COMPOSITION FOR SOLID PHARMACEUTICAL PREPARATIONS CONTAINING ACTIVE VITAMINS D3 AND PROCESS FOR PREPARATION THEREOF

Abstract: A composition for solid pharmaceutical preparations containing active vitamins D3 capable of permitting the active vitamins D3 to be significantly stabilized and being improved in handling. The composition includes hydroxypropylmethyl cellulose. To the cellulose are attached active vitamins D3 and a polymer which is readily soluble in an organic solvent.

Description: TITLE OF THE INVENTION COMPOSITION FOR SOLID PHARMACEUTICAL PREPARATIONS CONTAINING ACTIVE VITAMINS D AND PROCESS FOR PREPARATION THEREOF BACKGROUND OF THE INVENTION This invention relates to a composition for solid pharmaceutical preparations containing active vitamins D-, and a process for the preparation thereof, and more particularly to a composition for solid pharmaceutical preparations containing active vitamins D_, in which hydroxypropyl methyl cellulose is used as an excipient. In general, active vitamins D_ are labile and sensitive to heat and light and apt to be readily oxidized, so that the formation of pharmaceutical preparations containing active vitamins D-. requires to stabilize them. In order to stabilize active vitamins D-., some techniques were proposed such as a method for forming an inclusion compound between the vitamins and bile acids as disclosed in Japanese Patent Application Laid-Open Publication No. 69562/1980, a method for forming a complex between the vitamins and cholesterols as disclosed in Japanese Patent Application Laid-Open Publication No. 40461/1982, a method for dispersing the vitamins in polyvinyl pyrrolidone as disclosed in Japanese Patent Application Laid-Open Publication No. 206533/1983 and the like. In the proposed methods, the preparations are obtained by dissolving active vitamins D, together with bile acids, SUBSTI cholesterols or polyvinyl pyrrolidone in an alcoholic solvent such as ethanol, methanol, propanol or the like which permits both to be dissolved therein, followed by removal of the solvent under reduced pressure. Unfortunately, each of the proposed methods exhibits a disadvantage of causing the composition to be partially resinified during the removal of the solvent under reduced pressure. Also, each of the conventional methods proposed causes the composition to be rendered non-uniform in grain size when it is pulverized. In view of the above, a method was proposed wherein an excipient which is slightly soluble in an organic solvent is suspended in a solution in which active vitamins D-. are dissolved and then a solvent of the solution is removed according to a suitable procedure, to thereby obtain a composition for solid pharmaceutical preparations of active vitamins D^, as disclosed in Japanese Patent Application Laid- Open Publication No. 155309/1984. - - However, restrictions * in preparation of the composition cause a core material for the composition to be limited to an excipient which is slightly soluble in an organic solvent. Also, a large volume of organic solvent must be used to form an outer layer for the composition of an excipient which is readily soluble in an organic solvent, so that much energy is required to remove the organic solvent by drying. SUMMARY OF THE INVENTION The present invention has been made in view of the foregoing disadvantage of the prior art. The inventors have made a careful study for the purpose of preparing a composition for solid pharmaceutical preparations which is capable of stabilizing active vitamins D.,, having a uniform content and facilitating the handling. As a result, it has been found that a composition for solid pharmaceutical preparations containing active vitamins D_ which comprises hydroxypropylmethyl cellulose (hereinafter referred to as "HPMC" ) , and an active vitamins D, and a polymer which is readily soluble in an organic solvent each attached to HPMC meets such requirements. Accordingly, it is an object of the present invention to provide a composition for solid pharmaceutical preparations containing active vitamins D_, which is capable of permitting the active vitamins D, to be significantly thermally stabilized and being improved in handling. It is another object of the present invention to provide a process for preparing a composition for solid pharmaceutical preparations containing active vitamins D_, which is capable of highly facilitating the preparation while ensuring thermal stability of the vitamins D... In accordance with one aspect of the present invention, a composition for solid pharmaceutical preparations containing active vitamins D_, is provided. The composition comprises hydroxypropyl methyl cellulose, and an active vitamin D-, and a polymer which is readily soluble in an organic solvent each attached to the hydroxypropyl methyl cellulose. In accordance with another aspect of the present SUBSTITUTESHEET invention, a process for preparing such a composition as described above is provided. The method uses an alcoholic solvent. DETAILED DESCRIPTION OF THE INVENTION The polymer which is readily soluble in an organic solvent includes polyvinyl pyrrolidone (hereinafter referred to as "PVP"), HMPC and the like. The active vitamins D_ of the present invention include vitamins D, of which positions lo and/or 25 are subject to hydroxidation, such as, for example, 10 - hydroxycholecalciferol; 25-hydroxycholecalciferol; 10( , 25- dihydroxycholecalciferol; 26, 26, 26, 27, 27, 27-hexafluoro-l(X , 25-dihydroxycholecalciferol (hereinafter referred to as "ST- 630); 1C , 25-dihydroxycholecalciferol; 24, 25- dihydroxycholecalciferol,- 1( -dihydroxycholecalciferol; 1CX , 25- dihydroxy-26, 27-dimethylcholecalciferol; lσ( -hydroxy-26, 27- dimethylcholecalciferol; 25-hydroxy-26, 27- dimeth lcholecalciferol; 10( , 25-dihydroxy-24, 24-difluoro-26, 27-dimethylcholecalciferol; 1C , 25-dihydroxy-26, 27- diethylcholecalciferol; 25-hydroxy-26, 27- dimethylcholecalciferol; ; 25-hydroxy-26, 26, 26, 27, 27, 27- hexafluorocalciferol; 25-hydroxy-26, 26, 26, 27, 27, 27- hexafluoroepicalciferol; 1(X, 25-dihydroxy-24, 24- difluorohomocholecalciferol; l( r 25-dihydroxycholecalciferol- 26, 23-lactone; 1OC/ 25-dihydroxy-22-oxacholecalcif rol; 10(- hydroxy-22-oxacholecalciferol; and ergocalciferols corresponding to the above. HPMC used as an excipient in the composition of the present invention is loaded in an amount of from 50% to 99.9% by weight and preferably from 65% to 99.9% by weight in the composition. The polymer which is readily soluble in an organic solvent is loaded in an amount of from 0.1% to 50% by weight and preferably from 0.1% to 35% by weight in the composition. The composition of the present invention is obtained by preparing HPMC using an alcoholic solution in which the active vitamins D_ and the polymer which is readily soluble in an organic solvent are dissolved. The alcoholic solvent suitable for use for this purpose includes, for example, ethanol containing 20% or less water. In the preparation of the composition, HPMC acts as an excipient. Any prior art is silent concerning the use of HPMC as a sole excipient in wet granulation as in the present invention. The reason would be that HPMC highly exhibits a film forming property, therefore, the granulation of a composition using a solvent in which HPMC is dissolved causes removal and subsequent pulverization of the composition to be rendered difficult or troublesome. As described above, the composition of the present invention is prepared using the alcoholic solvent in which HPMC is dissolved. The use of the alcoholic solvent permits the surface of HPMC particles acting as a nucleus of the composition to be dissolved in the solvent, so that the active vitamins D, are taken in HPMC, resulting in being substantially stabilized. The composition thus obtained may be formed into pharmaceutical preparations as it is or, if necessary, while being mixed with at least one of any suitable additives known in the art such as an excipient, a degradative agent, a binder, a lubricant, an anti-oxidant, a coating agent, a coloring agent, a corrigent, a surface active agent and the like. The excipient includes, for example, lactose, starch, crystalline cellulose, calcium hydrogenphosphate, light silica, titanium oxide, magnesium metasilicate aluminate, polyethylene glycol and the like. The degradative agent includes, for example, carboxymethyl cellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, croscarmellose sodium. Type A (Ac-Di-Sol ) starch, crystalline cellulose, hydroxypropyl starch, starch of which a part is modified into £X-starch and the like. The binder includes, for example, hydroxypropyl cellulose, gelatin, gum arabic, ethyl cellulose, polyvinyl alcohol, pullulan and the like. The lubricant includes, for example, stearic acid, magnesium stearate, calcium stearate, talc, hardened oil, fatty saccharide and the like. The anti-oxidant includes, for example, dibutyl hydroxytoluene (BHT), gallic propyl, butylhydroxy anisole (BHA), t> -tocopherol, citric acid and the like. The coating agent includes, for example, HPMC, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropylmethyl cellulose phthalate, polyvinylacetal diethylaminoacetate, aminoalkyl methacrylate copolymer, hydroxypropylmethyl cellulose acetate succinate, methacrylic acid coplymer, cellulose acetate trimellitate (CAT), polyvinyl • acetate phthalate, and the like. The coloring agent includes, for example, a tar pigment, titanium oxide and the like. The corrigent includes, for example, citric acid, adipic acid, ascorbic acid, menthol and the like. The surface active agent includes, for example, glycerin monostearate, polysorbates, sodium lauryl sulfate, lauromacrogol, fatty saccharide, and the like. The composition for solid pharmaceutical preparations according to the present invention may be prepared according to a conventional wet granulation process. However, the composition is preferably prepared using an apparatus constructed so as to concurrently dry the alcoholic solution in which the active vitamins D_. and polymer are dissolved while spraying it. The apparatus includes, for example, a fluidized bed type apparatus, a rolling and flowing type apparatus, a centrifugal flowing type apparatus, a vacuum type apparatus. The present invention will be described in detail with reference to the following examples. Example 1 500g of HPMC 2910 (hereinafter referred to as "TC-5R") was subject to stirring granulation using a solution prepared by dissolving 5mg of ST-630, 12.5g of BHT and 125g of PVP-K30 in 187.5g of 90% ethanol and then pulverized after drying, to thereby provide a composition of the present invention. SUBSTITUTESHEET The composition was sealedly put in a glass bottle and stored at 40°C to examine the stability. A variation in residual rate of ST-630 with time was as indicated in Table 1. A composition for reference was prepared by adding 5ml of an ethanol solution containing ST-63 of lQO^μg/ml in concentration to 50g of lactose in a mortar and mixing them, followed by drying. Table 1 Samples Residual Rate of ST-630 (%) Storage Temperature: 40°C One Month Two Months Three Months Present Invention 97 95 98 Reference 64 46 38 Table 1 clearly reveals that in the reference, decomposition of ST-630 occurred rapidly, whereas ST-630 in the composition of the present invention was stabilized for a long period of time. Example 2 500g of TC-5R was subject to stirring granulation using a solution prepared by dissolving 5mg of ST-630, 12.5g of BHT and 125g of TC-5R in 187.5g of 90% ethanol and then pulverized after drying, to thereby provide a composition of the present invention. Example 3 500g of TC-5R was subject to agitating granulation using a solution prepared by dissolving 5mg of ST-630, 12.5g of BHT and 125g of PVP-K30 in 500g of ethanol and then pulverized after drying, to thereby provide a composition of the present invention. 127.5g of the so-obtained composition, 867.5g of mannitol and 200g of hydroxypropyl cellulose having a low degree of substitution were fully mixed together to prepare a mixture and then 450g of purified water was added to the mixture, followed by stirring granulation and pulverization after drying, resulting in a powder for preparation of tablets. Then, 5g of magnesium stearate was added to the powder, which was then formed into tablets of 7mm in diameter and 120mg in weight and containing ST-630 in an amount of about O.lug. Subsequently, the tablets each were sealedly put in a glass bottle and stored at 40°C to examine the stability. A variation in residual rate of ST-630 with time was as indicated in Table 2. Table 2 Sample Residual Rate of ST-630 (%) - " Storage Temperature: 40°C One Month Two Months Three Months Present Invention 100 98 95 Table 2 clearly indicates that in each of the tablets prepared using the composition of the present invention, ' ST-630 was kept stabilized for a long period of time. SUBSTITUTESH

Claims: What is Claimed is: 1. A composition for solid pharmaceutical preparations containing active-type vitamins D 3 , comprising hydroxypropylmethyl cellulose, and an active vitamins D, and a polymer which is readily soluble in an organic solvent each attached to said hydroxypropyl methyl cellulose. 2. A composition as defined in Claim 1, wherein said polymer is selected from the group consisting of polyvinyl pyrrolidone and hydroxypropylmethyl cellulose. 3. A composition as defined in Claim 1 or 2, wherein said active vitamin O- is 26, 26, 26, 27, 27, 27-hexafluoro-l 25-dihydroxycholecalciferol. 4. A process for preparing a composition defined in any one of Claims 1 to 3, wherein an alcoholic solvent is used. 5. A process as defined in Claim 4, wherein said alcoholic solvent comprises ethanol containing 20% or less water.

Inventors: ARIYOSHI MASAHIRO, NOGUCHI GO, OKUMURA SHINYA, ARIYOSHI, MASAHIRO, NOGUCHI, GO, OKUMURA, SHINYA
Applicants: SUMITOMO PHARMA, TAISHO PHARMACEUTICALS CO LTD, SUMITOMO PHARMACEUTICALS CO., LTD., TAISHO PHARMACEUTICALS CO., LTD.
Application year: 1991
Main classification: A61K17
IPC codes: A61K9, A61K31, A61K47