Biocompatibly coated medical implants

• US 20050079200A1
• Filed: 09/10/2004
• Published: 04/14/2005
• Est. Priority Date: 05/16/2003
• Status: Abandoned Application

• Current Assignee: Juergen Blersch
• Original Assignee: Juergen Blersch
• Inventors: Rathenow, Jorg, Kunstmann, Jurgen, Mayer, Bernhard, Asgari, Soheil, Ban, Andreas
• Application Number:
  US10/938,995
• Publication Number:
  US 20050079200A1
• Time in Patent Office: Days
• US Class Current: 424/423
• CPC Class Codes: A61L 2300/608 having two or more layers
• CPC Class Codes: A61L 27/303 Carbon
• CPC Class Codes: A61L 31/084 Carbon; Graphite
• CPC Class Codes: A61L 31/10 Macromolecular materials
• CPC Class Codes: A61L 31/16 Biologically active materials, e.g. therapeutic substances A61L31/047 takes precedence

Abstract

Implantable medical devices with biocompatible coatings and processes for their production are described. The present invention relates in particular to medical implantable devices coated with a carbon-containing layer which devices are produced by at least partially coating the device with a polymer film and heating the polymer film in an atmosphere which is essentially free from oxygen to temperatures in the region of 200° C. to 2500° C., a carbon-containing layer being produced on the implantable medical device.

Claims

1. A method for the production of biocompatible coatings on implantable medical devices comprising the following steps:

a) at least partially coating of the medical device with a polymer film by means of a suitable coating and/or application process;

b) heating of the polymer film in an atmosphere which is essentially free from oxygen to temperatures in the region of 200°

C. to 2500°

C., for the production of a carbon-containing layer on the medical device.

2. The method according to claim 1 wherein the implantable medical device consists of a material which is selected from carbon, carbon composite material, carbon fibre, ceramic, glass, metals, alloys, bone, stone, minerals or precursors of these or from materials which are converted under carbonisation conditions into their thermostable state.

3. The method according to claim 1 wherein the implantable medical device is selected from medical or therapeutic implants such as vascular endoprostheses, stents, coronary stents, peripheral stents, orthopaedic implants, bone or joint prostheses, artificial hearts, artificial heart valves, subcutaneous and/or intramuscular implants and such like.

4. The method according to claim 1 wherein the polymer film comprises:

homopolymers or copolymers of aliphatic or aromatic polyolefins such as polyethylene, polypropylene, polybutene, polyisobutene, polypentene;

polybutadiene;

polyvinyls such as polyvinyl chloride or polyvinyl alcohol, poly(meth)acrylic acid, polyacrylocyano acrylate;

polyacrylonitril, polyamide, polyester, polyurethane, polystyrene, polytetrafluoroethylene;

polymers such as collagen, albumin, gelatine, hyaluronic acid, starch, celluloses such as methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose phthalate;

waxes, paraffin waxes, Fischer-Tropsch waxes;

casein, dextrans, polysaccharides, fibrinogen, poly(D,L-lactides), poly(D,L-lactide coglycolides), polyglycolides, polyhydroxybutylates, polyalkyl carbonates, polyorthoesters, polyesters, polyhydroxyvaleric acid, polydioxanones, polyethylene terephthalates, polymaleate acid, polytartronic acid, polyanhydrides, polyphosphazenes, polyamino acids;

polyethylene vinyl acetate, silicones;

poly(ester urethanes), poly(ether urethanes), poly(ester ureas), polyethers such as polyethylene oxide, polypropylene oxide, pluronics, polytetramethylene glycol;

polyvinylpyrrolidone, poly(vinyl acetate phthalate) as well as their copolymers, mixtures and combinations of these homopolymers or copolymers.

5. The method according to claim 1 wherein the polymer film comprises alkyd resin, chlorinated rubber, epoxy resin, acrylate resin, phenol resin, amine resin, melamine resin, alkyl phenol resins, epoxidised aromatic resins, oil base, nitro base, polyester, polyurethane, tar, tar-like materials, tar pitch, bitumen, starch, cellulose, waxes, shellac, organic materials of renewable raw materials or combinations thereof.

6. The method according to claim 1 wherein the polymer film is applied as a liquid polymer or polymer solution in a suitable solvent or solvent mixture, if necessary with subsequent drying, or as a polymer solid, if necessary in the form of sheeting or sprayable particles.

7. The method according to claim 6 wherein the polymer film is applied onto the device by laminating, bonding, immersing, spraying, printing, knife application, spin coating, powder coating or flame spraying.

8. The method according to claim 1 wherein further comprising the step of depositing carbon and/or silicon by chemical or physical vapour phase deposition (CVD or PVD).

9. The method according to claim 1 wherein further comprising a sputter application of carbon and/or silicon and/or of metals.

10. The method according to claim 1 wherein the carbon-containing layer is modified by ion implantation.

11. The method according to claim 1 wherein the carbon-containing layer is post-treated with oxidising agents and/or reducing agents, preferably chemically modified by treating the coated device in oxidising acid or alkali.

12. The method according to claim 1 wherein the carbon-containing layer is purified by solvents or solvent mixtures.

13. The method according to claim 1 wherein steps a) and b) are carried out repeatedly in order to obtain a carbon-containing multi-layer coating, preferably with different porosities, by pre-structuring the polymer films or substrates or suitable oxidative treatment of individual layers.

14. The method according to claim 1 wherein several polymer film layers are applied on top of each other in step a).

15. The method according to claim 1 wherein the carbon-containing coated medical device is at least partially coated with at least one additional layer of biodegradable and/or resorbable polymers or non-biodegradable or resorbable polymers.

16. The method according to claim 15 wherein the biodegradable or resorbable polymers are selected from collagen, albumin, gelatine, hyaluronic acid, starch, celluloses such as methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose phthalate;

casein, dextrans, polysaccharides, fibrinogen, poly(D,L-lactides), poly(D,L-lactide coglycolides), polyglycolides, polyhydroxybutylates, polyalkyl carbonates, polyorthoesters, polyesters, polyhydroxyvaleric acid, polydioxanones, polyethylene terephthalates, polymaleate acid, polytartronic acid, polyanhydrides, polyphosphazenes, polyamino acids and their copolymers.

17. The method according to claim 1 wherein the carbon-containing coating on the device is loaded with at least one active principle, microorganisms or living cells.

18. The method according to claim 17 wherein the at least one active principle is applied and/or immobilised in pores on or in the coating by adsorption, absorption, physisorption, chemisorption, covalent bonding or non-covalent bonding, electrostatic fixing or occlusion.

19. The method according to claim 17 wherein the at least one active principle is immobilised essentially permanently on or in the coating.

20. The method according to claim 19 wherein the active principle comprises inorganic substances e.g. hydroxyl apatite (HAP), fluoroapatite, tricalcium phosphate (TCP), zinc;

and/or organic substances such as peptides, proteins, carbohydrates such as monosaccharides, oligosaccharides and polysaccharides, lipids, phospholipids, steroids, lipoproteins, glycoproteins, glycolipids, proteoglycanes, DNA, RNA, signal peptides or antibodies and/or antibody fragments, bioresorbable polymers, e.g. polylactonic acid, chitosan as well as pharmacologically active substances or mixtures of substances, combinations of these and such like.

21. The method according to claim 17 wherein the at least one active principle contained in or on the coating is releasable from the coating in a controlled manner.

22. The method according to claim 21 wherein the active principle releasable in a controlled manner comprises inorganic substances, e.g. hydroxyl apatite (HAP), fluoroapatite, tricalcium phosphate (TCP), zinc;

and/or organic substances such as peptides, proteins, carbohydrates such as monosaccharides, oligosaccharides and polysaccharides, lipids, phospholipids, steroids, lipoproteins, glycoproteins, glycolipids, proteoglycanes, DNA, RNA, signal peptides or antibodies and/or antibody fragments, bioresorbable polymers, e.g. polylactonic acid, chitosan and pharmacologically active substances or mixtures of substances.

23. The method according claim 20 or 21 wherein the pharmacologically active substances are selected from heparin, synthetic heparin analogues (e.g. fondaparinux), hirudin, antithrombin III, drotrecogin alpha;

fibrinolytics such as alteplase, plasmin, lysokinase, factor XIIa, prourokinase, urokinase, anistreplase, streptokinase;

thrombocyte aggregation inhibitors such as acetyl salicylic acid, ticlopidines, clopidogrel, abciximab, dextrans;

corticosteroids such as alclometasones, amcinonides, augmented betamethasones, beclomethasones, betamethasones, budesonides, cortisones, clobetasol, clocortolones, disunites, desoximetasones, dexamethasones, flucinolones, fluocinonides, flurandrenolides, flunisolides, fluticasones, halcinonides, halobetasol, hydrocortisones, methylprednisolones, mometasones, prednicarbates, prednisones, prednisolones, triamcinolones;

so-called non-steroidal anti-inflammatory drugs such as diclofenac, diflunisal, etodolac, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meclofenamates, mefenamic acid, meloxicam, nabumetones, naproxen, oxaprozin, piroxicam, salsalates, sulindac, tolmetin, celecoxib, rofecoxib;

cytostatics such as alkaloids and podophyllum toxins such as vinblastin, vincristin;

alkylants such as nitrosoureas, nitrogen lost analogues;

cytotoxic antibiotics such as daunorubicin, doxorubicin and other anthracyclines and related substances, bleomycin, mitomycin;

antimetabolites such as folic acid analogues, purine analogues or purimidine analogues;

paclitaxel, docetaxel, sirolimus;

platinum compounds such as carboplatinum, cisplatinum or oxaliplatinum;

amsacrin, irinotecan, imatinib, topotecan, interferon-alpha 2a, interferon-alpha 2b, hydroxycarbamide, miltefosin, pentostatin, porfimer, aldesleukin, bexarotene, tretinoin;

antiandrogens, and antiestrogens;

antiarrythmics, in particular antiarrhythmics of class I such as antiarrhythmics of the quinidine type, e.g. quinidine, dysopyramide, ajmaline, prajmalium bitartrate, detajmium bitartrate;

antiarrhythmics of the lidocain type, e.g. lidocain, mexiletin, phenyloin, tocainid;

antiarrhythmics of class I C, e.g. propafenone, flecainide (acetate);

antiarrhythmics of class II, betareceptor blockers such as metoprolol, esmolol, propranolol, metoprolol, atenolol, oxprenolol;

antiarrhythmics of class III such as amiodaron, sotalol;

antiarrhythmics of class IV such as diltiazem, verapamil, gallopamil;

other antiarrhythmics such as adenosine, orciprenaline, ipratropium bromide;

agents for stimulating angiogenesis in the myocardium such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), non-viral DNA, viral DNA, endothelial growth factors;

FGF-1, FGF-2, VEGF, TGF;

antibodies, monoclonal antibodies, anticalins;

stem cells, endothelial progenitor cells (EPC);

digitalis glycosides such as acetyl digoxin/methyldigoxin, digitoxin, digoxin;

heart glycosides such as ouabain, proscillaridin;

antihypertonics such as centrally effective antiadrenergic substances, e.g. methyldopa, imidazoline receptor agonists;

calcium channel blockers of the dihydropyridine type such as nifedipine, nitrendipine;

ACE inhibitors;

quinaprilate, cilazapril, moexipril, trandolapril, spirapril, imidapril, trandolapril;

angiotensin-II-antagonists;

candesartancilexetil, valsartan, telmisartan, olmesartan medoxomil, eprosartan;

peripherally effective alpha-receptor blockers such as prazosin, urapidil, doxazosin, bunazosin, terazosin, indoramin;

vasodilators such as dihydralazine, diisopropyl amine dichloroacetate, minoxidil, nitroprusside-sodium;

other antihypertonics such as indapamide, codergocrin mesilate, dihydroergotoxin methane sulphonate, cicletanin, bosentan, fludrocortisone;

phosphodiesterase inhibitors such as milrinone, enoximone and antihypotonics such as in particular adrenergics and dopaminergic substances such as dobutamine, epinephrine, etilefrine, norfenefrine, norepinephrine, oxilofrine, dopamine, midodrine, pholedrine, amezinium methyl; and

partial adrenoceptor agonists such as dihydroergotamine;

fibronectin, polylysines, ethylene vinyl acetates, inflammatory cytokines such as;

TGFβ

, PDGF, VEGF, bFGF, TNFα

, NGF, GM-CSF, IGF-a, IL-1, IL-8, IL-6, growth hormones;

as well as adhesive substances such as cyanoacrylates, beryllium, silica; and

growth factors such as erythropoietin, hormones such as corticotropins, gonadotropins, somatropin, thyrotrophin, desmopressin, terlipressin, oxytocin, cetrorelix, corticorelin, leuprorelin, triptorelin, gonadorelin, ganirelix, buserelin, nafarelin, goserelin, as well as regulatory peptides such as somatostatin, octreotide;

bone and cartilage stimulating peptides, bone morphogenetic proteins (BMPs), in particular recombinant BMPs such as e.g. recombinant human BMP-2 (rhBMP-2)), bisphosphonates (e.g. risedronates, pamidronates, ibandronates, zoledronic acid, clodronic acid, etidronic acid, alendronic acid, tiludronic acid), fluorides such as disodium fluorophosphate, sodium fluoride;

calcitonin, dihydrotachystyrene;

growth factors and cytokines such as epidermal growth factors (EGF), Platelet derived growth factor (PDGF), Fibroblast Growth Factors (FGFs), Transforming Growth Factors-b TGFs-b), Transforming Growth Factor-a (TGF-a), Ervthropoietin (Epo), Insulin-Like Growth Factor-I (IGF-I), Insulin-Like Growth Factor-II (IGF-II), Interleukin-1 (IL-1), Interleukin-2 (IL-2), Interleukin-6 (IL-6), Interleukin-8 (IL-8), Tumour Necrosis Factor-a (TNF-a), Tumour Necrosis Factor-b (TNF-b), Interferon-g (INF-g), Colony Stimulating Factors (CSFs);

monocyte chemotactic protein, fibroblast stimulating factor 1, histamine, fibrin or fibrinogen, endothelin-1, angiotensin II, collagens, bromocriptin, methylsergide, methotrexate, carbontetrachloride, thioacetamide and ethanol;

also silver (ions), titanium dioxide, antibiotics and antiinfectives such as in particular β

-lactam antibiotics, e.g. β

-lactamase-sensitive penicillins such as benzyl penicillins (penicillin G), phenoxymethylpenicillin (penicillin V);

β

-lactamase-resistant penicillins such as aminopenicillins such as amoxicillin, ampicillin, bacampicillin;

acylaminopenicillins such as meziocillin, piperacillin;

carboxypenicillins, cephalosporins such as cefazolin, cefuroxim, cefoxitin, cefotiam, cefaclor, cefadroxil, cefalexin, loracarbef, cefixim, cefuroximaxetil, ceftibutene, cefpodoximproxetil, cefpodoximproxetil;

aztreonam, ertapenem, meropenem;

β

-lactamase inhibitors such as sulbactam, sultamicillintosilates;

tetracyclines such as doxycycline, minocycline, tetracycline, chlorotetracycline, oxytetracycline;

aminoglycosides such as gentamicin, neomycin, streptomycin, tobramycin, amikacin, netilmicin, paromomycin, framycetin, spectinomycin;

makrolide antibiotics such as azithromycin, clarithromycin, erythromycin, roxithromycin, spiramycin, josamycin;

lincosamides such as clindamycin, lincomycin, gyrase inhibitors such as fluoroquinolones such as ciprofloxacin, ofloxacin, moxifloxacin, norfloxacin, gatifloxacin, enoxacin, fleroxacin, levofloxacin;

quinolones such as pipemidic acid;

sulphonamides, trimethoprim, sulphadiazin, sulphalene;

glycopeptide antibiotics such as vancomycin, teicoplanin;

polypeptide antibiotics such as polymyxins such as colistin, polymyxin-B nitroimidazol derivatives such as metronidazol, tinidazol;

aminoquinolones such as chloroquin, mefloquin, hydroxychloroquin;

biguanides such as proguanil;

quinine alkaloids and diaminopyrimidines such as pyrimethamine;

amphenicols such as chloramphenicol;

rifabutin, dapsone, fusidinic acid, fosfomycin, nifuratel, telithromycin, fusafungin, fosfomycin, pentamidindiisethionate, rifampicin, taurolidine, atovaquone, linezolid;

virostatics such as aciclovir, ganciclovir, famciclovir, foscarnet, inosine(dimepranol-4-acetamidobenzoate), valganciclovir, valaciclovir, cidofovir, brivudin;

antiretroviral active principles (nucleoside analogous reverse transcriptase inhibitors and derivatives) such as lamivudin, zalcitabin, didanosine, zidovudin, tenofovir, stavudin, abacavir;

non-nucleoside analogous reverse transcriptase inhibitors such as amprenavir, indinavir, saquinavir, lopinavir, ritonavir, nelfinavir;

amantadine, ribavirin, zanamivir, oseltamivir and lamivudine, as well as any desired combination and mixtures thereof.

24. The method according to claim 20 or 21, characterised in that, the pharmacologically active substances are incorporated into microcapsules, liposomes, nanocapsules, nanoparticles, micelles, synthetic phospholipids, gas dispersions, emulsions, micro-emulsions, or nanospheres which are reversibly adsorbed and/or absorbed in the pores or on the surface of the carbon-containing layer for later release in the body.

25. The method according to claim 1 wherein the implantable medical device consists of a stent consisting of a material selected from the group of stainless steel, platinum-containing radiopaque steel alloys, cobalt alloys, titanium alloys, high-melting alloys based on niobium, tantalum, tungsten and molybdenum, noble metal alloys, nitinol alloys as well as magnesium alloys and mixtures of the above-mentioned substances.

26. A biocompatibly coated implantable medical device comprising a carbon-containing surface coating, produced according to the method of claim 1.

27. The device according to claim 26, wherein the device further comprises metals such as stainless steel, titanium, tantalum, platinum, nitinol or nickel-titanium alloy;

carbon fibres, full carbon material, carbon composite, ceramic, glass or glass fibres.

28. The device according to claim 26, wherein the device further comprises several carbon-containing layers, preferably with different porosities.

29. The device according to claim 26, wherein the device further comprises a coating of biodegradable and/or resorbably polymers such as collagen, albumin, gelatine, hyaluronic acid, starch, celluloses such as methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethylcellulose phthalate;

waxes, casein, dextrans, polysaccharides, fibrinogen, poly(D,L-lactides), poly(D,L-lactide coglycolides), poly(glycolides), poly(hydroxybutylates), poly(alkyl carbonates), poly(orthoesters), polyesters, poly(hydroxyvaleric acid), polydioxanones, poly(ethylene terephthalates), poly(maleate acid), poly(tartronic acid), polyanhydrides, polyphosphazenes, poly(amino acids) and their copolymers.

30. The device according to claim 26, wherein the device further comprises a coating of non-biodegradable and/or resorbably polymers such as poly(ethylene vinyl acetate), silicones, acrylic polymers such as polyacrylic acid, polymethylacrylic acid, polyacrylocyanoacrylate;

polyethylenes, polypropylenes, polyamides, polyurethanes, poly(ester urethanes), poly(ether urethane), poly(ester ureas), polyethers, poly(ethylene oxide), poly(propylene oxide), pluronics, poly(tetramethylene glycol);

vinyl polymers such as polyvinylpyrrolidones, poly(vinyl alcohols)or poly(vinyl acetate phthalate) as well as their copolymers.

31. The device according to claim 26, wherein the device further comprises anionic or cationic or amphoteric coatings such as alginate, carrageenan, carboxymethylcellulose;

chitosan, poly-L-lysines; and

/or phosphoryl choline.

32. The device according to claim 26 wherein the carbon-containing surface coating is porous, preferably macroporous, with pore diameters in the region of 0.1 to 1000 μ

m, and particularly preferably nanoporous.

33. The device according to claim 26 wherein the carbon-containing surface coating is non-porous and/or essentially contains closed pores.

34. The device according to claim 26, wherein the device further comprises one or several active principles comprising inorganic substances e.g. hydroxyl apatite (HAP), fluoroapatite, tricalcium phosphate (TCP), zinc;

and/or organic substances such as peptides, proteins, carbohydrates such as monosaccharides, oligosaccharides and polysaccharides, lipids, phospholipids, steroids, lipoproteins, glycoproteins, glycolipids, proteoglycanes, DNA, RNA, signal peptides or antibodies and/or antibody fragments, bioresorbable polymers, e.g. polylactonic acid, chitosan as well as pharmacologically active substances or mixtures of substances, combinations of these and such like.

35. The device according to claim 34, wherein the device further comprises a coating influencing the release of the active principles, selected from pH-sensitive and/or temperature-sensitive polymers and/or biologically active barriers such as enzymes.

36. A coated stent comprising the device of claim 26.

37. The coated stent according to claim 36, wherein the stent comprises stainless steel, preferably Fe-18Cr-14Ni-2.5Mo (“

316LVM”

ASTM F138), Fe-21Cr-10Ni-3.5Mn-2.5Mo (ASTM F

     1586), Fe-22Cr-13Ni-5Mn (ASTM F

     1314), Fe-23Mn-21Cr-1Mo-1N (nickel-free stainless steel);

from cobalt alloys, preferably Co-20Cr-5W-10Ni (“

L605”

ASTM F90), Co-20Cr-35Ni-10Mo (“

MP35N”

ASTM F

     562), Co-20Cr-16Ni-16Fe-7Mo (“

Phynox”

ASTM F

     1058);

from titanium alloys are CP titanium (ASTM F 67, grade

     1), Ti-6A1-4V (alpha/beta ASTM F

     136), Ti-6A1-7Nb (alpha/beta ASTM F1295), Ti-15Mo (beta grade ASTM F2066);

from noble metal alloys, in particular iridium-containing alloys such as Pt-10Ir;

nitinol alloys such as martensitic, superelastic and cold worked nitinols as well as magnesium alloys such as Mg-3A1-1Z;

as well as at least one carbon-containing surface layer.

38. A coated heart valve comprising the device of claim 26.

39. The device according to claim 26 wherein the device is an orthopaedic bone prosthesis or joint prosthesis, a bone substitute or a vertebra substitute in the breast or lumbar region of the spine.

40. The device according to claim 26 wherein the device is a subcutaneous and/or intramuscular implant for the controlled release of active principle.