EP2125063A2 - Bioresorbable metal stent with controlled resorption - Google Patents

Abstract

The invention relates to a special type of bioresorbable metal stent with controlled resorption owing to a coating with a special polymer, guaranteeing a controlled resorption of the coated endoprothesis after implantation into a blood vessel. The resorbable implant consists of a magnesium alloy that is provided with a biodegradable coating. Said biodegradable coating consists preferably of biodegradable polymers and may additionally contain at least one pharmacologically active substance such as an antiproliferative, antimigration, antiangiogenic, anti-inflammatory, antiphlogistic, cytostatic, cytotoxic and/or antithrombotic agent, anti-restenosis agents, corticoids, sex hormones, statins, epothilones, prostacyclins and/or angiogenesis inducers.

Description

 Bioresorbable metal stent with controlled absorption

description

The present invention is a special form of bioresorbable metal stent (metallic endoprosthesis) with controlled resorption by a sheath with a special polymer that ensures controlled resorption of the sheathed endoprosthesis after implantation into a blood vessel. The present invention thus relates to resorbable implants containing the metal magnesium and provided with a biodegradable coating. The biodegradable coating preferably consists of biodegradable polymers and may additionally contain at least one pharmacologically active substance such as, for example, an antiproliferative, antimigrative, antiangiogenic, antiinflammatory, antiphlogistic, cytostatic, cytotoxic and / or antithrombotic active ingredient, anti-restenosis agents, corticoids, sex hormones, statins, Epothilones, prostacyclins and / or angiogenesis inducers.

Endoprostheses or stents which, after implantation into lesioned blood vessels, e.g. In Stenoses, dissections, etc. assume a supporting function and keeping the vessels open, have been known for a long time in minimally invasive interventional medicine. They are usually made of metals such as stainless steel or Nitinol. Such metal stents are known in large numbers and have proven themselves in practice. Due to their metal structure and carrying capacity such metal stents should ensure that the vessels remain open after implantation and the blood flow through the vessels is permanently guaranteed.

However, the support effect through the metal structure is often required only for a short time, since the body tissue can recover after implantation of the stent.

For this reason, in recent years stents of bioresorbable materials such as e.g. developed from polymers such as polylactide or from metals such as magnesium alloys and used in clinical trials.

Although in principle the desired goal of resorption of the implanted stent is achieved, there is the problem that the degradation of the stent is not defined in time. Depending on the choice of material, design and material thickness is the material degradation subjected to strong fluctuations, uncontrollable and generally too fast to ensure a secure ingrowth of the stent into the vessel wall. If absorption is too rapid, the stent can not grow into the vessel wall. Instead, it can detach and cause life-threatening problems for the patient.

For this reason, there is a need to develop absorbable stents with controlled and defined degradation rate.

The object of the present invention is to provide a prosthesis or vascular support which exercises its support function only until the regenerated tissue is again able to perform this function and which is controlled over a period of time during which the vessel regains its supporting function biodegradable.

This object is solved by the technical teaching of the independent claims of the present invention. Further advantageous embodiments of the invention will become apparent from the dependent claims, the description and the examples.

The present invention relates to resorbable implants primarily composed of zinc, calcium and / or magnesium which have a biodegradable coating and may also be capable of corticoids, sex hormones, statins, epothilones, prostacyclins, angiogenesis inducers or one or more antiproliferative, antimigrative, antiangiogenic to release antiinflammatory, antiinflammatory, cytostatic, cytotoxic and / or antithrombotic agents or anti-restenosis agents.

The resorbable implant according to the invention consists of at least 40% by weight, preferably at least 50% by weight, more preferably at least 60% by weight, more preferably at least 70% by weight, even more preferably at least 75% by weight more preferably at least 80 wt .-% and particularly preferably at least 85 wt .-% of the metal magnesium, which is contained in a magnesium alloy with other metals and possibly non-metals, metal salts, metal carbides, metal oxides and / or metal nitrides. That is, the weight percentage refers to magnesium metal atoms and, if present, magnesium ions in the composition (alloy) with the other ingredients. It is further preferred if the implant according to the invention additionally contains 0-20% by weight, preferably 0.01-13% by weight, more preferably 0.1-8% by weight, even more preferably 1-7% by weight. Calcium has. Particularly preferably, the mass of calcium is in the range of 1.2 to 6.5% by weight, 1.4 to 6.0% by weight, 1.6 to 5.5% by weight, 1.8%. 5.0 wt .-% and in particular from 2.0 to 4.5 wt .-%.

It is further preferred if the implant according to the invention additionally contains 0-20% by weight, preferably 0.1-12% by weight, more preferably 0.5-6% by weight, even more preferably 0.8-5% by weight. -% yttrium. More preferably, the mass of yttrium is in the range of 0.9-4.0 wt.%, 1.1-3.5 wt.%, 1.3-3.0 wt.%, 1.5. 2.5 wt .-% and in particular of 1, 7 - 2.3 wt .-%.

In addition to zinc and optionally calcium and / or magnesium, an implant according to the invention may further comprise at least one metal selected from the group consisting of lithium, beryllium, sodium, aluminum, potassium, scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, Zinc, gallium, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, indium, tin, lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holium, erbium, Thulium, ytterbium, lutetium, tantalum, tungsten, rhenium, platinum, gold, lead and / or at least one metal salt having a cation selected from the group consisting of Li ⁺ , Be ²⁺ , Na ⁺ , Mg ²⁺ , K ⁺ , Ca ^{2 +} , Sc ³⁺ , Ti ²⁺ , Ti ⁴⁺ , V ²⁺ , V ³⁺ , V ⁴⁺ , V ⁵⁺ , Cr ²⁺ , Cr ³⁺ , Cr ⁴⁺ , Cr ⁶⁺ , Mn ²⁺ , Mn ³⁺ , Mn ⁴⁺ , Mn ⁵⁺ , Mn ⁶⁺ , Mn ⁷⁺ , Fe ²⁺ , Fe ³⁺ , Co ²⁺ , Co ³⁺ , Ni ²⁺ , Cu ⁺ , Cu ²⁺ , Zn ²⁺ , Ga ⁺ , Ga ³⁺ , Al ³⁺ , Y ³⁺ , Zr ²⁺ , Zr ⁴⁺ , Nb ²⁺ , Nb ⁴⁺ , Nb ⁵⁺ , Mo ⁴⁺ , Mo ⁶⁺ , T c ²⁺ , Tc ³⁺ , Tc ⁴⁺ , Tc ⁵⁺ , Tc ⁶⁺ , Tc ⁷⁺ , Ru ³⁺ , Ru ⁴⁺ , Ru ⁵⁺ , Ru ⁶⁺ , Ru ⁷⁺ , Ru ⁸⁺ , Rh ^{3 +} , Rh ⁴⁺ , Pd ²⁺ , Pd ³⁺ , Ag ⁺ , In ⁺ , In ³⁺ , Ta ⁴⁺ , Ta ⁵⁺ , W ⁴⁺ , W ⁶⁺ , Pt ²⁺ , Pt ³⁺ , Pt ^{4 +} , Pt ⁵⁺ , Pt ⁶⁺ , Au ⁺ , Au ³⁺ , Au ⁵⁺ , Sn ²⁺ , Sn ⁴⁺ , Pb ²⁺ , Pb ⁴⁺ , La ³⁺ , Ce ³⁺ , Ce ⁴⁺ , Gd ³⁺ , Nd ³⁺ , Pr ³⁺ , Tb ³⁺ , Pr ³⁺ , Pm ³⁺ , Sm ³⁺ , Eu ²⁺ , Dy ³⁺ , Ho ³⁺ , Er ³⁺ , Tm ³⁺ , Yb ³⁺ contain. In addition to the aforementioned metals and metal salts, which are present together in masses of less than 10% by weight, preferably less than 6% by weight and more preferably less than 4% by weight, small amounts of non-metals, carbon , Sulfur, nitrogen, oxygen and / or hydrogen.

The masses of carbon (C), sulfur (S ₈ , S _x ), nitrogen (N ₂ ), oxygen (O ₂ ) and / or hydrogen (H ₂ ) including chemically bound carbon, sulfur, nitrogen, oxygen and / or hydrogen atoms, for example in the form of metal carbides, metal oxides, metal nitrides together with the mass of the rare earths and non-metals present, does not exceed the amounts of 10% by weight of the total composition. Rare earths, metal carbides, metal oxides, metal nitrides, nonmetals, carbon, sulfur, nitrogen, oxygen, hydrogen are in the alloy in unavoidable traces up to a maximum of 10 wt .-%, preferably in amounts of 0.1 to 8 wt .-%, more preferably 0, 5 to 7.0% by weight, more preferably 1 to 0 to 6.0% by weight and most preferably 1 to 5 to 5.0% by weight.

A preferred composition of an implant according to the invention comprises, for example

40% by weight - 90% by weight of magnesium

0.0% by weight - 20% by weight of calcium

0.0% by weight - 20% by weight of yttrium

0.0% by weight - 10% by weight of other metals or metal salts

0.0% by weight to 10% by weight of rare earths, metal carbides, metal oxides, metal nitrides, nonmetals, carbon, sulfur, nitrogen, oxygen, hydrogen.

The carbon, sulfur, nitrogen, oxygen, hydrogen or other non-metals or semimetals may be in the form of anions and / or polymers.

Further preferred compositions are: 60% by weight - 70% by weight of magnesium 10.0% by weight - 20% by weight of calcium 5.0% by weight - 15% by weight of yttrium 5.0% by weight -% - 10 wt .-% other metals or metal salts 2.0 wt .-% - 10 wt .-% rare earths, metal carbides, metal oxides, metal nitrides, non-metals, carbon, sulfur, nitrogen, oxygen, hydrogen.

70 wt% 80 wt% Magnesium 3.0 wt% 10 wt% Calcium 3.0 wt% 10 wt% Yttrium 1.0 wt% 7 wt% Other Metals or metal salts 0.5% by weight 3% by weight Rare earths, metal carbides, metal oxides, metal nitrides, nonmetals, carbon, sulfur, nitrogen, oxygen, hydrogen. 80% by weight - 90% by weight of magnesium

1, 0 wt .-% - 5 wt .-% calcium

1, 0 wt .-% - 3 wt .-% yttrium 0.5 wt .-% - 5 wt .-% other metals or metal salts

0.3% by weight - 1% by weight of rare earths, metal carbides, metal oxides, metal nitrides, nonmetals, carbon, sulfur, nitrogen, oxygen, hydrogen.

80% by weight - 90% by weight of magnesium

0.2% by weight - 2% by weight of calcium

0.0% by weight - 2% by weight of yttrium

8.0% by weight - 10% by weight of other metals or metal salts ^' \ 0.1% by weight - 1% by weight of rare earths, metal carbides, metal oxides, metal nitrides, nonmetals, carbon, sulfur, nitrogen, oxygen , Hydrogen.

75% by weight - 90% by weight of magnesium

0.1% by weight - 5% by weight of calcium

0.5% by weight - 3% by weight of yttrium

5.0 wt .-% - 10 wt .-% zinc, iron, other metals or

Metal salts 0.1% by weight - 10% by weight Rare earths, metal carbides, metal oxides, metal nitrides, nonmetals, carbon, sulfur, nitrogen, oxygen, hydrogen.

The term "resorbable" in the present invention means that the implant slowly dissolves in the organism over a certain period of time and at some point only its decomposition products are present in dissolved form in the body. At this time, solid components or fragments of the implant are no longer present. The degradation products should be physiologically largely harmless and lead to ions or molecules that can be present in the organism anyway or degraded by the organism to harmless substances or excreted. As metals which can be used in combination with the magnesium, the following are preferred according to the invention: lithium, beryllium, sodium, zinc, aluminum, potassium, calcium, scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper , Gallium, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, indium, tin, lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holium, erbium, thulium , Ytterbium, lutetium, tantalum, tungsten, rhenium, platinum, gold, lead. Especially preferred are zinc, calcium, iron, yttrium. Further, combinations of magnesium with or without the addition of one or more of the aforementioned metals with metal salts are preferred. Such combinations may be referred to as metal salt-containing zinc melts or metal salt-containing zinc alloys. The metal salt content may only be so high that there is still sufficient flexibility of the material. For stents in particular the expandability may not be significantly affected. Suitable metal salts are those mentioned below and in particular salts of magnesium, zinc, calcium, iron and yttrium.

On the other hand, the use of absorbable alloys, which may contain, for example, the following metals together with magnesium, is better than the use of metals: lithium, beryllium, sodium, zinc, aluminum, potassium, calcium, scandium, titanium, vanadium, chromium, manganese, iron, Cobalt, nickel, copper, gallium, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, indium, tin, lanthanum, cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, Holium, erbium, thulium, ytterbium, lutetium, tantalum, tungsten, rhenium, platinum, gold, lead. Such metals are sometimes contained only in small amounts.

Preference is given to magnesium-zinc alloys which contain zinc at from 0.1 to 10% by weight, preferably from 1.0 to 9.5% by weight and more preferably from 4.0 to 9.0% by weight. Further, it is preferable that this magnesium-zinc alloy further contains scandium, titanium, vanadium, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver or indium and especially yttrium in an amount of 0.3 to 11 , preferably 0.7 to 10, more preferably 1.1 to 8.5 and particularly preferably 2 to 7 wt .-%.

Preference is furthermore given to alloys which, in addition to magnesium, predominantly comprise calcium, zinc, iron, tin, zinc or lithium together with up to 10% by weight of scandium, yttrium, lanthanum, cerium, praseodymium, neodymium, promethium, samarium, Europium, gadolinium, terbium, dysprosium, holium, erbium, thulium and / or ytterbium.

Further, in particular, metal salt of the above-mentioned metals are preferable. Such metal salts preferably contain at least one of the following

Metal ions: Li ⁺ , Be ²⁺ , Na ⁺ , Mg ²⁺ , K ⁺ , Ca ²⁺ , Sc ³⁺ , Ti ²⁺ , Ti ⁴⁺ , V ²⁺ , V ³⁺ , V ⁴⁺ , V ⁵⁺ , Cr ²⁺ ,

Cr ³⁺ , Cr ⁴⁺ , Cr ⁶⁺ , Mn ²⁺ , Mn ³⁺ , Mn ⁴⁺ , Mn ⁵⁺ , Mn ⁶⁺ , Mn ⁷⁺ , Fe ²⁺ , Fe ³⁺ , Co ²⁺ , Co ^{3 +} , Ni ²⁺ , Cu ⁺ ,

Cu ²⁺ , Zn ²⁺ , Ga ⁺ , Ga ³⁺ , Al ³⁺ , Y ³⁺ , Zr ²⁺ , Zr ⁴⁺ , Nb ²⁺ , Nb ⁴⁺ , Nb ⁵⁺ , Mo ⁴⁺ , Mo ⁵⁺ , Tc ²⁺ , Tc ³⁺ ,

Tc ⁴⁺ , Tc ⁵⁺ , Tc ⁶⁺ , Tc ⁷⁺ , Ru ³⁺ , Ru ⁴⁺ , Ru ⁵⁺ , Ru ⁶⁺ , Ru ⁷⁺ , Ru ⁸⁺ , Rh ³⁺ , Rh ⁴⁺ , Pd ^{2 +} , Pd ³⁺ , Ag ⁺ , In ⁺ , In ³⁺ , Ta ⁴⁺ , Ta ⁵⁺ , W ⁴⁺ , W ⁶⁺ , Pt ²⁺ , Pt ³⁺ , Pt ⁴⁺ , Pt ⁵⁺ , Pt ^{6 +} , Au ⁺ , Au ³⁺ , Au ⁵⁺ , Sn ²⁺ , Sn ⁴⁺ ,

Pb ²⁺ , Pb ⁴⁺ , La ³⁺ , Ce ³⁺ , Ce ⁴⁺ , Gd ³⁺ , Nd ³⁺ , Pr ³⁺ , Tb ³⁺ , Pr ³⁺ , Pm ³⁺ , Sm ³⁺ , Eu ^{2 +} , Dy ³⁺ ,

Ho ³⁺ , Er ³⁺ , Tm ³⁺ , Yb ³⁺ .

The anions are halogens such as F ^" , Cl ^" , Br ^" , oxides and hydroxides such as OH ^" , O ^{2 "} , sulfates, carbonates, oxalates, phosphates such as HSO ₄ ^" , SO ₄ ^{2 "} , HCO ₃ ^" , CO ₃ ^{2 "} , HC ₂ O ₄ ^" , C ₂ O ₄ ^2" , H ₂ PO ₄ ^" , HPO ₄ ^2" , PO ₄ ^{3 "} , and in particular carboxylates such as HCOO ^" , CH ₃ COO ^" , C ₂ H ₅ COO ^" , C ₃ H ₇ COO ^" , C ₄ H ₉ COO ^" , C ₅ HnCOO ^" , C ₆ H ₁₃ COO ^" , C ₇ H ₁₅ COO ^" , C ₈ Hi ₇ COO ^" , C ₉ H ₁₉ COO ^" , PhCOO ^" , PhCH ₂ COO ^" .

Further, salts of the following acids are preferable: sulfuric acid, sulfonic acid, phosphoric acid, nitric acid, nitrous acid, perchloric acid, hydrobromic acid, hydrochloric acid, formic acid, acetic acid, propionic acid, succinic acid, oxalic acid, gluconic acid (glyconic, dextronic acid), lactic acid, malic acid, tartaric acid, Tartronic acid (hydroxymalonic acid, hydroxypropanedioic acid), fumaric acid, citric acid, ascorbic acid, maleic acid, malonic acid, hydroxymaleic acid, pyruvic acid, phenylacetic acid, (o-, m-, p-) toluic acid, benzoic acid, p-aminobenzoic acid, p-hydroxybenzoic acid, salicylic acid, p-aminosalicylic acid , Methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylene sulfonic acid, p-toluenesulfonic acid, naphthylsulfonic acid, naphthylamine sulfonic acid, sulfanilic acid, camphorsulfonic acid, quinic acid, quinic acid, o-methyl-mandelic acid, hydrogenbenzenesulfonic acid, methionine, tryptophan, lysine, arginine, picric acid (2,4,6-trin trophenol), adipic acid, d-o-toluenoic acid, glutaric acid,

Also preferred are salts of amino acids containing, for example, one or more of the following amino acids: glycine, alanine, valine, leucine, isoleucine, serine, threonine, phenylalanine, tyrosine, tryptophan, lysine, arginine, histidine, aspartate, glutamate, asparagine, glutamine , Cysteine, methionine, proline, 4-hydroxyproline, N, N, N-trimethyl-lysine, 3-methyl-histidine, 5-hydroxy-lysine, O-phosphoserine, γ- Carboxyglutamate, ε-N-acetyllysine, ω-N-methylarginine, citrulline, ornithine. Normally the amino acids with L-configuration are used. In a further preferred embodiment, at least a part of the amino acids used has D configuration.

Other preferred resorbable materials for the preparation of the implant are metal salts such as Caclicumchlorid, calcium sulfate, calcium phosphate, calcium citrate, zinc chloride, zinc sulfate, zinc oxide, Zinkeitrat, iron sulfate, iron phosphate, iron chloride, ironocide, zinc, magnesium chloride, magnesium sulfate, magnesium phosphate or magnesium citrate. Such metal salts are preferably used in masses of 0.01 to 10 wt .-%.

Another preferred embodiment is when the magnesium alloy contains small amounts of a resorbable polymer. These small amounts of resorbable polymer are incorporated into the magnesium alloy, i. mixed with the alloy. Possible suitable resorbable polymers are mentioned below.

According to the invention, a stent framework is made of the magnesium alloy which is expandable. This stent framework or this vascular support from the

Magnesium alloy is coated with a biodegradable polymer, i. each stent strut or strut of the vascular support is provided with a biodegradable polymeric layer or biodegradable polymeric coating.

Polymer claddings or coatings with a thickness of

0.2μm and less.

The following may be used as resorbable or biodegradable polymers according to the invention:

Polyvalerolactones, poly-ε-decalactones, polylactic acid, polyglycolic acid polylactides, polyglycolides, copolymers of polylactides and polyglycolides, poly-ε-caprolactone, polyhydroxybutyric acid, polyhydroxybutyrates, polyhydroxyvalerates,

Polyhydroxybutyrate-co-valerates, poly (1,4-dioxane-2,3-diones), poly (1,3-dioxan-2-ones), poly-para-dioxanones, polyanhydrides, polymaleic anhydrides,

Polyhydroxymethacrylates, fibrin, polycyanoacrylates,

Polycaprolactone dimethyl acrylates, poly-b-maleic acid polycaprolactone butyl acrylates, multiblock polymers of oligocaprolactone diols and oligodioxanonediols, polyetherester multiblock polymers of PEG and polybutylene terephthalate, Polypivotolactones, polyglycolic acid trimethylcarbonates, polycaprolactone glycolides, poly (g-ethylglutamate), poly (DTH-lminocarbonate), poly (DTE-co-DT-carbonate), poly (bisphenol A-iminocarbonate), polyorthoesters, poly (triglycyl), poly (trimethyl) poly (iminocarbonate), poly (N-vinyl) ) -Pyrrolidone, polyvinyl alcohols, polyester amides, glycolated polyesters, polyphosphoesters, polyphosphazenes, poly [p-carboxyphenoxy) propane], polyhydroxypentanoic acid, polyanhydrides, polyethylene oxide propylene oxide, soft polyurethanes, polyurethanes with amino acid residues in the backbone, polyether esters such as polyethylene oxide, polyalkene oxalates, polyorthoesters and copolymers thereof , Lipids, carrageenans, fibrinogen, starch, collagen, protein-based polymers, polyamino acids, synthetic polyamino acids, zein, polyhydroxyalkanoates, pectinic acid, actinic acid, carboxymethylsulfate, albumin, hyaluronic acid, chitosan and its derivatives, heparan sulfates and its derivatives, heparins, chondroitin sulfate, dextran . β-cyclodextrins, copolymers with PEG and polypropylene glycol, gum arabic, guar, gelatin, collagen collagen-N-hydroxysuccinimide, lipids, phospholipids, polyacrylic acid, polyacrylates, polymethylmethacrylate, polybutylmethacrylate, polyacrylamide, polyacrylonitriles, polyamides, polyetheramides, polyethyleneamine, polyimides, polycarbonates, Polycarbourethanes, polyvinyl ketones, polyvinyl halides, polyvinylidene halides, polyvinyl ethers, polyisobutylenes, polyvinylaromatics, polyvinyl esters, polyvinyl pyrollidones, polyoxymethylenes, polytetramethylene oxide, polyethylene, polypropylene, polytetrafluoroethylene, polyurethanes, polyether urethanes, silicone polyether urethanes, silicone polyurethanes, silicone polycarbonate urethanes, polyolefin elastomers, Polyisobutylenes, EPDM rubbers, fluorosilicones, carboxymethylchitosans, polyaryletheretherketones, polyetheretherketones, polyethylene terephthalate, polyvalerates, carboxymethylcellulose, cellulose, rayon, rayontriacetates, cellulose nitrates, cellulose acetates, hydroxyethylcel lulose, cellulose butyrates, cellulose acetate butyrates, ethylvinylacetate copolymers, polysulphones, epoxy resins, ABS resins, EPDM rubbers, silicones such as polysiloxanes, polydimethylsiloxanes, polyvinylhalogens and copolymers, cellulose ethers, cellulose triacetates, chitosans and copolymers and / or mixtures of the abovementioned polymers.

Preferred resorbable polymers are polymethylmethacrylates (PMMA), polytetrafluoroethylenes (PTFE), polyurethanes, polyvinylchlorides (PVC), polydimethylsiloxanes (PDMS), polyesters, nylons and polylactides. When

Polymer sheaths are also suitable in particular parylene, polyurethanes or amminopump or semipermeable membrane. Parylene is usually the name for completely linear, partially crystalline, uncrosslinked aromatic polymers.

The different polymers have different properties and can be divided into four basic types, namely the parylene C, parylene D, parylene N and parylene F, the structure of which is shown below:

Parylene C Parylene D Parylene N Parylene F

The simplest monomer of the parylene group is parylene N (poly-para-xylylene). Furthermore, the two chlorinated polymers parylene C (chloropoly-para-xylylene) and parylene D (di-chloro-poly-para-xylylene) exist. For parylene F (poly (tetrafluoro-para-xylylene)), the methylene units are fluorinated.

Parylene C has the lowest melting point of the aforementioned Parylene of only 290 ⁰ C, is characterized by good mechanical properties and corrosion resistance to corrosive gases and very low permeability to moisture. Parylene C is a biocompatible polymer and therefore suitable for use in a physiological environment.

Also particularly preferred are polyesters, polylactides and copolymers of diols and esters or diols and lactides. Ethane-1, 2-diol, propane-1, 3-diol or butane-1, 4-diol are used as diols, for example.

In particular, polyesters for the polymeric layer are used according to the invention. From the group of polyesters, in turn, those polymers are preferred which have the following repeating unit:

Structure A Structure B

In the repeating units shown, R, R ', R "and R" ^{1 is} an alkyl radical having 1 to 5 carbon atoms, in particular methyl, ethyl, propyl, isopropyl, n-butyl, DE2008 / 000161

11

s-butyl, t-butyl, iso-butyl, n-pentyl or cyclopentyl and preferably methyl or ethyl. Y is an integer from 1 to 9 and X is the degree of polymerization. Particular preference is given to the following polymers having the repeating units shown:

Structure A1 Structure B1

Particularly preferred are the polymers Resomer® R 203 and Resomer® LT 706.

The name Resomer® represents a high-tech product from Boehringer Ingelheim, a medical device made from resorbable polymers that offers an important alternative to conventional medical applications due to its versatility in modern medicine and advances in technology.

These absorbable polymers are manufactured on the basis of lactic and glycolic acids. Basically, the use of resorbable polymer is particularly preferred in the present invention. Homopolymers of lactic acid (polylactides) are mainly used in the production of resorbable medical implants. Copolymers of lactic and glycolic acids are used as raw materials for the production of active ingredient capsules for the controlled release of pharmaceutical active substances use.

Thus, for use in the present invention, especially lactic acid and glycolic acid based polymers as well as copolymers (alternating or random) and block copolymers (e.g., triblock copolymers) of both acids are preferred.

As further representatives of the resorbable polymers Resomer® may be mentioned the poly (L-lactide) s having the general formula - (C 6 H 8 O 4) n such as L 210, L 210 S, L 207 S,

L 209 S, the poly (L-lactide-co-D, L-lactide) s having the general formula - (C 6 H 8 O 4) n such as LR 706, LR 708, L 214 S, LR 704, the poly (L-lactide -co-trimethyl carbonate) having the general formula - [(C6H8O4) x- (C4H6O3) y] n- such as LT706, the poly (L-lactide-co-glycolide) s having the general formula - [(C6H8O4) x - (C4H4O4) y] n- such as LG 824, LG 857, the poly (L-lactide-co-ε-caprolactone) s with the general formula - [(C6H8O4) x- (C6H10O2) y] n- as LC 703, the poly (D, L-lactide-co-glycolide) s with the general formula - [(C6H8O4) x (C4H4O4) y] n- as RG 509 S ₁ RG 502 H, RG 503 H, RG 504 H, RG 502, RG 503, RG 504, the poly (D, L-lactide) s having the general formula - (C 6 H 8 O 4) n such as R 202 S, R 202 H, R 203 S and R 203 H. Resomer® 203 S represents the successor of the particularly preferred polymer Resomer® R 203. Particularly preferred is the use of R203 and LT 706 in a quantity ratio of 70% by weight to 30% by weight.

A particularly preferred embodiment of the present invention is applicable to implants such as e.g. Stents, which are biodegradable

Coating of a polymethyl methacrylate (PMMA), polytetrafluoroethylene

(PTFE), Polyurethane, Polyvinylchloride (PVC), Polydimethylsiloxane (PDMS), Polyester,

Nylon or polylactide and in particular a polyester and / or polylactide are provided. The metallic inner part of these implants has the composition of magnesium disclosed herein and optionally calcium or yttrium with the other ingredients mentioned above.

The resorbable implants of the present invention have an inner structure of the magnesium alloy encased in the biodegradable polymer, the coating or sheath being only about the individual struts and not having a full-area sheath or coating of the stent structure, i. the spaces between the individual struts are not covered by the biodegradable polymer.

In a preferred embodiment of the present invention, a controlled rate of resorption is achieved by enveloping a resorbable stent with a non-soluble or sparingly soluble polymer coating and providing the polymer wrapper, after application to the resorbable stent, with holes to ensure resorption of the internal stent.

Such holes may e.g. be produced mechanically, chemically or optically by laser. Instead of the perforated, non-soluble or only slightly soluble polymer shell, a continuous semipermeable polymer shell can also be applied to the stent.

With a suitable polymer choice and thickness can be ensured that this is also degraded after resorption of the stent and removed by macrophages in the blood. In a further preferred embodiment, the metallic stent is provided with a coating which permits a liquid permeation.

Particularly preferred is a bioresorbable magnesium stent with a coating of a polyurethane, a parylene or Ammini-ppx or a mixture of the aforementioned substances, wherein the coating contains holes, which subsequently after the application of the coating on the metal stent in a mechanical or chemical manner or by laser treatment be generated in an optical manner.

A preferred embodiment further constitutes a medical implant which contains more than 70% by weight, more preferably more than 80% by weight, even more preferably more than 85% by weight and most preferably more than 90% by weight The magnesium alloy is made and the remaining weight fraction is the biodegradable polymeric coating.

Further particularly advantageous embodiments of the present invention include resorbable implants which are at least one pharmacologically on the implant and / or in the implant or under the resorbable or biodegradable layer and / or in the biodegradable layer and / or on the biodegradable layer containing active substance. Preferred pharmacologically active substances are antiproliferative, antimigrative, antiangiogenic, antiinflammatory, antiphlogistic, cytostatic, cytotoxic and / or antithrombotic agents, anti-restenosis agents, anti-restenosis agents, corticoids, sex hormones, statins, epothilones, prostacyclins, angiogenesis inducers. Among these substances, in turn, the antiproliferative, anti-inflammatory, anti-inflammatory, cytostatic, cytotoxic and / or antithrombotic agents and anti-restenosis agents are preferred.

Examples of antiproliferative, antimigrative, antiangiogenic, anti-inflammatory, anti-inflammatory, cytostatic, cytotoxic, antithrombotic and / or anti-restenotic agents are: abciximab, acemetacin, acetylvismion B, aclarubicin, ademetionin, adriamycin, aescin, afromosone, akagerin, aldesleukin, amidorone , Aminoglutethemide, amsacrine, anakinra, anastrozole, anemonin, anopterin, antifungals, antithrombotics, apocymarin, argatroban, aristolactam-all, aristolochic acid, ascomycin, asparaginase, aspirin, atorvastatin, auranofin, azathioprine, azithromycin, baccatin, bafilomycin, basiliximab, bendamustine, benzocaine , Berberine, betulin, betulinic acid, bilobol, bisparthenolidine, bleomycin, Bombrestatin, boswellic acids and their derivatives, bruceanols A ₁ B and C, bryophyllin A, busulfan, antithrombin, bivalirudin, cadherins, camptothecin, capecitabine, o-carbamoylphenoxyacetic acid, carboplatin, carmustine, celecoxib, cepharantin, cerivastatin, CETP inhibitors, chlorambucil, chloroquine phosphate , Cictoxin, Ciprofloxacin, Cisplatin, Cladribine, Clarithromycin, Colchicine, Concanamycin, Coumadin, C-Type Natriuretic Peptide (CNP), Cudraisoflavone A, Curcumin, Cyclophosphamide, Cyclosporin A, Cytarabine, Dacarbazine, Daclizumab, Dactinomycin, Dapsone, Daunorubicin, Diclofenac, 1,11-Dimethoxycanthin-6-one, docetaxel, doxorubicin, Dunaimycin, epirubicin, epothilones A and B, erythromycin, estramustine, Etobosid, everolimus, filgrastim, Fluroblastin, fluvastatin, fludarabine, fludarabine-5 ^'- dihydrogen phosphate, fluorouracil, Folimycin, Fosfestrol, gemcitabine, ghalakinoside, ginkgol, ginkgolic acid, glycoside 1a, 4-hydroxyoxycyclophosphamide, idarubicin, ifosfamide, josamycin, lapachol, lomustine, Lovastatin, melphalan, midecamycin, mitoxantrone, nimustine, pitavastatin, pravastatin, procarbazine, mitomycin, methotrexate, mercaptopurine, thioguanine, oxaliplatin, irinotecan, topotecan, hydroxycarbamide, miltefosine, pentostatin, pegasparase, exemestane, letrozole, formestan, SMC proliferation inhibitor 2w, mitoxanthrone, mycophenolate mofetil, c-myc antisense, b-myc antisense, β-lapachone, podophyllotoxin, podophyllic acid 2-ethyl hydrazide, molgramostim (rhuGM-CSF), peginterferon α-2b, lanograstim (r-HuG-CSF) , Macrogol, selectin (cytokine antagonist), cytokine inhibitors, COX-2 inhibitor, NFkB, angiopeptin, monoclonal antibodies that inhibit muscle cell proliferation, bFGF antagonists, probucol, prostaglandins, 1-hydroxy-11-methoxycanthin-6-one, scopolectin, NO donors such as pentaerythrityl tetranitrate and syndnoeimines, S-nitrosated derivatives, tamoxifen, staurosporine, β-estradiol, α-estradiol, estriol, estrone, ethinylestradiol, medroxyprogesterone, estradiol cypionates, estradiol benzoates, Tranila st, kamebakaurin and other terpenoids used in cancer therapy, verapamil, tyrosine kinase inhibitors (tyrphostins), paclitaxel and its derivatives such as 6-α-hydroxy-paclitaxel, taxoters, carbon suboxide (MCS) and its macrocyclic oligomers, mofebutazone , Lonazolac, Lidocaine, Ketoprofen, Mefenamic Acid, Piroxicam, Meloxicam, Penicillamine, Hydroxychloroquine, Sodium Aurothiomalate, Oxaceprol, β-Sitosterol, Myrtecain, Polidocanol, Nonivamid, Levomenthol, Ellipticin, D-24851 (Calbiochem), Colcemid, Cytochalasin AE, Indanocine, Nocadazole , S 100 protein, bacitracin, vitronectin receptor antagonists, azelastine, guanidyl cyclase stimulator tissue inhibitor of metalloproteinase-1 and 2, free nucleic acids, nucleic acids incorporated in virus carriers, DNA and RNA fragments, plaminogen activator inhibitor-1, plasminogen Activator inhibitor-2, antisense oligonucleotides, VEGF-I inhibitors, IGF-1, active ingredients from the group of antibiotics such as cefadroxil, cefazolin, Cefaclor, cefotixin, tobramycin, gentamycin, penicillins such as dicloxacillin, oxacillin, Sulfonamides, metronidazole, Enoxoparin, desulphated and N-reacetylated heparin, tissue plasminogen activator, GPIIb / IIIa platelet membrane receptor, factor X _a - inhibitor antibody, heparin, hirudin, r-hirudin, PPACK, protamine, prourokinase, streptokinase, warfarin, Urokinase, vasodilators such as dipyramidol, trapidil, nitroprussides, PDGF antagonists such as triazolopyrimidine and seramin, ACE inhibitors such as captopril, cilazapril, lisinopril, enalapril, losartan, thioprotease inhibitors, prostacyclin, vapiprost, interferon α, ß and y, histamine antagonists, serotonin blockers, apoptosis inhibitors , Apoptosis regulators such as p65, NF-kB or Bcl-xL antisense oligonucleotides, halofuginone, nifedipine, tocopherol tranilast, molsidomine, tea polyphenols, epicatechin gallate, epigallocatechin gallate, leflunomide, etanercept, sulfasalazine, etoposide, dicloxacylline, tetracycline, triamcinolone, mutamycin, procainimide, Retinoic acid, quinidine, disopyrimide, flecainide, propafenone, sotalol, natural and sy nthetreated steroids such as inotodiol, maquiroside A, ghalacinoside, mansonin, strebloside, hydrocortisone, betamethasone, dexamethasone, nonsteroidal substances (NSAIDS) such as fenoporfen, ibuprofen, indomethacin, naproxen, phenylbutazone and other antiviral agents such as acyclovir, ganciclovir and zidovudine, clotrimazole, flucytosine , Griseofulvin, ketoconazole, miconazole, nystatin, terbinafine, antiprozoal agents such as chloroquine, mefloquine, quinine, further natural terpenoids such as hippocaesculin, barringtogenol C21-angelate, 14-dehydroagrostistachine, agroskin, agrostistachin, 17-hydroxy-agrostistachin, ovatodiolides, 4,7 Oxycycloanisomic acid, baccharinoids B1, B2, B3 and B7, tubeimoside, bruceantinosides C, yadanziosides N, and P, isodeoxyelephantopin, tomenphantopin A and B, coronarine A, B, C and D, ursolic acid, hyptate acid A, iso-iridogermanal. Maytenfoliol, Effusantin A, Excisanin A and B, Longikaurin B, Sculponeatin C, Kamebaunin, Leukamenin A and B, 13,18-Dehydro-6-alpha-Senecioyloxychaparrin, Taxamairin A and B, Regenilol, Triptolide, Cymarin, Hydroxyanopterin, Protoanemonin, Cheliburine chloride, sinococulin A and B, dihydronitidine, nitidine chloride, 12-beta-hydroxypregnadiene 3,20-dione, helenaline, indicin, indicin-N-oxide, lasiocarpine, inotodiol, podophyllotoxin, justicidin A and B, larreatin, malloterine, mallotochromanol, isobutyrylmallotochromanol , Maquisoside A, Marchantin A, Maytansin, Lycoridicin, Margetin, Pancratistatin, Liriodenin, Bispsrthenolidine, Oxoushinsunin, Periplocoside A ₁ Ursolic acid, Deoxypypsorospermine, Psycorubin, Ricin A, Sanguinarine, Manwuweiz acid, Methylsorbifolin, Sphatheliachromes, Stizophyllin, Mansonine, Strebloside, Dihydrousambaraensin, Hydroxyusambarin , Strychnopentamine, Strychnophyllin, Usambarin, Usambarensin, Liriodenin, Oxoushinsunin, Daphnoretin, Lariciresinol, Methoxylariciresinol, Syringaresin ol, sirolimus (rapamycin), somatostatin, tacrolimus, roxithromycin, troleandomycin, simvastatin, rosuvastatin, vinblastine, vincristine, vindesine, Teniposide, vinorelbine, tropfosfamide, treosulfan, tremozolomide, thiotepa, tretinoin, spiramycin, umbelliferone, desacetylvismion A, vismion A and B, zeorine.

Preferred active ingredients are paclitaxel and its derivatives such as 6-α-hydroxy-paclitaxel or baccatin or other taxotere, sirolimus, tacrolimus, everolimus, gleevec (imatinib), erythromycin, midecamycin, josamycin and triazolopyrimidines.

Particularly preferred are paclitaxel (Taxol ^®) and all derivatives of paclitaxel such as 6-α-hydroxy-paclitaxel.

The resorbable implants according to the invention are preferably supporting prostheses for canal-like structures and, in particular, vascular supports and stents for blood vessels, urinary tract, respiratory tract, biliary tract or the digestive tract.

Again, among these stents are the stents for blood vessels or, more generally, for the cardiovascular system, i. for the cardiovascular area.

As a rule, these are self-expanding or balloon-expandable stents which preferably contain an antiproliferative, antimigrative, anti-angiogenic, antiinflammatory, anti-inflammatory, cytostatic, cytotoxic, antirestenotic, antithrombotic active ingredient and / or an anti-restenosis active ingredient.

As a rule, the biodegradable polymeric layer serves as an active substance carrier for the at least one antiproliferative, antimigrative, antiangiogenic, antiinflammatory, antiphlogistic, cytostatic, cytotoxic, antithrombotic active ingredient and / or anti-restenotic active ingredient. This prevents inflammation, which can be caused by the stent and regulates the growth of mainly smooth muscle cells (coronary endothelial cells) on the stent. The stent allows regeneration of the supported tissue or supported vessel portion. If the tissue has regenerated, it can support the vessel independently and no further support by the stent is required. At this time, the stented in the vessel wall stent has already been significantly reduced. Degradation continued until the stent completely dissolved but did not break down into solid fragments that could move freely in the bloodstream. The terms "resorbable" or "degradable" or "biodegradable" or "biodegradable" refer to the fact that the human or animal body is capable of slowly dissolving the implant into components dissolved in the blood or other body fluids.

The preferred stents are formed like a lattice, wherein the individual webs of the lattice structure have similar cross-sectional areas. Preferably, a ratio of the largest to smallest cross-sectional area is less than 2. The similar cross-sectional areas of the webs cause the stent to be degraded evenly.

Furthermore, it is preferred if the web rings are connected by connecting webs, wherein the connecting webs preferably have a smaller cross-sectional area or a smaller minimum diameter than the webs which form the web rings. This ensures that the connecting webs are degraded faster in the human or animal body, as the web rings. As a result, the axial flexibility of the stent increases by dismantling the connecting webs faster than the load capacity of the stent decreases as a result of the degradation of the web rings.

The medical implant, in particular the stent, can be coated by spraying or dipping, whereby a polymer is dissolved in a solvent and this solution is applied to the implant.

Suitable solvents are water and preferably organic solvents such as chloroform, methylene chloride (dichloromethane), acetone, tetrahydrofuran (THF), diethyl ether, methanol, ethanol, propanol, isopropanol, diethyl ketone, dimethylformamide (DMF), dimethylacetamide, ethyl acetate, dimethyl sulfoxide (DMSO). , Benzene, toluene, xylene, t-butyl methyl ether (MTBE), petroleum ether (PE), cyclohexane, pentane, hexane, heptane, with chloroform and methylene chloride.

In a suitable solvent or together with the polymer and the at least one applied drug can be dissolved, emulsified, suspended or dispersed. Suitable substances to be applied are the abovementioned pharmacologically active substances and the polymers described above. 2008/000161

18

Examples

Example 1:

A stent according to the invention consists of:

89% by weight of magnesium

7% by weight of calcium

1% by weight of zinc

2% by weight of yttrium

1% by weight of other metals, metal salts, non-metals, rare earths, metal carbides, metal oxides, metal nitrides, non-metals,

Carbon, sulfur, nitrogen, oxygen, hydrogen.

The stent according to Example 1 is coated in the dipping process with a solution of a polyglycol and doxorubicin. After drying, the dipping process is repeated two more times.

Example 2:

A stent according to the invention consists of: 81% by weight of magnesium

11% by weight of calcium

2% by weight of zinc

3% by weight of yttrium

3% by weight of other metals, metal salts, non-metals, rare earths, metal carbides, metal oxides, metal nitrides, non-metals,

Carbon, sulfur, nitrogen, oxygen, hydrogen.

The stent according to Example 2 is spray-coated with a solution of a polylactide and the active ingredient paclitaxel in dimethyl sulfoxide or in methanol. The spraying process is repeated several times.

Example 3:

A stent according to the invention consists of: 72.0% by weight of magnesium

7.3% by weight of calcium

3.2% by weight of yttrium

2.1% by weight of manganese

2.8% by weight of iron 4.8% by weight of zinc

7.8% by weight of other metals, metal salts, nonmetals, rare earths, metal carbides, metal oxides, metal nitrides, nonmetals, carbon, sulfur, nitrogen, oxygen, hydrogen.

The stent according to Example 3 is spray-coated with a solution of a polyester containing the active substance rapamycin in chloroform. The spraying process is repeated several times.

Example 4:

A stent according to the invention consists of: 85.0% by weight of magnesium 4.6% by weight of calcium 2.9% by weight of yttrium

0.7% by weight manganese 3.8% by weight iron 2.5% by weight zinc

0.5% by weight of other metals, metal salts, non-metals, rare earths, metal carbides, metal oxides, metal nitrides, non-metals,

Carbon, sulfur, nitrogen, oxygen, hydrogen.

The stent according to Example 4 is spray-coated with a solution of a polyamide without a pharmacologically active substance in acetone. The spraying process is repeated several times.

Example 5:

Three uncoated stents of the composition according to Example 4 (length 27 mm, mass 26.5 mg) are coated as follows:

Stent no.1: uncoated

Stent # 2: CVD-coated with polyamino-p-xylylene-co-poly-p-xylylene (short:

Amino-ppx), coating with high pore number (total pore area about 25% of the stent surface) provided

Stent no.3: CVD coated with amino-ppx,

Coating with a lower pore number (total pore area approx.

10% of the stent surface) stent no. 4: CVD-coated with amino-ppx, T / DE2008 / 000161

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unmodified standard coating according to work instruction CVD coating

Thereafter, the tripping behavior was tested in aqua regia (conc. Hydrochloric acid / nitric acid conc. 3: 1 (v / v)). The four stents were simultaneously placed in four test tubes filled with aqua regia. The course of the dissolution of the stents was visually tracked and documented by means of video and photo recordings. The time to complete dissolution of the stents was recorded. Reference is made to FIGS. 1 and 2.

The times until complete dissolution of the stents are compared below:

Stent: time to complete oxidative dissolution: stent no.1 about 7 minutes

Stent No. 2 about 12 minutes Stent No. 3 about 15 minutes Stent No. 4 about 30 minutes

It becomes apparent that the CVD coating significantly increases the resistance of the metal to the oxidative reagent. The standard coating (stent No.4) results in a fourfold increase in the "lifetime" of the stent, and moreover, the experiment shows that the temporal course of the oxidative dissolution can be regulated by the porosity of the coating.

figure description

Figures 1 and 2 show the dissolution behavior of 4 stents according to the invention over time in aqua regia. FIG. 1 shows the state of dissolution of the stents according to the invention after approx. 9 minutes and FIG. 2 after approx. 16 minutes.

Claims

claims

A resorbable implant, wherein the resorbable implant consists of 40 wt .-% to 90 wt .-% of magnesium containing in a magnesium alloy, wherein the resorbable implant with a biodegradable

Coating is coated.

2. A resorbable implant according to claim 1, wherein the resorbable implant further contains up to 10 wt .-% calicium.

3. A resorbable implant according to claim 1 or 2, wherein the resorbable implant further contains up to 10 wt .-% yttrium.

4. A resorbable implant according to claim 1, wherein the resorbable implant has the following composition of the magnesium alloy:

40% by weight - 90% by weight of magnesium

0.0% by weight - 20% by weight of calcium

0.0% by weight - 20% by weight of yttrium

0.0% by weight - 10% by weight of other metals or metal salts 0.0% by weight - 10% by weight of rare earth metals, metal carbides, metal oxides, metal nitrides, nonmetals, carbon, sulfur, nitrogen, oxygen, hydrogen ,

5. A resorbable implant according to any preceding claim, wherein the resorbable implant further comprises at least one metal selected from the group consisting of lithium, beryllium, sodium, magnesium, aluminum, potassium, calcium, scandium, titanium, vanadium, chromium, manganese, iron, Cobalt, nickel, copper, zinc, gallium, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, silver, indium, tin, lanthanum,

Cerium, praseodymium, neodymium, promethium, samarium, europium, gadolinium, terbium, dysprosium, holium, erbium, thulium, ytterbium, lutetium, tantalum, tungsten, rhenium, platinum, gold, lead.

6. absorbable implant according to any one of the preceding claims, wherein the metal salt comprises at least one metal ion of the following oxidation states: Li ⁺ , Be ²⁺ , Na ⁺ , Mg ²⁺ , K ⁺ , Ca ²⁺ , Sc ³⁺ , Ti ²⁺ , Ti ⁴⁺ , V ²⁺ , V ³⁺ , V ⁴⁺ , V ⁵⁺ , Cr ²⁺ , Cr ³⁺ , Cr ⁴⁺ , Cr ⁵⁺ , Mn ²⁺ , Mn ³⁺ , Mn ⁴⁺ , Mn ^{5 +} , Mn ⁶⁺ , Mn ⁷⁺ , Fe ²⁺ , Fe ³⁺ , Co ²⁺ , Co ³⁺ , Ni ²⁺ , Cu ⁺ , Cu ²⁺ , Zn ²⁺ , Ga ⁺ , Ga ³⁺ , Al ^{3 +} , Y ³⁺ , Zr ²⁺ , Zr ⁴⁺ , Nb ²⁺ , Nb ⁴⁺ , Nb ⁵⁺ , Mo ⁴⁺ , Mo ³⁺ , Tc ²⁺ , Tc ³⁺ , Tc ⁴⁺ , Tc ⁵⁺ , Tc ⁶⁺ , Tc ⁷⁺ , Ru ³⁺ , Ru ⁴⁺ , Ru ⁵⁺ , Ru ⁶⁺ , Ru ⁷⁺ , Ru ⁸⁺ , Rh ^{3 +} , Rh ⁴⁺ , Pd ²⁺ , Pd ³⁺ , Ag ⁺ , In ⁺ , In ³⁺ , Ta ⁴⁺ , Ta ⁵⁺ , W ⁴⁺ , W ⁶⁺ , Pt ²⁺ , Pt ³⁺ , Pt ^{4 +} , Pt ⁵⁺ , Pt ⁶⁺ , Au ⁺ , Au ³⁺ , Au ⁵⁺ , Sn ²⁺ , Sn ⁴⁺ , Pb ²⁺ , Pb ⁴⁺ , La ³⁺ , Ce ³⁺ , Ce ⁴⁺ , Gd ³⁺ , Nd ³⁺ , Pr ³⁺ , Tb ³⁺ , Pr ³⁺ , Pm ³⁺ , Sm ³⁺ , Eu ²⁺ , Dy ³⁺ , Ho ³⁺ , Er ³⁺ , Tm ³⁺ , Yb ³⁺ ,

7. A resorbable implant according to any one of the preceding claims, wherein the biodegradable coating is a polymeric coating of natural, synthetic and semisynthetic polymers.

8. resorbable implant according to claim 7, wherein the biodegradable coating consists of at least one of the following biodegradable substances or mixtures of the following biodegradable substances: Polyvalerolactone, poly-ε-decalactones, polylactic acid, polyglycolic acid polylactides, polyglycolides, copolymers of

Polylactides and polyglycolides, poly-ε-caprolactone, polyhydroxybutyric acid, polyhydroxybutyrates, polyhydroxyvalerates, polyhydroxybutyrate-co-valerates, poly (1,4-dioxane-2,3-diones), poly (1, 3-dioxan-2-ones), Poly-para-dioxanones, polyanhydrides, polymaleic anhydrides, polyhydroxymethacrylates, fibrin, polycyanoacrylates, polycaprolactone dimethyl acrylates, poly-b-maleic acid

Polycaprolactone butylacrylates, multiblock polymers of oligocaprolactone diols and oligodioxanonediols, polyetherester multiblock polymers of PEG and polybutylene terephthalate, polypivotolactones, polyglycolic acid trimethylcarbonates, polycaprolactone glycolides, poly (g-ethylglutamate), poly (DTH-I-minocarbonate), poly (DTE-co-DT-carbonate), poly (bisphenol A) iminocarbonate), polyorthoesters,

Polyglycolic acid trimethyl carbonate, polytrimethyl carbonate

Polyiminocarbonates, poly (N-vinyl) pyrrolidone, polyvinyl alcohols,

Polyesteramides, glycolated polyesters, polyphosphoesters, polyphosphazenes, poly [p-carboxyphenoxy) propane], polyhydroxypentanoic acid, polyanhydrides, polyethylene oxide propylene oxide, soft polyurethanes, polyurethanes with

Amino acid residues in the backbone, polyether esters such as the polyethylene oxide, polyalkene oxalates, polyorthoesters and their copolymers, lipids, carrageenans, fibrinogen, starch, collagen, protein-based polymers, polyamino acids, synthetic polyamino acids, zein, polyhydroxyalkanoates, pectinic acid, actinic acid, carboxymethylsulfate,

Albumin, hyaluronic acid, chitosan and its derivatives, heparan sulphates and its derivatives, heparins, chondroitin sulphate, dextran, β-cyclodextrins, copolymers with PEG and polypropylene glycol, gum arabic, guar, gelatine, collagen collagen-N-hydroxysuccinimide, lipids, phospholipids, E2008 / 000161

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Polyacrylic acid, polyacrylates, polymethyl methacrylate, polybutyl methacrylate, polyacrylamide, polyacrylonitriles, polyamides, polyetheramides, polyethyleneamine, polyimide, polycarbonates, polycarbourethanes, polyvinyl ketones, polyvinyl halides, polyvinylidene halides, polyvinyl ethers, polyisobutylenes, polyvinylaromatics, polyvinyl esters, polyvinylpyrollidones, polyoxymethylenes,

Polytetramethylene oxide, polyethylene, polypropylene, polytetrafluoroethylene, polyurethanes, polyether urethanes, silicone polyether urethanes, silicone polyurethanes, silicone polycarbonate urethanes, polyolefin elastomers, polyisobutylenes, EPDM rubbers, fluorosilicones, carboxymethyl chitosans, polyaryletheretherketones, polyetheretherketones, polyethylene terephthalate,

Polyvalerates, carboxymethylcellulose, cellulose, rayon, rayontriacetates, cellulose nitrates, cellulose acetates, hydroxyethylcellulose, cellulose butyrates, cellulose acetate butyrates, ethylvinylacetate copolymers, polysulphones,

Epoxy resins, ABS resins, EPDM rubbers, silicones such as polysiloxanes, polydimethylsiloxanes, polyvinyl halogens and copolymers, cellulose ethers,

Cellulosetriacetates, chitosans and copolymers and / or mixtures of the aforementioned polymers.

The resorbable implant according to claim 8, wherein the biodegradable coating is made of a polyester, polyurethane, parylene, ammini-ppx,

Polylactide or a mixture of two or more of the aforementioned polymers.

10. Resorbable implant according to one of the preceding claims, wherein the coating permits a liquid permeation.

11. Resorbable implant according to one of the preceding claims, wherein the coating is a semipermeable membrane.

12. A resorbable implant according to any one of the preceding claims, wherein the coating has holes.

13. A resorbable implant according to claim 12, wherein the holes are produced after coating in a mechanical manner, in a chemical manner or by means of laser optically in the coating.

14. Resorbable implant according to one of the preceding claims, wherein there is at least one pharmacologically active substance on and / or in the resorbable implant.

15. Resorbable implant according to one of the preceding claims, wherein there is at least one pharmacologically active substance in, in and / or below the biodegradable coating.

16. A resorbable implant according to claim 14 or 15, wherein the at least one pharmacologically active substance is selected from the group comprising antiproliferative, antimigrative, antiangiogenic, antiinflammatory, antiphlogistic, cytostatic, cytotoxic and / or antithrombotic agents, anti-restenosis agents, corticoids,

Sex hormones, statins, epothilones, prostacyclins, angiogenesis inducers.

The resorbable implant of claim 16, wherein said at least one pharmacologically active substance is selected from the group comprising:

Abciximab, Acemetacin, Acetylvismion B, Aclarubicin, Ademetionin, Adriamycin, Aescin, Afromosone, Akagerin, Aldesleukin, Amidorone, Aminoglutethemide, Amsacrine, Anakinra, Anastrozole, Anemonin, Anopterin, Antifungals, Antithrombotics, Apocymarin, Argatroban, Aristolactam-All, Aristolochic Acid, Ascomycin , Asparaginase, aspirin, atorvastatin, auranofin,

Azathioprine, azithromycin, baccatin, bafilomycin, basiliximab, bendamustine, benzocaine, berberine, betulin, betulinic acid, bilobol, bisparthenolidine, bleomycin, bombrestatin, boswellic acids and their derivatives, bruceanols A ₁ B and C, bryophyllin A, busulfan, antithrombin, bivalirudin, cadherins , Camptothecin, capecitabine, o-carbamoylphenoxyacetic acid, carboplatin,

Carmustine, Celecoxib, Cepharantin, Cerivastatin, CETP Inhibitors, Chlorambucil, Chloroquine Phosphate, Cictoxin, Ciprofloxacin, Cisplatin, Cladribine, Clarithromycin, Colchicine, Concanamycin, Coumadin, C-Type Natriuretic Peptide (CNP), Cudraisoflavone A, Curcumin, Cyclophosphamide, Cyclosporin A , Cytarabine, dacarbazine, daclizumab, dactinomycin, dapsone,

Daunorubicin, diclofenac, 1,11-dimethoxycanthin-6-one, docetaxel, doxorubicin, dunaimycin, epirubicin, epothilones A and B, erythromycin, estramustine, etoboside, everolimus, filgrastim, fluroblastin, fluvastatin, fludarabine, fludarabine 5'-dihydrogen phosphate, Fluorouracil, folimycin, fosfestrol, gemcitabine, ghalacinoside, ginkgol, ginkgolic acid, glycoside 1a, 4-

Hydroxyoxycyclophosphamide, idarubicin, ifosfamide, josamycin, lapachol, lomustine, lovastatin, melphalan, midecamycin, mitoxantrone, nimustine, pitavastatin, pravastatin, procarbazine, mitomycin, methotrexate, mercaptopurine, thioguanine, oxaliplatin, irinotecan, topotecan, hydroxycarbamide, miltefosine, 2008/000161

25

Pentostatin, pegasparase, exemestane, letrozole, formestan, SMC proliferation inhibitor 2w, mitoxanthrones, mycophenolate mofetil, c-myc antisense, b-myc antisense, H-lapachone, podophyllotoxin, podophyllic acid 2-ethyl hydrazide, molgramostim (rhuGM- CSF), peginterferon α-2b, lanograstim (r -HuG-CSF), macrogol, selectiπ (cytokine antagonist), cytokine inhibitors,

COX-2 inhibitor, NFkB, angiopeptin, monoclonal antibodies that inhibit muscle cell proliferation, bFGF antagonists, probucol, prostaglandins, 1-hydroxy-11-methoxycanthin-6-one, scopolectin, NO donors such as pentaerythrityl tetranitrate and syndnoeimines, S- Nitrosated derivatives, tamoxifen, staurosporine, β-estradiol, α-estradiol, estriol, estrone,

Ethinyl estradiol, medroxyprogesterone, estradiol cypionates, estradiol benzoates, tranilast, kamebakaurin and other terpenoids used in cancer therapy, verapamil, tyrosine kinase inhibitors (tyrphostins), paclitaxel and its derivatives such as 6-α-hydroxy paclitaxel, taxoters, carbon suboxide ( MCS) and its macrocyclic oligomers, mofebutazone,

Lonazolac, lidocaine, ketoprofen, mefenamic acid, piroxicam, meloxicam, penicillamine, hydroxychloroquine, sodium aurothiomalate, oxaceprol, β-sitosterol, myrtainaine, polidocanol, nonivamide, levomenthol, eHipticin, D-24851 (Calbiochem), colcemid, cytochalasin AE, indanocine, nocadazole, S 100 protein, bacitracin, vitronectin receptor antagonists, azelastine,

Guanidyl cyclase stimulator Metalloproteinase 1 and 2 tissue inhibitor, free nucleic acids, nucleic acids incorporated in virus carriers, DNA and RNA fragments, plaque activator inhibitor-1, plasminogen activator inhibitor-2, antisense oligonucleotides, VEGF inhibitors, IGF-1 , Active ingredients from the group of antibiotics such as cefadroxil, cefazolin, cefaclor, cefotixin

Tobramycin, gentamycin, penicillins such as dicloxacillin, oxacillin, sulfonamides, metronidazole, enoxoparin, desulfated and N-reacetylated heparin, tissue plasminogen activator, Gpllb / Illa platelet membrane receptor, factor X _a inhibitor antibody, heparin, hirudin, r-hirudin, PPACK, protamine, prourokinase, streptokinase, warfarin, urokinase, vasodilators like

Dipyramidol, trapidii, nitroprussides, PDGF antagonists such as triazolopyrimidine and seramin, ACE inhibitors such as captopril, cilazapril, lisinopril, enalapril, losartan, thioprotease inhibitors, prostacyclin, vapiprost, interferon α, β and Y, histamine antagonists, serotonin blockers, apoptosis inhibitors, apoptosis regulators such as p65, NF-kB or Bcl-xL antisense oligonucleotides,

Halofuginone, nifedipine, tocopherol, tranilast, molsidomine, tea polyphenols, epicatechingallate, epigallocatechin gallate, leflunomide, etanercept, sulfasalazine, etoposide, dicloxacylline, tetracycline, triamcinolone, mutamycin, procainimide, retinoic acid, quinidine, disopyrimide, flecainide, propafenone, Sotolol, natural and synthetic steroids such as inotodiol, maquiroside A, ghalakinoside, mansonine, strebloside, hydrocortisone, betamethasone, dexamethasone, nonsteroidal substances (NSAIDS) such as fenoporfen, ibuprofen, indomethacin, naproxen, phenylbutazone and other antiviral agents such as acyclovir, ganciclovir and zidovudine , Clotrimazole,

Flucytosine, griseofulvin, ketoconazole, miconazole, nystatin, terbinafine, antiprozoal agents such as chloroquine, mefloquine, quinine, further natural terpenoids such as hippocaesculin, barriπgtogenol-C21-angelate, 14-dehydroagrostistachine, agroscerin, agrostistachin, 17-hydroxy-agrostistachin, ovatodiolides, 4 7-oxycycloanisomic acid, baccharinoids B1, B2, B3 and B7,

Tubeimoside, Bruceantinoside C, Yadanzioside N, and P, Isodeoxyelephantopin, Tomenphantopin A and B, Coronarin A, B, C and D, Ursolic Acid, Hyptate Acid A, Iso-Iridogermanal. Maytenfoliol, Effusantin A, Excisanin A and B, Longikaurin B, Sculponeatin C, Kamebaunin, Leukamenin A and B, 13,18-Dehydro-6-alpha-Senecioyloxychaparrin, Taxamairin A and B,

Regenilol, triptolide, cymarin, hydroxyanopterin, protoanemonin, cheliburine chloride, sinococulin A and B, dihydronitidine, nitidinium chloride, 12-beta-hydroxypregnadiene 3,20-dione, helenaline, indicine, indicin-N-oxide, lasiocarpine, inotodiol, podophyllotoxin, Justiddin A and B, Larreatin, Malloterine, Mallotochromanol, Isobutyrylmallotochromanol, Maquiroside A, Marchantin A,

Maytansine, lycoridicin, margetin, pancratistatin, liriodenin, bispsrthenolidine, oxoushinsunin, periplocoside A, ursolic acid, deoxypypsorospermine, psycorubin, ricin A, sanguinarine, manuwizic acid, methylsorbifolin, sphatheliachromes, stizophyllin, mansonine, strebloside, dihydrousambaraensine, hydroxyusambarin, strychnopentamine, strychnophyllin, usambarin,

Usambarensin, Liriodenin, Oxoushinsunin, Daphnoretin, Lariciresinol, Methoxylariciresinol, Syringaresinol, Sirolimus (rapamycin), Somatostatin, Tacrolimus, Roxithromycin, Troleandomycin, Simvastatin, Rosuvastatin, Vinblastine, Vincristine, Vindesine, Teniposide, Vinorelbine, Tropfosfamide, Treosulfan, Tremozolomide, Thiotepa, Tretinoin , Spiramycin, umbelliferone,

Desacetylvismion A, Vismion A and B, Zeorin.

18. Resorbable implant according to one of the preceding claims, wherein the resorbable implant is a stent for blood vessels, urinary tract, respiratory tract, biliary tract or the digestive tract.