WO2002080996A1

WO2002080996A1 - Medical implant and method for producing the same

Info

Publication number: WO2002080996A1
Application number: PCT/EP2001/003785
Authority: WO
Inventors: Franz Herbst; Christoph Klein
Original assignee: Franz Herbst; Christoph Klein
Priority date: 2001-04-03
Filing date: 2001-04-03
Publication date: 2002-10-17

Abstract

The invention relates to a medical implant, in particular to a stent or a bone implant with a long-term stable coating, which preferably consists of a complete diamond-like plasma polymer coating or a DLC (DLC = diamond-like-coating), said coating after successful implantation acting as protection against the undesirable release of implant metal ions and exhibiting excellent bio- and haemocompatible properties. A biodegradable coating, in particular a suitable polymer coating, containing at least one medical active substance is applied to the long-term stable coating, said polymer coating preferably having areas with different biological degradation rates and/or different active substances and/or different active substance concentrations and selectably releasing specifically effective active substances. According to requirements, said substances have a specific anti-coagulatory, anti-inflammatory, anti-metabolic, anti-mitotic, anti-stenotic, anti-thrombotic or immunomodulatory action, or act as inhibitors of platelet activity, metabolic activity or the cell cycle and/or contain zytostatics, signal-blocking nucleic acids or growth hormones. A suitable intermediate coating is applied between the two coatings, said intermediate coating being configured in particular to promote an improved adhesion of the biodegradable coating by means of ionic, hydrophilic, hydrophobic or covalent interactions. The invention also relates to a method for producing an implant of this type.

Description

Medical implant and process for its manufacture

description

The present invention relates to a medical implant with a long-term stable coating and a method for its production. The invention relates in particular to appropriately trained vascular prostheses or "stents" and orthopedic bone implants.

It is known from the prior art that uncoated medical implants made of medical stainless steel or nitinol (nickel-titanium alloy with shape memory) release nickel and chromium ions over time, which negatively influence the wound healing process after implantation and not only that Reduce overgrowth of the implant surface with new endothelium but can also lead to chronic inflammatory reactions.

To suppress these negative influences of the implant material, it is known to provide medical implants with a long-term stable polymer coating, which prevents direct body contact of the implant material. This polymer coating not only provides long-term, reliable protection of the surrounding body tissue or body fluid against diffusing implant metal ions, but also has good bio- and hamocompatible properties. The polymer coating is sufficiently stable for the entire expected life of the implant to ensure these good properties and to act as a barrier to undesired metal ion diffusion. The terms "long-term stable" and In the present context, “permanently” therefore describes a period of time that essentially corresponds to the life of the implant, which is usually a few years.

Regardless of this problem, it is also known from the prior art that medical devices or implants that come into contact with body fluids or body tissue - such as e.g. Catheters, electrodes, implants, etc. -, can lead to immune defense reactions, thrombus formation, inflammation, etc. In the case of stents in particular, ruptures and trauma can occur at the implantation sites, which can occur both when the occlusion in the blood vessel is opened and only afterwards. This traumatic work can lead to restenosis at the site of the implantation, i.e. that the wound healing process in the blood vessel can lead to hyperproliferation of the smooth muscle cells, which can grow into the vascular area of the stent and partially or completely occlude it.

In order to suppress such a body reaction, it is known from the prior art to coat the surface of medical implants or stents with a short-term stable biodegradable polymer in which a medicinal substance or a medicinal active substance is incorporated, which suppresses, for example, the proliferation of smooth muscle cells. After the implantation, the medicinal substance is released with the polymer degraded for a certain period of time directly at the implantation site and thereby prevents the proliferation of the smooth muscle cells. The time scale for the degradation of the surrounding short-term stable polymer matrix and the release of the medicinally active substance stored therein is usually of the order of a few days or weeks, so that this is a relatively short-term process compared to the expected life of the implant. As an alternative to this, the medicinal active ingredient can also be introduced into a sponge-like polymer bound to the stent surface by means of diffusion and then gradually released again later by diffusion from the pores of the polymer (WO 96/32907). Here too, the active ingredient is usually released over the course of several days or weeks.

With these two methods, a whole range of medicinal agents, medicines or pharmaceuticals, e.g. Anticoagulants, anti-inflammatory drugs, platelet activation inhibitors, cytostatics, antimitotic drugs, antimetabolic drugs, signal-blocking nucleic acids such as antisense RNA, growth hormones and much more, together with a stent or other medical implant to be introduced into a body, where they are implanted after implantation can be released directly at the implantation site in order to have an optimal effect there, for example, to prevent restenosis.

To date, however, no medical implants, in particular stents, are known from the prior art which both enable the targeted release of suitable medicaments, for example for the inhibition of hyperproliferation (late restenosis) of smooth muscle cells, and also long-term stable bio- and hamocompatible Have coating for the rapid formation of endothelium, which suppresses or at least minimizes any immunological reactions and promotes rapid integration of the implant as the body's own. Conventional implants therefore always have only one of the two advantages mentioned, because they either offer the possibility for targeted, targeted medicinal treatment of undesirable body reactions or reliable protection against the release of harmful metal ions and good bio- and hemocompatible properties lacking. The object of the present invention is therefore essentially to overcome this disadvantage of the medical implants known from the prior art and to create an implant, in particular a stent, which is capable of providing a medicament after the implantation has taken place , which is typically released over a period of a few days or weeks and, for example, suppresses the migration and proliferation of smooth muscle cells and thus inhibits the body reactions which are triggered by the traumatic work during the implantation of the stent and lead to late restenosis. However, the implant sought is also intended to present a long-term stable bio- and hamocompatible surface, which allows rapid proliferation of the endothelial cells above the implant and thus promotes rapid encapsulation of the implant with endothelium so that the foreign body implant is no longer immunologically visible to the body make and fully integrate into the body. However, this long-term stable surface or layer should not only be bio-compatible and hemocompatible, but also suppress the harmful influences by elution of heavy metal ions from the stent into the surrounding tissue and / or body fluids. The task is also to create a suitable manufacturing process for such implants.

The present object is achieved by a medical implant according to claim 1 and by a method for producing such an implant according to claim 20, preferred embodiments being apparent from the associated subclaims.

In order to produce a medical implant according to the invention, a suitable implant is first provided in a first step and is preferably completely provided with a long-term stable bio- and hemocompatible coating. A carbon-containing coating, in particular a plasma polymer coating, is preferably applied here. This coating is applied by means of a suitable plasma polymerization process, the process parameters preferably being chosen such that a diamond-like coating or, in short, also DLC coating (DLC = diamond-like coating) is formed, which, owing to its particularly favorable application properties and its good properties Body tolerance is particularly well suited for the present purposes. The general conditions for the construction of the plasma required for this are known from the prior art, reference being made in particular to the following publications: Comprehensive Polymer Sei. 4, 357-375. 2 Encycl. Polym. Be. Engeniering. 11, 248-261; Houben-Weyl E20 / 1, 361-368; gen .: J. Appl. Polym. Be. 38, 741-754 (1989), I. Yasuda, Plasma Polymerization and Plasma Treatment, New York: Wiley 1984, I. Yasuda, Plasma Polymerization, Orlando, Florida: Academic Press 1986.

To generate such a plasma polymer coating, in particular a diamond-like plasma polymer coating, by means of a plasma polymerization process, alkanes, alkenes or alkynes and halogenated — preferably fluorinated — hydrocarbons are preferably used as starting monomers for the polymer or copolymer formed. Preferred examples are tetrafluoroethylene, hexafluoroethane, perfluoropropylene, methane, acetylene, ethane, propane, butane, hexane, heptane, hexane etc., methane being very particularly preferred. Silicon- or nitrogen-containing hydrocarbons or mixtures of said hydrocarbons can also be used.

In addition, mixtures of the monomers mentioned with a carrier gas can also be used. Noble gases are used as carrier gases preferred, among which argon and / or helium are particularly preferred. The various processes for producing corresponding coatings are known from the prior art.

The plasma polymerization can also be used to apply differently designed polymer areas to the respective implant as required, which are arranged in a locally distributed manner on the implant surface and / or comprise different polymer layers lying one above the other.

In a second step, a short-term stable, drug-eluting layer is applied to this long-term stable bio- and hamocompatible coating. This is done using methods that are known from the prior art. For this purpose, for example, a biodegradable polymer (layer polymer), e.g. Poly-L-lactic acid, Poly-D; L-lactic acid-co-glycolide, poly-hydroxybutyrates, polyphosphoric esters, polyamino acids cellulose, hyaluronic acid, starch, fibrin, chitosan and many others, as well as a suitable drug, for example to suppress the clinical picture the late restenosis, suspended or dissolved.

One or more medicinal products are preferably introduced as the medicinal active ingredient, which are anticoagulant, anti-inflammatory, antimetabolic, antimitotic, antistenotic, antithrombotic, immunomodulatory, effective as inhibitors of platelet activation, as inhibitors of metabolic activity or as inhibitors of the cell cycle, or cytostatics, signal-blocking nucleic acids or include growth hormones.

In particular, acetylsalicylic acid (ASA), triclopidine-HCl, dipgridamole-ASA or other antitrombotics; Mistletoe, Nimustin-HCI, Melphalen, Carmustin, Lomustin, Cyclophosphamide, Ifosfamid, Trofosfamid, Chlorambucil, Busulfan, Treosulfan, bendamustine HCI, thiotepa, fluorauracil, cytasabin, methotroxate disodium, aemcitabine HCI, mercaptopurine, vinblastine sulfate, vinoristine sulfate, paclitaxel or other cytostatic agents; Warfarin sodium, phenprocoumon, heparin calcium. Enoxaparin sodium, reoiparin sodium, heparin sodium, dalteparin sodium, nadroparin calcium, tinzaparin sodium, certoparin sodium, sodium pantosan polysulfate or other anticoagulants; Bromelaine, Chamomile Blue Oil Extract, Willow Bark Extract, Yarrow Herb Extract, Aescin, Chymostrypsin, Sarrapeptase, Pancreatin, Arnica Tincture, Aluminum Acetate, Choline Stearate, Heparin Sodium, Dimethyl Sulfoxide, Cuajacolliquid or other anti-inflammatory agents; Cortisone, diclophenac sodium, ASA, phenylbutazone, indomethacin, ibuprofen, piroxicam, mofebutazone, preduison, cytasabine, dexamethasone, prednisolone, or other glucocorticoids; suramin; staurosporine; Actinomycin D; Called sirolimus or trapidil.

The medical implant is then immersed in this prepared solution or sprayed with this solution. The solvent is then evaporated. This process can be repeated several times, it being possible to incorporate different concentrations of the same medicament and / or different medicaments in different layers one above the other and / or to arrange the desired active substances in different, locally distributed areas on the implant. , The suitable choice of layer polymers also allows layers to be broken down at different speeds.

The implant according to the invention, in particular a stent, therefore consists of a base carrier material, such as medical stainless steel, nitinol, tantalum or other suitable metals or plastics, which is coated with one or more bio- and hemocompatible, long-term stable coatings, the service life of which is essentially at least the service life of the implant. On this coating (s) is then followed by one or more short-term stable biodegradable coatings or layers that release one or more stored drugs after implantation, for example to suppress the hyperproliferative event that leads to the formation of late restenosis with medication. This layer or layers are completely degraded within a period of a few days or weeks, so that the first bio- and hamo-compatible, long-term stable layer appears. This layer then has the task of ensuring an optimal overgrowth of endothelial cells and stimulating as few immunological, coagulatory or thrombotic responses as possible. The faster and better the implant is enclosed by endothelium, the faster and better the implant is tolerated by the body and integrated into it.

The implant can be provided with the biodegradable layer or coating either completely or only in regions. In the case of a stent, for example, one can face the surrounding vessel wall

Coating area or in a corresponding coating segment a later restenosis inhibiting drug are introduced, while the for

Lumen-facing side of this stent is provided with another specifically active drug that may be another one to be feared there

Complication, such as thrombosis, is prevented. The resulting stent then has a long-term stable, biocompatible layer that has a coating of a short-term, drug-eluting layer. This in turn comprises two differently designed areas or segments which simultaneously elute medicaments of different activity into different compartments of a vessel, namely towards the vessel wall and the vessel lumen.

Another variant of controlled drug release through biodegradable layers on long-term stable layers is only that of the coating To see the side of a stent facing the vessel wall with a biodegradable layer into which at least one drug that prevents restenosis is introduced. Upon contact with the surrounding vessel wall, this medicine can diffuse into the surrounding tissue and show its desired effect there. The side facing the lumen of the vessel can remain uncoated so that the good hemo- and biocompatible properties of the long-term stable layer, as are known, for example, particularly from DLC layers, are immediately effective.

For better adherence or integrity between the long-term stable. To achieve the coating and the biodegradable coating, an intercalating intermediate coating or intermediate layer can be applied between these two coatings, which ensures that there is no premature mechanical detachment of the biodegradable polymer from the long-term stable layer. This is of particular importance for mechanically stressed implants, e.g. in the case of stents or layers which do not show good adhesion to one another. When using carbon-containing coatings, such as diamond-like coatings, which have very good long-term biocompatible properties, but have only a slight tendency to bind other substances, difficulties can arise when applying the biodegradable layer, since there are only slight interactions between them occur in the layers and so there is only a reduced adhesion of the two layers to one another.

The adhesion-promoting layer can bond the long-term stable layer with the biodegradable layer, preferably via ionic, hydrophilic or hydrophobic interactions or via covalent bonds. Here, for example, adjacent coatings or layers with ionically interacting polycations or polyanions can be applied. However, a photochemically covalently crosslinking substance can also be applied as an intermediate layer or intermediate coating and activated or crosslinked by irradiation with an electromagnetic radiation having a suitable wavelength. 3-Trifluoromethyl-3- (m-isothiocyano-phenyl) diazinin (TRIMID) may be mentioned as a particularly suitable photoactive substance for this purpose.

The present invention is explained in more detail below on the basis of several preferred special exemplary embodiments.

The first embodiment relates to the production of a stent according to the invention with:

- a complete, long-term stable, bio- and hemocompatible first polymer coating and

- A complete, short-term stable resorbable second polymer coating applied to this first polymer coating with at least one introduced medical agent or drug.

A stent made of stainless steel 316 L is firstly coated in a conventional manner by means of a known plasma chemical method of the type mentioned above, such as, for example, plasma-assisted chemical vapor deposition (plasma-enhanced chemical vapor deposition or PECVD), with a carbon coating or Provide plasma polymer coating, which due to its diamond-like properties is usually referred to simply as a DLC layer (DLC = diamond jike coating) and, as already mentioned, not only as Protective layer against released metal ions serves but also has the desired good bio- and hemocompatible properties.

The plasma-polymer-coated stent pretreated in this way is then briefly immersed in a solution of poly-D; L-lactic acid-co-glycolide (Boehringer Mannheim Resomer RG 503 H) in acetone, which, in dissolved or suspended form, also contains one or more of the medicaments mentioned above contains.

Suramin, a growth antagonist that inhibits cell proliferation, is, for example, dissolved or suspended at a desired concentration in a 10% poly-D, L-lactic acid-co-glycoid / acetone solution. In the same way, other growth inhibitors, such as, for example, glucocorticoids, such as dexamethasone and prednisolone, inhibitors of metabolic activity and the cell cycle, such as staurosporine and actinomycin D, other substances, such as trapidil or antisense nucleic acids, can be applied to the biodegradable layer. The kinetics of the release of the active ingredients can be determined by the type and composition of the layer. Depending on the type of application, quickly or slowly degradable layers can be applied to the carbon-coated stent. It can be shown that dexamethasone and prednisolone have no antimigratory or antiproliferative influence on adult human endothelial cells. The overgrowth of the stent surface is not inhibited. It is known that glucocorticoids and dexamethasone inhibit smooth muscle cell migration and proliferation and have a beneficial effect on the restenosis rate. The migration and proliferation of smooth muscle cells provoked by activated platelets and leukocytes could be very strongly inhibited by adding trapidil. The expression of the PDGF-R by smooth muscle cells can be reduced by adding specific anti-sense cDNA, complementary to mRNA of the platelet-derived growth factor receptor (PDGF-R). Staurosporine and Actinomycin D reduce the migration and proliferation of smooth muscle cells, but also have similar effects on endothelial cells.

The stent is then removed and air-dried. This process can be repeated several times as required until the stent is provided with a sufficiently strong biodegradable polymer coating, the thickness of which is in the micrometer range and which contains the drug with the desired total concentration. After the last coating process, the stent is first dried at room temperature (RT) and then dried under vacuum in order to remove excess acetone as much as possible.

The procedure described gives a stent which is completely provided with a long-term stable first polymer coating, onto which a second complete layer of a biodegradable polymer with at least one embedded drug is applied, which after implantation has taken place due to the biodegradation of the polymer surrounding it a desired period of time eluted from the layer. After the biodegradation of the outer polymer coating, the long-term stable lower polymer coating remains which not only offers the desired reliable protection against the release of metal ions and the associated undesirable side effects, but also shows the desired good bio- and hemocompatible properties.

II.

The second embodiment relates to the production of a stent according to the invention with: - a complete, long-term stable, bio- and hemocompatible first polymer coating;

- a complete, intercalating ionic adhesion-promoting intermediate layer; and a complete, short-term stable, resorbable second polymer coating applied to the intermediate layer with at least one introduced medical agent or medicament.

As in the first exemplary embodiment, a stent made of stainless steel 316L is first completely provided with a carbon layer or DLC layer in a known manner using a conventional plasma chemical method.

The stent pretreated in this way is now used to apply an ionic adhesion promoter layer for 30 min. at room temperature in a solution of 100 μg / ml polyethyleneimine in PBS [phosphate buffer saline: 5 mmol NaH2Pθ4 + 100 mmol NaCl, pH 7.4]. The stent is then washed 3 times with PBS and washed once with water before it is dried at room temperature (RT).

The stent, which is now completely coated with the ionic coupling agent polyethyleneimine, is briefly immersed in a solution of poly-D; L-lactic acid-co-glycolide in acetone, which contains one or more of the above-mentioned drugs in dissolved or suspended form , The stent is now removed and air dried. This process can be repeated several times until the stent is provided with a sufficiently strong biodegradable layer in which the drug is contained at the desired total concentration. After the last coating process, the stent is dried at room temperature (RT) and then dried in vacuo. A stent is thus obtained which is provided with a long-term stable, completely bio- and hemocompatible first polymer coating, which carries a second complete coating made of a biodegradable polymer, in which at least one drug is embedded. This second coating is bound to the long-term stable coating via an ionic interaction with the cationic adhesion-promoting polyethyleneimine intermediate layer. In the present case, a cationic coupling agent is advantageous because the biodegradable layer is a polyanion and is well bound by the oppositional charge of the cationic coupling agent.

Of course, other well-bonded connections between the long-term stable coating and the layer containing biodegradable drugs can also be imagined. These layers can be covalently bonded to one another, for example via covalent crosslinkers such as photoactive crosslinkers, which generate reactive groups when irradiated, which produce a coavlent bond between the long-term stable layer and biodegradable polymer. These adhesion promoters are less preferred, however, since with these compounds it leads to covalent modifications of the long-term stable biocompatible layer and can therefore change the property of this layer, which can lead to an impairment of its biocompatible behavior. This is not to be feared in the case of ionically bonded adhesion promoters, since this adhesion-promoting layer also elutes from the long-term stable surface over time and does not leave any residues, which could influence the biocompatible properties of the long-term stable layer. The third exemplary embodiment relates to the production of a stent according to the invention with: a complete, long-term stable, biocompatible and hemocompatible first polymer coating and a short-term stable resorbable second polymer coating with at least one introduced medical agent or medicament, which, however, only on the side of the stent facing the vessel side is applied.

A stent made of stainless steel 316 L is first again provided in a known manner with a complete carbon coating (DLC coating) by means of a conventional plasma chemical method of the type mentioned above.

A balloon is then inserted into the lumen of the stent (PCTA catheter), which is subjected to a low pressure so that the balloon walls press against the inside of the stent, but no further deformation of the stent takes place. The stent is then briefly immersed in a solution of poly-D; L-lactic acid-co-glycolide in acetone, which contains one or more of the above-mentioned antistatic drugs in dissolved or suspended form, with the stent on its not containing the balloon in contact with the outside is coated accordingly. The stent is now removed and air dried. This process can be repeated several times until the stent is provided with a sufficiently strong biodegradable layer in which the medicament introduced is contained in the desired total concentration. After the last coating process, the stent is at room temperature (RT) dried, the pressure released from the balloon catheter and the balloon removed. The stent is then dried in vacuo.

A stent with two differently coated sides is thus obtained; an inner side facing the lumen of the stent, which is only provided with a long-term stable bio- and hemocompatible coating, and an outer side facing the vessel wall, which is provided with a second biodegradable polymer coating in addition to this lower long-term stable bio- and hemocompatible coating an antistatic drug is embedded.

IV.

Finally, the fourth exemplary embodiment relates to the production of a stent according to the invention with: - a complete, long-term stable, bio- and hemocompatible first polymer coating and - a complete short-term stable resorbable second polymer coating, at least one antistenotic on the outside of the stent and at least one on the inside of the stent antithrombotic drug is introduced into the polymer coating.

A stent made of stainless steel 316 L is first again completely coated with a carbon layer (DLC) in a conventional manner using a suitable plasma technology process. A balloon (PCTA catheter) is then inserted into the lumen of the stent, which is subjected to a low pressure so that the balloon walls press against the inside of the stent, but no further deformation of the stent takes place. Now the stent is briefly immersed in a solution of poly-D; L-lactic acid-co-glycolide in acetone, which in solution or suspended form contains at least one antistatic first drug. The stent is then removed and air dried. This process can be repeated several times until the outside of the stent is provided with a sufficiently strong, biodegradable coating which contains the at least one antistatic first drug with the desired total concentration. After the last coating process, the stent is dried at room temperature (RT), the pressure is released from the balloon catheter and the balloon is removed.

A balloon is then pressurized, which contains a lumen in the middle, which after being pressurized is slightly smaller than the cross section of the stent. The stent is now inserted into the balloon so that the balloon lumen covers the outside of the stent. The stent is then briefly immersed in a solution of poly-D; L-lactic acid-co-glycolide in acetone, which contains at least one antithrombotic agent of the type mentioned above in dissolved or suspended form. The stent is removed and air dried. This process can be repeated several times until the inside of the stent is provided with a sufficiently strong biodegradable coating which contains the at least one antithrombotic second drug in the desired total concentration. After the last coating process, the stent is dried at room temperature (RT), the pressure is released from the balloon and the balloon is removed. The stent is then dried in vacuo. A stent is thus obtained, with two differently coated sides A and B: an outer side, which in the later implant faces the vessel side, in which at least one antistotically active first drug is embedded in a biodegradable layer and an inner side, which in the later implant of the facing the luminal side of the vessel, in which at least one antithrombotic second drug is embedded in a biodegradable layer. This enables the stent to simultaneously elute at least two specifically effective different medicinal products that have a targeted effect at spatially separated locations after implantation.

In the present exemplary embodiment, the outside and inside of the stent are provided with the same biodegradable polymer layer, in which only at least one side-specific medicinal active ingredient is embedded. The polymer layer is therefore broken down at the same speed on the outside and inside of the stent after implantation, so that the different side-specific active ingredients contained therein are released uniformly quickly. By using suitable biodegradable polymers with different degradation speeds, the degradation time of the polymer layer can also be set in a targeted manner so that the medicinal active ingredient (s) contained therein are released at different speeds on the outside or inside of the stent, as required.

The exemplary embodiments described relate to the production according to the invention of differently designed stents for different purposes. However, it is obvious that this illustration is only exemplary and that the principles according to the invention are not only limited to the production of stents, but can also be used to advantage in all medical implants, such as, for example, bone implants. For an orthopedic bone implant according to the invention it can be shown, for example, that osteoblasts initially adhere better to the surface provided with a biodegradable polymer layer, the cell spread is complete and the implant is covered more quickly with a complete cell layer. In addition, the adhesion of germs to the surface is reduced. In addition, on the one hand antibiotic active ingredients and on the other hand promoting new bone formation, which are released from this resorbable polymer layer, can have favorable effects in vitro. It can be shown that released bacterial-specific antibiotics, such as ciprofloxacin, largely prevent early germ colonization with typical pathogens and that no biofilm formation occurs. By releasing osteoblast-specific growth promoters, the new formation of extracellular matrix and earlier events of new bone formation are increased and achieved earlier. By dissolving the resorbable layer, the beneficial effect is achieved that a firm, rigid connection of the newly growing bone only gradually takes place.

In addition, it should also be pointed out that the exemplary embodiments described can also be modified or supplemented as appropriate. In particular, individual exemplary embodiments can also be combined with one another.

Claims

claims

1.) Medical implant with a long-term stable coating, characterized by a biodegradable coating applied to the long-term stable coating with at least one medical agent.

2.) Medical implant according to claim 1, characterized in that the surface of the medical implant is completely coated with the long-term stable coating.

3.) Medical implant according to claim 1 or 2, characterized in that the long-term stable coating comprises a carbon-containing coating.

4.) Medical implant according to claim 3, characterized in that the carbon-containing coating comprises a plasma polymer coating.

5.) Medical implant according to claim 4, characterized in that the plasma polymer coating comprises differently formed polymer areas which are arranged locally distributed on the surface of the medical implant and / or comprise different polymer layers lying one above the other.

6.) Medical implant according to claim 4 or 5, characterized in that the plasma polymer coating is a polymer of an alkane, an alkene, an alkyne, a halogenated hydrocarbon, a silicon-containing hydrocarbon or a nitrogen-containing hydrocarbon or a

Includes copolymer of hydrocarbons mentioned.

7.) Medical implant according to claim 6, characterized in that the polymer or copolymer is polymerized methane, ethane,

Propane, butane, hexane, heptane, acetylene, tetrafluoroethylene, hexafluoroethane and / or perfluoropropylene.

8.) Medical implant according to one of the preceding claims, characterized in that the biodegradable coating comprises areas with different biodegradation speeds and / or different medicinal active substances and / or different active substance concentrations, these regions being arranged locally distributed on the surface of the medical implant and / or comprise a plurality of correspondingly formed layers one above the other.

9.) Medical implant according to one of the preceding claims, characterized in that the biodegradable coating comprises a polymer coating with at least one polymer from the following group: starch, fibrin, chitosan, hyaluronic acid, poly-L-lactic acid, poly-D; L- Lactic acid, poly-D, L-lactide-co-glycolide, poly-hydroxybutyrate, polyphosphoric ester and polyamino acid cellulose.

10.) Medical implant according to one of the preceding claims, characterized in that the at least one medicinal active ingredient is anticoagulant, anti-inflammatory, antimetabolitic, antimitotic, antistenotic, antithrom bototic, immunomodulatory, as an inhibitor of platelet activation, as an inhibitor of metabolic activity or as an inhibitor of Cell cycle is effective and / or includes cytostatics, signal-blocking nucleic acids or growth hormones.

11.) Medical implant according to one of the preceding claims, characterized in that the at least one medical active ingredient acetylsalicylic acid (ASS), TricIopidin-HCI, Dipgridamol-ASS or other antithrombotic agents; Mistletoe, Nimustin-HCI, Melphalen, Carmustin, Lomustin, Cyclophosphamide, Ifosfamid,

Trofosfamide, chlorambucil, busulfan, treosulfan, bendamustine-HCI, thiotepa, fluorauracil, cytasabine, methotroxate disodium, aemcitabine-HCl, mercaptopurine, vinblastine sulfate, vinoristine sulfate, paclitaxel or other zyostatics; Warfarin sodium, phenprocoumon, heparin calcium. Enoxaparin sodium, reoiparin sodium, heparin sodium, dalteparin sodium, nadroparin calcium, tinzaparin

Sodium, certoparin sodium, sodium pantosan polysulfate or other anticoagulants; Bromelaine, chamomile blue oil extract, willow bark extract, yarrow herb extract, aescin, chymostrypsin, sarrapeptase, pancreatin, amica tincture, aluminum acetate, choline stearate, heparin sodium, dimethyl sulfoxide, cuajacolliquid or other anti-inflammatory agents; cortisone,

Diclophenac sodium, ASA, phenylbutazone, indomethacin, ibuprofen, piroxicam, mofebutazone, preduison cytasabin, dexamethasone, prednisolone, or other glucocorticoids; suramin; staurosporine; Actinomycin D; Sirolimus or Trapidil.

12.) Medical implant according to one of the preceding claims, characterized by an intermediate coating applied between the long-term stable coating and the biodegradable coating.

13.) Medical implant according to one of the preceding claims, characterized in that adjacent coatings or layers are interconnected via ionic, hydrophilic, hydrophobic or covalent interactions.

14.) Medical implant according to claim 13, characterized in that adjacent coatings or layers comprise ionically interacting polyanions or polycations.

15.) Medical implant according to claim 13, characterized in that at least one coating or layer comprises a photochemically covalently crosslinking substance.

16.) Medical implant according to claim 15, characterized in that the photochemical substance comprises 3-trifluoromethyl-3- (m-isothiocyano-phenyl) diazinin (TRIMID).

17.) Medical implant according to one of the preceding claims, characterized in that the implant is an orthopedic bone implant or a stent.

18.) Medical implant according to claim 17, characterized in that the stent is completely provided with a biodegradable coating comprising at least one antistatic active medical agent.

19.) Medical implant according to claim 17, characterized in that the stent comprises on its outside a biodegradable coating with at least one antistotically active medicinal agent and / or on its inside a biodegradable coating with at least one antithrombotically active medicinal agent.

20.) Method for producing a medical implant according to one of the preceding claims by:

- Provision of a medical implant and

- Application of a long-term stable coating on this medical implant, characterized by

- Applying a biodegradable coating comprising at least one medicinal active ingredient to the long-term stable coating.

21.) Method according to claim 20, characterized in that the medical implant is completely coated with the long-term stable coating.

22.) Method according to claim 20 or 21, characterized in that a carbon-containing coating is applied as a long-term stable coating.

23.) The method according to claim 22, characterized in that the carbon-containing coating is applied by a plasma polymerization process.

24.) Method according to claim 23, characterized in that the plasma polymerization process applies a plasma polymer coating with differently designed polymer regions which are arranged locally distributed on the surface of the medical implant and / or comprise different polymer layers lying one above the other.

25.) Method according to claim 23 or 24, characterized in that a polymer from an alkane, an alkene, an alkyne, a halogenated hydrocarbon, a silicon-containing hydrocarbon or a nitrogen-containing hydrocarbon or a copolymer of said hydrocarbons is applied to the medical implant by the plasma polymerization process becomes.

26.) Method according to claim 25, characterized in that methane, ethane, propane, butane, hexane, heptane, acetylene, tetrafluoroethylene, hexafluoroethane and / or perfluoropropylene are used as starting monomers for the polymerization or copolymerization.

27.) Method according to claim 25 or 26, characterized in that a mixture of at least one of the hydrocarbons mentioned with at least one carrier gas is used in the plasma polymerization process.

28.) Method according to claim 27, characterized in that an inert gas is used as the carrier gas.

29.) Method according to claim 28, characterized in that argon and / or helium is used as the noble gas.

30.) The method according to any one of claims 20 - 29, characterized in that a biodegradable coating is applied with differently designed areas, which are characterized by different biodegradation rates and / or different medicinal agents and / or drug concentrations and locally distributed on the surface of the medical implant and / or in appropriately designed superimposed layers.

31.) Method according to one of claims 20 - 30, characterized in that as a biodegradable coating, a polymer coating with poly-L-lactic acid, poly-D; L-lactic acid, poly-D, L-lactide-co-glycolide, poly-hydroxy-butyrates, polyphosphoric esters, polyamino acids, cellulose, hyaluronic acid, starch, fibrin and / or chitosan is applied.

32.) Method according to any one of claims 20 - 31, characterized in that at least one medical agent is introduced into the biodegradable coating, which is anticoagulant, anti-inflammatory, antimetabolitic, antimitotic, antistenotic, antithrombotic, immunomodulatory, as an inhibitor of platelet activation, as an inhibitor of Metabolic activity or is effective as an inhibitor of the cell cycle or includes cytostatics, signal-blocking nucleic acids or growth hormones.

33.) Method according to claim 32, characterized in that as a medical agent acetylsalicylic acid (ASS), TricIopidin-HCI, Dipgridamol-ASS or other antitrombotics; Mistletoe, Nimustin-HCI, Melphalen, Carmustin, Lomustin, Cyclophosphamide, Ifosfamid, Trofosfamid, Chlorambucil, Busulfan, Treosulfan, Bendamustin-HCI, Thiotepa, Fluorauracil,

Cytasabine, methotroxate disodium, aemcitabine HCl, mercaptopurine,

Vinblastine sulfate, vinoristine sulfate, paclitaxel or other cytostatic agents; Warfarin sodium, phenprocoumon, heparin calcium. Enoxaparin sodium, reoiparin sodium, heparin sodium, dalteparin sodium, nadroparin calcium, tinzaparin sodium, certoparin sodium, sodium pantosan polysulfate or others

anticoagulants; Bromelaine, chamomile blue oil extract, willow bark extract, yarrow herb extract, aescin, chymostrypsin, sarrapeptase, pancreatin, arnica tincture, aluminum acetate, choline stearate, heparin sodium, dimethyl sulfoxide, cuajacolliquid or other anti-inflammatory agents; cortisone, Diclophenac sodium, ASA, phenylbutazone, indomethacin, ibuprofen, piroxicam, mofebutazone, preduison, cytasabin, dexamethasone, prednisolone, or other glucocorticoids; suramin; staurosporine; Actinomycin D; Sirolimus or Trapidil is introduced into the biodegradable coating.

34.) Method according to any one of claims 20-33, characterized in that an intermediate coating is first applied to the long-term stable coating before the biodegradable coating is applied.

35.) Method according to one of claims 20 - 34, characterized in that adjacent coatings or layers are connected to one another via ionic, hydrophilic, hydrophobic or covalent interactions.

36.) Method according to claim 35, characterized in that adjacent coatings or layers with ionically interacting polyanions or polycations are applied.

37.) Method according to claim 35, characterized in that a photochemically covalently crosslinking substance is applied as a coating or layer and is activated by irradiation with an electromagnetic radiation of a suitable wavelength.

38.) Method according to claim 37, characterized in that 3-trifluoromethyl-3- (m-isothiocyano-phenyl) diazinin (TRIMID) is used as the photoactive substance.

39.) Method according to one of claims 20 - 38, characterized in that an orthopedic bone implant or a stent is used as the medical implant.

40.) Method according to claim 39, characterized in that the stent is completely coated with a biodegradable coating comprising at least one antistatic active medical agent.

41.) Method according to claim 39, characterized in that a biodegradable coating with at least one antistotically active medicinal agent is applied to the outside of the stent and / or a biodegradable coating with at least one antithrombotically active medicinal agent is applied to the inside of the stent.