METHOD OF PRODUCING A BIOACTIVE GLASS OR GLASS CERAMIC PRECURSER GEL

Abstract: A method of producing a multicomponent gel as a precursor of a bio-active glass of glass-ceramics useful for artificial tooth roots or artificial bones, which comprises the step of reacting (A) at least one or the types of silicic acid ester such as tetramethoxysilane or tetraethoxysilane; (B) at least one of the types of phosphorous compound represented by general formulas [II], [III] or [IV]: (where each of R₅ to R₉ is hydrogen, an alkyl group, with 1 to 5 carbon atoms, a phenyl radical, or an aralkyl group with 7 to 10 carbon atoms in which at least one of R₁₀ to R₁₂ is hydrogen, and m: 0 to 10); and (C) an alkaline earth metal salt or an alkoxide thereof in the presence of water at pH of not higher than 8.

Description: BACKGROUND OF THE INVENTION (1) Field of the Invention This invention relates to a method of producing a multicomponent gel that is a precursor of a bio-active glass or glass-ceramics which is useful for artificial tooth roots or artificial bones. (2) Prior Art Traditionally, glass is produced by a melting method or a VAD (Vapor-Phase Axial Deposition) method, but sol-gel methods have recently become common because they enable a glass to be synthesized at a low temperature and with a high degree of purity, and because they are free from any restrictions on the range of vitrification. A sol-gel method is a method in which a metal alkoxide is hydrolyzed and polymerized so as to form a gel which is thereafter calcinated to produce glass or glass-ceramics. Sol-gel methods which use silicon, phosphorus, and alkaline earth metal as components are unknown. If trialkyl phosphate, which is an alkoxide of phosphorous, is used as a phosphorous component in accordance with the ordinary techniques of sol-gel methods, the hydrolyzation is so slow that unchanged trialkyl phosphate remains in the gel. Since the boiling point of trialkyl phosphate is comparatively low, the composition of the gel changes as the phosphorous component evaporates when the gel is calcinated. If phosphoric acid is used as a phosphorus component together with an alkaline earth metal, the phosphoric acid forms salts by reacting with Ca or the like, and the salts precipitate, so that the system tends not to be uniform. US-A-3,767,434 discloses the preparation of a 2-component gel comprising P₂O₅ and SiO₂ The oxide products prepared from the gel are useful for solid beds or sputterable targets. SUMMARY OF THE INVENTION It is therefore an object of the present invention to provide a method of producing a silicon-phosphorus-alkaline earth metal multicomponent gel which is free from changes in its components and which is uniform and of good quality. The present invention has been achieved based on the finding that, in the process of producing a silicic acid gel having as a component an alkaline earth metal, it is possible to effectively solve the above-described problems by using a special phosphorous compound and by gelling this compound at a specific pH. In accordance with the present invention, there is provided a method of producing a bioactive glass or glass ceramic precursor gel by reacting the following components (A), (B) and (C) in the presence of water at pH not higher than 8 so as to prepare a gel comprising 20 to 70 mol % of component (A) as SiO₂, 1 to 50 mol % of component (B) as P₂O₅ and 20 to 70 mol % of component (C) as CaO; (A) at least one of the types of silicic acid ester represented by a general formula [I]: (where each of R₁ to R₄ is hydrogen or a radical represented by C x H 2x+1 (OC₂H₄) y - (x: 1 to 5; y: 0 to 10), but R₁ to R₄ are not all hydrogen; and n: 0 to 20) (B) at least one of the types of phosphorous compound represented by general formulas [II], [III] or [IV]: (where each of R₅ to R₁₂ is hydrogen, an alkyl group with 1 to 5 carbon atoms, a phenyl radical, or an aralkyl group with 7 to 10 carbon atoms with the proviso that at least one of R₅ to R₁₂ is not hydrogen and at least one of R₁₀ to R₁₂ is hydrogen; and m: 0 to 10), and (C) at least one compound selected from the group consisting of calcium salt and alkoxides of calcium represented by a general formula [V]: Ca(OR)₂ [V] (where R is an alkyl group with 1 to 5 carbon atoms). DESCRIPTION OF THE PREFERRED EMBODIMENTS Silicic acid esters (A) usable in the present invention are, preferably, those as defined by Formula [1] where R₁ to R₄ are CH₃, C₂H₅, n-C₃H₇, iso-C₃H₇, n-C₄H₅, or - C₂H₄OCH₃. More preferably, R₁ to R₄ are the same radicals selected from this list. In accordance with the present invention, silicic acid esters defined by n = 0 are preferred, but condensates defined by n = 1 to 10 are also preferred. Examples of silicic acid ester represented by Formula [I] are tetramethoxysilane, tetraethoxysilane, tetra(n-propoxy)silane, tetraisopropoxysilane, tetrabutoxysilane, tetra(2-methoxyethoxy)silane, and oligomers (2 to 10 monomers) of these silicates. Of these examples, tetraethoxysilane Si(OC₂H₅)₄ can be readily obtained as Ethyl Silicate 28 from Colcoat Co., Ltd. and a 5-mol-average condensation product of ethyl silicate: can be obtained as Ethyl Silicate 40 from Colcoat. The concentration of the silicic acid ester in the mixture liquid can be selected as required. It may be adjusted to a level as represented by SiO₂ content of 0.1 to 40% by weight (hereinafter simply represented as %) or, more preferably, 2 to 30%. Phosphorous compounds (B) usable in the present invention include a phosphorous acid itself and phosphorous acid esters as represented by Formulas [II] and [III]. Preferably, the alkyl groups in Formulas [III and [III] have 1 to 4 carbon atoms, and phenyl radicals and benzyl radicals are also preferred. Examples of suitable compounds are those defined by Formulas [II] and [III] when R₅ to R₉ are methyl, ethyl, iso-propyl, n-propyl, butyl, phenyl, or benzyl groups. Phosphoric acids represented by the general formula [IV] or esters of such phosphoric acids can also be usable in the present invention. One of them or a mixture of two or more of them may be selected. It is preferable to use substances defined by Formula [IV] where m = 0 to 4. Preferably, the alkyl groups in Formula [IV] have 1 to 4 carbon atoms, and phenyl radicals and benzyl radicals are also preferred. It is possible to use, phosphoric acids in which all of R₁₀ to R₁₂ are hydrogen atoms and condensation products of these acids, and partial esters which contain both alkyl groups and hydrogen. It is most preferable to use chemical compounds as defined by Formula [IV] where at least one of R₁₀ to R₁₂ is hydrogen but, at the same time, R₁₀ to R₁₂ are not all hydrogen. Examples of these compounds are as follows: One or a mixture of two or more of these compounds are selected. In these formulas, R₁₀ to R₁₂ are the same as R₁₀ to R₁₂ in Formula [IV], except that hydrogen is excluded. Each of the above-mentioned phosphoric acid esters can readily be obtained by a method of effecting partial hydrolysis of a corresponding phosphoric acid ester, a method of adding alcohol to a corresponding phosphoric acid and esterifying it, or a method of making of making phosphorus pentoxide react with alcohol and thereafter hydrolyzing it. Examples of phosphoric acid are orthophosphoric acid, pyrophosphoric acid, tripolyphosphoric acid and metaphosphoric acid. Polyphosphoric acid may be obtained by condensing orthophosphoric acid, and orthophosphoric acid is obtained by hydrolyzing phosphorus pentoxide. Another essential component in accordance with the present invention is component (C) which is selected from the group consisting of calcium salts and their alkoxides represented by the general formula [V]. This is because it is necessary to add Ca to produce a bio-active glass or glass-ceramics. Specificaily, it is preferable to use Ca(OR)₂ (where R is an alkyl group with 1 to 5 carbon atoms), calcium nitrate, calcium acetate, calcium chloride, calcium hydroxide, calcium hydrogen citrate, calcium citrate, calcium oxalate, etc. It is essential for the present invention to form a multicomponent gel in a solution of a pH of 8 or less. This is because diethyl phosphite or phosphorous acid reacts with calcium ions to cause precipitation under alkaline conditions, thereby making the system non-uniform. In addition, the same problem of the system being non-uniform is caused by the known fact that trialkyl phosphite is hydrolyzed during sol-gel reactions to form diethyl phosphite or phosphorous acid. On the other hand, if a phosphorous compound as represented by Formula [IV] is used, calcium phosphate or hydroxyapatite may be precipitated by the reaction of phosphorous compound with calcium components if the pH exceeds 6. It is therefore suitable to form the multicomponent gel in a solution of a pH of 6 or less. Accordingly, it is necessary for the present invention to effect the formation in a range of pH of 8 or less, where the phosphorous components and calcium components are mutually dissolved so as to cause uniform gelation, preferably at a pH of 6 or less or, more preferably, at a pH of 4 or less. It is not necessary to add a pH regulating substance to the phosphorous acid, phosphoric acid, or partial esters of these acids usable in the present invention, since they are acids. However, if a calcium alkoxide is used as a calcium ion source, there is a possibility of the pH value being increased by substances formed by hydrolysis, so there is a necessity for pH adjustment in such a case. It is also preferable to adjust the pH to a value within the above-described pH range if the pH deviates from the desired pH value by the influence of the kind and concentration of the calcium salt, the concentration of the phosphorous compound, or other additives. To acidify the above aqueous solution, it is suitable to use a mineral acid such as hydrochloric acid, nitric acid, or sulfuric acid, or a organic acid such as acetic acid, citric acid or lactic acid. It is also possible to add an alkali such as aqueous ammonia in order to increase the pH. The pH of the solution may be maintained constant until gelation starts, or, in order to promote gelation, the pH may be increased to within a range which enables the maintenance of uniformity of the system. In accordance with the present invention, it is suitable to add a quantity of a silicic acid ester represented by an SiO₂ content of 10 to 80 molar percent or, preferably, 20 to 70 molar percent relative to the total amount of oxides when all of the constituent elements of the gel have been converted into oxides; a quantity of a phosphorous compound represented by a P₂O₅ content of 0.1 to 60 molar percent or, preferably, 1 to 50 molar percent; and a quantity of a calcium compound represented by a CaO content of 10 to 80 molar percent or, preferably, 20 to 70 molar percent. In addition, it is suitable to set the atomic ratio Ca/P to within a range of 1.0 to 5.7. In accordance with the present invention, it is possible to add elements other than the above constituent elements which can form constituent oxides of the gel. Example of such elements are Li, Na, K, Al, Zr, Ti, B, and so forth. These elements may also be used in the form of metal alkoxides or soluble salts. It is suitable to use each of them to a quantity defined by a content of its oxide of 0 to 20 molar percent relative to the total amount of oxides when the contents of all of the constituent elements of the gel have been converted into the contents of oxides. In this invention, there can be added fine particles or whiskers of ZrO₂, Al₂O₃, TiO₂, B₂O₃, Y₂O₃, SiC, Si₃N₄, AlN or the like singly or in combination in an amount of not more than 30% by weight relative to total amount of the constituent oxides of the gel. Furthermore, there can be added in an amount of 0 to 10% by weight of a halide such as hydrochloride, hydrofluoric acid, silicohydrofluoric acid, calcium chloride or calcium fluoride; a sulfide such as zinc sulfide; or a nucleating agent such as La₂O₃, CeO₂, SnO₂, Fe₂O₃, Li₂O, SrO, Nb₂O₅, Ta₂O₅, Ag, Au, Pt, Pd, Ph or the like. The present invention produces a multicomponent gel by using the above components on the basis of, for example, the methods listed below: (i) a method of adding a phosphorous compound to a silicic acid ester, partially hydrolyzing the silicic acid ester, and therefore adding a calcium ion forming compound, thereby completing gelation; (ii) a method of adding a phosphorous compound after partially hydrolyzing a silicic acid ester, and then adding a calcium ion forming compound, thereby completing gelation; (iii) a method of adding a calcium ion forming compound to a silicic acid ester, adding a phosphorous compound after partially hydrolyzing the silicic acid ester, thereby completing gelation; (iv) a method of adding a calcium ion forming compound after partially hydrolyzing a silicic acid ester, and then adding a phosphorous compound, thereby completing gelation; and (v) a method of adding a silicic acid ester to a solution of a phosphorous compound and a calcium ion forming compound, thereby effecting gelation. The above hydrolysis and gelation by polycondensation can be effected at a room temperature, but they are also possible under a heated condition. The hydrolysis and the gelation may be effected under pressure by using an autoclave or the like if they are effected under a heated condition and if the temperature thereof is higher than the boiling point of the solvent. Preparation of sintering gel As a method of preparing silica glasses by a sol-gel method, there is generally used a method comprising the steps of drying a gel under the condition of controlling the evaporation rate so as to form a dried gel which is free from cracks, and sintering the resulting gel, but it is difficult to prepare a dried gel by using a multiple component gel of the present invention without forming cracks in the gel. Therefore, in order to prepare a sintered gel of the multiple component gel, it is preferable to take the steps of powdering the dried gel followed by heating or the gel after heating; molding and sintering. Drying The gel is dried at a temperature of 0 to 200°C under a normal pressure or a reduced pressure. In this connection, the wet gel can be dried after being powdered or the dried gel can be powdered. Heating The resulting gel is subjected to heat treatment at a temperature of not less than 200°C, preferably not less than 400°C, and lower than the temperature at which the sintering of the gel starts so as to complete the reaction occurring between components by removing the residual alcoxyl groups on the atoms of Si, P and Ca, and by promoting further the condensation polymerization of the gel. In this regards, there cannot the obtained sufficient effects by heating at a temperature of lower than 200°C. Molding, Sintering One of the following method can be employed; (i) The heated powders are molded by a single-axis press or a cold isostatic press (CIP), after which they are sintered at a temperature of 800 to 1300°C under a normal pressure. (ii) The heated powders are sintered at a temperature of 800 to 1300°C by a hot-press. (iii) The heated powders are molded, and pressed directly by a hot isostatic press, or the heated powders sintered under a normal pressure are farther pressed by the hot isostatic press. The present invention enables a silicon-phosphorous-calcium-contained multicomponent gel having an uniform component distribution to be obtained easily. The gel thereby obtained can be used as a carrier for enzyme chromatography or a catalyst since it is porous and has OH radicals. It can form glass or glass-ceramics having a bioactive property when it is sintered. These material may be effectively utilized as materials for forming artificial bones and tooth roots. The examples of the present invention will be described below, but the present invention is not limited to these examples. Example 1 8.2 g of tetraethoxysilane, 3.6 g of diethyl phosphite and 7.1 g of water were mixed and then violently agitated at 45°C. After 1 hour 18.6 g of 41.7% aqueous solution of calcium nitrate was added to the mixture solution, and this solution was further agitated vigorously for 1 hour, thereby obtaining a transparent homogeneous gel of pH 1.5. This gel was dried in a constant-temperature room at 45°C for two weeks, and the molar ratio: SiO₂/P₂O₅/CaO thereafter measured by using fluorescent x-ray analysis was 40/13/47. This gel was pulverized and was calcined at 1000°C. The composition of the gel was thereafter examined and the compositional ratio was found unchanged. Example 2 7.6 g of tetramethoxysilane, 0.65 g of trimethyl phosphite and 4.5 g of water were mixed and then vigorously agitated at 45°C. 37.5 g of 20% aqueous solution of calcium acetate was added to the mixture solution, followed by agitation. A uniform solution of pH 6.6 was thereby obtained. The solution was moved into a vessel made of polypropylene and was left at rest at 45°C, and a transparent homogeneous gel was thereby obtained after about 10 minutes. This gel was dried in a constant-temperature room at 45°C for two weeks, and the molar ratio: of SiO₂/P₂O₅/CaO thereafter measured by using fluorescent x-ray analysis was 51/3/46. This gel was pulverized and was calcined at 1000°C. The composition of the gel was thereafter examined and the compositional ratio was found unchanged. Example 3 8.3 g of tetraethoxysilane, 13.2 g of triethyl phosphite and 15.4 g of 0.08 mol/l aqueous solution of hydrochloric acid were mixed and then vigorously agitated at 45°C. After 1 hour 5.2 g of 50% ethanol solution of diethoxycalcium (synthesized by the reaction of metallic calcium and ethyl alcohol) was added to the mixture solution, followed by agitation. A uniform solution of pH 3.2 was thereby obtained. The solution was transferred to a vessel made of polypropylene and was left at rest at 45°C, and a transparent homogeneous gel was thereby obtained after 48 hours. This gel was dried in a constant-temperature room at 45°C for two weeks, and the molar ratio: SiO₂/P₂O₅/CaO thereafter measured by using fluorescent x-ray analysis was 40/39/21. This gel was pulverized and was calcined at 1000°C. The composition of the gel was thereafter examined and the compositional ratio was found unchanged. Comparative Example 1 An experiment similar to Example 3 was performed by using 14.5 g of triethyl phosphate instead of triethyl phosphite. The solution was left at rest for about 72 hours, thereby obtaining a transparent homogeneous gel. This gel was dried in a constant-temperature room at 45°C for two weeks, and the molar ratio: SiO₂/P₂O₅/CaO thereafter measured by using fluorescent x-ray analysis was 41/37/22. This gel was pulverized and was calcined at 1000°C. After compositional analysis, SiO₂/P₂O₅/CaO = 57/12/31 was measured and a remarkable decrease in the P₂O₅ content was found. Comparative Example 2 An experiment similar to Example 3 was performed by using 0.5 mol/l aqueous ammonia solution instead of water, and white precipitates were formed when an aqueous solution of calcium acetate was added. At this time, the pH was 8.2. Example 5 7.1 g of 0.17 mol/l aqueous solution of hydrochloric acid was added to 8.2 g of tetraethoxysilane, after which it was mixed at a temperature of 45°C for 1 hour. 3.6 g of a mixture of diethyl phosphate and monoethyl phosphate (weight ratio of diethyl phosphate/monoethyl phosphate = 85/15) was added to the resulting solution, mixed for 1 hour, and 18.6 g of 41.7% aqueous solution of calcium nitrate was further added. The resulting mixture was mixed for 1 hour. The solution having pH 0.9 was transferred to a vessel made of polypropylene and was left at rest at 45°C, after which a transparent homogeneous gel was obtained after 24 hours. This gel was dried in a constant-temperature room at 45°C for two weeks, and the molar ratio: SiO₂/P₂O₅/CaO determined by fluorescent x-ray analysis was 40/13/47. This gel wad pulverized and was calcined at 1000°C. The composition of the gel was thereafter examined and the compositional ratio was found unchanged. Example 6 Water was added to silicic acid ester and phosphorous compound in such manner that the amount of the water was ten mole times that of the silicic acid ester, and then the resulting mixture was vigorously agitated at 45°C. After 1 hour 50% aqueous solution of calcium nitrate was further added thereto, and a uniform solution was obtained by agitating violently the solution. Kinds of silicic acid esters and the phosphorous compounds used in this Example and the ratio of three components (the ratio being calculated by using their oxide) are shown in Table 1. The resulting solution was then sealed in a vessel to obtain a gel by leaving the solution at rest at 45°C for 1 night. Thereafter, the lid of the vessel was opened to dry the gel at 45°C for 1 week. The dried gel was pulverized into powder, heated to 500°C at a heating rate of 20°C/hr, maintained at 500°C for 10 hours to subjected it to heat treatment, further water-ground by a ball mill, and then sintered at 1200°C for 1 hour by the hotpressing. The composition of the resulting sintered material was determined by fluorescent x-ray analysis. As a result, the analytical composition was identified with the starting composition. Rectangular bars of 3 x 4 x 30 mm were cut from the resulting sintered material and the surface of the specimens was polished. Bending strength of the material was measured using a three-point bending test. The results obtained are shown in Table 1. As is obvious from Table 1, in particular, Nos. 1 - 5 of the present invention show high bending strength, and contain large amount of apatite crystal which are important for making chemical bonds between bones. Example 7 Tetraethoxysilane was used as a silicic acid ester, and gelation and heat treatment of this Example was conducted by the same method as set out in Example 6 except for the condition shown in Table 2. The resulting dried powder was then water-ground by a ball mill, molded by a cold-isostatic press and sintered at 1200°C under a atmospheric pressure. The formed crystal is shown in Table 2. From Table 2, it is understood that the selectivity of the crystal phase is good and large amount of apatite crystals are formed in the case of using partial ester of phosphoric acid as a phosphorous compound, compared with the case of using orthophosphoric acid.

Claims: A method of producing a bioactive glass or glassceramic precursor gel which comprises the step of reacting the following components (A), (B) and (C) in the presence of water at pH of not higher than 8 so as to prepare a gel comprising 20 to 70 mol% of component (A) as SiO₂, 1 to 50 mol% of component (a) as P₂O₅ and 20 to 70 mol% of component (C) as CaO; (A) at least one of the types of silicic acid ester represented by a general formula [I]: (where each of R₁ to R₄ is hydrogen or a radical represented by C x H 2x+1 (OC₂H₄) y- (x: 1 to 5; y: 0 to 10); R₁ to R₄ are not all hydrogen; and n: 0 to 20) (B) at least one of the types of phosphorous compound represented by general formulas [II], [III] or [IV]: (where each of R₅, to R₁₂ is hydrogen, an alkyl group with 1 to 5 carbon atoms a phenyl radical, or an aralkyl group with 7 to 10 carbon atoms with a proviso that at least one of R₅ to R₁₂ is not hydrogen and at least one of R₁₀ to R₁₂ is hydrogen; and m: 0 to 10), and (C) at least one compound selected from the group consisting of calcium salt and alkoxides of calcium represented by a general formula [V]: Ca(OR)₂ [V] (where R is an alkyl group with 1 to 5 carbon atoms) A method according to claim 1, wherein each of R₁ to R₄ in Formula [I] is methyl, ethyl, n-propyl, iso-propyl, n-butyl, or methoxyethyl. A method according to claim 1 and/or 2, wherein n in Formula I is 0 to 10. A method according to any of claims 1 to 3, wherein each of R₅ to R₁₂ in Formulas II to IV is hydrogen, an alkyl group with 1 to 4 carbon atoms, a phenyl radical or a benzyl radical. A method according to any of claims 1 to 4, wherein the pH at the reaction is equal to or lower than 6. A method according to claim 5, wherein the pH at the reaction is equal to or lower than 4. A method according to any of claims 1 to 7, wherein the quantities of said component (C) and (B) are determined so as to set the atomic ratio of calcium and phosphorous to within a range of 1.0 to 5.7.

Inventors: GOTO, TUYOSHI, HORIGUCHI, YASUNOBU, YAMAMOTO, NOBUYUKI
Applicants: LION CORPORATION
Application year: 1987
Main classification: C03B8
IPC codes: A61K6, C03C1, C03B8, C03C10, A61F2, A61L27, C03C3, C03C4