JP2007508039A - Medical article surface coating with biocompatibility and biological stability - Google Patents

Abstract

  The present invention relates to medical products having at least one biocompatible biologically stable polysulfone coating, methods for producing these medical products and their use, particularly in the form of stents to prevent restenosis. About the use of. With the medical product of the present invention, the dissolution rate of at least one incorporated and / or attached anti-proliferative, anti-inflammatory, anti-inflammatory and / or anti-thrombotic agent is such that at least one suitable amount of hydrophilic It can be controlled by mixing the functional polymer. Furthermore, the positional separation of different active agents and active agent combinations can each be achieved by a biologically stable polymer layer system.

Description

  The present invention relates to a medical article surface having a biocompatible and biologically stable coating of polysulfone and / or polysulfone derivatives or respective copolymers. The polysulfone includes and / or is coated with at least one anti-proliferative agent, anti-inflammatory agent, anti-inflammatory agent, and / or anti-thrombotic agent. The present invention relates to a method for producing these surfaces and their use in the form of implants over a long period of time, in particular a stent for preventing restenosis.

  In recent years, stent implantation has increased in balloon expansion of occluded blood vessels. Although stents reduce the risk of recurrence of vascular occlusion, to date, stents cannot completely prevent such restenosis.

  An exact description of the term restenosis cannot be found in the technical literature. The most commonly used morphological definition of restenosis is the definition of restenosis after the PTCA (percutaneous transluminal coronary angioplasty) succeeds and the diameter of the blood vessel is reduced to less than 50% of normal . This is an empirically determined value, and the hemodynamic relationship and clinicopathological relationship of that value lack a stable scientific basis. In fact, patient clinical deterioration is often considered a sign of restenosis of previously treated vascular segments.

There are three different reasons for restenosis caused by a stent:
(A) Only after implantation, the stent surface is directly exposed to blood, and due to the existing foreign surface, acute thrombosis can occur and again occlude the blood vessel.
(B) Stent implantation causes vascular injury, which also causes an inflammatory response (in addition to the above thrombosis) and plays a crucial role in the recovery process for the first 7 days. The process that occurs here is inter alia related to the release of growth factors, which initiates an increase in smooth muscle cell proliferation, resulting in rapid recurrence of vascular occlusion due to uncontrolled growth.
(C) After several weeks, the stent begins to grow into the vascular tissue. This means that the stent is completely encased by smooth muscle cells and does not come into contact with blood. This scarring can be very pronounced (neointimal proliferation) and can be guided by the fact that not only the surface of the stent is covered, but it also occludes all internal spaces of the stent.

  Attempts to solve the restenosis problem by coating the stent with heparin failed (J. Whorle et al., European Heart Journal (2001) 22, 1808-1816). However, heparin is positioned as a blood coagulation inhibitor only for the first reason, and can exert its overall effect only in solution. This first problem can be almost completely avoided at the same time by medical treatment by the administration of anticoagulants. Currently, the second and third problems are sought to be solved by locally inhibiting the proliferation of smooth muscle cells on the stent. In this regard, for example, radioactive stents or stents containing pharmaceutically active agents have been attempted.

  For example, US-A-5 891 108 discloses a hollow molded stent that includes a pharmaceutically active agent therein that is released through a number of openings in the stent. EP-A-1 127 582, on the other hand, describes a stent showing a groove with a depth of 0.1 to 1 mm and a length of 7 to 15 mm on the surface, which is suitable for holding active agents. . These active drug reservoirs accurately release the pharmaceutically active drug contained therein at high concentrations and over a relatively long period of time, comparable to the openings of hollow molded stents. However, it leads to the fact that smooth muscle cells can no longer surround the stent or can only surround the stent in a very slow manner. Therefore, stents are exposed to blood longer, which leads to increased vascular occlusion caused by thrombosis (Liistro F., Colombo A., Late acute thrombosis after Paclitaxel eluting stent implantation. Heart (2001 ) 86, 262-4).

  One way to solve this problem is a biocompatible phosphorylcholine coating (WO010101957) whereby phosphorylcholine (which is a component of the erythrocyte cell membrane) is a non-biodegradable polymer attached to a stent. As a component of the layer, it is intended to create a non-thrombogenic surface. Thereby, the active agent is absorbed or adsorbed on the surface of the phosphorylcholine layer containing the polymer, depending on the molecular weight.

  It is an object of the present invention to provide a medical product having a blood compatible surface and a method for producing a medical product having this blood compatible surface.

  In particular, the blood compatible surface of the medical product allows continuous and controlled ingrowth into the vessel wall of the medical product.

  This object is solved by the technical teaching of the independent claims of the present invention. Furthermore, advantageous designs of the invention result from the dependent claims, the description, the drawings and the examples.

  The present invention relates to a medical product, the surface of which is at least partially coated with at least one biologically stable polysulfone layer.

  Surprisingly, a coating on a medical surface that is in permanent contact with blood, wherein the coating with polysulfone, polyethersulfone, and / or polyphenylsulfone and its derivatives is highly suitable for active agents. It has been found that it can be a compatible substrate. By mixing with a biocompatible hydrophilic polymer or using a polysulfone with conflicting properties (ie, lipophilic and hydrophilic portions), the pore size of the polysulfone matrix can be altered. Multiple possibilities can be achieved for the active agent used, the dosage applied, and the desired release rate. In particular, the dissolution rate of the at least one active agent can be adjusted by the pore size of the biologically stable layer. Similarly, the pore size is determined by the type and amount of hydrophilic polymer used or the respective amount of lipophilic and oleophobic groups in the polysulfone or polysulfone mixture. In addition to the effect of the added hydrophilic polymer, adding a small amount of water (or even ethyl acetate) to the coating solution will make the future of the coated implant (which is loaded with the active agent) Affects the characteristics of Drug load distribution settings, release characteristics settings (as a function of time and active drug elution amount), and spray characteristics of the coating solution are described in water (or more ethyl acetate or other below) in the spray solution. Is decisively influenced by the defined addition of additives).

  The use of nitrogen as a carrier gas for spray coating will load the polymer layer containing the active agent with nitrogen, nitrogen will remain in the layer, and thanks to the ability of nitrogen as a protective gas, It has been found advantageous to supply the active agent in its entirety here. Thereby, the shelf life of the active drug is permanently guaranteed in a way that the drug remains effective without alteration.

  Modifying the polysulfone backbone by polymer-analogous reactions, such as the preparation of new (eg, new as polysulfone block copolymers or new in statistical distribution) polysulfone copolymers, is the physical behavior of the resulting polymer And thereby the properties of the polymer can be controlled, which can be applied in combination with the unmodified polymer or individually as a novel blood compatible coating material. Thus, a polyethersulfone containing a carboxyl group can be prepared by reaction of a polysulfone copolymer with 4,4′-bis (hydroxyphenyl) pentanoic acid (BPA), thereby obtaining a clear hydrophilicity of the polymer. It is done. The properties of hydrophilic polysulfones can also be used as hydrophilic polymer additives for unmodified polysulfones, as already mentioned above. Depending on the setting of the degree of modification, the degree of hydrophilicity is affected, resulting in a polymer molecule that contains unmodified and modified regions per chain and combines itself with hydrophobic and hydrophilic properties. The polymer is given a modified, spaced arrangement of chain portions, the so-called secondary structure. It is therefore preferred to use polysulfone for the coating, and this polysulfone has a hydrophilic region and a hydrophobic region. Such a polysulfone can be prepared by providing a hydrophilic side chain or hydrophilic functional group to the polysulfone after polymerization by a polymer-analogous reaction if the polymer itself is hydrophobic, or vice versa. Can be prepared by providing hydrophobic polysulfone with hydrophobic side chains or hydrophobic functional groups. In this preferred embodiment, the hydrophilic and hydrophobic properties are generally combined within one polymer molecule with a statistical distribution as the polymer-like reaction proceeds with a statistical distribution. . Further, such a hydrophilic polysulfone and hydrophobic polysulfone system can be prepared by statistical polymerization of at least one hydrophilic monomer and at least one hydrophobic monomer. Thereby, the structure results very similar to the above-described embodiment of subsequent modification by polymer-analogous reaction. A third embodiment is a polysulfone comprising block copolymerization of at least one hydrophilic sulfone block polymer and at least one hydrophobic sulfone block polymer, thereby placing hydrophilic and hydrophobic properties in individual blocks, respectively. Is obtained. Another modification consists of converting at least one hydrophilic monomer by alternating copolymerization with at least one hydrophobic monomer. Thereby, in the resulting polysulfone, the hydrophilic and hydrophobic properties are alternately distributed in the polymer chain. In addition, a mixture of at least one hydrophilic polysulfone and at least one hydrophobic polysulfone can be applied to the coating of the present invention. Here, hydrophilic and hydrophobic properties are not incorporated into one polymer molecule, but are found again in the coating and produce the same effect as the above-described embodiment.

  For the preparation of polysulfones, any polymerization reaction known to those skilled in the art is suitable, for example radical polymerization, anionic polymerization, cationic polymerization or thermal polymerization. Examples of the above polysulfones and the possibilities for their preparation are described below.

  Furthermore, there is a possibility of derivatization of introduced functional groups, for example carboxyl groups (Macrom. Chem. Phys. 1994, 195, 1709). Thus, the hydrophobicity of the active agent can easily be enhanced to a level beyond the hydrophobic nature of the polymer used, for example by the introduction of fluorinated compounds (Coll. Polym. Sci. 2001, 279, 727). . By introduction of a functional group, a graft copolymer can be prepared, in which the side chain is a structural unit different from the main chain. For this purpose, biocompatible, biologically stable and biodegradable polymers can be used.

  Functional groups can also be used for bonds that are unstable to hydrolysis of active agents. Thus, the active agent is released in a controlled manner also by hydrolysis, which depends on the type of bond (thioester bond, ester bond). Here, an advantage is that the elution of an active drug can be controlled by the following method. That is, the release curve follows another trajectory, and adaptation to many different courses of the disease can be achieved with the implant, with different demands on the concentration of the active agent depending on time. . One variation consists of covalent attachment of desulfonated and N-reacetylated heparin and / or N-carboxymethylated and / or partially N-acetylated chitosan to the polymer chain, This improves the blood compatibility of the polymer with antithrombotic compounds.

  Due to the possibility of at least two-layer construction of the polymer that can vary in composition and in additive differences, a layer-dependent distinction can be made regarding the active agent and concentration applied. This adaptability distinguishes the polysulfone matrix as a universally applicable biologically stable coating material to prevent restenosis.

  In order to set the pore size and thus the amount of active agent in the polysulfone matrix, not only hydrophilic polymers but also inorganic salts and water can be used as additives. On the other hand, the pore size controls the release rate of the at least one anti-proliferative, anti-inflammatory, anti-inflammatory and / or anti-thrombotic agent and the amount of active agent in the determined manner. These are either incorporated into the polysulfone coating or are each attached to the polysulfone coating. This is because the pores of polysulfone serve as reservoirs for active drugs.

  For the formation of the pores of the polysulfone matrix to which these additives have been applied, different methods can be performed or each must be performed.

  In principle, the formation of the pores takes place in such a way that, together with the polysulfone that builds the matrix, the additives are attached to the medical product to be coated by a suitable method. Here, the uniform compartments in the additive polysulfone can be controlled by their size and are formed depending on the hydrophilicity of the applied additive and the hydrophilicity of the polysulfone constructing the matrix . The number of these uniform compartments per unit volume of polysulfone matrix can be controlled by the amount of additive added (%).

  As additives, amino acids, polyamino acids, hydrophilic polymers, carbohydrates, oligosaccharides, polysaccharides, oligopeptides, polyvinylpyrrolidone, polyethyleneimine, glycerin, polyethers, glycols, inorganic salts, and water are used in detail. Can be.

  In the case of amino acids, genetically encoded acidic amino acids aspartic acid and glutamic acid; neutral amino acids alanine, asparagine, cysteine, glutamine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan The basic amino acids arginine, histidine, and lysine; and the genetically non-encoded amino acids ornithine and taurine are preferred. In particular, the L form representing these amino acids is preferred. Furthermore, the D type representing these amino acids, and the D, L type mixture of one amino acid and the D, L type mixture of plural amino acids are preferred.

  In the case of polyamino acids, the amino acids poly-L-aspartic acid, poly-L-glutamic acid, poly-L-alanine, poly-L-asparagine, poly-L-cysteine, poly-L-glutamine, poly-L-glycine Poly-L-isoleucine, poly-L-leucine, poly-L-methionine, poly-L-phenylalanine, poly-L-proline, poly-L-serine, poly-L-threonine, poly-L-tryptophan, poly -L-tyrosine, poly-L-valine, poly-L-arginine, poly-L-histidine, poly-L-lysine, and polyornithine and polytaurine are preferred. Furthermore, D-types representing these polyamino acids, as well as D- and L-type mixtures of one polyamino acid and D- and L-type mixtures of several polyamino acids are suitable.

  In the case of hydrophilic polymers, spherical molecules such as organic nanoparticles, star polymers, dendrimers, and / or hyperbranched polymers are preferred.

  In the case of inorganic salts, carbonates, chlorates, phosphates, and sulfates of sodium, calcium, potassium, and / or magnesium which are cations are preferable.

  These compartments are then removed from the polysulfone matrix for the formation of a pore structure. What remains is a three-dimensional structure with a predetermined porosity, which can then be filled with an active agent.

  In the following, three preferred systems for the formation of pore structures will be briefly described based on the additive classes of polymers, inorganic salts, and water.

(System 1: Polymer)
As the polymer additive, for example, a specific hyperbranched polyester having a thermally labile triazene group in the main chain is used. A molecularly dispersed hyperbranched polymer is incorporated into the polysulfone matrix. The system heat treatment then decomposes the hyperbranched pore former into volatile degradation products under the formation of the corresponding nanoporous polymer layer. Polysulfones distinguish themselves by temperature stability and high dimensional stability in particular, so that this method is applicable by all means. Furthermore, since this heat treatment can be performed in combination with the sterilization step, such a heat treatment is an effective method.

(System 2: Inorganic salts)
As the inorganic salt additive, for example, calcium carbonate which is a physiologically harmless compound is applied. The polysulfone matrix consists of a double hydrophilic block copolymer. These double hydrophilic block copolymers include a hydrophilic block and a second polyelectrolyte block. This hydrophilic block does not interact with the inorganic salt additive and the second polyelectrolyte block strongly affects the surface of the inorganic salt additive. These block copolymers have a growth-modifying effect in the calcium carbonate crystallization process. The resulting inorganic salt compartment has an approximately oval, barbell, or spherical shape. Due to the excellent resistance and hydrolysis stability of polysulfone to chemical attack, inorganic salt additives can be completely removed in an acid bath. What remains is the nanopore structure of the desired polysulfone matrix.

(System 3: Water)
As a fluid additive, when a medical product is coated with a polar active agent, water is considered the most readily available solution. When using the spray method, the polysulfone is present in an organic solvent such as chloroform. A chloroform solution saturated with polysulfone is only conditionally capable of accepting more active agents. Thus, the active agent is mainly dissolved in the aqueous phase and forms a compartment after adhering to the surface of the medical product because the phases are separated. The water can then be completely removed from the system from these compartments, for example by lyophilization. What remains is a nanopore structure loaded with an active drug. The concentration of active agent in the pores can be increased by subsequent steps, ie using an active agent dissolved in water, and then preferably lyophilized. In the methods that exist to date, the active agent was also dissolved with polysulfone in chloroform. The subsequent increase in the concentration of active drug is also caused by the chloroform solution. Since chloroform can never be removed 100% from the layer, it becomes increasingly concentrated in the final product, causing unnecessary exposure of the patient to chloroform. By using water as the active agent substrate, chloroform is used only once for the deposition of the polysulfone matrix and exposure to chloroform is minimized.

  For the preparation of a spray solution comprising at least one polysulfone and at least one anti-proliferative, anti-inflammatory, anti-inflammatory and / or anti-thrombotic agent, the following solvents are further suitable: Such solvents are readily volatile or volatile solvents such as chloroform, methylene chloride, tetrahydrofuran, acetone, methanol, ethanol, isopropanol, diethyl ether, and ethyl acetate, such solvents Is a solvent that can be further saturated with water or can be prepared to have a specific moisture content. In this case, the moisture content is 1.6 to 15%, preferably 2.1 to 10%, more preferably 2.6 to 7.9%, particularly preferably 3.3 to 6.8%. . Furthermore, it is preferred if the organic solvent, water, polysulfone, and active agent form a uniform solution.

  By creating a copolymer, the hydrophilicity or hydrophobicity of polysulfone can also be modified. Therefore, for example, it is possible to synthesize a polysulfone copolymer with 4,4′-bis (hydroxyphenyl) pentanoic acid (BPA). In this method, a carboxyl group side chain is introduced, and the carboxyl group is converted into a polysulfone matrix. Reduce the hydrophobicity. Furthermore, it can be derivatized with introduced functional groups, for example carboxyl groups (Macrom. Chem. Phys. 195 (1994), 1709; Coll. Polym. Sci. 279 (2001), 727).

  Due to the possibility of forming at least two polymer layers (which may vary depending on their composition and additives), further layer-dependent distinctions can be made with regard to the active agent and concentration applied. This adaptability distinguishes polysulfone matrices as biologically stable coating materials that can be universally applied to prevent restenosis.

  Furthermore, it is preferable to use thermoplastic polysulfone. Thermoplastic polysulfones can be plastically deformed under the influence of thermo. In general, thermoplastic polysulfone is composed of linear or low-branched molecular chains. When heated, they can be stretched by stretching. Upon further heating, they can be completely dissolved and reconstituted. In particular, it is preferable if these thermoplastic polymers have hydrophilic and hydrophobic characteristics. A thermoplastic polysulfone having such contradictory characteristics can be synthesized by the above-described method by a polymer-like reaction, block copolymerization or block polymerization of a hydrophilic monomer and a hydrophobic monomer. Each of the thermoplastic polysulfones, or medical products coated with it, obtained in this way has multiple bactericidal properties, resistance to water vapor and hydrolysis, high dimensional stability, resistance to chemical attack, and excellent Differentiated by heat aging stability.

  Preferred thermoplastic polysulfones are synthesized from bisphenol A and 4,4'-dichlorophenylsulfone by a polycondensation reaction (see formula (II) below).

  Polysulfones that can be applied for coating according to the invention have the following general structure according to formula (I):

  Here, n represents the degree of polymerization, and n is in the range of 10 to 10000, preferably in the range of 20 to 3000, more preferably in the range of 40 to 1000, still more preferably in the range of 60 to 500, and still more preferably in the range of 80 to 250. And particularly preferably in the range of 100-200.

  Further, n is in such a range, and the weight average of the polymer is preferably 60000 to 120,000 g / mol, preferably 70000 to 99000 g / mol, more preferably 80000 to 97000 g / mol, and more preferably 84000 to 95000 g. / Mol, and particularly preferably 86000 to 93000 g / mol.

  Furthermore, n is such a range, and it is preferable if the number average of a polymer is 20000-70000 g / mol, Preferably it is 30000-65000 g / mol, More preferably, it is 32000-60000 g / mol, More preferably, it is 35000 It is 59000 g / mol, and particularly preferably 45000 to 58000 g / mol.

  Y and Z are integers in the range of 1 to 10, and R and R ′ are each independently an alkylene group having 1 to 12 carbon atoms, an aromatic group having 6 to 20 carbon atoms, Heteroaromatic group having 2 to 10 carbon atoms, cycloalkylene group having 3 to 15 carbon atoms, alkylene arylene group having 6 to 20 carbon atoms, arylene alkylene group having 6 to 20 carbon atoms, alkylene having 1 to 12 carbon atoms An oxy group, an aryleneoxy group having 6 to 20 carbon atoms, a heteroaryleneoxy group having 6 to 20 carbon atoms, a cycloalkyleneoxy group having 3 to 15 carbon atoms, an alkylene aryleneoxy group having 6 to 20 carbon atoms, Or an arylenealkyleneoxy group having 6 to 20 carbon atoms. The above-mentioned groups can have further substituents, in particular they are described below as “substituted” polysulfones.

For example, R and R ′ groups include —R ¹ —, —R ² —, —R ³ —, —R ⁴ —, —R ⁵ —, —R ⁶ —, —R ¹ —R ² —, — ^{R 3 -R 4 -, - R} 5 -R 6 -, - R 1 -R 2 -R 3 -, - R 4 -R 5 -R 6 -, - R 1 -R 2 -R 3 -R 4 - ^{, -R 1 -R 2 -R 3 -R} 4 -R 5 -, and ^{-R 1 -R 2 -R 3 -R 4} -R 5 -R 6 - is and ^wherein, R ^{1, R} 2, R ³ , R ⁴ , R ⁵ , and R ⁶ each independently represent the following group:

_{-CH 2 -, - C 2 H} 4 -, - CH (OH) -, - CH (SH) -, - CH (NH 2) -, - CH (OCH 3) -, - C (OCH 3) 2 - , —CH (SCH ₃ ) —, —C (SCH ₃ ) ₂ —, —CH (NH (CH ₃ )) —, —C (N (CH ₃ ) ₂ ) —, —CH (OC ₂ H ₅ ) — _{, -C (OC 2 H 5)} 2 -, - CHF -, - CHCl -, - CHBr -, - CF 2 -, - CCl 2 -, - CBr 2 -, - CH (COOH) -, - CH (COOCH _{3) -, - CH (COOC} 2 H 5) -, - CH (COCH 3) -, - CH (COC 2 H 5) -, - CH (CH 3) -, - C (CH 3) 2 -, - _{CH (C 2 H 5) -} , - C (C 2 H 5) 2 -, - CH (CONH 2) -, - CH (CONH (CH 3)) - _{-CH (CON (CH 3) 2} ) -, - C 3 H 6 -, - C 4 H 8 -, - C 5 H 9 -, - C 6 H 10 -, cyclo _-C 3 _{H 4} -, cyclo - C ₃ H ₄ -, cyclo _-C 4 _{H 6} -, cyclo _{-C 5 H 8 -, - OCH} 2 -, - OC 2 H 4 -, - OC 3 H 6 -, - OC 4 H 8 -, - OC _{5 H 9 -, - OC 6} H 10 -, - CH 2 O -, - C 2 H 4 O -, - C 3 H 6 O -, - C 4 H 8 O -, - C 5 H 9 O-, _{-C 6 H 10 O -, -} NHCH 2 -, - NHC 2 H 4 -, - NHC 3 H 6 -, - NHC 4 H 8 -, - NHC 5 H 9 -, - NHC 6 H 10 -, - CH _{2 NH -, - C 2 H} 4 NH -, - C 3 H 6 NH -, - C 4 H 8 NH -, - C 5 H 9 NH -, - C 6 H 10 NH -, - S _{, - - H 2 SC 2 H} 4 -, - SC 3 H 6 -, - SC 4 H 8 -, - SC 5 H 9 -, - SC 6 H 10 -, - CH 2 S -, - C 2 H 4 _{S -, - C 3 H 6} S -, - C 4 H 8 S -, - C 5 H 9 S -, - C 6 H 10 S -, - C 6 H 4 -, - C 6 H 3 (CH 3 )-, -C ₆ H ₃ (C ₂ H ₅ )-, -C ₆ H ₃ (OH)-, -C ₆ H ₃ (NH ₂ )-, -C ₆ H ₃ (Cl)-, -C _{6 H 3 (F) -, -} C 6 H 3 (Br) -, - C 6 H 3 (OCH 3) -, - C 6 H 3 (SCH 3) -, - C 6 H 3 (COCH 3) -, _{-C 6 H 3 (COC 2 H} 5) -, - C 6 H 3 (COOH) -, - C 6 H 3 (COOCH 3) -, - C 6 H 3 (COOC 2 H 5) -, - C 6 H ₃ (NH (C _{H 3)) -, - C} 6 H 3 (N (CH 3) 2) -, - C 6 H 3 (CONH 2) -, - C 6 H 3 (CONH (CH 3)) -, - C 6 H ₃ (CON (CH ₃ ) ₂ ) —, —OC ₆ H ₄ —, —OC ₆ H ₃ (CH ₃ ) —, —OC ₆ H ₃ (C ₂ H ₅ ) —, —OC ₆ H ₃ (OH) _{-, - OC 6 H 3 (} NH 2) -, - OC 6 H 3 (Cl) -, - OC 6 H 3 (F) -, - OC 6 H 3 (Br) -, - OC 6 H 3 (OCH ₃ )-, -OC ₆ H ₃ (SCH ₃ )-, -OC ₆ H ₃ (COCH ₃ )-, -OC ₆ H ₃ (COC ₂ H ₅ )-, -OC ₆ H ₃ (COOH)-,- _{OC 6 H 3 (COOCH 3)} -, - OC 6 H 3 (COOC 2 H 5) -, - OC 6 H 3 (NH (CH 3)) -, - OC _{6 H 3 (N (CH 3} ) 2) -, - OC 6 H 3 (CONH 2) -, - OC 6 H 3 (CONH (CH 3)) -, - OC 6 H 3 (CON (CH 3) 2 _{) -, - C 6 H 4} O -, - C 6 H 3 (CH 3) O -, - C 6 H 3 (C 2 H 5) O -, - C 6 H 3 (OH) O -, - C ₆ H ₃ (NH ₂ ) O—, —C ₆ H ₃ (Cl) O—, —C ₆ H ₃ (F) O—, —C ₆ H ₃ (Br) O—, —C ₆ H ₃ (OCH _{3) O -, - C 6} H 3 (SCH 3) O -, - C 6 H 3 (COCH 3) O -, - C 6 H 3 (COC 2 H 5) O -, - C 6 H 3 (COOH _{) O -, - C 6 H} 3 (COOCH 3) O -, - C 6 H 3 (COOC 2 H 5) O -, - C 6 H 3 (NH (CH 3)) O -, - C 6 H 3 (N ( _{CH 3) 2) O -,} - C 6 H 3 (CONH 2) O -, - C 6 H 3 (CONH (CH 3)) O -, - C 6 H 3 (CON (CH 3) 2) O- _{, -SC 6 H 4 -, -} SC 6 H 3 (CH 3) -, - SC 6 H 3 (C 2 H 5) -, - SC 6 H 3 (OH) -, - SC 6 H 3 (NH 2 )-, -SC ₆ H ₃ (Cl)-, -SC ₆ H ₃ (F)-, -SC ₆ H ₃ (Br)-, -SC ₆ H ₃ (OCH ₃ )-, -SC ₆ H ₃ ( _{SCH 3) -, - SC 6} H 3 (COCH 3) -, - SC 6 H 3 (COC 2 H 5) -, - SC 6 H 3 (COOH) -, - SC 6 H 3 (COOCH 3) -, _{-SC 6 H 3 (COOC 2 H} 5) -, - SC 6 H 3 (NH (CH 3)) -, - SC 6 H 3 (N (CH 3) _{2) -, - SC 6 H} 3 (CONH 2) -, - SC 6 H 3 (CONH (CH 3)) -, - SC 6 H 3 (CON (CH 3) 2) -, - C 6 H 4 S _{-, - C 6 H 3 (} CH 3) S -, - C 6 H 3 (C 2 H 5) S -, - C 6 H 3 (OH) S -, - C 6 H 3 (NH 2) S- _{, -C 6 H 3 (Cl)} S -, - C 6 H 3 (F) S -, - C 6 H 3 (Br) S -, - C 6 H 3 (OCH 3) S -, - C 6 H ₃ (SCH ₃ ) S—, —C ₆ H ₃ (COCH ₃ ) S—, —C ₆ H ₃ (COC ₂ H ₅ ) S—, —C ₆ H ₃ (COOH) S—, —C ₆ H _{3 (COOCH 3) S -, -} C 6 H 3 (COOC 2 H 5) S -, - C 6 H 3 (NH (CH 3)) S -, - C 6 H 3 (N (CH 3) 2) S -,- _{6 H 3 (CONH 2) S} -, - C 6 H 3 (CONH (CH 3)) S -, - C 6 H 3 (CON (CH 3) 2) S -, - NH-C 6 H 4 -, _{-NH-C 6 H 3 (CH} 3) -, - NH-C 6 H 3 (C 2 H 5) -, - NH-C 6 H 3 (OH) -, - NH-C 6 H 3 (NH 2 _{) -, - NH-C 6} H 3 (Cl) -, - NH-C 6 H 3 (F) -, - NH-C 6 H 3 (Br) -, - NH-C 6 H 3 (OCH 3) _{-, - NH-C 6 H} 3 (SCH 3) -, - NH-C 6 H 3 (COCH 3) -, - NH-C 6 H 3 (COC 2 H 5) -, - NH-C 6 H 3 _{(COOH) -, - NH-} C 6 H 3 (COOCH 3) -, - NH-C 6 H 3 (COOC 2 H 5) -, - NH-C 6 H 3 (NH (CH _{)) -, - NH-C} 6 H 3 (N (CH 3) 2) -, - NH-C 6 H 3 (CONH 2) -, - NH-C 6 H 3 (CONH (CH 3)) -, _{-NH-C 6 H 3 (CON} (CH 3) 2) -, - C 6 H 4 -NH -, - C 6 H 3 (CH 3) -NH -, - C 6 H 3
_{(C 2 H 5) -NH -} , - C 6 H 3 (OH) -NH -, - C 6 H 3 (NH 2) -NH -, - C 6 H 3 (Cl) -NH -, - C 6 _{H 3 (F) -NH -,} - C 6 H 3 (Br) -NH -, - C 6 H 3 (OCH 3) -NH -, - C 6 H 3 (SCH 3) -NH -, - C 6 _{H 3 (COCH 3) -NH -} , - C 6 H 3 (COC 2 H 5) -NH -, - C 6 H 3 (COOH) -NH -, - C 6 H 3 (COOCH 3) -NH-, _{-C 6 H 3 (COOC 2 H} 5) -NH -, - C 6 H 3 (NH (CH 3)) - NH -, - C 6 H 3 (N (CH 3) 2) -NH -, - C _{6 H 3 (CONH 2) -NH} -, - C 6 H 3 (CONH (CH 3)) - NH -, - C 6 H 3 (CON (CH 3) 2) -NH-.

Particularly preferably polysulfone, and mixtures thereof, ^{wherein, -R 1 -, - R 2} -, - R 3 -, - R 1 -R 2 -, and ^-R 1 ^-R 2 ^{-R 3} - groups , independently are the following _{groups: -C 6 H 4 O -,} - C (CH 3) 2 -, - C 6 H 4 -, - C 6 H 4 SO 2 -, - SO 2 C 6 H _{4 -, - OC 6 H 4} -, - C 6 H 4 OC (CH 3) 2 -C 6 H 4 -.

  Further, R and R 'may preferably be moieties independently bonded to the sulfone group in formulas (II) to (XV).

  According to the present invention, the one or more polysulfones for the biologically stable layer or layers are polyethersulfone, substituted polyethersulfone, polyphenylsulfone, substituted polyphenylsulfone, polysulfone block copolymer, respectively. Selected from the group comprising a polymer, a perfluoropolysulfone block copolymer, a semifluoropolysulfone block copolymer, a substituted polysulfone block copolymer, and / or a mixture of the aforementioned polymers.

The term “substituted” polysulfone is to be understood as a polysulfone having functional groups. In particular, the methylene unit can have 1 or 2 substituents, and the phenylene unit can have 1, 2, 3, or 4 substituents. These substituents (these also, X, X ', X'', that X''') as, for _{example, -OH, -OCH 3, -OC 2} H 5, -SH, -SCH 3, - _{SC 2 H 5, -NO 2,} -F, -Cl, -Br, -I, -N 3, -CN, -OCN, -NCO, -SCN, -NCS, -CHO, -COCH 3, -COC 2 _{H 5, -COOH, -COCN, -COOCH} 3, -COOC 2 H 5, -CONH 2, -CONHCH 3, -CONHC 2 H 5, -CON (CH 3) 2, -CON (C 2 H 5) 2 , —NH ₂ , —NHCH ₃ , —NHC ₂ H ₅ , —N (CH ₃ ) ₂ , —N (C ₂ H ₅ ) ₂ , —SOCH ₃ , —SOC ₂ H ₅ , —SO ₂ CH ₃ , — _{SO 2 C 2 H 5, -SO} 3 H, -SO 3 CH 3, -SO _{C 2 H 5, -OCF 3,} -O-COOCH 3, -O-COOC 2 H 5, -NH-CO-NH 2, -NH-CS-NH 2, -NH-C (= NH) -NH 2 _{, -O-CO-NH 2,} -NH-CO-OCH 3, -NH-CO-OC 2 H 5, -CH 2 F, -CHF 2, -CF 3, -CH 2 Cl, -CHCl 2, - _{CCl 3, -CH 2 Br, -CHBr} 2, -CBr 3, -CH 2 I, -CHI 2, -Cl 3, -CH 3, -C 2 H 5, -C 3 H 7, -CH (CH 3 ) ₂ , —C ₄ H ₉ , —CH ₂ —CH (CH ₃ ) ₂ , —CH ₂ —COOH, —CH (CH ₃ ) —C ₂ H ₅ , —C (CH ₃ ) ₃ , —H. . More preferred substituents or functional groups are —CH ₂ —X and —C ₂ H ₄ —X.

  The following general structural formula represents a preferred repeating unit of polysulfone. Preferably, the polymer consists only of these repeating units. However, in addition to the repeating units shown below, other repeating units or blocks may be present in one polymer. Preferably the following units:

  X, X ', n, and R' each independently have the above-mentioned meaning.

  X, X ', n, and R' each independently have the above-mentioned meaning.

  Furthermore, polysulfones of the following general formula (X) are preferred:

  Where Ar represents the following:

  X, X ', and n each independently have the above-mentioned meaning.

  Furthermore, the following repeating units are preferred:

X, X ′, X ″, X ′ ″, and n each independently have the above-mentioned meaning. R ″ and R ′ ″ may each independently represent a substituent, as defined for X or X ′, or each independently an —R ¹ —H or —R ² —H group. Can be represented.

  Another preferred repeating unit has a cyclic substituent between two aromatic rings, for example as in formula (XIV) or (XV):

R ″ preferably represents —CH ₂ —, —OCH ₂ —, —CH ₂ O—, —O—, —C ₂ H ₄ —, —C ₃ H ₆ —, —CH (OH) —. The group — ^* R—R ″ — preferably represents a cyclic ester, amide, carbonate, urea or urethane, for example —O—CO—O—, —O—CO—O—CH _{2 -, - O-CO-O} -C 2 H 4 -, - CH 2 -O-CO-O-CH 2 -, - C 2 H 4 -, - C 3 H 6 -, - C 4 H 8 -, _{-C 5 H 10 -, - C} 6 H 12 -, - O-CO-NH -, - NH-CO-NH -, - O-CO-NH-CH 2 -, - O-CO-NH-C 2 _{H 4 -, - NH-CO} -NH-CH 2 -, - NH-CO-NH-C 2 H 4 -, - NH-CO-O-CH 2 -, - NH-CO-O-C 2 H 4 _{-, - CH 2 -O-CO} -NH-CH 2 -, - C 2 H 4 -SO 2 -, - C 3 H 6 -SO 2 -, - C 4 H 8 -SO 2 -, - C _{H 4 -SO 2 -CH 2 -,} - C 2 H 4 -SO 2 -C 2 H 4 -, - C 2 H 4 -O -, - C 3 H 6 -O -, - C 4 H 8 -O _{-, - C 2 H 4 -O} -CH 2 -, - C 2 H 4 -O-C 2 H 4 -, - C 2 H 4 -CO -, - C 3 H 6 -CO -, - C 4 H _{8 -CO -, - C 2 H} 4 -CO-CH 2 -, - C 2 H 4 -CO-C 2 H 4 -, - O-CO-CH 2 -, - O-CO-C 2 H 4 - _{, -O-CO-C 2 H} 2 -, - CH 2 -O-CO-CH 2 -, or there is a cyclic ester which comprise an aromatic ring.

  In the following, polymer-like reactions are described. These are known to those skilled in the art and serve for modification of polysulfone.

A chloromethylene group can be introduced as a X and X ′ moiety by using formaldehyde, ClSiMe ₃ , and a catalyst (eg, SnCl ₄ ), and can be further substituted. By these reactions, for example, a hydroxyl group, an amino group, a carboxyl group, an ether group, or an alkyl group can be introduced by nucleophilic substitution and bonded to the aromatic ring via a methylene group. Reaction with alcoholates such as phenolate, benzylate, methanolate, ethanolate, propanolate, or isopropanolate yields polymers with substitutions in more than 75% of the chloromethylene groups. A polysulfone having the following lipophilic side chain is obtained:

Here, R ^** represents an alkyl part or an aryl part, for example.

  The following reaction can introduce X "and X" "moieties into the polymer until they are no longer present in the monomer.

  In addition to the ester group, various other substituents can be introduced. That is, the substituents can be introduced by first performing a single or double deprotonation with a strong base such as n-BuLi or tert-BuLi and then adding an electrophile. In the case illustrated above, carbon dioxide was added for ester group introduction and the resulting carbonate group was esterified in another step.

  The combination of a polysulfone having a lipophilic moiety and a polysulfone having an oleophobic moiety according to the present invention is achieved, for example, by using together a polysulfone represented by formula (IIB) and a polysulfone represented by formula (IIC). The amount ratio of each polysulfone can range from 98%: 2% to 2%: 98%. Preferred ratios are 10%: 90%, 15%: 85%, 22%: 78%, and 27%: 73%, 36%: 64%, 43%: 57%, and 50%: 50%. These percentages can be applied to any combination of hydrophilic and hydrophobic polysulfones, but are not limited to the mixtures described above.

  An example of a polysulfone having a hydrophilic portion and a hydrophobic portion in one molecule can be obtained, for example, by performing only incomplete esterification of the polysulfone represented by the formula (IIC). Therefore, a hydrophilic carboxyl group and a hydrophobic ester group exist in one molecule. The molar (number) ratio of carboxyl groups to ester groups can be 5%: 95% to 95%: 5%. These percentages can be applied to any combination of hydrophilic and hydrophobic groups and are not limited to the groups described above.

  It is believed that this combination of hydrophilic groups or hydrophilic polymers and hydrophobic groups or hydrophobic polymers according to the present invention results in the construction of an amorphous polymer layer in a medical product. It is very important that the polymer layer formed from polysulfone is crystalline or predominantly not crystalline. This is because crystallization hardens the layer, which causes the layer to begin to break and peel off. A flexible polysulfone coating that serves as a barrier layer can be achieved only with an amorphous or predominantly amorphous polysulfone layer.

  Of course, it is also possible to apply already substituted monomers after polymerization has been carried out in order to obtain the desired substitution type. The corresponding polymer is then obtained by known methods according to the following reaction scheme.

Here, L and L ′ each independently represent, for example, the following groups: —SO ₂ —, —C (CH ₃ ) ₂ —, —C (Ph) ₂ —, or —O—. Thus, L and L ′ may have the meaning of groups corresponding to formulas (I) to (XV). Such nucleophilic substitution reactions are known to those skilled in the art and are illustratively illustrated by the above scheme.

  As already mentioned, by using a combination of at least one hydrophilic polymer and at least one hydrophobic polymer on the one hand in one polymer on the other hand, the polymer has hydrophilic properties and hydrophobic properties. The case where it has a property is especially preferable. Thus, for example, it is preferred if X and X 'have a hydrophilic substituent and X "and X"' have a hydrophobic substituent or vice versa.

Examples of the hydrophilic substituent include —OH, —CHO, —COOH, —COO ⁻ , —CONH ₂ , —NH ₂ , —N ⁺ (CH ₃ ) ₄ , —NHCH ₃ , —SO ₃ H, —SO _{3. ^{-, -NH-CO-NH 2}} , -NH-CS-NH 2, -NH-C (= NH) -NH 2, -O-CO-NH 2, and in particular amino groups which are protonated may be applied .

The hydrophobic _{substituent, -H, -OCH 3, -OC 2} H 5, -SCH 3, -SC 2 H 5, -NO 2, -F, -Cl, -Br, -I, -N 3 , -CN, -OCN, -NCO, -SCN , -NCS, -COCH 3, -COC 2 H 5, -COCN, -COOCH 3, -COOC 2 H 5, -CONHC 2 H 5, -CON (CH 3 ) ₂ , —CON (C ₂ H ₅ ) ₂ , —NHC ₂ H ₅ , —N (CH ₃ ) ₂ , —N (C ₂ H ₅ ) ₂ , —SOCH ₃ , —SOC ₂ H ₅ , —SO _{2 CH 3, -SO 2 C 2 H} 5, -SO 3 CH 3, -SO 3 C 2 H 5, -OCF 3, -O-COOCH 3, -O-COOC 2 H 5, -NH-COOCH 3 _{, -NH-CO-OC 2 H} 5, -CH 2 F, -CHF 2, - _{CF 3, -CH 2 Cl, -CHCl} 2, -CCl 3, -CH 2 Br, -CHBr 2, -CBr 3, -CH 2 I, -CHI 2, -CI 3, -CH 3, -C 2 H _{5, -C 3 H 7, -CH} (CH 3) 2, -C 4 H 9, -CH 2 -CH (CH 3) 2, -CH 2 -COOH, -CH (CH 3) -C 2 H 5 , -C _{(CH 3) 3} can be applied.

  Furthermore, a cyclic polysulfone is preferred, which has a structure as shown, for example, in formula (XVI).

  The carboxyethylene group is not essential in the reaction exemplified above. In place of the carboxyethylene substituent and the methyl substituent, any other substituent or hydrogen can also be present.

  Polysulfones are characterized by a high resistance to chemical attack, they are hydrolytic and heat stable and have very good mechanical and friction properties (no surface wear). Furthermore, high dimensional stability and a plurality of bactericidal properties can be emphasized as specific properties as a material applied to a living body. Polysulfone has already been used for a long time as a medical polymer. The main use is concentrated in, for example, hollow fibers in hemodialysis machines, and Fresenius polysulfone fibers are leading the global market for their excellent blood compatibility and film-forming properties. According to it, the problem in dialysis is that during hemodialysis, there is a need that an anticoagulant, generally heparin, has to be administered, in which case a few Side effects increase after years. With 5 hours of treatment, about 75 liters of blood flows through the dialyzer, which is approximately equal to 15 times the amount of blood the patient has. It is therefore clear that the thin film must meet very high blood compatibility requirements.

  Another major area is the use of polysulfone capillaries in ophthalmology and in the form of flat membranes in ancillary means of various medical techniques.

  It is preferred if at least one hydrophilic polymer is added to the polysulfone used for the biologically stable layer. Thereby, in each polysulfone layer, the ratio of polysulfone to hydrophilic polymer can be from 50 wt% to 50 wt% to 99.999 wt% to 0.001 wt%.

  Examples of hydrophilic polymers include polyvinylpyrrolidone, glycerin, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyhydroxyethyl methacrylate, polyacrylamide, polyvalerolactone, poly-ε-decalactone, polylactic acid, polyglycolic acid, polylactide, and polyglycolide. , Copolymer of polylactide and polyglycolide, poly-ε-caprolactone, polyhydroxybutanoic acid, polyhydroxybutyrate, polyhydroxyvalerate, polyhydroxybutyrate-co-valerate, poly (1,4-dioxane-2 , 3-dione), poly (1,3-dioxane-2-one), poly-para-dioxanone, polyanhydrides such as polymaleic anhydride, fibrin, polycyanoacrylate, polycaprola Kuton dimethyl acrylate, poly-b-maleic acid, polycaprolactone butyl acrylate, for example, composite block polymers such as those derived from oligocaprolactone diol and oligodioxanone diol, polyether ester composite block weights such as PEG and polybutylene terephthalate Coalescence, polypivotolactone, polyglycolic acid trimethyl carbonate, polycaprolactone-glycolide, poly-g-ethyl glutamate, poly (DTH-imino carbonate), poly (DTE-co-DT-carbonate), poly (bisphenol-A- Iminocarbonate), polyorthoester, polyglycolic acid trimethyl carbonate, polytrimethyl carbonate, polyimino carbonate, poly (N-vinyl) -pyrrolidone Polyvinyl alcohol, polyester amide, glycolated polyester, polyphosphoester, polyphosphazene, poly [(p-carboxyphenoxy) propane], polyhydroxypentanoic acid, polyanhydride, polyethylene oxide-propylene oxide, soft polyurethane, amino acid in the skeleton Polyether esters such as polyurethanes with residues, polyethylene oxides, polyalkene oxalates, polyorthoesters and copolymers thereof, lipids, carrageenan, fibrinogen, starch, collagen, protein based polymers, poly Amino acids, synthetic polyamino acids, zeins, modified zeins, polyhydroxyalkanoates, pectic acids, actinic acids, modified and unmodified fibrin and casein Carboxymethyl sulfate, albumin, hyaluronic acid, chitosan and derivatives thereof, chondroitin sulfate, dextran, β-cyclodextrin, copolymer of PEG and polypropylene glycol, gum arabic, guar gum, gelatin, collagen, collagen-N-hydroxy Succinimides, lipids, phospholipids, modifications and copolymers and / or mixtures of the above substances are suitable, and polyvinylpyrrolidone, polyethylene glycol, and glycerin are preferably used.

  For example, polyvinylpyrrolidone (PVP) is added to increase viscosity in the production of polysulfone solutions, which dissolve in the precipitating agent and are removed again during the production of hollow fibers. The resulting porous hollow fiber still contains an average of 1-2% PVP. The addition of polyvinylpyrrolidone not only helps the viscosity in the manufacturing process, i.e. increases the viscosity, but also helps the factors that co-determine the pore size of the polysulfone, and is therefore decisive for the permeability of the final product. . This is because the permeability depends on the pore size and the particle size. Therefore, the pore size, i.e., permeability, of the produced polysulfone can be adjusted by the amount and molecular weight of added polyvinylpyrrolidone.

  Due to the biocompatibility and excellent mechanical properties of polysulfone and the possibility of adjusting the pore size by the addition of polyvinylpyrrolidone and / or another hydrophilic polymer and / or water (ethyl acetate), this polymer Is an ideal substrate for all pharmaceuticals. It can be applied to topical applications intended for the prevention of vascular re-occlusion, such as the heart.

  At the same time, the encapsulated nitrogen increases the shelf life of the active drug. The preferable amount of the polymer to be added is in the range of 0 to 50% by mass, more preferably 1 to 20% by mass, and particularly preferably 2 to 10% by mass. The amount added will substantially depend on the desired dissolution rate of the active agent applied.

  The medical product according to the present invention has a surface that can be formed of any material. This surface is preferably not blood compatible. Furthermore, this surface is preferably not coated, in particular not coated with polymers and / or organic polymers.

  A biologically stable polysulfone layer can be adhered to this surface by tackiness or covalently, and partially by tackiness and partially covalently. A covalent bond is preferred. The polysulfone layer at least partially but preferably completely covers the surface of the medical product. If the medical product is a stent, at least the surface exposed to blood is coated with polysulfone.

  Preferably, at least one layer comprising at least one anti-proliferative, anti-inflammatory, anti-inflammatory and / or anti-thrombotic agent is on and / or on this first biologically stable polysulfone layer. It can be deposited and / or incorporated into the first polysulfone layer. At least one layer comprising at least one anti-proliferative agent, anti-inflammatory agent, anti-inflammatory agent, and / or anti-thrombotic agent may be complete with one or more active agents; another biologically stable It can be a polysulfone layer (in which the active agent is contained); or it can be a blood compatible layer (in which the active agent is contained). On the other hand, hydrophobic active agents can be deposited in and / or on and / or under a biologically stable layer, while hydrophilic active agents are preferably biologically It can be deposited on and / or below the stable layer.

  Thus, the medical product according to the invention can have a surface coated with one layer, two layers, three layers or more layers, one layer, two layers or three layers and in particular two layers are preferred .

  Anti-proliferative, anti-inflammatory, anti-inflammatory and / or anti-thrombotic agents can be adhered to each layer by adhesiveness or covalently, or partially adhesively and partially covalently It is preferable that they are adhered by stickiness.

  In the case of a surface coating with a more biologically stable polysulfone layer and / or a blood-compatible layer and / or an active agent layer, these layers each have a different hydrophilic polymer and a different amount of It can consist of different polysulfones with hydrophilic polymers, as well as different blood compatible compounds or different active agents.

  Furthermore, it is preferred if the medical product has a surface comprising a layer that is compatible with blood, which layer is deposited and / or incorporated on or in the bottom first biologically stable polysulfone layer. It is. This blood compatible layer may also form a second or third layer and they may be on top of the bottom biologically stable layer and / or the active agent layer or the second layer. Located directly or indirectly above or below the biologically stable polysulfone layer. Furthermore, it is preferred if a blood compatible layer forms the bottom layer, and an active drug layer is provided on top of this layer, which can then be covered by a biologically stable polysulfone layer, or one of these. Preferably, a biologically stable polysulfone layer having an active agent or combination of active agents is deposited on the lower blood compatible layer.

  This blood compatible layer is preferably fully desulfonated and N-reacetylated heparin, desulfonated and N-reacetylated heparin, N-carboxymethylated, partially N-acetyl. Chitosan and / or a mixture of these substances. The blood compatible layer may include other blood compatible organic materials in addition to the above described materials, but preferably consists of only the above described materials.

  For the medical product according to the invention it is preferred if there is a single layer that is compatible with blood. Furthermore, it is preferred if this single layer that is compatible with blood forms the outer or lowermost layer.

  Furthermore, it is preferred that there is a layer that completely covers the underlying surface or the underlying layer. However, partial coatings are possible as well.

  Furthermore, it is particularly preferred if the medical product according to the invention is a stent. The stent can be formed of any material and material mixture. Preferred are metals and plastics, such as medical stainless steel, titanium, chromium, vanadium, tungsten, molybdenum, gold, and nitinol. The stent is preferably uncoated and / or conditionally not blood compatible. In particular, the stent does not have a coating formed of an organic material. Medical wires can be excluded as medical products.

  These stents according to the invention are provided with at least one biocompatible layer, preferably made of biologically stable polysulfone. This layer has or does not have a hydrophilic polymer in a predetermined ratio and contains at least one anti-proliferative agent, anti-inflammatory agent, anti-inflammatory agent, and / or anti-thrombotic agent, and the stent completely or Incomplete coating. Thereby, the active agent may be present in the matrix and / or coat the matrix as a second layer. In this specification, the second layer is referred to as a layer attached to the first layer.

  In another preferred embodiment of the stent of the present invention, it has a coating, the coating consisting of at least two polysulfone layers. According to this two-layer design, the first layer consists of a layer that is substantially completely covered by another biologically stable layer having the same or different pore size. One or both layers include at least one anti-proliferative agent, anti-inflammatory agent, anti-inflammatory agent, and / or anti-thrombotic agent. In addition, combinations of active agents are used, these agents supporting and / or complementing each other the effects obtained by them.

  Starting from this two-layer design, it is possible to incorporate different active agents separately from each other in each layer as appropriate for the corresponding active agent. So, for example, a hydrophobic active agent is placed in a more hydrophilic layer, and the agent is placed in a more hydrophobic polymer layer with another hydrophobic active agent. As is the case, it has a different dissolution rate. The reverse of the above may be used. This offers a wide range of possibilities to establish clear and reasonable results in the usefulness of the active drug and to control elution time and elution concentration.

  Another preferred embodiment of the stent according to the invention has a coating consisting of at least three layers. According to this three-layer design, the first layer is a layer that is substantially completely or incompletely covered by a second layer of another pure active agent or combination of active agents, The second layer is then coated with a layer of a biologically stable third polysulfone of the same or different pore size. The polysulfone layer does not contain an active agent, or one or both serve as a matrix for at least one anti-proliferative, anti-inflammatory, anti-inflammatory and / or anti-thrombotic agent. Combinations of active agents are also used and support and / or complement each other in their effects.

  This embodiment is particularly suitable for the use of hydrophilic active agents or active agent combinations in the formation of pure active agent layers. An overlying biologically stable polymer layer with a certain amount of hydrophilic polymer helps to control the dissolution of the active drug. Active drug combinations having at least one hydrophilic active drug result in different elution rates.

  As the top coating, a hydrophilic polymer can be used, which can be mixed with polysulfone, which can also be the underlayer.

  A biocompatible coating of the stent is provided for the required blood compatibility and active agent (or combination of active agents). This agent is present uniformly across the entire surface of the stent, so that proliferation of cells, particularly smooth muscle cells and endothelial cells, on the stent surface proceeds in a controlled manner. Thus, there is no rapid or abnormal growth of cells on the stent surface that causes restenosis. However, the proliferation of cells on the stent surface with the risk of thrombosis is not completely prevented by high concentrations of the drug.

  Thus, the use of polysulfone ensures that: That is, the active agent or combination of active agents (bonded to the underlying layer by adhesive and / or incorporated into the layer by adhesive) is released continuously and in small amounts, so that at the stent surface Although cell growth is not prevented, abnormal growth is prevented. The combination of both effects gives the stent of the present invention the ability to grow rapidly into the vessel wall and reduce the risk of restenosis and thrombus. The release of the active agent (s) is for a period of 1 to 24 months, preferably 1 to 12 months, particularly preferably 1 to 3 months after implantation.

  The release of the active agent can be adjusted by adjusting the pore size by the addition of polyvinylpyrrolidone or similar hydrophilic polymer. That is, the individual characteristics of the active agent, the dissolution rate, and its pharmacokinetics, and in the case of more than one active agent, the elution order can be adjusted to meet the required requirements.

As active agents, antiproliferative substances, anti-inflammatory agents, and antithrombotic agents are used. As the antiproliferative agent, a cell division inhibitor, a macrolide antibiotic, and / or a statin is preferably used. Applicable anti-proliferative agents include sirolimus (rapamycin), everolimus, pimecrolimus, somatostatin, tacrolimus, roxithromycin, dunaimycin, ascomycin, bafilomycin, erythromycin, midecamycin, josamycin, Kanamycin (concanamycin), clarithromycin, troleandomycin, folimycin, cerivastatin, simvastatin, lovastatin, fluvastatin, rosuvastatin, atorvastatin, pravastatin, pitavastatin, vinblastine, vincristine, vindesine, vinorelbine, etoposide, teniposide, nimus tin nimustine), carmustine, lomustine, cyclophosphamide, 4-hydroxycyclophosphami , Estramustine, melphalan, betulinic acid, camptothecin, rapacol, β-lapachone, podophyllotoxin, betulin, trofosfamide, 2-ethylhydrazide podophyllate, ifosfamide, chlorambucil, bendamustine, dacarbazine, busulfan , Procarbazine, treosulfan, temozolomide, thiotepa, daunorubicin, doxorubicin, aclarubicin, epirubicin, mitoxantrone, idarubicin, bleomycin, mitomycin, dactinomycin, methotrexate, fludarabine, fludarabine-5'-2 hydrogen phosphate , Mofebdazone, acemetacin, diclofenac, lonazolac, dapsone, o-carbamylphenoxyacetic acid, lidocaine, ke Profen, mefenamic acid, piroxicam, meloxicam, chloroquine phosphate, penicillamine, hydroxychloroquine, auranofin, gold sodium thiomalate, oxaceprol, celecoxib, β-sitosterine, ademethionine, myrtecaine ), Polidocanol, nonivamide, levomenthol, benzocaine, aesin, cladribine, mercaptopurine, thioguanine, cytarabine, fluorouracil, gemcitabine, capecitabine, docetaxel, carboplatin, cisplatin, oxaliplatin, antacrine, tecantoline, ricantoline Carbamide, miltefosine, pentostatin, aldesleukin, tretinoin, asparaginase, Guaspargase, anastrozole, exemestane, letrozole, formestane, aminoglutethimide, adriamycin, azithromycin, spiramycin, cepharantin, smc growth inhibitor-2w, epothilone A and B, mitoxan Throne, azathioprine, mycophenolatmofetil, c-myc-antisense, b-myc-antisense selectin (cytokine antagonist) CETP inhibitor, cadherines, cytokinin inhibitor, COX-2 inhibitor, NFkB, angiopeptin, ciprofloxacin, camptothecin, fluroblastin, monoclonal antibody (suppresses muscle cell proliferation), bFGF antagonist, probucol, pro Taglagins, folic acid and its derivatives, vitamin B derivatives, vitamin D derivatives such as calcipotriol and tacalcitol, thymosine α-1, fumaric acid derivatives such as fumaric acid and dimethyl fumarate, IL-1β inhibition Agents, colchicine, NO donors such as pentaerythritol tetranitrate and syndnoeimine, S-nitroso derivatives, tamoxifen, staurosporine, β-estradiol, α-estradiol, estrone, estriol, ethinylestradiol, Phosfestol, medroxyprogesterone, estradiol cypionate, estradiol benzoate, tranilast, kamebakaurine and other terpenoids (suitable for cancer treatment) ), Verapamil, tyrosine kinase inhibitor (tylophostin), cyclosporin A, paclitaxel and its derivatives (6-α-hydroxy-paclitaxel, baccatin, taxotere, and others), synthetically produced carbon dioxide macrocyclic oligomers (MCS) and derivatives thereof, and the like obtained from natural raw materials, morglamostim (rhuGM-CSF), peginterferon α-2b, lenograstim (r-HuG-CSF), filgrastim, macrogol, dacarbazine, basiliximab, daclizumab , Ellipticine, D-24851 (Calbiochem), colcemid, cytochalasin A to E, indanocine, nocodazole, S100 protein, PI-88, melanin Vesicle-stimulating hormone (α-MSH), bacitracin, vitronectin receptor antagonist, azelastine, guanidyl cyclase stimulator, metal proteinase-1 and 2 tissue inhibitors, free nucleic acids, nucleic acids incorporated into viral mediators, DNA and There are RNA fragments, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, antisense oligonucleotide, VEGF inhibitor called IGF-1. In addition, from the antibiotic group, cefadroxyl, cefazoline, cefaclor, cefotaxim, tobramycin, gentamicin are applied. Penicillin such as dicloxacillin, oxacillin, sulfonamide, metronidazole, argatroban, aspirin, abciximab, synthetic antithrombin drugs, bivalirudin, coumadin, enoxaparin, hemoparin (trademark) ) (desulfonation and N- reacetylated heparin), tissue plasminogen activator, GpIIb / IIIa platelet membrane receptor, the factor _{X a} inhibitor, activated protein C, antibodies, heparin, hirudin, r- hirudin, PPACK Antithrombotic drugs such as protamin, protamin, prourokinase, streptokinase, warfarin, urokinase; dipyramidole, triazolopyrimidine (registered trademark) Vasodilators such as rapidyl), nitroprusside; PDGF antagonists such as triazolopyrimidine and seramin; ACE inhibitors such as captopril, cilazapril, lisinopril, enalapril, losartan; Thioprotease inhibitors, caspase inhibitors, apoptosis inhibitors, apoptosis modulators such as p65NF-kB and Bcl-xL antisense oligonucleotides, and prostacyclin, vapiprost, interferon alpha,
β and γ, histamine antagonist, serotonin blocker, halofuginone, nifedipine, tocopherol, tranilast, molsidomine, tea polyphenol, epicatechin gallate, epigallocatechin gallate, boswellic acid and its derivatives, leflunomide, anakinra, etanercept, sulfasalazine, etoposide, Dicloxacillin, tetracycline, triamcinolone, mutamycin, procainamide, retinoic acid, quinidine, disopyramide, flecainide, propaphenone, sotalol, amidorone have positive effects during the postoperative period. Further active agents include steroids (hydrocortisone, betamethasone, dexamethasone), non-steroidal substances (NSAIDS) (such as fenoprofen, ibuprofen, indomethacin, naproxen, phenylbutazone). Antiviral agents such as acyclovir, ganciclovir, and zidovudine are also applicable. Different antifungal agents are used in this field. Examples include clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole, nystatin, terbinafine. Antiprotozoal drugs such as chloroquine, mefloquine, and quinine are active drugs that have equivalent effects. Furthermore, hippocaesculin, barringtogenol-C21-angelate, 14-dehydroagrostistachin, 14-dehydroagrostistachin, agroskerin, agrostistachin, 17 -Hydroxyagrostistachin, ovatodiolids, 4,7-oxycycloanisomelic acid, baccharinoid B1, B2, B3, tubeimoside, Bruceanol A, B and C, bruceantinoside C, yadanzioside N and P, isodeoxyelephantopin, tomenphantopin A and B, coronarin A B, C and D, ursolic acid, hypotatic acid A, zeolin, iso-iridogermanal, maytenfoliol, effusantin A, excisanin A and B Longikaurin B, sculponeatin C, kamebaunin, leukamenin A and B, 13,18-dehydro-6-α-senecioyloxychaparrin Natural such as 1,11-dimethoxycantin-6-one, 1-hydroxy-11-methoxycantin-6-one, scopoletin, taxamairin A and B, regenilol, triptolide Terpenoids; further simarin, apocymarin Aristolochic acid, anopterin, hydroxyanopterin, anemonin, protoanemonin, berberine, cheliburin chloride, cictoxin, sinococuline, bombrestatin A and B, Cudraisoflavone A, curcumin, dihydronitidine, nitidine chloride, 12-β-hydroxypregnadiene 4,16-diene-3,20-dione, biloba, gincol, ginkgolic acid, Helenaline, indicine, indicine-N-oxide, laciocarpine, inotodiol, glycoside 1a, podophyllotoxin, justicidin A and B, larea Larreatin, malloterin, malotochromanol, isobutyrylmallotochromanol, maquiroside A, marchantin A, maytansine, lycoridicin, marguetin ( margetine), pancratistatin, liriodenine, oxoushinsunine, aristolactam-AII, bisparthenolidine, periplocoside A, ghalakinoside, ursolic acid, deoxy Deoxypsorospermin, psychorubin, ricin A, sanguinarine, manwu wheat acid, methylsorbifolin, sphatheliachromen, Stizophyllin, mansonine, strebloside, akagerine, dihydrousambarensine, hydroxyusambarine, strychnopentamine, strychnopentamine strychnophylline, usambarine, usambarensine, berberine, liriodenine, oxoushinsunine, daphnoretin, lariciresinol, methoxylariciresinol, syringaresinol, syringaresinol umbelliferon), afromoson, acetylvismione B, desacetylvismione A, vismione A and B, and hipoca escri Hippocaesculin, 14-dehydroagrostistachin, C-type natriuretic peptide (CNP), agroskerin, agrostistachin, 17-hydroxyagrostistachin ), Ovatodiolid, 4,7-oxycycloanisomelic acid, yadanzioside N and P, isodeoxyelephantopin, tomenphantopin A and B , Coronarin A, B, C, and D, ursolic acid, hypotatic acid A, zeolin, iso-iridogermanal, maytenfoliol, effusantin A, Excisanin A and B, Rongikaurin (longikaurin) B, there is a natural terpenoids such as Sukuruponeachin (sculponeatin).

  The active agents are used separately or in combination at the same or different concentrations. Particularly preferred drugs have immunosuppressive properties in addition to antiproliferative effects. Among such active agents are erythromycin, midecamycin, tacrolimus, sirolimus, paclitaxel and its derivatives, and josamycin, and triazolopyrimidine (registered trademark, trapidil), D-24851, α- and β- Estradiol, macrocyclic carbon suboxide (MCS) and its derivatives, PI-88, sodium salt of 2-methylthiazolidine-1,4-dicarboxylic acid and its derivatives, and sirolimus.

  Furthermore, it is preferably a combination of an immunosuppressive active agent and several antiproliferative active substances or antiproliferative active agents.

  Particularly preferably, the active agent is paclitaxel and its derivatives, β-estradiol, simvastatin, PI-88 (sulfated oligosaccharides; Progen Ind.), Macrocyclic carbon suboxide (MCS) and their derivatives, trapidil (Registered trademark), N- (pyridin-4-yl)-[1-4- (4-chlorobenzyl) -indol-3-yl] -glyoxylamide (D-24851), and tacrolimus The

Active agent, preferably, be included in a pharmaceutically active concentration of 0.001~20mg / cm ² on the stent surface, more preferably 0.005~15mg / cm ² on the stent surface, particularly preferably 0. Contained at 01-10 mg / cm ² . Another active agent can be included in the same layer or in another layer at similar concentrations. It is noted that preferred embodiments include two different active agents in the same layer or different layers. A further preferred embodiment has a layer made of pure active agent as the top layer.

The amount of polymer deposited per medical product, and in particular the amount per layer per stent, is preferably in the range between 0.01 mg / cm ² · surface to 3 mg / cm ² · surface, more preferably Is 0.20 mg / cm ² · surface to 1 mg / cm ² · surface, and particularly preferably 0.2 mg / cm ² · surface to 0.5 mg / cm ² · surface.

  Furthermore, embodiments comprising active agents in two layers are preferred. Note that this can be two different active agents. If the same active agent is contained in two layers, it is preferred that the two layers have different concentrations of active agent. Furthermore, it is preferred that the lower layer has an active agent at a lower concentration than the upper layer.

  The stent according to the present invention can be manufactured by the coating method having biocompatibility of the stent, and the basic principle is as follows.

(A) providing a stent; and (b) depositing at least one biologically stable polysulfone layer with or without at least one hydrophilic polymer; and (c). Attaching and / or incorporating at least one anti-proliferative, anti-inflammatory, anti-inflammatory and / or anti-thrombotic agent on and / or in said biologically stable layer, or (b ′ ) At least one biologically stable polysulfone with or without at least one hydrophilic polymer together with at least one anti-proliferative, anti-inflammatory, anti-inflammatory and / or anti-thrombotic agent Depositing the layer.

  Preferably, step (b ') may be followed by step (c').

  (C ') depositing at least one anti-proliferative, anti-inflammatory, anti-inflammatory and / or anti-thrombotic agent on said biologically stable polymer layer.

  After steps (a), (b), and (c); steps (a), (b ′); or steps (a), (b ′), and (c ′), another step (d ) May follow.

  (D) depositing at least one second biologically stable polysulfone layer;

  On the other hand, this second biologically stable polysulfone layer can consist of a polysulfone other than that of the first underlying layer and, on the other hand, contain the same or another hydrophilic polymer in different amounts. obtain. It is preferred if this second biologically stable polysulfone layer contains at least one active agent. Particularly preferred are embodiments having a biologically stable polysulfone layer with or without a hydrophilic polymer as the outer layer.

  The anti-proliferative, anti-inflammatory, anti-inflammatory and / or anti-thrombotic agent is preferably selected from the above group.

  Furthermore, embodiments having a blood compatible layer are preferred. This blood-compatible layer is composed of the aforementioned blood-compatible substances, in particular fully desulfonated and N-reacetylated heparin, desulfonated and N-reacetylated heparin, N-carboxyl. It consists of methylated, partially N-acetylated chitosan, and / or a mixture of these substances, and is attached indirectly or directly to the lower biologically stable layer. This blood compatible layer can be placed between two other layers and can form the top layer, and embodiments having two layers compatible with blood are also possible. However, a layer that is compatible with only one blood is preferred. The blood compatible layer can be adhered to the underlying layer by tackiness and covalently, or partially by tackiness and partially covalently.

  Each layer is preferably deposited by dipping or spraying. Furthermore, the individual layers are preferably not deposited on it until the underlying layer is dry.

  A preferred method consists of two steps (a) and (b ').

  The principle of coating provides a wide variation on the requirements for active drugs and the nature of the applied polysulfone. Thus, different variations occur for the coating, which can also be combined with each other.

  The ability to influence the properties of polysulfone by the amount and molecular weight of the added hydrophilic polymer, such as PVP, makes it possible for each component to fit the optimal system in a wide range of fields with respect to the active drug applied. Indicated.

  Furthermore, polysulfone layers without the addition of PVP and / or polysulfone layers with the same or different PVP content, with and without active agents, are possible. Similarly, fully N-deacetylated and reacetylated heparin, desulfonated and N-reacetylated heparin, N-carboxymethylated and / or partially N-acetylated chitosan, And / or a layer of a mixture of these substances is preferably covalently bonded directly to the surface and the layer can be applied. The non-thrombogenic properties of this layer allow the underlying foreign surface to be masked if there is a scar on the biologically stable layer surface or layers above. This wound is, for example, a wound caused by mechanical destruction of the coating prior to implantation or when implantation is performed. If desired, this inert layer can be applied and further applied covalently or tacky between the two layers and / or as the top layer.

(Variation A)
a) supplying an uncoated stent;
b) depositing one biologically stable polysulfone layer with or without a hydrophilic polymer;
c) depositing the active agent or combination of active agents into and / or on the polysulfone layer by dipping or spraying;
d) substantially completely and / or incompletely coating a biologically stable polysulfone layer comprising an active agent with at least another layer of biologically stable polysulfone comprising The other polysulfone layer corresponds to the first layer or is a layer different from this first layer in the content of the hydrophilic polymer and the pore size,
e) depositing the same or another active agent or combination of active agents in and / or on the outer biologically stable layer, so that different active agents and / or The active agent combination can be attached to the stent in a targeted manner separately from each other by both layers, and if the polymer has different pore sizes, the active agent is loaded in different amounts. Obtaining and allowing for different elution rates of the same and / or another active agent.

  In particular, the term “attachment” in step c) and / or step e) means “diffusion” of the active agent into the respective layer.

  The medical product preferably has two biologically stable polysulfone layers and they may contain different hydrophilic polymers at different concentrations.

  If the same active agent or combination of active agents is to be included in both layers, all applied polymer layers must be deposited before the active agent diffuses into these layers. Can be broken.

  Furthermore, another layer of suitable polysulfone or even a layer of pure hydrophilic polymer can be applied as a diffusion barrier and top coating.

(Variation B)
a) supplying an uncoated stent;
b) depositing one biologically stable polysulfone layer with or without a hydrophilic polymer;
c) A biologically stable polysulfone layer with a combination of at least one anti-proliferative, anti-inflammatory and / or anti-thrombotic agent and / or active agent is substantially completely and / or non-resistant by spraying. Complete coating process,
d) coating the active agent layer substantially completely and / or incompletely with at least another biologically stable polysulfone layer, wherein the other polysulfone layer comprises Corresponds to one layer or contains an active agent and / or a combination of active agents, different from this first layer in the content of hydrophilic polymer and the pore size And / or d ′) a layer of active agent substantially completely and / or with a hydrophilic polymer with or without active agent and / or active agent combination. Alternatively, incompletely coating, and making the hydrophilic polymer layer a top coating layer.

  These variations allow the coating material to be adapted to the active agent. Furthermore, the amount of active agent released temporarily can be adapted to the requirements of the corresponding segment.

  In a multilayer system, the newly deposited layer substantially completely covers the underlying layer. “Substantially” means 50 to 100%, preferably 70 to 100%, more preferably 80 to 100%, more preferably 90 to 100%, and particularly preferably more than 96%. More particularly preferably, it exceeds 98%.

  The object of the present invention is also a medical product, in particular a stent, which can be produced by the method described above.

  The stent according to the present invention solves both the problem of acute thrombosis after stent implantation and new intimal thickening. Furthermore, the stent according to the invention, whether a single layer system or a multi-layer system, may be coated with one or more anti-proliferative, anti-inflammatory, anti-inflammatory, anti-thrombotic, and / or It is particularly suitable for continuous release of immunosuppressive active agents. Due to this ability to continuously release the required amount of active agent in the desired manner, the coated stent of the present invention almost completely prevents the risk of restenosis.

  Prevention or reduction of restenosis, on the other hand, is accomplished by the suppression of cellular responses by the selected active agent and active agent combination on the day immediately after implantation and the week immediately following implantation. On the other hand, this is done by providing a biocompatible surface, so that as the effect of the active agent decreases, vascular re-occlusion over a long period of time on the existing foreign surface. The reaction that causes it does not occur.

(Example 1) Coating of stent with polyethersulfone (spray solution)
a. PS solution:
176 mg of PS (polyethersulfone, Udel (registered trademark), commercially available from Solvay) is weighed, and chloroform is added to make 20 g (0.88% PS).

Example 2 Stent coating with polyethersulfone as the base coating and polyethersulfone with 0.04% PVP or 0.08% PVP as the top coating, respectively (spray solution)
a. Polysulfone solution:
17.6 mg of PS is weighed, and chloroform is added to make 2 g (0.88% PS).
b. Polysulfone / PVP solution:
Weigh 25.2 mg of PS and 1.2 mg of PVP, and add chloroform to make 3 g (0.84% PS, 0.04% PVP).
b '. Polysulfone / PVP solution:
24 mg of PS and 2.4 mg of PVP are weighed, and chloroform is added to make 3 g (0.80% PS, 0.08% PVP).

(Spray coating)
Pre-weighed stents are spray coated with the spray solution in the order indicated: a) 0.5 ml and b) 0.85 ml. Thereby, after each spraying step, at least 6 hours elapse until the next layer is deposited. After drying overnight at room temperature in a clean room, weigh again.

Example 3 Production of a stent with MCS and polyethersulfone by a three-layer system according to variation B (spray solution)
a) Polyethersulfone solution (first layer: basic coating):
70.4 mg of PS is weighed, and chloroform is added to make 8 g (0.88% PS).
b) MCS solution (second layer: intermediate coating):
Weigh 39.6 mg of MCS and add 20% aqueous ethanol solution to make 18 g (0.22% MCS).
c) Polyethersulfone / PVP solution (third layer: top coating):
100.8 mg of PS and 4.8 mg of polyvinylpyrrolidone are weighed, and chloroform is added to make 12 g (0.84% PS, 0.04% PVP).

(Spray coating)
A non-expanded stainless steel stent is weighed, cleaned and spray coated. The stent is sprayed with each spray solution in a) 0.5 ml, b) 1.5 ml, and c) 0.85 ml amounts and in the order indicated. Thereby, after each spraying step, at least 6 hours elapse until the next layer is deposited. After drying overnight at room temperature, weigh again. The average amount of active drug on the stent is 153 ± 9 μg.

Example 4 Measurement of the dissolution rate of MCS from polyethersulfone containing 4.5% PVP One stent was placed in each of the cups with snap-on lids and mixed with 2 ml of PBS buffer. And sealed with parafilm and incubated in a 37 ° C. drying room for a predetermined time. After the selected time has elapsed, the supernatant is pipetted and its UV absorption at 207 nm is measured. Each stent is again mixed with 2 ml PBS and incubated again at 37 ° C. Repeat this operation several times.

(Example 5) Coating of stent with polysulfone matrix loaded with simvastatin (spray solution)
a. PS / simvastatin solution:
Weigh 26.4 mg of PS and 8.8 mg of simvastatin, and add chloroform to make 4 g (0.66% PS, 0.22% simvastatin).
b. PS / simvastatin / PVP solution:
Weigh 24.8 mg of PS, 8.8 mg of simvastatin, and 1.6 mg of PVP, and add chloroform to make 4 g (0.62% PS, 0.22% simvastatin, 0.04% PVP).

Example 6 Stent coating with polysulfone matrix containing a high proportion of PVP and loaded with simvastatin (spray solution)
a. PS / simvastatin / PVP solution:
Weigh 23.2 mg PS, 8.8 mg simvastatin, and 3.2 mg PVP and add chloroform to 4 g (0.58% PS, 0.22% simvastatin, 0.08% PVP).

Example 7 Coating of Stent with Polysulfone Matrix Loaded with Paclitaxel (Spray Solution)
a. PS / paclitaxel solution:
Weigh 13.2 mg of PS and 4.4 mg of paclitaxel, and add chloroform to make 2 g (0.66% PS, 0.22% paclitaxel).
b. PS / PVP / paclitaxel solution:
Weigh 11.6 mg of PS, 1.6 mg of PVP, and 4.4 mg of paclitaxel, and add chloroform to make 2 g (0.58% PS, 0.08% PVP, 0.22% paclitaxel).

Example 8 Coating of stent with 17-β-estradiol in a polysulfone matrix (spray solution)
a. PS / 25% 17-β-estradiol solution:
46.2 mg of PS and 15.4 mg of 17-β-estradiol are weighed, and chloroform is added to 7 g (0.66% PS, 0.22% 17-β-estradiol).
b. PS / 20% 17-β-estradiol solution:
Weigh 28.2 mg of PS and 7 mg of 17-β-estradiol, and add chloroform to make 4 g (0.704% PS, 0.176% 17-β-estradiol).
c. PS / 15% 17-β-estradiol solution:
Weigh out 29.9 mg of PS and 5.3 mg of 17-β-estradiol and add chloroform to 4 g (0.748% PS, 0.132% 17-β-estradiol).

Example 9 Coating of a stent with a polysulfone matrix containing triazolopyrimidine (registered trademark, trapidil) (spray solution)
PS / Trapidyl® solution:
19.8 mg of PS and 6.6 mg of trapidil (registered trademark) are weighed, and chloroform is added to 7 g (0.66% PS, 0.22% trapidyl (registered trademark)).

Example 10 In Vivo Study of Stent Having Polyethersulfone with and Without Macrocyclic Suboxide as Matrix In the coronary artery of 20-25 kg domestic pigs of 13 different genders, polyethersulfone A stent coated with was implanted. Stents were divided into 3 groups. One group contained high doses of paclitaxel, the second group contained low doses of paclitaxel, and the last group were pure matrix stents with no active agent added. After 4 weeks, the stents were removed and analyzed for inflammatory response (around strut) and formation of new intima.

  All stents analyzed showed minimal inflammation around the stent struts and adventitia regardless of the coating. The higher average thickness of the stent intima with less active drug loading may be attributed to more vascular overdilatation during implantation. Pure matrix stents do not show any noticeable problems with the vascular response, which should be attributed to the polymer, which supports the hemocompatibility of the polymer and its compatibility as an active drug substrate .

Example 11 In Vivo Testing of Stent Having Polyethersulfone with and Without Paclitaxel as Matrix In a manner similar to Example 10 above, a stent coated with polyethersulfone was coated with polyethersulfone. Compared to a stent loaded with paclitaxel.

  The results of this study also show the advantages of a polysulfone coating.

Example 12 Preparation of Polysulfone of Formula (IIA) Polysulfone (IIA) was prepared according to the instructions of E. Avram et al., J. Macromol Sci. Pure Appl. Chem., 1997, A34, 1701.

  3 molar equivalents of benzyl alcohol are dissolved in toluene and deprotonated with sodium. One molar equivalent of polysulfone (IIA) is added and then the reaction mixture is heated to boiling point. The reaction product is obtained in a yield of 22%.

Example 13 Preparation of Polysulfone of Formula (IIC) Polysulfone (IIC) was prepared according to the instructions of MD Guiver et al., Brit. Polym. L. 1990, 23, 29.

  1 g of the resulting polysulfone (IIC) was esterified by using ethyl orthoacetate, toluene was used as the solvent, and volatile reaction products were removed from the equilibrium reaction mixture by distillation. 40% of the carboxyl groups were converted to ethyl ester groups.

  According to Example 7, the polymer was deposited on the stent with paclitaxel.

  The stent showed excellent blood compatibility and an amorphous polysulfone coating was suitable for controlling the release of paclitaxel.

(Example 14)
1 g of the polysulfone prepared according to Example 12 is mixed with 200 mg of the polysulfone of formula (IIC) and deposited on the stent with the active agent paclitaxel according to Example 7.

  The coated stent showed excellent blood compatibility, and the amorphous polysulfone coating was suitable for controlling the release of paclitaxel.

(Example 15) Introduction of chlorosulfone group into polysulfone 2.4 g of polysulfone is dissolved in 700 ml of chloroform and cooled to -20 ° C. Then 23.3 ml of chlorosulfonic acid are slowly added dropwise. Since the reaction is a vigorous exothermic reaction, the reaction vessel is cooled in an ice bath. After the addition of chlorosulfonic acid, the solution is allowed to warm to room temperature with stirring. After 30 minutes, the polymer is precipitated in ethanol and then rinsed with deionized water. Extract again with deionized water for 10 minutes to completely remove chlorosulfonic acid.

(Example 16) S-alkoxy dechlorination 10 g of ethanol is dissolved in 100 ml of water and mixed with 2 to 3 drops of methyl red dissolved in acetone. To this solution is added 5 g of fine granular chlorosulfonated polysulfone.

  To the solution, 5N KOH is added dropwise until the color changes from yellow to red. The container is then sealed and shaken thoroughly. Add caustic potash solution and shake until no color change occurs. The polysulfone ester formed is removed by suction, washed with water and recrystallized for purification.

Example 17 S-alkoxy dechlorination 10 g of dry ethanol are mixed with 60 ml of pyridine. This solution is added to 40 g of finely ground chlorosulfonated polysulfone while cooling with ice. It is then stirred overnight at room temperature under dehumidification. The suspension is then poured into ice water and carefully acidified with concentrated hydrochloric acid. Wash with aqueous bicarbonate solution. After filtration, the esterified polysulfone can be recrystallized.

(Example 18) Coating with a mixture of polysulfone and polysulfone of formula (IIC) 24 mg of PS and 2.4 mg of polysulfone of formula (IIC) are weighed, and chloroform is added to make 3 g (0.80% PS, 0 .08% PVP).

  A stent is coated by spraying with this mixture according to Example 7.

FIG. 5 is a graph showing the elution of macrocyclic carbon suboxide (MCS) from a three-layer system, the three-layer system having a polysulfone as a base coating, an active agent as an intermediate layer, and a polysulfone coating having an intermediate activity A complete layer of drug, which has a polyvinylpyrrolidone content of 0.04%. FIG. 7 is a graph showing elution of paclitaxel from a polysulfone matrix having an amount of 9.1% polyvinylpyrrolidone. FIG. 5 is a graph showing elution of simvastatin from a pure polysulfone matrix without a hydrophilic polymer. It is a graph which shows elution of (beta) -estradiol contained in the ratio of 15 mass% in the pure polysulfone matrix which does not contain a hydrophilic polymer. FIG. 6 is a graph showing elution of Trapidyl® from a polysulfone matrix having an amount of 4.5% polyvinylpyrrolidone. It is a graph which shows elution of trapidil (trademark) contained in the ratio of 50 mass% in a pure polysulfone matrix. FIG. 7A is a micrograph of a blood vessel portion 4 weeks after implantation in a pig, FIG. 7A shows an enlarged cross-section of a matrix stent, FIG. 7B shows a cross-sectional view of a blood vessel portion having a stent, the stent coated with polysulfone, MCS is loaded at a high concentration.

Claims (28)

A medical product,
A medical product, characterized in that the surface of the medical product is at least partly coated with at least one biologically stable polysulfone layer.   The polysulfone is polyethersulfone, substituted polyethersulfone, polyphenylsulfone, substituted polyphenylsulfone, polysulfone block copolymer, perfluoropolysulfone block copolymer, semifluoropolysulfone block copolymer, substituted polysulfone block copolymer, 2. Medical product according to claim 1, characterized in that it is selected from the group comprising and / or a mixture of said polymers.   The medical product according to claim 1 or 2, wherein the at least one biologically stable polysulfone layer comprises at least one hydrophilic polymer.   The medical product according to claim 3, wherein the polysulfone comprising the at least one hydrophilic polymer is present in a mixing ratio of 50% by weight to 50% by weight to 99.999% by weight: 0.001% by weight.   The hydrophilic polymer is polyvinyl pyrrolidone, glycerin, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyhydroxyethyl methacrylate, polyacrylamide, polyvalerolactone, poly-ε-decalactone, polylactone acid, polyglycolic acid, polylactide, polyglycolide. , Copolymer of polylactide and polyglycolide, poly-ε-caprolactone, polyhydroxybutanoic acid, polyhydroxybutyrate, polyhydroxyvalerate, polyhydroxybutyrate-co-valerate, poly (1,4-dioxane-2 3-dione), poly (1,3-dioxan-2-one), poly-para-dioxanone, polyanhydrides such as polymaleic anhydride, fibrin, polycyanoacrylate, polycap Complex block polymers such as those derived from lolactone dimethyl acrylate, poly-b-maleic acid, polycaprolactone butyl acrylate, oligocaprolactone diol and oligodioxanone diol, polyether ester complex block polymers such as PEG and polybutylene terephthalate , Polypivotolactones, polyglycolic acid trimethyl carbonate, polycaprolactone-glycolide, poly-g-ethyl glutamate, poly (DTH-iminocarbonate), poly (DTE-co-DT-carbonate), poly (bisphenol- A-imino carbonate), polyorthoester, polyglycolic acid trimethyl carbonate, polytrimethyl carbonate, polyimino carbonate, poly (N-vinyl) -pi Lidon, polyvinyl alcohol, polyesteramide, glycolated polyester, polyphosphoester, polyphosphazene, poly [(p-carboxyphenoxy) propane], polyhydroxypentanoic acid, polyanhydride, polyethylene oxide-propylene oxide, soft polyurethane, in the skeleton Polymers based on polyether esters, lipids, carrageenan, fibrinogen, starch, collagen, proteins such as polyurethanes, polyethylene oxides, polyalkene oxalates, polyorthoesters and copolymers thereof having amino acid residues in , Polyamino acids, synthetic polyamino acids, zein, modified zein, polyhydroxyalkanoates, pectic acid, actinic acid, modified and unmodified fibrin Zein, carboxymethyl sulfate, albumin, hyaluronic acid, chitosan and its derivatives, chondroitin sulfate, dextran, β-cyclodextrin, copolymer of PEG and polypropylene glycol, gum arabic, guar gum, gelatin, collagen, collagen-N 5. Medical product according to claim 3 or 4, characterized in that it is selected from the group comprising hydroxysuccinimide, lipids, phospholipids and variants and copolymers and / or mixtures of said substances.   The medical product according to claim 5, characterized in that the hydrophilic polymer is selected from the group comprising polyvinylpyrrolidone, polyethylene glycol, polypropylene glycol, and / or glycerin.   The medical device according to any one of claims 1 to 6, characterized in that the pore size of the polysulfone coating is determined by the mixing ratio of polysulfone and the at least one hydrophilic polymer. For products.   At least one anti-proliferative, anti-inflammatory, anti-inflammatory agent under and / or on at least one biologically stable polysulfone layer with or without said at least one hydrophilic polymer And / or an antithrombotic agent is present. The medical product according to claim 1.   9. The medical device according to claim 1, wherein the biologically stable layer is adhesively or covalently bonded to the surface of the medical product. Product.   The medical product according to any one of claims 1 to 9, wherein the coating on the surface of the medical product consists of one layer, two layers, three layers or more layers.   Fully desulfonated and N-reacetylated under and / or above at least one biologically stable polysulfone layer with or without said at least one hydrophilic polymer There is at least one layer of heparin, desulfonated and N-reacetylated heparin, N-carboxymethylated and / or partially N-acetylated chitosan, and / or a mixture of these substances The medical product according to any one of claims 1 to 10, wherein the medical product is characterized by that.   12. Medical according to any one of the preceding claims, characterized in that, in a multilayer system, the at least two biologically stable layers are different or not different in the proportion of the hydrophilic polymer. For products.   In a multilayer system, said at least one polysulfone layer with or without at least one mixture of hydrophilic polymers is said biologically stable with at least one layer of at least one biodegradable polymer. 13. A medical product according to any one of the preceding claims, characterized in that the polysulfone layer is at least partially coated. Said at least one anti-proliferative, anti-inflammatory, anti-inflammatory and / or anti-thrombotic agent is sirolimus (rapamycin), everolimus, somatostatin, tacrolimus, roxithromycin, dunaimycin, ascomycin, bafilo Bafilomycin, erythromycin, midecamycin, josamycin, concanamycin, clarithromycin, troleandomycin, folimycin, cerivastatin, simvastatin, lovastatin, fluvastatin, rosuvastatin, atorvastatin, pravastatin, pitavastatin, vinblastine, Vincristine, vindesine, vinorelbine, etoposide, teniposide, nimustine, carmustine, lomustine, cyclophosphamide, -Type natriuretic peptide (CNP), 4-hydroxycyclophosphamide, estramustine, melphalan, ifosfamide, trofosfamide, chlorambucil, bendamustine, dacarbazine, busulfan, procarbazine, treosulfan ), Temozolomide, thiotepa, daunorubicin, doxorubicin, aclarubicin, epirubicin, mitoxantrone, idarubicin, bleomycin, mitomycin, dactinomycin, methotrexate, fludarabine, fludarabine-5'-2 hydrogen phosphate, cladribine, mercaptopurine, thioguanine Cytarabine, fluorouracil, gemcitabine, capecitabine, docetaxel, carboplatin, cisplatin, crypt Ficin (cryptophycine), anginex (anginex), oxaliplatin, amsacrine, irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin, aldesleukin, tretinoin, asparaginase, pegaspargase, anastrozole, exemestane, letrozole, formestane ( formestane), aminoglutethimide, adriamycin, azithromycin, spiramycin, cepharantin, cemcrantin-2w, epothilone A and B, mitoxantrone, azathioprine, mycophenolatmofetil, c-myc- Antisense, b-myc-antisense, betulinic acid, camptothecin, rapacol, β-lapachone, podophyllotoxin, betulin, pod 2-ethyl hydrazide, morgramostim (rhuGM-CSF), peginterferon α-2b, lenograstim (r-HuG-CSF), filgrastim, macrogol, anginex, Na-diuretic peptide, dacarbazine, basiliximab , Daclizumab, selectin (cytokine antagonist), cryptophysin (chryptophycine), CETP inhibitor, cadherine, cytokinin inhibitor, COX-2 inhibitor, AE-941 (registered trademark, Neobasstat) NFkB, angiopeptin (Angiopeptin), ciprofloxacin, camptothecin, fluroblastin, monoclonal antibody (suppresses muscle cell proliferation), bFGF antagonist, probucol, prostaglandin, Ac-YVAD-CM NO donors such as 1,11-dimethoxycantin-6-one, 1-hydroxy-11-methoxycantin-6-one, scopoletin, colchicine, pentaerythritol tetranitrate and syndnoeimine, S-nitroso Derivatives, tamoxifen, staurosporine, β-estradiol, α-estradiol, estriol, estrone, ethinylestradiol, phosphatestrol, medroxyprogesterone, estradiol cypionate, estradiol benzoate, tranilast, camevacaurin And other terpenoids (applied in the treatment of cancer), verapamil, tyrosine kinase inhibitors (tylophostin), cyclosporin A, 6-α-hydroxy-paclita Paclitaxel and its derivatives, such as cell, baccatin, taxotere, and others, macrocyclic oligomers (MCS) and their derivatives, synthetically produced and derived from carbon dioxide, a natural source, mofebdazone, acemetacin, diclofenac, lonazolac , Dapsone, o-carbamylphenoxyacetic acid, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, chloroquine phosphate, penicillamine, hydroxychloroquine, auranofin, sodium gold thiomalate, oxaceprol, celecoxib, β -Sitosterin, ademethionine, myrtecaine, polidocanol, nonivamide, levomenthol, benzocaine, aesin, ellipse Synp (ellipticine), D-24851 (Calbiochem), colcemid, cytochalasin A to E, indanocine, nocodazole, S100 protein, bacitracin, vitronectin receptor antagonist, azelastine, guanidyl cyclase stimulant, metal Proteinase-1 and 2 tissue inhibitors, free nucleic acids, nucleic acids incorporated into viral mediators, DNA and RNA fragments, plasminogen activator inhibitor-1, plasminogen activator inhibitor-2, antisense oligonucleotide, VEGF inhibitor, IGF-1; cefadroxyl, cefazolin, cefaclor, cefotaxim, tobramycin,
Antibiotics such as gentamicin; penicillins such as dicloxacillin and oxacillin; sulfonamides, metronidazole, argatroban, aspirin, abciximab, synthetic antithrombin drugs, bivalirudin, coumadin, enoxaparin, desulfonation and N- reacetylated heparin (registered trademark, Hemoparin (hemoparin)), tissue plasminogen activator, GpIIb / IIIa platelet membrane receptor, the factor _{X a} inhibitor antibody, heparin, hirudin, r- hirudin, PPACK Antithrombotic agents such as protamin, protamin, prourokinase, streptokinase, warfarin, urokinase; dipyramidole, triazolopyrimidine Trademarks, Trapidil), Vasodilators such as nitroprusside; PDGF antagonists such as triazolopyrimidine and seramin; ACE inhibitors such as captopril, cilazapril, lisinopril, enalapril, losartan Agents, thioprotease inhibitors, prostacyclin, vapiprost, interferon alpha, beta, and gamma, histamine antagonists, serotonin blockers, apoptosis inhibitors, p65NF-kB or Bcl-xL antisense oligonucleotides such as Agent, halofuginone, nifedipine, tocopherol, tranilast, molsidomine, tea polyphenol, epicatechin gallate, epigallocatechin gallate, boswellic acid and its derivatives, leflunomide Anakinra, etanercept, sulfasalazine, etoposide, dicloxacillin, tetracycline, triamcinolone, mutamycin, procainamide, retinoic acid, quinidine, disopyrimide, flecainide, propaphenone, sotalol, amidolone, phylloline diol A (bryophyllin A) Natural and synthetically produced steroids such as (inotodiol), maquiroside A, ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone, dexamethasone; fenoprofen, ibuprofen , Non-steroidal substances (NSAIDS) such as indomethacin, naproxen, phenylbutazone; and acyclovir, cancer Other antiviral agents such as cyclovir and zidovudine; antifungal agents such as clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole, nystatin, terbinafine; antiprotozoal agents such as chloroquine, mefloquine, quinine; (Hippocaesculin), barringtogenol-C21-angelate, 14-dehydroagrostistachin, 14-dehydroagrostistachin, agroskerin, agrostistachin, 17-hydroxyagrostatin (17-hydroxyagrostistachin), ovatodiolids, 4,7-oxycycloanisomelic acid, baccharinoids B1, B2, B3, and B7, tubeymoside (t ubeimoside, bruceanol A, B, and C, bruceantinoside C, yadanzioside N and P, isodeoxyelephantopin, tomenphantopin A and B, coronaline (Coronarin) A, B, C, and D, ursolic acid, hyptatic acid A, zeolin, iso-iridogermanal,
Maytenfoliol, effusantin A, excisantin A and B, longikaurin B, sculponeatin C, kamebaunin, leukamenin A and B, 18, 18 Natural terpenoids such as dehydro-6-α-senecioyloxychaparrin, taxamairin A and B, regenilol, triptolide; further simarin, aposimmarin ( apocymarin, aristolochic acid, anopterin, hydroxyanopterin, anemonin, protoanemonin, berberine, cheliburin chloride, cictoxin, sinococuline, bombbres Bombrestatin A and B, cudraisoflavone A, curcumin, dihydronitidine, nitidine chloride, 12-β-hydroxypregnadien-4,16-diene-3,20- Dione, Virobol, Gincol, Ginkgolic acid, Helenaline, Indicine, Indicine-N-oxide, Laciocarpine, Inotodiol, Glycoside 1a, Podophyllotoxin, Justicidin ) A and B, larreatin, malloterin, malotochromanol, isobutyrylmallotochromanol, maquiroside A, marchantin A, maytansine, lycolidin ( lycor idicin), margetine, pancratistatin, liriodenine, bisparthenolidine, oxoushinsunine, aristolactam-AII, bisparthenolidine, periprocoside ( periplocoside A, bisparthenolidine, periplocoside A, ghalakinoside, ursolic acid, deoxypsorospermin, psychorubin, ricin A, sanguinarine, manu wheat acid ( manwu wheat acid, methylsorbifolin, sphatheliachromen, stizophyllin, mansonine, strebloside, akagerine, dihydro Sambarencin (dihydrousambarensine), hydroxyusambarine, strychnopentamine, strychnophylline, usambarine, usambarensine, berberine, liriodenine (oxorioninine) ), Daphnoretin, lariciresinol, methoxylariciresinol, syringaresinol, umbelliferon, afromoson, acetylvismione B, desacetylvismione 14. Medical product according to any one of claims 1 to 13, characterized in that it is selected from the group comprising A, vismione A and B.   Said at least one anti-proliferative, anti-inflammatory, anti-inflammatory and / or anti-thrombotic agent is paclitaxel and its derivatives, β-estradiol, simvastatin, PI-88 (Progen Ind.), Macrocyclic carbon suboxide (MCS) ) And their derivatives, trapidyl®, N- (pyridin-4-yl)-[1-4- (4-chlorobenzyl) -indol-3-yl] -glyoxylamide (D-24851), activity 12. The method according to claim 11, wherein the protein is selected from the group comprising proteinized protein C (aPC), Ac-YVAD-CMK, anginex (β-Pep25), neobastat (registered trademark), cryptophycin 52, tacrolimus. The medical product described. The at least one anti-proliferative agent, anti-inflammatory agent, anti-inflammatory agent, and / or anti-thrombotic agent is included at a pharmaceutically active concentration of 0.001-20 mg / cm ² · surface, characterized in that Item 16. The medical product according to any one of Items 1 to 15.   In a multilayer system, the at least two layers with or without the mixture of at least one hydrophilic polymer comprise at least one active agent at the same or different active agent concentration, The medical product according to any one of claims 1 to 16, characterized in that the drug is covalently and / or adhesively bonded.   18. Multilayer system according to any one of claims 1 to 17, characterized in that the last layer is a layer of pure active drug and is bonded covalently and / or adhesively. Medical product.   Said at least one biologically stable polysulfone layer comprising at least one active agent is coated with at least one active agent and / or does not contain an active agent or at the same or different concentration 19. A method according to any one of the preceding claims, characterized in that it is at least partly coated covalently and / or adhesively with a layer of biodegradable polymer comprising at least one active agent. The medical product described. A biocompatible coating method for a medical product, comprising:
(A) providing a stent; and (b) depositing at least one biologically stable polysulfone layer with or without at least one hydrophilic polymer; and (c). Attaching and / or incorporating at least one anti-proliferative, anti-inflammatory, anti-inflammatory and / or anti-thrombotic agent on and / or in said biologically stable layer, or (b ′ ) At least one biologically stable polysulfone with or without at least one hydrophilic polymer together with at least one anti-proliferative, anti-inflammatory, anti-inflammatory and / or anti-thrombotic agent Applying a layer;
Characterized by the method. Said step (b ′), and further (c ′) depositing at least one anti-proliferative, anti-inflammatory, anti-inflammatory and / or anti-thrombotic agent on said biologically stable polymer layer The process of
21. The method of claim 20, comprising: And (d) depositing at least one second biologically stable polysulfone layer, wherein the polysulfone layer has a hydrophilic polymer content equal to or different from the first layer. Or comprising and / or depositing the same or different concentration of at least one active agent upon deposition of the second polysulfone layer. Method to 20 or 21. And (d ′) depositing at least one further layer of at least one biodegradable polymer, wherein the same or different concentrations of at least one active agent are not used when depositing the layer. Or incorporating and / or attaching,
23. A method according to any one of claims 20 to 22 comprising:   Fully desulfonated and N-reacetylated heparin, N-carboxymethylated and / or partially N-acetylated above and / or below the at least one biologically stable polysulfone layer 19. A medical product according to any one of claims 16 to 18, characterized in that at least one layer of applied chitosan and / or a mixture of these substances is deposited.   A medical product obtainable by the method according to any of claims 16-19.   21. The method of claim 1 to 15 or 20, wherein the at least one anti-proliferative, anti-inflammatory, anti-inflammatory and / or anti-thrombotic agent is released in a controlled manner via a surface coating. A medical product according to any one of the items. Each of the anti-proliferative, anti-inflammatory, anti-inflammatory and / or anti-thrombotic agents is included in the medical product at a pharmaceutically active concentration of 0.001-10 mg / cm ² · surface, and The medical product according to any one of claims 1 to 15, 20 or 21, characterized in that it is included for each layer having an active agent.   23. The medical product according to claim 1-15 or 20-22, wherein the medical product is a stent.

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