Solid preparation of thiamine type

Abstract

The present invention provides a stable solid preparation comprising a nicotinic acid and a vitamin B1. The present invention relates to a solid preparation characterized by comprising a nicotinic acid, a vitamin B1 and an alpha-modified starch.

Description

Technical Field

[0001] The present invention relates to a solid preparation containing niacin and vitamin B1. Background Art

[0002] Medicines and supplements sold for the purpose of vitamin supplementation often contain multiple vitamins. Vitamin B1, a type of vitamin, is beneficial for producing energy from carbohydrates and maintaining nerve function. Known vitamin B1s include thiamine nitrate, thiamine chloride hydrochloride, fursultiamine hydrochloride, benfotiamine, dibenzoylthiamine disulfide, and dextrothiamine hydrochloride. Many medicines and supplements contain vitamin B1, and in many cases, vitamin B6 and vitamin B6 are also contained. 12 .

[0003] Niacin, a type of vitamin, is also added to pharmaceuticals and supplements in anticipation of its effects on maintaining skin function and improving blood flow. Niacin is often added together with vitamin C and vitamin E.

[0004] However, vitamins are known to affect each other's stability, so when combining multiple vitamins, careful attention should be paid to confirming the stability.

[0005] Patent document 1 discloses a method comprising fursultiamine hydrochloride, vitamin B2, vitamin B6, vitamin B 12 In the solid preparation, a composition containing calcium pantothenate is dry-blended to make vitamin B 12 The liquid prepared by dissolving or dispersing the above-mentioned substances in water is sprayed onto the drugs and / or excipients other than calcium pantothenate and dried to obtain the granules for compounding, thereby making calcium pantothenate and vitamin B6 12 All categories are stable.

[0006] Patent Document 2 discloses a composition for stabilizing calcium pantothenate, which is a preparation in which ascorbic acid, thiamine, or pyridoxine are blended with calcium pantothenate. This composition stabilizes the calcium pantothenate by mixing calcium pantothenate with a lactate or carbonate of magnesium or calcium, which is neutral to alkaline in nature, in the presence of water and / or a lower alcohol, and drying the mixture.

[0007] Patent Document 3 discloses a method of combining vitamin E and vitamin B 12 The invention relates to a granular composition of two vitamins in a stable state. In the granular composition, the pH of the solution in which the granular composition is dissolved / suspended is set to 4 or above, thereby suppressing the degradation of vitamin B. 12 Decomposition of classes.

[0008] Patent Document 4 discloses a method for making unstable vitamin B12 A stabilized preparation containing chondroitin and vitamin B 12 In this preparation, by adding vitamin B 12 And mucopolysaccharide is combined with silicic acid and / or magnesium oxide to make vitamin B 12 Stabilization.

[0009] Patent Document 5 discloses a fatigue-relieving pharmaceutical comprising adenosine 5'-triphosphate and two or more B vitamins. This pharmaceutical, through the combined use of adenosine 5'-triphosphate and two or more B vitamins, promotes the expression of the vasoactive intestinal polypeptide gene, thereby relieving mental fatigue.

[0010] Prior art literature

[0011] Patent Literature

[0012] Patent Document 1: Japanese Patent Application Laid-Open No. 2006-111535

[0013] Patent Document 2: Japanese Patent Application Laid-Open No. 03-123729

[0014] Patent Document 3: Japanese Patent Application Laid-Open No. 2006-143613

[0015] Patent Document 4: Japanese Patent Application Laid-Open No. 2007-297309

[0016] Patent Document 5: WO2006 / 126663 Summary of the Invention

[0017] Problems to be solved by the invention

[0018] The above-mentioned documents all describe preparations that contain multiple B vitamins, but they do not focus on the stability of vitamin B1 and niacin. There is no record of the effect of their combined use on tablet appearance stability, such as swelling, and no suggestion is given.

[0019] The present inventors have discovered that storage of solid preparations containing vitamin B1 compounds and niacin compounds, for example, at 60°C in sealed glass bottles or at 40°C and 75% RH in unsealed glass bottles, can lead to significant changes in appearance, such as thickness expansion and cracking. This phenomenon is particularly pronounced when using fursultiamine hydrochloride, a vitamin B1 compound, or niacinamide, a niacin compound.

[0020] Solutions to Problems

[0021] The present inventors conducted intensive studies and found that the aforementioned changes in the appearance of solid preparations containing vitamin B1 and niacin can be resolved by adding processed starches such as pregelatinized starch to the solid preparations.

[0022] That is, the present invention includes the following aspects.

[0023] [1] A solid preparation comprising niacin, vitamin B1 and processed starch.

[0024] [2] The solid preparation according to [1] above, wherein the processed starch is pregelatinized starch.

[0025] [3] The solid preparation according to [2] above, comprising 0.5 parts by mass or more of pregelatinized starch per 1 part by mass of nicotinic acid.

[0026] [4] The solid preparation according to any one of [1] to [3] above, wherein the nicotinic acid is nicotinamide.

[0027] [5] The solid preparation according to any one of [1] to [4] above, wherein the vitamin B1 compound is fursultiamine, fursultiamine hydrochloride, or thiamine nitrate.

[0028] [6] The solid preparation according to any one of [2] to [5] above, wherein the pregelatinized starch is partially pregelatinized starch.

[0029] [7] The solid preparation according to any one of [2] to [6] above, comprising niacin, vitamin B1, and pregelatinized starch in a state not physically separated.

[0030] [8] A method for suppressing changes in the appearance of a solid preparation containing niacin and vitamin B1, the method comprising: adding a processed starch.

[0031] Effects of the Invention

[0032] According to the present invention, a solid preparation containing niacin and vitamin B1 compounds can be provided that exhibits excellent appearance quality without experiencing significant changes in appearance, such as thickness expansion or cracking, during storage, for example, at 60°C when sealed in a glass bottle or at 40°C and 75% RH when opened. Such a solid preparation, with a stable shape, particularly thickness, is less susceptible to cracking and other appearance issues even when coated with a film or sugar coating layer, allowing for the provision of a solid preparation with extremely high commercial value. DETAILED DESCRIPTION

[0033] The "nicotinic acid derivative" of the present invention is, for example, nicotinic acid or a salt thereof (eg, nicotinamide), and nicotinamide is particularly preferred.

[0034] The content of the nicotinic acid compound in the solid preparation of the present invention is usually 1 mg to 100 mg, preferably 5 mg to 80 mg, per unit (1 tablet, 1 capsule, 1 pack).

[0035] The content of nicotinic acid in the solid preparation of the present invention is generally 0.1% to 30% by mass, preferably 0.5% to 20% by mass per unit (1 tablet, 1 capsule, 1 pack).

[0036] The "vitamin B1" of the present invention refers to vitamin B1 or its derivatives, or salts thereof, for example, fursultiamine, fursultiamine hydrochloride, thiamine chloride hydrochloride, thiamine nitrate, desultiamine hydrochloride hydrate, thiamine lipoate, cycotiamine, sulbutiamine, dibenzoyldisulfide thiamine, benfotiamine, etc., preferably fursultiamine, fursultiamine hydrochloride, thiamine nitrate, and particularly preferably fursultiamine hydrochloride.

[0037] The content of vitamin B1 in the solid preparation of the present invention is usually 1 mg to 200 mg, preferably 5 mg to 150 mg per unit (1 tablet, 1 capsule, 1 pack).

[0038] The content of vitamin B1 in the solid preparation of the present invention is usually 0.1% to 60% by mass, preferably 0.5% to 40% by mass per unit (1 tablet, 1 capsule, 1 pack).

[0039] The "processed starch" of the present invention is obtained by subjecting starch to various chemical modifications and processing to impart various functionalities, and examples thereof include glucose compounds (e.g., cyclodextrin), starch salts (e.g., sodium starch glycolate), and alpha-modified starch (e.g., partially alpha-modified starch). Among these, alpha-modified starch is preferred.

[0040] The "alpha-starch" of the present invention is starch that has been alpha-starched by heating starch and water together, and includes both starch that has been alpha-starched throughout (alpha-starch) and starch that has been partially alpha-starched (partially alpha-starch). Examples of the raw starch include corn starch, potato starch, and rice starch, with corn starch and potato starch being preferred. The swelling degree of the "alpha-starch" of the present invention is preferably 5 to 30 cm 3 / g, more preferably 7 to 25 cm 3 Specifically, the descriptions in the "Dictionary of Pharmaceutical Additives 2000" compiled by the Japan Pharmaceutical Additives Association can be cited, and commercially available products include, for example, partially alpha-starch PCS (R) , α-starch PD-1, α-starch WB-1 (all manufactured by Asahi Kasei Corporation), etc.

[0041] The content of the α-starch in the solid preparation of the present invention is usually 1% to 90% by mass per unit (1 tablet, 1 capsule, 1 package), preferably 3% to 60% by mass, more preferably 5% to 60% by mass.

[0042] In the present invention, preferably 0.5 parts by mass or more of pregelatinized starch is added per 1 part by mass of niacin, preferably 1 part by mass or more and 20 parts by mass or less, more preferably 3 parts by mass or more and 10 parts by mass or less, and even more preferably 3.5 parts by mass or more and 10 parts by mass or less.

[0043] The problem to be solved by the present invention is that significant changes in the appearance of a solid preparation containing niacin and vitamin B1, such as swelling and cracking, during storage are thought to occur due to contact between niacin and vitamin B1.

[0044] Therefore, examples of the solid preparation of the present invention particularly include a solid preparation containing niacins, vitamin B1 compounds, and pregelatinized starch in a state in which they are in contact with each other and are not physically separated.

[0045] Here, the term "not physically separated" is not particularly limited as long as niacin, vitamin B1, and pregelatinized starch are not physically separated and can be in contact with each other. Such solid preparations include, for example, tablets obtained by mixing and compressing vitamin B1, niacin, and pregelatinized starch, and tablets obtained by granulating vitamin B1 and niacin separately, then mixing and compressing them.

[0046] In the present invention, as drugs that can be incorporated in addition to vitamins B1 and niacin, there are vitamins, antipyretic analgesics, cough suppressants and expectorants, anti-inflammatory drugs, rhinitis drugs, gastrointestinal drugs, antidiarrheal drugs, herbal medicines, amino acids, etc. Examples of vitamins include vitamins A (retinyl acetate, retinyl palmitate, vitamin A oil, liver oil, liver oil), vitamin D (ergocalciferol, cholecalciferol), vitamin B2 (riboflavin, riboflavin sodium phosphate, riboflavin butyrate), vitamin B6 (pyridoxine hydrochloride, pyridoxal phosphate), vitamin B 12 Vitamins (Cyanocobalamin, Hydroxocobalamin Acetate, Methylcobalamin), Calcium Pantothenate, Calcium Pantothenate Type S, γ-Oryzanol, Orotic Acid, Glucuronolactone, Glucuronamide, Coix Lachryma-Job's Tears, Hesperidin, Biotin, Sodium Chondroitin Sulfate, Vitamin C (Ascorbic Acid, Calcium Ascorbate, Sodium Ascorbate), Vitamin E (dl-α-Tocopheryl Calcium Succinate, d-α-Tocopheryl Succinate, d-α-Tocopheryl Acetate).

[0047] Examples of the antipyretic and analgesic drugs include loxoprofen sodium hydrate, acetaminophen, ibuprofen, aspirin, ethsalamide, salicylamide, sodium salicylate, anhydrous caffeine, and caffeine.

[0048] Examples of the cough suppressant and expectorant include codeine phosphate, dihydrocodeine phosphate, dextromethorphan hydrobromide, methylephedrine hydrochloride, narcotine, methyl cysteine ​​hydrochloride, ethyl cysteine ​​hydrochloride, and carbocysteine.

[0049] Examples of the anti-inflammatory drug include lysozyme chloride, tranexamic acid, and sodium azulenesulfonate.

[0050] Examples of the rhinitis medication include pseudoephedrine hydrochloride, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, total belladonna alkaloids, isopropyl iodide, and dipotassium glycyrrhizate.

[0051] Examples of the gastrointestinal drugs include dried aluminum hydroxide gel, magnesium aluminum silicate, magnesium silicate, synthetic hydrotalcite, magnesium oxide, magnesium aluminum hydroxide, aluminum hydroxide gel, aluminum hydroxide / sodium bicarbonate coprecipitated product, aluminum hydroxide / magnesium carbonate mixed dried gel, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitated product, magnesium hydroxide, sodium bicarbonate, magnesium carbonate, precipitated calcium carbonate, magnesium aluminum metasilicate, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate, glycine, aluminum dihydroxyaminoacetate, scopolamine extract, aloe vera, fennel, turmeric, phellodendron, coptis root, processed garlic, red ginseng, magnolia bark, ginger, angelica root, cinnamon bark, rhubarb, ginseng japonica, tangerine peel, spruce, quassia, ginseng, mint, hops, fennel oil, cinnamon oil, ginger oil, spruce oil, mint oil, lemon oil, L-menthol, betaine hydrochloride, carnitine hydrochloride, dried yeast, starch-digesting enzymes, protein-digesting enzymes, fat-digesting enzymes, cellulose-digesting enzymes, ursodeoxycholic acid, and bile powder.

[0052] Examples of the antidiarrheal drug include rivanol, berberine hydrochloride, guaiacol, creosote, bismuth subsalicylate, bismuth subnitrate, bismuth subcarbonate, bismuth subgallate, tannic acid, kaolin, pectin, medicinal carbon, calcium lactate, precipitated calcium carbonate, calcium hydrogen phosphate, papaverine hydrochloride, ethyl aminobenzoate, sodium azulenesulfonate, aluminum allantoin, L-glutamine, potassium copper chlorophyllin, sodium copper chlorophyllin, methionine methylsulfonium chloride, and dimethylpolysiloxane.

[0053] Examples of the herbal medicine include: sycamore, catechu, catechu powder, sweet tea, sweet tea powder, aloe, aloe powder, benzoin, clematis, artemisia capillaris, epimedium, fennel, fennel powder, turmeric, lindera, bearberry, yingshi, yingshi powder, corydalis, astragalus, scutellaria, scutellaria powder, polygonatum, phellodendron, phellodendron powder, coptis root, coptis root powder, polygala, polygala powder, prunella vulgaris, polygonatum, polygonatum root, polygonatum root powder, kudzu root, radix polygonati, zedoaria, kudzu root, valerian ... Briq), broadleaf valerian powder, trichosanthes root, dried ginger, licorice, licorice powder, agar, agar powder, platycodon, platycodon powder, chrysanthemum, catalpa fruit, citrus aurantium, notopterygium wilfordii, apricot kernel, wolfberry fruit, sophora flavescens, sophora flavescens powder, schizonepeta tenuifolia, cinnamon bark, cinnamon bark powder, cassia seed, pharmacopeia seed, gentian, gentian powder, geranium tong's, geranium tong's powder, safflower, red ginseng, cyperus rotundus, cyperus rotundus powder, magnolia bark, magnolia bark powder, bezoar, ox knee, evodia rutaecarpa, burdock fruit, schisandra chinensis, rice starch, stephania africana, African Stephania powder, Condurango, Bupleurum, Asarum, Saffron, Chinese Poria, Chinese Poria powder, Gardenia, Gardenia powder, Cornus officinalis, Qinjiao, Qinjiao powder, Ziziphus jujuba seeds, Chinese yam, Chinese yam powder, Rehmannia root, Acanthopanax senticosus, Lycium bark, Lithospermum officinale, Tribulus terrestris, Peony, Peony powder, Cnidium monnieri, Plantago, Plantago, Houttuynia cordata, Amomum villosum, Amomum villosum powder, Ginger, Ginger powder, Cardamom, Cimicifuga heracleifolia, Magnolia, Gypsum, Polygala tenuifolia, Polygala tenuifolia powder, Chuanxiong, Chuanxiong powder, Chuangu, Toad Venom, Senna Leaves, Senna Leaves Powder, Dangyao, Dangyao Powder, Atractylodes, Atractylodes Powder, Morus Alba Bark, Sappan Wood, Perilla Leaves, Rhubarb, Rhubarb Powder, Jujube, Alisma, Alisma Powder, Japonica, Japonica Powder, Anemarrhena, Cloves, Clove Powder, Fishing Hook, Poria, Poria Powder, Tangerine Peel, Gastrodia, Tianmendong, Winter Melon Seeds, Chili, Chili Powder, Angelica, Angelica Powder, Peach Kernel, Peach Kernel Powder, Spruce, Ipecac, Ipecac Powder, Eucommia, Tragacanth, Tragacanth Powder, Quassia, Quassia Powder, Human Ginseng, ginseng powder, honeysuckle, fritillaria, ophiopogon, honey, mint, northern adenophora, pinellia, angelica dahurica, atractylodes, atractylodes powder, loquat leaf, betel nut, poria, poria powder, aconite, aconite powder, belladonna root, lentil, stephania tetrandra, cogongrass root, siler, peony bark, peony bark powder, strychnine seed, oyster, oyster powder, ephedra, seaweed, sesame seed, akebia, costus root, alpinia oxyphylla, bear bile, coix seed, coix seed powder, dragon bone, gentian, gentian powder, ginger, forsythia, lotus seed, rosin, henbane root, etc.

[0054] Examples of the amino acid include L-cysteine, a mixture of equal amounts of potassium and magnesium aspartate, L-valine, L-leucine, L-isoleucine, and taurine.

[0055] The solid preparation of the present invention may contain, in addition to the pregelatinized starch, additives such as excipients, binders, disintegrants, lubricants, glidants, colorants, pH adjusters, sweeteners, and flavorings that are commonly used for producing solid preparations.

[0056] Examples of the excipient include erythritol, maltitol, powdered reduced maltose syrup, mannitol, refined white sugar, white sugar, trehalose, sorbitol, xylitol, lactose, reduced maltose syrup, glucose, maltose, lactitol, corn starch, crystalline cellulose, powdered cellulose, calcium monohydrogen phosphate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, calcium lactate, and precipitated calcium carbonate.

[0057] Examples of the binder include gum arabic powder, hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, carboxymethyl ethyl cellulose, povidone (PVP), polyvinyl alcohol (PVA), pullulan, dextrin, hydroxypropyl starch, tragacanth gum powder, crystalline cellulose, and low-substituted hydroxypropyl cellulose (L-HPC).

[0058] Examples of the disintegrant include croscarmellose sodium, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose calcium, corn starch, sodium carboxymethyl starch, hydroxypropyl starch, and cross-linked polyvinylpyrrolidone.

[0059] Examples of the lubricant include magnesium stearate, calcium stearate, sucrose fatty acid ester, talc, and polyethylene glycol 6000.

[0060] Examples of the flow aid include light anhydrous silicic acid, hydrous silicon dioxide, and kaolin.

[0061] Examples of colorants include riboflavin, vitamin B 12 , titanium oxide, yellow iron oxide, red iron oxide, food coloring red No. 2, food coloring red No. 3, food coloring red No. 102, food coloring red No. 104, food coloring red No. 105, food coloring red No. 106, food coloring yellow No. 4, food coloring yellow No. 5, food coloring green No. 3, food coloring blue No. 1, food coloring blue No. 2, sodium copper chlorophyll, copper chlorophyll, etc.

[0062] Examples of the pH adjuster include sodium hydroxide, sodium citrate, hydrochloric acid, sodium bicarbonate, sodium carbonate, calcium lactate, phosphoric acid, dipotassium hydrogen phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, and sodium dihydrogen phosphate.

[0063] Examples of the sweetener include aspartame, stevia, dipotassium glycyrrhizate, acesulfame potassium, and sucralose.

[0064] Examples of the flavoring agent include L-menthol, peppermint oil, eucalyptus oil, orange oil, clove oil, turpentine oil, anise oil, and vanillin.

[0065] The solid preparation of the present invention can be coated with water-soluble polymers (hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, polyvinyl alcohol (PVA), etc.), insoluble polymers (ethyl cellulose, methacrylic acid copolymers, etc.), sugars (refined white sugar, erythritol, etc.), graft copolymers of polyvinyl alcohol (PVA) and polyethylene glycol (PEG) (Kollicoat IR, BASF), etc.

[0066] The coating can be formulated with excipients (such as talc, precipitated calcium carbonate, and titanium oxide), lubricants (such as polyethylene glycol 6000 and magnesium stearate), binders (such as gum arabic powder, crystalline cellulose, methylcellulose, hydroxypropyl cellulose, hypromellose, dextrin, and polyvinyl alcohol (PVA)), and pigments (such as riboflavin and yellow iron oxide). Premixed coating solutions (such as Opadry and Colorcon Japan) can also be used.

[0067] In the solid preparation of the present invention, the content of crystalline cellulose, which can be added as an additive, is preferably as low as possible. By reducing the crystalline cellulose content, changes in appearance can be more significantly suppressed. Specifically, the crystalline cellulose content in the solid preparation of the present invention is preferably 8% by mass or less, and more preferably 5% by mass or less.

[0068] The solid preparation of the present invention is preferably coated to prevent changes in appearance such as cracks. The coating agent is preferably a water-soluble polymer, and particularly preferably hypromellose.

[0069] The coating amount is preferably about 1 to 6%, particularly preferably about 2 to 4%, based on the mass ratio of the plain tablet.

[0070] Examples of the solid preparations of the present invention include various tablets, such as plain tablets, film-coated tablets, sugar-coated tablets, thin-layer sugar-coated tablets, sugar-free thin-layer sugar-coated tablets, rapidly disintegrating tablets in the oral cavity, chewable tablets, chocolate tablets, granules, fine granules, and capsules. Furthermore, examples include double-layer tablets, triple-layer tablets, and dry-coated tablets (core tablets).

[0071] The method for manufacturing the solid preparation of the present invention can use the common methods described in publications such as Granulation Handbook (edited by Japan Powder Industry Technology Association, Ohmsha Co., Ltd.), Formulation Design of Oral Preparations (edited by Professor Mitsuru Hashida of the Graduate School of Pharmaceutical Sciences, Kyoto University, Pharmaceutical Times), Compression Molding Technology of Powders (edited by Powder Engineering / Preparation and Particle Design Department, Nikkan Kogyo Shimbun), and Pharmaceutical Machinery Technology Handbook (2nd edition, edited by the Editorial Committee for the 20th Anniversary Commemoration of the Pharmaceutical Machinery Technology Research Society, Pharmaceutical Machinery Technology Research Society), without any particular restrictions.

[0072] The present invention also provides a method for suppressing changes in the appearance (such as thickness expansion and cracking) of a solid preparation containing niacin and vitamin B1. The method comprises adding a processed starch, such as pregelatinized starch. The elements of this method (such as the components, their amounts, and their ratios) are as described for the solid preparation of the present invention. For example, the processed starch is preferably added in an amount of 0.5 parts by mass or more, more preferably 3 parts by mass or more, and even more preferably 3.5 parts by mass or more and 10 parts by mass or less, per 1 part by mass of the niacin.

[0073] When the processed starch is pregelatinized starch, the amount of pregelatinized starch is preferably 0.5 parts by mass or more, preferably 1 part by mass or more and 20 parts by mass or less, more preferably 3 parts by mass or more and 10 parts by mass or less, and even more preferably 3.5 parts by mass or more and 10 parts by mass or less, per 1 part by mass of niacin.

[0074] Example

[0075] Hereinafter, the present invention will be described in further detail with reference to Examples, but the present invention is not limited thereto.

[0076] (Example 1)

[0077] Nicotinamide (Lonza Japan), riboflavin (BASF Japan), pyridoxine hydrochloride (BASF Japan), crystalline cellulose (CEOLUS PH-101, Asahi Kasei), and partially pregelatinized starch (PCS, Asahi Kasei) were placed in a fluidized bed granulator and sprayed with a hydroxypropyl cellulose (HPC, Nippon Soda) solution and a hypromellose (TC-5, Shin-Etsu Chemical) solution. Granulation and drying were then performed, followed by granulation using a Powermill to obtain granulated powder 1. The composition of granulated powder 1 was 11.1% nicotinamide, 3.3% riboflavin, 13.9% pyridoxine hydrochloride, 8.4% crystalline cellulose (CEOLUS PH-101, Asahi Kasei), 50.0% partially pregelatinized starch, 3.3% HPC, and 10% TC-5.

[0078] Separately, fursultiamine hydrochloride (Mikuni Pharmaceutical) and crystalline cellulose (CEOLUS PH-101, Asahi Kasei) were placed in a fluidized bed granulator and sprayed with a hydroxypropyl cellulose (HPC, Nippon Soda) solution. Granulation and drying were then performed, followed by granulation using a POWERMILL granulator to obtain granulated powder 2. The composition ratio of granulated powder 2 was 60.6% fursultiamine hydrochloride, 35.4% crystalline cellulose, and 4% HPC.

[0079] The resulting granulated powder 1 (720 g), granulated powder 2 (360 g), calcium pantothenate type S (BASF Japan) (92.4 g), VB12 fine granules (Mitsubishi-Chemical Foods) (13.2 g), crystalline cellulose (CEOLUS PH-101, Asahi Kasei) (127.3 g), and magnesium stearate (Taihei Chemical Industry) (6.6 g) were mixed to obtain a tableting mixture. The tableting mixture was compressed using a rotary tablet press (AQU3, Kikusui Seisakusho) with an 8.5 mm diameter pestle to obtain tablets weighing 220 mg and having a thickness of 4.8 mm.

[0080] Next, a base coating solution consisting of hypromellose (Shin-Etsu Chemical Co., Ltd.) and sterile talc (Matsumura Industry Co., Ltd.) dissolved or dispersed in purified water, and a build-up coating solution consisting of erythritol (Cargill Japan), sterile talc, precipitated calcium carbonate (Nitto Powder Industry Co., Ltd.), titanium oxide (Ishihara Industry Co., Ltd.), crystalline cellulose (CEOLUS PH-F20, Asahi Kasei Co., Ltd.), and gum arabic powder (Sanei Pharmaceutical Trading Co., Ltd.) dissolved or dispersed in purified water were applied using a coating machine (Doria Coater, Powrex) at a coating weight of 5 mg and 96 mg per tablet, respectively. Furthermore, a syrup consisting of refined white sugar (Mitsui Sugar Co., Ltd.), erythritol, and riboflavin dissolved in purified water was applied using a sugar coating machine (Kikusui Seisakusho Co., Ltd.) at a coating weight of 24 mg per tablet, thereby producing sugar-coated tablets.

[0081] (Example 2)

[0082] Nicotinamide (Lonza Japan), riboflavin (BASF Japan), pyridoxine hydrochloride (BASF Japan), crystalline cellulose (CEOLUS PH-101, Asahi Kasei), and pregelatinized starch (PD-1, Asahi Kasei) were placed in a fluidized bed granulator and sprayed with a hydroxypropyl cellulose (HPC, Nippon Soda) solution and a hypromellose (TC-5, Shin-Etsu Chemical) solution. Granulation and drying were then performed, followed by granulation using a Powermill to obtain granulated powder 1. The composition of granulated powder 1 was 12.4% nicotinamide, 3.7% riboflavin, 15.5% pyridoxine hydrochloride, 7.7% crystalline cellulose, 49.6% pregelatinized starch, 2.0% HPC, and 9.1% TC-5.

[0083] Separately, fursultiamine hydrochloride (Mikuni Pharmaceutical) and crystalline cellulose were placed in a fluidized bed granulator and sprayed with a hydroxypropyl cellulose (HPC, Nippon Soda) solution. Granulation and drying were then performed, followed by granulation using a POWERMILL granulator to obtain granulated powder 2. The composition of granulated powder 2 was 72.8% fursultiamine hydrochloride, 24.2% crystalline cellulose, and 3% HPC.

[0084] The resulting granulated powder 1: 644.8 g, granulated powder 2: 300 g, 92.4 g of calcium pantothenate type S (BASF Japan), 12 g of VB12 fine granules (Mitsubishi-Chemical Foods), 79.4 g of crystalline cellulose (CEOLUS PH-101, Asahi Kasei), 5.7 g of SYLYSIA (Fuji Silysia), and 5.7 g of magnesium stearate (Taihei Chemical Industry) were mixed to obtain a mixed powder for tableting. This mixed powder for tableting was compressed using a rotary tablet press (AQU3, Kikusui Seisakusho) using an 8.0 mm diameter pestle to obtain tablets with a mass of 190 mg and a thickness of 4.2 mm.

[0085] Next, a base coating solution consisting of hypromellose (Shin-Etsu Chemical Co., Ltd.) and sterile talc (Matsumura Industry Co., Ltd.) dissolved or dispersed in purified water, and a build-up coating solution consisting of erythritol (Cargill Japan), sterile talc, titanium oxide (Ishihara Industry Co., Ltd.), crystalline cellulose (CEOLUS PH-F20, Asahi Kasei Co., Ltd.), and gum arabic powder (Sanei Pharmaceutical Trading Co., Ltd.) dissolved or dispersed in purified water were applied using a coating machine (Doria Coater, Powrex) at a coating weight of 5 mg and 115 mg per tablet, respectively. Furthermore, a syrup consisting of refined white sugar (Mitsui Sugar Co., Ltd.), erythritol, and riboflavin dissolved in purified water was applied using a sugar coating machine (Kikusui Seisakusho Co., Ltd.) at a coating weight of 22 mg per tablet, thereby producing sugar-coated tablets.

[0086] (Example 3)

[0087] Nicotinamide (Lonza Japan), riboflavin (BASF Japan), pyridoxine hydrochloride (BASF Japan), lactose hydrate (GranuLac 200, Meggle), and partially pregelatinized starch (PCS, Asahi Kasei) were placed in a fluidized bed granulator and sprayed with a hydroxypropylcellulose (HPC, Nippon Soda) solution and a hypromellose (TC-5, Shin-Etsu Chemical) solution. Granulation and drying were performed, and the mixture was then granulated using a POWERMILL granulator to obtain granulated powder 1. The composition of granulated powder 1 was 12.1% nicotinamide, 3.6% riboflavin, 15.2% pyridoxine hydrochloride, 19.4% lactose hydrate, 36.4% partially pregelatinized starch, 3.3% HPC, and 10% TC-5.

[0088] Separately, fursultiamine hydrochloride (Mikuni Pharmaceutical) and crystalline cellulose (CEOLUS PH-101, Asahi Kasei) were placed in a fluidized bed granulator and sprayed with a hydroxypropyl cellulose (HPC, Nippon Soda) solution. Granulation and drying were then performed, followed by granulation using a granulator (POWERMILL) to obtain granulated powder 2. The composition ratio of granulated powder 2 was 60.6% fursultiamine hydrochloride, 35.4% crystalline cellulose (CEOLUS PH-101, Asahi Kasei), and 4% HPC.

[0089] The obtained whole granule powder 1: 660 g, whole granule powder 2: 360 g, calcium pantothenate type S (BASF Japan) 92.4 g, VB12 fine granules (Mitsubishi-Chemical Foods) 13.2 g, corn starch 69 g, crystalline cellulose (CEOLUS PH-101, Asahi Kasei) 78 g, SYLYSIA (Fuji Silysia) 5.7 g, magnesium stearate (Taihei Chemical Industry) 5.7 g were mixed to obtain a mixed powder for tableting. A rotary tablet press (AQU3, Kikusui Seisakusho) was used. The obtained tableting mixture was tableted with a pestle to obtain a tablet mass of 210 mg and a thickness of 4.3 mm.

[0090] Next, a base coating solution consisting of hypromellose (Shin-Etsu Chemical Co., Ltd.) and sterile talc (Matsumura Industry Co., Ltd.) dissolved or dispersed in purified water, and a build-up coating solution consisting of erythritol (Cargill Japan), sterile talc, precipitated calcium carbonate (Nitto Powder Industry Co., Ltd.), titanium oxide (Ishihara Industry Co., Ltd.), crystalline cellulose (CEOLUS PH-F20, Asahi Kasei Co., Ltd.), and gum arabic powder (Sanei Pharmaceutical Trading Co., Ltd.) dissolved or dispersed in purified water were applied using a coating machine (Doria Coater, Powrex) at a coating weight of 5 mg and 96 mg per tablet, respectively. Furthermore, a syrup consisting of refined white sugar (Mitsui Sugar Co., Ltd.), erythritol, and riboflavin dissolved in purified water was applied using a sugar coating machine (Kikusui Seisakusho Co., Ltd.) at a coating weight of 24 mg per tablet, thereby producing sugar-coated tablets.

[0091] (Example 4)

[0092] Riboflavin (BASF Japan), pyridoxine hydrochloride (BASF Japan), lactose hydrate (GranuLac 200, Meggle), and corn starch (Japan Corn Starch) were placed in a fluidized bed granulator and sprayed with a hydroxypropylcellulose (HPC, Nippon Soda) solution. Granulation and drying were performed, and then granulation was performed using a granulator (POWERMILL) to obtain granulated powder 1. The composition ratio of granulated powder 1 was riboflavin 8.8%, pyridoxine hydrochloride 37.0%, lactose hydrate 30.2%, corn starch 20%, and HPC 4%.

[0093] Separately, fursultiamine hydrochloride (Mikuni Pharmaceutical), niacinamide (Lonza Japan), corn starch, partially pregelatinized starch (PCS, Asahi Kasei), and crystalline cellulose were placed in a fluidized bed granulator and sprayed with a hydroxypropylcellulose (HPC, Nippon Soda) solution. Granulation and drying were then performed, followed by granulation using a POWERMILL granulator to obtain granulated powder 2. The composition of granulated powder 2 was 36.4% fursultiamine hydrochloride, 13.3% niacinamide, 4.8% corn starch, 40.0% partially pregelatinized starch, 2.0% crystalline cellulose, and 3.5% HPC.

[0094] The cyanocobalamin solution was further sprayed onto a portion of the pregelatinized starch and corn starch, followed by spraying with a hypromellose solution. Granulation and drying were then performed, followed by granulation using a Powermill to obtain granulated powder 3. The composition of granulated powder 3 was 0.09% cyanocobalamin, 90.76% partially pregelatinized starch, 0.06% corn starch, and 9.09% hypromellose.

[0095] The obtained whole granule powder 1: 270 g, whole granule powder 2: 600 g, whole granule powder 3: 132 g, calcium pantothenate type S (BASF Japan) 92.4 g, corn starch 21.6 g, crystalline cellulose (CEOLUS PH-101, Asahi Kasei) 72 g, SYLYSIA (Fuji Silysia) 6.0 g, magnesium stearate (Taihei Chemical Industry) 6.0 g were mixed to obtain a mixed powder for tableting. A rotary tablet press (AQU3, Kikusui Seisakusho) was used. The obtained tableting mixture was tableted with a pestle to obtain a tablet mass of 190 mg and a thickness of 4.2 mm.

[0096] Next, a base coating solution consisting of hypromellose (Shin-Etsu Chemical Co., Ltd.) and sterile talc (Matsumura Industry Co., Ltd.) dissolved or dispersed in purified water, and a build-up coating solution consisting of erythritol (Cargill Japan), sterile talc, titanium oxide (Ishihara Industry Co., Ltd.), crystalline cellulose (CEOLUS PH-F20, Asahi Kasei Co., Ltd.), and gum arabic powder (Sanei Pharmaceutical Trading Co., Ltd.) dissolved or dispersed in purified water were applied using a coating machine (Doria Coater, Powrex) at 6 mg and 94 mg per tablet, respectively. Furthermore, a syrup consisting of refined white sugar (Mitsui Sugar Co., Ltd.), erythritol, and riboflavin dissolved in purified water was applied using a sugar coating machine (Kikusui Seisakusho Co., Ltd.) at a sugar coating of 24 mg per tablet, thereby producing sugar-coated tablets.

[0097] (Example 5)

[0098] Nicotinamide (Lonza Japan), riboflavin (BASF Japan), pyridoxine hydrochloride (BASF Japan), lactose hydrate (GranuLac 200, Meggle), corn starch (Japan Corn Starch), and partially pregelatinized starch (PCS, Asahi Kasei) were placed in a fluidized bed granulator and sprayed with an HPC solution. Granulation and drying were performed, and the mixture was then granulated using a granulator (POWERMILL) to obtain granulated powder 1. The composition of granulated powder 1 was 13.3% nicotinamide, 3.9% riboflavin, 16.7% pyridoxine hydrochloride, 7.0% lactose hydrate, 2.1% corn starch, 50% partially pregelatinized starch, and 7% HPC.

[0099] Separately, fursultiamine hydrochloride (Mikuni Pharmaceutical), corn starch, and crystalline cellulose (CEOLUS PH-101, Asahi Kasei) were placed in a fluidized bed granulator and sprayed with an HPC solution. Granulation and drying were then performed, followed by granulation using a granulator (POWERMILL) to obtain granulated powder 2. The composition of granulated powder 2 was 77.4% fursultiamine hydrochloride, 9.0% corn starch, 6.4% crystalline cellulose, and 7.2% HPC.

[0100] The cyanocobalamin solution was further sprayed onto a portion of the pregelatinized starch and corn starch, followed by spraying with a hypromellose solution. Granulation and drying were then performed, followed by granulation using a Powermill to obtain granulated powder 3. The composition of granulated powder 3 was 0.09% cyanocobalamin, 90.76% partially pregelatinized starch, 0.06% corn starch, and 9.09% hypromellose.

[0101] The obtained whole grain powder 1: 600 g, whole grain powder 2: 282 g, whole grain powder 3: 132 g, calcium pantothenate type S (BASF Japan) 92.4 g, corn starch 8.4 g, crystalline cellulose (CEOLUS PH-F20, Asahi Kasei) 72 g, SYLYSIA (Fuji Silysia) 8.4 g, magnesium stearate (Taihei Chemical Industry) 4.8 g were mixed to obtain a mixed powder for tableting. A rotary tablet press (AQU3, Kikusui Seisakusho) was used. The obtained tableting mixed powder was tableted with a pestle to make the tablet mass 200 mg and obtain a tablet with a thickness of 4.3 mm.

[0102] Next, a base coating solution consisting of hypromellose (Shin-Etsu Chemical Co., Ltd.) and sterile talc (Matsumura Industry Co., Ltd.) dissolved or dispersed in purified water, and a build-up coating solution consisting of erythritol (Cargill Japan), sterile talc, precipitated calcium carbonate (Nitto Powder Industry Co., Ltd.), titanium oxide (Ishihara Industry Co., Ltd.), crystalline cellulose (CEOLUS PH-F20, Asahi Kasei Co., Ltd.), and gum arabic powder (Sanei Pharmaceutical Trading Co., Ltd.) dissolved or dispersed in purified water were applied using a coating machine (Doria Coater, Powrex) at 8 mg and 80 mg per tablet, respectively. Furthermore, a syrup consisting of refined white sugar (Mitsui Sugar Co., Ltd.), erythritol, and riboflavin dissolved in purified water was applied using a sugar coating machine (Kikusui Seisakusho Co., Ltd.) at a sugar coating of 20 mg per tablet, thereby producing sugar-coated tablets.

[0103] (Example 6)

[0104] Nicotinamide (Lonza Japan), riboflavin (BASF Japan), pyridoxine hydrochloride (BASF Japan), lactose hydrate (GranuLac 200, Meggle), corn starch (Japan Corn Starch), and partially pregelatinized starch (PCS, Asahi Kasei) were placed in a fluidized bed granulator and sprayed with an HPC solution. Granulation and drying were performed, and the mixture was then granulated using a granulator (POWERMILL) to obtain granulated powder 1. The composition of granulated powder 1 was 13.7% nicotinamide, 4.1% riboflavin, 17.2% pyridoxine hydrochloride, 7.2% lactose hydrate, 2.5% corn starch, 51.5% partially pregelatinized starch, and 3.8% HPC.

[0105] Separately, fursultiamine hydrochloride (Mikuni Pharmaceutical), corn starch, and crystalline cellulose (CEOLUS PH-101, Asahi Kasei) were placed in a fluidized bed granulator and sprayed with an HPC solution. Granulation and drying were then performed, followed by granulation using a granulator (POWERMILL) to obtain granulated powder 2. The composition of granulated powder 2 was 74.3% fursultiamine hydrochloride, 7.5% corn starch, 14.3% crystalline cellulose, and 3.9% HPC.

[0106] The obtained whole granule powder 1: 582 g, whole granule powder 2: 294 g, calcium pantothenate type S (BASF Japan) 92.4 g, VB12 fine granules (Mitsubishi-Chemical Foods) 13.2 g, corn starch 69 g, crystalline cellulose (CEOLUS PH-F20, Asahi Kasei) 78 g, SYLYSIA (Fuji Silysia) 5.7 g, magnesium stearate (Taihei Chemical Industry) 5.7 g were mixed to obtain a mixed powder for tableting. A rotary tablet press (AQU3, Kikusui Seisakusho) was used. The obtained tableting mixture was tableted with a pestle to obtain a tablet mass of 190 mg and a thickness of 4.2 mm.

[0107] Next, a base coating solution consisting of hypromellose (Shin-Etsu Chemical Co., Ltd.) and sterile talc (Matsumura Industry Co., Ltd.) dissolved or dispersed in purified water, and a build-up coating solution consisting of erythritol (Cargill Japan), sterile talc, precipitated calcium carbonate (Nitto Powder Industry Co., Ltd.), titanium oxide (Ishihara Industry Co., Ltd.), crystalline cellulose (CEOLUS PH-F20, Asahi Kasei Co., Ltd.), and gum arabic powder (Sanei Pharmaceutical Trading Co., Ltd.) dissolved or dispersed in purified water were applied using a coating machine (Doria Coater, Powrex) at a coating volume of 6 mg and 80 mg per tablet, respectively. Furthermore, a syrup consisting of refined white sugar (Mitsui Sugar Co., Ltd.), erythritol, and riboflavin dissolved in purified water was applied using a sugar coating machine (Kikusui Seisakusho Co., Ltd.) at a coating volume of 20 mg per tablet, thereby producing sugar-coated tablets.

[0108] (Example 7)

[0109] Sugar-coated tablets were obtained in the same manner as in Example 6 except that pregelatinized starch (PD-1, Asahi Kasei) was used instead of part of the pregelatinized starch.

[0110] (Example 8)

[0111] Sugar-coated tablets were obtained in the same manner as in Example 6 except that pregelatinized starch (WB-1, Asahi Kasei) was used instead of part of the pregelatinized starch.

[0112] (Example 9)

[0113] Nicotinamide (Lonza Japan), riboflavin (BASF Japan), pyridoxine hydrochloride (BASF Japan), lactose hydrate (GranuLac 200, Meggle), corn starch (Japan Corn Starch), and pregelatinized starch (PD-1, Asahi Kasei) were placed in a fluidized bed granulator and sprayed with an HPC solution. Granulation and drying were performed, and the mixture was then granulated using a granulator (POWERMILL) to obtain granulated powder 1. The composition of granulated powder 1 was 13.7% nicotinamide, 4.1% riboflavin, 17.2% pyridoxine hydrochloride, 7.2% lactose hydrate, 23.1% corn starch, 27.5% pregelatinized starch, and 7.2% HPC.

[0114] Separately, fursultiamine hydrochloride (Mikuni Pharmaceutical), corn starch, crystalline cellulose (CEOLUS PH-101, Asahi Kasei), and SYLYSIA (Fuji Silysia) were placed in a fluidized bed granulator and sprayed with an HPC solution. Granulation and drying were then performed, followed by granulation using a granulator (POWERMILL) to obtain granulated powder 2. The composition of granulated powder 2 was 77.4% fursultiamine hydrochloride, 8.6% corn starch, 0.4% SYLYSIA, 6.4% crystalline cellulose, and 7.2% HPC.

[0115] The obtained whole grain powder 1: 582 g, whole grain powder 2: 282 g, calcium pantothenate type S (BASF Japan) 92.4 g, VB12 fine granules (Mitsubishi-Chemical Foods) 13.2 g, corn starch 129 g, crystalline cellulose 30 g, SYLYSIA 5.7 g, magnesium stearate (Taihei Chemical Industry) 5.7 g were mixed to obtain a mixed powder for tableting. A rotary tablet press (AQU3, Kikusui Seisakusho) was used. The obtained tableting mixed powder was tableted with a pestle to make a tablet mass of 190 mg and a tablet with a thickness of 4.0 mm.

[0116] Next, a base coating solution consisting of hypromellose (Shin-Etsu Chemical Co., Ltd.) and sterile talc (Matsumura Industry Co., Ltd.) dissolved or dispersed in purified water, and a build-up coating solution consisting of erythritol (Cargill Japan), sterile talc, precipitated calcium carbonate (Nitto Powder Industry Co., Ltd.), titanium oxide (Ishihara Industry Co., Ltd.), crystalline cellulose (CEOLUS PH-F20, Asahi Kasei Co., Ltd.), and gum arabic powder (Sanei Pharmaceutical Trading Co., Ltd.) dissolved or dispersed in purified water were applied using a coating machine (Doria Coater, Powrex) at a coating rate of 10 mg and 80 mg per tablet, respectively. Furthermore, a syrup consisting of refined white sugar (Mitsui Sugar Co., Ltd.), erythritol, and riboflavin dissolved in purified water was applied using a sugar coating machine (Kikusui Seisakusho Co., Ltd.) at a coating rate of 20 mg per tablet, thereby producing sugar-coated tablets.

[0117] (Example 10)

[0118] Nicotinamide (Lonza Japan), riboflavin (BASF Japan), pyridoxine hydrochloride (BASF Japan), lactose hydrate (GranuLac 200, Meggle), corn starch (Japan Corn Starch), and pregelatinized starch (PD-1, Asahi Kasei) were placed in a fluidized bed granulator and sprayed with an HPC solution. Granulation and drying were performed, and the mixture was then granulated using a granulator (POWERMILL) to obtain granulated powder 1. The composition of granulated powder 1 was 13.7% nicotinamide, 4.1% riboflavin, 17.2% pyridoxine hydrochloride, 7.2% lactose hydrate, 36.8% corn starch, 13.7% pregelatinized starch, and 7.2% HPC.

[0119] Separately, fursultiamine hydrochloride (Mikuni Pharmaceutical), corn starch, crystalline cellulose (CEOLUS PH-101, Asahi Kasei), and SYLYSIA (Fuji Silysia) were placed in a fluidized bed granulator and sprayed with an HPC solution. Granulation and drying were then performed, followed by granulation using a granulator (POWERMILL) to obtain granulated powder 2. The composition of granulated powder 2 was 77.4% fursultiamine hydrochloride, 8.6% corn starch, 0.4% SYLYSIA, 6.4% crystalline cellulose, and 7.2% HPC.

[0120] The obtained whole grain powder 1: 582 g, whole grain powder 2: 282 g, calcium pantothenate type S (BASF Japan) 92.4 g, VB12 fine granules (Mitsubishi-Chemical Foods) 13.2 g, corn starch 129 g, crystalline cellulose 30 g, SYLYSIA 5.7 g, magnesium stearate (Taihei Chemical Industry) 5.7 g were mixed to obtain a mixed powder for tableting. A rotary tablet press (AQU3, Kikusui Seisakusho) was used. The obtained tableting mixed powder was tableted with a pestle to make a tablet mass of 190 mg and a tablet with a thickness of 4.0 mm.

[0121] Next, a base coating solution consisting of hypromellose (Shin-Etsu Chemical Co., Ltd.) and sterile talc (Matsumura Industry Co., Ltd.) dissolved or dispersed in purified water, and a build-up coating solution consisting of erythritol (Cargill Japan), sterile talc, precipitated calcium carbonate (Nitto Powder Industry Co., Ltd.), titanium oxide (Ishihara Industry Co., Ltd.), crystalline cellulose (CEOLUS PH-F20, Asahi Kasei Co., Ltd.), and gum arabic powder (Sanei Pharmaceutical Trading Co., Ltd.) dissolved or dispersed in purified water were applied using a coating machine (Doria Coater, Powrex) at a coating rate of 10 mg and 80 mg per tablet, respectively. Furthermore, a syrup consisting of refined white sugar (Mitsui Sugar Co., Ltd.), erythritol, and riboflavin dissolved in purified water was applied using a sugar coating machine (Kikusui Seisakusho Co., Ltd.) at a coating rate of 20 mg per tablet, thereby producing sugar-coated tablets.

[0122] (Example 11)

[0123] Nicotinamide (Lonza Japan), riboflavin (BASF Japan), pyridoxine hydrochloride (BASF Japan), lactose hydrate (GranuLac 200, Meggle), corn starch (Japan Corn Starch), and pregelatinized starch (PD-1, Asahi Kasei) were placed in a fluidized bed granulator and sprayed with an HPC solution. Granulation and drying were performed, and the mixture was then granulated using a granulator (POWERMILL) to obtain granulated powder 1. The composition of granulated powder 1 was 13.7% nicotinamide, 4.1% riboflavin, 17.2% pyridoxine hydrochloride, 7.2% lactose hydrate, 43.7% corn starch, 6.9% pregelatinized starch, and 7.2% HPC.

[0124] Separately, fursultiamine hydrochloride (Mikuni Pharmaceutical), corn starch, crystalline cellulose (CEOLUS PH-101, Asahi Kasei), and SYLYSIA (Fuji Silysia) were placed in a fluidized bed granulator and sprayed with an HPC solution. Granulation and drying were then performed, followed by granulation using a granulator (POWERMILL) to obtain granulated powder 2. The composition of granulated powder 2 was 77.4% fursultiamine hydrochloride, 8.6% corn starch, 0.4% SYLYSIA, 6.4% crystalline cellulose, and 7.2% HPC.

[0125] The obtained whole grain powder 1: 582 g, whole grain powder 2: 282 g, calcium pantothenate type S (BASF Japan) 92.4 g, VB12 fine granules (Mitsubishi-Chemical Foods) 13.2 g, corn starch 129 g, crystalline cellulose 30 g, SYLYSIA 5.7 g, magnesium stearate (Taihei Chemical Industry) 5.7 g were mixed to obtain a mixed powder for tableting. A rotary tablet press (AQU3, Kikusui Seisakusho) was used. The obtained tableting mixed powder was tableted with a pestle to make a tablet mass of 190 mg and a tablet with a thickness of 4.0 mm.

[0126] Next, a base coating solution consisting of hypromellose (Shin-Etsu Chemical Co., Ltd.) and sterile talc (Matsumura Industry Co., Ltd.) dissolved or dispersed in purified water, and a build-up coating solution consisting of erythritol (Cargill Japan), sterile talc, precipitated calcium carbonate (Nitto Powder Industry Co., Ltd.), titanium oxide (Ishihara Industry Co., Ltd.), crystalline cellulose (CEOLUS PH-F20, Asahi Kasei Co., Ltd.), and gum arabic powder (Sanei Pharmaceutical Trading Co., Ltd.) dissolved or dispersed in purified water were applied using a coating machine (Doria Coater, Powrex) at a coating rate of 10 mg and 80 mg per tablet, respectively. Furthermore, a syrup consisting of refined white sugar (Mitsui Sugar Co., Ltd.), erythritol, and riboflavin dissolved in purified water was applied using a sugar coating machine (Kikusui Seisakusho Co., Ltd.) at a coating rate of 20 mg per tablet, thereby producing sugar-coated tablets.

[0127] (Comparative Example 1)

[0128] Nicotinamide (Lonza Japan), riboflavin (BASF Japan), pyridoxine hydrochloride (BASF Japan), and crystalline cellulose (CEOLUS PH-101, Asahi Kasei) were placed in a fluidized bed granulator and sprayed with a hydroxypropylcellulose (HPC, Nippon Soda) solution. Granulation and drying were then performed, followed by granulation using a POWERMILL granulator to obtain granulated powder 1. The composition of granulated powder 1 was 11.1% nicotinamide, 3.3% riboflavin, 13.9% pyridoxine hydrochloride, 68.4% crystalline cellulose, and 3.3% HPC.

[0129] Separately, fursultiamine hydrochloride (Mikuni Pharmaceutical) and crystalline cellulose (CEOLUS PH-101, Asahi Kasei) were placed in a fluidized bed granulator and sprayed with a hydroxypropylcellulose solution. Granulation and drying were then performed, followed by granulation using a POWERMILL granulator to obtain granulated powder 2. The composition of granulated powder 2 was 60.6% fursultiamine hydrochloride, 35.4% crystalline cellulose, and 4% HPC.

[0130] The obtained whole granule powder 1: 720 g, whole granule powder 2: 360 g, calcium pantothenate type S (BASF Japan) 92.4 g, VB12 fine particles (Mitsubishi-Chemical Foods) 13.2 g, crystalline cellulose (CEOLUS PH-101, Asahi Kasei) 127.3 g, and magnesium stearate (Taihei Chemical Industry) 6.6 g were mixed to obtain a mixed powder for tableting. A rotary tablet press (AQU3, Kikusui Seisakusho) was used. The obtained tableting mixture was tableted with a pestle to obtain a tablet mass of 220 mg and a thickness of 4.7 mm.

[0131] Next, a base coating solution consisting of hypromellose (Shin-Etsu Chemical Co., Ltd.) and sterile talc (Matsumura Industry Co., Ltd.) dissolved or dispersed in purified water, and a build-up coating solution consisting of erythritol (Cargill Japan), sterile talc, precipitated calcium carbonate (Nitto Powder Industry Co., Ltd.), titanium oxide (Ishihara Industry Co., Ltd.), crystalline cellulose (CEOLUS PH-F20, Asahi Kasei Co., Ltd.), and gum arabic powder (Sanei Pharmaceutical Trading Co., Ltd.) dissolved or dispersed in purified water were applied using a coating machine (Doria Coater, Powrex) at a coating weight of 5 mg and 96 mg per tablet, respectively. Furthermore, a syrup consisting of refined white sugar (Mitsui Sugar Co., Ltd.), erythritol, and riboflavin dissolved in purified water was applied using a sugar coating machine (Kikusui Seisakusho Co., Ltd.) at a coating weight of 24 mg per tablet, thereby producing sugar-coated tablets.

[0132] (Comparative Example 2)

[0133] Nicotinamide (Lonza Japan), riboflavin (BASF Japan), pyridoxine hydrochloride (BASF Japan), crystalline cellulose (CEOLUS PH-101, Asahi Kasei), lactose hydrate (GranuLac 200, Meggle), and corn starch (Japan Corn Starch) were placed in a fluidized bed granulator and sprayed with a hydroxypropylcellulose (HPC, Nippon Soda) solution. Granulation and drying were performed, and the mixture was then granulated using a POWERMILL granulator to obtain granulated powder 1. The composition of granulated powder 1 was 13.7% nicotinamide, 4.1% riboflavin, 17.2% pyridoxine hydrochloride, 51.5% crystalline cellulose, 7.2% lactose hydrate, 2.5% corn starch, and 3.8% HPC.

[0134] Furthermore, thiamine nitrate (Watanabe Chemical Industries), corn starch, and crystalline cellulose (CEOLUS PH-101, Asahi Kasei) were added to a fluidized bed granulator and sprayed with a hydroxypropylcellulose solution. Granulation and drying were performed, and then granulation was performed using a granulator (POWERMILL) to obtain granulated powder 2. The composition ratio of granulated powder 2 was thiamine nitrate 74.3%, corn starch 7.6%, crystalline cellulose 14.3%, and HPC 3.9%.

[0135] The resulting whole grain powder 1: 582 g, whole grain powder 2: 294 g, calcium pantothenate type S (BASF Japan) 92.4 g, VB12 fine granules (Mitsubishi-Chemical Foods) 13.2 g, corn starch 69 g, crystalline cellulose (CEOLUS PH-F20, Asahi Kasei) 78 g, SYLYSIA (Fuji Silysia), 5.7 g, and magnesium stearate (Taihei Chemical Industry) 5.7 g were mixed to obtain a mixed powder for tableting. The mixed powder for tableting was compressed using a rotary tablet press (AQU3, Kikusui Seisakusho) using an 8.5 mm diameter pestle to obtain tablets with a mass of 190 mg and a thickness of 4.2 mm.

[0136] Next, a base coating solution consisting of hypromellose (Shin-Etsu Chemical Co., Ltd.) and sterile talc (Matsumura Industry Co., Ltd.) dissolved or dispersed in purified water, and a build-up coating solution consisting of erythritol (Cargill Japan), sterile talc, precipitated calcium carbonate (Nitto Powder Industry Co., Ltd.), titanium oxide (Ishihara Industry Co., Ltd.), crystalline cellulose (CEOLUS PH-F20, Asahi Kasei Co., Ltd.), and gum arabic powder (Sanei Pharmaceutical Trading Co., Ltd.) dissolved or dispersed in purified water were applied using a coating machine (Doria Coater, Powrex) at a coating volume of 6 mg and 80 mg per tablet, respectively. Furthermore, a syrup consisting of refined white sugar (Mitsui Sugar Co., Ltd.), erythritol, and riboflavin dissolved in purified water was applied using a sugar coating machine (Kikusui Seisakusho Co., Ltd.) at a coating volume of 20 mg per tablet, thereby producing sugar-coated tablets.

[0137] (Test Example 1)

[0138] Stability of sugar-coated tablets (evaluation of tablet appearance)

[0139] Sugar-coated tablets from Examples and Comparative Examples were stored in sealed glass bottles at 60°C and in open glass bottles at 40°C and 75% RH. Sugar-coated tablets with poor appearance after storage were removed and the remaining good tablet rate was calculated. Poor appearance refers to cracks in the sugar coating layer on the side of the tablet.

[0140] [Number 1]

[0141] Good product retention rate = (number of good products after storage / number of products before storage) × 100

[0142] In Comparative Examples 1 and 2, the remaining good product ratios after sealed storage at 60°C were 47.5% and 0%, respectively, indicating significant deterioration in tablet appearance. On the other hand, no appearance defects were observed in Examples 1 to 11, confirming stability.

[0143]

[0144]

[0145]

[0146] In Comparative Examples 1 and 2, the remaining good tablets after storage in the opened glass bottles at 40°C and 75% RH were 0% and 31.0%, respectively, demonstrating significant deterioration in tablet appearance quality. On the other hand, in Examples 1 to 11, the remaining good tablets were as high as 80% or more, confirming stability.

[0147]

[0148]

[0149]

[0150] Industrial Applicability

[0151] By adding processed starches such as pregelatinized starch, a solid preparation with a stable appearance can be provided even when containing niacin and vitamin B1. Such a solid preparation, for example, a tablet, exhibits excellent stability without causing appearance defects such as cracking or chipping.

Claims

1. A tablet comprising niacin, vitamin B1 and alpha-modified starch. in, The amount of pregelatinized starch is 3.5 parts by mass or more and 20 parts by mass or less relative to 1 part by mass of niacin. The nicotinic acid is nicotinamide, The vitamin B1 is fursultiamine or fursultiamine hydrochloride.

2. The tablet according to claim 1, wherein The alpha-starch is partially alpha-starched. The tablet according to claim 1 or 2, comprising niacin, vitamin B1 and pregelatinized starch in a state not physically separated.

4. A method for inhibiting expansion or cracking of a tablet containing niacin and vitamin B1, the method comprising: 3.5 parts by mass or more and 20 parts by mass or less of pregelatinized starch are added to 1 part by mass of niacin. The nicotinic acid is nicotinamide, The vitamin B1 is fursultiamine or fursultiamine hydrochloride.

Images