Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/28—Materials for coating prostheses
  • A61L27/34—Macromolecular materials
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L33/00—Antithrombogenic treatment of surgical articles, e.g. sutures, catheters, prostheses, or of articles for the manipulation or conditioning of blood; Materials for such treatment
  • A61L33/06—Use of macromolecular materials
  • A61L33/068—Use of macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

• the present invention relates to artificial implants with a biocompatible coating, which has antithrombogenic properties and also contains a pharmacologically active ingredient, and to processes for their production.
• DE-C-19613048 the polymeric compound poly [bis (trifluoroethoxy) phosphazene], the good antithrombogenic effect of Holleman Wiberg, "nitrogen compounds of phosphorus" Textbook of inorganic chemistry, 666-669, 91.-100. Edition, Walter de Gruyter Verlag (1985) and Tur, Vinogradova, among others "Development tendencies in polymer-analogous implementations of polyphosphazene", Acta Polymerica 39, 424-429, No. 8 (1988) was used for coating artificial implants.
• DE-C-19613048 describes an artificial implant, comprising an implant material as the substrate and one at least partially on the surface of the substrate applied, biocompatible coating, which is an antithrombogenic
• Polymer with the following general formula (I) contains:
• R 1 to R 6 are the same or different and is an alkoxy, alkylsulfonyl, dialkylamino or aryloxy radical or a heterocycloalkyl or heteroaryl radical with nitrogen as hetero atom; and manufacturing processes for such artificial implants.
• WO 99/16477 has described an alternative approach to preventing excessive cell proliferation and scarring.
• a raidio-labeled polymer of the formula (I) shown above preferably a polymer in which a radioactive phosphorus isotope is present, is applied to the implant.
• the emitted radioactive radiation (at 3 P ß radiation) is said to be uncontrolled
• the polymer of formula (I) defined above has excellent matrix properties for pharmacologically active substances and, when applied to an implant material, releases these substances to its environment in a controlled manner. Surprisingly, it was also found that there is no inflammatory reaction during the biodegradation of the polymer of the formula (I). Controlled release of active ingredients is thus made possible not only by diffusion and dissolution processes, but also by the biodegradation of the matrix and the associated release of integrated active ingredients, without an undesirable inflammatory reaction occurring.
• the present invention thus relates to an artificial implant comprising an implant material as the substrate and a biocompatible coating which is at least partially applied to the surface of the substrate and which comprises an antithrombogenic polymer having the following general formula (I) where R 1 to R 6 are the same or different and are an alkoxy, alkylsulfonyl, dialkylamino or aryloxy radical or a heterocycloalkyl or heteroaryl radical with nitrogen as hetero atom, and at least one further (additional) pharmacologically active substance (hereinafter "active substance”) ) includes.
• active substance further (additional) pharmacologically active substance
• At least one of the radicals R 1 to R 6 is an alkoxy radical which is substituted by at least one fluorine atom.
• the alkyl radicals in the alkoxy, alkylsufonyl and dialkylamino radicals are, for example, straight or branched chain alkyl radicals having 1 to 20 carbon atoms, the alkyl radicals being substituted, for example, by at least one hologue atom, such as a fluorine atom can.
• alkoxy radicals are methoxy, ethoxy, propoxy and butoxy groups, which can preferably be substituted by at least one fluorine atom.
• the 2,2,2-trifluoroethoxy group is particularly preferred.
• alkylsulfonyl radicals are methyl, ethyl, propyl and butylsulfonyl groups.
• dialkylamino radicals are dimethyl, diethyl, dipropyl and dibutylamino groups.
• the aryl radical in the aryloxy radical is, for example, a compound having one or more aromatic ring systems, it being possible for the aryl radical to be substituted, for example, by at least one alkyl radical defined above.
• aryloxy radicals are phenoxy and naphthoxy groups and derivatives thereof.
• the heterocydoalkyl radical is, for example, a ring system containing 3 to 7 atoms, at least one ring atom being a nitrogen atom.
• the heterocydoalkyl radical can be substituted, for example, with at least one alkyl radical defined above.
• Examples of heterocycloalkyl radicals are piperidinyl, piperazinyl, pyrrolidinyl and morpholinyl groups and derivatives thereof.
• the heteroaryl radical is, for example, a compound having one or more aromatic ring systems, at least one ring atom being a nitrogen atom.
• the heteroaryl radical can, for example, be substituted with at least one alkyl radical defined above.
• Examples of heteroaryl radicals are pyrrolyl, pyridinyl, pyridinolyl, isoquinolinyl and quinolinyl groups and derivatives thereof.
• the biocompatible coating contains the antithrombogenic polymer poly [bis (trifluoroethoxy) phosphazene].
• the further pharmacologically active ingredient is preferably an organic (low molecular weight or higher molecular weight) compound and is in particular an antimitogenic active ingredient, e.g. B. a cytostatic (such as paclitaxel, etc.), a PDGF inhibitor (such as tyrphostine, etc.), a Raf 1-kinase inhibitor, a monoclonal antibody for integrin blocking leukocytes, an antisense agent (such as plasmid DNA, etc.), Superoxide dismutase, a radical scavenger (such as Probucol, etc.), a steroid, a statin (such as Cerivastatin, etc.), a corticosteroid (such as methotrexate, dexamethasone, methylprednisolan, etc.), an adenylate cyclase inhibitor (such as Forskolin, etc.) Somatostatin analog (such as angiopeptin, etc.), an antithro
• Nitric oxide donor a glycoprotein IIb / IIIa receptor antagonist (such as Urokinase derivatives, abciximab, tirofiban, etc.), an antithrombotic
• Agents such as activated protein C, PEG-hirudin, prostglandin analogs, etc.), a vascular endothelial growth factor (VEGF), trapidil, etc. and
• the active substance content in the biocompatible coating be as high as possible. It could be shown that up to 50% by weight of the coating can consist of active ingredient without significantly impairing its mechanical properties.
• the proportion of the active ingredient in the coating is, according to the invention, in the range from 0.01 to 50% by weight, preferably 0.2 to 30% by weight, which is approximately a weight ratio of polymer to active ingredients of 1: 0.0001 to 1: 1 , preferably 1: 0.05 to 1: 0.5.
• the biocompatible coating of the artificial implant according to the invention has, for example, a thickness of 1 nm to approximately 100 ⁇ m, preferably 10 nm to 10 ⁇ m and particularly preferably up to approximately 1 ⁇ m.
• the implant material used as the substrate according to the invention has no particular restriction and can be any implant material such as plastics, metals, metal alloys and ceramics.
• the implant material can be an artificial heart valve made of pyrolyzed carbon or a stent as described in DE-A-197 53 123.
• a layer which contains an adhesion promoter is arranged between the surface of the substrate and the biocompatible coating.
• the adhesion promoter or spacer is, for example, an organosilicon compound, preferably an amino-terminated silane or a compound based on an aminosilane or a Alkylphosphonic. Aminopropyltrimethoxysilane is particularly preferred.
• the adhesion promoter in particular improves the adhesion of the coating on the surface of the implant material by coupling the adhesion promoter to the surface of the implant material, for example via ionic and / or covalent bonds, and by further coupling the adhesion promoter to reactive components, in particular to the antithrombogenic polymer, of the coating, for example ionic and / or covalent bonds.
• the biocompatible coating being obtained by reacting the substrate with
• the antithrombogenic polymer or a precursor thereof is applied to the substrate to obtain a primary polymer coating and subsequent application / penetration of the active ingredient into the primary polymer coating.
• process variant (a) is - since the active substance is often sensitive to drastic reaction conditions - a wet chemical process.
• the substrate is immersed in a solution containing the antithrombogenic polymer and active ingredient and, if appropriate, the solvent is subsequently removed by heating or applying a vacuum. This process is repeated until the desired layer thickness of the coating is obtained.
• Suitable solvents for these processes are selected from polar aprotic solvents such as esters (such as ethyl acetate, propyl acetate, butyl acetate, ethyl propionate, ethyl butyrate, etc.), ketones (such as acetone, ethyl methyl ketone, etc.), amides (such as dimethylformamide, etc.), sulfoxides (such as DMSO etc.) and sulfones (they sulfolane etc.). Especially ethyl acetate is preferred.
• esters such as ethyl acetate, propyl acetate, butyl acetate, ethyl propionate, ethyl butyrate, etc.
• ketones such as acetone, ethyl methyl ketone, etc.
• amides such as dimethylformamide, etc.
• sulfoxides such as DMSO etc.
• the concentration of the polymer in the solution is 0.001 to 0.5 M, preferably 0.01 to 0.1 M, the concentration of the active ingredient depends on the desired polymer / active ingredient ratio.
• the immersion time is preferably in the range from 10 s to 100 h.
• the drying steps are carried out in vacuo, under air or in a protective gas in the temperature interval from, for example, about -20 ° C. to about 300 ° C., preferably 0 ° C. to 200 ° C. and particularly preferably from 20 ° C. to 100 ° C.
• a mixture of polydichlorophosphazene and active ingredient is applied to the surface of the substrate and with at least one reactive compound selected from aliphatic or aromatic alcohols or their salts, alkyl sulfones, dialkylamines and aliphatic or aromatic heterocycles with nitrogen as hetero atom, corresponding to the above definition of R 1 to R 6 implemented.
• the polydichlorophosphazene is preferably applied to the surface of the substrate in an inert gas atmosphere, optionally coupled to the adhesion promoter and reacted with the reactive compound.
• polydichlorophosphazene can be applied under reduced pressure or in an air atmosphere and, if appropriate, coupled to the adhesion promoter.
• an adhesion promoter as defined above is applied to the surface of the substrate and, for example, via ionic and / or covalent bonds to the before the application of the mixture of polymer or polymer precursor and active ingredient or before the application of polymer or polymer precursor Surface coupled. Then the antithrombogenic polymer z. B. of polydichlorophosphazene applied to the surface coated with the adhesion promoter of the substrate and coupled, for example, via ionic and / or covatent bonds to the adhesion promoter.
• the adhesion promoter can be applied to the substrate by wet chemistry or in solution or from the melt or by sublimation or by spraying.
• the wet chemical coupling of an adhesion promoter, based on amino acids to hydroxylated surfaces, is described in Marco Mantar, diploma thesis, p. 23, Univ. Heidelberg (1991).
• the surface of the substrate may e.g. B. can be oxidatively cleaned with Caro's acid.
• the artificial implants according to the invention surprisingly are the excellent ones Maintain mechanical properties of the implant material as a substrate and by the invention.
• applied coating for example by direct deposition from the solution, not only have antithrombogenic but also antirestenose properties, which drastically improves the biocompatibility and usability of such artificial implants.
• XPS X-ray photoelectron
• the polydichlorophosphazene on which the poly [bis (trifluoroethoxy) phosphazene] is based is prepared by polymerizing hexachlorocyclotriphosphazene in an ampoule with a diameter of 5.0 mm at 250 ° C. + 1 ° C. and a pressure of 1.3 Pa in the ampoule (10 "2 mm Hg).
• a 0.1 M polydichlorophosphazene solution is first prepared under an inert gas atmosphere (0.174 g to 5 ml solvent). Absolute toluene is used as the solvent.
• 2,2,2-sodium fluoroethanoate in absolute solution is then used in this solution Tetra hydrofuran as a solvent (8 ml absolute tetrahydrofuran, 0.23 g sodium, 1.46 ml 2,2,2-trifluoroethanol) esterified.
• the substrate is placed in a mixture of 30% H 2 O 2 and concentrated sulfuric acid (Caro's acid) in a ratio of 1: 3 for 2 hours at a reaction temperature of 80 ° C. After this treatment, the substrate is washed with 0.5 l demineralized water of 18 M ⁇ »cm and about pH 5 and then dried in a stream of nitrogen.
• C To coat the implant surface with an adhesion promoter, the artificial implant oxidatively cleaned according to Example 1B with Caro's acid is immersed in a 2% aminopropyltrimethoxysilane solution in absolute ethanol for 30 minutes at room temperature. The substrate is then washed with 4-5 ml of absolute ethanol and left in the drying cabinet at 105 ° C. for 1 hour.
• Example IB An artificial implant pretreated according to Example IB and IC was placed in a 0.1 M poly [bis (trifluoroethoxy) phosphazene] solution in ethyl acetate (0.121 g to 5 ml ethyl acetate) containing 0.0121 g probucol for 24 hours at room temperature , The artificial implant thus produced was then washed with 4-5 ml of ethyl acetate and dried in a stream of nitrogen.
• Example B An artificial implant pretreated according to Example IB and IC was placed in a 0.1 M poly [bis (trifluoroethoxy) phosphazene] solution in ethyl acetate (0.121 g to 5 ml ethyl acetate) containing 0.0242 g trapidil for 24 hours at room temperature , The artificial implant thus produced was then washed with 4-5 ml of ethyl acetate and dried in a stream of nitrogen.
• An artificial implant cleaned according to Example IB was at 70 ° C. in a 0.1 M poly [bis (trifluoroethoxy) phosphazene] solution in ethyl acetate
• the implant is washed with 4-5 ml of ethyl acetate and dried in a stream of nitrogen.
• the artificial implant thus produced was examined with the aid of photoelectron spectroscopy for the elemental composition, stoichiometry and coating thickness.
• the results show that the coupling of the poly [bis (trifluoroethoxy) phosphazene] to the implant surface has taken place and layer thicknesses of over 2.1 nm have been achieved , It was also shown that the probucol was stored in the coating in the appropriate amount.
• Example IB An artificial implant pretreated according to Example IB and IC was placed in a 0.1 M poly [bis (trifluoroethoxy) phosphazene] solution in ethyl acetate (0.121 g to 5 ml of ethyl acetate) for 24 hours at room temperature. The artificial implant thus produced was then washed with 4-5 ml of ethyl acetate and dried in a stream of nitrogen.

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• Oral & Maxillofacial Surgery (AREA)
• Engineering & Computer Science (AREA)
• Transplantation (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
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• Materials For Medical Uses (AREA)
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• 2000
  • 2000-08-11 EP EP00117191A patent/EP1179353A1/de not_active Withdrawn
• 2001
  • 2001-08-01 JP JP2002519020A patent/JP4886156B2/ja not_active Expired - Lifetime
  • 2001-08-01 AT AT01976054T patent/ATE374626T1/de active
  • 2001-08-01 CA CA2424359A patent/CA2424359C/en not_active Expired - Lifetime
  • 2001-08-01 WO PCT/EP2001/008913 patent/WO2002013882A1/de not_active Ceased
  • 2001-08-01 EP EP01976054A patent/EP1337285B1/de not_active Expired - Lifetime
  • 2001-08-01 AU AU2001295447A patent/AU2001295447B2/en not_active Expired
  • 2001-08-01 ES ES01976054T patent/ES2296811T3/es not_active Expired - Lifetime
  • 2001-08-01 DE DE50113094T patent/DE50113094D1/de not_active Expired - Lifetime
  • 2001-08-01 KR KR1020037001952A patent/KR100809134B1/ko not_active Expired - Fee Related
  • 2001-08-01 AU AU9544701A patent/AU9544701A/xx active Pending
  • 2001-08-01 DK DK01976054T patent/DK1337285T3/da active
  • 2001-08-01 BR BRPI0113184-2A patent/BR0113184B1/pt not_active IP Right Cessation
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