JP5524130B2 - Stabilized vitamin preparation - Google Patents

Description

The present invention, fursultiamine hydrochloride, vitamin B ₆ such, and calcium pantothenate in the vitamin formulation of solids containing vitamin B ₁₂ acids and calcium pantothenate, relates to both stabilize and vitamin B ₁₂ compound.

It is known that calcium pantothenate has poor compoundability with ascorbic acid and its stability is lowered. It is also unstable to moisture. For this reason, in a preparation containing ascorbic acid or a salt thereof and calcium pantothenate, a method of stabilizing by using a calcium pantothenate-containing composition and reducing the water content is known (Patent Documents 1 and 2). .
On the other hand, vitamin B ₁₂ is unstable to moisture and is known to be unstable when it is combined with vitamin B ₆ and several methods for stabilizing vitamin B ₁₂ have been proposed (Patent Documents 3 to 3). 6).
However, these are unstable and fursultiamine hydrochloride, vitamin B ₆ such, and vitamin B ₁₂ compound, blended with calcium pantothenate, low moisture reduction calcium pantothenate in the formulation and vitamin B ₁₂ compound There is no clarification regarding the conversion, and there is no disclosure or suggestion of a solution.
Japanese Patent No. 2891744 JP 2003-128543 A JP 2000-16940 A JP-A-9-124480 Japanese Patent No. 2916227 Japanese Patent No. 2689458

The solid object of the present invention, fursultiamine hydrochloride, vitamin B ₆ such, a vitamin formulation solids containing vitamin B ₁₂ acids and calcium pantothenate, calcium pantothenate and vitamin B ₁₂ compounds are both stabilized It is to provide a formulation.

The present inventors have made intensive studies in order to achieve the above object, fursultiamine hydrochloride, vitamin B ₆ such, in the solid preparation containing vitamin B ₁₂ acids and calcium pantothenate, calcium pantothenate-containing composition By blending with a granule obtained by spraying and drying a solution obtained by dissolving or dispersing vitamin B ₁₂ in water in a drug and / or excipient other than calcium pantothenate, If, it found that vitamin B ₁₂ compound can both stabilize, and have completed the present invention.

That is, the present invention
(1) and fursultiamine hydrochloride, vitamin B ₆ such, and vitamin B ₁₂ compound, a solid preparation containing the calcium pantothenate, calcium pantothenate, calcium pantothenate, it to itself not neutral A solid preparation characterized by containing a basic magnesium or calcium lactate or carbonate in the presence of water and / or a lower alcohol and then drying the mixture. ,
(2) The solid preparation according to (1) above, containing vitamin B ₁₂ as a granule obtained by spraying and drying an aqueous solution or aqueous dispersion thereof on a drug and / or excipient other than calcium pantothenate,
(3) The solid preparation according to (1), which is coated,
(4) By mixing calcium pantothenate with a neutral or basic magnesium or calcium lactate or carbonate in the presence of water and / or a lower alcohol, and then drying the mixture. The composition obtained is blended in a dry manner with granules obtained by spraying and drying an aqueous solution or aqueous dispersion of vitamin B ₁₂ to drugs and / or excipients other than calcium pantothenate. And (5) calcium pantothenate and neutral or basic magnesium or calcium lactate or carbonate, water and / or lower alcohol a composition obtained by mixing in the presence of, and then drying the mixture, vitamin B ₁₂ compound, an aqueous solution thereof or Spraying the dispersion in drug and / or excipients other than calcium pantothenate, and grain obtained by drying and fursultiamine hydrochloride, characterized by mixing a dry and a vitamin B _6, vitamin B _{The present} invention provides a method for stabilizing both vitamin B ₁₂ and calcium pantothenate in a solid preparation containing ₁₂ and calcium pantothenate.

According to the present invention, by using calcium pantothenate in the form of a calcium pantothenate-containing composition and vitamin B ₁₂ in a predetermined dry granular form, fursultiamine hydrochloride, vitamin B ₆ and vitamin B _{12 are used.} a vitamin preparations of solid containing class and calcium pantothenate can provide a solid preparation calcium pantothenate and vitamin B ₁₂ compounds are both stabilized.

Fursultiamine hydrochloride used in the present invention, vitamin B _6, vitamin B ₁₂ acids and calcium pantothenate may be those commonly used in vitamin preparations, similarly if its amount is also not limited particularly, definitive normal vitamin preparations Various amounts can be used.
For example, vitamin B ₆ such that can be incorporated in the present invention, pyridoxine hydrochloride, pyridoxal phosphate and the like. The vitamin B ₁₂ compound, cyanocobalamin, hydrochloric hydroxocobalamin acetate hydroxocobalamin include mecobalamin.

  The calcium pantothenate-containing composition used in the present invention is described in the above-mentioned Japanese Patent No. 2891744 and can be produced according to the method described in the specification. Can be obtained by mixing neutral or basic magnesium or calcium lactate or carbonate in the presence of water and / or lower alcohol, and then drying the mixture. Preferably, the composition is obtained by mixing calcium pantothenate and calcium lactate in the presence of water, and then drying the mixture. The composition is also available as a commercial product (trade name: calcium pantothenate type S, BASF Takeda vitamin).

In the present invention, vitamins other than the above, for example, vitamin B ₂ (riboflavin, riboflavin phosphate, riboflavin butyrate, etc.), vitamin E (dl-α-tocopherol calcium succinate, succinate d) are used as necessary. -Α-tocopherol, acetic acid d-α-tocopherol, etc.), nicotinic acid, nicotinamide, gamma-oryzanol, orotic acid, glucuronolactone, glucuronic acid amide, yocuinine, hesperidin, biotin, vitamin C (ascorbic acid, ascorbic acid) Calcium, sodium ascorbate, etc.), L-cysteine, sodium chondroitin sulfate, etc. may be blended.

In the present invention, as the drug for spraying an aqueous solution or dispersion of vitamin B ₁₂ compound, fursultiamine hydrochloride, vitamin B ₆ compound (pyridoxine hydrochloride, pyridoxal phosphate), vitamin B ₂ compounds (riboflavin, riboflavin phosphate, Riboflavin butyrate), vitamin E (dl-α-tocopherol calcium succinate, d-α-tocopherol succinate, d-α-tocopherol acetate, etc.), nicotinic acid, nicotinamide, gamma-oryzanol, orotic acid, glucurono Examples thereof include lactone, glucuronic acid amide, yocuinine, hesperidin, biotin, vitamin Cs (ascorbic acid, calcium ascorbate, sodium ascorbate, etc.), L-cysteine, sodium chondroitin sulfate and the like. Particularly preferred are fursultiamine hydrochloride and sodium chondroitin sulfate.
In the present invention, excipients spraying an aqueous solution or dispersion of vitamin B ₁₂ compound, partially α-starch, corn starch, wheat starch, rice starch, potato starch, crystalline cellulose, powdered cellulose, low substituted hydroxypropylcellulose Cellulose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethyl ethyl cellulose, carmellose, lactose, mannitol, erythritol, powdered reduced maltose water candy, maltitol, xylitol, sorbitol, trehatose, glucose, glucosamine hydrochloride, talc, sedimentation Examples thereof include calcium carbonate, calcium hydrogen phosphate, and anhydrous calcium hydrogen phosphate. Particularly preferred are partially pregelatinized starch, crystalline cellulose, and powdered reduced maltose water candy.
In the present invention, the aqueous solution or dispersion of vitamin B ₁₂ compounds, as binder, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, hydroxyethyl cellulose, pullulan, gum arabic powder, dextrin, polyvinyl pyrrolidone, polyvinyl alcohol, copolyvidone, etc. May be dissolved or suspended.

In the present invention, vitamin B ₁₂ is a granule obtained by spraying and drying an aqueous solution or aqueous dispersion of an appropriate concentration of such vitamin B _{12 on} a drug and / or excipient according to a conventional method. Included in solid formulation.
Such particles may be coated by a conventional method using a coating agent. Examples of the coating agent include hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, pullulan, gum arabic powder, polyvinylpyrrolidone, polyvinyl alcohol, copolyvidone, polyvinyl acetal diethylaminoacetate, methacrylic acid copolymer L, methacrylic acid copolymer LD. , Methacrylic acid copolymer S, aminoalkyl methacrylate copolymer E, aminoalkyl methacrylate copolymer RS, macrogol 6000, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, and the like.

  The solid preparation of the present invention can be made into dosage forms such as granules, fine granules, uncoated tablets, film tablets, thin-layer sugar-coated tablets, sugar-coated tablets, and chewable tablets. You may make it contain the component normally used for a formulation.

The solid preparation of the present invention includes, for example, a granulation handbook (edited by Japan Powder Industrial Technology Association, Ohm Co., Ltd.), a prescription design for an orally administered preparation (Professor Mitsuru Hashida, Graduate School of Pharmaceutical Sciences, Kyoto University), powder It can be produced by a general method described in publications such as body compression molding technology (powder engineering / preparation and particle design division, edited by Nikkan Kogyo Shimbun).
Particularly, in the present invention, it is preferred to blend the above calcium pantothenate-containing composition, a particle of vitamin B ₁₂ compound in dry. This can be carried out, for example, by granulating vitamin B ₁₂ grains and then mixing the obtained sized powder with a calcium pantothenate-containing composition. Then, the mixture may be made into a solid preparation while still in a dry state.

Furthermore, since fursultiamine hydrochloride has an unpleasant odor and taste, in the present invention, it is preferable to coat a solid preparation for masking, thereby obtaining a solid preparation excellent in dosing. The coating in the present invention includes film coating, sugar coating and the like, and is not particularly limited. However, it is preferable to apply a thin layer sugar coating (Japanese Patent Laid-Open No. 2002-179559) invented by the present inventors. There is no restriction | limiting in particular in the saccharide | sugar, excipient | filler, and binder which are used for thin layer sugar coating. As the thin layer sugar coating, it is preferable to apply three layers of undercoating (UC), build-up coating (BC), and syrup coating (SC). As UC, water-soluble polymers such as hydroxypropylmethylcellulose, excipients such as talc, etc., and as BC, carbohydrates such as erythritol, talc, excipients such as precipitated calcium carbonate, arabi rubber powder, crystalline cellulose As the SC, a binder such as erythritol and a coloring agent such as riboflavin are preferably added as SC. At this time, other sugars such as sucrose (purified sucrose, sucrose), trehalose, maltitol, powdered reduced maltose syrup, mannitol, sorbitol, xylitol, lactose and the like may be combined with erythritol.
The present invention will be described in more detail with reference to the following examples, but the present invention is not limited thereto.

Fluidized bed granulator (FD-) prepared by dissolving 1142 g of fursultiamine hydrochloride, 118.8 g of riboflavin, 200 g of pyridoxine hydrochloride, 1950 g of lactose, 439.2 g of corn starch and 170 g of hydroxypropylcellulose (HPC-L) in 2660 g of purified water. 5S, Paulek) and granulated. The obtained granulated powder was sized with a sizing machine (Power Mill, Showa Mechanics) to obtain a sized powder. An aqueous solution in which 1.921 g of cyanocobalamin was dissolved in 708 g of purified water in 1797 g of partially pregelatinized starch and 1.079 g of corn starch was sprayed with a fluidized bed granulator (FD-5S, Paulek) to obtain a cyanocobalamin adsorption powder. Subsequently, an aqueous solution in which 180 g of hydroxypropylmethylcellulose (TC-5MW) was dissolved in 1320 g of purified water was sprayed with a fluidized bed granulator (FD-5S, Powrec) to obtain cyanocobalamin coated granules. The obtained coated particles were sized using a sizing machine (Power Mill, Showa Chemical Machinery).
3216g of sized powder, 528g of sized cyanocobalamin coated particles, calcium pantothenate type S189.4g, 240g of crystalline cellulose (Asahi Kasei PH101), 125g of corn starch, 21.6g of magnesium stearate (tumbler mixer (15L)), Mixed by Showa Chemical Machinery Co., Ltd.) to obtain a mixed powder. The resulting mixed powder was mixed with a rotary tableting machine (collect 12HUK, Kikusui Seisakusho) using a pestle having a diameter of 8 mm, a radius of curvature of 9 mm, and a radius of 2 mm, and a weight of 180 mg and a thickness of 3.90 mm. I got a tablet.
3240 g of the obtained uncoated tablet is charged into a coating machine (Dria Coater DRC-500, Paulek), and 108 g of hydroxypropylmethylcellulose (TC-5MW) and 12 g of talc are dissolved and suspended in 1080 g of purified water. Spraying and coating 4 mg per tablet gave undercoating (UC) tablets. Subsequently, 1003 g of erythritol, 189.2 g of talc, 340.6 g of precipitated calcium carbonate, 37.85 g of titanium oxide, 94.62 g of crystalline cellulose (Avicel PH-F20), 227.1 g of gum arabic powder, and 2839 g of purified gum powder were added to UC tablets. The coating solution dissolved and suspended in was sprayed, and 76 mg per tablet was coated to obtain build-up coating (BC) tablets. Subsequently, a BC tablet was coated with 20 mg per tablet using a coating solution in which 418.8 g of purified white sugar, 179.5 g of erythritol and 1.707 g of riboflavin were dissolved and suspended in 300.9 g of purified water, and syrup coating (SC ) I got a tablet. A glaze solution in which carnauba wax, shellac pearl, castor oil, ethanol, and n-hexane were dissolved in SC tablets was poured and dried to obtain a glaze thin-layer sugar-coated tablet.

An aqueous solution prepared by dissolving 28 g of fursultiamine hydrochloride and 714.5 g of crystalline cellulose (Asahi Kasei PH101) in 40 g of cyanocobalamin in 3000 g of purified water was sprayed with a fluidized bed granulator (FD-5S, Powrec). Thereafter, an aqueous solution in which 112.5 g of HPC-L was dissolved in 1763 g of purified water was sprayed and granulated with a fluidized bed granulator (FD-5S, Powrec). The obtained granulated powder was sized with a sizing machine (Power Mill, Showa Mechanics) to obtain a T group sized powder. Dissolve HPC-L203g in purified water 3181g in 1544g succinic acid dl-α-tocopherol calcium 1544g, pyridoxine hydrochloride 1400g, gamma-oryzanol 143.1g, light anhydrous silicic acid (Silysia 320) 216.3g, crystalline cellulose (Asahi Kasei KG802) 554g The aqueous solution was sprayed and granulated with a fluidized bed granulator (FD-5S, Powrec). The obtained granulated powder was sized using a sizing machine (Power Mill, Showa Chemical Machinery) to obtain Group E sized powder.
Group T sized powder 1800 g, Group E sized powder 3480 g, calcium pantothenate type S562.7 g, light anhydrous silicic acid (Silysia 320) 66.6 g, crystalline cellulose (Asahi Kasei KG802) 354.7 g, L-HPC (LH31) 336 g and magnesium stearate 60 g were mixed in a mixer (tumbler mixer (60 L), Showa Chemical Machinery) to obtain a mixed powder. The obtained mixed powder was rotograted with a rotary tableting machine (collect 12HUK, Kikusui Seisakusho) using a 8.3 mm diameter mortar and a radius of 9.3 mm and a radius of 3.1 mm and a two-stage radius R, weight 185 mg, thickness A 4.11 mm uncoated tablet was obtained.
A coating solution in which 3330 g of the resulting uncoated tablet was charged into a coating machine (Dria Coater DRC-500, Paulek), and 129.6 g of hydroxypropylmethylcellulose (TC-5MW) and 14.4 g of talc were dissolved and suspended in 1152 g of purified water. Was sprayed onto the uncoated tablets and coated with 4 mg per tablet to obtain undercoating (UC) tablets. Subsequently, 1082 g of erythritol, 204.1 g of talc, 367.4 g of precipitated calcium carbonate, 40.82 g of titanium oxide, 102.1 g of crystalline cellulose (Avicel PH-F20), 244.9 g of gum arabic powder and 3062 g of purified water powder were added to the UC tablet. The coating solution dissolved and suspended in was sprayed and coated with 81 mg per tablet to obtain build-up coating (BC) tablets. Subsequently, 35 mg of purified white sugar, 150.8 g of erythritol, and 1.428 g of riboflavin were dissolved and suspended in 252.8 g of purified water on BC tablets, and 20 mg per tablet was coated with syrup coating (SC ) I got a tablet. A glaze solution in which carnauba wax, shellac pearl, castor oil, ethanol, and n-hexane were dissolved in SC tablets was poured and dried to obtain a glaze thin-layer sugar-coated tablet.

Fluidized bed granulator with an aqueous solution prepared by dissolving 0.35.8 g of cyanocobalamin in 100 g of purified water in 545.8 g of fursultiamine hydrochloride, 59.27 g of riboflavin, 100 g of pyridoxine hydrochloride, 122.63 g of lactose and 340 g of crystalline cellulose (Avicel PH101) ( (FD-3SN, Paulek), followed by spraying and granulating an aqueous solution in which 70 g of HPC-L was dissolved in 1097 g of purified water. The obtained granulated powder was sized with a sizing machine (Power Mill, Showa Mechanics) to obtain a sized powder.
Mixing machine (tumbler mixing) 1870.4g of sized powder, 61.6g of calcium pantothenate type, 120g of crystalline cellulose (Asahi Kasei PH101), 98g of low substituted hydroxypropyl cellulose (L-HPC) (LH31), 10g of magnesium stearate (15L), Showa Chemical Machinery Co., Ltd.) to obtain a mixed powder. The resulting mixed powder was mixed with a rotary tableting machine (collect 19AWC, Kikusui Seisakusho) using a pestle having a diameter of 8 mm, a radius of curvature of 9 mm, and a radius of 3 mm and a two-step radius of 180 mg and a thickness of 3.90 mm. I got a tablet.
300 g of the obtained uncoated tablet was charged into a coating machine (Hicoater MINI, Freund), and erythritol 530 g, talc 100 g, precipitated calcium carbonate 180 g, titanium oxide 20 g, crystalline cellulose (Avicel PH-F20) 50 g, and gum arabic powder 120 g were purified. A coating solution dissolved and suspended in 1632 g of water was sprayed to coat 60 mg per tablet. Subsequently, 530 g of purified sucrose, 170 g of talc, 170 g of precipitated calcium carbonate, 20 g of titanium oxide, 60 g of gum arabic powder, 50 g of PEG 6000 were dissolved in 1632 g of purified water and sprayed with a coating solution, and 20 mg per tablet was coated. Build-up coating (BC) tablets were obtained. Subsequently, 20 mg per tablet was coated on BC tablets using a coating solution obtained by dissolving and suspending 748.3 g of purified white sugar and 1.7 g of riboflavin in 374.3 g of purified water to obtain syrup-coated (SC) tablets. . A glaze solution in which carnauba wax, shellac pearl, castor oil, ethanol, and n-hexane were dissolved in SC tablets was poured and dried to obtain a glaze thin-layer sugar-coated tablet.

Comparative Example 1
An aqueous solution in which 0.3g of cyanocobalamin was dissolved in 100g of purified water in 545.8g of fursultiamine hydrochloride, 59.27g of riboflavin, 100g of pyridoxine hydrochloride, 50g of calcium pantothenate crystals, 1249.63g of lactose, and 340g of crystalline cellulose (Asahi Kasei PH101). Was sprayed with a fluidized bed granulator (FD-3SN, Paulek), and then an aqueous solution in which 70 g of HPC-L was dissolved in 1097 g of purified water was sprayed and granulated. The obtained granulated powder was sized with a sizing machine (Power Mill, Showa Mechanics) to obtain a sized powder.
In a blender (tumbler blender (15L), Showa Kagaku Kikai) 1932g of sized powder, 120g of crystalline cellulose (Asahi Kasei PH101), 98g of low substituted hydroxypropylcellulose (L-HPC) (LH31), 10g of magnesium stearate And mixed to obtain a mixed powder. The resulting mixed powder was mixed with a rotary tableting machine (collect 19AWC, Kikusui Seisakusho) using a pestle having a diameter of 8 mm, a radius of curvature of 9 mm, and a radius of 3 mm and a two-step radius of 180 mg and a thickness of 3.90 mm. I got a tablet.
The obtained uncoated tablet was coated by the same operation as in Example 3 to obtain a glazed thin-layer sugar-coated tablet.

Test example 1
Stability of cyanocobalamin and calcium pantothenate content in thin-layer sugar-coated tablets The thin-layer sugar-coated tablets of Example 1, Example 2, Example 3, and Comparative Example 1 that had been reduced in water to an equilibrium relative humidity (ERH) of 40% or less were 40 ° C. The glass bottle was sealed for 1 month and the residual ratio of cyanocobalamin and calcium pantothenate content was measured.
The results are shown in Table 1.

  The purified water in which 40 g of cyanocobalamin in Example 2 was dissolved was changed to 1000 g, and a suspension in which cyanocobalamin was dispersed in purified water was used.

Comparative Example 2
40 g of cyanocobalamin in Example 2 was charged into a fluidized bed granulator (FD-5S, Paulek) as a powder, and thereafter, a thin-layer sugar-coated tablet was obtained in the same manner as in Example 2.

Test example 2
Stability of cyanocobalamin content in thin-layer sugar-coated tablets The thin-layer sugar-coated tablets of Examples 2, 4 and Comparative Example 2 whose moisture content was reduced to an equilibrium relative humidity (ERH) of 40% or less were stored in glass bottles sealed at 60 ° C. for 4 weeks, and cyanocobalamin was stored. The residual rate of content was measured.
The results are shown in Table 2.

As described above, according to the present invention, fursultiamine hydrochloride, vitamin B ₆ such, a vitamin formulation solids containing vitamin B ₁₂ acids and calcium pantothenate, calcium pantothenate and vitamin B ₁₂ compounds are both A stabilized solid formulation can be provided.

Claims (3)

And fursultiamine hydrochloride, vitamin B ₆ such, and vitamin B ₁₂ compound, a solid preparation containing the calcium pantothenate,
Calcium pantothenate is mixed with calcium pantothenate and itself a neutral or basic magnesium or calcium lactate or carbonate in the presence of water and / or a lower alcohol, and then the mixture is dried. Containing vitamin B ₁₂ as granules obtained by spraying an aqueous solution or aqueous dispersion thereof onto an excipient and drying; and Is partially pregelatinized starch, corn starch, wheat starch, rice starch, potato starch, crystalline cellulose, powdered cellulose, low-substituted hydroxypropylcellulose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethylethylcellulose, and carmellose Select from Is is one or more of those;
A solid preparation characterized by A composition obtained by mixing calcium pantothenate and a neutral or basic magnesium or calcium lactate or carbonate in the presence of water and / or a lower alcohol and then drying the mixture. objects and, vitamin B ₁₂ compounds were formulated spraying the aqueous solution or dispersion in an excipient, a particle obtained by drying in a dry, excipient is partially α-starch, corn starch, wheat One or more selected from starch, rice starch, potato starch, crystalline cellulose, powdered cellulose, low substituted hydroxypropylcellulose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethylethylcellulose, and carmellose Solid, characterized by being The method of production. A composition obtained by mixing calcium pantothenate and a neutral or basic magnesium or calcium lactate or carbonate in the presence of water and / or a lower alcohol and then drying the mixture. objects and, vitamin B ₁₂ compounds were formulated spraying the aqueous solution or dispersion in an excipient, a particle obtained by drying in a dry, excipient is partially α-starch, corn starch, wheat One or more selected from starch, rice starch, potato starch, crystalline cellulose, powdered cellulose, low substituted hydroxypropylcellulose, carmellose calcium, carmellose sodium, croscarmellose sodium, carboxymethylethylcellulose, and carmellose Hydrochloric acid hydrochloride characterized by being And Suruchiamin, and vitamin B ₆ compound, and vitamin B ₁₂ compound, method for stabilizing both the vitamin B ₁₂ compound with calcium pantothenate in the solid preparations containing calcium pantothenate.