxel to be dissolved or dissolved during the manipulation of the folded balloon through the blood vessels to the stenotic site and thus no longer available at the actual site. This effect is enhanced by the commonly used hydrophilic additives. This is especially true when the additives are water-soluble, which severely affects the stability of the coating during the passage of the balloon through the blood vessels to the stenotic site. This disadvantageous circumstance is mentioned, for example, in the publications B. Elsch et al., Investigative Radiology 46 (4), 2011, 255-263 and A. De Labriolle et al., Catheterization and Cardiovascular Interventions 73, 2009, 643-652. However, the concentration of the active ingredient on the surface of the surface at the site of dilatation is not only significantly lower than the originally coated amount, but above all is not reproducible or controllable, which can significantly reduce the success of the therapy. Several approaches have been described in the literature to circumvent the described fundamental problem of current developments. For example, US 2011/0054396 specifies a coating on the balloon which, during the dilatation of the balloon, breaks up into small parts and is transferred to the surrounding body tissue. Here, however, there is a risk that the resulting particles of the original coating not only transferred to the body tissue, but also be registered in the bloodstream. Any development of particles in the bloodstream is undesirable because of possible side effects. For example, in the medical technology industry, usually all interventional devices are checked to ensure that a limit value of particle concentrations is not exceeded (USP788).

Another approach is pursued in WO 2010/133557, which proposes the use of microparticles in a balloon coating. These microparticles contain an active substance which releases the active substance contained under pressure. This process is very complex, since the microparticles with the active ingredient must be prepared in a separate step and then incorporated into a coating.

Hydrogels have long been used as a matrix for drug-eluting systems. These polymers are hydrophilic three-dimensional networks that are insoluble due to their crosslinking in solvents or water. The use of such hydrogels for coating of balloon surfaces is therefore not possible and thus became hardly used for the coating of medical technology surfaces. It is therefore proposed in EP 1 364 664 to provide a stent surface first with an adhesion promoter layer and then with a polysaccharide or hyaluronic acid, which is subsequently reacted by chemically induced cross-linking to form a hydrogel. This layer can be incorporated into a pharmacologically active substance. Such a method is very complicated, since usually first a bonding agent layer must be applied. In addition, the cross-linking is carried out with chemical reagents. However, it can not be avoided in this process that some of these reagents do not react with the polymer and thus remain as elutable component in the hydrogel. This means an increased toxicological risk, which can only be reduced or eliminated by very careful removal of any remaining low molecular weight materials. Carrying out such a purification and the analytical validation of the complete separation means a high technical effort.

The object of the present invention was to provide an improved method for coating medical devices, wherein the coatings obtainable on the one hand enables a reliable transfer of pharmacologically active substances contained in the coating, but during the transfer through the patient's body stenotic site shows the lowest possible loss of active ingredient.

This object is achieved by a method / provision of a medical device intended to be introduced into the human or animal body with a coating containing at least one pharmacologically active substance, the method comprising the following steps:

Coating at least part of the surface of the medical device with a crosslinkable polymer, impregnating the polymer with the pharmacologically active substance and

Post-crosslinking of the crosslinkable polymer on the surface of the medical device by exposure to radiation.

The medical device can therefore be partially or fully coated. In this case, preferably that surface of the medical device is completely coated, the in contact with the vessel wall during use. This is usually the outside 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 method.

In the context of the process according to the invention, it may be provided that the impregnation with the active ingredient is carried out before the postcrosslinking of the polymer having crosslinkable groups. In this case, however, the radiation source used for postcrosslinking or the energy of the radiation used should be adjusted with respect to the stability of the active ingredient, so that not too much Wirki t ⁾ amount of material is degraded by the radiation. This can be checked for example on the basis of the spectroscopic absorption behavior of the active substance or, in the simplest case, on a test object impregnated with the active substance, which is exposed to the corresponding radiation in the power density and irradiation time required for postcrosslinking.

However, in the context of the process according to the invention, it is preferred to carry out the postcrosslinking of the polymer having crosslinkable groups before the impregnation of the polymer with the pharmacologically active substance. This can circumvent the above problems. However, all embodiments of the method described below can be readily applied to both process sequences. Surprisingly, it has been found that the use of radiation-induced postcrosslinking can produce a polymer coating on the surface of the medical device in which a pharmakologis active agent can be embedded. The active substance depot produced on the surface of the medical device can transfer the active substance by pressing it against the wall of a vessel in the body of the patient in large quantities. At the same time, however, only a comparatively low loss of the active ingredient is observed during transport through the vessel to the desired location. As a result, not only is a larger amount of active ingredient available when the desired site is reached, but the amount of active ingredient is simultaneously more predictable. Overall, this leads to a reproducible applicability of the medical device and to an improved healing success while at the same time reducing the risk of complications. The use of radiation for crosslinking, for example in the form of UV light, is particularly advantageous because this method of crosslinking does not use any chemical reagents that might remain in the coating. If high-polymer compounds are already used which do not contain low molecular weight constituents, only additional bonds between the polymer chains are formed by the irradiation. For toxicological reasons, this method is therefore particularly advantageous. In this context, a high-polymer compound is understood as meaning a polymer having crosslinkable groups and a number-average molecular weight of 200,000 g / mol or more. In a further development of the method according to the invention, the medical device is an implant, in particular a stent, a catheter or a balloon catheter.

The medical device to be coated may, in principle, have any surface suitable for such devices. Thus, the device (before the coating) have a metal, glass or plastic surface, or even consists of these materials, in particular magnesium or a magnesium alloy, titanium or a titanium alloy, stainless steel, palladium, platinum, gold, rubber. Latex, PVC, silicones, polyether

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

In a further embodiment of the method according to the invention, the medical device is designed to be expandable, wherein the coating with the polymer having crosslinkable groups, and optionally also the post-crosslinking and / or the impregnation, takes place in the expanded state of the medical device. For this purpose, in particular devices from the aforementioned polymeric materials into consideration. This procedure is advantageous because a better anchoring of the polymer layer is achieved, so that during the expansion of the medical device inside the body, the polymer layer does not tear or even partially delaminate. This further reduces the risk of particle entry.

In the context of the process according to the invention, it is possible in principle to use all polymers which can be postcrosslinked in a radiation-induced manner. For this purpose, the polymer having crosslinkable groups can be selected from the group comprising polyvinylpyrrolidone, acrylate polymers, polyurethanes, polyureas, polyesters, polyethers, polyols, polyether polyols, polyester polyols, polyether ester polyols, polycarbonate polyols, polyester carols. carbonate polyols, polyether carbonate polyols, poly-lactones, poly-lactides, poly-glycolides, or mixtures or copolymers of these.

Of the aforementioned polymers, polyvinylpyrrolidone is particularly preferred. Polyvinylpyrrolidone (PVP) is a hydrophilic polymer that is soluble in organic solvents or in water and can be applied to the surface of the device. As a permanent coating of a balloon catheter, it can only be used by the postcrosslinking provided according to the invention since, in the non-crosslinked state, it would be washed off the balloon surface in a short time due to its good water solubility during contact with the blood stream. It has now surprisingly been found that polyvinylpyrrolidone after coating on the balloon membrane can be converted by irradiation with UV light into a stable hydrogel, which can then be incorporated with active ingredients such as paclitaxel. The active substance remains in the matrix of the polymer before dilation at the site of the stenosis, but can then be transferred very rapidly to the surrounding tissue by dilatation. This was surprising in that even hydrophobic drugs in this very hydrophilic

Stable hydrogel matrix of polyvinylpyrrolidone store. Optionally, adjuvants can also be impregnated in the UV-cured polyvinylpyrrolidone layer in addition to the active ingredient in order to modulate the release kinetics of the active ingredient. This will be explained in more detail later. In a further advantageous embodiment of the process according to the invention, the polymer having crosslinkable groups has a number-average mass 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 at least 360,000 g / mol, especially when using polyvinylpyrrolidone.

In the coating of the medical device, the polymer having crosslinkable groups can be applied, for example, in a layer thickness of from 0.5 μm to 100 μm, in particular from 1 μm to 50 μm. These layer thicknesses are advantageous because, on the one hand, they represent a sufficient depot function for the pharmacologically active substance and at the same time have only a slight influence on the mechanical properties of the medical device. In addition, polymer layers in these thicknesses have less of a tendency to delaminate during device expansion, such as with a balloon catheter.

Another advantage of the method according to the invention is that no adhesion promoter layer has to be applied to the surface of the medical device. A corresponding embodiment therefore provides that the polymer having crosslinkable groups is applied directly to the surface of the medical device and that, in particular, no adhesion promoter layer is previously produced on the medical device.

According to a further variant of the method according to the invention, the coating of at least a part of the surface of the medical device with the polymer having crosslinkable groups is carried out several times, the polymer being post-crosslinked either after a single coating pass or post-crosslinking of the polymer taking place only after the last coating pass , As a result, a greater layer thickness can also be produced. The same or different polymers can be used for the individual layers. The crosslinkable polymer may be applied to the surface of the medical device in any suitable manner. This can be done for example from a solution of the polymer in a suitable solvent or a melt of the polymer. In particular, the job can be done by brushing, printing. Transfers, spin coating, doctoring, spraying, or dipping. After application, a drying step may expediently be provided before the post-crosslinking.

Suitable solvents for the polymer having crosslinkable groups are a multiplicity of solvents, for example water, ethanol or other alcohols and also other organic solvents such as chloroform, acetone or the like. Mixtures of these solvents can also be used. The appropriate concentration of the polymer solution depends on the desired application method, the molecular weight of the polymer and the type of polymer. A suitable concentration can be determined in a few experiments.

The radiation-induced postcrosslinking can be carried out by all types of radiation that are suitable for this, such as electron, alpha, beta, gamma and / or UV radiation. As far as the pharmacologically active agent is concerned, it is preferably local

Treatment of diseased tissues suitable.

Specific examples of pharmacologically active agents include, but are not limited to, thrombore-resistant (non-thrombogenic) agents or other agents for suppressing acute thrombosis, stenosis or late re-stenosis of the arteries. These are, for example, heparin, streptokinase, urokinase, tissue plasminogen activator, anti-thromboxane B2 agents; Anti-B-thromboglobulin, prostaglandin-E, aspirin, dipyrimidol, anti-thromboxane A2 agents, murine monoclonal antibody 7E3, triazolopyrimidine, ciprostene, hirudin, ticlopidine. Nicorandil, etc. A growth factor may also be used as a pharmacologically active agent to suppress intimal fibromuscular hyperplasia at the arterial stenosis site, or any other cell growth inhibitor may be employed at the stenotic site.

The pharmacologically active agent may also consist of a vasodilator to counteract vasospasm. This may, for example, be an antispasmodic such as papaverine. The pharmacological agent may be a vasoactive agent per se, such as calcium antagonists or α and β adrenergic agonists or antagonists. In addition, the pharmacological agent may be a biological adhesive such as medical grade cyanoacrylate or fibrin. As the pharmacologically active agent, an antineoplastic agent such as 5-fluorouracil can also be used, preferably with a controlling releasing carrier for the agent, e.g. for the application of a sustained controlled release anti-neoplastic agent at a tumor site.

The pharmacologically active agent may be an antibiotic, preferably in combination with a controlling sustained-release carrier from the coating of a medical article to a localized site of infection within the body. Similarly, the pharmacological 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 homologues, analogues, fragments, derivatives and pharmaceutical salts thereof;

(b) antibiotic agents such as penicillins, cephalosporins, vacomycins, aminoglycosides, quinolones, polymyxins, erythromycins; Tetracyclines, chloramphenicols, clindamycins, lincomycins, sulfonamides, their homologues, analogues, derivatives, pharmaceutical salts and mixtures thereof;

(c) paclitaxel, docetaxel, immunosuppressants such as sirolimus or sirolimus-related limus derivatives such as everolimus, Biolimus A9, tacrolimus or zotarolimus, alkylating agents including mechlorethamine, chlorambucil, cyclophosphamide, melphalan and ifosfamide; Antimetabolites including methotrexate, 6-mercaptopurine, 5-fluorouracil and cytarabine; Plant alcohols including vinblastine; Vincristine and etoposide; Antibiotics including doxorubicin, daunomycin, bleomycin and mitomycin; Nitrosurea including carmustine and lomustine; inorganic ions including cisplatin; biological reaction modifiers including interferon; angiostatic and endostatic agents; Enzymes including asparaginase; and hormones including tamoxifen and flutamide, their homologues, analogs, fragments, derivatives, pharmaceutical salts and mixtures thereof;

(d) antiviral agents such as amantadine, rimantadine. Rabavirin, idoxuridine, vidarabine, trifuridine, acyclovir, ganciclorir, zidovudine, phosphonoformates, interferons, their homologues,

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

(e) anti-inflammatory agents such as ibuprofen, dexamethasone or methylprednisolone.

Of the aforementioned pharmacologically active agents, paclitaxel, docetaxel, immunosuppressants such as sirolimus or sirolimus-related limus derivatives, as well as combinations thereof are particularly preferred.

According to a preferred variant of the method according to the invention, the impregnation with the pharmacologically active ingredient is carried out from a solution of this active ingredient in a suitable solvent, the impregnation in particular via brushes, printing. Transfer coating, spin coating, knife coating, spraying or dipping is performed. The Impregnation can also be repeated at least once. Subsequently, the coated and impregnated device is expediently dried and is then ready for use.

Suitable solvents for the pharmacologically active ingredient are a variety of solvents, in particular water, ethanol or other alcohols, as well as other organic solvents such as chloroform, acetone or the like. Mixtures of these solvents may also be used, with a mixture of water and ethanol being particularly preferred. The mixing ratio of ethanol to water can be for example 1: 1 to 10: 1 parts by volume, in particular 2: 1 to 5: 1. If the impregnation is carried out on a polymer which has not yet been cross-linked, care should be taken that the applied polymer layer does not penetrate dissolves the solvent used for the drug solution.

The concentration of the active ingredient solution can vary over a wide range and depends inter alia on the medically meaningful loading of the surface of the device with the respective active ingredient. For paclitaxel, a concentration of from 0.1% by weight to 25% by weight, preferably from 0.5 to 10% by weight, is suitable. As the solvent, a water / ethanol mixture of the aforementioned type is particularly suitable.

Among the coating options specified above, the one in which the medical device provided with the polymer is immersed in the solution of the pharmacologically active substance is particularly preferred, because in this case the impregnated amount of active substance can be controlled by the residence time in the solution. Thus, the residence time may preferably be at least 30 minutes, in particular at least 1 hour, preferably at least 2 hours, more preferably at least 4 hours or even at least 6 hours.

According to a particularly preferred embodiment of the method according to the invention, the medical device provided with the polymer is impregnated with an adjuvant. When

Excipients may be mentioned, for example: contrast agents, matrix and gel-forming excipients, eg. As lipids or polymers commonly used in pharmacy. Sugar. Sugar derivatives, dextrins, low molecular weight polyethylene glycol (PEG), organic or inorganic salts, benzoates, urea, citric acid ester, salicylates, polymers such as. Starch, gelatins, PEG, albumins, chitosan, β-cyclodextrins, hydroxycellulose and lipids, linoleic acid, linolenic acid, oleic acid, stearic acid, phenyl salicylate, vitamin E, tocotrienols, tocopherols, B is ethylhexyls ebacate, diisododecyl phthalate, N-methylpyrrolidone, butylhydroxyanisole, butylhydroxytoluene, phosphorylcholine, oils, fatty acids, fatty acid esters, contrast agent derivatives, amino acids, peptides, vitamins, neutral and charged amphiphiles, salts, polyethyleneglycol esters, fatty acid esters of sugars, polyglyceryl-6 Fatty acid esters, polyglyceryl-10-fatty acid esters, sucrose monopalmitates, lipid chain surfactants, surfactants, organic acids and esters, and salts.

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

Suitable anionic surfactants are, in principle, all anionic surface-active substances suitable for use on the human body. These are characterized by a water-solubilizing, anionic group such as. Example, a carboxylate, sulfate, sulfonate or phosphate group and a lipophilic alkyl group having about 8 to 30 C atoms. In addition, glycol or polyglycol ether groups, ester, ether and amide groups as well as hydroxyl groups may be present in the molecule. Examples of suitable anionic surfactants are, in each case in the form of the sodium, potassium and ammonium as well as the mono-, di- and trialkanolammonium salts having 2 to 4 C atoms in the alkanol group, linear and branched fatty acids having 8 to 30 ° C -atoms,

- Ethercarbonsäuren the formula R ¹⁴ -0- (CH ² -CH 2 O) x-CH 2 -COOH, in which R ^{14 is} a linear alkyl group having 8 to 30 carbon atoms and x = 0 or 1 to 16, - acylsarcosides having 8 to 24 C atoms in the acygroup,

Acyltaurides having 8 to 24 carbon atoms in the acetic acid group,

Acyl isethionates having 8 to 24 carbon atoms in the acetic acid group,

Sulfosuccinic acid mono- and dialkyl esters having 8 to 24 C atoms in the alkyl group and sulfosuccinic acid monoalkylpolyoxyethyl esters having 8 to 24 C atoms in the alkyl group and 1 to 6 oxyethyl groups, linear alkanesulfonates having 8 to 24 C atoms, linear alpha Olefin sulfonates having 8 to 24 carbon atoms, Alpha sulfo fatty acid methyl esters of fatty acids with 8 to 30 C atoms.

Alkyl sulfates and alkyl polyglycol ether sulfates of the formula R "- () (CII: -C l l -OK-OSO,] in which R ^'is a preferably linear acyl group having 8 to 30 C atoms and x = 0 or 1 to 12,

Mixtures of hydroxysulfonate surfactants, sulfated hydroxyalkyl polyethylene and / or hydroxyalkylene glycol ethers,

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

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

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

O

I i

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

OX in the R ^{i6 is} preferably an aliphatic hydrocarbon ^radical having 8 to 30 carbon atoms, R ^{17 is} hydrogen, a radical (CH ₂ CH ₂ O) "R ¹⁸ or X, h is from 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 represent hydrogen or a C 1 to C 4 hydrocarbon radical, is a sulfated fatty acid alkylene glycol ester of the formula (II-II) R ²² CO (AlkO) _h S0 ₃ M (El -II) in the R ²² CO- for a linear or branched, aliphatic, saturated and / or unsaturated acyl radical having 6 to 22 C atoms, Alk for CH ₂ CH ₂ , (Ί 1 (1 Ι Ί I · and / or CH 2 CHCH 3, h is a number from 0.5 to 5 and M is a cation,

Monoglyceride sulfates and monoglyceride ether sulfates of the formula (El-III) CH ₂ O (CH ₂ CH ₂ O) _x - COR

CHO (CH ₂ CH ₂ O) _y H

in which R ²³ CO is a linear or branched acyl radical having 6 to 22 carbon atoms, x, y and i total 0 or numbers from 1 to 30, preferably 2 to 10, and X is an alkali or alkaline earth metal. Typical examples of monoglyceride (ether) sulfates suitable for the purposes of the invention are the reaction products of lauric acid monoglyceride, coconut oil monoglyceride, permutinic acid monoglyceride, stearic acid monoglyceride, oleic acid monoglyceride and tallow fatty acid monoglyceride and their ethylene oxide adducts with sulfur trioxide or chlorosulfonic acid in the form of its sodium salts. Preferably, monoglyceride sulfates of the formula (III-III) are used in which R ²³ CO is a linear acyl radical having 8 to 18 carbon atoms,

Amide ethers carboxylic acids,

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 C atoms in the alkyl group and up to 12 glycol ether groups in the molecule, sulfosuccinic acid mono- and dialkyl esters having 8 to 18 C atoms in the alkyl group and sulfo alkylpolyoxyethyl esters having 8 to 18 C atoms in the alkyl group and 1 to 6 oxyethyl groups, monoglycerol disulfates, alkyl and alkenyl ether phosphates and egg white fatty acid condensates.

It is likewise possible to use cationic surfactants.

Cationic surfactants of the quaternary ammonium compounds, esterquats and amidoamines type are preferred according to the invention. Preferred quaternary ammonium compounds are ammonium halides, especially chlorides and bromides. such as alkyltrimethylammonium chlorides, dialkyldimethylammonium chlorides and trialkylmethylammonium chlorides, for example cetyltrimethylammonium chloride, stearyltrimethylammonium chloride, distearea ryldimethylammonium chloride, lauryldimethylammonium chloride, lauryldimethylbenzylammonium chloride and tricetylmethylammonium chloride, as well as the imidazolium compounds known under the I CI names Quaternium-27 and Quaternium-83. The long alkyl chains of the above-mentioned surfactants preferably have 10 to 18 carbon atoms. Esterquats are known substances which contain both at least one ester function and at least one quaternary ammonium group as a structural element. Preferred esterquats are quaternized ester salts of fatty acids with triethanolamine, quaternized ester salts of fatty acids with diethanolalkylamines and quaternized ester salts of fatty acids with 1,2-dihydroxypropyldialkylamines. Such products are sold, for example, under the trademarks Stepantex®, Dehyquart® and Armocare®. The products Armo Care® VG! 1-70. N, N-bis (2-palmitoyloxyethyl) dimethylammonium chloride, as well as Dehyquart® F-75, Dehyquart® C-4046, Dehyquart® L80 and Dehyquart® AU-35 are examples of such esterquats.

The alkylamidoamines are usually prepared by amidation of natural or synthetic fatty acids and fatty acid cuts with dialkylaminoamines. A particularly suitable compound according to the invention from this group of substances is stearamidopropyl-dimethylamine, which is commercially available under the name Tegoamid® S 18.

In addition to or instead of the cationic surfactants, the agents may contain other surfactants or emulsifiers, in principle, 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 may already have emulsifying effect.

Zwitterionic surfactants are those which are surface-active compounds which carry at least one quaternary ammonium group and at least one -COO ^H or -SO 3 ^H group in the molecule. Particularly suitable zwitterionic surfactants are the so-called betaines such as N-alkyl-N, N-dimethylammonium glycinates, for example cocoalkyldimethylammonium glycinate, N-acylaminopropyl-N, N-dimethylammonium glycinates, for example cocoacylaminopropyl-dimethylammonium glycinate, and Alkyl-3-carboxymethyl-3-hydroxyethyl-imidazolines having in each case 8 to 18 carbon atoms in the alkyl or acyl group and the Kokosacylaminoethylhydroxyethylcarboxymethylglycinat. A preferred - Nonionic surfactant is the fatty acid amide derivative known by the INCI name Cocamidopropyl Betaine.

Ampholytes are to be understood as meaning those surface-active compounds which, apart from a Cs-C2-alkyl or acyl group in the molecule, contain at least one free amino group and at least one -COOH or -SOJ I group and are capable of forming internal salts, examples of suitable salts Ampholytes are N-alkylglycines, N-alkylpropionic acids, N-alkylaminobutyric acids, N-alkyliminodipropionic acids, N-hydroxyethyl-N-alkylamidopro- pylglycines, N-alkyltaurines, N-alkylsarcosines, 2-alkylaminopropionic acids and alkylaminoacetic acids each having about 8 to 24 C In the alkyl group, particularly preferred ampholytes are N-cocoalkylaminopropionate, cocoacylaminoethylaminopropionate and C12-cis-acylsarcosine,

Nonionic surfactants contain, for example, a polyol group, a polyalkylene glycol ether group or a combination of polyol and polyglycol ether groups as the hydrophilic group. Such compounds are, for example - addition products of 2 to 50 moles of ethylene oxide and / or 1 to 5 moles of propylene oxide to linear and branched fatty alcohols having 8 to 30 C atoms, to fatty acids having 8 to 30 C atoms and to alkylphenols having 8 to 15 C. Atoms in the alkyl group. with a methyl or C 2 -C 6 -alkyl radical end-capped adducts of 2 to 50 moles of ethylene oxide and / or 1 to 5 moles of propylene oxide with linear and branched fatty alcohols having 8 to 30 C atoms, of fatty acids having 8 to 30 C atoms and on 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 the formula (E4-I)

R ²⁴ CO- (OCH ₂ CHR ²⁵ ) _w OR ²⁶ (E4-I) in the R ²⁴ CO for a linear or branched, saturated and / or unsaturated acyl radical having 6 to 22 carbon atoms, R ^{25 is} hydrogen or methyl, R ^{26 is a} linear or branched alkyl radical having 1 to 4 carbon atoms and is a hydrogen atom from 1 to 20,

Amine oxides,

Hydroxymethyl ether,

S orbitan fat ester eester and Anlagerungeprodukie of ethylene oxide on S orbitanfetts ure ester such as the polysorbates,

Sugar fatty acid esters and addition products of ethylene oxide with sugar fatty acid esters,

Addition products of ethylene oxide onto fatty acid alkanolamides and fatty amines,

Sugars of the type of the alkyl and alkenyl oligoglycosides according to formula (E4-II),

R ^{27 is} O- [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 from 1 to 10. They can be obtained by the relevant methods of preparative organic chemistry.

The alkyl and alkenyl oligoglycosides can be derived from aldoses or ketoses with 5 or 6 carbon atoms, preferably glucose. The preferred alkyl and / or alkenyl oligoglycosides are thus alkyl and / or alkenyl oligoglucosides. The index number 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 integer and here before For all given values p = 1 to 6, the value p for a given alkyloligoglycoside is an analytically determined arithmetic quantity, which usually represents a fractional number. Preferably are used alkyl and / or alkenyl oligoglycosides having a mean degree of oligomerization p of 1, 1 to 3.0. From an application point of view, those alkyl and / or alkenyl oligoglycosides whose degree of oligomerization is less than 1.7 and in particular between 1.2 and 1.4 are preferred. The alkyl or alkenyl radical R ²⁷ can be derived from primary alcohols having 4 to 11, preferably 8 to 10 carbon atoms. Typical examples are butanol, caproic alcohol, caprylic alcohol, capric alcohol and un- decyl alcohol, and technical mixtures thereof, as are obtained, for example, in the hydrogenation of technical ethyl ethers or in the course of the hydrogenation of aldehydes from crude oxo synthesis. Preference is given to alkyloligogoglucosides of the chain length Cs-C10 (DP = 1 to 3) which are obtained as a feedstock in the distillative separation of technical Cs-cis coconut fatty alcohol and in an amount of less than 6% by weight C12 alcohol may be contaminated and alkyl oligoglucosides based on technical Cg _/ n-oxo alcohols (DP = 1 to 3). The alkyl or alkenyl radical R ²⁷ can furthermore 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 alcohol, stearyl alcohol, isostearyl alcohol, oleyl alcohol, elaidyl alcohol, petroselinyl alcohol, arachyl alcohol, gadoleyl alcohol, behenyl alcohol, erucyl alcohol, brassidyl alcohol, and technical mixtures thereof which can be obtained as described above. Preference is given to alkyl oligoglucosides based on hydrogenated C 12/14 coconut alcohol having a DP of 1 to 3.

Sugars of the fatty acid N-alkyl polyhydroxyalkylamide type, a non-ionic one

Surfactant of the formula (E4-III),

R ²⁹

 !

R ²⁸ CO-N- [Z] (Ε4-ΠΙ) in the R ²⁸ CO for an aliphatic acyl radical having 6 to 22 carbon atoms, R ^{29 is} hydrogen, an alkyl or hydroxyalkyl radical having 1 to 4 carbon atoms and [Z] for a linear or branched polyhydroxyalkyl having 3 to 12 carbon atoms and 3 to 10 hydroxyl groups. The fatty acids eN-alkylpolyhydroxyalkylamides are known substances which are usually prepared by reductive amination of a reducing sugar with ammonia, an alkylamine or an alkanolamine and subsequent acylation with a fatty acid, a fatty acid alkyl ester or a fatty acid chloride can be obtained. The fatty acids eN-alkylpolyhydroxyalkylamides are preferably derived from reducing sugars having 5 or 6 carbon atoms, in particular from glucose. The preferred fatty acid N-alkylpolyhydroxyalkylamides are therefore fatty acid N-alkylglucamides as represented by the formula (E4-IV):

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

It is preferable to use, as fatty acids, e-N-alkylpolyhydric oxyalkylamides of the formula (E4-IV) in which R ^! is hydrogen or an alkyl group and R ³⁰ CO is the acyl radical of caproic acid, caprylic acid, capric acid, lauric acid, myristic acid,

Palmitic acid, palmitoleic acid, stearic acid, isostearic acid, oleic acid, elaidic acid, petanselic acid, linoleic acid, linolenic acid, arachidic acid, gadoleic acid, behenic acid or erucic acid or technical mixtures of these acids. Particular preference is given to fatty acid N-alkylglucamides of the formula (E4-IV) which are obtained by reductive amination of glucose with methylamine and subsequent acylation with lauric acid or C12 / 14

Coconut fatty acid or a corresponding derivative can be obtained. Furthermore, the polyhydroxyalkylamides can also be derived from maltose and palatinose.

As preferred nonionic surfactants, the alkylene oxide adducts to saturated linear fatty alcohols and fatty acids having in each case 2 to 30 moles of ethylene oxide per mole of fatty alcohol or fatty acid have been found. Preparations with excellent properties are also obtained if they contain fatty acid esters of ethoxylated glycerine as nonionic surfactants.

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

The compounds used as surfactant with alkyl groups may each be uniform substances. However, it is generally preferred to use native plant or animal raw materials in the production of these substances, so that mixtures of substances having different alkyl chain lengths depending on the respective raw material are obtained.

In the case of surfactants which are adducts of ethylene oxide and / or propylene oxide with fatty alcohols or derivatives of these storage products, both products having a "normal" homolog distribution and those having a narrow homolog distribution can be used. By "normal" homolog distribution are meant mixtures of homologs obtained in the reaction of fatty alcohol and alkylene oxide using alkali metals, alkali metal hydroxides or alkali metal alcoholates as catalysts. Narrowed homolog distributions, on the other hand, are obtained when, for example, hydrotalcites, alkaline earth metal salts of ether carboxylic acids, alkaline earth metal oxides, hydroxides or alcoholates are used as catalysts. The use of products with narrow homolog distribution may be preferred.

The agents may further contain at least one emulsifier. Emuigators which can be used according to the invention are, for example

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

C 12 -C 22 -fatty acid mono- and diesters of addition products of from 1 to 30 mol of ethylene oxide onto polyols having from 3 to 6 carbon atoms, in particular to glycerol,

Ethylene oxide and polyglycerol addition products to methyl glucoside fatty acid esters, fatty acid alkanolamides and fatty acids egluc amide,

C 8 -C 22 -alkylmono- and -oligoglycosides and their ethoxylated analogues, with degrees of oligomerization of from 1.1 to 5, in particular from 1.2 to 2.0, and glucose as the sugar component being preferred, Mixtures of alkyl (oligo) glucosides and fatty alcohols, for example, land in 1! available product Montanov * 68,

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

22 C atoms,

Sterols. Sterols are understood to mean a group of steroids which have a hydroxyl group on C-atom 3 of the steroid skeleton and are isolated both from animal tissue (zoosterone) and from vegetable fats (phytosterols). Examples of zoosterines are cholesterol and lanosterol. Examples of suitable phytosterols are ergosterol, stigmasterol and sitosterol. Fungi and yeasts are also used to isolate sterols, the so-called mycosterols.

Phospholipids. Of these, especially the glucose phospholipids, e.g. as lecithins or phosphatidylcholines from e.g. Egg yolk or plant seeds (e.g., soybeans).

Fatty acid esters 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 albumins such as lactalbumin, ovalbumin, bovine albumin. Pig albumin or combinations thereof. The impregnation with the adjuvant may be upstream or downstream of the impregnation with the pharmacologically active ingredient. Preferably, the impregnation takes place at the same time. This may, for example, be accomplished by carrying out the impregnation of the polymerized medical device with a mixture of the pharmacologically active agent and the excipient. Regardless of the impregnation order, surprisingly pointed out that when using albumins as an excipient, a significantly higher amount of active ingredient can be transferred by pressure application to a vessel wall. This effect is particularly pronounced when using paclitaxel as an active ingredient. Also, a lesser loss of pharmacologically active agent may be observed during manipulation of the medical device within the body.

The concentration of albumins in the impregnation solution can vary over a wide range. Particularly advantageous is a concentration of 0.001% by weight to 15% by weight, preferably from 0.01% by weight to 8% by weight. This is especially true in combination with paclitaxel as an active ingredient. As already discussed at the outset, the present invention also relates to a medical device which is obtainable by the method according to the invention. The medical device can be provided, in particular, for widening vessel narrowings, preferably for widening vessel narrowings in the human or animal body.

In an advantageous development of the medical device according to the invention, this is configured expansible, in particular as a balloon catheter. At least 5% by weight of the pharmacologically active substance is transferred to the inner wall of the vessel, in particular at least 8% by weight, in each case based on this expandable medical device when expanded for one minute and then contracted in a vessel of a human or animal body the total amount of the active ingredient. According to a particularly preferred embodiment of the medical device according to the invention, less than 10% by weight of the pharmacologically active substance is present in this substance when it is 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. delivered 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 FastGradient RP18e 50-2 mm (Knauer Wissenschaftlicher Gerätebau GmbH, Berlin, Germany) Mobile phase: acetonitrile / 'phosphate buffer (0.005 M, pH 3.5) in a mixing ratio of 50:

50, isocratic driving style

Flow rate 0.3 ml / min

UV detection at 230 nm

Sample volume 20 μΐ Measuring range between 0.1 - 20 mg / L Detection limit approx. 0.01 mg / L

UV lamp: 3UV, P / N 95-0343-02, 3UV-38, 8 Watt from Ultra Violet Products Ltd., Upland, USA

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

Used substances:

Balloon used: PTA catheter, 4.0 x 40 mm. 0.035 wire, FI manufacturer Bavaria Medi / intechnik Chloroform 99% (Mallinckrodt Baker Chemikalien, Griesheim, Germany)

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

Polyvinylpyrrolidone (PVP K 90, number average molecular weight 360000 Da, Carl Roth Gmbl 1 and Co. KG, Karlsruhe, Germany) Dulbecco's Phosphate Buffered Saline Solution (PBS, PAA Laboratories, Cölbe, Germany)

Tween 20 (Sigma Aldrich, Taufkirchen, Germany) Paclitaxel (Cfm Oskar Tropitzsch, Marktredwitz, Germany) Ethanol Absolutely (Zentralapotheke Universität Rostock)

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

Example 1 Coating of a Catheter Balloon Surface with PVP, Crosslinking of the PVP Coating by UV and Impregnation of the Crosslinked PVP Coating with Paclitaxel (According to the Invention)

The surface of a balloon was coated with polyvinylpyrrolidone (PVP) by a spray method described in WO 2011/082946 in Example 8. The balloons are in the expanded state in that they were dilated with a pump with air to about 2 bar before the coating process. In order to maintain the pressure during the spraying process, a valve was placed at the end of the catheter, which was closed after dilation. The balloon was clamped on the tip and on the catheter and moved both vertically / around the spray jet and rotated around its own axis to ensure homogeneous coating of the entire balloon surface.

A total of 2000 μg of polyvinylpyrrolidone were sprayed from a 0.25% by weight solution in chloroform onto the balloon surface. Before further processing, the balloon surfaces were dried for 24 hours at room temperature.

The crosslinking of the dried polyvinylpyrrolidone layer was carried out by irradiation with UV light of 254 .mu.m. Each balloon side was irradiated at room temperature for 15 minutes with the above power density. The distance between the lamp and the balloon side to be irradiated was 1 cm. The balloon was also in the expanded state during this process step.

Subsequently, the layer thickness of the applied polymer layer was determined by means of Laser Measuring Microscope (LEXT OLS3 100, Olympus). For this purpose, a coated Ion embedded in EpoThin by the company Buchler. In the course of the following processing, the sample was sanded and polished longitudinally. The resulting surface structure has a slight depression due to the nature of the material at the location of the coating. The layer thickness was then determined across the trench at 6 different positions, with each of the measurements taken twice (as well as at two different locations). An exemplary microscopic image of the sample is shown in FIG. 1, in which the positions of the layer thickness specifications are marked with the numbers 1 to 6. The following layer thicknesses were determined:

Measurement of layer thickness [μηι]

 1 6.9747

 2 8,4965

 3 7,6088

 4 8.1 161

 5,78624

 6 10,3987 The average layer thickness was therefore about 8.2 μιη.

The expanded balloon with the crosslinked polyvinylpyrrolidone coating was then immersed for 16 h at room temperature in 900 μl of a paclitaxel solution with a concentration of 15 mg ml in ethanol / water (8: 2). Thereafter, the paclitaxel-impregnated crosslinked PVP coating was dried at room temperature for 24 hours. This gave a balloon surface with a paclitaxel concentration of 0.37 μ ^ 'ητπι ² With the thus coated balloon surfaces investigations were carried out for drug delivery.

Elution in aqueous medium

The elution of paclitaxel from the balloon assembly by immersing the balloon in aqueous 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! PVP and paclitaxel coated and manually refolded balloon after air pumping immersed for 1 min at room temperature in 20 ml of Dulbecco's phosphate buffered saline (PBS, pl I 7.2 with 0.06 wt% Tween 20) immersed. For the determination of paclitaxel concentration by HPLC chromatography, the sample was diluted with methanol to half the initial concentration.

Dilatation of the balloon in a silicone tube

In a second step, the manually folded balloon was dictated at 8 bar in a silicone tube (outside diameter 4, 1 mm, inside diameter 2.7 mm). The silicone tube simulates a vessel in the human or animal body. This balloon dilatation in the silicone tubing was performed in 20 ml PBS / 0.06% Tween. For the HPLC assay, the sample was diluted to half of the starting concentration with methanol. Extraction of silicone tube and balloon after dilatation

Both silicone tubing and balloon were extracted into methanol after balloon dilatation to determine the amount of paclitaxel transferred to the silicone tubing and the remaining amount on the balloon surface. The silicone tube was extracted for this purpose for 1 hour at 37 ° C in 3 ml of methanol, the balloon in 20 ml of methanol also for 1 hour at 37 ° C.

The total loading of paclitaxel was calculated from the sum of the measured quantities of pallitaxel in the 4 solutions. The amount of paclitaxel transferred to the silicone tube was obtained by adding the amount in the aqueous medium after dilation and the amount after extraction of the silicone solution. Results

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

Eluted paclitaxel: 0.02 μg / mm ² (5% by weight of total loading)

Paclitaxel transferred to silicone tubing: 0.08 μg / mm ² (20% by weight of total loading)

The cross-linked PVP coating significantly reduces the premature elution of paclitaxel prior to balloon dilatation. Only 5% by weight of the total load is lost by a pure elution process. One-fifth of the total amount of paclitaxel can be transferred to the silicone tube as a model for a blood vessel. Example 2 Coating of a Balloon Catheter Surface with Polyvinylpyrrolidone, Crosslinking of Polyvinylpyrrolidone Obtainment by UV and Impregnation with Paclitaxel with Addition of Bovine Serum Albumin (BSA) (According to the Invention)

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

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

Eluted paclitaxel: 0.04 μg / mm ² (5% by weight of total loading) Paclitaxel transferred to silicone tube: 0.16 μg / mm ² (37% by weight of total loading)

The addition of bovine serum albumin significantly increases the transmission of paclitaxel to the silicone tubing compared to experiment 1 (pure paclitaxel). The premature loss of paclitaxel by pure elution processes is very low as in experiment 1.

Example 3 Coating of a Balloon Catheter Surface with Polyvinylpyrrolidone, Shortened Crosslinking of the Polyvinylpyrrolidone View by UV Light and Impregnation with Paclitaxel with Addition of Bovine Serum Albumin (BSA) (According to the Invention)

Experiment 2 was repeated with the change that the polyvinylpyrrolidone coating was irradiated for 15 minutes, but only for 5.5 minutes at 254 nm from both sides of the balloon. Paclitaxel and BSA were not incorporated into the polyvinylpyrrolidone coating by immersing the balloon in the solution of paclitaxel and BSA in ethanol / water, as done for Examples 1 and 2, but by pipetting up to the cross-linked poly vinylpyrr olidone coating applied. In contrast to example 2, a coating solution of paclitaxel with the concentration of 10 mg / ml paclitaxel and 1 mg / mL BSA in ethanol / water (8/2). 450 μl of this paclitaxel / B SA solution were pipetted.

The paclitaxel elution tests and the transfer of paclitaxel to a silicone tube were performed as described in Example I. The following results were achieved:

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

Eluted paclitaxel: 0.074 μιηιιιι ² (2 wt .-% of the total load)

Paclitaxel transferred to silicone tubing: 2,195 μιηιη ² (62% by weight of the total load) Compared to Experiments 1 and 2, significantly higher loadings of paclitaxel on the coating were achieved with this test set-up.

Example 4 Simultaneous Coating of a Glass Decking Case with a Mixture of Paclitaxel and Polyvinylpyrrolidone and UV Crosslinking (According to the Invention) For Comparison with the Two-Stage Process (Coating with Polyvinylpyrrolidone and UV)

Crosslinking, then incorporation of paclitaxel), a mixture of polyvinylpyrrolidone and paclitaxel was simultaneously coated on a coverslip, and then the polyvinylpyrrolidone was crosslinked by UV irradiation for 12 minutes at 254 nm. ! A mixture of 100 μl of a polyvinylpyrrolidone solution (5% by weight in chloroform) and 10 μl of an ethanolic solution of paclitaxel (1.5 mg / ml) was spin-coated onto a small coverslip (15 mm thickness) (130 revolutions door for 1 min) and dried for 24 h at room temperature.

The coated coverslip was stored in methanol at 37 ° C for 1 h to extract paclitaxel. The methanolic solution was analyzed directly by HPLC and the extracted paclitaxel amount was determined.

Total load Paclitaxel on coverslip: 15 μg

Eluted paclitaxel: 0.46 μg (3% by weight of total loading) A simultaneous coating of polyvinylpyrrolidone and paclitaxel with subsequent crosslinking of the PVP by UV light is unsuitable because this particular drug is decomposed by the action of irradiation. For UV-stable drugs, however, this approach is conceivable. Example 5 Simultaneous Coating of a Balloon Catheter with a Mixture of Paclitaxel and Polyvinylpyrrolidone Without UV Crosslinking (Comparison)

A dictated balloon became 900 μΐ at room temperature for 30 seconds. an ethanolic solution containing paclitaxel at a concentration of 15 mg ml and polyvinylpyrrolidone at a concentration of 30 mg ml. After drying, the balloon was dried at room temperature for 24 hours.

The resulting coated balloon was tested without crosslinking with UV light as described in Example 1. The eluted amounts in buffer and the amounts of paclitaxel transferred after dilation and mechanical contact with the silicone tube were determined.

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

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

Paclitaxel transferred to silicone tubing: 0.26 μg / mm ² (22% by weight of total loading)

Compared to Example 1, almost half of the paclitaxel is lost by elution in this experiment. Without crosslinking by irradiation with UV light, the coating is so unstable that there are very large premature losses of paclitaxel.

Example 6 Simultaneous Coating of a Balloon Catheter with a Mixture of Paclitaxel and Polyvinylpyrrolidone Without UV Regeneration with Addition of BSA (Comparison)

As described in Example 5, a balloon was coated by dipping. In contrast to example 5, here the coating consisted of 900 .mu.l of an ethanolic solution containing paclitaxel in a concentration of 15 mg ml and polyvinylpyrrolidone in a concentration of 30 mg ml, and 100 .mu.l · of an aqueous B SA solution with a Concentration of 15 mg mL. The further processing and examination was carried out as described in Example 4.

The following results were achieved:

Total loading of paclitaxel on the balloon: 1.04 μg / mm ² Eluted paclitaxel: 0.59 μg / mm ² (57% by weight of the total load)

Paclitaxel transferred to silicone tubing: 0.07 μg / mm ² (7% by weight of total loading)

Compared to Example 1, more than half of the paclitaxel was lost by elution in this experiment. Only a small part of the total loading of paclitaxel is transferred to the silicone tube by mechanical pressure. Without crosslinking by ultraviolet light irradiation, the coating is so unstable that very large premature losses of paclitaxel occur. As in Example 2, the addition of BSA leads to a greater release of paclitaxel. In Example 2, however, using crosslinked polyvinylpyrrolidone, the greater part is transferred to the silicone tube as intended by mechanical pressure. In this example, without prior crosslinking of polyvinylpyrrolidone, most of it is lost in advance by elution.

Example 7 Coating of a Balloon Catheter with Paclitaxel and Polyvinylpyrrolidone as a Two-Layer Structure (Comparison)

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

Room temperature dried.

Then a polyvinylpyrrolidone layer was applied over the dried cellulose layer using the spray technique described in Example 1. It was sprayed with a 0.25 wt .-% polyvinylpyrrolidone solution in chloroform and a layer of 500 μ ^/ cm ² applied.

The study of elution and mechanical trans er of paclitaxel was carried out as described in Example I. The following results were achieved:

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

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

Paclitaxel transferred to silicone tubing: 0.003 ji mm (1 wt% of total loading) The result shows that with this two-ply layered structure and paclitaxel as the lowest

Layer no significant elution and no significant transfer can be achieved by mechanical pressure. This experiment confirms the information provided in the literature that paclitaxel coated directly on the balloon surface adheres so well that it can no longer be eluted or transferred.

Example 8 Coating of a Balloon Catheter with Paclitaxel and Polyvinylpyrrolidone / BSA as a Two-Layer Structure (Comparison)

This experiment was carried out as experiment 7. However, not pure paclitaxel but a mixture of paclitaxel and BSA was coated. For this purpose, a mixture of 900 paclitaxel solution in ethanol at a concentration of 15 mg / mL and 100 μΐ, an aqueous BSA solution with a concentration of 15 mg / mL was coated as described in Example 7 and dried. Then, as described in Example 7, a polyvinylpyrrolidone layer was sprayed over the paclitaxel layer as described in Example 7 and dried at room temperature for 24 hours. The study of elution and mechanical transfer of the paclitaxel was carried out as described in Example 1.

The following results were achieved:

Total loading of paclitaxel on the balloon: 1.28 μg / 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 adding BSA to the paclitaxel, the paclitaxel coated on the balloon surface is easier to elute from the balloon surface. However, the premature loss in elution is very high and therefore unacceptable. During mechanical transfer, only a small fraction of the paclitaxel used is transferred to the tube wall in the desired manner.

Example 9 Evaluation of the Balloon of the Invention in an In Vitro Vascular Model

Balloons were coated with 2000 μg of polyvinylpyrrolidone as described in Example 1. The coatings were then irradiated for 5.5 minutes per balloon side at 254 nm. The distance between the lamp and the balloon membrane was 1 cm. After drying the radiation crosslinked coatings (24 hours at room temperature), paclitaxel and BSA were incorporated into this coating. For this purpose, 450 μl of a 10 mg / ml paclitaxel solution and 1 mg / ml BSA in ethanol / water (8: 2) were applied to the polyvinylpyrrolidone coating.

After drying the coating at room temperature for 24 h, the balloon was manually folded by removing the introduced air through the pump after opening the valve (see also Example 1).

The operation of the balloon coated according to this invention was tested with an in vitro vascular model which was described in the publication by W. Schmidt et al., Catheterization and Cardiovascular Interventions 73, 350-360 (2009). The investigations were carried out with the distance 5 in Fig. 3 on page 352 of said publication in a water bath at a temperature of 37 ° C. Each balloon was mounted in a guide catheter (Cordis Vista brite tip 5F, 100 cm, 1, 4 mm diameter) on a guidewire (Biotronik Cruiser Hydro 0.014 ") and an 80 mm long silicone tube was inserted into the distal end of the trial Hose serves as a model for a stenotic region in which the medicated balloon is dictated.

A hemostatic rotary valve was connected to the proximal end of the guidewire. Through this valve, the test section before each new test with 0.9 wt .-% saline rinsed. To position the balloon at the distal end of the trial section in the silicone tube (stenotic site model), the proximal end of the guidewire was inserted into the distal end of the guide catheter lumen. The hemostatic rotary valve was opened and the balloon catheter was manually passed through the guide catheter through the vessel model to the silicone tube. The entire length of the vascular model with the guidewire was rinsed several times with a total of 27 ml of 0.9 wt% saline to collect paclitaxel, which prematurely detached from the bone marrow during introduction of the balloon catheter through the vascular model into the silicone tube was (elution solution 1). When the balloon is positioned in the silicone tube, the balloon is inflated to 7 bar and held for 30 seconds. During this time, the surface of the surface presses against the silicone tube and transfers the active ingredient to the silicone surface. After relaxation of the balloon, the solution was recovered in the silicone tube and made up to 27 ml of 0.9 wt .-% saline solution (solution 1 after dilation). I lier parts of paclitaxel are included, which have been eluted by the balloon dilatation in the silicone tube in the saline. These amounts were also analyzed.

The silicone tube was removed from the vascular model. The tube was extracted with methanol to determine the amount of paclitaxel still adherent. This corresponds to the levels of paclitaxel that are desired to be transferred to the stenotic site by pressing the balloon against the vessel wall (solution 2 after dilation, see below paclitaxel analysis).

After removal of the balloon, the entire experimental section of the vessel model was extracted once with 27 ml of methanol. This collected in the model remaining amounts of paclitaxel, which were undesirably lost prior to balloon dilatation at the stenotic site by elution processes (elution solution 2). The balloon after dilation was dissected and extracted with methanol (see below paclitaxel analysis) to determine the balloon residual levels of paclitaxel (solution of balloon residual loading).

Paclitaxel analysis

Both the cut balloon and the silicone tube were extracted with 20 ml of methanol at room temperature for 30 min. The extracts were again washed with methanol diluted tenth part and then as described in Example 1, the Paclitaxelkonzentration determined by HPLC analysis.

The collected saline solutions (elution solution I and solution 1 after dilation) and the methanolic eluting solution 2 were also diluted to the tenth with methanol and the paclitaxel concentration was determined by HPLC.

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

Elution solution 1: 270.3 μg, 0.54 μg / mm ² (15.4% by weight of total paclitaxel amount)

Elution solution 2: 295.1 μg, 0.59 μg / ml (16.8% by weight of total amount of paclitaxel) b) Paclitaxel amount delivered during balloon dilatation:

Solution 1 after dilatation: 13.0 μg, 0.026 μ ² , 0.7% by weight of total amount of paclitaxel)

Solution 2 after dilation: 353.6 μM, 0.70 μL ² %, 20.2% by weight of total amount of paclitaxel c) amount of paclitaxel remaining on the balloon:

Solution of residual balloon load: 822.2 μg, 1.64 μ ^ 'ΐΏΐη ² , 46.9% by weight of total amount of paclitaxel

The balloon according to the invention shows a total loss of 32% of the total paclitaxel load in the model. By contrast, 21% of the total load was delivered during the dilation.

Example 10: Evaluation of the control balloon in an in vitro vascular model

As described in Example 9, a commercially available paclitaxel coated balloon (In.Pact Falcon paclitaxel releasing PTCA balloon, 20 x 4 mm) was evaluated in the described vascular model. In total, 5 of these balloons were examined. The analysis of the various solutions was also carried out as described in Example 9. The values given are the average values of the five experiments. Results of the HPLC determination: a) prematurely lost amount of paclitaxel by elution:

Elution solution 1: 437.9 μg (standard deviation 160.7), 1.7425 (ig itnr (standard deviation 0.6395), 44.3% by weight of total paclitaxel amount (standard deviation 14.1) Elution solution 2: 217.9 μg (Standard deviation 73.8), 0.8670 μg / ml (standard deviation

0.2938), 22.5% by weight of total paclitaxel (standard deviation 7.9) b) paclitaxel delivered during balloon dilatation:

Solution 1 after dilation: 33.4 μg (standard deviation 27.8), 0.133 μg / mm ² (standard deviation 0.1106), 3.2% by weight of total amount of paclitaxel (standard deviation 2.5) Solution 2 after dilation: 89 , 6 μg (standard deviation 32.5), 0.3567 μg / mm ² (standard deviation 0.1294), 9.0% by weight of the total amount of paclitaxel (standard deviation 2.9) c) amount of paclitaxel remaining on the balloon:

Solution of residual balloon load: 205.3 μg (standard deviation 82.9), 0.8169 μg / mm ² (standard deviation 0.3301), 21.0% by weight of total paclitaxel (standard deviation 9.4).

The control balloon loses more paclitaxel by unwanted elution than the inventive

Coating and transfers less paclitaxel in the desired manner to the blood vessel than the inventive coating.

Claims

claims:

A method of providing a medical device intended for insertion into the human or animal body, comprising 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 crosslinkable polymer;

* impregnating the polymer with the pharmacologically active agent and

Post-crosslinking of the crosslinkable polymer on the surface of the medical device by exposure to radiation.

2. The method according to claim 1, characterized in that the post-crosslinking of the polymer having crosslinkable groups is carried out before the impregnation of the polymer with the pharmacologically active ingredient.

3. The method according to claim 1 or 2, characterized in that the medical device is an implant, in particular 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 designed to be expandable, wherein the coating with the polymer having crosslinkable groups, and optionally also the post-crosslinking of the polymer and / or the impregnation with the pharmacologically active ingredient in the expanded Condition of the medical device is done.

5. The method according to any one of the preceding claims, characterized in that the polymer having crosslinkable groups has a number average mass 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 polymer having crosslinkable groups in a layer thickness of 0.5 .mu.m to 100 μηι is applied, in particular from 1 μιη to 50 μηι.

7. The method according to any one of the preceding claims, characterized in that the polymer having crosslinkable groups is applied directly to the surface of the medical device and that in particular no adhesive layer is previously produced on the medical device. 8. The method according to any one of the preceding claims, characterized in that the

Coating of at least a portion of the surface of the medical device with the polymer having crosslinkable groups is carried out several times, either after a single coating pass, the polymer is postcrosslinked or the post-crosslinking of the polymer takes place only after the last B chichtungsdur chlauf. 9. The method according to any one of the preceding claims, characterized in that the polymer having crosslinkable groups is applied from a solution in a suitable solvent or as a melt, in particular via brushes, printing. Transfer, spincoating, doctoring, spraying or dipping.

10. The method according to any one of the preceding claims, characterized in that the post-crosslinking takes place by electron, alpha, beta, gamma and / or UV radiation.

1 1. Method according to one of the preceding claims, characterized in that the pharmacologically active agent is suitable for the local treatment of diseased tissues and in particular selected from the group comprising immunosuppressants, cancer therapeutics, analgesics, anticoagulants, blood liquefying agents, thromboresistant agents and other means for Suppression of acute thrombosis, stenosis or late re-stenosis of arteries, growth factors, vasodilators, anti-neoplastic agents, antibiotics, preferably in combination with a controlling release-release vehicle for sustained release from the coating of a medical article to one localized source of infection within the body,

Steroids for the purpose of suppressing inflammation in localized tissue, antiviral agents, antiinflammatory agents and combinations thereof.

Method according to one of the preceding claims, characterized in that the pharmacologically active ingredient is selected from paclitaxel, docetaxel, immune suppressants 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 with the pharmacologically active ingredient is carried out from a solution of this active ingredient in a suitable solvent, wherein the impregnation is carried out in particular in such a way that provided with the polymer medical device in the Solution of the pharmacologically active substance is immersed, wherein the residence time is at least 30 minutes, preferably at least 1 hour, preferably at least 2 hours, more preferably at least 4 hours or even at least 6 hours.

14. The 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 provided with the polymer medical device is impregnated with at least one excipient, which is in particular selected from contrast agents, contrast agent derivatives, matrix and gel-forming excipients, sugar. Sugar derivatives, dextrins, β-cyclodextrins, organic or inorganic salts, benzoates, salicylates, polymers. Albumins, chitosan, hydroxycellulose, lipids. Linoleic acid, linolenic acid, oleic acid, stearic acid, phenyl salicylate, vitamin E, tocotrienols, tocopherol, bisethylhexyl sebacate, diododecyl phthalate, N-methylpyrrolidone, butylhydroxyanisole, butylhydroxytoluene, phosphorylcholine, oils, fatty acids, fatty acid esters, amino acids, peptides. Vitamins, neutral and charged amphiphilic substances, polyethyleneglycol esters, polyglyceryl-6-fatty acid esters, polyglyceryl-10-fatty acid esters, sucrosemonopalmitates, whether or not containing surfactants with lipid chains, surfactants, organic acids and esters and combinations thereof, where the albumin is preferably selected from lactalbumin, ovalbumin, bovine albumin. Pig albumin or combinations thereof.

16. The method according to claim 15, characterized in that the impregnation of the medical device provided with the polymer from a mixture of the pharmacologically active ingredient and the excipient takes place. A medical device obtainable by a method according to any one of claims 1 to 16, wherein the medical device is provided in particular for widening vessel narrowings, preferably for widening vessel narrowings in the human or animal body.

Medical device according to claim 17, characterized in that the medical device is designed to be expandable, in particular as a balloon catheter, and that of this upon expansion for one minute and subsequent contraction in a vessel of a human or animal body at least 5 wt .-% of the pharmacologically active 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 phosphate-buffered saline, within a period of 10 minutes at 37 ° C less than 10 wt .-% of the pharmacological ch active ingredient are dispensed into the solution, in particular less than 8% by weight, each based on the total amount of the active ingredient.