Medical products comprising a haemocompatible coating, production and use thereof
First Claim
1. Medical device, wherein at least one part of the surface of the medical device is coated directly or via at least one interjacent biostable and/or biodegradable layer with a hemocompatible layer comprising at least one compound of the formula 1
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Accused Products
Abstract
The invention relates to the use of polysaccharides, that comprise the sugar building unit N-acylglucosamine, for the preparation of hemocompatible surfaces as well as methods for the hemocompatible coating of surfaces with these polysaccharides, which are classified to be the common biosynthetic precursor substances of heparin and heparansulphates. Described are medical devices coated according to invention, especially stents, which comprise paclitaxel as antiproliferative active agent as well as the use of these stents for the prevention of restenosis.
205 Citations
35 Claims
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1. Medical device, wherein at least one part of the surface of the medical device is coated directly or via at least one interjacent biostable and/or biodegradable layer with a hemocompatible layer comprising at least one compound of the formula 1
- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35)
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2. Medical device according to claim 1, wherein Y represents the residue —
- CHO, —
COCH3, —
COC2H5, —
COC3H7, as well as salts of these compounds.
- CHO, —
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3. Medical device according to claim 2, wherein Y is —
- COCH3.
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4. Medical device according to claim 1, wherein the hemocompatible layer is directly placed on the surface of the medical device and onto said hemocompatible layer paclitaxel as well as mixtures of these active agents are deposited.
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5. Medical device according to claim 1, wherein under the hemocompatible layer or between two hemocompatible layers at least one biostable and/or biodegradable layer is present.
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6. Medical device according to claim 1, wherein the hemocompatible layer is coated completely or/and incompletely with at least one additional, above lying biostable and/or biodegradable layer.
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7. Medical device according to claim 1, in which at least one active agent layer of paclitaxel is present between the biostable and the hemocompatible layer.
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8. Medical device according to claim 1, in which paclitaxel is bound covalently and/or adhesively in and/or on the hemocompatible layer and/or the biostable and/or the biodegradable layer.
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9. Medical device according to claim 1, characterised in, that as biodegradable substances for the biodegradable layer polyvalerolactones, poly-ε
- -decalactones, polylactonic acid, polyglycolic acid, polylactides, polyglycolides, copolymers of the polylactides and polyglycolides, poly-ε
-caprolactone, polyhydroxybutanoic acid, polyhydroxybutyrates, polyhydroxyvalerates, polyhydroxybutyrate-co-valerates, poly(1,4-dioxane-2,3-diones), poly(1,3-dioxane-2-one), poly-para-dioxanones, polyanhydrides as polymaleic anhydrides, polyhydroxymethacrylates, fibrin, polycyanoacrylates, polycaprolactonedimethylacrylates, poly-b-maleic acid, polycaprolactonebutyl-acrylates, multiblock polymers as e.g. from oligocaprolactonedioles and oligodioxanonedioles, polyetherester multiblock polymers as e.g. PEG and poly(butyleneterephtalates), polypivotolactones, polyglycolic acid trimethyl-carbonates, polycaprolactone-glycolides, poly(g-ethylglutamate), poly(DTH-iminocarbonate), poly(DTE-co-DT-carbonate), poly(bisphenol-A-iminocarbonate), polyorthoesters, polyglycolic acid trimethyl-carbonates, polytrimethylcarbonates, polyiminocarbonates, poly(N-vinyl)-pyrrolidone, polyvinylalcoholes, polyesteramides, glycolated polyesters, polyphosphoesters, polyphosphazenes, poly[p-carboxyphenoxy)propane], polyhydroxypentane acid, polyanhydrides, polyethyleneoxide-propyleneoxide, soft polyurethanes, polyurethanes with amino acid rests in the backbone, polyetheresters as polyethyleneoxide, polyalkeneoxalates, polyorthoesters as well as their copolymers, lipids, carrageenans, fibrinogen, starch, collagen, protein based polymers, polyamino acids, synthetic polyamino acids, zein, modified zein, polyhydroxyalkanoates, pectic acid, actinic acid, modified and non modified fibrin and casein, carboxymethylsulphate, albumin, moreover hyaluronic acid, chitosane and its derivatives, heparansulphates and its derivatives, heparin, chondroitinsulphate, dextran, b-cyclodextrins, copolymers with PEG and polypropyleneglycol, gummi arabicum, guar, gelatine, collagen, collagen-N-Hydroxysuccinimide, lipids, phospholipids, modifications and copolymers and/or mixtures of afore mentioned substances are used.
- -decalactones, polylactonic acid, polyglycolic acid, polylactides, polyglycolides, copolymers of the polylactides and polyglycolides, poly-ε
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10. Medical device according to claim 1, characterised in, that as biostable substances for the biostable layer polyacrylic acid and polyacrylates as polymethylmethacrylate, polybutylmethacrylate, polyacrylamide, polyacrylonitriles, polyamides, polyetheramides, polyethylenamine, polyimides, polycarbonates, polycarbourethanes, polyvinylketones, polyvinylhalogenides, polyvinylidenhalogenides, polyvinylethers, polyisobutylenes, polyvinylaromates, polyvinylesters, polyvinylpyrollidones, polyoxymethylenes, polytetramethyleneoxide, polyethylene, polypropylene, polytetrafluoroethylene, polyurethanes, polyetherurethanes, silicone-polyetherurethanes, silicone-polyurethanes, silicone-polycarbonate-urethanes, polyolefine elastomeres, polyisobutylenes, EPDM gums, fluorosilicones, carboxymethylchitosanes, polyaryletheretherketones, polyetheretherketones, polyethylenterephthalate, polyvalerates, carboxymethylcellulose, cellulose, rayon, rayontriacetates, cellulosenitrates, celluloseacetates, hydroxyethylcellulose, cellulosebutyrates, celluloseacetatebutyrates, ethylvinylacetate copolymers, polysulphones, epoxy resins, ABS resins, EPDM gums, silicones as polysiloxanes, polydimethylsiloxanes, polyvinylhalogenes and copolymers, celluloseethers, cellulosetriacetates, chitosanes and copolymers and/or mixtures of these substances are used.
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11. Medical device according to claim 1, whereas instead of the active agent paclitaxel one of the following active agents is used:
- simvastatin, 2-methylthiazolidine-2,4-dicarboxylic acid and the correspondent sodium salt, macrocyclic suboxide (MCS), derivatives of MCS, activated protein C (aPC), PETN, trapidil, β
-estradiol as well as mixtures of these active agents or mixtures of one of these active agents with paclitaxel.
- simvastatin, 2-methylthiazolidine-2,4-dicarboxylic acid and the correspondent sodium salt, macrocyclic suboxide (MCS), derivatives of MCS, activated protein C (aPC), PETN, trapidil, β
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12. Medical device according to claim 1, characterised in, that the medical device comprises prostheses, organs, vessels, aortas, heart valves, tubes, organ spareparts, implants, fibers, hollow fibers, stents, hollow needles, syringes, membranes, tinned goods, blood containers, titrimetric plates, pacemakers, adsorbing media, chromatography media, chromatography columns, dialyzers, connexion parts, sensors, valves, centrifugal chambers, recuperators, endoscopes, filters, pump chambers.
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13. Medical device according to claim 12, characterised in, that the medical device is a stent.
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14. Stents according to claim 13, wherein the polymer is deposited in amounts between 0.01 mg to 3 mg/layer, preferred between 0.20 mg to 1 mg and especially preferred between 0.2 mg to 0.5 mg/layer.
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15. Stent according to claim 13, characterised in, that the active agent is used in a pharmaceutically active concentration of 0.001-10 mg per cm2 stent surface and per layer.
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16. Use of the stent according to claim 13 for the prevention or reduction of restenosis.
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17. Use of the stent according to claim 13 for continuous release of paclitaxel, simvastatin, 2-methylthiazolidine-2,4-dicarboxylic sodium salt, macrocyclic suboxide (MCS), derivatives of MCS, activated protein C (aPC), PETN, trapidil and/or β
- -estradiol.
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18. Use of the medical device according to claim 1 for the direct contact with blood.
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19. Use of the medical device according to claim 1 for prevention or reduction of the unspecific adhesion and/or deposition of proteins on the coated surfaces of the medical devices.
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20. Use according to claim 18, characterised in, that the hemocompatibly coated surface of the medical device is a surface of micro-titer plates or other carrier media for detection processes.
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21. Use according to claim 18, characterised in, that the hemocompatibly coated surface of the medical device is the surface of adsorber media or chromatography media.
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22. Method for the hemocompatible coating of biological and/or artificial surfaces of medical devices comprising the following steps:
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a) providing a surface of a medical device and b) deposition of at least one compound of the general formula 1 according to claim 1 as hemocompatible layer on this surface and/or b′
) deposition of a biostable and/or biodegradable layer on the surface of the medical device or the hemocompatible layer.
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23. Method according to claim 22, wherein the hemocompatible layer or the biostable and/or biodegradable layer is coated via dipping or spraying method with at least one biodegradable and/or biostabile layer which conspires paclitaxel covalently and/or adhesively bound.
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24. Method according to claim 22 comprising the further step c):
c. deposition of paclitaxel in and/or on the hemocompatible layer or the biostable and/or biodegradable layer.
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25. Method according to claim 24, wherein paclitaxel is implemented and/or deposited via dipping or spraying methods on and/or in the hemocompatible layer or the biostable and/or biodegredable layer and/or is bound via covalent and/or adhesive coupling to the hemocompatible layer or the biostable and/or biodegradable layer.
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26. Method according to claim 22, comprising the further step d) or d′
- );
d. deposition of at least one biodegradable layer and/or at least one biostable and/or biodegradable layer on the hemocompatible layer or the layer of paclitaxel respectively, or d′
) deposition of at least one compound of the general formula 1 according to claim 1 as hemocompatible layer on the biostable and/or biodegradable layer or the layer of paclitaxel.
- );
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27. Method according to claim 22, comprising the further step e.):
e. deposition of paclitaxel in and/or on the at least one biodegradable and/or biostable layer or the hemocompatible layer.
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28. Method according to claim 27, wherein paclitaxel is deposited and/or implemented via dipping or spraying methods on and/or in the at least one biodegradable and/or biostable layer or the hemocompatible layer and/or is bound via covalent and/or adhesive coupling to the at least one biodegradable and/or biostable layer or the hemocompatible layer.
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29. Method according to claim 22, wherein the biostable and/or biodegradable layer is covalently and/or adhesively bound on the surface of the medical device and the hemocompatible layer is covalently bound to the biostable and/or biodegradable layer and covers it completely or incompletely.
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30. Method according to claim 22, characterised in, that the hemocompatible layer comprises heparin of native origin of regioselectively synthesised derivatives of different sulphation coefficients and acylation coefficients in the molecular weight range of the pentasaccharide, which is responsible for the antithrombotic activity, up to the standard molecular weight of the purchasable heparin of 13 kD, heparansulphate and its derivatives, oligo- and polysaccharides of the erythrocytic glycocalix, desulphated and N-reacetylated heparin, N-carboxymethylated and/or partially N-acetylated chitosan as well as mixtures of these substances.
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31. Method according to claim 22, characterised in, that as biodegradable substances for the biodegradable layer polyvalerolactones, poly-e-decalactones, polylactonic acid, polyglycolic acid, polylactides, polyglycolides, copolymers of the polylactides and polyglycolides, poly-ε
- -caprolactone, polyhydroxybutanoic acid, polyhydroxybutyrates, polyhydroxyvalerates, polyhydroxybutyrate-co-valerates, poly(1,4-dioxane-2,3-diones), poly(1,3-dioxane-2-one), poly-para-d ioxanones, polyanhydrides as polymaleic anhyd rides, polyhydroxymethacrylates, fibrin, polycyanoacrylates, polycaprolactonedimethylacrylates, poly-b-maleic acid, polycaprolactonebutyl-acrylates, multiblock polymers as e.g. from oligocaprolactonedioles and oligodioxanonedioles, polyetherester multiblock polymers as .e.g. PEG and poly(butyleneterephtalates), polypivotolactones, polyglycolic acid trimethyl-carbonates, polycaprolactone-glycolides, poly(g-ethylglutamate), poly(DTH-iminocarbonate), poly(DTE-co-DT-carbonate), poly(bisphenol-A-iminocarbonate), polyorthoesters, polyglycolic acid trimethyl-carbonates, polytrimethylcarbonates, polyiminocarbonates, poly(N-vinyl)-pyrrolidone, polyvinylalcoholes, polyesteramides, glycolated polyesters, polyphosphoesters, polyphosphazenes, poly[p-carboxyphenoxy)propane], polyhydroxypentane acid, polyanhydrides, polyethyleneoxide-propyleneoxide, soft polyurethanes, polyurethanes with amino acid rests in the backbone, polyetheresters as polyethyleneoxide, polyalkeneoxalates, polyorthoesters as well as their copolymers, lipides, carrageenanes, fibrinogen, starch, collagen, protein based polymers, polyamino acids, synthetic polyamino acids, zein, modified zein, polyhydroxyalkanoates, pectic acid, actinic acid, modified and non modified fibrin and casein, carboxymethylsulphate, albumin, moreover hyaluronic acid, chitosane and its derivatives, heparansulphates and its derivatives, heparin, chondroitinsulphate, dextran, β
-cyclodextrins, copolymers with PEG and polypropyleneglycol, gummi arabicum, guar, gelatine, collagen, collagen-N-Hydroxysuccinimide, lipids, phospholipids, modifications and copolymers and/or mixtures of afore mentioned substances are used.
- -caprolactone, polyhydroxybutanoic acid, polyhydroxybutyrates, polyhydroxyvalerates, polyhydroxybutyrate-co-valerates, poly(1,4-dioxane-2,3-diones), poly(1,3-dioxane-2-one), poly-para-d ioxanones, polyanhydrides as polymaleic anhyd rides, polyhydroxymethacrylates, fibrin, polycyanoacrylates, polycaprolactonedimethylacrylates, poly-b-maleic acid, polycaprolactonebutyl-acrylates, multiblock polymers as e.g. from oligocaprolactonedioles and oligodioxanonedioles, polyetherester multiblock polymers as .e.g. PEG and poly(butyleneterephtalates), polypivotolactones, polyglycolic acid trimethyl-carbonates, polycaprolactone-glycolides, poly(g-ethylglutamate), poly(DTH-iminocarbonate), poly(DTE-co-DT-carbonate), poly(bisphenol-A-iminocarbonate), polyorthoesters, polyglycolic acid trimethyl-carbonates, polytrimethylcarbonates, polyiminocarbonates, poly(N-vinyl)-pyrrolidone, polyvinylalcoholes, polyesteramides, glycolated polyesters, polyphosphoesters, polyphosphazenes, poly[p-carboxyphenoxy)propane], polyhydroxypentane acid, polyanhydrides, polyethyleneoxide-propyleneoxide, soft polyurethanes, polyurethanes with amino acid rests in the backbone, polyetheresters as polyethyleneoxide, polyalkeneoxalates, polyorthoesters as well as their copolymers, lipides, carrageenanes, fibrinogen, starch, collagen, protein based polymers, polyamino acids, synthetic polyamino acids, zein, modified zein, polyhydroxyalkanoates, pectic acid, actinic acid, modified and non modified fibrin and casein, carboxymethylsulphate, albumin, moreover hyaluronic acid, chitosane and its derivatives, heparansulphates and its derivatives, heparin, chondroitinsulphate, dextran, β
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32. Method according to claim 22, characterised in, that as biostable substances for the biostable layer polyacrylic acid and polyacrylates as polymethylmethacrylate, polybutylmethacrylate, polyacrylamide, polyacrylonitriles, polyamides, polyetheramides, polyethylenamine, polyimides, polycarbonates, polycarbourethanes, polyvinylketones, polyvinylhalogenides, polyvinylidenhalogenides, polyvinylethers, polyisobutylenes, polyvinylaromates, polyvinylesters, polyvinylpyrollidones, polyoxymethylenes, polytetramethyleneoxide, polyethylene, polypropylene, polytetrafluoroethylene, polyurethanes, polyetherurethanes, silicone-polyetherurethanes, silicone-polyurethanes, silicone-polycarbonate-urethanes, polyolefine elastomeres, polyisobutylenes, EPDM gums, fluorosilicones, carboxymethylchitosanes, polyaryletheretherketones, polyetheretherketones, polyethylenterephthalate, polyvalerates, carboxymethylcellulose, cellulose, rayon, rayontriacetates, cellulosenitrates, celluloseacetates, hydroxyethylcellulose, cellulosebutyrates, celluloseacetatebutyrates, ethylvinylacetate copolymers, polysulphones, epoxy resins, ABS resins, EPDM gums, silicones as polysiloxanes, polydimethylsiloxanes, polyvinylhalogenes and copolymers, celluloseethers, cellulosetriacetates, chitosanes and copolymers and/or mixtures of these substances are used.
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33. Method according to claim 22, characterised in, that the deposition of the polysaccharides of the formula 1 according to claim 1 is achieved via hydrophobic interactions, van der Waals forces, electrostatic interactions, hydrogen bonds, ionic interactions, cross-linking and/or covalent bonding.
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34. Method according to claim 22, wherein instead of the active agent paclitaxel one of the following active agents is used:
- simvastatin, 2-methylthiazolidine-2,4-dicarboxylic sodium salt, macrocyclic suboxide (MCS), derivatives of MCS, activated protein C (aPC), PETN, trapidil, β
-estradiol as well as mixtures of these active agents or mixtures of one of these active agents with paclitaxel.
- simvastatin, 2-methylthiazolidine-2,4-dicarboxylic sodium salt, macrocyclic suboxide (MCS), derivatives of MCS, activated protein C (aPC), PETN, trapidil, β
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35. Medical device available by the method according to claim 22.
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2. Medical device according to claim 1, wherein Y represents the residue —
Specification
- Resources
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Current AssigneeHemoteq AG (Freudenberg & Company KG), Hemoteq GmbH
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Original AssigneeHemoteq AG (Freudenberg & Company KG)
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InventorsHoffmann, Michael, Horres, Roland, Faust, Volker, Hoffmann, Erika, Di Biase, Donato, Linssen, Marita Katarina
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Application NumberUS10/483,545Publication NumberTime in Patent OfficeDaysField of SearchUS Class Current424/426CPC Class CodesA61K 31/045 Hydroxy compounds, e.g. alc...A61K 31/075 Ethers or acetalsA61K 31/095 Sulfur, selenium, or tellur...A61K 31/11 AldehydesA61K 31/12 KetonesA61K 31/13 Amines A61K31/04 takes prec...A61K 31/21 Esters, e.g. nitroglycerine...A61K 31/28 Compounds containing heavy ...A61K 31/33 Heterocyclic compoundsA61K 31/722 Chitin, chitosanA61K 31/727 Heparin; HeparanA61L 31/10 Macromolecular materialsA61L 31/16 Biologically active materia...A61L 33/08 PolysaccharidesA61P 19/06 Antigout agents, e.g. antih...A61P 29/00 Non-central analgesic, anti...A61P 3/06 AntihyperlipidemicsA61P 35/00 Antineoplastic agentsA61P 37/06 Immunosuppressants, e.g. dr...A61P 7/02 Antithrombotic agents; Anti...C08B 37/0075 : Heparin; Heparan sulfate; D...C08L 5/10 : Heparin; Derivatives thereofC09D 105/08 : Chitin; Chondroitin sulfate...Y02A 50/30 : Against vector-borne diseas...