EP2254606A2 - Implant et procédé de fabrication - Google Patents

Implant et procédé de fabrication

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Publication number
EP2254606A2
EP2254606A2 EP09714030A EP09714030A EP2254606A2 EP 2254606 A2 EP2254606 A2 EP 2254606A2 EP 09714030 A EP09714030 A EP 09714030A EP 09714030 A EP09714030 A EP 09714030A EP 2254606 A2 EP2254606 A2 EP 2254606A2
Authority
EP
European Patent Office
Prior art keywords
water
coating
statin
implant
component
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP09714030A
Other languages
German (de)
English (en)
Inventor
Matthias Schnabelrauch
Armin Rex Kautz
Falko Schlottig
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Thommen Medical AG
Original Assignee
Thommen Medical AG
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Thommen Medical AG filed Critical Thommen Medical AG
Publication of EP2254606A2 publication Critical patent/EP2254606A2/fr
Withdrawn legal-status Critical Current

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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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • 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
    • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
    • A61L27/54—Biologically active materials, e.g. therapeutic substances

Definitions

  • the present invention relates to a method for producing an implant, in particular a dental implant, as well as an implant produced therewith, which at least partially in the implanted state in the surface areas, which are in contact with hard and / or soft tissue having a coating.
  • the mechanical properties such as structure and geometry of the implants contribute significantly to the mechanical stability of the implants.
  • the nature of the surface is important for the implant to grow into the bone.
  • the stability of the implant in the hard tissue is critically dependent on the interactions at the implant surface / surrounding tissue interface as well as the microscopic and macroscopic morphology of the implant.
  • a change in the implant surface can improve the anchoring of the implant in the hard tissue as well as the implant compatibility and thereby increase the osseointegration of the implant, which accelerates the healing process.
  • the osseointegration of the implant into the bone can be improved by machining the implant surface.
  • the sandblasting and / or a treatment with an acid to offer that roughen the implant surface can be used by which different, often porous layers can be applied to the surface of the implants.
  • the osseointegration of implants can also be increased by a biological functionalization of their surface. In this case, a molecular layer of the active substance is applied to a pretreated surface by means of a chemical bond.
  • statins such as simvastatin (INN) have been reported to promote the formation of bone in vitro as well as in vivo.
  • Simvastatin in particular is a fat-soluble member of the group of statins.
  • Statins belong to the pharmacological
  • Methylglutaryl coenzyme A to mevalonate the rate-limiting step in the synthesis of human cholesterol.
  • These drugs are potent inhibitors of cholesterol biosynthesis and are used e.g. to lower cholesterol
  • simvastatin is [(IS, 3R, 7R, 8S, 8aR) -8- [2 - [(2R, 4R) -4-hydroxy-6-oxo-oxan-2-yl] ethyl] -3 , 7-dimethyl-1, 2,3,7,8,8a-hexahydronaphthalene-1-yl] -2,2-dimethylbutanoate.
  • simvastatin is available in the lactone form (see Figure above). However, simvastatin has its physiological action in the metabolically active form, the so-called open-chain or ⁇ -hydroxy acid form, into which it first has to be converted from the lactone form. Synthetic instructions for the opening of the lactone ring are known to the person skilled in the art.
  • BMP-2 is responsible for the differentiation of a multipotent stem cell line into osteoblast-like cells.
  • BMPs are thus important regulators in the differentiation of bone cells during bone fracture healing.
  • statins enhance this expression of BMP-2 mRNA.
  • the pharmacological action of the statins is thus probably due to an increased expression of the genes for BMP-2 in bone cells.
  • the inductive effect of simvastatin on the formation of new bone has already been investigated. For these in vitro and in vivo studies, different administration forms of simvastatin were used.
  • Simvastatin has also been used with calcium sulfate as a carrier material that is biocompatible and bioresorbable. To do this, the two powders were mixed to form discs that were inserted into the bones of rats. Eight weeks after incorporation of the discs with simvastatin, a significant increase in bone mineral density, bone mineral density and bone mineral density over the control groups was observed with calcium sulfate alone or both.
  • Collagen or gelatin was also used as the matrix for simvastatin. Used were collagen sponges of purified bovine collagen soaked in an aqueous simvastatin solution to treat fractures in the parietal bone of rabbits. Growth factors that are important for the healing of the bones could be detected earlier. Simvastatin initiated the early expression of growth factors, differentiation of bone cells, and osteogenesis, leading to accelerated formation of new bone. Furthermore, simvastatin has already been incorporated into sponges of gelatin for the treatment of fractures in rat jaw bones. Again, the bone density was 190-240% higher than the control group without active ingredient. In histological studies, an increased formation of new bone could be detected.
  • the in vitro release of simvastatin from granules and gels has also been investigated.
  • the starting materials for the granules and gels were the biocompatible and degradable polymers hydroxypropylmethylcellulose and carboxymethylcellulose.
  • the release profiles show a cumulative release of simvastatin in granules and gels after 24 hours.
  • the polymers and simvastatin were used to make the granules only mixed, with different mixtures of alcohol and water or dilute lactic acid Weglsässt and pressed through a sieve and then dried. This granules were obtained with a size of 800-1500 ⁇ m.
  • the polymers were gradually dispersed in water, this polymer dispersion was frozen and the simvastatin was applied to the gel system before the start of the release.
  • simvastatin no interaction between side-by-side systems simvastatin and the polymers can form, which manifests itself in the rapid release within the first 24 hours.
  • a NO-providing system and a phosphodiesterase (PDE) system for promoting bone growth is described in WO 2004/091626, and inter alia, it is noted that such a combined controlled release preparation the active substances can be introduced into films, which can then be wrapped around implants prior to their installation.
  • EP 1159934 describes a tubular deformable implant which can carry a "medicine", wherein at least a part of this implant can be provided with a coating material consisting of a biocompatible material, a biodegradable material or a synthetic resin Material to which a "medicine", a bioprosthetic material or a biosynthetic material can be added.
  • This is a coating material consisting of a biocompatible material, a biodegradable material or a synthetic resin.
  • a polymeric composition of synthetic block copolymers is disclosed which can be used for the release of therapeutic agents, for example in the form of a coating.
  • US 2007/0048351 discloses a method for treating plaque formations in vessels by introducing a tubular body containing one or more active ingredients, wherein the active ingredient is applied alone or in combination with a polymer on the implant surface.
  • the active ingredient is applied alone or in combination with a polymer on the implant surface.
  • the invention relates to the production of an improved implant, preferably a dental implant, which has a good osseointegration or osteointegration and yet can be produced in a simple and cost-effective method.
  • the coating comprises both a statin in the hydrolyzed or unhydrolysed form or pharmaceutically acceptable salts thereof and at least one further component selected from the group of branched or linear, substituted or unsubstituted, saturated or partially unsaturated C10-C30 Alkyl, alkenyl, alkylaryl, aryl, cycloalkyl, alkylcycloalkyl, alkylcycloaryl amines or mixtures thereof and / or at least one water-soluble ionic polymeric component.
  • the statin is present in the coating in the form of a pharmaceutically acceptable salt derived from an open-chain, biologically active, dihydroxy-acid form having at least one further component.
  • the dihydroxy acid form first allows the formation of mixed salts with the above-mentioned components.
  • At least one layer of the coating (or the whole) of such a layer substantially without further constituents.
  • Coating material consisting of a biocompatible material, a biodegradable material or a synthetic resin.
  • a fundamental distinguishing feature of the prior art is therefore that no coating material consisting of a biocompatible material, a biodegradable material or a synthetic resin is used, but that by the particular chemical structure of the active ingredient component (low molecular weight or polymeric, slightly water-soluble ammonium salt) entirely on Such a coating material can be dispensed with and thus all known and proven disadvantages of such materials (including uncontrolled degradation, foreign body reactions, spalling of polymer particles from the coating) can be avoided.
  • the special chemical structure of the active substance salts ensures that the active ingredient component adheres to the implant surface, which normally can not be assumed for conventional active substances and therefore requires the use of additional coating materials.
  • additional coating materials such as e.g.
  • EP 1159934 is reproduced with respect to the application of drugs on implant surfaces only known from many publications and patents prior art, without going beyond. This is illustrated just now with reference to Example 2, where a coating is prepared in which a mixture of the active ingredient (cerivastatin) and a polymer (polylactide) in an organic solvent is used. It is also apparent from the background of this document that the field of application relates essentially to the treatment of vascular stenoses or occlusions where an antiproliferative action is to be achieved. The field of application of this invention, on the other hand, concerns an improvement of the ingrowth behavior of implants into the surrounding tissue, ie a stimulation of the proliferation of surrounding cells. The transfer of an anti-proliferative implant coating on a coating that is supposed to trigger a proliferation-promoting effect, is not obvious.
  • a statin is understood to mean a statin as such, this is preferred.
  • Statin equivalent component that is, a component, such as apamine or zaragozaic acid to understand, which is also effective in the context of the isoprenoid / steroid pathway, but not directly the targets of the statins as such (ie HMG-CoA reductase) influenced.
  • the statin may in principle be hydrolyzed or unhydrolysed at the end, so it may have a closed or open lactone ring.
  • the proposed coating is characterized in that it releases the statin, preferably simvastatin, to the environment after being inserted into human or animal bones.
  • the statin is a component selected from the following group: atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin or rosuvastatin, mevastatin, squalestatin, simvastatin, or a mixture of such components. It is particularly preferred that the statin is simvastatin.
  • the coating contains the statin and the further component and / or the water-soluble ionic polymeric component as a complex or mixed salt with low solubility in water.
  • the complex or the mixed salt preferably has a solubility in pure water of less than 1 mg / ml at room temperature, preferably in the range of less than 0.05-0.9 mg / ml at room temperature.
  • the further component is at least one unbranched, preferably unsubstituted C 10 -C 20 -alkyl-amine (the amine may be substituted here) and / or its alkali metal or alkaline earth metal salt, preferably selected from the following group: decylamine , Tetradecylamine, hexadecylamine, octadecylamine, dodecylamine.
  • the further component is an amphiphilic component.
  • the further component preferably has a cationic character, particularly preferably carrying a monovalent positive charge.
  • the implant is characterized in that the statin is present in the free dihydroxy acid form and preferably at least partly as alkali metal, alkaline earth metal, ammonium and / or magnesium salt form and / or salt form with the further component as ammonium cation.
  • the water-soluble ionic polymeric component it is preferred that the water-soluble ionic polymeric component is a polymeric component having free cationic groups, particularly a polymeric component derived from biocompatible biopolymers.
  • the water-soluble ionic polymeric component may preferably be amino group-containing derivatives of natural polysaccharides, more preferably polysaccharides selected from the group: dextran, cellulose, starch, pullulan or chitosan or mixtures thereof.
  • the preferred statin present in the free dihydroxy acid form and the further component preferably selected as alkyl amine are preferably present in the coating in a molar ratio between 10: 1 and 1: 5, preferably in a molar ratio of 2: 1 to 1: 2 ,
  • statin preferably selected in the free dihydroxy acid form and the water-soluble ionic polymeric component are preferably present in the coating in a molar ratio between 10: 1 and 1: 5, preferably in a molar ratio of 2: 1 to 1: 2, based on the carboxyl groups of the statins used in the free dihydroxy acid form and the cationic groups of the polymeric component present.
  • a further preferred embodiment is characterized in that the coating is applied to a smooth, porous and / or roughened surface without a carrier, the implant preferably consisting at least partially or in sections of metal and / or ceramic and / or polymers and / or of native origin
  • the coating is preferably applied directly and without an intermediate layer to such an implant, and wherein the implants are preferably calcium phosphate ceramics, alumina and zirconia ceramics, bioglass, glass ceramics, calcium carbonate, calcium sulfate, organic polymers or composites of said materials, or surfaces of metallic implants of pure titanium, titanium alloys, cobalt-chromium alloys or stainless steel, or native implant surfaces made of collagen, gelatin or materials of allogeneic origin.
  • the thickness of the coating is typically between 1 and 10 .mu.m, preferably 0.5 and 5 .mu.m.
  • it is a dry, substantially solvent-free and prior to implantation substantially anhydrous coating.
  • a further preferred embodiment is characterized in that the coating is applied as a slurry or suspension in an organic solvent, optionally in admixture with water, preferably in a dipping or spraying process, and subsequently dried substantially completely.
  • the present invention thus relates to a method for producing an implant, as has been described above.
  • This method is preferably characterized in that either a suspension and / or solution of the statin and the at least one component and / or the water-soluble ionic polymeric component is prepared in a suspending agent or solvent, that the coating by spraying, dripping or dipping this suspension or Solution is applied to the surface to be coated of the implant and that the suspending agent or solvent, preferably by evaporation or evaporation, to form a sparingly soluble in water statin-containing dry coating is removed.
  • the procedure is such that a first suspension and / or solution of the at least one component and / or the water-soluble ionic polymeric component is prepared in a suspending agent or solvent and a second suspension and / or solution of the statin in a suspending agent or solvent is prepared that the first or the second suspension and / or solution by spraying, dropping or dipping is applied to the surface to be coated, and the suspending agent or solvent, preferably by evaporation or evaporation, is removed, and then the other suspension and / or solution by spraying, dripping or dipping is applied to the surface to be coated, and the suspending agent or solvent, preferably by evaporation or evaporation, is removed to form a sparingly soluble in water statin-containing dry coating.
  • a first preferred embodiment of the proposed method is characterized in that the concentrations of the suspension (s) and / or solution (s) containing the statin and / or the further component and / or ionic polymeric component are chosen such that in the result of an in-situ salt formation
  • Component in a ratio of 10: 1 to 1: 5, preferably between 2: 1 and 1: 2, are present.
  • the suspension and / or solution containing the statin and the further component and / or ionic polymeric component prepared by reacting in at least one alcohol or an alcohol-water mixture, preferably in the ratio of 25: 75 dissolved dihydroxy Acid form of the statin and a dissolved in at least one alcohol or an alcohol-water mixture further component and / or water-soluble ionic polymeric component are mixed, the precipitate is isolated as a mixed salt, and then dissolved this mixed salt in a suspension or solvent or to be suspended in this.
  • the suspension or solvent may be a suspension or solvent mixture.
  • a further preferred embodiment of the proposed method is characterized in that water or one or more organic suspension and / or solvents are used as suspension or solvent, preferably chloroform as suspension medium or ethanol and / or methanol as solvent, or mixtures of these systems as far as chemically possible in view of miscibility.
  • the coating is applied as a suspension or slurry in an organic solvent, preferably in a spraying or dipping process, and then completely dried.
  • the present invention relates to a statin-containing composition in the sense of the above suspension / solution.
  • This composition is in the form of a low solubility mixed salt in an aqueous medium containing both a closed or open lactone-containing statin, preferably selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, mevastatin, squalatin, rosuvastatin, Simvastatin or pharmaceutically acceptable salts thereof as well as at least one further component selected from the group consisting of the branched or linear, substituted or unsubstituted, saturated or partially unsaturated C 10 -C 30 alkyl, alkenyl, alkylaryl, aryl, cycloalkyl, alkylcycloalkyl, Alkylcycloaryl-amines or mixtures thereof and / or a water-soluble ionic polymeric component.
  • statin preferably selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, pitava
  • statin the further component as well as the water-soluble ionic polymeric component, the preferred embodiments given above in connection with the implant apply, that is, these are expressly described and disclosed in connection with the claimed composition.
  • a first preferred embodiment of the composition is characterized in that the mixed salt has a solubility at room temperature in pure water of less than 1 mg / ml, more preferably in the range of less than 0.05-0.9 mg / ml at room temperature
  • the further component is at least one unbranched, preferably unsubstituted C 10 -C 20 -alkyl-amine and / or its alkali metal or alkaline earth metal salt, preferably selected from the following group: Decylamine, tetradecylamine, hexadecylamine, octadecylamine, dodecylamine.
  • water-soluble ionic polymeric component is amino-containing derivatives (eg, diethylaminoethyl, ethylenediamino or amino groups) of natural polysaccharides, more preferably polysaccharides selected from the group: dextran, Cellulose, starch, pullulan or chitosan or mixtures thereof.
  • amino-containing derivatives eg, diethylaminoethyl, ethylenediamino or amino groups
  • the present invention relates to the use of a composition, as described above, in the context of a method as described above, that is, for coating metallic, non-metallic or native implant surfaces, wherein the implant surfaces particularly preferably smooth, structured and / or are porous, and wherein the implant is preferably a dental implant.
  • the dental implant having a specific coating in the region of the surface in which it is in contact with the hard and / or soft tissue in the implanted state.
  • the contact to hard and / or soft tissue can be made directly or indirectly via openings, channels and / or further layer or layers.
  • the release of the statin, in particular preferably of the simvastatin, should not be changed or only slightly changed by the described surface structure.
  • the coating contains at least one statin and preferably amino-containing water-soluble ionic polymers and / or alkanes.
  • statins mixtures of different statins and mixtures of different amino-containing water-soluble ionic polymers and / or alkanes are possible.
  • the invention is essentially based on the fact that statins would be removed very quickly from the surface of the implants after their incorporation, while a mixed salt of the above-mentioned components, the statins after placing the implant in the human or animal body longer at the interface between the implant and surrounding hard and / or soft tissue, thereby These can exert their effect over a longer period of time.
  • a release of the statins and thus their biological availability on the surface of the implants and in the immediate environment derselbigen can be achieved over a period of several days to weeks after a coating of the dental implants.
  • the two components of the coating according to this invention are present as a mixture or complex, preferably as a mixed salt with low solubility in water.
  • the statins contained in the mixed salts adhere better than statins alone on the surface of the dental implant materials, the mixed salts can be applied as a dry coating.
  • the open-chain acid form of simvastatin already dissolves in an ethanol / water mixture with 25% ethanol.
  • the release of a low-molecular-weight active substance from an implant coating into the surrounding, aqueous medium is essentially determined by its diffusion out of the coating. The diffusion in turn depends on the solubility of the drug in the surrounding aqueous medium. Due to the conversion of the water-insoluble lactone form of simvastatin into the water-soluble, open-chain dihydroxy acid form, it is to be expected that the simvastatin will be rapidly absorbed and transported away from the physiological environment of the dental implant due to its better solubility and therefore can not use a retarding effect at the site of action.
  • One of the basic ideas of the invention is, therefore, to convert the biologically active but water-soluble open-chain form of simvastatin (or active ingredient) into a sparingly soluble salt form which can be applied as a dry layer.
  • the availability of the active ingredient is determined by a solubility weight between the free drug and the drug present as part of a sparingly soluble salt.
  • the diffusion of the active ingredient is therefore preceded by a solubility equilibrium, this being Equilibrium which replaces diffusion as a rate-determining step.
  • simvastain or statins in general
  • they form water-sparingly soluble salts with corresponding cationic reactants, such as the water-soluble ionic polymers or amino-containing compounds listed in the invention.
  • Simvastatin represents the anionic component and the amino-containing water-soluble ionic polymers or low-molecular amino-containing compounds in the salts mentioned from the open-chain dihydroxy acid form of simvastatin (the statins in general) and the amino-containing water-soluble ionic polymers or low molecular weight amino-containing compounds the cationic component.
  • These salts can be used as a coating for metallic or non-metallic surfaces on dental implants.
  • the coating of the dental implants with these salts can be applied according to the prior art directly on the dental implants and without the use of an intermediate layer or an additional carrier. Therefore, the coating consists essentially or completely of the already mentioned mixed salts.
  • dental implants for the coatings may include dental implants of calcium carbonate, calcium sulfate, calcium phosphate ceramics, glass ceramics, bioglass, organic materials or composites of the materials mentioned as well as dental implants of pure titanium, titanium alloys, alloys of cobalt and chromium or stainless steel or dental implants of native components such as gelatin , Collagen or allogeneic materials.
  • Other non-metallic materials suitable for such a coating process are alumina and zirconia ceramics.
  • These dental implants may have a smooth, porous and / or roughened surface.
  • the surface structure may be made by mechanical methods (e.g., sand blasting) and / or chemical methods (e.g., acid treatment, molten salt treatment), with the use of structured surfaces being preferred.
  • simvastatin-containing (generally statin-containing) coating which is only sparingly soluble in the water.
  • the mixed salts of simvastatin (generally statin) and the amino-containing water-soluble ionic polymers or low molecular weight amino-containing compounds according to the invention as finely divided suspensions of water or as solutions in volatile organic solvents such. used in alcohols or chloroform for the coating process.
  • the coated implants may be removed by a known drying method, e.g. be dried by drying at elevated temperature and / or drying by vacuum or by drying in the gas stream.
  • the coating described in the invention is preferably characterized by the fact that, after the surgical implantation into the human or animal tissue or the bone, it gives the simvastatin (gen. Statin) delayed over a longer period of time to the immediate surroundings of the implant , whereby this can achieve its effect there.
  • simvastatin Dihydroxy Acid Form To form the sparingly sparingly soluble salts of simvastatin with the listed ionic polymers (or the unsaturated alkyl compounds with amino groups), the simvastatin must be converted into the acid form.
  • the lactone form of simvastatin is converted into the open-chain, biologically active dihydroxy acid form. 25 mg (59.72 .mu.mol) Simvastatin in the lactone form are dissolved in 0.625 ml of ethanol and, after addition of 0.9375 ml of 0.1 N sodium hydroxide solution stirred for 2 hours at 50 0 C.
  • the pH of this solution is adjusted to 2.5 or 7.2 with a 0.1 N hydrochloric acid solution.
  • the open-chain acid form by extraction with chloroform (5 times per 2.5 ml) under Obtained with the help of a saturated saline solution.
  • the chloroform is removed on a rotary evaporator and the clear product dried under vacuum (10 mbar).
  • the simvastatin is then dissolved in 2.5 ml of ethanol or 5 ml of an ethanol-water mixture (1: 1). For complete solution of the acid form of simvastatin, which was adjusted to pH 7.2, it had to be stirred for 18 hours at 50 ° C.
  • the open-chain simvastatin can be used after adjustment of the pH to 7.2 even without extraction with chloroform after filling with water to 2.5 ml.
  • simvastatin chitosan 25 mg (59.72 ⁇ mol) of the open-chain acid form of simvastatin (adjusted to pH 7.2 without chloroform extraction) in a mixture of 25% ethanol and 75% water and chitosan as 1% solution dissolved in 1% acetic acid.
  • simvastatin solution is added 0.962 ml of the chitosan solution, ie 9.62 mg (59.72 ⁇ mol) of chitosan.
  • the resulting fibrous precipitate is stirred for a further 18 hours at room temperature, centrifuged (10 min, 14000 rpm) and washed with distilled water.
  • the thus treated precipitate is dried in a desiccator for at least 2 days under vacuum (10 mbar).
  • the obtained yield of simvastatin chitosan is 73.9%
  • the suspension is stirred for 18 hours at room temperature. After centrifugation (10 min, 14,000 rpm), the clear supernatant is removed and the precipitate is washed with distilled water. The product obtained is dried under vacuum in a desiccator for at least 2 days.
  • the ratio simvastatin: diethylaminoethyldextran: carboxymethylcellulose was varied from 1: 1: 1 over 1: 1: 2 to 2: 2: 1. The yields of the respective mixtures are 65.6% for 1: 1: 1, 56.4% for 1: 1: 2 and 41.0% for 2: 2: 1.
  • simvastatin 25 mg (59.72 ⁇ mol) of simvastatin, which has been converted into the open-chain acid form in 0.625 ml of ethanol with ethanolic sodium hydroxide solution, is placed in a
  • Octadecylamine dissolved in 2.5 ml of ethanol, is stirred for 24 hours at room temperature.
  • the surface of dental implants of titanium or a titanium alloy is roughened by means of a sandblasting and acid etching process in the areas which are in contact with the bone.
  • 41 mg of the simvastatin octadecylamine salt are distributed in 1 ml of ethanol with stirring within 10 minutes.
  • an ultrasonic homogenizer (20 watts total power) a homogeneous suspension is obtained.
  • the dental implants After heating the dental implants to 70 0 C, they are sprayed several times with appropriate amounts of the suspension described with a conventional spray gun. During this spraying process, the implants clamped in a suitable device rotate uniformly about their longitudinal axis. After the end of each spraying process, the dental implants are dried at 7O 0 C until the suspension medium is completely evaporated. If the dental implants coated with the simvastatin salt diethylaminoethyldextran, so 10 mg of this salt in 1 ml of ethanol are dissolved with stirring at 5O 0 C within 5 min.
  • the resulting viscous solution is homogenized with an ultrasonic homogenizer (20 watts total power) and sprayed on the heated dental implants as described above.
  • the implants produced in this way showed better behavior both in vitro and improved ingrowth behavior in vivo.

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  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oral & Maxillofacial Surgery (AREA)
  • Transplantation (AREA)
  • Engineering & Computer Science (AREA)
  • Dermatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Molecular Biology (AREA)
  • Materials For Medical Uses (AREA)

Abstract

L'invention concerne un implant présentant au moins partiellement un revêtement, à l'état implanté, dans les zones de surface se trouvant au moins indirectement en contact avec des tissus durs et/ou mous. L'implant est de préférence caractérisé en ce que le revêtement contient une statine telle qu'une simvastatine sous forme hydrolysée ou non, ou des sels pharmaceutiquement acceptables de celle-ci, et au moins un autre constituant du groupe des C10-C30 alkyle-, alcényle-, alkylaryle-, aryle-, cycloalkyle-, alkylcycloalkyle-, alkylcycloaryle-amines linéaires ou ramifiées, substituées ou non, saturées ou partiellement insaturées, ou des mélanges de celles-ci, et/ou au moins un constituant polymère ionique hydrosoluble. L'invention concerne également un procédé de fabrication d'un tel implant et une composition pouvant être employée dans un tel procédé.
EP09714030A 2008-02-27 2009-02-23 Implant et procédé de fabrication Withdrawn EP2254606A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CH2812008 2008-02-27
PCT/EP2009/052112 WO2009106502A2 (fr) 2008-02-27 2009-02-23 Implant et procédé de fabrication

Publications (1)

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EP2254606A2 true EP2254606A2 (fr) 2010-12-01

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EP09714030A Withdrawn EP2254606A2 (fr) 2008-02-27 2009-02-23 Implant et procédé de fabrication

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US (1) US8414958B2 (fr)
EP (1) EP2254606A2 (fr)
JP (1) JP5492790B2 (fr)
KR (1) KR20100125346A (fr)
CN (1) CN102089016A (fr)
AU (1) AU2009218573A1 (fr)
CA (1) CA2716671A1 (fr)
WO (1) WO2009106502A2 (fr)

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BR112014002528A2 (pt) 2011-09-06 2017-03-14 Vita Zahnfabrik H Rauter Gmbh & Co Kg processo para preparação de implantes cerâmicos para propósitos médicos
DE102013201885A1 (de) * 2013-02-05 2014-08-07 Urs Brodbeck Keramikkörper, insbesondere zur Verwendung in einem Knochenimplantat, insbesondere als Dentalimplantat
KR20160061991A (ko) * 2013-09-27 2016-06-01 비타 찬파브릭 하. 라우터 게엠베하 & 코.카게 분해가능한 코팅을 포함하는 임플란트
WO2016029207A1 (fr) * 2014-08-22 2016-02-25 Cummins Inc. Système et procédé d'amélioration du post-traitement dans un moteur à combustion interne
CN105214140B (zh) * 2015-09-22 2018-02-09 重庆大学 协同调控骨质疏松症中局部骨重建及愈合的钛合金的功能化界面构建方法
CN106729964A (zh) * 2016-12-02 2017-05-31 江苏师范大学 一种兼具促进骨形成和抑制骨吸收作用的二氧化钛纳米管及其制备方法
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CN110709074B (zh) 2017-05-15 2023-02-17 辛辛那提大学 通过直接施用辛伐他汀的一种或多种代谢物来治疗无血管软骨组织中的缺损的组合物和方法
CN113368314A (zh) * 2021-05-20 2021-09-10 沈阳理工大学 一种镁基金属高分子复合骨引导再生膜及其制备方法

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Also Published As

Publication number Publication date
US8414958B2 (en) 2013-04-09
CA2716671A1 (fr) 2009-09-03
JP5492790B2 (ja) 2014-05-14
KR20100125346A (ko) 2010-11-30
WO2009106502A2 (fr) 2009-09-03
US20110053113A1 (en) 2011-03-03
JP2011512921A (ja) 2011-04-28
CN102089016A (zh) 2011-06-08
WO2009106502A3 (fr) 2010-07-01
AU2009218573A1 (en) 2009-09-03

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