JP2011068614A - Vitamin preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a vitamin preparation which stabilizes a vitamin B1 derivative, and suppresses discoloration and a reduction in content. <P>SOLUTION: The vitamin preparation includes fursultiamine or a salt thereof, and ascorbic acid 2-glucoside. The ratio of ascorbic acid 2-glucoside is 6 to 90 pts.mass in the total amount of 100 pts.mass, and 0.01 to 20 pts.mass to fursultiamine or the salt thereof of 1 pt.mass. <P>COPYRIGHT: (C)2011,JPO&INPIT

Description

  The present invention relates to a preparation containing fursultiamine or a salt thereof and ascorbic acids (vitamin Cs), a method for producing the same, and a method for stabilizing the preparation components.

  Due to its excellent absorbability, fursultiamine hydrochloride, which is a vitamin B1, is blended in many pharmaceuticals and quasi drugs as vitamin B1 having a high bioavailability. On the other hand, ascorbic acids belonging to vitamin C are vitamins that have vitamin supplementation effect, antioxidant effect, anti-fatigue recovery effect, stain / freckle mitigation effect, etc. Ascorbic acids are also included in many pharmaceuticals and quasi drugs Has been. However, it is known that vitamins B1 and vitamins C have poor compounding properties. In the preparation, the drug tends to cause decomposition of the drug and discoloration of the preparation.

  For example, JP-A-61-257923 (Patent Document 1) discloses a solid pharmaceutical composition containing granules containing vitamin B1 salt or vitamin B1 derivative and cyclodextrin and vitamin C, and vitamins. It is described that B1 and vitamin C can be stabilized and the color change can be reduced. Patent Document 1 describes that the amount of vitamin C is about 1 to 50 times the amount of vitamin B1, and that vitamin B1 is about 0.1 to 50% by weight based on the total amount. Formulations such as tablets (total amount 500 mg) containing 5 mg of sulfurtiamine and 100 mg of L-ascorbic acid (vitamin C) are described.

  Japanese Unexamined Patent Publication No. 2001-10955 (Patent Document 2) discloses an internal liquid composition containing at least one selected from ascorbic acid, vitamin B1 and biotin and sucralose.

  In recent years, ascorbic acid 2-glucoside (AA2G) has been developed as an ascorbic acid. Since ascorbic acid 2-glucoside has a molecular structure in which the hydroxyl group at the 2-position, which is an unstable factor of ascorbic acid, is modified with glucose, it is known to have extremely high stability. It is also clear that ascorbic acid 2-glucoside is hydrolyzed by α-glucosidase present in each tissue in the living body such as the small intestine and kidney to release ascorbic acid and exerts physiological action as vitamin C in vivo. (Hitoshi Mitsumata, Characteristics and Uses of Newly Specified Additive L-Ascorbic Acid 2-Glucoside, FFI Journal, 211, 435-444 (2006)).

  As a method of using ascorbic acid 2-glucoside, JP-A-2007-63177 (Patent Document 3) describes L-ascorbic acids (L-ascorbic acid 2-glucoside, etc.) when converted into hyaluronic acid and L-ascorbic acid. ) And the composition for oral intake for skin beautification, wherein the composition ratio is 1: 4 to 4: 1 by mass, and this composition may further contain chondroitin sulfate and / or glucosamine. It is also described. In addition, it is also described that the composition for oral consumption may contain vitamin B1, vitamin B2, etc., and in the examples, for oral consumption containing 50 parts by mass of L-ascorbic acid 2-glucoside and 0.01 parts by mass of thiamine. The composition (total amount about 980 parts by weight) is described.

  JP-A-2006-320223 (Patent Document 4) discloses thiamines and a vitamin C-enhanced thiamine-containing food containing ascorbic acid glucoside as a vitamin C source, and is incorporated into a vitamin C-enhanced thiamine-containing composition There is also disclosed a method for suppressing the generation of off-flavor caused by heat and / or light of a vitamin C-enhanced thiamine-containing composition using ascorbic acid glucoside as a vitamin C source. In this document, as thiamines, in addition to thiamine, fursultiamine, octothiamine and the like are described, and not only foods, but also oral compositions containing vitamin C-enhanced thiamines (medicines containing vitamin C-enhanced thiamines, etc.) It is also described that the blending ratio of ascorbic acid glucoside in this case is 0.001 to 5% by weight per 100% by weight of the composition (pharmaceutical or the like). Further, in the examples, examples using dibenzoyl thiamine hydrochloride, thiamine hydrochloride, and thiamine nitrate are described.

  US Patent Application Publication US 2004/0156923 A1 (Patent Document 5) contains an oil cake component, a glucosamine component, an acid component, a mineral component, a vitamin component, and a functional food component. Ascorbic acid, sodium ascorbate, glucodite ascorbate and the like are described as the acid component, and thiamine is described as the vitamin component. This document also describes a composition containing 100 g of sodium ascorbate and 11.362 g of thiamine hydrochloride (87.4%) (total amount of 880 g).

  WO 2006/022174 A1 (Patent Document 6) discloses a browning inhibitor containing ascorbic acid 2-glucoside as an active ingredient and a browning inhibiting method using the same. In this document, as a browning inhibitor, about 10001 parts by mass of alcorbic acid 2-glucoside is converted to ascorbic acid with respect to 100 parts by mass of the composition, preferably about 0.001 to 10 parts by mass, Desirably, about 0.04 to 5 parts by mass is blended, and even if 10 parts by mass or more is blended with respect to 100 parts by mass of the composition, there is no difference in the browning inhibiting effect. It is also described that a strong antioxidant component such as vitamin E may be used in combination.

  However, it does not specifically describe stabilization of fursultiamine hydrochloride. In addition, combination with vitamin C (ascorbic acid 2-glucoside, etc.), depending on the type of vitamin B1, causes a change in shape due to storage over a long period of time, and the powdery form is melted and solidified into a candy form. , The form stability may be impaired.

JP-A-61-257923 (claims, page 3, lower right column, examples) JP 2001-10955 A (Claims) JP 2007-63177 A (claims, paragraph [0017] and examples) JP 2006-320223 A (claims, paragraphs [0019] [0025], examples) US 2004/0156923 A1 (Claims, paragraphs [0068] [0091]) WO 2006/022174 A1 (Claims, paragraphs [0009] [0011])

  An object of the present invention is to provide a vitamin preparation containing vitamin B1 and vitamin C, wherein vitamin B1 and vitamin C are stabilized, and a method for producing the same.

  Another object of the present invention is to provide a vitamin preparation capable of suppressing discoloration and content reduction, and a method for stabilizing vitamin B1.

  Still another object of the present invention is to provide a composition (or vitamin preparation) that can prevent morphological changes even when vitamin B1 and vitamin C are used in combination.

  The present inventor uses fursultiamine or a salt thereof as vitamin B1 and ascorbic acid 2-glucoside as ascorbic acid (vitamin C) in stabilizing a preparation containing vitamin B1 and vitamin C. In addition, it is possible to stabilize the fursultiamine or a salt thereof and prevent discoloration and content reduction of the preparation. In particular, ascorbic acid 2-glucoside is used in a content different from the range disclosed in the above-mentioned patent documents (eg, Patent Document 6). And, it is possible to remarkably suppress browning and content reduction, and in combination with fursultiamine or a salt thereof and ascorbic acid 2-glucoside, even if stored for a long period of time, it is possible to prevent changes in the form of each of these components, The inventors have found that the particles and powders can be maintained and stabilized, and the present invention has been completed.

  That is, the vitamin preparation of the present invention contains fursultiamine or a salt thereof and ascorbic acid 2-glucoside. About 6-90 mass parts may be sufficient as content of ascorbic acid 2-glucoside in 100 mass parts of total amounts of a formulation. Moreover, about 0.01-20 mass parts may be sufficient as the ratio of ascorbic acid 2-glucoside with respect to 1 mass part of fursultiamine or its salt. More specifically, the vitamin preparation contains 8-85 parts by mass of ascorbic acid 2-glucoside in a total amount of 100 parts by mass, and 0.1-0.1 parts of ascorbic acid 2-glucoside with respect to 1 part by mass of fursultiamine or a salt thereof. 10 mass parts may be included.

  The present invention allows a preparation to contain fursultiamine or a salt thereof and ascorbic acid 2-glucoside to produce a vitamin preparation, and a preparation containing fursultiamine or a salt thereof to contain ascorbic acid 2-glucoside. Also included is a method of stabilizing fursultiamine or a salt thereof.

  In the present invention, fursultiamine or a salt thereof and ascorbic acid 2-glucoside come into contact with each other in the preparation without granulating at least one component of fursultiamine or a salt thereof and ascorbic acid 2-glucoside. Even if contained in a form (for example, in the form of a powdery mixture), fursultiamine or a salt thereof (or disulfide-type vitamin B1 derivative) can be stabilized, and each component can be maintained in a particulate or powdery form. Furthermore, the preparation of the present invention may not contain hyaluronic acid, sucralose, or glucosamine, and chondroitin sulfate is not necessarily required. The preparation of the present invention exhibits high stability even without such components.

  The present invention is not limited to fursultiamine or a salt thereof, but can be applied to other disulfide-type vitamin B1 derivatives.

  In the present specification, the “formulation” is not limited to a “pharmaceutical composition” used exclusively for the prevention and / or treatment of human diseases, but can be widely applied to uses such as nutritional supplements (eg supplements). Means a thing.

  In the present invention, since it contains disulfide-type vitamin B1 derivative fursultiamine or a salt thereof and ascorbic acid 2-glucoside, a vitamin preparation in which vitamin B1 derivative and vitamin C are stabilized can be obtained. Moreover, while being able to suppress discoloration (browning etc.) of a formulation, the content fall of a fursultiamine or its salt and ascorbic acid 2-glucoside can be suppressed, and a fursultiamine or its salt can be stabilized. And even if it preserve | saves for a long period of time, a full sultiamine or its salt, and ascorbic-acid 2-glucoside do not harden | cure in a lump shape, and can maintain forms, such as a particulate form and a powder form. Therefore, storage stability (or storage property), handleability, and production efficiency of the preparation can be improved.

  The vitamin preparation (formulation) of the present invention contains fursultiamine or a salt thereof as vitamin B1 and contains ascorbic acid 2-glucoside as ascorbic acid (vitamin C).

  Examples of the salt of fursultiamine include inorganic acid salts (for example, hydrochloride, nitrate, sulfate, phosphate, etc.), organic acid salts (for example, acetate, citrate, etc.), and the like. These fursultiamines or salts thereof can be used alone or in combination of two or more. Of these fursultiamine or salts thereof, fursultiamine hydrochloride and the like are preferably used. Fursultiamine or a salt thereof belongs to a disulfide-type vitamin B1 derivative having a group —S—S—R (R represents 2- (oxolan-2-yl) ethyl group), and has a disulfide bond. When it coexists with ingredients, it tends to be unstable and easily causes discoloration (browning, etc.) and content reduction.

  Ascorbic acid 2-glucoside is a compound in which the hydroxyl group at the 2-position of ascorbic acid is modified with glucose, liberates ascorbic acid by hydrolysis, and exhibits physiological activity as vitamin C in vivo. Even if it is a fursultiamine or a salt thereof that is destabilized when blended with ascorbic acid, it can be stabilized by combining it with an ascorbic acid 2-glucoside. Further, when fursultiamine or a salt thereof and ascorbic acid 2-glucoside are used in combination, at least one of these components, particularly the form of both components can be stably maintained over a long period of time. That is, as described in the comparative example, a vitamin B1 derivative, bisibutiamine (in powder form) and ascorbic acid 2-glucoside (in powder form) are used in combination, and the powder mixture of both is stored (for example, at room temperature, particularly When stored under heating), the powdered bisibutiamine and the powdered ascorbic acid 2-glucosides turn brown and fuse together to form one candy-like lump, greatly reducing the handleability. Such a phenomenon also occurs in preparations containing bisibuthiamine and ascorbic acid 2-glucosides. In contrast, in the present invention, powdered fursultiamine or a salt thereof and powdered ascorbic acid 2-glucoside are mixed and stored in the form of a mixture (or in a state where both components are in contact) (for example, room temperature, Even when stored under heating in particular, not only does it not be colored or discolored, but it can also maintain a powdery form for a long period of time without causing a change in form. Therefore, fursultiamine or a salt thereof and ascorbic acid 2-glucoside can be stably stored in the form of a powder mixture, and storage stability, handleability, and productivity of the preparation can be improved.

  The content of ascorbic acid 2-glucoside is 6 to 90 parts by mass (for example, 8 to 85 parts by mass), preferably 10 to 85 parts by mass (for example, 20 to 85 parts by mass), in a total amount of 100 parts by mass of the preparation. More preferably, it is about 25-85 mass parts (for example, 30-80 mass parts). The content of ascorbic acid 2-glucoside is about 20 to 75 parts by mass (for example, 25 to 70 parts by mass), particularly about 25 to 65 parts by mass (for example, 30 to 60 parts by mass), in a total amount of 100 parts by mass of the preparation. There are many cases.

  The ratio of ascorbic acid 2-glucoside to the fursultiamine or a salt thereof can be selected from a range of about 0.01 to 20 parts by mass with respect to 1 part by mass of the fursultiamine or a salt thereof, and 0.1 to 15 parts by mass. (E.g. 0.3-12 parts by mass), preferably 0.5-10 parts by mass (e.g. 0.7-8 parts by mass), more preferably 1-7 parts by mass (e.g. 2-7 parts by mass). Degree. The proportion of ascorbic acid 2-glucoside is 0.1 to 10 parts by weight, preferably 0.1 to 5 parts by weight (for example, 0.5 to 5 parts by weight), based on 1 part by weight of fursultiamine or a salt thereof. More preferably, it may be about 1 to 5 parts by mass (for example, 2 to 5 parts by mass), particularly about 2.5 to 4.5 parts by mass.

  The total amount of fursultiamine or a salt thereof and ascorbic acid 2-glucoside (ascorbic acid equivalent) can be selected from the range of about 6 to 93% by weight with respect to the whole preparation, and is usually 10 to 80% by weight, preferably 15 It may be about ˜60% by weight.

  In the present invention, it can be applied to a disulfide-type vitamin B1 derivative instead of fursultiamine or a salt thereof. That is, the preparation of the present invention may be a vitamin preparation containing a disulfide-type vitamin B1 derivative and ascorbic acid 2-glucoside.

  Examples of the disulfide type vitamin B1 derivative include prosultiamine, octothiamine, bisbenchamine, thiamine disulfide and the like. These vitamin B1 derivatives may be in the form of a salt (an inorganic acid salt such as hydrochloride, nitrate or sulfate, or an organic acid salt such as acetate). These vitamin B1 derivatives can be used alone or in combination of two or more. Of these vitamin B1 derivatives, prosultiamine, octothiamine, bisbenchamine or salts thereof are preferably used. In particular, among disulfide-type vitamin B1 derivatives, the group —S—S—R (where R is an alkyl group such as a propyl group, or an alkyl group having a substituent ((3-acetylthioxy-3- (4-methoxycarbonylbutyl Vitamin B1 derivatives having a propyl group, etc.), such as prosultiamine, octothiamine, etc. Disulfide type vitamin B1 derivatives, especially disulfide type vitamin B1 having the group -S-S-R Since the derivative has a disulfide bond as in the case of the aforementioned fursultiamine or a salt thereof, it tends to be unstable when coexisting with other components, and easily causes discoloration (browning, etc.) and content reduction.

  Even if the disulfide-type vitamin B1 derivative is unstable, the vitamin B1 derivative can be stabilized by using it in combination with ascorbic acid 2-glucoside. In addition, by using a disulfide-type vitamin B1 derivative and ascorbic acid 2-glucoside in combination, it is possible to expect stabilization of the form of each component over a long period of time even when heated and stored.

  When fursultiamine or a salt thereof and the disulfide-type vitamin B1 derivative are used in combination, the ratio (mass ratio) of both is, for example, the former / the latter = 1 / 0.01 to 1/10, preferably 1 / 0.0. It may be about 05 to 1/5, more preferably about 1 / 0.1 to 1/1.

  The proportion of ascorbic acid 2-glucoside relative to 1 part by mass of the disulfide-type vitamin B1 derivative may be the same as the proportion relative to the aforementioned fursultiamine or a salt thereof. That is, the ratio of ascorbic acid 2-glucoside to the disulfide-type vitamin B1 derivative can be selected from a range of about 0.01 to 20 parts by mass with respect to 1 part by mass of the disulfide-type vitamin B1 derivative. (E.g. 0.3-12 parts by mass), preferably 0.5-10 parts by mass (e.g. 0.7-8 parts by mass), more preferably 1-7 parts by mass (e.g. 2-7 parts by mass). Degree. The proportion of ascorbic acid 2-glucoside is 0.1 to 10 parts by weight, preferably 0.1 to 5 parts by weight (for example, 0.5 to 5 parts by weight), based on 1 part by weight of the disulfide-type vitamin B1 derivative. It may be preferably 1 to 5 parts by mass (for example, 2 to 5 parts by mass), particularly about 2.5 to 4.5 parts by mass.

  The total amount of vitamin B1 derivative, disulfide-type vitamin B1 derivative and ascorbic acid 2-glucoside (ascorbic acid equivalent) can also be selected from the range of about 6 to 93% by weight with respect to the whole preparation, and usually 10 to 80% by weight, Preferably, it may be about 15 to 60% by weight.

  In the vitamin preparation of the present invention, it is not necessary to granulate or granulate the vitamin B1 derivative beforehand with cyclodextrin or the like. Even if the vitamin B1 derivative and ascorbic acid 2-glucoside are contained in the preparation, the vitamin B1 derivative Can be effectively stabilized. Moreover, even if it is a vitamin B1 derivative with small reducibility, a vitamin B1 derivative can be stabilized effectively. That is, without the granulation of at least one component of fursultiamine or a salt thereof (or disulfide type vitamin B1 derivative) and ascorbic acid 2-glucoside, fursultiamine or a salt thereof (or disulfide type) Even if the vitamin B1 derivative) and ascorbic acid 2-glucoside are in contact with each other (for example, a carrier component may be included or a powdery mixture of these components), fullsultiamine or a salt thereof (Or disulfide-type vitamin B1 derivative) can be stabilized. Therefore, even if a powder mixture of fursultiamine or a salt thereof (or disulfide type vitamin B1 derivative) and ascorbic acid 2-glucoside is granulated using a binder, an excipient, etc., a stable solid preparation is obtained. be able to. Accordingly, the present invention provides a composition and a method for preventing morphological change by maintaining fursultiamine or a salt thereof (or disulfide-type vitamin B1 derivative) and ascorbic acid 2-glucoside in a particulate or powder form. Is also included.

  In addition to fursultiamine or a salt thereof (or disulfide-type vitamin B1 derivative) and ascorbic acid 2-glucoside, the preparation of the present invention contains other physiologically active or pharmacologically active ingredients such as vitamins, antipyretic analgesics, anti-inflammatory Drugs, antitussive expectorants, anti-asthma drugs or bronchodilators, anti-allergic drugs, parasympathomimetic drugs, sympathomimetic drugs or alpha receptor stimulants, anti-inflammatory drugs or anti-inflammatory enzymes drugs, central nervous stimulants, gastrointestinal drugs Acidic drugs or mucosal protective drugs, including stomachic drugs and digestive drugs), antidiarrheals, herbal medicines, amino acids, minerals and the like may be included. In addition, the preparation of the present invention may contain γ-oryzanol, orotic acid, yoquinin, glucuronic acid (such as glucuronic acid, glucuronolactone, glucuronic acid amide), chondroitin sodium sulfate and the like. These components can be used alone or in combination.

  The vitamins may be either water-soluble vitamins or fat-soluble vitamins. Vitamins such as vitamin B1 (thiamine hydrochloride, thiamine nitrate, dicetiamine hydrochloride, chicotiamine, benfotiamine, bisibutiamine, etc.), vitamin B2 (riboflavin, sodium riboflavin phosphate, riboflavin butyrate, sodium flavin adenine dinucleotide, etc.) Riboflavins, etc.), vitamin B6 (pyridoxine such as pyridoxine and pyridoxal or salts thereof (pyridoxine hydrochloride, pyridoxine acetate, pyridoxal phosphate, etc.)), nicotinic acid (nicotinic acid, nicotinamide, etc.), vitamin B12 ( Mecobalamin, cyanocobalamin, hydroxocobalamin, cobalamin such as methylcobalamin or salts thereof (hydroxocobalamin hydrochloride, hydroxocobalamin acetate, etc.)), folic acid, punt Acids (pantenol, pantothenic acid or salts thereof (calcium pantothenate, calcium pantothenate type S, etc.)), vitamin C (ascorbic acid, calcium ascorbate, sodium ascorbate, potassium ascorbate, etc.), vitamin A ( Retinol acetate, retinol palmitate, vitamin A oil, liver oil, strong liver oil, etc.), vitamin D (ergocalciferol, cholecalciferol, etc.), vitamin E (d-α-tocopherol, dl-α-tocopherol, succinic acid) and d-α-tocopherol, dl-α-tocopherol calcium succinate, d-α-tocopherol acetate, dl-α-tocopherol acetate, etc.), biotin, vitamin K, vitamin P (eg hesperidin) and the like. These vitamins may be used alone or in combination of two or more, and may form a complex vitamin preparation.

  Antipyretic analgesics include acetaminophen, ibuprofen, ketoprofen, aspirin, aspirin aluminum, etenzaamide, salicylamide, methyl salicylate, sodium salicylate, loxoprofen sodium, ampenac sodium, indomethacin farnesyl, mefenamic acid, flufenamic acid, piroxicam, etc. .

  Examples of antitussive expectorants include codeine phosphate, dihydrocodeine phosphate, dextromethorphan hydrobromide, methylephedrine hydrochloride, noscapine, methylcysteine hydrochloride, ethylcysteine hydrochloride, carbocysteine and the like.

  Anti-asthma drugs or bronchodilators include, for example, aminophylline, diprofylline, theophylline, ephedrine, ephedrine hydrochloride, epinephrine, dl-methylephedrine hydrochloride, salbutamol sulfate, procaterol hydrochloride, isoprenaline hydrochloride, isoproterenol sulfate, methoxyphenamine hydrochloride, Orciprenaline sulfate, chlorprenalin hydrochloride, trimethoquinol hydrochloride, salbutamol sulfate, terbutaline sulfate, hexoprenaline sulfate, formoterol fumarate, tubrobuterol hydrochloride, fenoterol hydrobromide, procaterol hydrochloride, plubuterol hydrochloride, clenbuterol hydrochloride, mabuterol choline theophylline , Including proxyphylline.

  Antiallergic agents include, for example, ketotifen fumarate, azelastine hydrochloride, oxatomide, emedastine fumarate, epinastine hydrochloride, ebastine, diphenhydramine hydrochloride, clemastine fumarate, chlorpheniramine maleate, chlorpheniramine maleate, plan Examples include lucast hydrate, zafirlukast, montelukast calcium, suplatast tosilate, cromoglycate sodium, tranilast, repirinast, ibudilast, tazanolast, pemirolast potassium and the like.

  Examples of parasympathetic blocking agents include natural alkaloids (eg, belladonna total alkaloids, belladonna extract, atropine, scopolamine, funnel extract, duck extract, etc.), natural alkaloid derivatives, iodopropamide iodide, methylbenactidium bromide, bromide Propanthelin and the like can be exemplified.

  Examples of sympathomimetic drugs or alpha receptor stimulants include phenylpropanolamine hydrochloride, pseudoephedrine hydrochloride, phenylephrine hydrochloride, methylephedrine hydrochloride, ephedrine hydrochloride, norepinephrine, naphazoline nitrate, gyrometazoline, middolin, methoxamine hydrochloride, tetrahydrozoline hydrochloride, etc. It can be illustrated.

  Examples of the anti-inflammatory agent or anti-inflammatory enzyme include lysozyme chloride, serrapeptase, tranexamic acid, sodium azulene sulfonate, and the like.

  Examples of the central nervous stimulant include caffeine or xanthines (for example, anhydrous caffeine, sodium benzoate caffeine, caffeine silate, caffeine (monohydrate), etc.) and the like.

  As a gastrointestinal agent, dry aluminum hydroxide gel, magnesium aluminate silicate, magnesium silicate, synthetic hydrotalcite, magnesium oxide, magnesium hydroxide alumina, aluminum hydroxide gel, aluminum hydroxide / sodium bicarbonate coprecipitation product, Aluminum hydroxide / magnesium carbonate mixed dry gel, aluminum hydroxide / magnesium carbonate / calcium carbonate coprecipitation product, magnesium hydroxide, sodium bicarbonate, magnesium carbonate, precipitated calcium carbonate, magnesium metasilicate aluminate, anhydrous calcium hydrogen phosphate , Calcium hydrogen phosphate, aminoacetic acid, dihydroxyaluminum aminoacetate, funnel extract, aloe, fennel, turmeric, oak, auren, processed daikon, kojin, kokuboku, ginger Assembly, Keihi, Daio, Chikutsutsujinjin, Chimpi, Spruce, Nigaki, Carrot, Pepper, Hop, Fennel Oil, Keihi Oil, Pepper Oil, Spruce Oil, Pepper Oil, Lemon Oil, L-Menthol, Betaine Hydrochloride, Carnitine Chloride Examples thereof include dry yeast, starch digestive enzyme, protein digestive enzyme, fat digestive enzyme, fibrin digestive enzyme, ursodeoxycholic acid, and bile powder.

  Antidiarrheal agents include acrinol, berberine chloride, guaiacol, creosote, bismuth subsalicylate, bismuth hyponitrite, bismuth subcarbonate, bismuth subgallate, tannic acid, kaolin, pectin, medicinal charcoal, calcium lactate, precipitated calcium carbonate , Calcium hydrogen phosphate, papaverine hydrochloride, ethyl aminobenzoate, sodium azulene sulfonate, aldioxa, L-glutamine, copper chlorophyllin potassium, copper chlorophyllin sodium, methylmethionine sulfonium chloride, dimethylpolysiloxane and the like.

  Herbal medicines include Akamegashiwa, Asenyaku, Asenyaku powder, Achacha, Achacha powder, Aloe, Aloe powder, Ansokkou, Ireisen, Inchinko, Yinakukaku, Fennel, Fennel powder, Turmeric, Uyaku, Uwaurushi, Ages, Ages powder, Engosaku, Ogi , Ogon powder, Ousei, Oubak, Oubak powder, Ouren, Ourem powder, Onji, Onji powder, Kagosou, Kashu, Gadju, Kakon, Kanoko, Ganoderma powder, Carocon, Citrus, Licorice, Licorice powder, Kangten, Kantou Kyoku powder, Kikuka, Kisage, Kijitsu, Kyokatsu, Kyonin, Kokushi, Kujin, Kukujin powder, Keigai, Keihi, Keihi powder, Ketsumeishi, Kengoshi, Gentiana, Gentiana powder, Gennoshokou, Gen Ginger powder, Koko, Koji, Koji, Kowushi powder, Kokuboku, Kokuboku powder, Gou, Goshitsu, Goshuyu, Goboushi, Gomin, Rice starch, Colombo, Colombo powder, Kuzurango, Psycho, Saishin, Saffron, Sankirai, Sankirai powder, Sanshishi, Sangshi powder, Sanshuyu, Salamander, Salamander powder, Sangyonin, Sanyaku, Sanyaku powder, Giant, Shigoka, Zikoppi, Sikon, Shitsurishi, Peonies, Peonies, Jashou, Shazenshi, Shazensou, Zyuyaku, Shukusha, Shukusha, Syakusha, Showa powder, Shozuk, Shouma, Shini, Gypsum, Senega, Senega powder, Senkyu, Senkyu powder, Senkotsu, Senso, Senna, Senna powder, Assembly, Assembly powder, Sojutsu powder, Sojutsu powder Sakuhakuhi, Soboku, Soyo, Daio, Daio powder, Daiso, Takusha, Takusha powder, Chikusetuninjin, Chikutsuninjinjin powder, Timo, Choji, Choji powder, Butterflyfish, Chorei, Chorei powder, Chimpi, Tenma, Tenmondou, Togashi , Red pepper, red pepper powder, red pepper, red powder, red pepper, red pepper powder, red spider, tokon, powdered red pepper, carrot, powdered carrot, powdered carrot, red pepper, honey, mint, mint, Hamaboufu, Hange, Beakshi, Byakujutsu, Byakujutsu powder, Biwayo, Binrouji, Bukuryu, Bukkyou powder, Bushi, Bushi powder, Belladon Nakhon, Hens, Bowie, Bowcon, Bowfish, Buttonpi, Buttonpi powder, Homica, Boray, Bore Examples include a powder, mah, macri, machinin, mokutsu, mokko, yak, yutan, yokoinin, yokuinin powder, ryukotsu, ryutan, ryutan powder, ryokyo, forsythia, rennik, rosin, rotokon.

  Examples of amino acids include L-cysteine, potassium / magnesium aspartate equivalent mixture, L-valine, L-leucine, L-isolosin, taurine and the like.

  In the present invention, by containing 2-glucoside ascorbic acid in a preparation containing a disulfide-type vitamin B1 derivative, the disulfide-type vitamin B1 derivative can be stabilized, and the discoloration of the preparation and active ingredients (disulfide-type vitamin B1 derivative, etc. ) Can be effectively prevented.

  The preparation of the present invention can be produced by incorporating fursultiamine or a salt thereof (or disulfide type vitamin B1 derivative) and ascorbic acid 2-glucoside by a conventional method according to the form of the preparation. The preparation of the present invention can be used in various forms, for example, film coating agents such as solid preparations (powder, fine granules or granules, pills, tablets (plain tablets or uncoated tablets), capsules, film-coated tablets (sugar-coated tablets), etc. ), Semi-solid preparations (creams, jellies, ointments, gels, gel creams, gummi, etc.) and liquids (liquids, elixirs, suspensions, emulsions, syrups, internal use liquids (so-called drinks)) Etc.). Further, the preparation may be a business-soluble dry syrup, a foaming agent, or the like. Examples of the tablet include a plain tablet, a film tablet, a sugar-coated tablet, a thin-layer sugar-coated tablet, a sugarless thin-layer sugar-coated tablet, an intraoral quick disintegrating tablet, a chewable tablet, and a chocolate agent. Further, the tablet may be a bilayer tablet, a trilayer tablet, a dry-coated tablet, or the like, or a tablet containing granules or fine granules. Examples of capsules include hard capsules and soft capsules. Furthermore, the preparation of the present invention may be a preparation for oral administration (such as an internal preparation) or a preparation for parenteral administration (such as an external preparation such as a patch). The vitamin preparation of the present invention is often a solid preparation for oral administration.

  In the preparation of the present invention, various carrier components or additives can be used depending on the form of the preparation. In solid preparations, at least one of an excipient, a binder and a disintegrant is often used as a carrier component or additive.

  Examples of excipients include sugar alcohols such as erythritol, maltitol, mannitol, sorbitol, xylitol, and lactitol, purified sucrose, sucrose, trehalose, lactose, reduced maltose water candy, powdered reduced maltose water candy, glucose, maltose, and the like. Examples include saccharides, corn starch, crystalline cellulose, powdered cellulose, calcium monohydrogen phosphate, calcium hydrogen phosphate, anhydrous calcium hydrogen phosphate, calcium lactate, precipitated calcium carbonate, light anhydrous silicic acid, hydrous silicon dioxide, silicon dioxide and the like. Examples of the binder include gum arabic powder, hydroxyethylcellulose, hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), cellulose derivatives such as methylcellulose, carboxymethylcellulose, carboxymethylethylcellulose, povidone (PVP), vinylpyrrolidone copolymer Examples include coalescence (copolyvidone), polyvinyl alcohol (PVA), acrylic polymer, pullulan, dextrin, pregelatinized starch, hydroxypropyl starch, tragacanth powder, crystalline cellulose, low-substituted hydroxypropylcellulose (L-HPC), and the like. . Examples of the disintegrant include croscarmellose sodium, low-substituted hydroxypropyl cellulose, carmellose calcium, crospovidone, corn starch, sodium carboxymethyl starch, hydroxypropyl starch, and partially pregelatinized starch.

  In the preparation, further additives such as a lubricant, a fluidizing agent, a coloring agent, a pH adjusting agent, a sweetening agent, a fragrance, and an antiseptic may be used. Other carrier components or additives include lubricants (eg, magnesium stearate, calcium stearate, talc, sucrose fatty acid ester, glycerin fatty acid ester, hydrogenated oil, macrogol 6000, etc.), fluidizing agents (eg, light Silicic anhydride, hydrous silicon dioxide, kaolin, etc.), antioxidants (eg, dibutylhydroxytoluene (BHT), propyl gallate, butylhydroxyanisole (BHA), tocopherol, citric acid, etc.), preservatives (paraoxybenzoic acid esters) Etc.), coloring agent (for example, riboflavin, vitamin B12, titanium oxide, yellow ferric oxide, ferric oxide, edible red No. 2, edible red No. 3, edible red No. 102, edible red No. 104, edible red No. 105) , Edible red No. 106, Edible yellow No. 4, Edible yellow No. 5, Edible green No. 3, Edible Blue No. 1, Edible Blue No. 2, Copper Chlorophyll Sodium, Copper Chlorophyll, etc.), pH adjuster (eg, sodium hydroxide, sodium citrate, hydrochloric acid, sodium bicarbonate, sodium carbonate, calcium lactate, phosphoric acid) , Dipotassium phosphate, sodium hydrogen phosphate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, etc.), sweeteners (eg, sucrose, mannitol, D-sorbitol, xylitol, aspartame, stevia, stevia, dipotassium glycyrrhizinate, acese LeFarm K, sucralose, etc.), flavor (for example, L-menthol, peppermint oil, eucalyptus oil, orange oil, clove oil, turpentine oil, fennel oil, vanillin, etc.), surfactant (polyoxyethylene hydrogenated castor oil, monostearin) Acid glycerin, sorbitan fat Acid esters (such as sorbitan monostearate and sorbitan monolaurate), polyoxyethylene polyoxypropylene, polysorbates, sodium lauryl sulfate, macrogol, sucrose fatty acid esters, etc., plasticizers (triethyl citrate, polyethylene glycol, triacetin) , Cetanol, etc.), flavoring agents or flavoring agents (menthol, etc.), adsorbents, preservatives, wetting agents, antistatic agents and the like.

  If necessary, the solid preparation may be a water-soluble base (or polymer) such as HPC, HPMC, or povidone, an insoluble base (or polymer) such as ethyl cellulose, an enteric base, a gastric base, or a saccharide. It may be coated.

  The solid agent can be produced by a conventional method. The active ingredient and the carrier component may be mixed to prepare a powder. Usually, the active ingredient and the carrier component are granulated, and if necessary, the granulated product is granulated to give granules (fine granules or granules). An uncoated tablet can be prepared by tableting a mixture containing the granulated product (particularly a mixture of the granulated product and the carrier component). Capsules can be prepared by filling capsules with the granules.

  Granulation can be performed by a conventional method, for example, stirring granulation method, fluidized bed granulation method, extrusion granulation method, dry granulation method and the like. A preferred granulation method is a fluidized bed granulation method. In granulation, an active ingredient and a carrier component are often granulated using a solution containing a binder. For example, by spraying a solution containing a binder on a fluidized bed of the active ingredient and the carrier component. Can be granulated. The coating preparation can be obtained by spraying a coating agent containing a coating base onto an uncoated preparation (elementary granule, plain tablet, etc.) using a film coating machine.

  In the liquid agent, an aqueous medium (purified water, ethanol-containing purified water, etc.), alcohols (ethanol, glycerin, etc.), a water-soluble polymer, etc. can be used as the carrier component. As the carrier component, purified water, ethanol-containing purified water and the like are often used. As the carrier component of the semi-solid preparation, an oily base (lipid such as vegetable oil, petrolatum, liquid paraffin, etc.), a hydrophilic base (emulsion base) and the like can be used. Examples of additives include disintegration aids, antioxidants or antioxidants, surfactants, emulsifiers, dispersants, suspension agents, solubilizers, thickeners, pH adjusters or buffers, preservatives or Preservatives (such as parabens), bactericides or antibacterial agents, antistatic agents, taste-masking agents or masking agents (such as sweeteners), cooling agents, coloring agents, flavoring agents, and fragrances.

  The liquid preparation can be prepared by dissolving or dispersing each component in a carrier component, filtering or sterilizing if necessary, and filling a predetermined container. A semi-solid preparation can also be prepared by a conventional method, for example, by mixing each component and a carrier component, sterilizing if necessary, filling a predetermined container, or applying to a substrate.

  The preparation of the present invention may contain hyaluronic acid, sucralose, glucosamine, etc., but often does not contain hyaluronic acid, sucralose, glucosamine. Moreover, although chondroitin sulfate may be included, it is not necessarily required in the present invention. The preparation of the present invention exhibits high stability even without such components.

  The formulations of the present invention can be applied to mammals and are suitable for administration to humans. The dosage of the preparation of the present invention can be selected according to the degree of symptoms, age, sex, body weight, administration route, etc. The unit dosage of fursultiamine or a salt thereof (or disulfide vitamin B1 derivative) is, for example, It may be about 1 to 300 mg (for example, 10 to 250 mg), preferably 50 to 200 mg, more preferably about 75 to 150 mg. The unit dose of ascorbic acid 2-glucoside may be, for example, 10 to 1000 mg (for example, 25 to 750 mg), preferably 50 to 600 mg, and more preferably about 100 to 500 mg in terms of ascorbic acid.

  The dose of fursultiamine or a salt thereof (or disulfide type vitamin B1 derivative) and ascorbic acid 2-glucoside (ascorbic acid equivalent) is 20 to 1500 mg, preferably 50 to 1000 mg (for example, 75 to 750 mg) per day. More preferably, it may be about 100 to 750 mg (for example, 150 to 600 mg).

  The preparation of the present invention can be administered once or a plurality of times (for example, 2 to 6 times) per day.

  Hereinafter, the present invention will be described in more detail based on test examples and examples, but the present invention is not limited to these examples.

[Test Examples 1 to 4]
Weigh ascorbic acid 2-glucoside (AA2G) or ascorbic acid (AsA) as vitamin Cs and fursultiamine hydrochloride (TTFD-HCL) as vitamins B1 at the quantitative ratios shown in Table 1, Dry-mixed in a mortar to obtain a powder.

Appearance stability test powders of Examples 1 to 4 were stored in a glass bottle, stored at 40 ° C. and 75% RH for 2 weeks with the glass bottle open, and the appearance change after storage was checked with a color computer (S & M color computer, Suga test machine). Measured and evaluated by color difference (ΔE). The results are shown in Table 1.

Ratio of VCs 1: Ratio of VCs to 100 parts by mass of composition Ratio of VCs 2: Ratio of VCs to 1 part by mass of TTFD-HCL VCs: Vitamin Cs AA2G: Ascorbic acid 2-glucoside AsA: Ascorbic acid ΔE (AA2G): Color difference ΔE value of powder containing AA2G ΔE (AsA): Color difference ΔE value of powder containing AsA As can be seen from Table 1, when ascorbic acid is added as VCs, ΔE is 10 or more. In contrast, when the ascorbic acid 2-glucoside is added as a VC, the ΔE is 4 or less and there is almost no discoloration, and discoloration can be remarkably suppressed. In Test Example 1, instead of AA2G 100 mg, AA2G 10 (mg) has ΔE (AA2G) 1.4, AA2G 50 (mg) has ΔE (AA2G) 1.9, and AA2G 20000 (mg) Then, it is (DELTA) E (AA2G) 2.0, and discoloration can be suppressed remarkably by mix | blending ascorbic acid 2-glucoside instead of ascorbic acid as VCs. From these results, the ratio of AA2G is 6 to 90 parts by mass with respect to 100 parts by mass of the whole composition, and the ratio of AA2G is 0.1 to 15 parts by mass (for example, 0.1 to 1 part by mass of TTFD-HCL). -5 mass parts), the discoloration can be remarkably suppressed.

[Test Example 5]
Ascorbic acid 2-glucoside (AA2G) or ascorbic acid (AsA) as vitamins C and thiamine nitrate (VB1) as vitamins B1 are weighed in the quantitative ratios shown in Table 2, and dry-mixed in a mortar. , Got powder. And external appearance stability was evaluated similarly to Test Examples 1-4.

  As can be seen from Table 2, when thiamin nitrate is used as vitamin B1 and AsA is blended as VCs, its ΔE is 21.6, discoloration is remarkable, and even when AA2G is blended as VCs, its ΔE Is 15.5, and the discoloration cannot be remarkably suppressed.

[Test Example 6]
Ascorbic acid 2-glucoside (AA2G) or ascorbic acid (AsA) as vitamin Cs and disulfide-type vitamin B1 derivative bisivethiamine (Bis) in vitamins B1 are weighed in the quantitative ratios shown in Table 3. The mixture was dry-mixed in a mortar to obtain a powder. And external appearance stability was evaluated similarly to Test Examples 1-5.

ΔE (AA2G): parentheses () indicate the form after storage ΔE (AsA): parentheses () indicate the form after storage As is clear from Table 3, bibisbutiamine was used as vitamin B1 class, When AsA is blended as VCs, its ΔE is 60.4, and the color change is extremely remarkable. Even when AA2G is blended as VCs, its ΔE is 43.8, and the color change cannot be remarkably suppressed. Furthermore, in Test Example 6, when the cap was opened at 40 ° C. and 75% RH and stored for 2 weeks, all became paste-like, and the shape change that did not occur in Test Examples 1 to 5 occurred. In addition, even when only bibisbutiamine was opened at 40 ° C. and 75% RH and stored for 2 weeks, the shape did not change (white powder), and ΔE was 1.2.

[Test Example 7]
Formulation Example 1 (tablet)
Ascorbic acid 2-glucoside (250 g), fursultiamine hydrochloride (54.6 g), and crystalline cellulose (Ceolus PH101, Asahi Kasei) (110.6 g) were added to a 6% hydroxypropyl cellulose (HPC) in a fluidized bed granulator (LAB-1, Paulek). -L) The aqueous solution 240g was granulated by spraying, dried, and then sized with a sizing machine (power mill, screen diameter 1.5 mm). 343.7 g of the obtained sized powder is added to 19.2 g of crystalline cellulose (Theorus PH101, Asahi Kasei), 19.2 g of low-substituted hydroxypropyl cellulose (LH31, Shin-Etsu Chemical), magnesium stearate (light, vegetable, Taihei Chemical Industry) ) 1.9 g was mixed with a tumbler mixer (15 L) at a rotation speed of 30 rpm for 3 minutes to obtain a mixed powder. The obtained mixed powder was tableted with a rotary tableting machine (collect 19K, Kikusui Seisakusho) using a 8.5 mmφ, 7R punch at a rotation speed of 20 rpm and a tableting pressure of 7 kN, and an uncoated tablet (mass 240 mg, thickness) 4.6 mm). The obtained uncoated tablet had an equilibrium relative humidity (ERH) of 27.0%.

Comparative Example 1
An uncoated tablet (mass 240 mg, thickness 4.6 mm) was obtained in the same manner as in Preparation Example 1 except that ascorbic acid was used instead of ascorbic acid 2-glucoside. The uncoated tablet obtained had an equilibrium relative humidity (ERH) of 27.2%.

Drug content stable preparation Example 1 and Comparative Example 1 uncoated tablets were stored tightly in glass bottles at 60 ° C., and the content of fursultiamine hydrochloride in the uncoated tablets after storage was measured by HPLC method. The residual rate (%) was calculated. The results are shown in Table 4.

  As is clear from Table 4, when ascorbic acid 2-glucoside is added instead of ascorbic acid, fursultiamine hydrochloride can be remarkably stabilized.

The preparation of the present invention comprises physical fatigue, mental fatigue, eye strain, cataract, neuralgia, muscle pain, joint pain (back pain, stiff shoulders, fifty shoulders, etc.), neck stiffness, rheumatism, numbness of limbs, peripheral neuritis, peripheral nerve palsy , Diabetic neuropathy, myocardial metabolism disorder, constipation, gastrointestinal motility disorder, postoperative intestinal paralysis, beriberi, hemorrhoids, blotches, freckles, pigmentation due to sunburn and rash, bleeding from gums, nasal bleeding, immune function disease, nerve function It is effective for preventing, treating, or alleviating diseases. Also, during physical fatigue, after sickness, anorexia, malnutrition, febrile wasting disease, postpartum, pregnancy / lactation, during physical / post-health decline, development, old age, hyperthyroidism, Wernicke encephalopathy, mental and psychological modulation (inability to concentrate, nervousness, insomnia, non-enhancement) supplementation of vitamin B ₁ class and vitamin C in such, nutrition is effective tonic nourishment, the frail.

Claims (5)

  A vitamin preparation containing fursultiamine or a salt thereof and ascorbic acid 2-glucoside.   The vitamin preparation according to claim 1, comprising 6 to 90 parts by mass of ascorbic acid 2-glucoside in a total amount of 100 parts by mass.   The vitamin preparation according to claim 1 or 2, comprising 0.01 to 20 parts by mass of ascorbic acid 2-glucoside with respect to 1 part by mass of fursultiamine or a salt thereof.   4 to 85 parts by mass of ascorbic acid 2-glucoside in a total amount of 100 parts by mass, and 0.1 to 10 parts by mass of ascorbic acid 2-glucoside to 1 part by mass of fursultiamine hydrochloride. A vitamin preparation according to any one of the above.   A method of stabilizing a fursultiamine or a salt thereof by adding ascorbic acid 2-glucoside to a preparation containing the fursultiamine or a salt thereof.