Medical material, method for production thereof, and medical apparatus

Abstract: A medical material having a higher alcohol and/or a higher alcohol macromer bound to the surface of a substrate formed of a polymer containing a functional group either directly or through the medium of a polymer.

Description: Field of the Invention: This invention relates to a medical material, a method for the production thereof, and a medical apparatus which stably exhibits high biocompatiblility and excellent safety for a long time. In recent years, artificial internal organs such as artificial kidneys, artificial lungs, and blood separating devices have been produced and put to use. The materials of which these artificial internal organs are formed are requested to possess excellent biocompatiblility. Use of an artificial internal organ devoid of biocompatibility is highly dangerous because the contact of the material thereof with blood or vital tissue has the possibility of injuring hemocytes in the blood and inducing the formation of plasma protein and thrombosis. For imparting biocompatibility to the materials forming artificial internal organs, therefore, various methods for reformation have been heretofore proposed. Particularly the practice of effecting graft polymerization by the use of a macromer has been recently in vogue. The formation of a graft copolymer, for example, has been attained by copolymerizing the macromer of a methacrylic ester with 2-hydroxyethyl methacrylate. It has been known that this graft copolymer has a better antithrombic property than countertype homopolymers and random copolymers ("Medical Materials and Organism," page 37 and pages 287 to 289, compiled by Yukio Imanish et al. and published by Kodansha Scientific K.K., 1982). In the graft copolymer produced by this polymerization of a macromer with other monomer, the graft chain is formed not only on the surface of the polymer but in the interior of the polymer. The graft copolymer, therefore, has the problem of entailing a change in the internal quality of the polymer. The method for enhancing the biocompatibility of a medical material by physically coating this material on the surface with an oil-soluble vitamin has been known to the art (US-A-4,588,407 = EP 0 103 816, for example). The medical material having the surface thereof coated with the oil-soluble vitamin brings about a secondary effect sparingly on organisms and avoids causing any transient decrease in leukocyte. The coating of an oil-soluble vitamin deposited only physically on the surface of the material, however, exhibits to the substratal material such a weak binding force as to entail possible migration of the vitamin into the blood. EP O 335 972 relates to a medical material in which a graft layer is formed by bonding a macromer having an unsaturated fatty acid residue on one end thereof and an epoxy group on the other end on the surface of a base material formed of a regenerated cellulose having a hydroxyl group. Further, a medical material wherein a fatty acid or a derivative thereof is fixed through or without a copolymer to a functional group of a polymer having a functional group is disclosed in EP 404 683. This invention, therefore, has as an object thereof the provision of a novel medical material and a method for the production thereof. Another object of this invention is to provide a medical material which exhibits high biocompatibility stably for a long time and excels in safety. SUMMARY OF THE INVENTION The objects described above are accomplished by a medical material produced by causing at least one member selected from the group consisting of higher alcohols and higher alcohol macromers to be bound either directly or through the medium of a polymer to a substrate. The objects are further accomplished by a medical apparatus of which at least the portions destined to contact blood are formed of the medical material set forth in the preceding paragraph. Further, the medical material of this invention can be stably manufactured because it uses a higher alcohol and, as a result, the reaction which proceeds during the manufacture does not easily entail a secondary reaction or decomposition. Morever, the activation of the complement system is inhibited and the substrate is endowed with lasting stable biocompatibility because a higher alcohol and/or a higher alcohol macromer is bound to the substrate directly or through the medium of a polymer. EXPLANATION OF THE PREFERRED EMBODIMENT Now, this invention will be described in detail below. In the medical material of this invention, the polymer of which the substrate is formed has no particular restriction except for the sole requirement that it should possess repeating units containing a functional group. The functional groups which the repeating unit is allowed to contain include hydroxyl group, amino group, carboxyl group, epoxy group, and aldehyde group, for example. As polymers possessing a hydroxyl group as the functional group, regenerated cellulose and cellulose derivatives may be cited. In the unit of regenerated cellulose shown below, for example, the hydroxyl group indicated by an asterisk (*) is a functional group. Incidentally, the hydroxyl group not indicated by an asterisk (*) and attached to the 3 position possesses poor reactivity from the standpoint of the construction of cellulose. The other polymers which are effectively usable herein include polyvinyl alcohol, partially saponified polyvinyl acetate, ethylene-vinyl alcohol copolymers, partially saponified ethylene-vinyl acetate polymers, polyacrylic acid and polymethacrylic acid and copolymers thereof, polyhydroxy methacrylate, chitin, chitosan, collagen, and polyacrylamide, for example. The term "macromer" as used in this invention refers to a macromolecular compound containing a reactive functional group. The spacers which are effectively usable herein include alkylene glycol diamines such as polyethylene glycol diamine, polypropylene glycol diamine, and polytetramethylene glycol diamine, for example. The average degree of polymerization of the alkylene glycol diamine is preferable to be approximately in the range of from 1 to 100, though it is variable with the kind of the alkylene. In this invention, the macromer (hereinafter the "macromer" will be occasionally understood in a broad sense of the word such as to embrace the spacer) is preferable to be formed by being bound to the surface of the substrate through the medium of a copolymer containing a reactive group capable of forming a covalent bond with the functional group of the polymer of which the substrate is formed. The copolymer serving as the medium has no particular restriction except for the requirement that it should contain a reactive group capable of forming a covalent bond with the functional group of the polymer as described above. As the reactive group, the copolymer is preferable to contain an epoxy group, a carboxyl group, a group of the ester thereof, and/or an aldehyde group. The copolymer and the hydrophobic moiety mentioned above can be bound to each other by graft copolymerizing the hydrophobic moiety through the medium of the epoxy group of the copolymer, for example. The monomer as the raw material for the copolymer containing an epoxy group is preferable to be the glycidyl ester of a (meth)acrylic acid. The monomer as the raw material for the copolymer containing a carboxyl group is preferable to be a (meth)acrylic acid. The raw materials which are effectively usable as the raw material for the copolymer include esters such as (meth)acrylic esters represented by methyl (meth)acrylates, ethyl (meth)acrylates, propyl (meth)acrylates, isopropyl (meth)acrylates, butyl (meth)acrylates, isobutyl (meth)acrylates, hydroxyethyl (meth)acrylates, and mixtures thereof, for example. The use of a polymerization initiator such as, for example, ammonium ceric nitrate or ferrous salt of hydrogen peroxide is sufficient to produce the copolymer from the aforementioned monomer. The weight ratio of the epoxy group-containing monomer to the copolymer is preferable to be in the range of from 0.01 to 60% by weight, preferably from 1 to 10 % by weight. The average molecular weight of the copolymer is preferable to be approximately in the range of from 500 to 500,000, preferably from 5,000 to 100,000. The covalent bond between the functional group of the macromer and the reactive group of the copolymer can be formed by any of the known methods available for this purpose. The formation of a covalent bond between the polymer forming the substrate and the product of union of the macromer and the copolymer obtained by the method described above (hereinafter referred to as a "macromolecular derivative") is effected by dissolving the macromolecular derivative in a suitable organic solvent, adding a Lewis acid catalyst and/or a basic catalyst to the resultant solution, and establishing contact between the polymer and the macromolecular derivative as by immersing the polymer in the solution. The amount of the catalyst is in the range of from 0.01 to 20 % by weight, preferably from 0.5 to 5 % by weight. The temperature of the reaction is in the range of from 10 to 300°C, preferably 20 to 150°C. The Lewis acid catalysts which are effectively usable herein include boron trifluoride, tin tetrachloride, and zinc chloride, for example. The basic catalysts which are effectively usable herein include hydroxides of alkaline earth metals, particularly calcium, strontium, barium, and radium and hydroxides of alkali metals such as lithium hydroxide, potassium hydroxide, rubidium hydroxide, cesium hydroxide, and francium hydroxide, for example. The organic solvents which are effectively usable herein include dioxane, acetone, diethyl ketone, methy ethyl ketone, ethyl acetate, isoamyl acetate, tetrahydrazine, and the like. The concentration of the macromolecular derivative in the solution is in the range of from 0.01 to 40 % by weight, preferably from 0.1 to 10 % by weight. Now, the medical apparatus of this invention will be described below. To be specific, the medical apparatus of this invention is constructed so that at least the portions thereof destined to contact blood are formed of the medical material described above. As typical examples of the medical apparatus, extracorporeal circulation systems such as artificial lung circuit systems, artificial dialysis systems such as an artificial kidney, blood plasma separation systems, and various catheters and artificial organs such as artificial blood vessels which are buried in human bodies may be cited. The medical apparatus of this invention for a long time and manifests stable biocompatibility and excellent safety because at least the portions of the apparatus destined to contact blood are formed of the medical material described above. Further, since the medical material of this invention is so constructed that a higher alcohol and/or a higher alcohol macromer is bound directly or through the medium of a polymer to the substrate, it exhibits prominent biocompatibility originating in the higher alcohol. Since the hydroxyl group of the higher alcohol reacts with the functional group of the substrate or the polymer to give rise to an ether bond therebetween, the bond in the medical apparatus is stronger than the ester bond resulting from the reaction of the caraboxyl group as the reactive terminal of a fatty acid with the functional group of the substrate or the polymer. This fact explains why the medical apparatus of this invention exhibits lasting stable biocompatibility without entailing liberation of the higher alcohol. The hydroxyl group of a higher alcohol is used for the production of a higher alcohol macromer, the bond can be easily formed by the addition polymerization of a molecular chain (spacer) under the conditions incapable of readily inducing a secondary reaction. The use of a higher alcohol macromer enables the medical apparatus to curb the adhesion of blood platelets by virtue of the interposition of a molecular chain (spacer) between the higher alcohol and the substrate or the polymer, acquire high biocompatibility, obtain easy control of the molecular chain length, and ensure stable mobility of the molecular chain. The higher alcohol in this invention is preferable to be a monohydric alcohol from the standpoint of adjustment of the molecular chain and manufacture of the medical material. The alcohol is preferable to be in an unsaturated form in point of resistance to thrombosis. To be specific, the higher alcohols having 4-30 carbon atoms, preferably 10-20 carbon atoms which are effectively usable herein include oleyl alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, and stearyl alcohol, for example. Among other alcohols, oleyl alcohol proves to be particularly desirable in point of compatibility for blood. In this invention, for the purpose of enhancing the biocompatibility, particularly the adaptability for blood, the higher alcohol may be bound in the form of a higher alcohol macromer preferably through the medium of a hydrophilic spacer. As a typical spacer, an alkylene glycol having highly reactive functional groups attached one each to the opposite terminals thereof may be cited. The alkylene glycols which fulfil this description include polyethylene glycol diamine, polypropylene glycol diamine, and polytetramethylene glycol diamine, for example. When the spacer to be used has an alkylene glycol skeleton, for example, the degree of polymerization thereof is preferable to be approximately in the range of from 1 to 100, though variable with the kind of the alkylene. Among other alkylene glycols mentioned above, polyethylene glycol and polypropylene glycol prove to be preferable. It is particularly preferable to use polyethylene glycol having a degree of polymerization in the range of from 20 to 90 or polypropylene glycol having a degree of polymerization in the range of from 10 to 50. The polymer for this invention is as already described. The substrate is used in any of various forms such as, for example, a sheet, a tube (inclusive of a hollow fiber), and fibers. Though the method to be employed for the production of the medical material of this invention is not particularly restricted, the following method can be used preferably. Specifically, this method comprises a step of forming a covalent bond between the functional group of a higher alcohol and/or a higher alcohol macromer and part of the functional group of a polymer and a step of forming a covalent bond between part of the functional group of the polymer and the functional group of the substrate. These steps may be carried out either simultaneously or sequentially in any desired order. When a higher alcohol and/or a higher alcohol macromer containing amino groups at the opposite terminals, for example, a polymer containing an epoxy group and the higher alcohol macromer form a graft copolymer through the medium of the epoxy group contained in the polymer or a copolymer containing an epoxy group and a carboxyl group and a higher alcohol and/or a higher alcohol macromer form a macromolecular derivative in the form of a graft copolymer through the medium of the carboxyl group of the polymer. For the reaction resulting in the formation of the graft copolymer, any of the known conventional methods of synthesis can be used. Now, this invention will be described more specifically below with reference to working examples. Example 1 (1) Synthesis of oleyl alcohol macromer In 50 ml of dioxane, 20.00 g of polyethylene glycol monooleyl ether (average molecular weight 4,268) obtained by addition of ethylene oxide to an oleyl alcohol in the presence of an alkali catalyst and 1.90 g of triethyl amine were dissolved. The resultant solution and a solution of 1.85 g of p-toluenesulfonyl chloride in 10 ml of dioxane slowly added dropwise thereto were left reacting at 60 C for two hours. The reaction product was refined by being dissolved with 200 ml of acetone added thereto, then cooled to 0°C, and left standing to allow sedimentation of the product aimed at. Then, a solution of 6.50 g of the product mentioned above in 30 ml of DMF and 0.55 g of potassium phthalimide added thereto were left reacting at 90°C for two hours. The reaction product was refined by being dissolved with 60 ml of acetone added thereto, then cooled to 0°C, and left standing to allow sedimentation of the product aimed at. Subsequently, a solution of 6.00 g of the product mentioned above in 30 ml of ethanol and 1.00 g of hydrazine hydrate added thereto were left reacting as refluxed for two hours. The reaction product was refined by being dissolved with 60 ml of acetone added thereto, then cooled to 0°C, and left standing to allow sedimentation of the product aimed at. Consequently, 5.20 g of an oleyl alcohol macromer possessed of amino groups at the terminals thereof was obtained. (2) Synthesis of copolymer A polymerization tube made of glass was charged with 0.15 part by weight of azo-bis-isobutylonitrile as a catalyst, 7.5 part by weight of methyl methacrylate, 15 parts by weight of glycidyl methacrylate, 6 parts by weight of 3-methacryloxypropyl tris(methoxyethoxy) silane (produced by Chisso Corporation), and 1.5 parts by weight of methacrylic acid, cooled and solidified with liquefied nitrogen, alternately subjected to evacuation of air by a vacuum pump and displacement of the entrapped air with nitrogen repeatedly, and thereafter sealed tightly. In a constant temperature bath, the polymerization tube was heated at a prescribed temperature for a prescribed time. It was cooled and opened to remove the content. The polymerization mixture was dissolved in tetrahydrofuran and reprecipitated in methanol. Consequently, a white polymer was obtained. Similarly, a copolymer containing no methacrylic acid was synthesized. The copolymer was dissolved in methylethyl ketone. The solution was titrated with a 0.01N perchloric acid/acetic solution in the presence of ethyl bromide trimethyl ammonium as a catalyst and crystal violet as an indicator to find an epoxy equivalent and the composition of glycidyl methacrylate (Table 1). Charged monomer Copolymer Nov. Polymerization Temperature (°C) Polymerization time (min) Content of glycidyl methacrylate (wt %) A 1 60 50 52.9 B 2 60 50 52.7 A: MMA/GMA/MPTMS/MA = 7.5/15/6/1.5 (wt. ratio) B: MMA/GMA/MPTMS = 7.5/15/7.5 (wt. ratio) MMA: methyl methacrylate GMA: glycidyl methacrylate MPTMS: 3-methacryloxypropyltris (methoxyethoxy) silane MA: methacrylic acid (3) Reaction of oleyl alcohol macromer with copolymer In a flask, 4.00 g of the aforementioned copolymer No. 1, 0.718 g of dicyclohexylcarbodiimide, and 100 ml of a mixed solvent of carbon tetrachloride/acetonitril (1 : 1 by volume) were stirred as kept swept with nitrogen for 60 minutes. The resultant solution and a solution of 9.92 g of the oleyl alcohol macromer in 20 ml of carbon tetrachloride/acetonitrile (1 : 1 by volume) gradually added dropwise thereto were stirred at room temperature for 60 minutes and further stirred at 60 C for 60 minutes. The content of the flask was cooled to normal room temperature and then passed through a glass filter. When the filtrate was distilled gently to expel the solvent by evaporation, there was obtained a yellow highly viscous crude product. The crude product and 200 ml of methanol added thereto were stirred at normal room temperature for about 30 minutes until lumps ceased to exist. The resultant solution was centrifuged and the supernatant was removed by decantation. This procedure was repeated twice more. The final residue was dried under a vacuum, to produce 8.75 g of a macromolecular derivative. (4) Bonding of macromolecular derivative to regenerated cellulose membrane The macromolecular derivative was bonded to the surface of regenerated cellulose as follows. First, 0.3 g of regenerated cellulose membrane (0.2 mm in membrane thickness) was kept immersed in 100 ml of an aqueous 0.5 (W/V)% sodium hydroxide solution for 30 minutes. Then, the cellulose membrane was immersed in an acetone solution of 0.5 (W/V)% of the macromolecular derivative and left reacting therein at normal room temperature for 24 hours. After the reaction was completed, the regenerated cellulose membrane was taken out of the solution and thoroughly washed with acetone, ethanol, and distilled water sequentially in the order mentioned, to obtain a sample 1 of the medical material embodying this invention. Controls 2 and 3 A mixture of 0.04 g of pyridine with 30 ml of dry dioxane was prepared. Then, 0.90 g of linolic acid was introduced by the use of this mixture into a flask. The resultant mixture in the flask was stirred as kept swept with nitrogen at 80°C for 30 minutes. The content of the flask and a solution of 3.00 g of the copolymer No. 2 in 70 ml of dry dioxane added thereto were stirred at 80°C for six hours. The resultant reaction mixture was cooled to normal room temperature and subjected to gentle distillation to expel the solvent by evaporation. Consequently, a light brown highly viscous crude product was obtained. The crude product and 100 ml of methanol added thereto were stirred at normal room temperature for about 30 minutes (until lumps ceased to exist) and subjected to centrifugal separation. The supernatant was removed by decantation. When this procedure was repeated twice more and the final residue was subjected to vacuum drying, 3.05 g of a macromolecular derivative was obtained. A sample 2 (Control 2) was obtained by bonding the macromolecular derivative to regenerated cellulose membrane by following the procedure of Example. A regenerated cellulose membrane was used as Sample 3 (Control 3). Evaluation Test 1 The samples of Example 1 and Controls 2 and 3 were tested for change of correction value in accordance with the original Mayer method indicated below. The results of the test are shown in Table 2. Each sample was preparatorily brought to an equilibrium state of sorption by immersion in physiological saline solution. The sample was gently wiped to remove water from the surface and trimmed into a small piece 20 cm 2 in surface area. The cut sample was placed in a plastic blood collecting tube and 1 ml of the serum extracted from an adult dog was automatically added to the cut sample in the tube. The contents of the tube were kept at 370°C for three hours to activate the cut sample to determine the change in the correction value CH50 (correction value determined by the 50% hemolysis method) and calculate the ratio of consumption. Sample Consumption rate of CH50 Example 1 (Sample 1) 13.5 Control 2 (Sample 2) 14.2 Control 3 (Sample 3) 35.7 It is clearly noted from Table 2 that the medical material of this invention brings about a very small decrease of the correction value CH50 in the serum as compared with the untreated sample.

Claims: A medical material characterized in that a C 4 -C 30 alcohol and/or a C 4 -C 30 alcohol macromer is bound to the functional group of a substrate formed of a polymer containing a functional group either directly or through the medium of a polymer. A medical material according to claim 1 wherein a C 4 -C 30 alcohol and/or a C 4 -C 30 alcohol macromer is bound to the surface of the substrate through the medium of a copolymer containing a reactive group capable of forming a covalent bound with the functional group of the polymer. A medical material according to claim 1 or 2, wherein said alcohol is a monohydric alcohol having from 10 to 20 carbon atoms. A medical material according to any one of claims 1, 2 and 3, wherein said alcohol is oleyl alcohol. A medical material according to any one of claims 1 to 4, wherein said alcohol macromer is the reaction product of said alcohol with a spacer. A medical material according to claim 5, wherein said spacer is an alkylene glycol diamine. A medical material according to any one of claims 2 to 6, wherein said copolymer contains an epoxy group, a carboxyl group or an ester thereof, and/or an aldehyde group. A medical material according to claim 7, wherein said copolymer is formed of monomers selected from (meth)acrylic acid, esters thereof and glycidyl esters thereof. A medical material according to any one of claims 1 to 8, wherein said polymer forming the substrate is a polymer containing at least one group selected from hydroxyl group, amino group, carboxyl group, epoxy group, and aldehyde group. A medical material according to claim 9, wherein said polymer is a polymer containing a hydroxyl group. A medical material according to claim 10, wherein said polymer containing a hydroxyl group is regenerated cellulose or cellulose derivative. A medical apparatus having at least the portions thereof for contact with blood formed of a medical material according to any one of claims 1 to 11. A medical apparatus according to claim 12, wherein said medical apparatus is an artificial kidney.

Inventors: SAKAKIBARA HIROKI, SARUHASHI MAKOTO, SASAKI MASATOMI, TATEGAMI SHINICHI, SAKAKIBARA, HIROKI, SARUHASHI, MAKOTO, SASAKI, MASATOMI, TATEGAMI, SHINICHI, Sakakibara, Hiroki, c/o Terumo K.K., Saruhashi, Makoto, c/o Terumo K.K., Sasaki, Masatomi, c/o Terumo K.K., Tategami, Shinichi, c/o Terumo K.K.
Applicants: TERUMO CORP, TERUMO KABUSHIKI KAISHA
Application year: 1992
Main classification: A61L33
IPC codes: A61L33, B01D67