MXPA06003270A - Biocompatible, biostable coating of medical surfaces - Google Patents

Abstract

The invention relates to medical products comprising at least one biocompatible biostable polysulfone coating. Said polysulfone coating makes it possible, via the admixture of an adequate quantity of at least one hydrophilic polymer, to control the elution kinetics of the at least one antiproliferative, anti-inflammatory, antiphlogistic, and/or antithrombogenic agent that is introduced and/or applied while allowing different agents or agent concentrations to be spatially separated with the aid of the layer system of biostable polymers. Also disclosed are a method for producing said medical products and the use thereof particularly in the form of stents for preventing restenosis.

Description

Biocompatible, biostable coating of medical surfaces Description The invention relates to medical surfaces having a biocompatible, biostable coating of polysulfones or / and polysulfone derivatives or copolymers, respectively, with polysulfone containing at least one antiproliferative, anti-inflammatory, antiphlogistic and / or antithrombotic active agent and / or covered with agent, methods for the manufacture of these surfaces as well as their use in the form of long-term implants, in particular stents for the prevention of restenosis.

In recent years, the implantation of stents in the dilation of the balloon of occluded blood vessels has increased more and more. Although stents reduce the risk of reoccurrence of vessel occlusion, they are not able to completely prevent such restenosis until today.

An exact description of the term of restenosis does not exist in the technical literature. The morphological definition of restenosis most frequently used is that which defines restenosis as a reduction in vessel diameter to less than 50% of normal after successful PTCA. { percutaneous transluminal coronary angioplasty, transluminal percutaneous coronary angioplasty). This is an empirically determined value of which the odinámica relevance and relation with the clinical pathology lacks a massive scientific basis. In praxis, a patient's clinical deterioration is often considered a sign of restenosis of the previously treated vessel segment.

There are three different reasons for restenosis caused by the stent: a.) In the first time after implantation, the surface of the stent is directly exposed to the blood and, due to the foreign surface now present, an acute thrombosis may occur , which again occludes the blood vessel. b.) Implantation of the stent causes vessel injuries, which, in addition to the aforementioned thrombosis, also cause inflammation reactions, which play a decisive role in the healing process during the first seven days. The processes that occur here are related, among others, to the release of growth factors, which initiate an increased proliferation of smooth muscle cells, which rapidly leads to a reappearance of vessel occlusion due to unbridled growth. c.) After a few weeks, the stent begins to grow into the tissue of the blood vessel. This means that the stent is completely surrounded by smooth muscle cells and has no contact with the blood. This scarring may be too pronounced (neointima hyperplasia) and may lead to not only coverage of the stent surface but also to the fact that the entire interior space of the stent is occluded.

Attempts were made in vain to solve the problem of restenosis by coating the stents with heparin (J. Whorle et al., European Heart Journal (2001) 22, 1808-1816). Heparin as an anticoagulant, however, only treats the cause mentioned above and also can only have its total effect in solution. This first problem in the meantime is almost completely avoidable by means of medical treatment by administration of anticoagulants. Currently, the second and third problem is attempted by local inhibition of the growth of smooth muscle cells in the stent. This is attempted, for example, with radioactive stents or stents containing pharmaceutically active agents.

Thus, US-A-5 891 108 describes, for example, a hollow molded stent, which can contain pharmaceutically active agents in its interior that are released through a multitude of outlets in the stent. EP-A-1 127 582 on the other hand describes a stent that shows on its surface channels of 0.1-1 mm in depth and 7-15 mm in length that are designed for the implementation of an active agent. These stores of active agent release, similarly to the outputs in the hollow stent, the pharmaceutically active agent contained in a high concentration and for a relatively long period of time, which nevertheless leads to the fact that the smooth muscle cells no longer they are able, or only in a very delayed manner, to surround the stent.

As a consequence, the stent is exposed to the blood for much longer, which again leads to an increased number of vessel occlusions caused by thrombosis.

(Lustro F., Colombo A., Late acute thrombosis after Paclitaxel eluting stent implantation, Heart (2001) 86, 262-4).

One approach to solving this problem is presented by the biocompatible phosphorylcholine coating (WO 0101957), as herein phosphorylcholine, a component of the erythrocytic cell membrane, must create a non-thrombogenic surface as a composite of the coated, non-biodegradable polymer layer on the stent. Depending on its molecular weight, the active agent is absorbed by the phosphorylcholine layer containing polymer or absorbed on the surface.

Objective of the present invention is to provide a medical product having a hemocompatible surface as well as a manufacturing method for this medical product having the hemocompatible surface.

In particular, the hemocompatible surface of the medical product is intended to allow a continuous and controlled growth of the medical product into the vessel wall.

This object is solved by means of the technical teaching of the independent claims of the present invention. Other advantageous designs of the invention result from the dependent claims, the description, the figures, as well as the examples.

The present invention relates to medical products whose surface / s are at least partially coated with at least one biostable layer of polysulfone.

Surprisingly it was found that the coating of medical surfaces that permanently contact blood, with polysulfone, polyethersulfone and / or polyphenylsulfon and its derivatives represents an extremely suitable biocompatible substrate for active agents. By adding biocompatible hydrophilic polymers or by using polysulfones with ambivalent properties, ie with lipophilic and hydrophilic functional groups, the pore size of the polysulfone matrix can be varied so that a plurality of possibilities with respect to the active agents used, the applicable amount as well as the desired release rate. In particular, the elution kinetics of the at least one active agent can be regulated by the pore size in the biostable layer. The pore size again is determined by the type and amount of the hydrophilic polymer used, or, respectively, the amount of lipophilic and lipophobic groups in the polysulfone or polysulfone mixture. In addition to the impact of the added hydrophilic polymer, the addition of small amounts of water (or also ethyl acetate) in the coating solution has an impact on the future properties of the coated implant loaded with active agent. The adjustment of the charge distribution, the release properties (as a function of time and the eluted amount of active agent) and the spray properties of the coating solution are decisively affected by the defined addition of water (or also ethyl acetate or other additives described below) to the spray solution.

It was also found to be advantageous that the use of nitrogen as a carrier gas for the spray coating leads to a loading of the polymer layer containing the active agent with nitrogen remaining in the layer and procures the integrity of the active agent here due to its protective gas capacity. Thus, the half-life of the active agent is permanently ensured in a form that remains effective unaltered.

Modification of the polysulfone structure by analog polymer reactions such as the preparation of novel polysulfone copolymers (for example as polysulfone block copolymers or in statistical distribution) has an impact on the physical behavior of the resulting polymers, so that the properties of the polymer can be controlled, and are applicable or in combination with the unmodified polymers or individually as a new hemocompatible coating material. Thus, a polyethersulfone containing carboxylic groups can be prepared by the reaction of polysulfone copolymers with 4,4-bis (hydroxyphenyl) pentanoic acid (4,4'-bis (hydroxyphenyl) pentane ic acid BPA), which leads to a hydrophilicity other than polymer The properties of the hydrophilic polysulfone can also be used as a hydrophilic polymer additive to the unmodified polysulfone, as already mentioned above. By adjusting the degree of modification, the degree of hydrophilicity is influenced, such that a polymer molecule results in each chain containing unmodified and modified regions and thus combines hydrophobic and hydrophilic properties in itself, - which transmit to the polymer also an altered spatial structure of the chain segments, the so-called secondary structure. Therefore, it is preferred to use for the coating a polysulfone having hydrophilic regions as well as hydrophobic regions. Such polysulfones can be prepared by providing a polysulfone with side chains or hydrophilic functional groups after polymerization by means of analog polymer reactions, provided that the polymer itself is hydrophobic, or vice versa by provision of a hydrophilic polysulfon with side chains or hydrophobic functional groups. In this preferred embodiment, the hydrophilic and hydrophobic properties are combined within a polymer molecule, generally with a statistical distribution, as the analog reactions of polymers are proceeded with a statistical distribution. In addition, such hydrophilic polysulfone with hydrophobic polysulfone systems can be prepared by statistical polymerization of at least one hydrophilic monomer and at least one hydrophobic monomer. This results in structures that are similar to the aforementioned embodiment of the subsequent modification by analog polymer reactions. A third embodiment consists of the block copolymerization of at least one hydrophilic sulfon block polymer with at least one hydrophobic polymer of a sulfon block to a polysulfone having respectively the hydrophilic and hydrophobic properties in the individual blocks. Another variant consists in converting at least one hydrophilic monomer into an alternating copolymerization with at least one hydrophobic monomer. There, the hydrophilic and hydrophobic properties in the obtained polysulfone are alternately distributed in the polymer chain. In addition, a mixture of at least one hydrophilic polysulfone with at least one hydrophobic polysulfone can be applied to the coating according to the invention. There, the hydrophilic and hydrophobic properties are not combined in a polymer molecule but can be found again in the coating and lead to the same effects as in the above-mentioned embodiments.

For the preparation of the polysulfones, all polymerization reactions known to a person skilled in the art are suitable, such as radical, anionic, cationic polymerization or thermal polymerization. Examples for the polysulfones mentioned above as well as possibilities for the preparation thereof will be described below.

In addition, there is the possibility of derivatizing introduced functional groups, for example the carboxylic group (Macrom. Chem. Phys. 1994, 195, 1709). In that way, the hydrophobicity of the active agent can easily be increased to more than the hydrophobic properties of the polymer used for example by introduction of fluorinated compounds (Coll. Polym, Sci. 2001, 279, 727). By introducing functional groups, graft copolymers can be prepared, wherein the side chains now consist of other units of structure than the prinical chain. For this purpose, biocompatible, biostable and biodegradable polymers can be used.

The functional groups can also be used for a relase that is unstable to hydrolysis of active agents. Thus, the active agent is released in a form that is likewise controlled by hydrolysis and dependently on the type of linkage (thioester bond, ester bond). Here, the advantage is the possibility of controlling the elution of the active agent in such a way that the release curve follows another trajectory and that adaptations to many different disease processes with various requirements can be achieved with the implant with respect to the concentration of the agent active dependent on time. One variation consists of the covalent linkage of desulfated and N-reacetylated heparin and / or N-carboxymethylated and / or partially N-acetylated chitosan to the polymer chain, whereby the haemocompatibility of the polymer is enhanced by the atomic compound.

Due to the possibility of construction of at least two layers of the polymer that is variable in its composition, as well as the variation of the additives, a differentiation depending on the layer with respect to the active agent applied as well as with respect to the concentration You can proceed. This adaptability distinguishes the polysulfone matrix as a universally applicable, biostable coating material for the prevention of restenosis.

For the adjustment of the pore size and thus, of the amount of active agent in the polysulfone matrix, not only hydrophilic polymers, but also minerals and even water can be used as additives. The pore size controls on the one hand the release kinetics of the at least one antiproliferative, anti-inflammatory, antiphlogistic and / or antithrombotic active agent as well as the amount of active agent in certain embodiments, which can be incorporated or deposited in a polysulfone coating , as the pores in the polysulfone can serve as a reservoir of active agent.

For the creation of pores in the polysulfone matrix in the application of these additives, different strategies can be, or respectively, have to be followed.

In principle, the creation of pores is carried out in such a way that the additives are deposited together with the polysulfone that builds the matrix on the medical product that must be coated according to an appropriate method. There, homogeneous polysulfone compartments of the additive, which can be controlled in terms of their dimension, are formed dependently on the differences in the hydrophilicity of the additives applied as well as the polysulfone that builds the matrix. The number of these homogeneous compartments per unit volume of the polysulfone matrix can be controlled by the amount added per percentage of the additive.

As additives, amino acids, polyamino acids, hydrophilic polymers, saccharides, oligosaccharides, polysaccharides, oligopeptides, polyvinyl pyrrolidone, polyethyleneimine, glycerin, polyethers, glycol, minerals and water can be used in detail.

In the case of amino acids, the genetically encoded amino acids aspartic acid, glutamic acid, the neutral amino acids alanine, asparagine, cysteine, glutamine, glycine, isoleucine, leucine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, valine and the basic amino acids arginine, histidine, lysine as well as the uncoded genetic amino acids ornithine and taurine are preferred. In particular, representatives of the L-series of these amino acids are preferred. In addition, representatives of the D series of these amino acids as well as D, L mixtures of an amino acid as well as D, L mixtures of more than one amino acid 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 as well as polyornithine and polyitaurine are preferred.

In addition, also representatives of the D series of these polyamino acids, as well as D, L mixtures of a polyamino acid and mixtures D, L of more than one polyamino acid are suitable.

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

In the case of the minerals, cabonatos, chlorates, phosphates and sulfates of the cations sodium, calcium, potassium and / or magnesium are preferred.

For the creation of the pore structure, said compartments are subsequently removed from the polysulfone matrix. What remains is the three-dimensional structure with the predetermined degree of porosity, which is then "" filled "with the active agent.

Next, three preferred systems for the creation of the pore structure are briefly described based on the classes of polymer, mineral and water additives.

System 1: Polymer As polymeric additives, for example, special highly branched polyesters with triazene-thermoisepable groups in the main chain are used. The highly branched, molecularly dispersed polymer is integrated into the polysulfone matrix. The subsequent thermal treatment of the deco system puts the highly branched pore maker into volatile decomposition products under creation of a corresponding nanoporous layer of polymer. Polysulfones are distinguished among others for their stability to temperature and high dimensional stability, so this strategy is applicable anyway. In addition, this thermal treatment can be connected to the sterilization step, resulting in an effective method.

System 2: Mineral As a mineral additive, for example, the physiologically harmless calcium carbonate compound is applied. The polysulfone matrix consists of hydrophilic block double copolymers. These hydrophilic block double copolymers comprise a hydrophilic block which does not react with the mineral additive, and a second polyelectrolyte block, which reacts strongly with the surfaces of the mineral additive. These block copolymers have growth modifying effects on the crystallization of calcium carbonate. The resulting mineral compartments have an approximately oval shape, a bar shape with weights or a spherical shape. Due to the excellent resistance of the polysulfone to chemical substances as well as the stability against hydrolysis, the mineral additives can be completely eliminated in the acid bath. What remains is the desired nanoporous structure of the polysulfone matrix.

System 3: Water As a fluid additive, water comes into consideration as the easiest solution in the case of the coating of the medical product with polar active agents. In the use of the spray method, the polysulfone is present in an organic solvent such as chloroform. The solution of chloroform saturated with polysulfone is only conditionally capable of the subsequent reception of the active agent. Thus, the active agent dissolves mainly in the aqueous phase, which, due to the separation of the phases, forms compartments after deposition on the surface of the medical product. Subsequently, the water in these compartments can be completely eliminated from the system by means of, for example, freeze-drying. What remains are nanoporous structures loaded with the active agent. The active agent concentration of the pores can be increased in consecutive steps with active agent dissolved in water and preferably subsequent freeze drying. In the methods that exist up to the present day, the active agent was likewise dissolved together with the polysulfone in chloroform. The next increase in concentration of the active agent is likewise effected in a chloroform solution. Since chloroform can in no way be eliminated at 100%, chloroform concentrates more and more in the final finished product, which leads to unnecessary exposure of the patient. By using water as an active agent substrate, chloroform is only used once for the deposition of the polysulfone matrix and the exposure is reduced to a minimum.

For the preparation of the spray solution containing at least one polysulfone and at least one antiproliferative, anti-inflammatory, antiphlogistic and / or antithrombotic active agent, more preferably solvents are suitable that evaporate easily, i.e., that they are volatile, such as by Examples are chloroform, dichloromethane, tetrahydrofuran, acetone, methanol, ethanol, isopropanol, diethyl ether and ethyl acetate and can also be saturated with water or prepared containing a particular water content. There, water contents of 1.6 - 15%, preferably 2.1 - 10%, more preferably 2.6 - 7.9% and especially preferably 3.3 - 6.8% are appropriate. In addition, it is preferable if organic solvent, water, polysulfone and active agent form a homogeneous solution.

By the creation of copolymers, the hydrophilicity, or respectively, the hydrophobicity of the polysulfone can be varied. Thus, it is possible for example to synthesize polysulfone copolymers by means of 4,4-bis (hydroxyphenyl) pentanoic acid (4,4'-bis (hydroxyphenyl) pentanoic acid, BPA), so, in this way, carboxylic side groups are introduced, which lower the hydrophobicity of the polysulfone matrix. In addition, it is now possible to derivatize introduced functional groups, for example the carboxylic group (Macrom. Chem. Phys. 195 (1994), .1709; Coll. Polym. Sci. 279 (2001), 727).

By the possibility of forming at least two layers of the polymer, which is variable in its composition, as well as in the variation of the additives, additionally a differentiation that depends on the layer with respect to the active agents applied as well as with respect to the concentration can be conducted. This adaptability distinguishes the polysulfone matrix as a universally applicable, biostable coating material for the prevention of restenosis.

In addition, the use of thermoplastic polysulfones is preferred. Thermoplastic polysulfones can deform plastically (plastic) under the influence of heat (thermo). Generally, thermoplastic polysulfones consist of chains of linear or less branched molecules. When heated, they can be expanded by extension. When they are heated more, they can completely melt and be rebuilt. In particular, it is preferred if these thermoplastic polysulfones have hydrophilic properties as well as hydrophobic properties. Such thermoplastic polysulfones having these ambivalent properties can be synthesized according to the methods described above by analog reactions of polymers, block copolymerizations or polymerization of hydrophilic monomers with hydrophobic monomers. The thermoplastic polymers obtained in this way, or, respectively, the medical products coated therewith, are distinguished by multiple sterilizability, hot steam resistance and hydrolysis, high dimensional stability, resistance to aggressive chemical substances as well as good stability against thermal aging. .

A preferred thermoplastic polysulfone is synthesized from bisphenol A and 4,4'-dichlorophenylsulfon by polycondensation reactions (see following formula (II)).

Poly [oxy-1 r 4-f-ene-sulfonyl-1-r 4-f-eneylene-oxy- (4,4'-isopropylidenedifenylene)] The polysulfones which are applicable for the coating according to the invention have the following general structure according to formula (I): wherein n represents the degree of polymerization, which is in the region of n = 10 to n = 10,000, preferably in the area of n = 20 to n = 3,000, more preferably in the area of n = 40 to n = 1,000, more preferably in the area of n = 60 to n = 500, more preferably in the area of n = 80 to n = 250 and particularly preferable in the area of n = 100 to n = 200- In addition, it is preferred that the zone of n be such that an average polymer weight of 60,000-120,000 g / mol, preferably 70,000 to 99,000 g / mol, more preferably 80,000-97,000 g / mol, still more preferably 84,000 -95,000 g results. / mol, and particularly preferably 86,000 -93,000 g / mol.

In addition, it is preferred that the zone of n be such that the average number of the polymer results in the area of 20,000-70,000 g / mol, preferably 30,000-65,000 g / mol, more preferably 32,000-60,000, still more preferably 35,000. - 59,000, and particularly preferably 45,000 - 58,000 g / mol.

Y and z are integers in the region of 1 to 10, and R and R 'stand for each other independently of an alkylene group having 1 to 12 carbon atoms, an aromatic group having 6 to 20 atoms, a heteroaromatic group having 2 to 10 carbon atoms, a cycloalkene group having 3 to 15 carbon atoms, an alkylene group having 6 to 20 carbon atoms, an arylene group having 6 to 20 carbon atoms, an alkylene group which has 1 to 12 carbon atoms, a group of arylenoxy having 6 to 20 carbon atoms, a heteroaryloxy group having 6 to 20 carbon atoms, a cycloalkyleneoxy group having 3 to 15 carbon atoms, an alkylene dyleneoxy group having 6 to 20 carbon atoms or an arylene-alkanoxy group having 6 to 20 carbon atoms. The foregoing groups may have other substituents, in particular those which are described below with the term "substituted" polysulfones.

Examples of the groups R and R 'are -R1-, -R2-, -R3-r _R4- / -R5-, -R6-, -R1-R2 ~, -R3-R4-, -R5-R6-, -Rx-R2-R3-, -R4-R5-R6-, - ^ R ^ R3- R4- , -Rx-R2-R3-R4-R5- as well as -R1-R2-R3-R4-R5-R eenn ddoonnddee RR11, RR22, RR33, RR44, RR55 and RR66 are independent of each other. following groups: -CH2-, -C2H4-, -CH (OH) -, -CH (SH) -, -CH (NH2) ~, -CH (OCH3) -, -C (OCH3) 2-, -CH (SCH3) -, -C (SCH3) 2-, -CH (NH (CH3)) -, C (N (CH3) 2) -, -CH (OC2H5) -, -C (OC2H5) 2-y, -CHF-, -CHC1-, -CHBr-, -CF2-, -CC12-, -CBr2 ^ - , -CH (COOH) -, -CH (COOCH3) -, -CH (COOC2H5) -, CH (COCH3) -, -CH (COC2H5) -, -CH (CH3) -, -C (CH3) 2-, -CH (C2H5) -, -C (C2H5) 2- / -CH (CONH2) -, -CH (CONH (CH3)) -, -CH (CON (CH3) 2) -, -C3H6-, -C4H8-, -C5H9-, -C6H? O-, cyclo-C3H4- , cycl? -C3H4-, cyclo-C4H6-, cyclo-C5H8-, -OCH2-, -OC2H4-, -OC3H6-, -OC4H8-, -OC5H9-, -OC6H? O-, -CH2O-, -C2H40-, -C3H60-, -C4H80-, C5H9O-, -CgHioO-, -NHCH2-, -NHC2H4-, -NHC3H6-, -NHC4H8-, -NHC5H9-, -NHC6H10-, -CH2NH-, -C2H4NH-, -C3H6NH-, -C4H8NH-, -C5H9NH- , -C6H10NH-, -SCH2-, -SC2H4-, -SC3H6-, -SC4H8-, -SC5H9-, SCgHio-, - CH2S-, - C2H S-, - C3HgS-, - C H8S-, - C5H9S-, - CgHioS-, -C6H4-, -C6H3 (CH3) -, -C6H3 (C2H5) -, -C6H3 ( OH) -, -C6H3 (NH2) -, -C6H3 (C1) -, -C6H3 (F) -, -C6H3 (Br) -, -C6H3 (0CH3) -, C6H3 (SCH3) -, -C6H3 (C0CH3) -, -C6H3 (C0C2H5) -, -C6H3 (COOH) -, -C6H3 (COOCH3) -, -C6H3 (C00C2H5) -, -C6H3 (NH (CH3)) -, -C6H3 (N (CH3) 2) -, C6H3 (CONH2) -, -C6H3 (C0NH (CH3)) -, -C6H3 (C0N (CH3 ) 2) -, -0C6H4-, -0C6H3 (CH3) -, -0C6H3 (C2H5) -, -0C6H3 (0H) -, 0C6H3 (NH2) -, -0C6H3 (C1) -,. -0C6H3 (F) ~, -0C6H3 (Br) -, -0CSH3 (OCH3) -, 0C6H3 (SCH3) -, -0C5H3 (C0CH3) -, -0C6H3 (C0C2H5) -, -0C6H3 (COOH) -, OC6H3 (COOCH3) -, -OC6H3 (COOC2H5) -, -OC6H3 (NH (CH3)) -, -OC6H3 (N (CH3) 2) -, -OC6H3 (CONH2) -, -OC6H3 (CONH (CH3)) -, -OC6H3 (CON (CH3) 2) -, -C6H40-, -C6H3 (CH3) 0-, -C6H3 (C2H5) 0-, -C6H3 (OH) 0-, C6H3 (NH2) 0-, -C6H3 (C1) 0-, -C6H3 (F) 0-, -C6H3 (Br) 0-, -C6H3 (0CH3) O-, C6H3 (SCH3) 0-, -C6H3 (COCH3) 0-, -C6H3 (COC2H5) 0-, -C6H3 (COOH) O-, C6H3 (COOCH3) 0-, -C6H3 (COOC2H5) 0-, -C6H3 (NH (CH3)) 0-, -CSH3 (N (CH3) 2) O-, C6H3 (CONH2) 0-, -C6H3 (CONH (CH3)) O-, -C6H3 (CON (CH3) 2) O-, -SC6H4-, -SC6H3 (CH3) -, -SC6H3 (C2H5) -, -SC6H3 (OH) -, SC6H3 (NH2) -, -SC5H3 (C1) -, -SC6H3 (F) -, -SC6H3 (Br) -, -SC6H3 (OCH3) -, SCgH3 (SCH3) -, -SC6H3 (COCH3) -, -SC6H3 (COC2H5) -, -SC6H3 (COOH) -, SC6H3 (COOCH3) -, -SC6H3 (COOC2H5) -, -SC6H3 (NH (CH3)) -, -SC6H3 (N (CH3) 2) ~, -SC6H3 (CONH2) -, -SC5H3 (CONH (CH3)) -, -SC6H3 (CON (CH3) 2) -, -C6H4S-, -C6H3 (CH3) S-, -C6H3 (C2H5) S-, -C6H3 (OH S-, C6H3 (NH2) S-, -C6H3 (C1) S-, -C6H3 (F) S-, -C6H3 (Br) S-, -C6H3 (OCH3) S-, CeH3 (SCH3) S-, -C6H3 (COCH3) S-, -C6H3 (COC2H5) S-, -C6H3 (COOH) S-, C6H3 (COOCH3) S-, -C6H3 (COOC2H5) S-, -C6H3 (NH (CH3)) S-, -C6H3 (N (CH3) 2) S-, -C6H3 (CONH2) S-, -C6H3 (CONH (CH3)) S-, -C6H3 (CON (CH3) 2) S-, -NH-C6H4-, -NH-C6H3 (CH3) -, ~ NH-C6H3 (C2H5) -, -NH-C6H3 (OH) -, -NH-C6H3 (NH2) -, -NH-C6H3 (C1) -, -NH-C6H3 (F) -, -NH ~ C6H3 (Br) -, -NH-C6H3 (OCH3) - ', -NH-C6H3 (SCH3) -, -NH-C6H3 (COCH3) -, -NH-C6H3 (COC2H5) -, -NH-C6H3 (COOH) -, -NH-C6H3 (COOCH3) -, -NH-C6H3 (COOC2H5) -, -NH-C6H3 (NH (CH3)) -, -NH -C6H3 (N (CH3) 2) -, -NH-C6H3 (CONH2) -, -NH-C6H3 (CONH (CH3)) -, -NH-C6H3 (CON (CH3) 2) -, -C6H4-NH-, -C6H3 (CH3) -NH-, -C6H3 (C2H5) -NH-, -C6H3 (OH) -NH-, -C6H3 (NH2) -NH-, -CSH3 (C1) -NH-, -C6H3 (F) -NH-, -C6H3 (Br) -NH-, -C3H3 (OCH3) -NH-, -C6H3 (SCH3) -NH-, -C6H3 (COCH3) -NH-, -C6H3 (COC2H5) -NH-, -C6H3 (COOH) -NH-, -C6H3 (COOCH3) -NH-, -C5H3 (COOC2H5) -NH-, -C6H3 (NH (CH3)) -NH-, -C6H3 (N (CH3) 2) -NH-, -C6H3 (CONH2) -NH-, -C6H3 ( CONH (CH3)) -NH-, -C6H3 (CON (CH3) 2) -NH-.

Particularly preferred are polysulfones as well as their mixtures, wherein the groups - 1 -, R 2 - / - R 3 - - R 1 - R 2 -, - R x - R 2 - R 3 - represent independently of each other the following groups: -C 6 H 40 - , -C (CH3) 2-, -C6H4-, -C6H4S02-, -S02C6H4-, -0C6H4-, -C6H40-C (CH3) 2-C6H4-.

R and R 'may furthermore independently represent one of the other preferably a functional group which is linked to the sulfon group in formulas (II) to (XV).

According to the invention, the polysulfone or the polysulfones, respectively, for the biostable layer or biostable layers are selected from the group comprising the following: polyethersulfon, substituted polyethersulfon, polyphenylsulfon, substituted polyphenylsulfon, polysulfone block copolymers, polysulfone block polymers perfluorinated, semifluorinated polysulfone block polymers, substituted polysulfon block copolymers and / or mixtures of the preceding polymers.

The term "substituted polysulfones" should be understood as polysulfones having functional groups. In particular the methylene units may possess one or two substituents and the phenylene units one, two, three or four substituents. Examples for these substituents (also referred to under: X, X ', X1', X'1 ') are: -OH, -0CH3, -0C2H5, -SH, -SCH3, -SC2H5, -N02, - F, -Cl, -Br, -I, ~ N3, -CN, -OCN, -NCO, -SCN, -NCS, -CHO, -C0CH3, -COC2H5, -COOH, -COCN, -COOCH3, -COOC2H5, -CONH2, -CONHCH3, -CONHC2H5, -CON (CH3) 2, -CON (C2H5) 2, -NH2, -NHCH3, -NHC2H5, N (CH3) 2, -N (C2H5) 2, -SOCH3, -SOC2H5, -S02CH3, -S02C2H5, -S03H, -S03CH3, -S03C2H5, -OCF3, -0-COOCH3, -0-COOC2H5, -NH-CO-NH2, -NH-CS-NH2, -NH -C (= NH) -NH2, -0-CO-NH2, -NH-CO-OCH3, -NH-CO-OC2H5, CH2F-CHF2, -CF3, -CH2C1 -CHC12, -CC13, -CH2Br -CHBr2, CBr, -CH2I -CHI2, -CI3, -CH3, -C2H5, -C3H7, -CH (CH3) 2, -C4H9, -CH2-CH (CH3) 2, -CH2-COOH, -CH (CH3) -C2H5 -C (CH3) 3, -H. Other preferred substituents or functional groups are -CH2-X and -C2H-X.

The following general structural formulas represent preferred repeating units for polysulfones. Preferably, the polymers only consist of those repeating units. However, it is also possible that other repeating units or blocks are present in a polymer in addition to the repeating units shown. Preferred: formula (III) formula (IV) X, X ', n and R' independently of each other have the above-mentioned meaning. formula (VII) formula (VIII) X, X ', n and R' independently of each other have the above-mentioned meaning. formula (IX) In addition, polysulfones having the following structural formula (X) are preferred: where? r represents: X, X 'and n have independently of one another the above mentioned meaning.

In addition, the following repeat units are preferred: formula (XI) formula (XII) formula (XIII) X, X ', X' ', X' '' and n have independently of one another the above mentioned meaning. R '' and R '' 'may independently represent one of the other a substituent, as defined for X or X', or may independently represent a group -R1-H or -R2-H independently of one another.

Another preferred repeat unit has a cyclic substituent between two aromatic rings such as for example formula (XIV) or (XV): formula (XIV) formula (XV) R "preferably represents -CH2-, -0CH2-, -CH20-, -0-, -C2H4-, -C3H6-, -CH (OH) -. The group - * R-R11- preferably represents a cyclic ester, amide, carbonate, urea or urethane such as: -O-CO-O-, -0-C0-0-CH2-, -0-CO-0-C2H4-, -CH2-0-C0-0-CH2-, ~ C2H4-, -C3H6-,. -C4H8-, -C5H10-, -C6H12-, -0-C0-NH-, -NH-CO-NH-, -0-CO-NH-CH2-, -0-C0-NH-C2H4-, -NH -CO-NH-CH2-, -NH-C0-NH-C2H4-, -NH-C0-0-CH2-, -NH-CO-0-C2H4-, -CH2-0-CO-NH-CH2-, -C2H4-S02-, -C3H6-S02-, -C4H8-S02-, -C2H4-S02-CH2-, -C2H4-S02-C2H4-, -C2H4-0-, -C3H6-0-, -C4H8-0-, -C2H4-0-CH2-, -C2H4-0-C2H4-, -C2H4-CO-, -C3H6-CO-, -C4H8-CO-, -C2H4 -CO-CH2-, -C2H4 ~ CO-C2H4-, -0-C0- CH2-, -0-C0-C2H4-, -0-C0-C2H2 -, -CH2-0-CO-CH2-, or cyclic esters containing an aromatic ring.

Analogous reactions of polymers, which are known to a person skilled in the art and serve for the modification of polysulfones, will now be described. formula (IIA) Groups of chloromethylene as functional groups X and X 'can be introduced by means of the use of formaldehyde, ClSiMe3 and a catalyst such as SnCl4, which can then continue to be replaced. By means of these reactions, for example hydroxyl groups, amino groups, carboxylate groups, ether or alkyl groups can be introduced by a nucleophilic substitution, which are linked to the aromato by a methylene group. A reaction with alcoholates, such as for example a phenolate, benzilate, methanolate, ethanolate, propanolate or isopropanolate results in a polymer in which a substitution occurred in more than 75% of the chloromethylene groups. The following polysulfone with lipophilic side groups is obtained: formula (IIB) wherein R ** for example represents an alkyl or aryl functional group.

The functional groups X '' and X '' 'may be introduced, unless they are not present in the monomers, in the polymer by the following reaction: formula (I1D) In addition to an ester group, several other substituents can be introduced, by first proceeding a single or double deprotonization by means of a strong base, for example n-BuLi or tert-BuLi and by subsequently adding an electrophile. In the exemplary case mentioned above, carbon dioxide was added for the introduction of the ester group and the carbonic acid group obtained was esterified during another step.

A combination according to the invention of a polysulfone with lipophilic functional groups and a polysulfone with lipophobic functional groups is achieved, for example, by the use of polysulfone according to formula (IIB) together with polysulfone according to formula (IIC). The ratio of the amounts between the two polysulfones can vary from 98%: 2% to 2%: 98%.

Preferred relationships are 10% to 90%, 15% to 85%, 22% to 78% and 27% to 73%, 36% to 64%, 43% to 57% and 50% to 50%. These percentage values are applied for any combination of hydrophilic and hydrophobic polysulfones and are not limited to the aforementioned mixture.

An example of a polysulfone with hydrophilic and hydrophobic functional groups within a molecule can be obtained for example by only incomplete esterification of the polysulfone according to the formula (IIC) and thus, hydrophilic groups carboxylates and hydrophobic ester groups are present within a molecule. The molar ratio (number) between carboxylate groups and ester groups can be 5%: 95% to 95%: 5%. These percentage values apply for any combination of hydrophilic and hydrophobic groups and are not limited to those mentioned above.

It is assumed that by means of this combination according to the invention hydrophilic groups, or, respectively, polymers with hydrophobic groups, or, respectively, polymers, amorphous polymer layers are constructed on the medical product. It is very important that the layers of polymer composed of polysulfone are not crystalline or mainly crystalline, as crystallinity leads to rigid layers that begin to break and separate. Flexible polysulfone coatings that serve as a barrier layer are only achieved with amorphous or mostly amorphous polysulfone layers.

Of course it is also possible to apply monomers that are still correspondingly substituted to obtain the desired substitution sample after the polymerization. The corresponding polymers then result in the known manner according to the following reaction scheme: where L and L 'represent for example the following groups independently of one another': -S02-, -C (CH3) 2-, -C (Ph) 2- or -0-. L and L 'may thus have the meanings of the corresponding groups in formulas (I) to (XV). Such nucleophilic substitution reactions are known to one skilled in the art, which are illustrated in exemplary manner by the above scheme.

As already mentioned, it is especially preferred if the polymers have hydrophilic and hydrophobic properties, on the one hand inside a polymer and on the other hand by using at least one hydrophilic polymer in combination with at least one hydrophobic polymer. It is thus preferred if, for example, X and Y 'have hydrophilic substituents and X' 'and X' '' have hydrophobic substitutes, or vice versa.

Hydrophilic substituents can be used: -OH, -CHO, -COOH, -COO ", -CONH2, -NH2 / -N + (CH3) 4, -NHCH3, -S03H, -S0 ~, -NH-CO-NH2, -NH-CS-NH2, -NH-C (= NH) -NH2, -0 -CO-NH2 and particularly protonated amino groups.

As hydrophobic substituents, the following may be used: -H, -OCH3, -OC2H5, -SCH3, -SC2H5, -N02, -F, -Cl, -Br, -I, -N3, -CN, -OCN, NCO, -SCN, -NCS, -COCH3, -COC2H5, -COCN, -COOCH3, -COOC2H5, -CONHC2H5, -CON (CH3) 2, -CON (C2H5) 2, -NHC2H5, -N (CH3) 2, -N (C2H5) 2, SOCH3 , -SOC2H5, -S02CH3, -S02C2H5, -S03CH3, -S03C2H5, -OCF3, -0-C00CH3, -0-C00C2H5, -NH-C0-0CH3, -NH-C0-0C2H5, -CH2F CHF2, -CF3, -CH2C1-CHC12, -CC13, -CH2Br -CHBr2, -CBr3, -CH2I CHI2, -CI3, -CH3, -C2H5, -C3H7, -CH (CH3) 2, -C4H9, CH2-CH (CH3) 2, -CHz-COOH, -CH (CH3) -C2H5, -C (CH3) 3.

In addition, cyclic polysulfones are preferred, which possess for example a structure as shown in formula (XVI): formula (XVI) The carboxyethylene group is not essential for the exemplary reaction shown above. Instead of the carboxyethylene and methyl substituents, any other substituents or also hydrogen may be present.

Polysulfones are characterized by their high resistance to aggressive chemicals, they are stable against hydrolysis and heat and have very good mechanical and tribological properties (no abrasion of the surface). As other particular properties as material for the application in the living organism, the high stability of dimension and the multiple sterilization can be accentuated. Polysulfones have been used for a long time as medical polymers. The main use is concentrated in hollow fibers, for example in blood dialyzers where the polysulfone fibers of the Fresenius company are leaders in the global market due to their good hemocompatibility and membrane-forming properties. There, the dialysis problem consists primarily of the need that during hemodialysis, an anticoagulant, usually heparin, has to be administered, the side effects of which multiply after a few years. During a five-hour treatment, approximately 75 liters of blood - which corresponds to approximately 15 times the amount of blood the patient possesses - flows through the dialyzer. Thus, it is clear that the membrane has to meet very high requirements in terms of hemocopathy.

Another extensive field is the use of polysulfone capillaries in ophthalmology and in the form of flat membranes in various medical technology aids.

It is preferred if at least one hydrophilic polymer is added to the polysulfone which is used for the biostable layer. There, the ratio of polysulfone to hydrophilic polymer can be from 50% by weight to 50% by weight up to 99.999% by weight to 0.001% by weight in the respective polysulfone layer.

Suitable hydrophilic polymers are: polyvinyl pyrrolidone, glycerin polyethylene glycol, propylene glycol, polyvinyl alcohol, polyhydroxyethyl methacrylates, polyacrylamide polyvalerylactones, poly-e-decalactones, polylactonic acid, polyglycolic acid, polylactides, • polyglucolides, copolymers of polylactides and polyglucides, poly-e-caprolactone, polyhydroxybutanoic acid, polyhydroxybutyrates, polyhydroxyvalerates, polyhydroxybutyrate-co-valerate, poly (1,4-dioxane-2, 3-diones), poly (1,3-dioxane-2-ones), poly-para-dioxanones, polyanhydrides such as polymaleic anhydrides, fibrin, polycyanoacrylates, polycaprolactonadimethylacrylates, poly-b-maleic acid, polycaprolactonebutylacrylates, multiblock polymers such as PEG and polybutylene terephthalate, polyvinylactones, polyglycolic acid trimethyl carbonates, polycaprolactone-glycolides, poly (g-ethylglutamate), poly (DTH-iminocarbonate) , poly (DTE-co-DT-carbonate), poly (bisphenol-A-iminocarbonate), polyorthoesters, trimethyl carbonates polyglycolic acid, polytrimethylcarbonates, polyiminocarbonates, poly (N-vinyl) -pyrrolidone, polyvinylalcohols, polyesteramides, glycolated polyesters, polyphosphoesters, polyphosphodies, poly [p-carboxyphenoxy] propane], polyhydroxypentanoic acid, polyanhydrides, polyethylene oxide-propolenoxide, soft polyurethanes, polyurethanes with amino acid residues in the main chain, polyether esters such as polyethyleneoxide, polyalkene oxalates, polyorthoesters as well as copolymers thereof, lipids, carrageen, fibrinogen, starch, collagen, protein-based polymers, polyamino acids, synthetic polyamino acids, zein, zein modified, polyhydroxyalkanoates, pectic acid, actinic acid, casein and unmodified and modified fibrin, carboxymethyl sulfate, albumin, harluronic acid chitosan and its derivatives, tives, chondroitin sulfate, dextran, b-cyclodextrins, copolymers with PEG and polypropylene glycol, gum arabic, guar, gelatin, collagen ene, collagen-N-hydroxysuccinimide, phospholipids, modifications and copolymers and / or mixtures of the above-mentioned substances, polyvinyl pyrrolidone, polyethylene glycol and glycerin are preferably used.

For example, to increase the viscosity in the production of the polysulfone solution, polyvinyl pyrrolidone (PVP) is added, which is soluble in the precipitating agent during the manufacture of the hollow fibers and thus, is removed again. The completed porous and hollow fiber still contains an average amount of 1 - 2% PVP. The addition of polyvinyl pyrrolidone is not only conducive to viscosity during production, that is, it increases the viscosity, but also a factor that co-determines the pore size of the polysulfone and thus is decisive for the permeability properties of the final product because that is dependent on pore size and particle size. Thus, the pore size and thus the permeability of the produced polysulfone can be regulated by the amount and molecular weight of the polyvinyl pyrrolidone added.

The biocompabible property and the good mechanical properties of the polysulfone and the possibility of regulating the pore size by the addition of polyvinyl pyrrolidone and / or other hydrophilic polymer and / or water (ethyl acetate) make this the ideal substrate for all pharmaceuticals which can be applied for the local targeted application, as well as for example in cardiology for the prevention of reoccurrence of blood vessel occlusion.

Simultaneously, the enclosed nitrogen provides the half-life of the active agent. The preferred amount of the added polymer is in the region of 0-50% by weight, more preferred 1-20% by weight, particularly preferably 2-10% by weight. The amount added is substantially independent of the desired elution rate of the active agent applied.

The medical products according to the invention have a surface that can be composed of any material.

This surface is preferably non-hemocompatible. In addition, this surface is preferably uncoated, especially not with polymers and / or organic macromolecules.

The biostable polysulfone layer can be bonded adhesively or covalently as well as partially adhesively and partially covalently to this surface. Covalent bonding is preferred. The polysulfone layer covers the surface of the medical product at least partially, but preferably completely. If the medical product is a stent, at least the surface that is exposed to the blood is coated with the polysulfone.

Preferably at least one layer containing at least one antiproliferative, anti-inflammatory, antiphlogistic and / or antithrombotic active agent can be deposited and / or incorporated on this first biostable polysulfone layer and / or on this first polysulfone layer. The at least one layer containing at least one antiproliferative, antiinflammatory, antiphlogistic and / or antithrombotic active agent may completely consist of one or more active agents or may be another biostable layer of polysulfone, in which the active agent or the agents assets are located. While hydrophobic active agents can be deposited in and / or on and / or under a biostable layer, hydrophilic active agents are preferably deposited on and / or under a biostable layer.

In this way, the medical products according to the invention can have surfaces that are coated with one, two, three or more layers, wherein one, two or three layers and particularly two layers are preferred.

The antiproliferative agent (s) active, anti-inflammatory (s), antiphlogistic (s) and / or antithrombotic (s) can be linked to the corresponding layer in an adhesive or covalent or partially adhesively or partially covalently, wherein the adhesive bond is preferred.

In case the surface coating has more biostable layers of polysulfone and / or hemocompatible layers and / or layers of active agent, each of these layers may consist of different polysulfones with different hydrophilic polymers and different amounts of hydrophilic polymers as well as different hemocompatible compounds or different active agents.

Furthermore, it is preferred if the medical product has a surface comprising a hemocompatible layer, which is deposited and / or incorporated on the lower first biostable layer of polysulfone. This hemocompatible layer can also form a second or third layer that rests directly or indirectly on the lowest biostable layer and / or on or under an active agent or a second biostable layer of polysulfone. In addition, it is preferred if the hemocompatible layer forms the lowest layer and if on this layer a layer of active agent, covered on its part by a biostable layer of polysulfone, or a biostable layer of polysulfone with an active agent or a Active agent combination is deposited on the lowest hemocompatible layer. This hemocompatible layer preferably consists of fully desulfated and N-reacetylated heparin, desulfated and N-reacetylated heparin, N-carboxymethylated, partially N-acetylated chitosan and / or mixtures of these substances. The hemocompatible layer may comprise, in addition to the above-mentioned substances, other hemocompatible organic substances, but preferably consists only of the abovementioned substances.

As for the medical products according to the invention, it is preferred if a single hemocompatible layer is present. It is also preferred if this single hemocompatible layer forms the outer or lower layer.

Furthermore, it is preferred if a layer completely covers the underlying surface or the underlying layer, wherein however a partial coating is also possible.

Furthermore, it is particularly preferred if the medical product according to the invention is a stent. This stent can be formed from any material and material mixtures. Metals and plastics such as for example medical stainless steel, titanium, chromium, vanadium, tungsten, molybdenum, gold and nitinol are preferred. The stent is preferably uncoated and / or not or only conditionally hemocompatible. In particular, the stent does not have a coating of organic material. Medical wires can be excluded as medical products.

These stents according to the invention are preferably provided with at least one biocompatible layer of biostable polysulfone covering the stent completely or incompletely with or without a defined proportion of a hydrophilic polymer and with at least one antiproliferative, anti-inflammatory, antiphlogistic and / or active agent. antithrombotic There, the active agent may be present in the matrix and / or cover the matrix as a second layer. In this context, it refers to the second layer as the layer that is deposited on the first layer, etc.

Another preferred embodiment of the stents according to the invention has a coating consisting of at least two layers of polysulfone. According to this double layer design, the first layer consists of a layer that is substantially completely covered by another biostable layer thereof or a different pore size. One or both layers contain at least one antiproliferative, anti-inflammatory, antiphlogistic and / or antithrombotic active agent. Also, combinations of active agent are used that support and / or complement each other in the effect they perform. Starting from this double layer design, it is possible to incorporate different active agents separately from each other in the layer which is respectively appropriate for the corresponding active agent, so that for example a hydrophobic active agent is located in the layer which is more hydrophilic or has other elution kinetics as another hydrophobic active agent, which is located in the more hydrophobic polymer layer, or vice versa. This offers an extensive field of possibilities to establish a reasonable different sequence in the availability of the active agents as well as to control the time and concentration of elution.

Another preferred embodiment of the stent according to the invention has a coating consisting of at least three layers. According to this triple layer design, the first layer consists of a layer that is covered substantially completely or incompletely by a second layer of combinations of pure active agent, which in turn is covered by a third biostable layer of polysulfone thereof or a different pore size. The polysulfone layers or do not contain active agent or one or two represent matrices for at least one antiproliferative, anti-inflammatory, antiphlogistic and / or antithrombotic active agent. Active agent combinations that mutually support and / or complement each other in their effect are also used.

This embodiment is particularly suitable for the use of hydrophilic active agents or combinations of active agents in the form of a pure layer of active agent. The superstable biostable polymer layer with a defined content of hydrophilic polymer serves for the controlled elution of the active agent. Combinations of active agent with at least one hydrophilic active agent result in different kinetics of elution.

As the top coating, the hydrophilic polymer, which can be admixed to the polysulfone, can also be used. which is also underlying.

The biocompatible coating of a stent provides the necessary hemocompatibility and the active agent (or combination of active agent), which is equally distributed on the total surface of the stent, results in the growth of cells on the surface of the stent, particularly smooth muscle cells and endothelial cells, proceeds in a controlled manner. Thus, rapid growth and proliferation of cells on the surface of the stent does not occur which could lead to restenosis, however the growth of cells on the surface of the stent is not completely prevented by a high concentration of medication, which entails, the risk of thrombosis.

Thus, the use of polysulfones ensures that the active agent or combination of active agent, adhesively bonded to the underlying layer and / or adhesively incorporated in the layer, is released continuously and in small dosages, so that cell growth on the surface of the stent is not prevented, but a proliferation. This combination of both effects confers on the stent according to the invention the ability to rapidly grow into the vessel wall and reduces the risk of restenosis, as well as the risk of thrombosis. The release of the active agent or of the active agents extends over a period of time of 1 to 24 months, preferably about 1 to 12 months after implantation, in particular preferably 1 to 3 months after implantation.

The release of the active agent can be adapted by regulating the pore size with the addition of the polyvinyl pyrrolidone or a similar hydrophilic polymer so that the individual characteristics of the active agent, the elution rate as well as the pharmacological kinetics and, in the In case of more than one active agent, also the elution sequence can meet the required requirements.

Antiproliferative substances, antiphlogistic agents as well as antithrombotic agents are used as active agents. Preferably, the macrolide, cytostatic and / or statin antibiotics are used as antiproliferative active agents. Applicable antiproliferative agents are sirolimus (rapamycin), everolimus, pimecrolimus, somatostatin, tacrolimus, roxithromycin, dunaimycin, ascomycin, bafilomycin, erythromycin, midecamycin, josamycin, concanamycin, clarithromycin, troleandomycin, folimycin, cerivastatin, simvastatin, lovastatin, fluvastatin, rosuvastatin. , atorvastatin, pravastatin, pitavastatin, vinblastine, vincristine, vindesine, vinorelbine, etoposide, teniposide, nimustine, carmustine, lomustine, cyclophosphamide, 4-hydroxycyclophosphamide, estramustine, melphalan, betulinic acid, camptothecin, lapacol, ß-lapacona, podophyllotoxin, betulin, trofosfamide, podophylic acid, 2-ethylhydrazide, ifosfamide, chlorambucil, bendamustine, dacarbazine, busulfan, procarbazine, treosulfan, temozolomide, thiotepa, daunorubicin, doxorubicin, aclarubicin, epirubicin, mitoxantrone, idarubicin, bleomycin, mitomycin, dactinomycin, methotrexate, fludarabine, fludarabine -5'-dihydrogen phosphate, mofebutazone, acemetacin, diclofenac, lonazolac, dapsone, o-carbamoylphenoxyacetic acid, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, chloroquine phosphate, penicillamine, hydroxychloroquine, auranofin, sodium aurothiomalate, oxaceprol, celecoxib, beta-sitosterin, ademetionine, mirtecaine, polidocanol, nonivamide, levomenthol, benzocaine, aescin, cladribine, mercaptopurine, thioguanine, cytarabine, fluorouracil, gemcitabine, capecitabine, docetaxel, carboplatin, cisplatin, oxaliplatin, amsacrine, irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin, aldesleukin , tretinoin, asparaginase, pegaspargase, anastrozole, exemestane, letrozole, formestane, aminoglutethimide, adriamycin, azithromycin, spiramycin, cepharanthin, smc 2w proliferation inhibitor, epothilone A and B, mitoxantrone, azathioprine, mycophenolatemofetil, c-mic-antisense, b- mic-antisense, selectin (cytokine antagonist), CEPT inhibitor, cadherins, cytokinin inhibitors, inhibitor -COX-2, NFkB, angiopeptin, ciprofloxacin, camptothecin, fluroblastine, monoclonal antibodies, which inhibit muscle cell proliferation, bFGF antagonists, probucol, prostaglandins, folic acid and its derivatives, vitamins of the B series, vitamin derivatives na D such as calcipotriol and tacalcitol, thymosin a-1, fumaric acid and its derivatives such as dimethyl fumarate, IL-lß inhibitor, colchicine, NO donors such as pentaerythritol tetranitrate and sindnoeimines, S-nitrosoderivatives, tamoxifen, staurosporine, β-estradiol , a-estradiol, estrone, estriol, ethinylestradiol, fosfestrol, medroxyprogesterone, estradiol cypionates, estradiol benzoates, tranilast, kamebakaurin and other terpenoids, which are applied in cancer therapy, verapamil, tyrosine kinase inhibitors (tyrphostins), Cyclosporin A, paclitaxel and its derivatives (6-a-hydroxy-paclitaxel, baccatin, taxotere and others), synthetically produced as well as native sources obtained from macrocilic carbon superoxide oligomers (MCS) and derivatives thereof, molgramostim ( rhuGM-CSF), peginterferone a-2b, lenograstim (r-HuG-CSF), filgrastim, macrogol, dacarbazine, basiliximab, daclizumab, ellipticine, D-24851 (Calbiochem), colcemid, cit ocalasin AE, indanocin, nocodazole, S 100 protein, PI-88, melanocyte stimulating hormone (a-MSH), bacitracin, vitronectin receptor antagonists, azelastine, guanidyl cyclase stimulator tissue inhibitor of metal proteinase 1 and 2, free nucleic acids, nucleic acids incorporated in virus transmitters, DNA and RNA fragments, plasminogen activator inhibitor 1, plasminogen activator inhibitor 2, antisense oligonucleotides, VEGF inhibitors, called IGF-1. From the group of antibiotics in addition cefadroxil, cefazolin, cefaclor, cefotixina, tobramycin, gentamicin, are used. Positive influence on the postoperative phase also have penicillins such as' dicloxacillin, oxacillin, sulfonamides, metronidazole, antithrombotic drugs such as argatroban, aspirin, abciximab, synthetic antithrombin, bivalirudin, coumadin, enoxaparin, hemoparin (heparin desulfatad and N-reacetylated), activator of tissue plasminogen, platelet membrane receptor GpIIb / IIIa, factor Xa inhibitor, activated protein C, antibodies, heparin, hirudin, r-hirudin, PPACK, protamine, prourokinase, streptokinase, warfarin, urokinase, vasodilators such as dipiramidol, trapidil, nitroprussides, PDGF antagonists such as triazolopyrimidine and seraine, ACE inhibitors such as captopril, cilazapril, lisinopril, enalapril, losartan, thiol protease inhibitors, caspase inhibitors, apoptosis inhibitors, apoptosis regulators such as antisense oligonucleotides p65 NF-kB and Bcl-xL and prostacyclin, vapiprost, a, ß and? interferon, histamine antagonists, serotonin blockers, halofuginone, nifedipine, tocopherol, tranirast, molsidomine, tea polyphenols, epicatechin gallate, epigallocatechin gallate, Boswellic acids and derivatives thereof, leflunomide, anakinra, etanercept, sulfasalazine, etoposide, dicloxacillin, tetracycline , triamcinolone, mutamycin, procainmide, retinoic acid, quinidine, disopyramide, flecainide, propafenone, sotalol, amidorone. In addition, the active agents are steroids (hydrocortisone, betamethasone, dexamethasone), non-steroidal substances (NSAIDS) such as fenoprofen, ibuprofen, indomethacin, naproxen, phenylbutazone and others. Antiviral agents such as acyclovir, ganciclovir and zidovudine are also applicable. Different antifungals are used in this area. Examples are clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole, nystatin, terbinafine. Antiprozoal agents such as chloroquine, mefloquine, quinine are effective agents in equal measure, in addition to natural terpenoids such as hypocaesculin, barringtogenol-C21-angelato, 14-dehydroagrostistaquine, agroskerin, agrostistaquine, 17-hydroxyagrostistaquine, ovatodiolides, acid 4,7 -oxicyanoanisomeric, bacarinoides Bl, B2, B3, pellimoside, bruceanol A, B, C, bruceantinoside C, yadanziosides N and P, isodeoxielefantopina, tomenfantopina A and B, coronarin A, B, C and D, ursolic acid, hypatic acid A, zeorine, iso-iridogermanal, aytenfoliol, efusanthin A, excisanin A and B, longikaurin B, sculponeatin C, kamebaunin, leukamenin A and B, 13, 18-dehydro-6-a-senecioyloxyhaparrin, 1,11-dimethoxycantin-6-one , l-hydroxy-ll-methoxycantin-6-one, scopoletin, taxamairin A and B, regenylol, triptolide, in addition cimarin, apocimarin, aristolochic acid, anopterin, hydroxianopterin, anemonin, protanemonin, berberine, cheliburin chloride, cictoxin, sinoc oculina, btastatin A and B, cudraisoflavone A, curcumin, dihydronitidine, nitidine chloride, 12-β-hydroxypregnadien-3,20-dione, bilobol, ginkgol, ginkgolic acid, helenalin, indicin, indicin-N-oxide, lasiocarpine, inotodiol , glycoside A, podophyllotoxin, justicidin A and B, larreatin, maloterin, malotocromanol, isobutyrylmalotocromanol, macrucoside A, marcantin A, maytansin, licoridicin, margetine, pancratistatin, liriodenine, oxoushinsunin, aristolactam-All, bispartenolidine, periplocoside A, galakinoside, acid ursolic, deoxypyrospermine, psychorubin, ricin A, sanguinarine, manwu wheat acid, methylsorbifoline, sfateliacromen, stizophylline, mansonin, strelloside, akagerine, dihydrousambarensin, hydroxiusambarine, strichnopentamine, strichnophylline, usberna, usbarensin, berberine, liriodenine, oxoshinsunin, dafnoretin, lariciresinol, metoxilariciresinol, siringaresinol, umbeliferon, afromoson, acetilvismiona B, desacetylvimione A, vismiona A and B, additional natural terpenoids such as hypocaesculin, 1,4-dehydroagrostistaquine, natriuretic peptide type c (CNP) agroskerin, agrostistaquine, 17-hydroxyagrostistaquine, ovatodiolides, 4, 7-oxocycloanisomelic acid, yadanziosides N and P, isodeoxyelephantopine, tomenphantopin A and B, coronarin A, B, C and D, ursolic acid, hippatic acid A, zeorine, iso-iridoger anal, maytenfoliol, efusanthin A, excisanin A and B, longikaurin B, sculponeatin.

The active agents are used separately or combined in the same or different concentration. Especially preferred are the active agents which have, in addition to their antiproliferative effect, also immunosuppressive properties. Among such active agents are erythromycin, midecamycin, tacrolimus, sirolimus, paclitaxel and its derivatives and josamycin as well as triazolopyrimidines (trapidil®), D-24851, a- 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, a combination of various substances that act in an antiproliferative manner or of antiproliferative active agents with immunosuppressive active agents is preferred.

Especially preferably, the active agents are selected from a group comprising paclitaxel and its derivatives β-estradiol, simvastatin, PI-88 (sulphated oligosaccharide, Progen Ind.), Macrocyclic carbon suboxide (MCS) and its derivatives, trapidil®, N - (pyridin-4-yl) - [1-4- (4-chlorobenzyl) -indol-3-yl] -glyoxylamide (D-24851), and tacrolimus.

The active agent is preferably contained in a pharmaceutically active concentration of 0.001 - 20 mg per cm2 of stent surface, more preferred 0.005 - 15 and especially preferred 0.01 - 10 mg per cm2 of stent surface. Other active agents can be contained in a similar concentration in the same or in other layers. Also preferred is an embodiment that contains two different active agents in the same layer or in different layers. Furthermore, an embodiment having a pure active agent layer as the top layer is preferred.

The amounts of polymer deposited per medical product and especially per stent per layer are preferably in the region between 0.01 mg / cm2 to 3 mg / cm2 of surface, more preferably 0.20 mg to 1 mg and especially preferably 0.2 mg to 0.5 mg / cm2 of surface.

In addition, embodiments containing an active agent in two layers are preferred. This can also be two different active agents. If the same active agent is contained in two layers, it is preferred that the two layers have a different concentration of active agent. It is further preferred that the lower layer has a lower concentration of active agent than the upper layer.

The stents according to the invention can be manufactured by a method for the biocompatible coating of stents whose base is the following principle: to. Provide a stent, and b. Depositing at least one biostable layer of polysulfone with or without at least one hydrophilic polymer, and c. Deposit and / or incorporate at least one antiproliferative, anti-inflammatory, antiphlogistic and / or antithrombotic active agent on and / or in the biostable layer, or b '. Depositing at least one biostable layer of polysulfone with or without the at least one hydrophilic polymer together with at least one antiproliferative, anti-inflammatory, antiphlogistic or antithrombotic active agent.

After step b ', preferably also step c' may follow: c 'depositing at least one antiproliferative, anti-inflammatory, antiphlogistic and / or antithrombotic active agent on the biostable polymer layer.

After steps a, b and c or steps a, b 'or steps a, b' and e ', you can still follow another step d: d. Deposit at least a second biostable layer of polysulfone.

This second biostable layer of polysulfone may consist on the one hand of a polysulfone different from the first underlying layer and may on the other hand contain a different amount of the same or another hydrophilic polymer. It is preferred if this second biostable layer of polysulfone contains at least one active agent. In particular, embodiments are preferred, with a biostable layer of polysulfone with or without a hydrophilic polymer as the outer layer.

The antiproliferative, anti-inflammatory, antiphlogistic and / or antithrombotic active agent is preferably selected from the group listed above.

In addition, embodiments having a hemocompatible layer are preferred. This hemocompatible layer consists of the above mentioned substances, especially of fully desulfated and N-reacetylated heparin, desulfated and N-reacetylated heparin, N-carboxymethyllated, partially N-acetylated chitosan and / or in mixtures of these substances and is directly or indirectly deposited on the lowest layer. This hemocompatible layer can be placed between two other layers as well as forming the upper layer.

Embodiments with two hemocompatible layers are also possible, in which however only one hemocompatible layer is preferred. The hemocompatible layer can be bonded adhesively as well as covalently or partially adhesively and partially covalently to the underlying layer.

The respective layers are preferably deposited by the dipping or spraying method. In addition, the individual layers are preferably not deposited on the underlying layer until it is dry.

Preferred is a method consisting of two steps a) and b ').

The coating principle offers a wide field of variation with respect to the requirements for the active agent and also the properties of the applied polysulfone, so that different coating variants result that can also be combined with each other.

The possibility of influencing the properties of the polysulfone by the amount and molecular weight of the polymer added as PVP, represents with respect to the applied active agents an extensive field of adaptability of the compounds to an adjusted system.

Other layers of polysulfone without addition of PVP and / or with equal or different content of PVP with or without active agent are possible. In the same manner, a layer, which is preferably covalently bound directly to the surface, of completely N-deacetylated and reacetylated heparin, desulfated and N-reacetylated heparin, N-carboxymethylated and / or partially N-acetylated qaitosan and / or mixtures of these substances can be deposited whose atomic-generating properties can provide the mask of the foreign underlying surface in case of injury of the surface of the layer or of the biostable superjacent layer (s), as is the case, for example, preliminarily to or similarly during implantation by mechanical destruction of the coating. This inert layer can be applied, if necessary, optionally covalently or adhesively between two layers as well as and / or as top layer.

Variant A: a.) Provide an uncoated stent, b.) Deposit a biostable layer of polysulfone with or without a hydrophilic polymer, c.) Deposit an active agent or combination of active agent in and / or on the polysulfone layer by dipping or spraying, d.) Substantially and / or incompletely coating the biostable layer of polysulfone containing the active agent with at least one other biostable layer of polysulfone which corresponds to the first layer or which is different from this first layer as to its content of hydrophilic polymer and thus in terms of pore size e.) Depositing the same or another active agent or combination of active agent in and / or on the biostable outer layer, so that different active agents and / or combinations of active agents can be deposited on the stent in a manner pointed out separately from each other by means of both layers, as well as in case of different pore size of the polymer, a charge Different with active agent can be performed as well as a different speed of elution thereof and / or other active agent is possible.

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

Medical products are preferred with two biostable layers of polysulfone, which may contain different hydrophilic polymers at different concentrations.

The deposition of all the provided polymer layers can be performed prior to diffusion of the active agent into these layers, when the active agent or combinations of active agent must be contained in both layers.

Additionally, another layer of an appropriate polysulfone or even pure hydrophilic polymer can be deposited as a barrier and topcoat.

Variant B a.) Provide an uncoated stent, b.) Deposit a biostable layer of polysulfone with or without a hydrophilic polymer, c.) Substantially and / or incompletely coat the biostable polysulfone layer with at least one antiproliferative active agent, anti-inflammatory, antiphlogistic and / or antithrombotic and / or active agent combination by the spraying method, d.) Substantially and / or incompletely coating the active agent layer with at least one other biostable layer of polysulfone, corresponding to the first or layer is different from this first layer in terms of its hydrophilic polymer content and thus, in terms of pore size, with or without active agent and / or combination of active agent, and / or d '..) Coating substantially completely and or incompletely the active agent layer with a hydrophilic polymer as top coating with or without active agent and / or combination of active agent.

By means of these variants, it is possible to adapt the coating material to the active agent and also the temporarily released amount of active agent to the requirements of the corresponding segment.

In multi-layer systems, the layer that has been newly deposited substantially covers the underlying layer completely. "Substantially" means at 50-100%, preferably 70-100%, more preferably 80-100%, more preferably up to more than 98%.

Objecto of the invention are also the medical products that can be manufactured according to the above-mentioned methods and particularly stents.

The stents according to the invention solve both the problem of watery thrombosis and the problem of neointimal hyperplasia after a stent implantation. Furthermore, the stents according to the invention, as a single-layer or multi-layer system, are particularly suitable for the continuous release of one or more antiproliferative agent (s), anti-inflammatory (s), antiphlogistic agent (s). ), antithrombotic (s) and / or immunosuppressant (s) due to its coating. Because of this ability to continuously release the active agent in a targeted manner in a required amount, the stents coated according to the invention almost completely prevent the risk of restenosis.

The prevention or reduction of restenosis is effected on the one hand by suppression of cellular reactions during the first days and weeks after implantation by means of the active agents chosen and combinations of. active agents and on the other hand by providing a biocompatible surface, so that with the decrease in the influence of the active agent, does not start any reaction on the foreign surface present, which would likewise lead to a reoccurrence of occlusion of long blood vessels term.

Description of the figures Figure 1: Elution diagram of macrocyclic carbon suboxide (MCS, macrocyclic carbon suboxide) in a triple layer system with polysulfone as the base coat, the active agent as the middle layer and a polysulfone coating that completely covers the middle layer of the agent active with a proportion of 0.04% polyvinyl pyrrolidone.

Figure 2: Paclitaxel elution diagram of a polysulfone matrix with an amount of 9.1% polvinyl pyrrolidone.

Figure 3: Elution diagram of simvastatin of pure polysulfone matrix without hydrophilic polymer ratio.

Figure 4: Elution diagram of ß-estradiol with a proportion of 15% by weight of the pure polysulfone matrix without hydrophilic polymer content.

Figure 5: Trapidil® elution diagram of a polysulfone matrix with 4.5% polyvinyl pyrrolidone.

Figure 6: Elution diagram of trapidil® with a quantity of 50% of the pure polysulfone matrix.

Figure 7: photomicrography of the vessel segments 4 weeks after implantation in the pig. Figure A shows an enlarged section of the stent matrix. Figure B shows a cross section of the vessel segment- with the stent being coated with polysulfone and loaded with MCS (macrocyclic carbon suboxide, macrocyclic carbon suboxide) at a higher concentration.

Examples Example 1 Coating of stents with polyethersulfone Sprinkler solution a. PS solution: 176 mg of PS (polyethersulfone, Udel®, available from Solvay) are rocked and filled to 20 g with chloroform - 0.88% PS Example 2 Coat stents with polyethersulfone (base coat) and polyethersulfone with 0.04% PVP or 0.08% PVP as top coat Rolling solutions a. Polysulfone solution: 17.6 mg of PS are rocked and filled to 2 g with chloroform. ^ 0.88% of PS b. Polysulfone / PVP solution 25.2 mg of PS and 1.2 mg of PVP are rocked and filled to 3 g with chloroform. - »0.84% of PS, 0.04% of PVP b '. Polysulfone / PVP solution 24 mg of PS and 2.4 mg of PVP are balanced and filled into 3 g with chloroform - > 0.80% of PS, 0.08% of PVP Spray coating: The stents that have been balanced are coated by spraying with the spray solutions in the order indicated with a.) 0.5 ml and b.) 0.85 ml. There, after each spraying process, a lapse of time of at least 6 hours passes until the next layer is deposited. After drying out at night in the clean room, it sways again.

Example 3 Manufacturing of stents with MCS and polyethersulfone in the three layer system according to variant B Sprinkler solutions a) Polyethersulfone solution: (1st layer: base coat): 70.4 mg of PS are rocked and filled to 8 g with chloroform. - 0.88% of PS b) MCS solution (2nd layer: medium coating): 39.6 mg of MCS are rocked and filled to 18 g with 20% ethanol in water. - 0.22% of MCS c) polyethersulfon / PVP solution (3rd layer: top coating) 100.8 mg of PS and 4.8 mg of polyvinyl pyrrolidone are rocked and filled to 12 g with chloroform. - > 0.84% of PS, 0.04% of PVP Spraying Revista: Stainless steel non-expanded stents swing and are spray-coated after cleaning. The stents are sprayed with the corresponding amount of the respective spray solution with a) 0.5 ml; b.) 1.5 ml and c.) 0.85 ml in the order indicated. There, after each layer a lapse of time of at least 6 hours passes until the next layer is sprayed. After drying at room temperature at night, it swings by nine. The mean value of the content of the active agent on the stents is 153 ± 9 μg.

Example 4 Determination of elution kinetics of MCS from polyethersulfone with 4.5% PVP A stent is placed in each of vessels with pressure layer, is mixed with 2 ml of PBS buffer, closed with parafilm and incubated for defined periods of time in the drying cabinet at 37 ° C. After having passed the chosen time lapse, the excess is depiped and its UV absorption at 207 nm is measured. The respective stent is mixed again with 2 ml of PBS and incubated again at 37 ° C. This operation is repeated several times.

Example 5 Coat stents with polysulfone matrix that is loaded with simvastatin Rolling solutions: a. PS / simvastatin solution: 26.4 mg of PS and 8.8 mg of simvastatin are rocked and filled to 4 g with chloroform. - 0.66% of PS, 0.22% of simvastatin b. PS / simvastatin / PVP solution 24.8 mg of PS, 8.8 mg of simvastatin and 1.6 mg of PVP are rocked and filled to 4 g with chloroform. - > 0.62% of PS, 0.22% of Simvastatin, 0.04% of PVP Sten solution before after mass dough sprayer coating coating simvastatin coating Example 6 Coat stents with a polysulfone matrix that is loaded with simvastatin with a high proportion of PVP.

Sprinkler solution: a. PS / simvastatin / PVP solution: 23.2 mg of PS, 8.8 mg of simvastatin and 3.2 mg of PVP are rocked and filled to 4 g with chloroform. - > 0.58% of PS, 0.22% of simvastatin, 0.08% of PVP Example 7 Coat stents with polysulfone matrix that is loaded with paclitaxel Rolling solutions: a. PS / paclitaxel solution: 13.2 mg of PS and 4.4 mg of paclitaxel are rocked and filled to 2 g with chloroform. - 0.66% of PS, 0.22% of paclitaxel b. PS / PVP / paclitaxel solution 11.6 mg of PS, 1.6 mg of PVP and 4.4 mg of paclitaxel are rocked and filled to 2 g with chloroform. - > 0.58% of PS, 0.08% of PVP, 0.22% of paclitaxel Example 8 Coat stents with 17-β-estradiol on a polysulfone matrix Rolling solutions: a. PS / 25% solution 17-ß-estradiol: 46.2 mg of PS and 15.4 mg of 17-ß-estradiol are rocked and filled to 7 g with chloroform. - 0.66% of PS, 0.22% of 17-ß-estradiol b. PS / 20% solution 17-ß-estradiol: 28.2 mg of PS and 7 mg of 17-ß-estradiol are rocked and filled to 4 g with chloroform. - 0.704% PS, 0.176% 17-ß-estradiol c. PS / 15% solution 17-ß-estradiol: 29.9 mg of PS and 5.3 mg of 17-ß-estradiol are rocked and filled to 4 g with chloroform. - 0.748% of PS, 0.132% of 17-ß-estradiol Example 9 Coat stents with a polysulfone matrix containing triazolopyrimidine (trapidil®) Spray solution: PS / trapidil® solution: 19.8 mg of PS and 6.6 mg of trapidil® are balanced and filled to 3 g with chloroform - 0.66% PS, 0.22% trapidil® Example 10 In vivo examination of stents with polyethersulfone as matrix with and without macrocyclic suboxide.

In the coronary arteries of 13 domestic pigs of different sex weighing 20-25 kg, stents covered with polyethersulfone were implanted. Three groups of stents were distinguished. One group contained a high dosage of paclitaxel, the second contained a low dosage of paclitaxel and the last group was the pure matrix stent without active agent additive. After four weeks, the stents were removed and analyzed for inflammation reactions (peri-strut) and neointima formation.

Histomorphometric evaluation after 4 weeks of implantation time Coating Number of stenosis thickness Degree of intima [mm] [%] injury All the stents analyzed independently of the coating showed only minimal inflammations around the struts and in the adventitia. The highest average thickness of the intima of the stents with the low loading of active agent could be attributed to the strongest overexpansion of the vessel during implantation. The pure matrix stent does not show any noticeable problem attributed to the polymer, which speaks in favor of its haemocomatibility and appropriateness as an active agent substrate.

Example 11 In vivo examination of stents with polyethersulfone as a matrix and without paclitaxel Analogously to the previous example 10, stents that had been covered with polyethersulfon were compared with stents that had been covered with polyethersulfone and loaded with paclitaxel: Histomorphic evaluation after 4 weeks of implantation time Coating Amount Stenosis thickness Degree of intima [mm] '[%] injury The results of this study also show the benefit of the polysulfone coating.

Example 12 Preparation of the polysulfone according to formula (IIA). The polysulfone (IIA) was prepared according to the instructions of E. Avram et al. J. Macromol Sci. Puré Appl. Chem., 1997, A34, 1701. 3 molar equivalents of benzyl alcohol are dissolved in toluene and deprotonated with sodium. 1 molar equivalent of polysulfon (IIA) is added and subsequently, the reaction mixture is heated to boiling temperature. The reaction product is obtained in a yield of 22%.

Example 13 Preparation of polysulfone according to formula (IIC). The polysulfone (IIC) was prepared according to the instructions of M. D. Guiver et al.Brit. Polym. L. 1990, 23, 29. 1 g of the obtained polysulfone (IIC) was esterified by the use of ortho ethyl acetate while toluene was applied as a solvent and the volatile reaction products were removed from the reaction equilibrium by distillation. 40% of the carboxylate groups were converted to ethyl ester groups. According to example 7, this polymer was deposited together with paclitaxel on a stent. The stent shows good hemocompatibility and an amorphous polysulfone coating, which was appropriate for the controlled release of paclitaxel.

Example 14 1 g of the polysulfone prepared according to example 12 is mixed with 200 mg of the polysulfone according to formula (IIC) and deposited according to example 7 together with the active agent paclitaxel on a stent. The coated stent has a good hemocompatibility and an amorphous coating, which was appropriate for the controlled release of paclitaxel.

Example 15 Introduction of chlorosulfon groups onto polysulfone. 2.4 g of polysulfone are dissolved in 700 ml of chloroform and cooled to -20 ° C. Subsequently, 23.3 ml of chlorosulfonic acid are added slowly dropwise. As the reaction is strongly exothermic, the reaction vessel is cooled in the ice bath. After addition of the chlorosulfonic acid, the solution is heated to room temperature under stirring. After 30 minutes, the polymer is precipitated in ethanol and then rinsed with deionized water. To completely remove the chlorosulfonic acid, it is extracted again for 10 minutes in deionized water.

Example 16 De-chlorination S-alkoxy (S-alkoxy-de-chlorination) 10 g of ethanol are dissolved in 100 ml of water and mixed with 2-3 droplets of methyl red in acetone. This solution is placed on 5 g of fine-grained chlorosulfonated polysulfone. The solution is mixed dropwise with 5N KOH until the color change from yellow to red occurs. Subsequently, the container is closed and shaken well. Caustic potash is added and shaken until the color change no longer occurs. The polysulfone ester formed is aspirated, rinsed with water and recrystallized for purification.

Example 17 De-chlorination S-alkoxy (S-alkoxy-de-chlorination) 10 g of dry ethanol are mixed with 60 ml of pyridine. This solution is added under ice cooling to 40 g of finely pulverized chlorosulfonated polysulfon. Subsequently, it is agitated under the exclusion of humidity at night at room temperature. Subsequently, the suspension is poured into ice water and acidified carefully with concentrated hydrochloric acid. The washing is carried out with an aqueous solution of hydrogen carbonate. After filtration, the esterified polysulfone can be recrystallized.

Example 18 Coating with a mixture of polysulfone and polysulfone according to formula (IIC). 24 mg of PS and 2.4 mg of polysulfone according to the formula (IIC) are baled and filled to 3 g with chloroform. - 0.80% PS, 0.08% PVP A stent is coated according to example 7 with this mixture by the spraying method.

Claims (28)

Claims

1. Medical product, characterized in that its surface is at least partially coated with at least one biostable layer of polysulfone.

2. Medical product according to claim 1, characterized in that the polysulfone is selected from the group comprising the following: polyethersulfone, substituted polyethersulfon, polyphenylsulfon, substituted polyphenylsulfon, polysulfone block copolymers, perfluorinated polysulfone block polymers, semifluorinated polysulfone block polymers, substituted polysulfon block copolymers and / or mixtures of the above-mentioned polymers.

3. Medical product according to claim 1 or 2, characterized in that the at least one biostable layer of polysulfone contains at least one hydrophilic polymer.

4. Medical product according to claim 3, characterized in that the polysulfone containing the at least one hydrophilic polymer is present in a mixture ratio of 50% by weight: 50% by weight up to 99.999% by weight: 0.001% by weight .

5. Medical product according to claim 3 or 4, characterized in that the hydrophilic polymer is selected from the group comprising the following: polyvinyl pyrrolidone, glycerin polyethylene glycol, polypropylene glycol, polyvinyl alcohol, polyhydroxyethyl methacrylates, polyacrylamide polyvalerylactones, poly-decalactones, polylactonic acid , polyglycolic acid, polylactides, polyglucides, copolymers of polylactides and polyglycolides, poly-caprolactone, polyhydroxybutanoic acid, polyhydroxybutyrates, polyhydroxyvalerate, polyhydroxybutyrate-co-valerate, poly (1,4-dioxane-2, 3-diones), poly (1,3-dioxane-2-ones), poly-para-dioxanones, polyanhydrides such as polymaleic anhydrides, fibrin, polycyanoacrylates, polycaprolactonadimethylacrylates, poly-b-maleic acid, polycaprolactone butylacrylates, multi-block polymers such as, for example, oligo-caprolactone-diols and oligodioxanonadiols, polyether ester multiblock polymers such as PEG and polybutylene terephthalate, polipivotolactones, polyglycolic acid trimethyl carbonates, polycaprolactone-glucolides, polyg-ethylglutamate, poly (DTH-iminocarbonate), poly (DTE-co-DT-carbonate), poly (bisphenol-A-iminocarbonate), polyorthoesters, polyglycolic acid trimethylcarbonates, polytrimethylcarbonates, polyiminocarbonates, poly (N-vinyl) -pyrrolidone, polyvinylalcohols, polyesteramides, glycolated polyesters, polyphosphoesters, polyphosphozenes, poly [p-carboxyphenoxy] propane], polyhydroxypentanoic acid, polyanhydrides, polyethylene oxide-propolenoxide, polyurethanes soft, polyurethanes with amino acid residues in the main chain, polyether esters such as polyethylene oxide, polyalkene oxalates, polyorthoesters as well as copolymers thereof, lipids, carrageen, fibrinogen, starch, collagen, protein-based polymers, polyamino acids, polyamino acids synthetics, zein, modified zein, polyhydroxyalkanoates, pec tactic, actinic acid, casein and modified unmodified fibrin, carboxymethyl sulfate, albumin, harluronic acid chitosan and its derivatives, chondroitin sulfate, dextran, b-cyclodextrins, copolymers with PEG and polypropylene glycol, gum arabic, guar, gelatin, collagen, collagen-N -hydroxysuccinimide, lipids, phospholipids, modifications and copolymers and / or mixtures of the above-mentioned substances.

6. Medical product according to claim 5, characterized in that the hydrophilic polymer is selected from the group comprising: polyvinyl pyrrolidone, polyethylene glycol, polypropylene glycol and / or glycerin.

7. Medical product according to any one of the preceding claims, characterized in that the pore size of the polysulfone coating is determined by the ratio of the polysulfone mixture to the at least one hydrophilic polymer.

8. Medical product according to any one of the preceding claims, characterized in that under and / or on the at least one biostable layer of polysulfone with or without the at least one hydrophilic polymer is present at least one active agent antiproliferative, anti-inflammatory, antiphlogistic and / or antithrombotic.

9. Medical product according to any one of the preceding claims, characterized in that the biostable layer is bonded adhesively or covalently on the surface of the medical product.

10. Medical product according to any one of the preceding claims, characterized in that the coating of the surface of the medical product consists of one, two, three or more layers.

11. Medical product according to any one of the preceding claims, characterized in that under and / or on the at least one biostable layer of polysulfone with or without the at least one hydrophilic polymer there is present at least one layer of fully desulfated heparin and N -tetracetylated, desulfated and N-reacetylated heparin, N-carboxymethylated and / or partially N-acetylated chitosan and / or mixtures of these substances.

12. Medical product according to any one of the preceding claims, characterized in that in multilayer systems the at least two biostable layers are different or are not different as regards the proportion of the hydrophilic polymer.

13. medical product according to any one of the preceding claims, characterized in that in multilayer systems the at least one layer of polysulfone with and / or without addition of at least • a hydrophilic polymer covering the biostable layer polysulfone at least partially with at least one layer of at least one biodegradable polymer.

14. medical product according to any one of the preceding claims, characterized in that the at least one active agent antiproliferative, antiinflammatory, antiphlogistic and / or antithrombotic is selected from the group comprising the following: sirolimus (rapamycin), everolimus, somatostatin, tacrolimus, roxithromycin, dunaimycin, ascomycin, baphyromycin, 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, natriuretic peptide type c (CNP), 4-hydroxycyclophosphamide, estramustine, melphalan, ifosfamide, trofosfamide, chlorambucil, bendamustine, dacarbazine, busulfan, procarbazine, treosulfan, temozolomide, thiotepa, daunorubicin, doxorubicin, aclarubicin, epirubicin, mitoxantrone, idarubi Cina, bleomycin, mitomycin, dactinomycin, methotrexate, fludarabine, fludarabine-5 '-dihydrogen phosphate, cladribine, mercaptopurine, thioguanine, cytarabine, fluorouracil, gemcitabine, capecitabine, docetaxel, carboplatin, cisplatin, cryphoticine, anginex, oxaliplatin, amsacrine, irinotecan, topotecan , hydroxycarbamide, miltefosine, pentostatin, aldesleukin, tretinoin, asparaginase, pegaspargase, anastrozole, exemestane, letrozole, formestane, aminoglutethimide, adriamycin, azithromycin, spiramycin, cefarantine, smc 2w proliferation inhibitor, epothilone A and B, mitoxantrone, azathioprine, mycophenolate mofetil, c-mic-antisense, b-mic-antisense, betulinic acid, camptothecin, lapachol, beta-lapachone, podophyllotoxin, betulin, podofílico, 2-ethylhydrazide, molgramostim (rhuGM-CSF), peginterferona-2b, lenograstim (r-HuG -CSF), filgrastim, macrogol, anginex, a-uretic peptides, dacarbazine, basiliximab, daclizumab selectin (cytokine antagonist), cryptophycins, inhibitor CEPT, cadherins, cytokinin inhibitors, COX-2 inhibitor, AE-941 (Neovastat®) NFkB, angiopeptin, ciprofloxacin, camptothecin, fluroblastina, monoclonal antibodies, which inhibit the muscle cell proliferation, bFGF antagonists, probucol, prostaglandins, Ac -YVAD-CMK, 1, 11-dimetoxicantin-ß-one, 1-hydroxy-ll-metoxicantin-6-one, scopoletin, colchicine, NO donors such as pentaerythritol tetranitrate and sindnoeiminas, S-nitrosoderivados, tamoxifen, staurosporine, ß -estradiol, a-estradiol, estriol, estrone, ethinylestradiol, fosfestrol, medroxyprogesterone, estradiol cypionates, estradiol benzoates, tranilast, kamebakaurin and other terpenoids, which are applied in cancer therapy, verapamil, tyrosine kinase inhibitors (tyrphostins), cycloscoporin A, paclitaxel and derivatives thereof such as 6-a-hydroxy-paclitaxel, baccatin, taxotere, and others, synthetically and from native sources obtained from macrocyclic carbon superoxide oligomers (MCS) and derivatives thereof, mofebutazone, acemetacin, diclofenac, lonazolac, dapsone, acid or carbamoylphenoxyacetic acid, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, chloroquine phosphate, penicillamine, hydroxychloroquine, auranofin, sodium aurothiomalate, oxaceprol, celecoxib, beta-sitosterin, ademetionin, mirtecaine, polidocanol, nonivamide, levomenthol, benzocaine, aescin, ellipticine , D-24851 (Calbiochem), colcemide, cytochalasin AE, indanocin, nocadazol, S100 protein, bacitracin, vitronec receptor antagonists tub, azelastine, guanidyl cyclase stimulator tissue inhibitor of metal proteinase 1 and 2, free nucleic acids, nucleic acids incorporated in virus transmitters, DNA and RNA fragments, plasminogen activator inhibitor 1, plasminogen activator inhibitor 2 , antisense oligonucleotides, VEGF inhibitors, IGF-1, active agents from the group of antibiotics such as cefadroxil, cefazolin, cefaclor, cefotixina, tobramycin, gentamicin, penicillins such as dicloxacillin, oxacillin, sulfonamides, metronidazole, antithrombotics such as argatroban, - aspirin, abciximab, synthetic antithrombin hirudin-r, bivalirudin, coumadin, enoxaparin, desulfated and N-reacetilatada heparin (hemoparina®), tissue plasminogen activator, platelet membrane receptor GPIIb / IIIa, factor Xa inhibitor, heparin, hirudin, , PPACK, protamine, prourokinase, streptokinase, warfarin, urokinase, vasodilators such as dipiramidol, triazolopyrimidine (Trapidil®) nitroprusiddos, PDGF antagonists such as triazolopyrimidine and seramina, ACE inhibitors such as captopril, cilazapril, lisinopril, enalapril, losartan, thioprotease inhibitors prostacyclin, vapiprost alpha, beta and Y interferon, histamine antagonists, serotonin blockers, inhibitors of apotosis, apoptosis regulators such as p65, antisense oligonucleotides NF-kB or Bcl-xL, halofuginone, nifedipine, tocopherol, tranirast, molsidomine, polyphenols tea, epicatechin gallate, epigallocatechin gallate, boswellic acids and derivatives thereof, leflunomide, anakinra , etanercept, sulfasalazine, etoposide, dicloxacillin, tetracycline, triamcinolone, mutamycin, procainmida, retinoic acid, quinidine, disopyramide, flecainide, propafenone, sotalol, -amidorona, the synthetically obtained steroids such as natural and briofilina A, inotodiol, maquirosida A, galakinosida , mansonine, strelloside, hydrocortisone, betamethasone, dexamethasone, substances n or steroidal (NSAIDS) such as fenoprofen, ibuprofen, indomethacin, naproxen, phenylbutazone and other antiviral agents such as acyclovir, ganciclovir, zidovudine and antifungals such as clotrimazole, flucytosine, griseofulvin, ketoconazole, miconazole, nystatin, terbinafine, antiprozoal agents such as chloroquine , mefloquine, quinine, moreover natural terpenoids such as hipocaesculina, barringtogenol-C21-angelate, 14-dehidroagrostistaquina, agroskerina, agrostistaquina, 17-hidroxiagrostistaquina, óvatodiolides, 4,7-oxicicloanisomélico acid, bacarinoides Bl, B2, B3 and B7, tubeimosida, bruceanol A, B, C, bruceantinoside C, yadanziosidas N and P, isodeoxielefantopina, tomenfantopina A and B, coronarina A, B, C and D, ursolic acid, hipática A, zeorina, iso-iridogermanal, maytenfoliol, efusanthin A, excisanina A and B, longikaurin B, sculponeatin C, kamebaunin, leukamenin A and B, 13, 18-dehydro-6- -senecioyloxyhaparrin, taxamairin A and B, regenylol, tript olida, besides cimarina, apocimarina, aristoloquico acid, anopterin, hydroxianopterin, anemonin, protanemonin, berberine, cheliburin chloride, cictoxin, sinococculin, blastatin A and B, cudraisoflavone A, curcumin, dihydronitidine, nitidine chloride, 12-ß-hydroxipregnadien-4, 16-diene-3.20 -dione, bilobol, ginkgol, ginkgolic acid, helenalin, indicin, indicin-N-oxide, lasiocarpine, inotodiol, glycoside la, podophyllotoxin, justicidin A and B, larreatin, maloterin, malotocromanol, isobutyrylmalotocromanol, maquiroside A, marcantin A, maytansin, licoridicina, margetina, pancratistatina-, liriodenina, bispartenolidina, oxoushinsunina, aristolactam-All, bispartenolidina, periplocosida A, galaquinoside, ursolic acid, deoxipsorospermina, psicorubina, ricina A, sanguinarina, wheat acid manwu, metilsorbifolina, sfateliacromen, stizofilina, mansonina, streblosida , akagerina, dihidrousambarensina, hidroxiusambarina, strichnopentamina,. strichnophylline, usambarine, usambarensin, berberine, liriodenine, oxoshinsunin, dafnoretin, lariciresinol, methoxylariciresinol, syringaresinol, umbeliferon, afromoson, acetilvismione B, desacetylvimione A, visiona A and B.

15. Medical product according to claim 11, characterized in that the at least one antiproliferative, anti-inflammatory, antiphlogistic and / or antithrombotic active agent is selected from the group comprising the following: paclitaxel and its derivatives, β-estradiol, simvastatin, PI-88 (Progen Ind. ), macrocyclic carbon suboxides (MCS) and their derivatives, trapidil®, N- (pyridine-4-yl) - [1-4- (4-chlorobenzyl) -indol-3-yl] -glyoxylamide (D-24851) , activated protein C (aPC), Ac-YVAD-CMK, Anginex (ß-Pep25), Neovastat®, Criptophicin 52, tacrolimus.

16. Medical product according to any one of the preceding claims, characterized in that the at least one antiproliferative, anti-inflammatory, antiphlogistic and / or antithrombotic active agent is contained in a pharmaceutically active concentration of 0.001-20 mg per cm2 of surface.

17. Medical product according to any one of the preceding claims, characterized in that in multi-layer systems, the at least two layers with o / and without addition of at least one hydrophilic polymer contain at least one active agent in the same or different concentration of active agent that is covalently bound or / and adhesively bonded.

18. Medical product according to any one of the preceding claims, characterized in that in multi-layer systems, the last layer is a pure layer of active agent is bound covalently or / and adhesively.

19. Medical product according to any one of the preceding claims, characterized in that the at least one biostable layer of polysulfone containing at least one active agent or / and is covered with at least one active agent is covered at least partially with a biodegradable polymer layer containing covalently and / or adhesively or no active agent or at least one active agent in the same or different concentration.

20. Biocompatible coating method of medical products, characterized by the following steps: a. Provide a stent, and b. Depositing at least one biostable layer of polysulfone with or without at least one hydrophilic polymer, and c. Deposit and / or incorporate at least one antiproliferative, anti-inflammatory, antiphlogistic and / or antithrombotic active agent on and / or in the biostable layer, or b '. Depositing at least one biostable layer of polysulfone with or without the at least one hydrophilic polymer together with at least one antiproliferative, anti-inflammatory, antiphlogistic and / or antithrombotic active agent.

21. Method according to claim 20, comprising step b 'and the additional step: c' depositing at least one antiproliferative, anti-inflammatory, antiphlogistic and / or antithrombotic agent on the biostable layer of polymer.

22. Method according to claim 20 or 21, further comprising the step of: d. Deposit at least a second biostable layer of polysulfone with or without a content of hydrophilic polymers that is equal to or different from the first layer without or with incorporating and / or depositing at least one active agent in the same or different concentration.

23. Method according to any one of the preceding claims, further comprising the step of d '. Depositing at least one other layer of at least one biodegradable polymer without or incorporating and / or depositing at least one active agent in the same or different concentration.

24. Method according to any one of claims 16-18. characterized in that on and / or under the at least one biostable layer of polysulfone is deposited at least one layer of fully desulfated and N-reacetylated heparin, N-carboxymethylated and / or partially N-acetylated chitosan and / or mixtures of these substances.

25. Medical products obtainable according to a method according to any one of claims 16-19.

26. Medical products according to any one of claims 1 - 15 or 20, characterized in that the at least one antiproliferative, anti-inflammatory, antiphlogistic and / or antithrombotic active agent is released in a controlled manner through the surface coating.

27. Medical products according to any one of claims 1 - 15, 20 or 21, characterized in that the respective antiproliferative, anti-inflammatory, antiphlogistic and / or antithrombotic active agent is contained in a pharmaceutically active concentration of 0.001 - 10 mg per cm2 of product surface doctor and by layer that carries the active agent.

28. Medical products according to any one of claims 1 - 15 or 20 - 22, characterized in that the medical product is a stent.