JP2007182386A - Powdery composition - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain a powdery composition of stabilized vitamin B12s and a tablet using the powdery composition. <P>SOLUTION: The powdery composition (composition A) of stabilized vitamin B12s is obtained by further dispersing a composition in which a particle of vitamin Es containing vitamin B12s is in a dispersed state in a starch into calcium silicate. The powdery composition (composition B) is obtained by mixing a solution obtained by dissolving vitamin Es in an alcohol with calcium silicate to give powder, mixing the powder with vitamins except the vitamin B12s, anhydrous calcium hydrogen phosphate, a starch, a binder and water and drying the mixture. The powdery composition (composition C) of stabilized vitamin B12s is obtained by mixing the composition A with the composition B. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a stable granular or powdery vitamin B12-containing powdered composition, and powders, fine granules, granules, capsules, pills or tablets using the composition.

  In general, the amount of vitamin B12 such as mecobalamin blended in a solid preparation such as a pharmaceutical is extremely small. For example, the daily administration or blending amount of cyanocobalamin and hydroxocobalamin is 1-1500 μg, and when blended into a solid preparation, for example, inactive substances such as lactose and starches are used in order to achieve uniform content. It is used as a powdered powder adsorbed on various excipients.

  However, vitamin B12 is generally known to have poor compounding properties with other drugs or additives, and its stability decreases when diluted therein. For example, it is known that vitamin B12 becomes unstable due to the presence of ascorbic acid, nicotinamide, thiamine, talc, sucrose, metal ions, and the like (Non-patent Document 1).

As a method for stabilizing an oral solid preparation containing vitamin B12,
(1) A method of coating fine vitamin B12 with a starch derivative (Patent Document 1),
(2) A method for dispersing vitamin B12 in a mixture of starch and dextrin (Patent Document 2),
(3) After adsorbing a mixed aqueous solution of vitamin B12s and gelatin onto a powder carrier, drying this, and then coating the adsorbate with a coating agent, vitamin B12-containing pharmaceutical particles (Patent Document 3),
(4) Addition of sodium citrate and citric acid as pH adjusters to various additives such as modified food starch and anhydrous silicic acid to stabilize vitamin B12 in the powder. Furthermore, vitamin B12 adsorbed powder added with sodium benzoate and sorbic acid as preservatives,
Etc. exist in the market.

These adsorbent powders are generally produced by spray drying a suspension or solution of an adsorbent and vitamin B12 in water, but shellac and macrogol 6000 are used for further stabilization. The microencapsulation by the emulsion method has been proposed by Gupta et al. (Non-patent Document 2). Also,
(5) A stabilized granular or powder composition of vitamin B12 in which vitamin B12 is dispersed in pregelatinized starch or partially pregelatinized starch (Patent Document 4),
Etc. have been reported.

However, with respect to the above (1) and (2), the method using starch, its derivatives or dextrins was not practical because satisfactory stability could not be obtained.
As for the above (3) and (4), the method using gelatin is stable when vitamin B12 alone is used as a preparation. However, since the ratio of gelatin increases, there is a problem caused by gelatin. In addition, there is a problem in that the stability of a compounded solid preparation with other easily changeable drugs, particularly with other types of vitamins, is lowered. These have complicated manufacturing techniques and leave room for improvement in terms of stability.

  As for the above (5), vitamin B12s are dissolved or suspended in water or an aqueous organic solvent diluted with water, added to pregelatinized starch powder, and mixed so that vitamin B12s are uniformly dispersed. Thereafter, the obtained composition is dried, and vitamin B12 is not diluted with water or water to obtain a uniform dispersed powder. In addition, when water is used, decomposition may occur due to water remaining in the composition. Furthermore, when producing a granular or powdery composition, it can be seen that expensive vitamin B12 adheres to the inner wall of the can body of the mixer, resulting in a low recovery rate, and there is room for improvement.

  In order to blend vitamin B12 into a pharmaceutical or food sugar solid preparation, the use of a stable adsorbent powder as described above for the purpose of separation from other drugs or ensuring the uniformity of the contents, other drugs To form a group, separated from this and other drug groups that impair the stability of vitamin B12, and in the case of tablets, separation or coating with so-called dry tablets or laminated tablets In the case of tablets, it is devised by adding it to the coating layer.

Accordingly, there has been a demand for the development of a stable preparation that is easy to prepare vitamin B12, easy to mix, and does not change its mixing.
Campbell, J. A ,; J. Pharm. Sci.,; 44,263,1955 RG Gupta and BC Rao: Drug Devel. And lnd. Pharm., 11 (1), 41-53 (1985) JP-A-49-108224 JP-A-3-173823 Japanese Patent No. 29987334 Japanese Patent No. 2689458

  In view of the above-mentioned present situation, an object of the present invention is to provide a stable preparation that is easy to be formulated with vitamin B12, easy to mix, and does not change in mixing. More specifically, vitamin B12 coated with tocopherols is a starch and a stabilized powdered composition of vitamin B12 dispersed in calcium silicate, and this powdered composition was used. The purpose is to provide tablets.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors adsorbed a suspension of vitamin B12s and tocopherols on a powder carrier such as pregelatinized starch and calcium silicate, thereby producing vitamins. It has been found that a powdery composition (hereinafter referred to as a powdery composition) in which B12s are stably dispersed in a powder carrier can be obtained, and that this powdery composition can be stably blended with other drugs. The invention has been completed.

That is, the present invention has the following configuration.
(1) A powdery composition stabilized with vitamin B12, wherein a composition in which vitamin E particles containing vitamin B12 are dispersed in starch is further dispersed in calcium silicate (Composition A);
(2) The powdery composition according to 1 above, wherein the total amount of vitamin E and vitamin B12 is in the range of 0.05 to 160 parts by weight with respect to 100 parts by weight of starches;
(3) The powdery composition according to 1 or 2 above, wherein the amount of calcium silicate is in the range of 0.05 to 150 parts by weight with respect to 100 parts by weight of starches;
(3) The powdery composition according to any one of 1 to 3 above, wherein the vitamin B12 is mecobalamin;
(5) One or more kinds selected from vitamins other than the above-mentioned vitamin B12, powdered calcium hydroxide and a solution obtained by mixing vitamin E in alcohols and calcium silicate, anhydrous calcium hydrogen phosphate, starch A powdery composition (composition B) obtained by adding a mixture, binder and water, mixing and drying;
(6) The powder composition according to 5 above, wherein the vitamins excluding the vitamin B12 are fursultiamine hydrochloride and pyridoxine hydrochloride;
(7) The powdery composition as described in 5 above, wherein the amount of vitamin E is 100 to 150 parts by weight per 100 parts by weight of calcium silicate;
(8) A stabilized powdery composition (composition C) of vitamins B12 obtained by mixing the composition A described in 1 and the composition B described in 5 above;
(9) (a) A powdery composition in which vitamin E12 particles containing vitamin B12 are dispersed in starch and further stabilized by vitamin B12 dispersed in calcium silicate And (b) a powder obtained by mixing a solution of vitamin E in an alcohol and calcium silicate, and at least one selected from vitamins other than the vitamin B12, phosphoric anhydride The vitamin B12 of the above-mentioned 8 obtained by mixing calcium hydride, partially pregelatinized starch, polyvinylpyrrolidone and water, mixing and drying a powdery composition (composition B) obtained by drying. A stabilized powdery composition (Composition C);
(10) The powder composition according to 9 above, wherein the vitamins excluding the vitamin B12 are fursultiamine hydrochloride and pyridoxine hydrochloride;
(11) The powdery composition according to the above 1 to 10, wherein the starch is one or more selected from the group consisting of pregelatinized starch and partially pregelatinized starch;
(12) (a) A powdered composition in which vitamin E12 particles containing vitamin B12 are dispersed in starch and further stabilized by vitamin B12 dispersed in calcium silicate And (b) vitamins excluding the above-mentioned vitamin B12 in a powder in which vitamin E obtained by mixing vitamin E with alcohol and calcium silicate is adsorbed on calcium silicate. It is obtained by mixing and tableting a powdered composition obtained by adding one or more kinds selected from anhydrous calcium hydrogen phosphate, partially pregelatinized starch, polyvinylpyrrolidone and water, mixing and drying. Stabilized tablets of vitamin B12s;
(13) The tablet according to 12 above, wherein the vitamins excluding the vitamin B12 are fursultiamine hydrochloride and pyridoxine hydrochloride;
It is.

If the composition containing vitamin B12 and vitamin E (composition A) provided by the present invention is used, a stable vitamin B12 preparation can be provided. Moreover, the stable composite pharmaceutical formulation of this invention can be provided by combining this vitamin B12 containing particle | grain and other pharmaceutical containing particle | grains.
When producing the powdery composition of the present invention (Composition A), there is little adhesion to the inside of the mixer wall, and it is stable by itself, and changes in quality over time such as a decrease in the content of vitamin B12 during storage are extremely high. Few. In addition, when various preparations are produced by blending with other drugs, they are stable and hardly affected by other drugs.

Moreover, since the powdery composition (composition A) of this invention is excellent in the fluidity | liquidity and storage stability of powder, it is easy to prepare and is excellent in the compoundability with other agents. Therefore, the powdery composition of the present invention can be directly blended with pharmaceuticals and foods as a powdered powder.
Furthermore, the powdered composition of the present invention is prepared by uniformly mixing other drugs having a medicinal effect, and then mixing the mixture according to a conventional method, for example, tablets, capsules, powders, granules, fine granules, dry syrups, etc. It can be formulated into a dosage form suitable for oral administration.

  Examples of the vitamin B12 used for the preparation of the powdery composition of the present invention (composition A) include cyanocobalamin, hydroxocobalamin, methylcobalamin (mecobalamin) and the like, and organic salts thereof such as hydroxocobalamin acetate or inorganic salts. Examples thereof include hydroxocobalamin hydrochloride.

  As vitamin E, eight types of tocopherol homologues (α, β, γ, δ) and four tocotrienol homologues (α, β, γ, δ) are known. As what is used in this invention, what becomes liquid or oily at a comparatively low temperature range temperature (30-50 degreeC) is preferable, More preferably, it is a semi-solid state when it returns to room temperature (1-30 degreeC) Examples thereof include d-α-tocopherol acetate. Tocotrienol contains at least one tocotrienol such as α-, β-, γ-, and δ-tocotrienol as a component. These may be isomers of d-, l-, and dl types, and the composition ratio of each isomer is not particularly limited, and may be a synthetic or naturally derived product.

  As the carrier used in the composition A, any carrier that can adsorb a vitamin E suspension of vitamin B12 can be used without particular limitation, but preferably crystalline cellulose, corn starch, d-mannitol, Examples thereof include lactose, anhydrous calcium hydrogen phosphate, pregelatinized starch, partially pregelatinized starch, dextrin, light anhydrous silicic acid, and calcium silicate.

  The pregelatinized starch is, for example, a variety of starches such as corn starch, potato starch, wheat starch, rice starch, tapioca starch, etc. Examples include starch or partially pregelatinized starch.

  The particle size of these pregelatinized starches is not particularly limited, but a powder having an average particle size of usually 1000 μm or less, preferably 5 to 700 μm, more preferably 5 to 500 μm is used.

  Drying of the powdery composition (composition A) of the present invention is not particularly required. If necessary, it varies depending on the model used for drying and is not particularly limited. However, in consideration of the characteristics of vitamin B12, it is preferably performed at a temperature as low as possible up to about 50 ° C., for example.

  The particle size of the powdery composition is not particularly limited, but in consideration of handling in the next step, the particle size is sized so that the particle size is 1000 μm or less, preferably 10 to 700 μm, more preferably about 20 to 700 μm. Is good.

  If necessary, the particles of the powdery composition (composition A) can be further coated with a coating agent according to a conventional method. Examples of the coating agent include saccharides, gelatin, and hydroxypropylmethylcellulose. This granulation coating is performed by, for example, a method of spraying and coating the powdery composition of the present invention (composition A) according to a conventional method, for example, a solution in which a coating agent is dissolved.

  The coating layer on the particles may be about 10 to 50 μm. The resulting coated particles can be made into a vitamin B12 preparation by themselves, but can also be made into a solid oral combined pharmaceutical preparation by combining it with particles containing other drugs.

  The composition may be coated using 0.1 to 10% by weight waxes based on the total composition.

  Examples of waxes include carnauba wax, white beeswax, paraffin, and macrogol.

  The powdery composition (composition A) containing vitamin B12 of the present invention can be blended with other drug particles as it is. For example, particles of various vitamins that have medicinal effects due to redox action in the body, and generally include drugs that are easily changed, for example, drugs that are decomposed or altered by oxidation / reduction actions. it can.

  Vitamin B12s in the powdery composition (composition A) of the present invention can exist stably. Reasons for stability include the absence of water in the preparation of Composition A, and vitamin B12, such as vitamin E, which easily liquefies the surface of mecobalamin at 40-50 ° C., for example, acetic acid d -Α-tocopherols coat the surface of the particles of vitamin B12, so that the formulated vitamin B12 is kept stable without being directly exposed to the outside, and the carrier powder adheres to the coated particles. It is thought that it is further stabilized by adsorption. Furthermore, since mecobalamin, which is hygroscopic and changes with light, does not come into direct contact with the drug components contained in other drug particles, there is no interaction between drugs, so it can be stored stably as a combined drug. It is considered possible.

  The blending ratio of vitamin B12 and vitamin E used in the powdery composition of the present invention (composition A) is not particularly problematic even if vitamin E is excessive. For example, vitamin B12 is mecobalamin. In this case, it is 10 to 400 parts by weight, preferably 100 to 300 parts by weight, of d-α-tocopherol acetate with respect to 100 parts by weight of mecobalamin.

  The total amount of vitamin B12 and vitamin E that can be dispersed in the powdery composition A of the present invention is usually in the range of 0.05 to 200 parts by weight with respect to 100 parts by weight of starch. Preferably, it is in the range of 0.05 to 180 parts by weight, more preferably in the range of 0.05 to 160 parts by weight. If it is 0.05 parts by weight or less, there is a disadvantage that the amount of the composition is very large when mixed with other drugs. On the other hand, when it exceeds 200 parts by weight, there is a possibility that uniform dispersion of the powdery composition may not be sufficient.

  The compounding amount of calcium silicate is 0.05 to 300 parts by weight, preferably 0.05 to 200 parts by weight, more preferably 0.05 to 150 parts by weight with respect to 100 parts by weight of starches. .

The powdery composition (composition A) of the present invention can be prepared using the following method.
A stabilized powdery composition of Vitamin B12 (Composition A) by dispersing a composition in which Vitamin E particles containing Vitamin B12 are dispersed in starches and further in calcium silicate. Can be prepared.
More specifically, vitamin E12, for example, mecobalamin, is stirred in a container in which vitamin E, for example, d-α-tocopherol acetate is heated, preferably in the range of 40-50 ° C. Add and stir until the mecobalamin is uniformly dispersed to obtain a suspension. Then, the suspension obtained by the above-mentioned production method is adsorbed on a powdery carrier, for example, starch, preferably α-starch, with stirring, and further, the powdery carrier (for example, silicic acid, for example) is stirred. It can be obtained by adding calcium. The obtained powdery composition can be sized by sieving with a sieve according to a conventional method. The obtained powder is usually kept airtight under light shielding.

  A method of adding a suspension of vitamin B12 suspended in warmed vitamin E to a powdered carrier, for example, starch powder, and mixing is not particularly limited. You may mix until it mixes well using powder mixers, such as kneading, a ball mill type, and a hammer mill type, or a mortar. In addition, when using pregelatinized starch, it can be prepared by adding a suspension of vitamin B12 and vitamin E as they are in the process line for pregelatinizing starch and mixing well with pregelatinized starch. it can.

  After mixing the suspension so that it is homogeneously dispersed in the powdered carrier material, the resulting composition is dried if necessary.

  By mixing or granulating, the suspension of vitamin B12 coated with vitamin E is uniformly dispersed in the carrier powder substance and adhered or adsorbed on the carrier powder.

  In the production of the powdery composition of the present invention (composition A), additives usually used, such as lactose, sucrose, d-, in an amount that does not impair the stability of vitamins B12 and tocopherols. Excipients such as mannitol, erythritol, xylitol, dextrin, crystalline cellulose, anhydrous calcium hydrogen phosphate, precipitated calcium carbonate, binders such as gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, pullulan, propylene oxide-ethylene oxide copolymer, Lubricants such as polyethylene glycol, colorants such as tar pigments, caramels and bengara, hiding agents such as titanium oxide, and sweeteners may be incorporated into the composition.

  In addition, the above powdery composition (composition A) of the present invention is stable vitamin B12 by sieving or granulated granules as they are or by mixing with other drug particles (composition B) and tableting. -Containing pharmaceutical tablets can be prepared.

  The above-mentioned pharmaceutical tablet is obtained by mixing the powdery composition of the present invention (Composition A) and particles containing other drugs at a necessary ratio and tableting according to a conventional method. More specifically, it can be mixed with other drug particles obtained by the preparation method described later, and itself can be produced in accordance with a conventional method, and further, a film-coated tablet and a sugar-coated tablet can be prepared using this uncoated tablet.

These details are described below.
(A) Manufacturing method of uncoated tablet Uncoated tablet was manufactured with the method described below.
(A) A stabilized powder of vitamin B12, characterized in that a powdered composition in which vitamin E particles containing vitamin B12 are dispersed in starches is further dispersed in calcium silicate A composition (Composition A);
(B) One or more kinds selected from vitamins other than the vitamin B12, an anhydrous calcium hydrogen phosphate, a part obtained by mixing a solution obtained by dissolving vitamin E in alcohols with calcium silicate Powdered composition obtained by adding at least one selected from the group consisting of pregelatinized starch and polyvinylpyrrolidone and water, mixing, and drying [hereinafter, vitamin-containing granulated product (composition B)],
Were mixed and tableted to obtain tablets stabilized with vitamin B12.
Upon mixing, if necessary, anhydrous calcium hydrogen phosphate was further added and further mixed to obtain a mixed powder.
The drying of the mixed powder varies depending on the model used for drying and is not particularly limited. However, considering the characteristics of vitamin B12, it is preferable to perform drying at as low a temperature as possible, for example, up to about 50 ° C.

  Examples of the vitamins excluding the vitamin B12 include, for example, fat-soluble vitamins or water-soluble vitamins which are naturally derived or synthetic products, and ester derivatives or salts thereof, and vitamin A (retinol). , Retinol palmitate, etc.), vitamin B1 (thiamine, thiamine nitrate, thiamine hydrochloride, cocarboxylase, octothiamine, dicetiamine hydrochloride, thiamine disulfide, bisibutiamine, bisbenchamine, fursultiamine hydrochloride, fursultiamine hydrochloride , Prosultiamine, benfotiamine), vitamin B2 (riboflavin, sodium riboflavin phosphate, riboflavin butyrate, sodium flavin adenine dinucleotide, etc.), vitamin B6 (pyridoxal hydrochloride, pyridoxal calcium phosphate) Pyridoxal phosphate, etc.), pantothenic acids (calcium pantothenate, panthenol, pantethine, etc.), folic acids (proteyl glutamic acid), vitamins H (biotin), nicotinic acids (niacin), vitamins C (ascorbic acid), vitamins D (calciferol, alphacalcidol, calcitriol, fareccalcitol, maxacalcitol, etc.), vitamin K (phylloquinone, phytonadione, menatetrenone, etc.) and the like. One or more of these vitamins can be used in combination.

(B) Manufacturing method of film-coated tablet A water / ethanol solution (50:42) coating solution 1 of hydroxypropylmethylcellulose 2208 was prepared, and the above preparation method was used using a high coater [HCT-30, manufactured by Freund Corporation]. The obtained uncoated tablet was coated with the coating liquid 1 to obtain a film-coated tablet.

(C) Method for producing sugar-coated tablets An aqueous solution (hereinafter referred to as coating solution 2) of sucrose, talc, precipitated calcium carbonate, titanium oxide and hydroxypropylmethylcellulose 2208 was prepared. According to a conventional method, for example, using a coating pan, the film tablet obtained by the above production method was coated with the coating liquid 2. Next, using a coating pan, the sugar-coated tablet 1 was coated with a white sugar aqueous solution. By coating this sugar-coated tablet 2 with carnauba wax, the intended sugar-coated tablet can be obtained.

  The production method itself of the uncoated tablet, film-coated tablet, sugar-coated tablet, etc. of the present invention can be carried out according to a known method, and the above-mentioned excipients, binders, lubricants, coating agents, brighteners and the like are appropriately used. Can be used.

EXAMPLES Hereinafter, although an Example is given and this invention is demonstrated in more detail, this invention is not restrict | limited at all by these Examples.
In addition, the quantitative operation of vitamin B12 was performed using a light-shielded container avoiding direct sunlight.
The content of vitamin B12 was measured by high performance liquid chromatography, and a visible spectrophotometer (measurement wavelength: 266 nm) was used as a detector.
The sieve mesh used in the present invention is in accordance with Japanese Industrial Standard (JIS).

Example 1: Production method of adsorbed powder Mecobalamin [Eisai Co., Ltd.] was prepared by heating 6.21 g of d-α-tocopherol acetate (manufactured by Riken Vitamin Co., Ltd.) in a beaker at 40 to 50 ° C. in a beaker. ) Made] 4.78 g was added with stirring and stirred with a spatula until the mecobalamin was uniformly dispersed to obtain a deep red suspension. Next, 6.16 g of pregelatinized starch (manufactured by Asahi Kasei Chemicals Co., Ltd .; grade) was placed in a mortar, and the suspension obtained by the above production method was adsorbed while stirring. Furthermore, pink powder was obtained by adding 8.40 g of calcium silicate [FLORITE RE, Eisai Co., Ltd.] while stirring. This powder was sieved using an 83 mesh sieve. The powder adhering to the mortar and the sieve was added with 2.70 g of the above fluorite RE and washed together to obtain 27.7 g of a pink powder (recovery rate 98.1%).
The obtained powder was stored in a light-tight and airtight manner.

Example 2: Preparation of vitamin-containing granulated product 263.8 g of d-α-tocopherol acetate (manufactured by Riken Vitamin Co., Ltd.) was diluted with ethanol to prepare a 66 wt% solution, and this solution and the above-mentioned Florite RE189. 0 g was adsorbed and powdered by stirring at high speed using a high speed mixer [FS-GS-25, manufactured by Freund Sangyo Co., Ltd.]. Furthermore, 81.08 g of fursultiamine hydrochloride [manufactured by Kongo Chemical Co., Ltd.], 141.8 g of pyridoxine hydrochloride [manufactured by Daiichi Fine Chemical Co., Ltd.], 205.74 g of Fujicalin SG [manufactured by Fuji Chemical Industry Co., Ltd.], partial alpha A conventional stirring granulation method using purified water and 390.88 g of modified starch [Asahi Kasei Chemicals Corporation] and 64.80 g of polyvinylpyrrolidone [PVP-K30, manufactured by BASF Japan Ltd.] using purified water. A wet powder was obtained. The powder was sieved with a sieve and dried with a flow coater [FLO-5, manufactured by Freund Sangyo Co., Ltd.] to obtain 1268 g of a vitamin-containing granulated product.

Example 3: Preparation of uncoated tablet The powder obtained in Example 1 after stirring 23.04 g of the above-mentioned florite RE for 5 minutes with a Boule container mixer [LM-20 type (MC5), manufactured by Kotobuki Giken Co., Ltd.] The composition and talc (manufactured by Hayashi Kasei Co., Ltd.) 28.16 g were added and further mixed for 10 minutes. Next, 1268 g (d-α-tocopherol acetate, pyridoxine hydrochloride, fursultiamine acetate) of vitamin-containing granulated product obtained by the preparation method of Example 2 and anhydrous calcium hydrogen phosphate [trade name, Fujicalin SG, Fuji Chemical Co., Ltd. ) 36.72 g was added and mixed for another 30 minutes to obtain a mixed powder. The mixed powder obtained by the above production method was tableted (P-22, manufactured by Hata Iron Works Co., Ltd.) according to a conventional method to obtain an uncoated tablet (diameter 8.1 mm, thickness 4.0 mm).

Example 4: Preparation of film-coated tablet Hydroxypropyl methylcellulose 2208 (manufactured by Shin-Etsu Chemical Co., Ltd.) Water / ethanol solution (50:42) coating solution 1 was prepared. Using a high coater [HCT-30, manufactured by Freund Corporation], the uncoated tablet obtained in Example 2 was coated with the coating solution 1. The coating amount was finished when the tablet weight increased by 5.56% to obtain a film tablet.

Example 5: Preparation of sugar-coated tablets Sucrose (Nisshin Seika Co., Ltd.) 66.92%, Talc 15.38%, Precipitated calcium carbonate (Bihoku Flour Industry Co., Ltd.) 7.69%, Titanium oxide [( Co., Ltd. Freund Sangyo Co., Ltd.] 7.69% and hydroxypropylmethylcellulose 2208 [SB-4, Shin-Etsu Chemical Co., Ltd.] 2.31% aqueous solution (hereinafter referred to as coating solution 2) was prepared. The film tablet obtained in Example 3 was coated with the coating solution 2 using a coating pan (manufactured by Universal Prototype Machine, manufactured by Hata Iron Works Co., Ltd.). The coating amount was finished when the tablet weight increased by 68.42%, and white round dragees 1 were obtained.
Using a coating pan, the sugar-coated tablet 1 was coated with a sucrose aqueous solution according to a conventional method. The coating amount was finished when the tablet weight increased by 6.25%, and dragee 2 was obtained.
Carnauba wax (manufactured by Kongo Chemical Co., Ltd.) was applied to the sugar-coated tablet 2 by 0.07% with respect to the weight of the sugar-coated tablet 2 to obtain the intended sugar-coated tablet (diameter 9.3 mm, thickness 5.3 mm).

Test Example 1: Variation in mecobalamin content in tablets Tableting of the powder composition obtained in the formulations of Example 1, Comparative Example 1 and Comparative Example 2 For each 10 tablets, the content uniformity was cv. Evaluated by value.

Content Test Tablets were prepared using the powder produced in each of the above Examples, and the average content (%) of mecobalamin in each 10 tablets was quantified, and the uniformity was compared.
As a result, in the tablet obtained by blending (a) mecobalamin + vitamin E + florite + pregelatinized starch, vitamin E-containing granulated product and calcium phosphate obtained in Example 5, the mixture had an average content of mecobalamin in 10 tablets each. 105%, and a formulation that does not use starches, for example, (b) 10 tablets each of tablets containing a mixture of mecobalamin + vitamin E (warmed and dissolved) + fluorite blended with vitamin E granulated product The average content of mecobalamin was 104.5%. (C) Mecobalamin + Vitamin E (use as it is without heating) + tablets blended with fluorite and vitamin E granulated product, the average content of mecobalamin in each 10 tablets is 98.8%, (a ) Was found to have the least amount of adhesion.

On the other hand, when mecobalamin and vitamin E are not used in combination, for example, in the combination of (d) mecobalamin + talc and vitamin E granulated product, the average content of mecobalamin in each 10 tablets is 82.5% In addition, (e) the average content of mecobalamin in each 10 tablets in the combination of a composition using talc for pre-adhesion, Fujicalin for coarse mixing, and fluorite for trituration and a vitamin E granulated product In this case, the average content was 86.4%, and the adsorption rate to the inner wall of the tube was high.
As a result, it was found that the composition A of the present invention hardly adheres to the inside of the mixer can.

  Regarding the variation of mecobalamin in the composition, when calcium silicate and pregelatinized starch were added, the variation was reduced by about 20% compared to the addition of calcium silicate alone.

Test Example 2: Stability of tablets Using the sugar-coated tablets obtained in Example 5 and commercially available tablets, the stability of d-α-tocopherol acetate, fursultiamine hydrochloride, pyridoxine hydrochloride and mecobalamin in the tablets was compared. did.

Test method of subject Accelerated test (40 ° C / 75% RH) 6 months, open test (25 ° C / 75%: glass bottle open) 6 months, long-term storage test (25 ° C / 60% RH) 6 months storage The stability was compared by the residual ratio.

  In the accelerated test specimen (40 ° C./75% RH) for 6 months, no significant difference was observed for d-α-tocopherol acetate, fursultiamine hydrochloride, pyridoxine hydrochloride, and mecobalamin in the tablet of the present invention and the commercially available tablet. I couldn't. In addition, in the open test (25 ° C./75%: glass bottle open) for 6 months, there was no significant difference between d-α-tocopherol acetate, fursultiamine hydrochloride and pyridoxine hydrochloride in the tablet of the present invention and the commercially available tablet. I couldn't. Regarding mecobalamin, the residual rate of mecobalamin after 6 months of the tablet of the present invention was 96.9%, whereas the residual rate of the commercial product was 47.3%.

From the above results, it was found that the stability of the tablet of the present invention was very good.
Moreover, there was no problem about the disintegration property of the tablet of this invention.

As described above, according to the present invention, it is easy to prepare vitamin B12, easy to mix, and provides a stable preparation that does not change its formulation, and has great medical value.

Claims (13)

  Vitamin B12-containing powdered composition (composition) characterized in that vitamin E12 particles containing vitamin B12 are dispersed in starch and further dispersed in calcium silicate A).   The powdery composition according to claim 1, wherein the total amount of vitamin E and vitamin B12 is in the range of 0.05 to 160 parts by weight with respect to 100 parts by weight of starch.   The powdered composition according to claim 1 or 2, wherein the amount of calcium silicate is in the range of 0.05 to 150 parts by weight with respect to 100 parts by weight of starches.   The powdery composition according to any one of claims 1 to 3, wherein the vitamin B12 is mecobalamin.   One or more selected from vitamins other than the above-mentioned vitamin B12, anhydrous calcium hydrogenphosphate, starches, and binding to powder obtained by mixing a solution obtained by dissolving vitamin E in alcohol and calcium silicate A powdery composition (Composition B) obtained by adding an agent and water, mixing and drying.   The powder composition according to claim 5, wherein the vitamins excluding the vitamin B12 are fursultiamine hydrochloride and pyridoxine hydrochloride.   The powdery composition according to claim 5, wherein the amount of vitamin E is in the range of 100 to 150 parts by weight with respect to 100 parts by weight of calcium silicate.   A stabilized powder composition of Vitamin B12 obtained by mixing the composition A according to claim 1 and the composition B according to claim 5 (composition C). (A) a powdered composition in which vitamin E12 particles containing vitamin B12 are dispersed in starches, and a powdered composition in which vitamin B12 dispersed in calcium silicate is further stabilized;
(B) at least one selected from vitamins excluding the vitamin B12, an anhydrous calcium hydrogen phosphate, in a powder obtained by mixing a solution obtained by dissolving vitamin E in alcohols and calcium silicate; A powdered composition (composition B) obtained by adding partially pregelatinized starch, polyvinylpyrrolidone and water, mixing and drying;
A stabilized powdery composition (composition C) of vitamin B12 according to claim 8, obtained by mixing.   The powder composition according to claim 9, wherein the vitamins excluding the vitamin B12 are fursultiamine hydrochloride and pyridoxine hydrochloride.   The powdered composition according to any one of claims 1 to 10, wherein the starch is at least one selected from the group consisting of pregelatinized starch and partially pregelatinized starch. (A) a powdered composition in which vitamin E12 particles containing vitamin B12 are dispersed in starches, and a powdered composition in which vitamin B12 dispersed in calcium silicate is further stabilized;
(B) Vitamin E obtained by mixing a solution prepared by dissolving vitamin E in alcohols and calcium silicate is selected from vitamins other than the above-mentioned vitamin B12 in powder adsorbed on calcium silicate. Vitamin B12s obtained by adding one or more kinds, anhydrous calcium hydrogen phosphate, partially pregelatinized starch, polyvinylpyrrolidone and water, mixing and drying the powdered composition, and tableting Stabilized tablets. The tablet according to claim 12, wherein the vitamins excluding vitamin B12 are fursultiamine hydrochloride and pyridoxine hydrochloride.