DE10333098A1 - New biocompatible, coated, implantable medicinal devices, e.g. stents, obtained by thermally carbonizing a polymeric coating, useful e.g. for controlled drug release - Google Patents

Abstract

New biocompatible, coated, implantable medicinal devices are obtained by: (a) partially coating a medicinal device with a film of polymer (I); and (b) heating the film in an oxygen-free atmosphere at 200-2500 [deg]C, to provide a carbon-containing layer on the device.

Description

The The present invention relates to implantable medical devices with biocompatible coatings and a process for their preparation. In particular, the present invention relates to a carbonaceous Layer coated medical implantable devices, by at least partially coating the device with a polymer film and heating the polymer film in an atmosphere, the is essentially free of oxygen, at temperatures in the range from 200 ° C up to 2500 ° C available are, with a carbonaceous layer on the implantable medical device is generated.

medical Implants such as surgical or orthopedic screws, plates, Joint prostheses, artificial Heart valves, vascular prostheses, Stents, as well as subcutaneously or intramuscularly implantable drug depots are made of a variety of materials, according to the specific biochemical and mechanical properties are selected produced. These materials need for the permanent use in the body be suitable to release no toxic substances and certain mechanical and biochemical properties.

The for example Stents and joint prostheses often used metals or metal alloys, as well as ceramic materials however, they often especially in continuous use, disadvantages in terms of their biocompatibility. implants solve chemical and / or physical irritation, among other inflammatory Tissue and immune reactions, causing it to intolerance reactions in the Meaning of chronic inflammatory reactions with defense and rejection reactions, excessive scarring or tissue degradation, which in extreme cases must result in the implant being removed and must be replaced or additional therapeutic interventions invasive or noninvasive type.

lack compatibility with the surrounding tissue leads For example, in coronary stents to high restenosis rates, on the one hand the intima of the vessel wall too inflammation-related Macrophage reaction with scarring tends, and on the other hand both the direct surface properties as well as the pathologically changed Vascular wall in Area of the stent to aggregation of platelets on the vascular graft itself, as well as on flammable changed Vessel walls leads. Both Mechanisms maintain a mutually influencing inflammatory and incompatibility process, in 20-30% interventionally stented patients to be treated again narrowing the coronary artery leads.

For this reason, there have been various attempts in the prior art to suitably coat the surfaces of medical implants in order to increase the biocompatibility of the materials used and to prevent rejection reactions. In the US 5,891,507 For example, methods for coating the surface of metal stents with silicone, polytetrafluoroethylene and biological materials such as heparin or growth factors are described which increase the biocompatibility of metal stents.

Next Plastic layers have become carbon-based layers as proved particularly advantageous.

For example, from the DE 199 51 477 Coronary stents with a coating on amorphous silicon carbide known, which increases the biocompatibility of the stent material. U.S. Patent 6,569,107 describes carbon coated stents in which the carbon material has been applied by chemical or physical vapor deposition (CVD or PVD) methods. Also, U.S. Patent 5,163,958 describes tubular endoprostheses or stents having a carbon coated surface which has antithrombogenic properties. WO 02/09791 describes intravascular stents with coatings produced by CVD of siloxanes.

The Deposition of pyrolytic carbon under PVD or CVD conditions requires the careful Selection of suitable gaseous or vaporizable carbon precursors, often at high temperatures, partly under plasma conditions, deposited in an inert gas or high vacuum atmosphere on the implant become.

In addition to the CVD processes for the deposition of carbon, the prior art describes various sputtering processes in a high vacuum for the preparation of pyrolytic carbon layers of various structures, see, for example, US Pat US 6,355,350 ,

Alles common to these prior art methods is that the Deposition of carbon substrates under extreme temperature and / or pressure conditions and by using complex process control takes place.

One Another disadvantage of the prior art methods is that that due to different thermal expansion coefficients of materials from which the implants are made, and The applied CVD layers often only a low adhesion of Layer is achieved on the implant, causing it to flake off, Cracks and deterioration of the surface quality comes, which is disadvantageous affect the usability of the implants.

It There is therefore a need for easy-to-use and cost-effective Method for coating implantable medical devices with a carbon-based material that are capable of being biocompatible surface coatings made of carbonaceous material available.

Further there is a need for low cost to be produced biocompatible coated medical implants with improved properties.

A Object of the present invention is therefore to provide a method for Producing biocompatible coatings on implantable medical Devices available to provide that with cost-effective and varied in their properties variable starting materials and easy controllable Applying processing conditions.

A Another object of the present invention is to use carbonaceous Coatings provided implantable medical devices to disposal to put, which increased one biocompatibility or biocompatibility exhibit.

A Another object of the present invention is biocompatible coated medical implants to provide their coating allows the application of medical agents on or in the implant surface.

A Yet another object of the present invention is coated medical implants available to provide which applied pharmacologically active substances targeted after insertion of the implant into the human body and, where appropriate, release in a controlled manner.

A Another object of the invention is implantable drug depots with a coating which promotes the release of Control active ingredients from the depot.

The inventive solution of The above-mentioned objects consists in a method as well as available therewith coated medical implants as defined in the independent claims. Preferred embodiments the method according to the invention or the products according to the invention arise from the dependent ones Dependent claims.

in the Within the scope of the present invention it has been found that carbonaceous Layers on implantable medical devices of various kinds Making it easy and reproducible, that device first is at least partially coated with a polymer film, the subsequently in a substantially oxygen-free atmosphere at high Temperatures carbonized or pyrolyzed.

• a) mindestens partielles Beschichten der medizinischen Vorrichtung mit einem Polymerfilm mittels eines geeigneten Beschichtungs- bzw. Auftragungsverfahrens;
• b) Erhitzen des Polymerfilms in einer Atmosphäre, die im Wesentlichen frei von Sauerstoff ist, bei Temperaturen im Bereich von 200°C bis 2500°C,

zur Erzeugung einer kohlenstoffhaltigen Schicht auf der medizinischen Vorrichtung.Accordingly, the method according to the invention for producing biocompatible coatings on implantable, medical devices comprises the following steps:

• a) at least partially coating the medical device with a polymeric film by a suitable coating or application method;
• b) heating the polymer film in an atmosphere substantially free of oxygen at temperatures in the range of 200 ° C to 2500 ° C,

for producing a carbon-containing layer on the medical device.

Under Carbonation or pyrolysis is within the scope of the present Invention, the partial thermal decomposition or coking carbonaceous Starting compounds understood, which are usually oligo- or polymeric materials are hydrocarbon based, which after carbonation dependent on from the chosen ones Temperature and pressure conditions and the type of polymer material used leave carbonaceous layers behind, in their structure from amorphous to highly ordered crystalline graphitic structures, as well as in their porosity and surface properties can be set exactly.

IMPLANTS

With the method according to the invention can biocompatible carbonaceous coatings on implantable be applied to medical devices.

The Terms "implantable, medical device "and" implant "will be discussed below used synonymously and include medical or therapeutic Implants such as vascular endoprostheses, intraluminal Endoprostheses, stents, coronary stents, peripheral stents, surgical or orthopedic implants for temporary purposes like surgical screws, plates, nails and other fasteners, permanent surgical or orthopedic Implants such as bone or joint prostheses, for example artificial ones Hip or hip Knee joints, socket inserts, Screws, plates, nails, implantable orthopedic Fixing aids, vertebral body replacement, and artificial hearts and parts thereof, artificial heart valves, pacemaker housings, electrodes, subcutaneous and / or intramuscular usable implants, drug depots and microchips, and the like.

The biocompatible with the method of the present invention Implants can take off almost any, preferably substantially temperature-stable Materials consist, in particular of all materials, from which Implants are made.

Examples therefor are amorphous and / or (partially) crystalline carbon, all-carbon material, porous carbon, Graphite, carbon composites, carbon fibers, ceramics such as z. Zeolites, silicates, aluminas, aluminosilicates, silicon carbide, silicon nitride; Metal carbides, metal oxides, metal nitrides, metal carbonitrides, Metal oxycarbides, metal oxynitrides and metal oxycarbonitrides of transition metals such as titanium, zirconium, hafnium, vanadium, niobium, tantalum, chromium, molybdenum, tungsten, Manganese, rhenium, iron, cobalt, nickel; Metals and metal alloys, in particular the precious metals gold, silver, ruthenium, rhodium, palladium, Osmium, iridium, platinum; Metals and metal alloys of titanium, Zirconium, hafnium, vanadium, niobium, tantalum, chromium, molybdenum, tungsten, Manganese, rhenium, iron, cobalt, nickel, copper; Steel, in particular stainless steel, shape memory alloys like nitinol, nickel-titanium alloy, glass, stone, glass fibers, minerals, natural or synthetic bone substance, bone imitations based on alkaline earth metal carbonates like calcium carbonate, magnesium carbonate, strontium carbonate, as well as any combination of said materials.

Besides can Also, materials are coated only under the carbonation conditions be converted into their final form. Examples of these are shaped bodies Paper, fiber materials and polymeric materials after coating with the polymer film together with this carbon implant to be coated being transformed.

in the inventive method Furthermore, the production of coated implants is also basically starting from ceramic precursors of the implant such as Ceramic green bodies possible, the after coating with the polymer film together with the carbonization of the polymer film to its final Application hardened or sintered.

The coatable according to the invention Implantable medical devices can have almost any external shape exhibit; the inventive method is not limited to specific structures. The implants can after the method according to the invention wholly or partially coated with a polymer film, the subsequently carbonated to a carbonaceous layer.

POLYMER FILM

According to the method of the invention, the implants are at least partially attached to one of them outer surfaces, in preferred applications coated on its entire outer surface with one or more polymer film layers.

Of the Polymer film may in one embodiment of the invention in the form of a polymer film, by means of suitable methods, for example by film shrinking, is applied to the implant or can be glued on. Thermoplastic polymer films can be applied to most substrates especially in heated Apply state essentially firmly.

Further the polymer film can also be a coating of the implant with paints, polymeric or semi-polymeric paints, dip coatings, spray coatings or coatings Polymer solutions or suspensions, as well as laminated polymer layers.

For the polymer films in the form of films, lacquers, polymeric paints, dip coatings, spray coatings or coatings as well laminated polymer layers can for example, homo- or copolymers of aliphatic or aromatic Polyolefins such as polyethylene, polypropylene, polybutene, polyisobutene, polypentene; polybutadiene; Polyvinyls such as polyvinyl chloride or polyvinyl alcohol, Poly (meth) acrylic acid, Polyacrylcyanoacrylat; Polyacrylonitrile, polyamide, polyester, polyurethane, Polystyrene, polytetrafluoroethylene; Polymers such as collagen, albumin, Gelatin, hyaluronic acid, Strength, Celluloses such as methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, Carboxymethylcellulose phthalate; Casein, dextrans, polysaccharides, Fibrinogen, poly (D, L-lactide), poly (D, L-lactide-co-glycolide), polyglycolide, Polyhydroxybutylates, polyalkylcarbonates, polyorthoesters, polyesters, Polyhydroxyvalerinsäure, Polydioxanone, polyethylene terephthalate, polymalate acid, polytartronic acid, polyanhydrides, Polyphosphazenes, polyamino acids; polyethylene vinyl acetate, silicones; Poly (ester urethanes), poly (ether urethanes), poly (ester ureas), polyethers such as polyethylene oxide, polypropylene oxide, Pluronics, polytetramethylene glycol; Polyvinyl pyrrolidone, poly (vinyl acetate phatalate), and their copolymers, Mixtures and combinations of these homo- or copolymers used become.

Particularly preferred are suitable paint-based polymer films, for example films or coatings prepared from a one- or two-component paint comprising a binder base of alkyd resin, chlorinated rubber, epoxy resin, formaldehyde resin, (meth) acrylate resin, phenolic resin, alkylphenol resin, amine resin, melanin resin, oil base , which have nitro-based, Vinylesterharz, novolac ^®, polyester, polyurethane, tar, tar-like materials, tar pitch, bitumen, starch, cellulose, shellac, organic materials from renewable raw materials or combinations thereof.

Especially preferred are paints based on phenolic and / or melanin resins, which may optionally be completely or partially epoxidized, for. B. commercial Emballagelacke, as well as one or two-component paints based optionally epoxidized aromatic hydrocarbon resins.

In certain embodiments In the present invention, the polymer film may be provided with additives. which the carbonation behavior of the film and / or the macroscopic Properties of the carbon-based resulting from the process Influence substrate coating. Examples of suitable additives are fillers, Pore formers, metals and metal powders, etc. Examples of inorganic additives or fillers are silicon oxides or aluminum oxides, aluminosilicates, zeolites, Zirconium oxides, titanium oxides, talc, graphite, carbon black, clay materials, phyllosilicates, Silicides, nitrides, metal powders, in particular of catalytically active transition metals such as copper, gold and silver, titanium, zirconium, hafnium, vanadium, niobium, Tantalum, chromium, molybdenum, Tungsten, manganese, rhenium, iron, cobalt, nickel, ruthenium, rhodium, Palladium, osmium, iridium or platinum.

through Such additives in the polymer film can be, for example biological, mechanical and thermal properties of the films as well as the resulting carbon coatings modify and to adjust. Thus, e.g. by the incorporation of phyllosilicates, Nanoparticles, inorganic nanocomposites metals, metal oxides the thermal expansion coefficient of the carbon layer the a ceramic substrate are aligned so that the applied carbon-based coating even at high temperature differences firmly adheres. The skilled person will be due to simple routine experiments select a suitable combination of polymer film and additive to for each Implant material the desired Adhesion and expansion properties of the carbonaceous layer to obtain. Also, the biocompatibility of the resulting layers modified by suitable choice of additives in the polymer film and additionally elevated become.

In preferred embodiments of the invention, further coating of the poly merfilms with epoxy resins, phenolic resin, tar, tar pitch, bitumen, rubber, polychloroprene or poly (styrene-co-butadiene) latex materials, siloxanes, silicates, metal salts or metal salt solutions, for example transition metal salts, carbon black, fullerenes, activated carbon powder, carbon molecular sieve, perovskite, aluminum oxides , Silicon oxides, silicon carbide, boron nitride, silicon nitride, noble metal powders such as Pt, Pd, Au or Ag; and combinations thereof, or by targeted incorporation of such materials in the polymer film structure, the properties of the resulting after pyrolysis and / or carbonization porous carbon-based coatings targeted influence and refine, or produce multilayer coatings, in particular multiple coatings with layers of different porosity.

at the preparation according to the invention of coated substrates, consists of the incorporation of the above Additives in the polymer film the possibility of adhesion of the applied layer on the substrate to improve and, for example the thermal expansion coefficient of the outer layer that of the Substrate adapt, so that these coated substrates more resistant to cracks in and flaking the coating. These coatings are thus more durable and long-term stable in concrete use than conventional ones Products of this kind.

The Application or incorporation of metals and metal salts, in particular also of precious metals and transition metals allows it, the chemical, biological and adsorptive properties of resulting carbon-based coatings respectively desired Adjust requirements so that the resulting coating for special Applications, for example, with heterogeneous catalytic properties equipped can be. So can by incorporation of silicon, titanium, zirconium or tantalum salts while carbonization formed the corresponding metal carbide phases become, the u. A. increase the oxidation resistance of the layer.

The in the process according to the invention used polymer films have the advantage that they are easy can be produced in almost any dimensions or commercially available are. Polymer films and paints are readily available, inexpensive and Easy to apply on implants of all kinds and shapes. The inventively used Polymer films can before pyrolysis or carbonization by folding, embossing, punching, Printing, extruding, shirring, injection molding and the like in appropriate Be patterned before or after placing on the implant be applied. In this way can be in the after the inventive method produced carbon coating certain structures more regularly or irregular type Install.

APPLICATION THE POLYMER FILM

The usable according to the invention Polymer films of coatings in the form of paints or coatings can be made the liquid, mushy or pasty Condition, for example by painting, painting, varnishing, doctoring, Spin coating, dispersion or melt coating, extrusion, To water, Diving, spraying, Printing or as hotmelts, from the solid state by means of powder coating, spraying of sprayable particles, Flame spraying, sintering or the like according to known methods apply to the implant. Optionally, the polymeric material for this purpose in suitable solvents solved or suspended. Also the laminating of suitably shaped Substrates with suitable for this Polymeric materials or films is a usable according to the invention Method for coating the implant with a polymer film.

In preferred embodiments the polymer film becomes liquid Polymer or polymer solution in a suitable solvent or solvent mixture, if necessary with subsequent Drying, applied. Suitable solvents include, for example Methanol, ethanol, n-propanol, isopropanol, butoxydiglycol, butoxyethanol, Butoxyisopropanol, butoxypropanol, n-butyl alcohol, t-butyl alcohol, Butylene glycol, butyloctanol, diethylene glycol, dimethoxy diglycol, Dimethyl ether, dipropylene glycol, ethoxydiglycol, ethoxyethanol, ethylhexanediol, Glycol, hexanediol, 1,2,6-hexanetriol, hexyl alcohol, hexylene glycol, Isobutoxypropanol, isopentyldiol, 3-methoxybutanol, methoxydiglycol, Methoxyethanol, methoxyisopropanol, methoxymethylbutanol, methoxy PEG-10, methylal, methyl-hexylether, methylpropanediol, neopentylglycol, PEG-4, PEG-6, PEG-7, PEG-8, PEG-9, PEG-6 methyl ether, pentylene glycol, PPG-7, PPG-2-buteth-3, PPG-2 butyl ether, PPG-3 butyl ether, PPG-2 Methyl ether, PPG-3 methyl ether, PPG-2 propyl ether, propanediol, Propylene glycol, propylene glycol butyl ether, propylene glycol propyl ether, Tetrahydrofuran, trimethylhexanol, phenol, benzene, toluene, xylene; when also water, optionally in admixture with dispersion aids, and Mixtures of the above.

Preferred solvents include one or more organic solvents from the group of ethanol, isopropanol, n-propanol, dipropylene glycol methyl ether and butoxyisopropanol (1,2-propylene glycol col-n-butyl ether), tetrahydrofuran, phenol, benzene, toluene, xylene, preferably ethanol, isopropanol, n-propanol and / or dipropylene glycol methyl ether, in particular isopropanol and / or n-propanol.

In preferred embodiments of the present invention the implantable medical devices also with multiple Polymer films of the same polymers of the same or different Film thickness or different polymers of the same or different Film thickness be coated several times. That way you can For example, deeper porous layers with overlying pores Layers combining the release of in the more porous layer deposited active ingredients can delay appropriately.

alternative for coating the implant with a polymer film and a subsequent one Carbonation step, it is also possible according to the invention, on a preheated Implant a polymer film-forming coating system, for example a varnish based on aromatic resins, to be sprayed directly, if necessary with the help of overpressure, around the sprayed Film layer directly on the hot Implant surface too carbonize.

carbonation

Of the if necessary, the polymer film applied to the implant is dried and subsequently a pyrolytic decomposition under Karbonisierungsbedingungen subjected. In this case, the one or more coated on the implant (s) Polymer film (s) heated, i. in a substantially oxygen-free state the atmosphere at elevated Temperature carbonized. The temperature of the carbonation step is preferably in the range of 200 ° C to 2500 ° C and is dependent on the skilled person from the specific temperature-dependent properties of the used Polymer films and implants selected.

preferred general temperatures for the carbonation step the method according to the invention are at 200 ° C up to about 1200 ° C. In some embodiments Temperatures in the range of 250 ° C to 700 ° C are preferred. Generally, the Temperature depending on the properties of the materials used chosen so that the polymer film with as possible low temperature consumption substantially completely carbonaceous solid is transferred. By the appropriate choice or control of the pyrolysis temperature can the porosity, the strength and rigidity of the material and other properties targeted be set.

Depending on the type of polymer film used and the chosen carbonization conditions, in particular the atmospheric composition, the chosen one Temperatures or temperature programs and pressure conditions can with the method according to the invention the nature and structure of the deposited carbonaceous layer be adjusted or varied. This is how it works, for example Use of pure hydrocarbon based polymer films in oxygen-free atmosphere at temperatures up to approx. 1000 ° C for deposition of substantially amorphous carbon, whereas at temperatures above 2000 ° C highly ordered crystalline Graphite structures are obtained. In the area between these two Temperatures can be semi-crystalline carbonaceous layers of different densities and porosities.

One Another example is the use of foamed polymer films, for example foamed Polyurethanes which, upon carbonization, are relatively porous carbon layers with pore sizes in the lower millimeter range receive. Also, by the thickness of the applied polymer film and the chosen ones Temperature and pressure conditions during pyrolysis the layer thickness the deposited carbonaceous layer within wide limits be varied, from carbon monolayers to nearly invisible layers in the nanometer range up to paint layer thicknesses of 10 to 40 micrometers Dry layer, up to thicker depot layer thicknesses in the Millimeter range to centimeter range.

The latter is particularly preferred for implants made of full carbon materials, especially in bone implants.

By suitable choice of polymer film material and carbonization conditions can so molecular sieve-like Depot layers with specifically controllable pore sizes and sieving properties are obtained which are the covalent, adsorptive or absorptive or even electrostatic Enable connection of active ingredients or surface modifications.

The atmosphere in the carbonation step of the process of the invention is essentially free of oxygen, preferably with O ₂ contents below 10 ppm, more preferably below 1 ppm. Preference is given to the use of inert gas atmospheres, for example of nitrogen, noble gases such as argon, neon and any other inert, non-carbon-reactive gases or gas compounds as well as mixtures of inert gases. Preference is given to nitrogen and / or argon.

The Carbonation becomes common at atmospheric pressure in the presence of inert gases such as those mentioned above carried out. Optionally, however, higher inert gas pressures are also advantageous usable. In certain embodiments the method according to the invention Carbonation can also be carried out under reduced pressure or in a vacuum.

Of the Carbonation step is preferably in a discontinuous Process in suitable ovens but can also be carried out in continuous furnace processes, which may optionally also be preferred. The possibly structured, pretreated polymer film-coated implants are included fed to the stove on one side and exit at the other end of the oven. In preferred embodiments the polymer film-coated implant in the oven on a perforated plate, a sieve or the like, so that through the polymer film while the pyrolysis or

carbonation Vacuum can be applied. This not only allows a simple Fixation of the implants in the oven, but also a suction and optimal flow the films or assemblies with inert gas during pyrolysis and / or Carbonation.

Of the Oven can by appropriate inert gas locks into individual segments in which one or more pyrolysis or carbonation steps, if necessary with different pyrolysis or carbonization conditions such as different Temperature stages, different inert gases or vacuum can be performed can.

Further can in appropriate segments of the furnace optionally also post-treatment steps such as after-activation by reduction or oxidation or impregnation with metal salt solutions etc. are performed.

alternative Carbonation can also be done in a closed oven carried out be, which is particularly preferred when the pyrolysis and / or Carbonation should be carried out in vacuo.

During the Pyrolysis and / or carbonization in the process according to the invention usually occurs one Weight reduction of the polymer film from about 5% to 95%, preferably about 40% to 90%, especially 50% to 70%, depending on the starting material used and pretreatment.

The produced according to the invention carbon-based coating has, depending on the starting material, amount and type of filling materials, a carbon content of at least 1% by weight, preferably at least 25%, possibly also at least 60% and in particular preferably at least 75%. Particularly preferred coatings according to the invention have a carbon content of at least 50% by weight.

TREATMENT

In preferred embodiments the method according to the invention Be the physical and chemical properties of the carbon-based Coating after pyrolysis or carbonization by suitable Post-treatment steps further modified and the respectively desired Use adapted.

Suitable aftertreatments are, for example, reducing or oxidative aftertreatment steps in which the coating is treated with suitable reducing agents and / or oxidizing agents such as hydrogen, carbon dioxide, nitrogen oxides such as N ₂ O, water vapor, oxygen, air, nitric acid and the like, and optionally mixtures thereof.

The after-treatment steps may optionally at elevated temperature, but below the pyrolysis, for example from 40 ° C to 1000 ° C, preferably 70 ° C to 900 ° C, more preferably 100 ° C to 850 ° C, particularly preferably 200 ° C to 800 ° C and in particular be carried out at about 700 ° C. In particularly preferred embodiments, the coating produced according to the invention becomes reductive or oxidatively, or modified with a combination of these aftertreatment steps at room temperature.

By oxidative or reductive treatment, or the incorporation of additives, fillers or functional materials can be the surface properties the invention produced Specifically influence or change coatings. For example, by Incorporation of inorganic nanoparticles or nanocomposites such as phyllosilicates the surface properties the coating be hydrophilized or hydrophobized.

Also can the inventively prepared Coatings later by incorporating suitable additives with biocompatible surfaces and as a drug carrier or depots. For this, e.g. Medicines or Enzymes are introduced into the material, the former possibly by suitable retardation and / or selective permeation properties the coatings can be released controlled.

Also can by the method according to the invention the coating on the implant can be suitably modified, e.g. by varying the pore sizes by means suitable oxidative or reductive aftertreatment steps, such as Oxidation in air at elevated temperatures Temperature, boiling in oxidizing acids, alkalis, or interference volatile Ingredients that during carbonation completely be degraded and leave pores in the carbonaceous layer.

The Carbonated coating may optionally also in another optional process step, a so-called CVD process (Chemical Vapor Deposition, chemical vapor deposition) or CVI process (Chemical Vapor infiltration) to the surface or Pore structure and their properties continue to modify. For this the carbonated coating will be with suitable, carbon donating ends Precursorgasen treated at high temperatures. Also other elements can do that are deposited, such as silicon. Such methods have long been known in the art.

Almost all known saturated and unsaturated hydrocarbons having sufficient volatility under CVD conditions are suitable as carbon-eliminating precursors. Examples of these are methane, ethane, ethylene, acetylene, linear and branched alkanes, alkenes and alkynes having carbon numbers of C ₁ -C ₂₀ , aromatic hydrocarbons such as benzene, naphthalene, etc., and mono- and polyalkyl-, alkenyl- and alkynyl-substituted aromatics such as toluene, xylene, cresol, styrene, etc.

The ceramic precursors used may be BCl ₃ , NH ₃ , silanes such as SiH ₄ , tetraethoxysilane (TEOS), dichlorodimethylsilane (DDS), methyltrichlorosilane (MTS), trichlorosilyldichloroborane (TDADB), hexadichloromethylsilyloxide (HDMSO), AlCl ₃ , TiCl ₃ or mixtures thereof become.

These Precursors are usually in low concentration in CVD processes from about 0.5 to 15% by volume in admixture with an inert gas, such as Nitrogen, argon or the like applied. Also the addition of Hydrogen to corresponding deposition gas mixtures is possible. at Temperatures between 500 and 2000 ° C, preferably 500 to 1500 ° C and especially preferably 700 to 1300 ° C, cleave the compounds mentioned hydrocarbon fragments or Carbon or ceramic precursors that are in the pore system the pyrolyzed coating substantially evenly distributed knock down, there modify the pore structure and so to a result in substantially homogeneous pore size and pore distribution.

through CVD methods can be targeted pores in the carbonaceous Reduce the layer on the implant to complete closure / sealing the pores. This allows the sorptive properties, such as also tailored the mechanical properties of the implant surface to adjust.

By CVD of silanes or siloxanes, optionally mixed with hydrocarbons let the carbon-containing implant coatings pass through For example, modify carbide or oxycarbide oxidation resistant.

In preferred embodiments can the coated according to the invention Implants additionally coated or modified by sputtering become. You can do this Carbon, silicon or metals or metal compounds of suitable Sputtering targets are applied by methods known per se. Examples of this Ti, Zr, Ta, W, Mo, Cr, Cu are those in the carbonaceous layers be dusted can, usually forming the corresponding carbides.

Further can by ion implantation the surface properties of the coated Implant modified. Thus, by implanting Nitrogen nitride, carbonitride or oxynitride phases with intercalated transition metals be formed, indicating the chemical resistance and mechanical resistance the carbonaceous implant coatings significantly increased.

In certain embodiments it may be advantageous to use the coated implantable device with at least one additional Layer of biodegradable or resorbable polymers such as collagen, albumin, gelatin, hyaluronic acid, starch, celluloses such as methylcellulose, Hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose phthalate; Casein, dextrans, polysaccharides, fibrinogen, poly (D, L-lactides), poly (D, L-lactide-co-glycolides), Poly (glycolides), poly (hydroxybutylates), poly (alkylcarbonates), poly (orthoesters), Polyester, poly (hydroxyvaleric acid), Polydioxanone, poly (ethylene terephthalate), poly (malic acid), poly (tartronic acid), polyanhydrides, Polyphosphazenes, poly (amino acids), and their co-polymers or non-biological degradable or absorbable polymers at least partially coat. Particular preference is given to anionic, cationic or amphoteric coatings, e.g. Alginate, carrageenan, carboxymethylcellulose; Chitosan, poly-L-lysine; and / or phosphorylcholine.

Provided required in particularly preferred embodiments, the coated Implant after carbonation and / or as appropriate Post-treatment steps other chemical or physical surface modifications be subjected. Also cleaning steps to remove any Residues and Impurities can be provided here. For this purpose, acids, in particular oxidizing acids, or solvents be used, preferred is the decoction in acids or Solvents.

In front of medical use the coated according to the invention Implants with usual Sterilized methods, for example by autoclaving, Ethylene oxide sterilization or gamma irradiation.

According to the invention of polymer films generated pyrolytic carbon itself is usually high biocompatible Material used in medical applications such as the outer coating can be used by implants. The biocompatibility of the invention coated Implants can also be prepared by incorporation of additives, fillers, Proteins or functional materials and / or drugs in specifically influences the polymer films before or after carbonation, or changed be as mentioned above. This can be repulsive phenomena in body produced according to the invention Reduce implants or switch off completely.

In particularly preferred embodiments can produced according to the invention Carbon-coated medical implants through targeted adjustment the porosity the applied carbon layer for the controlled release of Active ingredients from the substrate can be used in the external environment. Preferred coatings are porous, in particular nanoporous. Here in For example, medical implants can be used as a drug carrier Use depot effect, wherein the carbon-based coating of the implant can be used as a release-regulating membrane can.

Also can on the biocompatible Coatings drugs are applied. This is special because useful, where agents are not applied directly in or on the implant can be like metals.

Further can the inventively prepared Coatings in a further step with drugs or drugs, or with markers, contrast agents for localizing coated implants in the body be, for example, with therapeutic or diagnostic Amounts of radioactive sources. For the latter are the coatings of the invention carbon-based, as it is unlike Polymer layers of radioactive radiation does not deteriorate or attacked.

in the In the medical field, the coated according to the invention prove Implants are particularly long-term stable, since the carbon-based Coatings in addition to their high strength and sufficiently elastic and can be adjusted flexibly, allowing them to move of the implant, especially in highly loaded joints follow can, without the risk of cracks or the layer forming peel.

The porosity of coatings applied according to the invention on implants can in particular also be adapted by means of aftertreatment with oxidizing agents, for example activation at elevated temperature in oxygen or oxygen-containing atmospheres or use of strongly oxidizing acids such as concentrated nitric acid and the like, so that the carbonaceous surface on the implant enables and promotes the ingrowth of body tissue. Suitable layers for this purpose are macroporous, with a pore size of 0.1 .mu.m to 1000 .mu.m, preferably 1 .mu.m to 400 .mu.m. The suitable porosity can also be influenced by a corresponding pre-structuring of the implant or of the polymer film. Suitable measures for this purpose are, for. B. embossing, punching, perforating, foaming the polymer film.

ACTIVE COATING

In preferred embodiments can the invention biocompatible coated implants are loaded with active ingredients. The loading with active ingredients may be in or on the carbonaceous coating by means of suitable sorptive methods such as adsorption, absorption, Physisorption, chemisorption occur in the simplest case impregnation the carbon-containing coating with drug solutions, drug dispersions or drug suspensions in suitable solvents. Also covalent or noncovalent attachment of drugs in or on the carbonaceous Coating can here according to dependence the active ingredient used and its chemical properties preferred option.

In porous carbonaceous coatings can occlude drugs into pores become.

The Drug loading may be temporary be, d. H. The active ingredient may be after implantation of the medical Device are released, or else the active ingredient is in or permanently immobilized on the carbonaceous layer. That way you can medicated implants with static, dynamic or combined static and dynamic drug loadings generated become. This results in multifunctional coatings based on the invention produced carbonaceous layers.

at Static loading with active substances become active ingredients substantially permanently immobilized on or in the coating. Suitable for this purpose Active ingredients are inorganic substances, e.g. Hydroxyapatite (HAP), Fluoroapatite, tricalcium phosphate (TCP), zinc; and / or organic Substances such as peptides, proteins, carbohydrates such as mono-, and polysaccharides, lipids, phospholipids, steroids, lipoproteins, Glycoproteins, glycolipids, proteoglycans, DNA, RNA, signal peptides or antibodies or antibody fragments, bioresorbable polymers, e.g. Polylactonic acid, chitosan, as well as pharmacologically effective substances or mixtures, combinations of these and the like.

at Dynamic drug loading is the release of the applied Active ingredients provided after implantation of the medical device in the body. That way you can the coated implants used for therapeutic purposes be, with the applied to the implant drugs locally be gradually released at the site of the implant. In dynamic Drug loadings for the Release of active substances useful agents are, for example Hydroxyapatite (HAP), fluorapatite, tricalcium phosphate (TCP), zinc; and / or organic substances such as peptides, proteins, carbohydrates such as mono-, oligo- and polysaccharides, lipids, phospholipids, steroids, Lipoproteins, glycoproteins, glycolipids, proteoglycans, DNA, RNA, Signal peptides or antibodies or antibody fragments, bioresorbable polymers, e.g. Polylactic acid, chitosan, and the like, as well as pharmacologically active substances or substance mixtures.

Suitable pharmacologically active substances or mixtures for the static and / or dynamic loading of implantable medical devices coated according to the invention comprise active substances or combinations of active substances selected from heparin, synthetic heparin analogues (eg fondaparinux), hirudin, antithrombin III, drotrecogin alpha; Fibrinolytica such as alteplase, plasmin, lysokinases, factor XIIa, prourokinase, urokinase, anistreplase, streptokinase; Platelet aggregation inhibitors such as acetylsalicylic acid, ticlopidine, clopidogrel, abciximab, dextrans; Corticosteroids such as Alclometasone, Amcinonide, Augmented Betamethasone, Beclomethasone, Betamethasone, Budesonide, Cortisone, Clobetasol, Clocortolone, Desonide, Desoximetasone, Dexamethasone, Flucinolone, Fluocinonide, Flurandrenolide, Flunisolide, Fluticasone, Halcinonide, Halobetasol, Hydrocortisone, Methylprednisolone, Mometasone, Prednicarbate, Prednisone , Prednisolone, triamcinolone; non-steroidal anti-inflammatory drugs such as diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, salsalates, sulindac, tolmetin, celecoxib, rofecoxib; Cytostatic drugs such as alkaloids and podophyllum toxins such as vinblastine, vincristine; Alkylating agents such as nitrosoureas, nitrogen mustard analogues; cytotoxic antibiotics such as daunorubicin, doxorubicin and other anthracyclines and related substances, bleomycin, mitomycin; Antimetabolites such as folic acid, Purine or pyrimidine analogs; Paclitaxel, docetaxel, sirolimus; Platinum compounds such as carboplatin, cisplatin or oxaliplatin; Amsacrine, irinotecan, imatinib, topotecan, interferon-alpha 2a, interferon-alpha 2b, hydroxycarbamide, miltefosine, pentostatin, porfimer, aldesleukin, bexarotene, tretinoin; Antiandrogens, and antiestrogens; Anti-arrhythmic agents, in particular class I antiarrhythmics, such as quinidine-type antiarrhythmics, for example quinidine, dysopyramide, ajmaline, prallybium tartrate, detalobium bitartrate; Lidocaine-type antiarrhythmics, eg lidocaine, mexiletine, phenytoin, tocainide; Class IC antiarrhythmics, eg propafenone, flecainide (acetate); Class II antiarrhythmics, beta-receptor blockers such as metoprolol, esmolol, propranolol, metoprolol, atenolol, oxprenolol; Class III antiarrhythmics such as amiodarone, sotalol; Class IV antiarrhythmics such as diltiazem, verapamil, gallopamil; other antiarrhythmics such as adenosine, orciprenaline, ipratropium bromide; Agents to stimulate angiogenesis in the myocardium such as Vascular Endothelial Growth Factor (VEGF), Basic Fibroblast Growth Factor (bFGF), non-viral DNA, viral DNA, endothelial growth factors: FGF-1, FGF-2, VEGF, TGF; Antibodies, monoclonal antibodies, anticalins; Stem Cells, Endothelial Progenitor Cells (EPC); Digitalis glycosides such as acetyldigoxin / metildigoxin, digitoxin, digoxin; Cardiac glycosides such as ouabain, proscillaridin; Antihypertensive agents such as centrally acting anti-adrenergic agents, eg methyldopa, imidazoline receptor agonists; Dihydropyridine-type calcium channel blockers such as nifedipine, nitrendipine; ACE inhibitors: quinaprilat, cilazapril, moexipril, trandolapril, spirapril, imidapril, trandolapril; Angiotensin II antagonists: candesartan cilexetil, valsartan, telmisartan, olmesartan medoxomil, eprosartan; peripherally acting alpha-receptor blockers such as prazosin, urapidil, doxazosin, bunazosin, terazosin, indoramine; Vasodilators such as dihydralazine, diisopropylamine dichloroacetate, minoxidil, nitroprusside sodium; other antihypertensive agents such as indapamide, co-dergocrin mesilate, dihydroergotoxine methanesulfonate, cicletanine, bosentan, fludrocortisone; Phosphodiesterase inhibitors such as milrinone, enoximone and antihypotonics, such as in particular adrenergic and dopaminergic substances such as dobutamine, epinephrine, etilefrine, norfenefrine, norepinephrine, oxilofrin, dopamine, midodrine, pholedrine, aminotetium; and partial adrenoceptor agonists such as dihydroergotamine; Fibronectin, polylysines, ethylene-vinylacetates, inflammatory cytokines such as: TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF, IGF-α, IL-1, IL-8, IL-6, Growth Hormone; and adhesive substances such as cyanoacrylates, beryllium, silica; and Growth Factors such as erythropoietin, hormones such as corticotropins, gonadotropins, somatropin, thyrotrophin, desmopressin, terlipressin, oxytocin, cetrorelix, corticorelin, leuprorelin, triptorelin, gonadorelin, ganirelix, buserelin, nafarelin, goserelin, as well as regulatory peptides such as somatostatin, octreotide ; Bone and cartilage stimulating peptides, bone morphogenetic proteins (BMPs), in particular recombinant BMPs such as recombinant human BMP-2 (rhBMP-2)), bisphosphonates (eg risedronate, pamidronate, ibandronate, zoledronic acid, clodronic acid, etidronic acid, alendronic acid, tiludronic acid), Fluorides such as disodium fluorophosphate, sodium fluoride; Calcitonin, dihydrotachystyrene; Growth Factors and Cytokines such as Epidermal Growth Factor (EGF), Platelet-Derived Growth Factor (PDGF), Fibroblast Growth Factors (FGFs), Transforming Growth Factors-b TGFs-b), Transforming Growth Factor-a (TGF-a), Erythropoietin (Epo), Insulin-Like Growth Factor-I (IGF-I), Insulin-Like Growth Factor-II (IGF-II), Interleukin-1 (IL-1), Interleukin-2 (IL-2), Interleukin 6 (IL-6), Interleukin-8 (IL-8), Tumor Necrosis Factor-a (TNF-a), Tumor Necrosis Factor-b (TNF-b), Interferon-g (INF-g), Colony Stimulating Factors (CSFs); Monocyte chemotactic protein, fibroblast stimulating factor 1, histamine, fibrin or fibrinogen, endothelin-1, angiotensin II, collagens, bromocriptine, methylsergide, methotrexate, carbon tetrachloride, thioacetamide, and ethanol; furthermore silver (ions), titanium dioxide, antibiotics and anti-infective agents, in particular β-lactam antibiotics, for example β-lactamase-sensitive penicillins such as benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V); β-lactamase resistant penicillins such as aminopenicillins such as amoxicillin, ampicillin, bacampicillin; Acylaminopenicillins such as mezlocillin, piperacillin; Carboxypenicillins, cephalosporins such as cefazolin, cefuroxime, cefoxitin, cefotiam, cefaclor, cefadroxil, cefalexin, loracarbef, cefixime, cefuroximaxetil, ceftibuten, cefpodoxime proxetil, cefpodoxime proxetil; Aztreonam, Ertapenem, Meropenem; β-lactamase inhibitors such as sulbactam, sultamicillin tosilate; Tetracyclines such as doxycycline, minocycline, tetracycline, chlortetracycline, oxytetracycline; Aminoglycosides such as gentamicin, neomycin, streptomycin, tobramycin, amikacin, netilmicin, paromomycin, framycetin, spectinomycin; Macrolide antibiotics such as azithromycin, clarithromycin, erythromycin, roxithromycin, spiramycin, josamycin; Lincosamides such as clindamycin, lincomycin, gyrase inhibitors such as fluoroquinolones such as ciprofloxacin, ofloxacin, moxifloxacin, norfloxacin, gatifloxacin, enoxacin, fleroxacin, levofloxacin; Quinolones such as pipemic acid; Sulfonamides, trimethoprim, sulfadiazine, sulfals; Glycopeptide antibiotics such as vancomycin, teicoplanin; Polypeptide antibiotics such as polymyxins such as colistin, polymyxin B, nitroimidazole derivatives such as metronidazole, tinidazole; Aminoquinolones such as chloroquine, mefloquine, hydroxychloroquine; Biguanides such as proguanil; Quinine alkaloids and diaminopyrimidines such as pyrimethamine; Amphenicols such as chloramphenicol; Rifabutin, dapsone, fusidic acid, fosfomycin, nifuratel, telithromycin, fusafungin, fosfomycin, pentamidine diisethionate, rifampicin, taurolidine, atovaquone, linezolid; Antivirals such as acyclovir, ganciclovir, famciclovir, foscarnet, inosine (dimepranol-4-acetamidobenzoate), valganciclovir, valaciclovir, cidofovir, brivudine; antiretroviral agents (nucleoside analogue reverse transcriptase inhibitors and derivatives) such as lamivudine, zalcitabine, didanosine, zidovudine, tenofovir, stavudine, abacavir; non-nucleoside analogue reverse transcriptase inhibitors: amprenavir, indinavir, saquinavir, lopinavir, ritonavir, nelfinavir; Amantadine, ribavirin, zanamivir, oseltamivir and lamivudine, and any combinations and mixtures thereof.

STENT

Especially preferred embodiments The present invention relates to coated vascular endoprostheses (intraluminal Endoprostheses) such as stents, coronary stents, intravascular stents, peripheral stents and the like.

These can with the method according to the invention be coated in a simple way biocompatible, which, for example in percutaneous transluminal angioplasty with conventional Stents frequently occurring restenoses can be prevented.

In preferred embodiments of the invention can be achieved by activation of the carbonaceous coating, For example, with air at elevated Temperature, the hydrophilicity of the coating can be increased, indicating the biocompatibility additionally increases.

In particularly preferred embodiments, stents provided by the method according to the invention with a carbon-containing layer, in particular coronary stents and peripheral stents, are loaded with pharmacologically active substances or substance mixtures. For example, the stent surfaces for the local suppression of cell adhesion, platelet aggregation, complement activation or inflammatory tissue reactions or cell proliferation can be equipped with the following active substances:
Heparin, synthetic heparin analogues (eg fondaparinux), hirudin, antithrombin III, drotrecogin alpha, fibrinolytica (alteplase, plasmin, lysokinases, factor XIIa, prourokinase, urokinase, anistreplase, streptokinase), platelet aggregation inhibitors (acetylsalicylic acid, ticlopidine, clopidogrel, abciximab , Dextrans), corticosteroids (alclometasone, amcinonide, augmented betamethasone, beclomethasone, betamethasone, budesonide, cortisone, clobetasol, clocortolone, desonide, desoximetasone, dexamethasone, flucinolone, fluocinonide, flurandrenolide, flunisolide, fluticasone, halcinonide, halobetasol, hydrocortisone, methylprednisolone, mometasone , Prednicarbate, prednisone, prednisolone, triamcinolone), so-called non-steroidal anti-inflammatory drugs (diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, Piroxicam, salsalates, sulindac, tolmetin, celecoxib, ro fecoxib), cytostatics (alkaloids and podophyllum toxins such as vinblastine, vincristine; Alkylating agents such as nitrosoureas, nitrogen mustard analogues; cytotoxic antibiotics such as daunorubicin, doxorubicin and other anthracyclines and related substances, bleomycin, mitomycin; Antimetabolites such as folic acid, purine or pyrimidine analogs; Paclitaxel, docetaxel, sirolimus; Platinum compounds such as carboplatin, cisplatin or oxaliplatin; Amsacrine, irinotecan, imatinib, topotecan, interferon-alpha 2a, interferon-alpha 2b, hydroxycarbamide, miltefosine, pentostatin, porfimer, aldesleukin, bexarotene, tretinoin; Antiandrogens, antiestrogens).

For systemic cardiac effects, the stents coated according to the invention can be loaded with:
Antiarrhythmics, in particular class I antiarrhythmics (quinidine type antiarrhythmics: quinidine, dysopyramide, ajmaline, prallybium tartrate, detajmium bitartrate; lidocaine-type antiarrhythmics: lidocaine, mexiletine, phenytoin, tocainide; class IC antiarrhythmic drugs: propafenone, flecainide (acetate)), class antiarrhythmic drugs II (beta-receptor blockers) (metoprolol, esmolol, propranolol, metoprolol, atenolol, oxprenolol), class III antiarrhythmics (amiodarone, sotalol), class IV antiarrhythmics (diltiazem, verapamil, gallopamil), other antiarrhythmics such as adenosine, orciprenaline, ipratropium bromide; Stimulation of myocardial angiogenesis: Vascular Endothelial Growth Factor (VEGF), Basic Fibroblast Growth Factor (bFGF), non-viral DNA, viral DNA, endothelial growth factors: FGF-1, FGF-2, VEGF, TGF; Antibodies, monoclonal antibodies, anticalins; Stem Cells, Endothelial Progenitor Cells (EPC). Other cardiac drugs are: digitalis glycosides (acetyldigoxin / metildigoxin, digitoxin, digoxin), other cardiac glycosides (ouabain, proscillaridin). Antihypertensive agents (centrally effective anti-adrenergic agents: methyldopa, imidazoline receptor agonists, calcium channel blockers: dihydropyridine type such as nifedipine, nitrendipine, ACE inhibitors: quinaprilat, cilazapril, moexipril, trandolapril, spirapril, imidapril, trandolapril, angiotensin II antagonists: candesartancilexetil, valsartan, telmisartan , Olmesartan medoxomil, eprosartan, peripherally acting alpha-receptor blockers: prazosin, urapidil, doxazosin, bunazosin, terazosin, indoramine, vasodilators: dihydralazine, diisopropylamine dichloroacetate, minoxidil, nitroprusside sodium), other antihypertensive agents such as indapamide, co-dergocrine mesilate, dihydroergotoxine methanesulfonate, cicletanine, bosentan. Furthermore, phosphodiesterase inhibitors (milrinone, enoximone) and antihypotonics, especially adrenergic and dopaminergic substances (dobutamine, epinephrine, etilefrine, norfenefrine, norepinephrine, oxilofrin, dopamine, midodrine, pholedrine, ameziniummetil), partial adrenoceptor agonists (dihydroergotamine), and finally other antihypotonics such fludrocortisone.

Components can be used to increase tissue adhesion, especially in peripheral stents the extracellular matrix, fibronectin, polylysines, ethylene-vinylacetates, inflammatory cytokines such as: TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF, IGF-α, IL-1, IL-8, IL-6, Growth Hormone; and adhesive substances such as: Cyanoacrylate, Beryllium, or Silica are used:
Other substances suitable for this purpose, systemic and / or locally acting, are growth factors (growth factor), erythropoietin.

Also Hormones can be provided in the stent coatings, such as Corticotropins, Gonadotropins, Somatropin, Thyrotrophin, Desmopressin, Terlipressin, oxytocin, cetrorelix, corticorelin, leuprorelin, triptorelin, Gonadorelin, ganirelix, buserelin, nafarelin, goserelin, as well as regulatory peptides like somatostatin, and / or octreotide.

ORTHOPEDIC IMPLANTS

in the There may be cases of surgical and orthopedic implants be advantageous, the implants with one or more carbon-containing Equip layers that are macroporous. Suitable pore sizes are in the range of 0.1 to 1000 μm, preferably at 1 to 400 μm, to better integration of the implants by ingrowth into the support surrounding cell or bone tissue.

For orthopedic and not orthopedic Implants and coated according to the invention Heart valves or artificial heart parts may also be provided with these Active substances should be loaded for local suppression of cell adhesion, Platelet aggregation, complement activation or inflammatory Tissue reaction or cell proliferation using the same drugs be as in the stent applications described above.

Further can for the stimulation of tissue growth especially in orthopedic Implants for a better implant integration uses the following drugs Bone and Cartilage Stimulating Peptides, bone morphogenetic proteins (BMPs), in particular recombinant BMPs (e.g., recombinant human BMP-2 (rhBMP-2)), Bisphosphonates (e.g., risedronates, pamidronates, ibandronates, zoledronic acid, clodronic acid, etidronic acid, alendronic acid, tiludronic acid), fluorides (Disodium fluorophosphate, sodium fluoride); Calcitonin, dihydrotachystyrene. Then all growth factors and cytokines (epidermal growth factor (EGF), Platelet Derived Growth Factor (PDGF), Fibroblast Growth Factors (FGFs), Transforming Growth Factors-b TGFs-b), Transforming Growth Factor-a (TGF-a), Erythropoietin (Epo), Insulin-Like Growth Factor-I (IGF-I), insulin-like growth factor-II (IGF-II), interleukin-1 (IL-1), Interleukin-2 (IL-2), interleukin-6 (IL-6), interleukin-8 (IL-8), Tumor Necrosis Factor-a (TNF-a), Tumor Necrosis Factor-b (TNF-b), Interferon-g (INF-g), Colony Stimulating Factors (CSFs)). Further adhesion- and integration-promoting Substances are in addition to the already mentioned inflammatory cytokines the monocyte chemotactic protein, fibroblast stimulating factor 1, histamine, fibrin or fibrinogen, endothelin-1, angiotensin II, Collagens, bromocriptine, methylsergide, methotrexate, carbon tetrachloride, Thioacetamide, ethanol.

SPECIAL EMBODIMENTS

In addition, the implants, stents and the like coated according to the invention can also be provided instead of pharmaceuticals or additionally with antibacterial-anti-infective coatings, the following substances or mixtures being usable: silver (ions), titanium dioxide, antibiotics and anti-infective agents. In particular, beta-lactam antibiotics (β-lactam antibiotics: β-lactamase-sensitive penicillins such as benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V); β-lactamase-resistant penicillins such as aminopenicillins such as amoxicillin, ampicillin, bacampicillin; acylaminopenicillins such as mezlocillin , Piperacillin, carboxypenicillins, cephalosporins (cefazolin, cefuroxime, cefoxitin, cefotiam, cefaclor, cefadroxil, cefalexin, loracarbef, cefixime, cefuroxime axetil, ceftibuten, cefpodoxime proxetil, cefpodoxime proxetil) or others such as aztreonam, ertapenem, meropenem, etc. Other antibiotics are β-lactamase inhibitors (Sulbactam, sultamicillin tosilate), tetracyclines (doxycycline, minocycline, tetracycline, chlortetracycline, oxytetracycline), aminoglycosides (gentamicin, neomycin, streptomycin, tobramycin, amikacin, netilmicin, paromomycin, framycetin, spectinomycin), macrolide antibiotics (azithromycin, clarithromycin, erythromycin, roxithromycin, Spiramycin, josamycin), lincosamides (Clindam ycin, lincomycin), gyrase inhibitors (fluoroquinolones such as ciprofloxacin, ofloxacin, moxifloxacin, norfloxacin, gatifloxacin, enoxacin, fleroxacin, levofloxacin; other quinolones such as pipemic acid), sulfonamides and trimethoprim (sulfadiazine, sulfates, trimethoprim), glycopeptide antibiotics (vancomycin, teicoplanin), polypeptide antibiotics (polymyxins such as colistin, polymyxin-B), nitroimidazole derivatives (metronidazole, tinidazole), aminochinolones (chloroquine, mefloquine, Hydroxychloroquine), biguanides (proguanil), quinine alkaloids and diaminopyrimidines (pyrimethamine), amphenicols (chloramphenicol) and other antibiotics (rifabutin, dapsone, fusidic acid, fosfomycin, nifuratel, telithromycin, fusafungin, fosfomycin, Pentamidine diisethionate, rifampicin, taurolidine, atovaquone, linezolide). Among the antivirals may be mentioned acyclovir, ganciclovir, famciclovir, foscarnet, inosine (dimepranol-4-acetamidobenzoate), valganciclovir, valaciclovir, cidofovir, brivudine. These include antiretroviral agents (nucleoside analogue reverse transcriptase inhibitors and derivatives: lamivudine, zalcitabine, didanosine, zidovudine, tenofovir, stavudine, abacavir, non-nucleoside analogue reverse transcriptase inhibitors: amprenavir, indinavir, saquinavir, lopinavir, ritonavir, nelfinavir) and other antivirals such as amantadine, ribavirin, zanamivir, oseltamivir, lamivudine.

In particularly preferred embodiments of the present invention the inventively prepared carbonaceous layers before or after drug loading by means of other agents in their chemical or physical properties be suitably modified, for example, the hydrophilicity, Hydrophobicity, electrical conductivity, Adhesion or other surface properties to modify. Therefor usable substances are biodegradable or non-degradable Polymers, such as the biodegradable: collagens, Albumin, gelatine, hyaluronic acid, Strength, Cellulose (methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, Carboxymethylcellulose phthalate; casein, dextrans, polysaccharides, Fibrinogen, poly (D, L-lactide), poly (D, L-lactide-co-glycolide), poly (glycolide), poly (hydroxybutylate), Poly (alkylcarbonates), poly (orthoesters), polyesters, poly (hydroxyvaleric Acid), polydioxanone, poly (ethylene terephthalate), poly (malic acid), poly (tartronic acid), polyanhydrides, Polyphosphohazenes, poly (amino acids), and all their co-polymers.

To the non-biodegradable count: Poly (ethylene vinyl acetates), silicones, acrylic polymers such as polyacrylic acid, polymethylacrylic acid, polyacrylic cyanoacrylate; Polyethylenes, polypropylenes, polyamides, polyurethanes, poly (ester-urethanes), Poly (ether urethanes), poly (ester ureas), polyethers such as polyethylene oxide, Polypropylene oxide, Pluronics, polytetramethylene glycol; vinyl polymers such as polyvinyl pyrrolidones, poly (vinyl alcohols), poly (vinyl acetate phatalate.

As a general rule that polymers with anionic (e.g., alginate, carrageenan, carboxymethylcellulose) or cationic (e.g., chitosan, poly-L-lysines etc.) or both properties (phosphorylcholine) can.

to Modification of the release properties of active ingredient coated according to the invention Implants can by applying, for example, further polymers specific pH or temperature dependent Release properties are generated. PH-sensitive polymers are, for example Poly (acrylic acid) and derivatives, for example: homopolymers such as poly (aminocarboxylic acid), poly (acrylic acid), poly (methylacrylic acid) and their co-polymers. This also applies to polysaccharides such as cellulose acetate phthalate, Hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose succinate, Cellulose acetate trimellitate and chitosan. Thermosensitive polymers are, for example, poly (N-isopropylacrylamide-co-sodium-acrylate-co-n-N-alkylacrylamide), Poly (N-methyl-N-n-propylacrylamide), Poly (N-methyl-N-isopropylacrylamide), poly (N-n-propylmethacrylamide), poly (N-isopropylacrylamide), Poly (N, n-diethylacrylamide), poly (N-isopropylmethacrylamide), poly (N-cyclopropylacrylamide), Poly (N-ethylacrylamide), poly (N-ethylmethacrylamide), Poly (N-methyl-N-ethylacrylamide), poly (N-cyclopropylacrylamide). Further Thermogel-type polymers are hydroxypropyl cellulose, Methyl cellulose, Hydroxypropylmethyl cellulose, ethylhydroxyethyl cellulose and Pluronics like F-127, L-122, L-92, L-81, L-61.

The Active ingredients can on the one hand adsorbed in the pores of the carbonaceous layer be (non-covalent, covalent), with their release primarily by Pore size and geometry are controllable. additional Modifications of the porous Carbon layer by chemical modification (anionic, cationic) allow to modify the release, for example, pH-dependent. A further application is the release of active substance-containing carriers, namely Microcapsules, liposomes, nanocapsules, nanoparticles, micelles, synthetic phospholipids, gas dispersions, emulsions, microemulsions, Nanospheres etc., which adsorbs in the pores of the carbon layer and then released therapeutically. By additional covalent or non-covalent modification of the carbon layer can occlude the pores, leaving biologically active agents protected are. In question are the polysaccharides already mentioned above, Lipids etc., but also the mentioned polymers.

The additional coating of the porous carbonaceous layers produced according to the invention therefore makes it possible to distinguish between physical barriers such as inert biodegradable substances (poly-1-lysine, fibronectin, chitosan, heparin, etc.) and biologically active barriers. The latter may be sterically hindering molecules that become physiologically bioactivated and permit the release of drugs or their carriers. For example, enzymes that mediate release, activate biologically active substances or bind non-active coatings and lead to the exposure of drugs. All of the mechanisms and properties specifically listed herein are applicable to both the primary carbon layer produced according to the present invention and layers additionally applied thereto.

The coated according to the invention Implants can in special applications also with living cells or microorganisms be loaded. these can in suitable porous settle carbonaceous layers, the so colonized Implant can then be provided with a suitable membrane coating, the for nutrient and active substances produced by the cells or microorganisms are permeable, not for the cells themselves.

On This can be done using the technology of the invention For example, implants that produce insulin-producing cells which after implantation in the body depending on the glucose level produce and release insulin.

The The following examples serve to illustrate the principles according to the invention and are not limiting thought. In detail, different implants or implant materials according to the inventive method coated and their properties, in particular in terms of biocompatibility, certainly.

Example 1: Carbon

A carbon material coated according to the invention was produced as follows: A polymer film was applied to a paper of 38 g / m ² basis weight by coating the paper several times with a doctor blade with a commercially available epoxidized phenolic resin paint and drying at room temperature. Dry weight 125g / m ² . The pyrolysis at 800 ° C for 48 hours under nitrogen at a shrinkage of 20% and a weight loss of 57% provides an asymmetric carbon sheet with the following dimensions: total thickness 50 microns, with 10 microns of a dense carbonaceous layer according to the invention on an open-pored carbon support with a Thickness of 40 microns, which formed under the pyrolysis conditions in situ from the paper. The absorbency of the coated carbon material was up to 18 g ethanol / m ² .

Example 2: Glass

Duroplan ^® glass is left for 15 min. Subjected to ultrasonic cleaning in a surfactant-containing water bath, rinsed with distilled water and acetone and dried. This material is coated by dip coating with a commercial packaging on Phenoharzbasis with 2.0 x 10 ^-4 g / cm ² coating weight After subsequent carbonization at 800 ° C for 48 hours under nitrogen occurs a weight loss of the coating to 0.33 * 10 ^-4 g / cm ² . The previously colorless coating turns black, and is hardly transparent after carbonization. A test of coating hardness with a pencil drawn over the coated surface at a 45 ° angle weighing 1 kg will not result in any optically noticeable damage to the surface up to a hardness of 5H.

Example 3: Glass, CVD coating (Comparative Example)

Duroplan ^® glass is left for 15 min. Subjected to ultrasonic cleaning, with dist. Rinsed with water and acetone and dried. This material is coated by chemical vapor deposition (CVD) with 0.05 × 10 ^-4 g / cm ² carbon. To this end, benzene is brought into contact with the 1000 ° C glass surface at 30 ° C in a bubbler by nitrogen flow for 30 minutes deposited as a film on the glass surface. The previously colorless glass surface becomes shiny gray and is subdued transparent after deposition. A coating hardness test with a pencil pulled over the coated surface at a 45 ° angle weighing 1kg will not result in any visually noticeable damage to the surface up to a hardness of 6B.

Example 4: Glass Fiber

Duroplan ^® glass fibers with a diameter of 200 microns are heated for 15 min. Subjected to ultrasonic cleaning, with dist. Rinsed with water and acetone and dried. This material is coated by dip coating with a commercial packaging with 2.0 x 10 ^-4 g / cm ² coating weight. After subsequent pyrolysis with carbonization at 800 ° C for 48 hours, a weight loss of the coating occurs 0.33 x 10 ^-4 g / cm ² . The previously colorless coating turns black, and is hardly transparent after carbonization. A test of the adhesion of the coating by bending in the radius of 180 ° results in no flaking, ie visually perceptible damage to the surface.

Example 5: Stainless steel

Stainless steel 1.4301 as 0.1 mm film (Goodfellow) is a 15 min. Subjected to ultrasonic cleaning, with dist. Rinsed with water and acetone and dried. This material is coated by dip coating with a commercial packaging with 2.0 x 10 ^-4 g / cm ² coating weight. After subsequent pyrolysis with carbonization at 800 ° C for 48 hours under nitrogen, a weight loss of the coating to 0.49 · 10 ^-4 g / cm ^{2 occurs} . The previously colorless coating becomes matt black after carbonization. A coating hardness test with a pencil pulled over the coated surface at a 45 ° angle of 1 kg will not result in any visually noticeable surface damage up to 4B hardness.

An adhesive tape peeling test in which a Tesa ^® strips is adhered to at least 3 cm in length for 60 seconds with the thumb on the surface and then peeled off at an angle of 90 ° from the surface again, hardly resulting buildup.

Example 6: stainless steel, CVD coating (comparative example)

Stainless steel 1.4301 as 0.1 mm film (Goodfellow) is a 15 min. Subjected to ultrasonic cleaning, with dist. Rinsed with water and acetone and dried. This material is coated by chemical vapor deposition (CVD) at 0.20 x 10 ^-4 g / cm ² . For this purpose, benzene is brought at 30 ° C in a bubbler by a flow of nitrogen over 30 minutes in contact with the 1000 ° C hot metal surface, decomposed at high temperatures and deposited as a film on the metal surface. The previously metallic surface becomes shiny black after deposition. A coating hardness test with a pencil pulled over the coated surface at a 45 ° angle of 1 kg will not result in any visually noticeable surface damage up to 4B hardness. A Tesafilm peel test, in which a Tesa ^® strip of at least 3 cm in length is glued to the surface for over 60 seconds with a thumb and then pulled off the surface at an angle of 90 °, produces clearly visible, gray adhesions.

Example 7: Titanium

Titanium 99.6% as 0.1 mm film (Goodfellow) is a 15 min. Subjected to ultrasonic cleaning, with dist. Rinsed with water and acetone and dried. This material is coated by dip coating with a commercial Emballagelack with 2.2 · 10 ^-4 g / cm ² . After subsequent pyrolysis with carbonization at 800 ° C for 48 hours under nitrogen, a weight loss of the coating to 0.73 · 10 ^-4 g / cm ^{2 occurs} . The previously colorless coating becomes matt, gray-black glossy. A coating hardness test with a pencil pulled over the coated surface at a 45 ° angle of 1 kg will not result in optical damage to the surface up to a hardness of 8H. Also, for example, with a paper clip, the coating can not be scratched.

A peel test, in which a Tesa ^® strips is adhered to at least 3 cm in length for 60 seconds with the thumb on the surface and then peeled off at an angle of 90 ° from the surface again, does not result in buildup.

Example 8: Titanium, refined with CVD

Titanium 99.6% as 0.1 mm film (Goodfellow) is a 15 min. Subjected to ultrasonic cleaning, with dist. Rinsed with water and acetone and dried. This material is coated by dip coating with a commercial Emballagelack with 2.2 · 10 ^-4 g / cm ² . After subsequent pyrolysis with carbonization at 800 ° C for 48 hours under nitrogen, a weight loss of the coating to 0.73 · 10 ^-4 g / cm ^{2 occurs} . This material is further coated by chemical vapor deposition (CVD) at 0.10 x 10 ^-4 g / cm ² . For this purpose, benzene is brought at 30 ° C in a bubbler by a nitrogen flow over 30 minutes in contact with the 1000 ° C hot, coated metal surface, decomposed and deposited as a film on the surface. The previously metallic surface becomes shiny black after deposition. After cooling to 400 ° C, the surface is oxidized by passing air over a period of 3 hours. A coating hardness test with a pencil placed at an angle of 45 ° with a weight of 1 kg over the be stratified surface results in no visually noticeable damage to the surface up to a hardness of 8H.

A peel test, in which a Tesa ^® strip of at least 3 cm in length is glued to the surface with a thumb for 60 seconds and then peeled off again at a 90 ° angle to the surface, results in gray adhesions.

Example 9

The titanium surfaces are tested on the in vitro Petri dish model for their biocompatibility by means of conventional test methods. 16 cm ² pieces of the coated materials of Examples 2, 7 and 8 are punched out and incubated with blood at 37 ° C., 5% CO ₂ for 3 h. For comparison, equal areas of uncoated titanium and glass were investigated. The experiments are carried out with n = 3 donors and measured per surface with three test specimens. The samples are prepared accordingly and the various parameters (platelets, TAT (thrombin-antithrombin complex) and C5a activation) are determined.

The measured values are tested against a blank value as a control, according to an almost ideal, extremely optimized biocompatibility, and two commercially available dialysis membranes (Cuprophan ^® and Hemophan ^®), to obtain a comparative scale. The results are summarized in Table I. Table I: Biocompatibility test

The Results show a significant improvement in the biocompatibility of the inventive examples, both opposite the dialysis membranes as well as the uncoated samples.

Example 10: Cell growth test

The coated titanium surface of Example 8 and the amorphous carbon of Example 1 were further assayed for cell growth of mouse L929 fibroblasts. As a comparison serves an uncoated titanium surface. For this purpose, 3 × 10 ⁴ cells per specimen were applied to the previously steam-sterilized samples and incubated for 4 days under optimal conditions. Subsequently, the cells were harvested and the number per 4 ml of medium determined automatically. Each sample was measured twice and the mean was formed. The results are given in Table II: Table II: Cell growth on coated titanium

This Experiment shows impressively biocompatibility and cell growth promoting Effect of the coated according to the invention Surfaces, especially when comparing the two titanium surfaces.

Example 11: Coated stent

A commercially available metal stent Fa. Baun Melsungen AG, type Coroflex 2.5 × 19mm is a 15 min. Subjected to ultrasonic cleaning in surfactant-containing water bath, rinsed with distilled water and acetone and dried. This material is coated by dip coating with a commercial packaging on phenolic resin / melamine resin base with 2.0 x 10 ^-4 g / cm ^2. After subsequent pyrolysis with carbonization at 800 ° C for 48 hours under nitrogen, a weight loss of the coating to 0.49 · 10 ^-4 g / cm ^{2 occurs} . The previously metallic high-gloss surface becomes matt black. For a test of the adhesion of the coating by expanding the stent 6 bar to the nominal size of 2.5 mm, the coated stent was inflated with a balloon catheter. The subsequent optical inspection with a magnifying glass showed microscopically no flaking of the homogeneous coating from the metal surface. The absorbency of this porous layer was up to 0.005 g of ethanol.

Example 12: Coated Carbostent

A commercially available carbon-coated metal stent Fa. Sorin Biomedica, type Radix Carbostent 5 × 12mm is a 15 min. Subjected to ultrasonic cleaning, rinsed with distilled water and acetone and dried. This material is dip-coated with a commercial phenolic resin / melamine resin based embossing lacquer at a coating weight of 2.0 × 10 ^-4 g / cm ² . After subsequent pyrolysis with carbonization at 800 ° C for 48 hours under nitrogen, a weight loss of the coating to 0.49 · 10 ^-4 g / cm ^{2 occurs} . The previously black surface becomes dull black after carbonization. For a test of the adhesion of the coating by expanding the stent at 6 bar to the nominal size of 5 mm, the coated stent was stretched. The subsequent optical inspection with a magnifying glass showed microscopically no flaking of the homogeneous coating from the metal surface. The absorption capacity of this porous layer of the abovementioned stent model was up to 0.005 g of ethanol.

Example 13: Activation

Of the coated stent of Example 12 is activated by air at 400 ° C for 8 hours activated. Here, the carbon coating is converted into porous carbon. For one Test the adhesion of the coating by expanding the stent with 6 bar to the nominal size of 5 mm, the coated stent was expanded. The subsequent optical Inspection with a magnifying glass showed microscopically no flaking the homogeneous coating of the metal surface. The absorption capacity of this now porous Layer of the o.g. Stent model was up to 0.007 g of ethanol, which shows that an extra Activation of the carbonaceous layer additionally increases the absorption capacity.

Claims (34)

Process for producing biocompatible coatings on implantable medical devices, including following steps: a) at least partial coating of medical device with a polymer film by means of a suitable Coating or application method; b) heating the Polymer film in an atmosphere which is essentially free of oxygen, at temperatures in the Range of 200 ° C up to 2500 ° C, to Generation of a carbonaceous layer on the medical Contraption. A method according to claim 1, characterized in that the implantable medical device is made of a material selected from carbon, carbon composite, carbon fibers, ceramics, glass, metals, alloys, bones, stone, minerals or precursors of these or other materials which are converted to their thermostable state under carbonization conditions. Method according to one of the preceding claims, characterized characterized in that the implantable medical device selected is from medical or therapeutic implants such as vascular endoprostheses, Stents, Coronary Stents, Peripheral Stents, Orthopedic Implants, Bone or joint prostheses, artificial hearts, artificial heart valves, subcutaneous and / or intramuscular Implants and the like. Method according to one of the preceding claims, characterized in that the polymer film comprises: homopolymers or copolymers of aliphatic or aromatic polyolefins such as polyethylene, Polypropylene, polybutene, polyisobutene, polypentene; polybutadiene; Polyvinyls such as polyvinyl chloride or polyvinyl alcohol, poly (meth) acrylic acid, polyacrylcyanoacrylate; Polyacrylonitrile, polyamide, polyester, polyurethane, polystyrene, polytetrafluoroethylene; Polymers such as collagen, albumin, gelatin, hyaluronic acid, starch, celluloses such as methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, Carboxymethylcellulose phthalate; Casein, dextrans, polysaccharides, Fibrinogen, poly (D, L-lactides), poly (D, L-lactide-co-glycolides), polyglycolides, polyhydroxybutylates, Polyalkylcarbonates, polyorthoesters, polyesters, polyhydroxyvaleric acid, polydioxanones, polyethylene terephthalate, Polymalatsäure, Polytartronsäure, Polyanhydrides, polyphosphazenes, polyamino acids; polyethylene vinyl acetate, silicones; Poly (ester urethanes), poly (ether urethanes), poly (ester ureas), polyethers such as polyethylene oxide, polypropylene oxide, Pluronics, polytetramethylene glycol; Polyvinyl pyrrolidone, poly (vinyl acetate phatalate), and their copolymers, Mixtures and combinations of these homo- or copolymers. Method according to one of claims 1 to 3, characterized that the polymer film is alkyd resin, chlorinated rubber, epoxy resin, acrylate resin, Phenolic resin, amine resin, melamine resin, alkylphenol resins, epoxidized aromatic Resins, oil base, Nitrobase, polyester, polyurethane, tar, tarry materials, Tar pitch, bitumen, starch, Cellulose, shellac, organic materials from renewable Raw materials or combinations thereof. Method according to one of the preceding claims, characterized characterized in that the polymer film as a liquid polymer or polymer solution in a suitable solvent or solvent mixture, if necessary with subsequent Drying, or as a polymer solid, e.g. in the form of slides or sprayable Particles is applied. Method according to Claim 6, characterized that the polymer film by lamination, gluing, dipping, spraying, printing, Squeegee, spincoating, powder coating, or flame spraying on the device is applied. The method of any one of the preceding claims, further comprising the step of depositing carbon and / or silicon by chemical or physical vapor deposition (CVD or PVD). The method of any one of the preceding claims, further comprising the sputtering of carbon and / or silicon and / or of metals. Method according to one of the preceding claims, characterized characterized in that in the carbonaceous layer by means of ion implantation is modified. Method according to one of the preceding claims, characterized characterized in that the carbonaceous layer with oxidizing agents and / or reducing agents, preferably treated by treatment the coated device chemically modified in oxidizing acid or alkali becomes. Method according to one of the preceding claims, characterized characterized in that the carbonaceous layer by means of a solvent or solvent mixtures is cleaned. Method according to one of the preceding claims, characterized characterized in that steps a) and b) are carried out several times, to obtain a carbonaceous multilayer coating, preferably with different porosities by pre-structuring the polymer films or substrates or suitable oxidative treatment of individual layers. Method according to one of the preceding claims, characterized characterized in that the carbon-containing coated medical Device with at least one additional layer of biological degradable or resorbable polymers such as collagen, albumin, Gelatin, hyaluronic acid, Strength, Celluloses such as methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, Carboxymethylcellulose phthalate; Casein, dextrans, polysaccharides, Fibrinogen, poly (D, L-lactides), Poly (D, L-lactide-co-glycolide), poly (glycolide), poly (hydroxybutylate), Poly (alkyl carbonates), poly (orthoesters), polyesters, poly (hydroxyvaleric acid), polydioxanones, Poly (ethylene terephthalate), poly (malic acid), poly (tartronic acid), polyanhydrides, Polyphosphazenes, poly (amino acids), and their co-polymers or non-biological degradable or resorbable polymers at least partially coated becomes. Method according to one of the preceding claims, characterized characterized in that the coating on the device with at least an active substance, is loaded with microorganisms or living cells. Method according to claim 15, characterized in that that the at least one active substance is adsorbed, absorbed, Physisorption, chemisorption, covalent bonding, or non-covalent Binding, electrostatic fixation, or occlusion in pores or applied or immobilized in the coating. Method according to one of claims 15 or 16, characterized that the at least one active substance is substantially permanent or is immobilized in the coating and inorganic substances, e.g. Hydroxyapatite (HAP), fluorapatite, tricalcium phosphate (TCP), Zinc; and / or organic substances such as peptides, proteins, carbohydrates such as mono-, oligo- and polysaccharides, lipids, phospholipids, steroids, lipoproteins, Glycoproteins, glycolipids, proteoglycans, DNA, RNA, signal peptides or antibodies or antibody fragments, bioresorbable polymers, e.g. Polylactonic acid, chitosan, as well as pharmacologically effective substances or mixtures, combinations of these and the like includes. Method according to one of claims 15 or 16, characterized that the at least one contained on or in the coating Active ingredient from the coating is controlled releasable and inorganic substances, e.g. Hydroxylapatite (HAP), fluorapatite, Tricalcium phosphate (TCP), zinc; and / or organic substances like Peptides, proteins, carbohydrates such as mono-, oligo- and polysaccharides, Lipids, phospholipids, steroids, lipoproteins, glycoproteins, glycolipids, Proteoglycans, DNA, RNA, signal peptides or antibodies or Antibody fragments, bioresorbable polymers, e.g. Polylactic acid, chitosan, and the like, and pharmacologically active substances or mixtures. Method according to one of claims 17 or 18, characterized in that the pharmacologically active substances are selected from heparin, synthetic heparin analogues (eg fondaparinux), hirudin, antithrombin III, drotrecogin alpha; Fibrinolytica such as alteplase, plasmin, lysokinases, factor XIIa, prourokinase, urokinase, anistreplase, streptokinase; Platelet aggregation inhibitors such as acetylsalicylic acid, ticlopidine, clopidogrel, abciximab, dextrans; Corticosteroids such as Alclometasone, Amcinonide, Augmented Betamethasone, Beclomethasone, Betamethasone, Budesonide, Cortisone, Clobetasol, Clocortolone, Desonide, Desoximetasone, Dexamethasone, Flucinolone, Fluocinonide, Flurandrenolide, Flunisolide, Fluticasone, Halcinonide, Halobetasol, Hydrocortisone, Methylprednisolone, Mometasone, Prednicarbate, Prednisone , Prednisolone, triamcinolone; non-steroidal anti-inflammatory drugs such as diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamate, mefenamic acid, meloxicam, nabumetone, naproxen, oxaprozin, piroxicam, salsalates, sulindac, tolmetin, celecoxib, rofecoxib; Cytostatic drugs such as alkaloids and podophyllum toxins such as vinblastine, vincristine; Alkylating agents such as nitrosoureas, nitrogen mustard analogues; cytotoxic antibiotics such as daunorubicin, doxorubicin and other anthracyclines and related substances, bleomycin, mitomycin; Antimetabolites such as folic acid, purine or pyrimidine analogs; Paclitaxel, docetaxel, sirolimus; Platinum compounds such as carboplatin, cisplatin or oxaliplatin; Amsacrine, irinotecan, imatinib, topotecan, interferon-alpha 2a, interferon-alpha 2b, hydroxycarbamide, miltefosine, pentostatin, porfimer, aldesleukin, bexarotene, tretinoin; Antiandrogens, and antiestrogens; Anti-arrhythmic agents, in particular class I antiarrhythmics, such as quinidine-type antiarrhythmics, for example quinidine, dysopyramide, ajmaline, prallybium tartrate, detalobium bitartrate; Lidocaine-type antiarrhythmics, eg lidocaine, mexiletine, phenytoin, tocainide; Class IC antiarrhythmics, eg propafenone, flecainide (acetate); Class II antiarrhythmics, beta-receptor blockers such as metoprolol, esmolol, propranolol, metoprolol, atenolol, oxprenolol; Class III antiarrhythmics such as amiodarone, sotalol; Class IV antiarrhythmics such as diltiazem, verapamil, gallopamil; other antiarrhythmics such as adenosine, orciprenaline, ipratropium bromide; Agents to stimulate angiogenesis in the myocardium such as Vascular Endothelial Growth Factor (VEGF), Basic Fibroblast Growth Factor (bFGF), non-viral DNA, viral DNA, endothelial growth factors: FGF-1, FGF-2, VEGF, TGF; Antibodies, monoclonal antibodies, anticalins; Stem Cells, Endothelial Progenitor Cells (EPC); digitalis such as acetyldigoxin / metildigoxin, digitoxin, digoxin; Cardiac glycosides such as ouabain, proscillaridin; Antihypertensive agents such as centrally acting anti-adrenergic agents, eg methyldopa, imidazoline receptor agonists; Dihydropyridine-type calcium channel blockers such as nifedipine, nitrendipine; ACE inhibitors: quinaprilat, cilazapril, moexipril, trandolapril, spirapril, imidapril, trandolapril; Angiotensin II antagonists: candesartan cilexetil, valsartan, telmisartan, olmesartan medoxomil, eprosartan; peripherally acting alpha-receptor blockers such as prazosin, urapidil, doxazosin, bunazosin, terazosin, indoramine; Vasodilators such as dihydralazine, diisopropylamine dichloroacetate, minoxidil, nitroprusside sodium; other antihypertensive agents such as indapamide, co-dergocrin mesilate, dihydroergotoxine methanesulfonate, cicletanine, bosentan, fludrocortisone; Phosphodiesterase inhibitors such as milrinone, enoximone and antihypotonics, such as in particular adrenergic and dopaminergic substances such as dobutamine, epinephrine, etilefrine, norfenefrine, norepinephrine, oxilofrin, dopamine, midodrine, pholedrine, aminotetium; and partial adrenoceptor agonists such as dihydroergotamine; Fibronectin, polylysines, ethylene-vinylacetates, inflammatory cytokines such as: TGFβ, PDGF, VEGF, bFGF, TNFα, NGF, GM-CSF, IGF-α, IL-1, IL-8, IL-6, Growth Hormone; and adhesive substances such as cyanoacrylates, beryllium, silica; and Growth Factors such as erythropoietin, hormones such as corticotropins, gonadotropins, somatropin, thyrotrophin, desmopressin, terlipressin, oxytocin, cetrorelix, corticorelin, leuprorelin, triptorelin, gonadorelin, ganirelix, buserelin, nafarelin, goserelin, as well as regulatory peptides such as somatostatin, octreotide ; Bone and cartilage stimulating peptides, bone morphogenetic proteins (BMPs), in particular recombinant BMPs such as recombinant human BMP-2 (rhBMP-2)), bisphosphonates (eg risedronate, pamidronate, ibandronate, zoledronic acid, clodronic acid, etidronic acid, alendronic acid, tiludronic acid), Fluorides such as disodium fluorophosphate, sodium fluoride; Calcitonin, dihydrotachystyrene; Growth Factors and Cytokines such as Epidermal Growth Factor (EGF), Platelet-Derived Growth Factor (PDGF), Fibroblast Growth Factors (FGFs), Transforming Growth Factors-b TGFs-b), Transforming Growth Factor-a (TGF-a), Erythropoietin (Epo), Insulin-Like Growth Factor-I (IGF-I), Insulin-Like Growth Factor-II (IGF-II), Interleukin-1 (IL-1), Interleukin-2 (IL-2), Interleukin 6 (IL-6), Interleukin-8 (IL-8), Tumor Necrosis Factor-a (TNF-a), Tumor Necrosis Factor-b (TNF-b), Interferon-g (INF-g), Colony Stimulating Factors (CSFs); Monocyte chemotactic protein, fibroblast stimulating factor 1, histamine, fibrin or fibrinogen, endothelin-1, angiotensin II, collagens, bromocriptine, methylsergide, methotrexate, carbon tetrachloride, thioacetamide, and ethanol; furthermore silver (ions), titanium dioxide, antibiotics and anti-infective agents, in particular β-lactam antibiotics, for example β-lactamase-sensitive penicillins such as benzylpenicillin (penicillin G), phenoxymethylpenicillin (penicillin V); β-lactamase resistant penicillins such as aminopenicillins such as amoxicillin, ampicillin, bacampicillin; Acylaminopenicillins such as mezlocillin, piperacillin; Carboxypenicillins, cephalosporins such as cefazolin, cefuroxime, cefoxitin, cefotiam, cefaclor, cefadroxil, cefalexin, loracarbef, cefixime, cefuroxime axetil, ceftibuten, cefpodoxime proxetil, cefpodoxime proxetil; Aztreonam, Ertapenem, Meropenem; β-lactamase inhibitors such as sulbactam, sultamicillin tosilate; Tetracyclines such as doxycycline, minocycline, tetracycline, chlortetracycline, oxytetracycline; Aminoglycosides such as gentamicin, neomycin, streptomycin, tobramycin, amikacin, netilmicin, paromomycin, framycetin, spectinomycin; Macrolide antibiotics such as azithromycin, clarithromycin, erythromycin, roxithromycin, spiramycin, josamycin; Lincosamides such as clindamycin, lincomycin, gyrase inhibitors such as fluoroquinolones such as ciprofloxacin, ofloxacin, moxifloxacin, norfloxacin, gatifloxacin, enoxacin, fleroxacin, levofloxacin; Quinolones such as pipemic acid; Sulfonamides, trimethoprim, sulfadiazine, sulfals; Glycopeptide antibiotics such as vancomycin, teicoplanin; Polypeptide antibiotics such as polymyxins such as colistin, polymyxin B, nitroimidazole derivatives such as metronidazole, tinidazole; Aminoquinolones such as chloroquine, mefloquine, hydroxychloroquine; Biguanides such as proguanil; Quinine alkaloids and diaminopyrimidines such as pyrimethamine; Amphenicols such as chloramphenicol; Rifabutin, dapsone, fusidic acid, fosfomycin, nifuratel, telithromycin, fusafungin, fosfomycin, pentamidine diisethionate, rifampicin, taurolidine, atovaquone, linezolid; Antivirals such as acyclovir, ganciclovir, famciclovir, foscarnet, inosine (dimepranol-4-acetamidobenzoate), valganciclovir, valaciclovir, cidofovir, brivudine; antiretroviral agents (nucleoside analogue reverse transcriptase inhibitors and derivatives) such as lamivudine, zalcitabine, didanosine, zidovudine, tenofovir, stavudine, abacavir; non-nucleoside analogue reverse transcriptase inhibitors: amprenavir, indinavir, saquinavir, lopinavir, ritonavir, nelfinavir; Amantadine, ribavirin, zanamivir, oseltamivir and lamivudine, and any combinations and mixtures thereof. Method according to one of Claims 16 to 19, characterized that the pharmacologically active substances in microcapsules, liposomes, Nanocapsules, nanoparticles, micelles, synthetic phospholipids, Gas dispersions, Emulsions, microemulsions, or nanospheres are incorporated, those in the pores or on the surface of the carbonaceous Layer for a later one Release in the body reversibly adsorbed and / or absorbed. Biocompatible coated, implantable medical Device producible according to one of the preceding claims. Apparatus according to claim 21 consisting of metals such as stainless steel, titanium, tantalum, platinum, nitinol, or nickel-titanium alloy; Carbon fibers, full carbon, carbon composite, ceramics, glass or Glass fibers. Apparatus according to claim 21 or 22, comprising a plurality of carbonaceous layers, preferably with different ones Porosities. Device according to one of claims 21 to 23, comprising a Coating of biodegradable or resorbable polymers such as collagen, albumin, gelatin, hyaluronic acid, starch, celluloses such as methylcellulose, Hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose phthalate; Casein, dextrans, polysaccharides, fibrinogen, poly (D, L-lactides), Poly (D, L-lactide-co-glycolides), Poly (glycolides), poly (hydroxybutylates), poly (alkylcarbonates), poly (orthoesters), Polyester, poly (hydroxyvaleric acid), Polydioxanone, poly (ethylene terephthalate), poly (malic acid), poly (tartronic acid), polyanhydrides, Polyphosphazenes, poly (amino acids), and their co-polymers. Device according to one of claims 21 to 23, comprising a Coating of non-biodegradable or absorbable Polymers such as poly (ethylene vinyl acetates), silicones, acrylic polymers such as polyacrylic acid, polymethyl, Polyacrylcyanoacrylat; Polyethylenes, polypropylenes, polyamides, polyurethanes, Poly (ester urethanes), poly (ether urethanes), poly (ester ureas), Polyethers (poly (ethylene oxide), poly (propylene oxide), Pluronics, poly (tetramethylene glycol); Vinyl polymers such as polyvinylpyrrolidones, poly (vinyl alcohols), or Poly (vinyl acetate phatalate), and their copolymers. Apparatus according to any one of claims 21 to 25, further comprising anionic or cationic or amphoteric coatings, such as e.g. Alginate, carrageenan, carboxymethylcellulose; Chitosan, poly-L-lysine; and or Phosphoryl choline. Device according to one of claims 21 to 26, characterized that the carbonaceous layer is porous, preferably macroporous with pore diameters in the range of 0.1 to 1000 μm, and particularly preferably nanoporous is. Device according to one of claims 21 to 26, characterized that the carbonaceous layer is non-porous or substantially closed-pored is. Device according to one of claims 21 to 28, containing a or more active ingredients as mentioned in claim 19. The device of claim 29, further comprising the release of the active substances influencing coating selected from pH-sensitive and / or temperature-sensitive polymers and / or biologically active Barriers such as Enzymes. A coated stent according to any one of claims 21 to 30th Coated heart valve according to one of claims 21 to 30th Device according to one of claims 21 to 30, in the form of a orthopedic Bone or joint prosthesis, a bone substitute or a Vertebral substitute in the thoracic or lumbar region of the spine. Device according to one of claims 21 to 30, in the form of a subcutaneous and / or intramuscular implant for controlled release of active ingredient.