Vitamin b12 containing solid preparation

Abstract

To provide a solid preparation containing vitamin B12, vitamin B1 derivatives or their salts, other vitamins and crude drugs.SOLUTION: A solid preparation containing the following components (1) - (3): (1) a vitamin B12 compound, (2) (2-1) a vitamin B1 derivative or a salt thereof, (2-2) at least one member selected from a vitamin B2 compound, a vitamin B6 compound, and a nicotinic acid compound, and (3) a crude drug or an extract of the crude drug or the vitamin B1 derivative or the salt thereof, wherein: The solid preparation is characterized in that the component (1) and the component (2) are separate granules, or only one of the component (1) and the component (2) is a granule and the other component is not contained in the granule.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention is directed to the use of vitamin B 12 The present invention relates to a solid preparation containing a vitamin B1 derivative or a salt thereof, at least one selected from the group consisting of vitamin B2, vitamin B6 and nicotinic acid, and a herbal medicine or an extract thereof, and a method for producing the same. [Background technology]

[0002] Pharmaceutical preparations containing multiple medicinal ingredients are widely used, and pharmaceutical preparations containing B vitamins and herbal medicines are commercially available. Some medicinal ingredients are subject to a decrease in stability, particularly in the amount of the ingredient, during storage. If the amount of the active ingredient decreases significantly, the desired effect may not be achieved or unexpected adverse events may occur, so the stability of pharmaceutical preparations is extremely important.

[0003] Patent Document 1 describes a combination of cinnamon bark, thiamine nitrate (vitamin B1), and cyanocobalamin (vitamin B 12 ) are disclosed. Patent Documents 2 and 3 also disclose tablets containing the herbal medicine of cinnamon bark or ginseng extract, vitamin B1, and vitamin B 12 However, Patent Documents 1 to 3 do not specifically describe the manufacturing method of the tablets, such as granulation. In addition, the examples in Patent Document 4 include a combination of dried shigoka extract, bis-ibutiamine (a vitamin B1 derivative), and vitamin B 12 It is also described that all of the tablet components are mixed and ground, and then wet granulated. Furthermore, Patent Document 5 discloses a liquid preparation containing carrots and B vitamins.

[0004] All of the above documents contain information on the use of herbal medicines or their extracts with vitamin B1 or its derivatives and vitamin B 12 It has been reported that vitamin B 12In a solid preparation containing a compound of a vitamin B1 derivative or its salt, at least one selected from a vitamin B2 derivative, a vitamin B6 derivative and a nicotinic acid derivative, and a herbal medicine or an extract thereof, the compound is characterized in that the vitamin B 12 There is no mention of a significant decrease in the content of these compounds. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] JP 6-107553 [Patent Document 2] Patent Publication No. 2003-88329 [Patent Document 3] Special Publication 2006-503844 [Patent Document 4] JP 9-143088 [Patent Document 5] Patent Publication No. 2004-189619 Summary of the Invention [Problem to be solved by the invention]

[0006] The present inventors have investigated the effects of (1) vitamin B 12 (2) In a solid preparation containing (2-1) a vitamin B1 derivative or its salt, (2-2) at least one selected from vitamin B2, vitamin B6 and nicotinic acid, and (3) a herbal medicine or an extract thereof, the amount of vitamin B during storage of the solid preparation is 12 Therefore, it has been found that the content of vitamin B in a solid preparation containing the above ingredients (1) to (3) is significantly reduced. 12 The object of the present invention is to provide a stable solid preparation in which a decrease in the content of In this specification, with regard to component (2), "a vitamin B1 derivative or a salt thereof, and at least one selected from vitamins B2, vitamin B6, and nicotinic acids" may be collectively referred to as "other vitamins." [Means for solving the problem]

[0007] As a result of extensive research to solve the above problems, the present inventors have found that a solid preparation containing the above ingredients (1) to (3) contains: (1) vitamin B 12 (1) Vitamin B1 and (2) other vitamins are made into separate granules, or 12 By granulating only one of the vitamins from (1) and (2) other groups and not including the other component in the granules, the vitamin B 12 The inventors discovered that the decrease in the content of these compounds can be suppressed, and thus completed the invention. That is, the present invention includes the following aspects. [1] The following ingredients (1) to (3): (1) Vitamin B 12 kind, (2) (2-1) a vitamin B1 derivative or a salt thereof, (2-2) at least one selected from vitamin B2, vitamin B6, and nicotinic acid, and (3) Herbal medicines or their extracts A solid formulation comprising: Component (1) and component (2) are separate granules, or Only one of component (1) and component (2) is a granulated product, and the other component is not contained in the granulated product. A solid formulation characterized by: [2] Vitamin B 12 The solid formulation according to [1], wherein the compound is cyanocobalamin. [3] The solid formulation according to [1] or [2], wherein the vitamin B1 derivative or its salt is fursultiamine or its salt. [4] The solid formulation according to any one of [1] to [3], wherein the herbal medicine or extract thereof comprises at least one selected from Astragalus Root, Schizosaccharum Root, Ginseng, Eucommia Root, Peony Root, Poria Coccus, Dioscorea Root, Cinnamon Bark, Lycium Bark, and Atractylodes Rhizome, and extracts thereof. [5] The following ingredients (1) to (3): (1) Vitamin B 12 kind, (2) (2-1) a vitamin B1 derivative or a salt thereof, (2-2) at least one selected from vitamin B2, vitamin B6, and nicotinic acid, and (3) Herbal medicines or their extracts A method for producing a solid formulation comprising: Component (1) and component (2) are separately granulated to produce a solid dosage form, or The composition is produced by granulating only one of the components (1) and (2) and then adding the other component. Manufacturing method. [Effects of the Invention]

[0008] According to the present invention, (1) vitamin B 12 (2) A solid preparation containing (2-1) a vitamin B1 derivative or its salt, (2-2) at least one selected from vitamin B2, vitamin B6 and nicotinic acid, and (3) a herbal medicine or an extract thereof, 12 Therefore, according to the present invention, it is possible to provide a solid preparation containing the above components (1) to (3), in which the decrease in the content of the components in the preparation is suppressed. DETAILED DESCRIPTION OF THE INVENTION

[0009] As used herein, vitamin B 12 "Vitamin B" refers to a general term for vitamins containing cobalt. 12 Vitamin B 12 , its derivatives and salts thereof. 12 Examples of "vitamin B" include hydroxocobalamin, adenosylcobalamin, methylcobalamin, cyanocobalamin, sulfidocobalamin, aquacobalamin, mecobalamin, and deoxyadenosylcobalamin, as well as salts thereof. Examples of the salts include inorganic acid salts such as hydrochlorides, and organic acid salts such as acetates. 12The vitamin B serotonin may be in the form of a solvate (e.g., a hydrate). 12 The "vitamin B" is preferably hydroxocobalamin hydrochloride, hydroxocobalamin acetate, cyanocobalamin, mecobalamin or hydroxocobalamin, more preferably cyanocobalamin. 12 The classes may be used alone or in combination of two or more. These B vitamins 12 The compounds of the type are known compounds and can be produced by known methods, or commercially available compounds can be used. Vitamin B contained in the solid preparation of the present invention 12 The amount of such compounds is not particularly limited, but may be, for example, a lower limit of 0.002% by mass or more, 0.003% by mass or more, 0.005% by mass or more, or 0.006% by mass or more, and an upper limit of 3% by mass or less, 1% by mass or less, or 0.1% by mass or less, relative to the entire solid preparation, and may be, for example, 0.002 to 3% by mass, preferably 0.003 to 1% by mass, and more preferably 0.003 to 0.1% by mass or 0.005 to 1% by mass.

[0010] As used herein, vitamin B1 refers to thiamine. As used herein, "vitamin B1 derivatives or salts thereof" refers to thiamine derivatives or salts thereof. As used herein, "vitamin B1 derivatives or salts thereof" includes, for example, bisthiamine, thiamine disulfide, dicethiamine, fursultiamine, octotiamine, sicotiamine, bis-ibutiamine, bis-bentiamine, prosultiamine, and benfotiamine, as well as salts thereof. Examples of such salts include inorganic acid salts such as hydrochlorides, nitrates, nitrates, and sulfates. The vitamin B1 derivatives or salts thereof may be in the form of a solvate (e.g., hydrate). In this specification, the "vitamin B1 derivative or its salt" is preferably bisthiamine nitrate, thiamine disulfide, dicethiamine hydrochloride, fursultiamine, fursultiamine hydrochloride, octotiamine, sicotiamine, bis-ibutiamine, bis-bentiamine, prosultiamine or benfotiamine, more preferably fursultiamine or its salt, particularly preferably fursultiamine or fursultiamine hydrochloride. These vitamin B1 derivatives or their salts can be used alone or in combination of two or more. These vitamin B1 derivatives or salts thereof are known compounds and can be produced by known methods, or commercially available products can be used. The amount of vitamin B1 derivative or its salt contained in the solid preparation of the present invention is not particularly limited, but may be, for example, a lower limit of 0.1 mass% or more, 0.3 mass% or more, or 0.5 mass% or more, and an upper limit of 50 mass% or less, 40 mass% or less, or 20 mass% or less, relative to the entire solid preparation, and may be, for example, 0.1 to 50 mass%, preferably 0.3 to 40 mass%, and more preferably 0.5 to 20 mass%.

[0011] As used herein, vitamin B2 refers to riboflavin. The term "vitamin B2s" as used herein encompasses vitamin B2, its derivatives, and salts thereof. Examples of "vitamin B2s" as used herein include riboflavin, riboflavin esters such as riboflavin phosphate, riboflavin acetate, and riboflavin butyrate, and flavin adenine dinucleotide, as well as salts thereof. Examples of such salts include alkali metal salts such as sodium salts. Vitamin B2s may be in the form of solvates (e.g., hydrates). As used herein, "vitamin B2s" is preferably riboflavin, riboflavin sodium phosphate, riboflavin butyrate, or flavin adenine dinucleotide sodium, more preferably riboflavin. These vitamin B2s may be used alone or in combination. These vitamin B2 compounds are known compounds and can be produced by known methods, or commercially available products can be used. The amount of vitamin B2 contained in the solid preparation of the present invention is not particularly limited, but may be, for example, a lower limit of 0.001% by mass or more, 0.01% by mass or more, or 0.5% by mass or more, and an upper limit of 5% by mass or less, 3% by mass or less, or 2% by mass or less, relative to the entire solid preparation, and may be, for example, 0.001 to 5% by mass, preferably 0.01 to 3% by mass, and more preferably 0.5 to 2% by mass.

[0012] As used herein, vitamin B6 refers to compounds having vitamin B6 activity. The term "vitamin B6s" as used herein encompasses vitamin B6, its derivatives, and their salts. Examples of "vitamin B6s" as used herein include pyridoxine, pyridoxal, and pyridoxamine, as well as their salts or esters. Examples of such salts include alkali metal salts such as sodium salts, and inorganic acid salts such as hydrochlorides. Examples of such esters include phosphate esters such as pyridoxine phosphate, pyridoxal phosphate, and pyridoxamine phosphate. Vitamin B6s may be in the form of solvates (e.g., hydrates). The term "vitamin B6s" as used herein is preferably pyridoxine hydrochloride, pyridoxal phosphate ester, or pyridoxal phosphate ester hydrate, more preferably pyridoxine hydrochloride. These vitamin B6s may be used alone or in combination. These vitamin B6 compounds are known compounds and can be produced by known methods, or commercially available products can be used. The amount of vitamin B6 contained in the solid preparation of the present invention is not particularly limited, but may be, for example, a lower limit of 0.01% by mass or more, 0.1% by mass or more, or 1% by mass or more, and an upper limit of 30% by mass or less, 25% by mass or less, or 10% by mass or less, relative to the entire solid preparation, and may be, for example, 0.01 to 30% by mass, preferably 0.1 to 25% by mass, and more preferably 1 to 10% by mass.

[0013] As used herein, "nicotinic acids" encompass nicotinic acid, its derivatives, and salts thereof. Examples of "nicotinic acids" as used herein include nicotinic acid, nicotinamide, nicotinic acid esters (e.g., nicotinic acid methyl ester, nicotinic acid β-butoxyethyl ester, nicotinic acid benzyl ester, inositol hexanicotinate, and hepronicate), nicotinamide adenine dinucleotide, and nicotinamide adenine dinucleotide phosphate, as well as salts thereof. Examples of such salts include alkali metal salts such as sodium salts. As used herein, nicotinic acid and nicotinamide are collectively referred to as "niacin." As used herein, "nicotinic acids" are preferably nicotinic acid, nicotinamide, niacin, sodium nicotinate, or nicotinic acid methyl ester, more preferably nicotinic acid, nicotinamide, or niacin, and particularly preferably nicotinamide. These nicotinic acids may be used alone or in combination. These nicotinic acids are known compounds and can be produced by known methods, or commercially available products can be used. The amount of nicotinic acids contained in the solid preparation of the present invention is not particularly limited, and may be, for example, a lower limit of 0.1% by mass or more, 0.5% by mass or more, or 1% by mass or more, and an upper limit of 50% by mass or less, 40% by mass or less, or 25% by mass or less, relative to the entire solid preparation, and may be, for example, 0.01 to 50% by mass, preferably 0.5 to 40% by mass, and more preferably 1 to 25% by mass.

[0014] In this specification, the herbal medicines may be in the form of bulk powder, chopped or cut herbal medicine, or powdered herbal medicine. "Chopped herbal medicine" or "cut herbal medicine" refers to whole herbal medicines cut or crushed into small pieces or chunks, or roughly, medium, or finely chopped, while "powdered herbal medicine" refers to whole or cut herbal medicines that have been made into a coarse, medium, fine, or fine powder. In this specification, powdered herbal medicines made by powdering herbal medicines such as Astragalus Root and Shigoka may be referred to as Astragalus Root powder, Shigoka powder, etc.

[0015] As used herein, "herbal extract" refers to a product obtained by subjecting herbal medicines to extraction processing and contains extracted components of the herbal medicines. Herbal extracts can be obtained by conventional methods, for example, by extracting raw materials using an extraction solvent at an appropriate temperature (low temperature or high temperature). The extraction solvent can be selected appropriately, for example, water, a hydrophilic solvent, or a mixture thereof. Ethanol is preferably used as the hydrophilic solvent. The herbal extract may be a liquid extract as is, a liquid extract diluted with water, a liquid extract concentrate, or a liquid extract dried. Therefore, as used herein, "herbal extract" includes liquid extracts, extracts, dried extracts, extract powders, soft extracts, liquid extracts, tinctures, etc.

[0016] In this specification, the amount of a herbal medicine or its extract may be expressed in terms of the amount of the original herbal medicine. When the herbal medicine extract is a liquid extract or a liquid extract diluted with a solvent such as water, the amount may be expressed in terms of mass.

[0017] The total amount of herbal medicines or extracts thereof contained in the solid preparation of the present invention is not particularly limited, but may be, for example, a lower limit of 1% by mass or more, 10% by mass or more, or 20% by mass or more, and an upper limit of 250% by mass or less, 200% by mass or less, 150% by mass or less, or 100% by mass or less, and may be, for example, 1 to 250% by mass, preferably 1 to 200% by mass, in terms of the amount of crude herbal medicine relative to the entire solid preparation. Furthermore, the total amount of herbal medicines or extracts thereof contained in the solid preparation of the present invention is not particularly limited, but when each herbal medicine is an extract, for example, the lower limit may be 0.5% by mass or more, 1% by mass or more, or 3% by mass or more, and the upper limit may be 50% by mass or less, 30% by mass or less, or 20% by mass, and may be, for example, 0.5 to 50% by mass, preferably 1 to 30% by mass, and more preferably 3 to 20% by mass. Furthermore, the total amount of herbal medicines or extracts thereof contained in the solid preparation of the present invention is not particularly limited, but when each herbal medicine is in the form of bulk powder, for example, the lower limit may be 1% by mass or more, 3% by mass or more, or 5% by mass or more, and the upper limit may be 50% by mass or less, 30% by mass or less, or 20% by mass, and may be, for example, 1 to 50% by mass, preferably 3 to 30% by mass, and more preferably 5 to 20% by mass. The total amount of the herbal medicine or extract thereof contained in the solid preparation of the present invention is not particularly limited, but when the herbal medicine contains a combination of an extract and bulk powder, for example, the lower limit is 1% by mass or more, 5% by mass or more, or 10% by mass or more, and the upper limit is 80% by mass or less, 50% by mass or less, or 30% by mass, and can be, for example, 1 to 80% by mass, preferably 5 to 50% by mass, and more preferably 10 to 30% by mass.

[0018] Examples of "crude drugs or extracts thereof" in the present specification include Mallotus japonicus, Acacia japonica, Hydrangea tea, Gum arabic, Aloe vera, Anthocephalum chinensis, Irei saffron, Inchinko, Echinacea chinensis, Fennel, Turmeric, Uva-ursi, Atractylodes oryzae, Corydalis chinensis, Astragalus chinensis, Scutellaria baicalensis, Phellodendron bark, Coptis chinensis, Onion root, Spirea chinensis, Kagosou, Zedoary, Cuckoo Root, Pueraria lobata, Kasseki, Valerian, Kalocornis chinensis, Kankyo, Glycyrrhiza uralensis, Agar, Platycodon grandiflorum, Chrysanthemum chrysanthemum, Catalpa, Phellodendron chinensis, and Kyo. Licorice, Chinese laurel, Goji berry, Sophora root, Cinnamon bark, Cassia japonica, Gentian, Gentian laurel, Koi, Kouka, Kojin, Magnolia, Kobushi, Kobei, Kobo, Goshitsu, Goshuyu, Burdock, Sesame, Gomizushi, Colombo, Condoranguo, Bupleurum, Spice, Saffron, Japanese hawthorn, Japanese hawthorn, Chinese laurel, Japanese pepper, Chinese laurel, Dioscorea root, Rehmannia root, Dioscorea, Lithospermum root, Lithospermum root, Shakanzo, Peony, Jasmine, Chinese laurel, Chinese laurel, Chinese laurel , Ginger, Garlic, Cardamom, Ginger, Shini, Shingi, Sekko, Senega, Cnidium, Zenko, Senkotsu, Senso, Senna, Swertia, Soju, Sohakuhi, Sobok, Soybean, Rhubarb, Chinese ginseng, Chimo, Clove, Chotoko, Chorei, Chinpi, Tenma, Tenmondou, Togashi, Togashi, Togashi, Tonin, Touhi, Pork cutlet, Ipecac, Eucommia, Tragacanth, Bitter gourd, Cistanche, Myrrh, Carrot, Bean, Ba Examples of such herbs include potato, burdock root, honey, mint, litchi (thin pea), asiatic flower, white berry, angelica tree, white atractylodes, locust, betel nut, poria, bush clover, belladonnacon, henzu, bowie, scutellaria root, scutellaria bark, scutellaria root, boxwood, moutan pea, vomica, bolei, ephedra, makuri, mashinin, scutellaria root, mukko, yakuchi, yakumosou, yutan, coix seed, longan nut, scutellaria root, scutellaria, rye, forsythia, lotus fruit, rosin, scolyus root, royal jelly, and extracts thereof.Preferably, the "herbal medicine or extract thereof" in the present specification is selected from Astragalus Root, Shigoka Root, Ginseng, Eucommia Root, Peony Root, Poria Cocos, Dioscorea Root, Cinnamon Bark, Lycium Fruit, Atractylodes Rhizome, Astragalus Root, Red Ginseng, Chinese Herb, Cistanche, Longan Fruit, and Atractylodes Rhizome, and extracts thereof, and particularly preferably selected from Astragalus Root, Shigoka Root, Ginseng, Eucommia Root, Peony Root, Poria Cocos, Dioscorea Root, Cinnamon Bark, Lycium Fruit, and Atractylodes Rhizome, and extracts thereof.

[0019] As used herein, "Astragalus membranaceus Bunge" refers to the root of Astragalus membranaceus Bunge or Astragalus mongholicus Bunge (Leguminosae). Astragalus Root or an extract thereof is a known herbal medicine or an extract thereof, and can be produced by a known method or commercially available products can be used. Preferably, Astragalus Root listed in the 18th Edition of the Japanese Pharmacopoeia can be used. The amount of Astragalus membranaceus or an extract thereof contained in the solid preparation of the present invention is not particularly limited, but may be, for example, a lower limit of 0.1% by mass or more or 1% by mass or more and an upper limit of 200% by mass or less or 100% by mass or less, for example, 0.1 to 200% by mass, preferably 1 to 100% by mass, in terms of the amount of crude drug relative to the entire solid preparation. The amount of Astragalus membranaceus or an extract thereof contained in the solid preparation of the present invention is not particularly limited, but in the case of a herbal extract, the amount may be, for example, 0.1% by mass or more or 1% by mass or more as the lower limit and 20% by mass or less or 10% by mass or less as the upper limit, for example, 0.1 to 20% by mass, preferably 1 to 10% by mass, based on the total mass of the solid preparation.

[0020] "Shigoka" as used herein refers to the rhizome, often accompanied by roots, of Eleutherococcus senticosus Maximowicz (Acanthopanax senticosus Harms) (Araliaceae). "Shigoka" as used herein may also be referred to as "Eleutherococcus senticosus." Shigoka or its extract is a known herbal medicine or extract thereof, and can be produced by known methods or commercially available products can be used. Preferably, Shigoka listed in the 18th Edition of the Japanese Pharmacopoeia can be used. The amount of Schizosaccharum or an extract thereof contained in the solid formulation of the present invention is not particularly limited, but may be, for example, a lower limit of 0.1% by mass or more or 1% by mass or more, and an upper limit of 400% by mass or less or 300% by mass or less, and may be, for example, 0.1 to 400% by mass, preferably 1 to 300% by mass, in terms of the amount of the crude drug relative to the entire solid formulation. The amount of Schizosaccharum or an extract thereof contained in the solid formulation of the present invention is not particularly limited, but in the case of a herbal extract, the amount may be, for example, 0.1% by mass or more or 1% by mass or more as a lower limit and 50% by mass or less or 30% by mass or less as an upper limit, for example, 0.1 to 50% by mass, preferably 1 to 30% by mass, relative to the entire solid formulation.

[0021] "Ginseng" in this specification refers to the root of Panax ginseng CA Meyer (Panax schinseng Nees) (Araliaceae) with the fine roots removed or lightly blanched. Preferably, when quantifying ginseng, the content of ginsenoside Rg1 (C 42 H 72 O 14 :801.01) 0.10% or more and ginsenoside Rb1 (C 54 H 92 O 23 :1109.29) Contains 0.20% or more. Ginseng or its extract is a known herbal medicine or extract thereof, and can be produced by known methods or commercially available products can be used. Preferably, ginseng or ginseng powder listed in the 18th Edition of the Japanese Pharmacopoeia can be used. The amount of ginseng or an extract thereof contained in the solid preparation of the present invention is not particularly limited, but may be, for example, a lower limit of 1% by mass or more or 10% by mass or more, and an upper limit of 700% by mass or less or 500% by mass or less, and may be, for example, 1 to 700% by mass, preferably 10 to 500% by mass, in terms of the amount of the crude drug relative to the entire solid preparation. The amount of ginseng or an extract thereof contained in the solid preparation of the present invention is not particularly limited, but in the case of a herbal extract, the amount can be, for example, 0.1% by mass or more or 1% by mass or more as the lower limit and 50% by mass or less or 40% by mass or less as the upper limit, for example, 0.1 to 50% by mass, preferably 1 to 40% by mass, relative to the entire solid preparation.

[0022] "Eucommia" in this specification refers to the bark of Eucommia ulmoides Oliver (Eucommiaceae). Eucommia or its extract is a known herbal medicine or extract thereof, and can be produced by known methods or commercially available products can be used. Preferably, Eucommia listed in the 18th Edition of the Japanese Pharmacopoeia can be used. The amount of Eucommia or an extract thereof contained in the solid preparation of the present invention is not particularly limited, but may be, for example, a lower limit of 0.01% by mass or more or 0.1% by mass or more, and an upper limit of 100% by mass or less or 75% by mass or less, expressed as the amount of the crude drug relative to the entire solid preparation, and may be, for example, 0.01 to 100% by mass, preferably 0.1 to 75% by mass. The amount of Eucommia or an extract thereof contained in the solid preparation of the present invention is not particularly limited, but in the case of a herbal extract, the amount may be, for example, 0.001% by mass or more or 0.01% by mass or more as the lower limit and 30% by mass or less or 15% by mass or less as the upper limit, for example, 0.001 to 30% by mass, preferably 0.01 to 15% by mass, relative to the entire solid preparation.

[0023] The term "peony" as used herein refers to the root of Paeonia lactiflora Pallas (Paeoniaceae). Preferably, when quantifying peony, the content of paeoniflorin (C 23 H 28 O 11 :480.46) Contains 2.0% or more. Peony or its extract is a known herbal medicine or extract thereof, and can be produced by known methods or commercially available products can be used. Preferably, peony or peony powder listed in the 18th revised Japanese Pharmacopoeia can be used. The amount of peony or an extract thereof contained in the solid preparation of the present invention is not particularly limited, but may be, for example, a lower limit of 0.01% by mass or more or 0.1% by mass or more, and an upper limit of 80% by mass or less or 50% by mass or less, expressed as the amount of crude drug relative to the entire solid preparation, and may be, for example, 0.01 to 80% by mass, preferably 0.1 to 50% by mass. The amount of peony or an extract thereof contained in the solid preparation of the present invention is not particularly limited, but in the case of a herbal extract, the amount may be, for example, 0.1% by mass or more or 1% by mass or more as the lower limit and 20% by mass or less or 10% by mass or less as the upper limit, for example, 0.1 to 20% by mass, preferably 1 to 10% by mass, relative to the entire solid preparation.

[0024] In this specification, "pokryo" refers to the sclerotium of Wolfiporia cocos Ryvarden et Gilbertson (Poria cocos Wolf) (Polyporaceae), usually with most of the outer layer removed. Poria cocos or an extract thereof is a known herbal medicine or an extract thereof, and can be produced by a known method or commercially available products can be used. Preferably, Poria cocos or Poria cocos powder listed in the 18th revised Japanese Pharmacopoeia can be used. The amount of Poria cocos or an extract thereof contained in the solid preparation of the present invention is not particularly limited, but may be, for example, a lower limit of 0.01% by mass or more or 0.1% by mass or more and an upper limit of 150% by mass or less or 100% by mass or less, e.g., 0.01 to 150% by mass, preferably 0.1 to 100% by mass, calculated as the amount of the crude drug relative to the entire solid preparation. The amount of Poria cocos or an extract thereof contained in the solid preparation of the present invention is not particularly limited, but in the case of a herbal extract, the amount may be, for example, 0.1% by mass or more or 1% by mass or more as the lower limit and 30% by mass or less or 20% by mass or less as the upper limit, for example, 0.1 to 30% by mass, preferably 1 to 20% by mass, relative to the entire solid preparation.

[0025] In this specification, "Sanyaku" refers to the rhizome (rhizophore) of Dioscorea japonica Thunberg (Japanese yam) or Dioscorea batatas Decaisne (Dioscoreaceae) from which the periderm has been removed. The dioscorea root or its extract is a known herbal medicine or extract thereof, and can be produced by known methods or commercially available products can be used. Preferably, the dioscorea root or dioscorea root powder listed in the 18th revised Japanese Pharmacopoeia can be used. The amount of Dioscorea or its extract contained in the solid formulation of the present invention is not particularly limited, but may be, for example, a lower limit of 0.01% by mass or more or 0.1% by mass or more, and an upper limit of 200% by mass or less or 150% by mass or less, for example, 0.01 to 200% by mass, preferably 0.1 to 150% by mass, in terms of the amount of raw herbal medicine relative to the entire solid formulation. The amount of Dioscorea or its extract contained in the solid formulation of the present invention is not particularly limited, but in the case of a herbal extract, the amount may be, for example, 0.1% by mass or more or 1% by mass or more as the lower limit and 80% by mass or less or 50% by mass or less as the upper limit, for example, 0.1 to 80% by mass, preferably 1 to 50% by mass, relative to the entire solid formulation.

[0026] "Cinnamon" in this specification refers to the bark or bark of Cinnamomum cassia J. Presl (Lauraceae) excluding a portion of the periderm. "Cinnamon oil" in this specification refers to an essential oil obtained by steam distillation of the leaves, twigs, or bark of Cinnamomum cassia J. Presl or the bark of Cinnamomum zeylanicum Nees (Lauraceae). Preferably, the cinnamon oil contains 60 vol% or more of total aldehydes when quantified. Cinnamon bark or its extract is a known herbal medicine or extract thereof, and can be produced by known methods or commercially available products can be used. Preferably, cinnamon bark, cinnamon powder, or cinnamon oil listed in the 18th revised Japanese Pharmacopoeia can be used. The amount of cinnamon or its extract contained in the solid preparation of the present invention is not particularly limited, but may be, for example, a lower limit of 0.1% by mass or more or 1% by mass or more, and an upper limit of 100% by mass or less or 50% by mass or less, for example, 0.1 to 100% by mass, preferably 1 to 50% by mass, in terms of the amount of the crude drug relative to the entire solid preparation. The amount of cinnamon or an extract thereof contained in the solid preparation of the present invention is not particularly limited, but in the case of a herbal extract, the amount can be, for example, 0.01% by mass or more or 0.1% by mass or more as the lower limit and 20% by mass or less or 10% by mass or less as the upper limit, for example, 0.01 to 20% by mass, preferably 0.1 to 10% by mass, relative to the entire solid preparation.

[0027] "Lycium chinense" as used herein refers to the fruit of wolfberry Lycium chinense Miller or Lycium barbarum Linne (Solanaceae). Lycium chinense or an extract thereof is a known herbal medicine or an extract thereof, and can be produced by known methods or commercially available products can be used. Preferably, Lycium chinense listed in the 18th Edition of the Japanese Pharmacopoeia can be used. The amount of lycium bark or an extract thereof contained in the solid preparation of the present invention is not particularly limited, but may be, for example, a lower limit of 0.1% by mass or more or 1% by mass or more, and an upper limit of 400% by mass or less or 350% by mass or less, for example, 0.1 to 400% by mass, preferably 1 to 350% by mass, in terms of the amount of the crude drug relative to the entire solid preparation. The amount of lycium bark or an extract thereof contained in the solid preparation of the present invention is not particularly limited, but in the case of a herbal extract, the amount may be, for example, 1% by mass or more or 2% by mass or more as the lower limit and 80% by mass or less or 50% by mass or less as the upper limit, for example, 1 to 80% by mass, preferably 2 to 50% by mass, relative to the entire solid preparation.

[0028] "Shuksha" as used herein refers to the seed masses of Amomum villosum Loureiro var. xanthioides TL Wu et SJ Chen, Amomum villosum Loureiro var. villosum or Amomum longiligulare TL Wu (Zingiberaceae). The Shakusha or its extract is a known herbal medicine or extract thereof, and can be produced by known methods or commercially available products can be used. Preferably, the Shakusha or Shakusha powder listed in the 18th Edition of the Japanese Pharmacopoeia can be used. The amount of Atractylodes or an extract thereof contained in the solid preparation of the present invention is not particularly limited, but may be, for example, a lower limit of 0.01% by mass or more or 0.1% by mass or more, and an upper limit of 200% by mass or less or 100% by mass or less, and may be, for example, 0.01 to 200% by mass, preferably 0.1 to 100% by mass, in terms of the amount of the crude drug relative to the entire solid preparation. The amount of Atractylodes or an extract thereof contained in the solid preparation of the present invention is not particularly limited, but in the case of a herbal extract, the amount may be, for example, 0.1% by mass or more or 1% by mass or more as the lower limit and 50% by mass or less or 25% by mass or less as the upper limit, for example, 0.1 to 50% by mass, preferably 1 to 25% by mass, relative to the entire solid preparation.

[0029] In the solid formulation of the present invention, the above-mentioned herbal medicines or extracts thereof may be used alone or in combination of two or more. The "herbal medicines or extracts thereof" in the present invention is, for example, at least one selected from Astragalus Root, Schizosaccharum Root, Ginseng Root, Eucommia Root, Peony Root, Poria Coccus Root, Dioscorea Root, Cinnamon Bark, Lycium Bark, and Atractylodes Rhizome, and extracts thereof.

[0030] The solid preparation of the present invention may contain any of the above vitamin B 2 as long as it does not inhibit the effects of the present invention. 12 Active ingredients other than vitamin B, vitamin B1 derivatives or salts thereof, vitamin B2, vitamin B6, nicotinic acid, and herbal medicines or extracts thereof, such as antipyretics, analgesics, rhinitis medications, antihistamines, antitussives, expectorants, bronchodilators, gastric mucosa protectants, caffeine, vitamins, hypnotics and sedatives, phlegm dissolving agents, anti-inflammatory agents, anticholinergic agents, and Chinese herbal medicine prescriptions, may also be blended. 12 Active ingredients other than vitamin B1 derivatives or their salts, vitamin B2 derivatives, vitamin B6 derivatives, nicotinic acid derivatives, and herbal medicines or their extracts may be collectively referred to as "other active ingredients."

[0031] Examples of antipyretic analgesics include aspirin (acetylsalicylic acid), aluminum aspirin, acetaminophen, ibuprofen, salicylamide, sodium salicylate, ethenzamide, sazapyrine, lactylphenetidine, ketoprofen, isopropylantipyrine, and loxoprofen sodium. Examples of drugs for rhinitis include pseudoephedrine hydrochloride, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, belladonna total alkaloids, isopropamide iodide, and dipotassium glycyrrhizinate. Examples of antihistamines include diphenhydramine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, alimemazine tartrate, isothipendyl hydrochloride, promethazine methylenedisalicylate, diphenylpyraline hydrochloride, diphenylpyraline teoclate, difeterol hydrochloride, difeterol phosphate, triprolidine hydrochloride hydrate, tripelennamine hydrochloride, thondylamine hydrochloride, fenethazine hydrochloride, methdilazine hydrochloride, carbinoxamine diphenyldisulfonate, mebhydroline napadisilate, carbinoxamine maleate, iproheptine hydrochloride, promethazine hydrochloride, alimemazine tartrate, fenethazine tannate, clemastine fumarate, and mequitazine. Examples of narcotic antitussives include codeine phosphate hydrate, dihydrocodeine phosphate, etc. Examples of non-narcotic antitussives include alloclamide, isoaminil, eprazinone, oxeladin, clofedanol, clobutinol, cloperastine, dibunate, dimemorfan, tipepidine, dextromethorphan, noscapine, hydrocotalnin, pentoxyverine, benproperine, and fominoben, as well as salts and hydrates thereof. Examples of salts and hydrates thereof include alloclamide hydrochloride, cloperastine hydrochloride, cloperastine fendizoate, dibunate sodium, dimemorfan phosphate, tipepidine hibenzate, tipepidine citrate, dextromethorphan hydrobromide, dextromethorphan phenolphthalin salt, pentoxyverine citrate, and hydrates thereof. Examples of expectorants include potassium guaiacolsulfonate, bromhexine hydrochloride, guaifenesin, tipepidine citrate, L-carbocysteine, ammonium chloride, l-menthol, ammonia-fennel extract, and potassium cresolsulfonate. Examples of bronchodilators include dl-methylephedrine hydrochloride, dl-methylephedrine saccharin salt, trimetoquinol hydrochloride, phenylpropanolamine hydrochloride, methoxyphenamine hydrochloride, l-methylephedrine hydrochloride, pseudoephedrine hydrochloride, aminophylline, diprophylline, theophylline, and proxyphylline. Examples of gastric mucosa protective agents include glycine, aminoacetic acid, magnesium silicate, synthetic aluminum silicate, synthetic hydrotalcite, magnesium oxide, dihydroxyaluminum aminoacetate, aluminum hydroxide gel, dried aluminum hydroxide gel, aluminum hydroxide-magnesium carbonate mixed dried gel, co-precipitation product of aluminum hydroxide-sodium bicarbonate, co-precipitation product of aluminum hydroxide-calcium carbonate-magnesium carbonate, co-precipitation product of magnesium hydroxide-aluminum potassium sulfate, and magnesium carbonate. Examples of caffeine compounds include sodium caffeine benzoate, caffeine hydrate, and anhydrous caffeine. Examples of vitamins include vitamin B5 or a derivative or a salt thereof, such as pantothenic acid, vitamin C or a derivative or a salt thereof, such as ascorbic acid, vitamin P (hesperidin) or a derivative or a salt thereof, and the like. Examples of hypnotics and sedatives include allylisopropylacetylurea and bromvalerylurea. Examples of sputum dissolving agents include lysozyme chloride, L-ethylcysteine ​​hydrochloride, and methylcysteine ​​hydrochloride. Examples of anti-inflammatory agents include lysozyme chloride, serraptase, glycyrrhizic acid and its salts, and tranexamic acid and its salts. Examples of anticholinergic agents include belladonna total alkaloids and isopropamide iodide. Examples of Chinese herbal medicine prescriptions include Kakkonto, Kakkonto-ka-kikyo, Keipito, Kososan, Saiko-keipito, Sho-saikoto, Sho-seiryuto, Bakumondo-to, Hange-koboku-to, and Mao-to.

[0032] In addition to the above-mentioned components, the solid preparation of the present invention may further contain pharmaceutically acceptable carriers or additives conventionally used in the pharmaceutical technology field, so long as they do not impair the effects of the present invention. Examples of carriers or additives include excipients, disintegrants, binders, fluidizing agents, lubricants, colorants, pH adjusters, surfactants, stabilizers, flavorings, and fragrances. These carriers or additives are used in amounts conventionally used in the pharmaceutical technology field.

[0033] Examples of excipients include starches such as corn starch, potato starch, wheat starch, rice starch, partially pregelatinized starch, pregelatinized starch, and porous starch; sugars or sugar alcohols such as lactose hydrate, refined sucrose, fructose, glucose, mannitol, sorbitol, erythritol, xylitol, trehalose, maltitol, powdered reduced maltose syrup, and lactitol; anhydrous calcium hydrogen phosphate, crystalline cellulose, powdered cellulose, precipitated calcium carbonate, calcium carbonate, and calcium silicate. Examples of disintegrants that can be used include carmellose, carmellose calcium, sodium carboxymethyl starch, carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose (L-HPC), and hydroxypropyl starch, and preferred are croscarmellose sodium and L-HPC. Examples of binders that can be used include hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), polyvinylpyrrolidone, copolyvidone, powdered gum arabic, methylcellulose, low-substituted hydroxypropyl cellulose, carmellose sodium, dextrin, partially pregelatinized starch, pullulan, gum arabic, agar, gelatin, tragacanth, and sodium alginate, with hydroxypropyl cellulose and hydroxypropyl methylcellulose being preferred. Examples of the fluidizing agent include light anhydrous silicic acid, hydrous silicon dioxide, calcium silicate, magnesium silicate, magnesium aluminometasilicate, and talc, with light anhydrous silicic acid and magnesium aluminometasilicate being preferred. Examples of lubricants include stearic acid, magnesium stearate, calcium stearate, talc, and sucrose fatty acid esters. Examples of coloring agents include yellow ferric oxide, ferric oxide, Food Blue No. 1, Food Blue No. 2, Food Yellow No. 4, Food Yellow No. 5, Food Green No. 3, Food Red No. 2, Food Red No. 3, Food Red No. 102, Food Red No. 104, Food Red No. 105, Food Red No. 106, food lake color, riboflavin, riboflavin sodium phosphate, and titanium oxide. Examples of pH adjusters include citric acid, phosphoric acid, carbonic acid, tartaric acid, fumaric acid, acetic acid, amino acids, and salts thereof. Examples of surfactants include sodium lauryl sulfate, polysorbate 80, polyoxyethylene (160) polyoxypropylene (30) glycol, and the like. Examples of stabilizers include tocopherol, tetrasodium edetate, nicotinamide, and cyclodextrins. Examples of flavoring agents include ascorbic acid, erythritol, citric acid, tartaric acid, malic acid, sucralose, and stevia extract. Examples of flavoring agents include L-menthol, mint oil, lemon oil, and vanillin.

[0034] In one embodiment, the solid formulation of the present invention comprises the following components (1) to (3): (1) Vitamin B 12 kind, (2) (2-1) a vitamin B1 derivative or a salt thereof, (2-2) at least one selected from vitamin B2, vitamin B6, and nicotinic acid, and (3) Herbal medicines or their extracts Includes.

[0035] In one embodiment, the solid formulation of the present invention comprises the following components (1) to (3): (1) Vitamin B 12 kind, (2) Vitamin B1 derivatives or salts thereof, vitamin B2s, vitamin B6s, and nicotinic acids, and (3) Herbal medicines or extracts thereof, preferably at least one selected from Astragalus Root, Shigoka, Ginseng, Eucommia Root, Peony Root, Poria Coccus, Dioscorea Root, Cinnamon Bark, Lycium Bark, and Licorice Root, and extracts thereof Includes.

[0036] In one embodiment, the present invention provides a solid preparation comprising the above-mentioned components (1) to (3), Component (1) and component (2) are separate granules, or Only one of component (1) and component (2) is a granulated product, and the other component is not contained in the granulated product. It is characterized by:

[0037] Therefore, in the solid preparation of the present invention, vitamin B 12 Vitamin B1 derivatives or salts thereof and at least one selected from vitamin B2, vitamin B6, and nicotinic acid are not contained in the same granule. 12 The granules of this type do not contain vitamin B1 derivatives or their salts, vitamin B2, vitamin B6, or nicotinic acid, while the granules of other vitamin groups do not contain vitamin B 12 No species are included. Alternatively, in the solid preparation of the present invention, vitamin B 12 When vitamin B1 derivatives or their salts, vitamin B2, vitamin B6 and nicotinic acid are granulated, 12 If other vitamins are granulated, vitamin B is not included in the granulated form, and other vitamins are included in the solid formulation as non-granulated forms. 12 Vitamin B is not included in the granulation of other vitamin groups. 12This type is included in solid dosage forms as a non-granulated substance.

[0038] Vitamin B in the present invention 12 The granulated product of this type is not considered to be a vitamin B1 derivative or its salt, vitamin B2, vitamin B6, or nicotinic acid derivative. 12 In addition to the above, the solid preparation of the present invention may contain herbal medicines or extracts thereof, other active ingredients and additives as needed. 12 Such granules can be mixed with herbal medicines or their extracts, other active ingredients and additives as needed to prepare formulations.

[0039] The granules of other vitamins (vitamin B1 derivatives or salts thereof and at least one selected from vitamin B2, vitamin B6 and nicotinic acid) of the present invention are vitamin B 12 If the granules do not contain any of the vitamins listed above, they may contain, in addition to other vitamins, herbal medicines or extracts thereof, other active ingredients and additives as needed. Furthermore, in the solid preparation of the present invention, the granules of other vitamins may be mixed with herbal medicines or extracts thereof, other active ingredients and additives as needed to be formulated.

[0040] The other vitamin group in the present invention (vitamin B1 derivatives or salts thereof, and at least one selected from vitamin B2, vitamin B6, and nicotinic acid) is vitamin B 12 If the vitamin B1 derivative or its salt does not contain a vitamin B1 derivative, the components may be in the same granule or in separate granules. For example, a vitamin B1 derivative or its salt and at least one selected from vitamin B2, vitamin B6, and nicotinic acid may be contained in the same granule.

[0041] In the solid preparation of the present invention, the herbal medicines or their extracts each contain vitamin B 12The herbal medicines or their extracts may be contained in a granulated product of the herbal medicines or extracts thereof, or in a granulated product of other vitamins (vitamin B1 derivatives or their salts and at least one selected from vitamin B2, vitamin B6 and nicotinic acid), or in a granulated product of other ingredients, or may be granulated products of only these. Alternatively, the herbal medicines or their extracts may be contained in a solid preparation as non-granulated products.

[0042] Examples of solid preparations of the present invention include tablets (including plain tablets, coated tablets, film-coated tablets, sugar-coated tablets, thin-layer sugar-coated tablets, orally disintegrating tablets, chewable tablets, etc.), capsules, granules, powders, and pills, with tablets being preferred. When the solid preparation of the present invention is a tablet, it may be a multi-layer tablet, for example, a bi-layer tablet. In this specification, a multilayer tablet is a tablet formed from two or more layers having different compositions, and a bilayer tablet is a tablet formed from two layers having different compositions.

[0043] In one embodiment, the present invention provides a composition comprising the following components (1) to (3): (1) Vitamin B 12 kind, (2) (2-1) a vitamin B1 derivative or a salt thereof, (2-2) at least one selected from vitamin B2, vitamin B6, and nicotinic acid, and (3) Herbal medicines or their extracts A method for producing a solid formulation comprising: Component (1) and component (2) are separately granulated to produce a solid dosage form, or The composition is produced by granulating only one of the components (1) and (2) and then adding the other component. Includes manufacturing methods.

[0044] Therefore, in the method for producing the solid preparation of the present invention, 12 When vitamin B1 derivatives or salts thereof and other vitamins (vitamin B2 derivatives, vitamin B6 derivatives, and at least one selected from nicotinic acid derivatives) are separately granulated, vitamin B 12The vitamin B group and other vitamin groups are granulated separately, and then a solid preparation is produced. 12 After granulating the vitamins, other vitamins are added to produce a solid preparation. Alternatively, after granulating the other vitamins, vitamin B 12 and the like to prepare a solid preparation.

[0045] The solid preparation of the present invention can be manufactured using conventional methods, for example, methods described in publications such as Granulation Handbook (edited by the Japan Powder Industry and Engineering Association, Ohmsha), Formulation Design of Orally Administered Preparations (edited by Hashida Mitsuru, Professor, Graduate School of Pharmaceutical Sciences, Kyoto University, Yakugyo Jihosha), Powder Compression Molding Technology (edited by the Powder Engineering, Formulation and Particle Design Committee, Nikkan Kogyo Shimbun), and Pharmaceutical Machinery Technology Handbook (2nd edition, edited by the Editorial Committee for the Publication Commemorating the 20th Anniversary of the Establishment of the Pharmaceutical Machinery Technology Research Association, Pharmaceutical Machinery Technology Research Association).

[0046] The granulation method is not particularly limited, and known methods can be used, such as extrusion granulation, tumbling granulation, stirring granulation, fluidized bed granulation, spray-drying granulation, crushing granulation, melt granulation, etc. If necessary, the obtained granules may be dried, sized, etc. by a method generally used for pharmaceutical preparations.

[0047] For example, when the solid preparation of the present invention is a tablet, vitamin B 12 Vitamin B1 derivatives or salts thereof and at least one selected from vitamin B2, vitamin B6 and nicotinic acid derivatives are separately granulated to obtain a vitamin B1 compound. 12 The granulated products of the above group and the granulated products of other vitamin groups, as well as herbal medicines or extracts thereof, can be compressed into tablets, if necessary, together with further additives, using methods described in publications such as the above-mentioned Granulation Handbook, for example, using various tablet presses commonly used for pharmaceutical preparations (e.g., rotary tablet presses, etc.). Alternatively, vitamin B 12 The vitamin B 12The granulated product of the above group and other vitamins and herbal medicines or extracts thereof may be compressed into tablets together with further additives as needed. Alternatively, the other vitamins may be granulated, and the granulated product of the other vitamins and vitamin B may be compressed into tablets. 12 The herbs and crude drugs or extracts thereof may be compressed into tablets, if necessary, together with further additives.

[0048] When the solid preparation of the present invention is a capsule, vitamin B 12 Vitamin B1 derivatives or salts thereof and at least one selected from vitamin B2, vitamin B6 and nicotinic acid derivatives are separately granulated to obtain a vitamin B1 compound. 12 The granulated product of the vitamin group and the granulated product of other vitamin groups, herbal medicines or extracts thereof, and, if necessary, further additives can be filled into capsules to produce capsules. Alternatively, vitamin B 12 The vitamin B 12 Alternatively, the granulated product of the vitamin group, other vitamins and herbal medicines or extracts thereof, and, if necessary, further additives may be filled into capsules to produce capsules. Alternatively, the other vitamin group may be granulated, and the granulated product of the other vitamin group and vitamin B may be filled into capsules. 12 The herbal medicines and crude drugs or extracts thereof, and optionally further additives, may be filled into capsules to produce capsules.

[0049] The solid preparation of the present invention may be coated by a conventional method using a coating base that is usually blended. For example, a tablet may be coated with a coating base, a sugar coating agent, etc. to form a coated tablet or a sugar-coated tablet. Examples of coating bases include water-soluble bases such as hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose, methylcellulose, povidone, copolyvidone, polyvinyl alcohol, polyvinyl alcohol copolymers, and macrogol; water-insoluble bases such as ethyl cellulose; enteric bases such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, methacrylic acid copolymers, acrylic acid copolymers, and carboxyvinyl polymers; gastrosoluble bases such as polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymers, and polyvinyl acetate diethylaminoacetate; gum arabic, pullulan, carnauba wax, shellac, macrogols, glycerin fatty acid esters, and magnesium stearate. In the present invention, the coating base may be one type or two or more types. Examples of sugar-coating agents include gum arabic, powdered gum arabic, ethyl cellulose, erythritol, carnauba wax, carmellose sodium, crystalline cellulose, titanium oxide, stearic acid, polyoxyl stearate, purified gelatin, purified shellac, purified sucrose, gelatin, shellac, talc, precipitated calcium carbonate, white shellac, sucrose, hydroxypropyl cellulose, hypromellose, povidone, polyoxyethylene polyoxypropylene glycol, polyvinyl alcohol, macrogol, D-mannitol, methylcellulose, etc. In the present invention, one type of sugar-coating agent may be used, or two or more types may be used. Furthermore, coating additives may be used in the coating, such as light blocking agents, fluidizing agents, colorants, and plasticizers. Examples of plasticizers include copolyvidone, polyethylene glycol, triethyl citrate, castor oil, and polysorbate.

[0050] As mentioned above, according to the present invention, vitamin B 12In a solid preparation containing a compound of a vitamin B1 derivative or its salt, at least one selected from a vitamin B2 derivative, a vitamin B6 derivative and a nicotinic acid derivative, and a herbal medicine or an extract thereof, the compound is characterized in that the vitamin B 12 It is possible to suppress the decrease in the content of these compounds.

[0051] As used herein, vitamin B 12 The reduction in the content of these compounds and the suppression thereof can be evaluated using evaluation methods and standards commonly used in the formulation technical field. In one embodiment, "vitamin B 12 The "decrease in vitamin B12 content" refers to the decrease in vitamin B12 content in solid preparations due to storage for a certain period of time. 12 For example, the amount of vitamin B at the start of storage decreases. 12 Vitamin B content after storage compared to the 12 If the content of vitamin B is less than 90%, 12 The content of vitamin B in solid preparations after storage for a certain period of time decreased. 12 The content of vitamin B 12 This can be expressed as the survival rate of a species. In one embodiment, "vitamin B 12 "Suppresses the decrease in vitamin B content" refers to the decrease in vitamin B content in solid preparations after a certain period of storage. 12 For example, the amount of vitamin B at the start of storage is reduced. 12 Vitamin B content after storage compared to the 12 Vitamin B12 is present in foods containing 90% or more of the vitamin B 12 It can be said that the decrease in the content of these compounds was suppressed.

[0052] Vitamin B in the solid formulation herein 12 The content of these compounds can be measured, for example, by the quantitative method described in the section on "hydroxocobalamin acetate," "cyanocobalamin," or "mecobalamin" in the 18th Edition of the Japanese Pharmacopoeia, or by liquid chromatography using high-performance liquid chromatography (HPLC).

[0053] The storage method, period, temperature, humidity, etc. of the solid preparation herein are not particularly limited as long as they are commonly used in the pharmaceutical technical field, and may be, for example, 1, 2, 3, 6, 9, 12, 18, 24, 30, or 36 months at 25° C., 1, 2, 3, 4, 5, or 6 months at 40° C., 1, 2, 4, 6, 8, or 12 weeks at 50° C., or 7, 14, or 21 days at 60° C. When stored at 25° C., the relative humidity may be, for example, 60% RH, and when stored at 40° C., the relative humidity may be 75% RH. [Example]

[0054] The present invention will be described in more detail below with reference to examples, but the present invention is not limited to these examples.

[0055] (Reference example) According to Table 1, each granulated powder was produced by spraying the binding solution into a tank using a fluidized bed granulator at an inlet air temperature of approximately 70 to 80°C and drying it to produce granulation. Calcium pantothenate (Type S), excipients, lubricants, and disintegrants were added to the resulting granulated powders 1 to 3, mixed, and compressed using a rotary tablet press to obtain uncoated tablets. The obtained plain tablets were then coated with a sugar-coating solution containing hypromellose, sterilized talc, erythritol, precipitated calcium carbonate, titanium oxide, crystalline cellulose, gum arabic powder, refined sucrose, and riboflavin to give sugar-coated tablets weighing 250 mg each. The compositions of the solid preparations of Reference Examples 1 and 2 are shown in Table 1. [Table 1]

[0056] (Test Example 1) The sugar-coated tablets obtained in the Reference Example were placed in glass bottles and stored with the stopper tightly closed at 40°C and 50°C. After storage, the cyanocobalamin content was measured by HPLC. The residual cyanocobalamin content (%) from the initial value was calculated. The results are shown in Table 2. Survival rate from initial (%) = (cyanocobalamin content after storage) / (initial cyanocobalamin content immediately after storage) × 100

[0057] [Table 2] Vitamin B when not containing herbal medicines or their extracts 12 When other vitamins including vitamin B1 derivatives are granulated separately (Reference Example 1), 12 Regardless of whether the vitamin B1 derivative was granulated in the same group (Reference Example 2), the content only decreased by about 5% when stored at 40°C, and the stability was similar in Reference Example 1 and Reference Example 2. Furthermore, even when stored at 50°C, the residual rate exceeded 90%, and there was little loss of content despite storage at high temperatures.

[0058] (Example 1, Comparative Example 1) According to Table 3, the ingredients were granulated with an appropriate amount of purified water using a stirring granulator and then dried to produce granulated powder 4. This was added to granulated powders 1 to 3 produced in the Reference Examples, and calcium pantothenate (Type S), excipients, lubricants, and disintegrants were further added and mixed, and the mixture was compressed using a rotary tablet press to obtain uncoated tablets. The obtained plain tablets were then coated with a sugar-coating solution containing hypromellose, sterilized talc, erythritol, precipitated calcium carbonate, titanium oxide, crystalline cellulose, gum arabic powder, refined white sugar, and riboflavin to give sugar-coated tablets weighing 290 mg each. [Table 3]

[0059] As in the Reference Example, the obtained sugar-coated tablets were stored in a sealed glass bottle at 50°C, and after storage, the cyanocobalamin content was measured by HPLC. From the measured cyanocobalamin content, the residual rate (%) from the initial value was calculated according to the following formula. The results are shown in Table 4. Survival rate from initial (%) = (cyanocobalamin content after storage) / (initial cyanocobalamin content immediately after storage) × 100

[0060] [Table 4] As shown in Table 4, vitamin B 12 In preparations containing other vitamins including vitamin B1 derivatives and herbal medicines or their extracts, vitamin B 12 When vitamin B1 derivatives and other vitamins were granulated separately (Example 1), vitamin B 12 The decrease in vitamin B content was stable at about 2%. 12 When vitamin B1 derivatives were granulated in the same batch (Comparative Example 1), vitamin B 12 The residual rate of vitamin B12 was about 30%, which was a significant decrease. 12 This caused a significant destabilization of the

[0061] Each granulated powder was produced using a fluidized bed granulator and an agitator granulator according to Table 5. Calcium pantothenate (Type S), excipients, lubricants, and disintegrants were added to the resulting granulated powders 5 to 8, mixed, and compressed into tablets using a rotary tablet press to obtain uncoated tablets. The obtained plain tablets were then coated with a sugar-coating solution containing hypromellose, polyvinyl alcohol, sterilized talc, erythritol, methylcellulose, and riboflavin to give sugar-coated tablets weighing 275 mg to 300 mg per tablet. [Table 5-1] [Table 5-2]

[0062] The obtained sugar-coated tablets were placed in a glass bottle, sealed, and stored at 50°C. After storage, the cyanocobalamin content was measured by HPLC. The residual rate (%) from the initial value was calculated from the measured cyanocobalamin content using the following formula. The results are shown in Table 6. Survival rate from initial (%) = (cyanocobalamin content after storage) / (initial cyanocobalamin content immediately after storage) × 100

[0063] [Table 6] As shown in Table 6, vitamin B 12 In preparations containing other vitamins including vitamin B1 derivatives and herbal medicines or their extracts, vitamin B 12 When granulated with other vitamins including vitamin B1 derivatives, the vitamin B 12 The residual rate was equal to or higher than those in Reference Examples 1 and 2 above, and it was confirmed that the compound was stable.

[0064] As examples of solid preparations included in the present invention, Formulation Examples 1 to 3 are shown in Table 7. All of these are sugar-coated tablets weighing 265 mg to 275 mg per tablet, coated with a sugar-coating solution containing hypromellose, polyvinyl alcohol, sterilized talc, erythritol, methylcellulose, and riboflavin. Formulation Examples 1 to 3 below also show good stability after storage. [Table 7-1] [Table 7-2] [Industrial Applicability]

[0065] The solid preparation of the present invention contains vitamin B 12 This makes it possible to provide a solid preparation that has good stability even after storage.

Claims

1. The following ingredients (1) to (3): (1) Vitamin B 12 kind, (2)(2-1) Vitamin B 1 a derivative or a salt thereof, (2-2) Vitamin B 2 Vitamin B 6 at least one selected from the group consisting of nicotinic acid and nicotinic acid; (3) Herbal medicines or their extracts A solid formulation comprising: Component (1) and component (2) are separate granules, or Only one of component (1) and component (2) is a granulated product, and the other component is not contained in the granulated product. A solid formulation characterized by:

2. Vitamin B 12 2. The solid formulation of claim 1, wherein the compound is cyanocobalamin.

3. Vitamin B 1 3. The solid formulation according to claim 1, wherein the derivative or its salt is fursultiamine or its salt.

4. 3. The solid formulation according to claim 1, wherein the herbal medicine or extract thereof comprises at least one selected from Astragalus Root, Shigoka, Ginseng, Eucommia Root, Peony Root, Poria Coccus, Dioscorea Root, Cinnamon Bark, Lycium Bark, and Atractylodes Rhizome, and extracts thereof.

5. The following ingredients (1) to (3): (1) Vitamin B 12 kind, (2)(2-1) Vitamin B 1 a derivative or a salt thereof, (2-2) Vitamin B 2 Vitamin B 6 at least one selected from the group consisting of nicotinic acid and nicotinic acid; (3) Herbal medicines or their extracts A method for producing a solid formulation comprising: Component (1) and component (2) are separately granulated to produce a solid dosage form, or The composition is produced by granulating only one of the components (1) and (2) and then adding the other component. Manufacturing method.

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