JP2013032406A - Amino sugar-containing preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To stabilize vitamin B1or the like in a preparation and to improve disintegrability of a solid preparation containing a glycosaminoglycan such as chondroitin sulfate.SOLUTION: Vitamin B1 or the like are stabilized by incorporating amino sugars (such as glucosamine) into a preparation containing vitamin B1 or the like. The amount of the amino sugars to be used is an effective amount for stabilizing vitamin B1 or the like, for example, at least 0.1 pt.wt. based on 1 pt.wt. of vitamin B1 or the like. Incorporation of the amino sugars improves disintegrability of a solid preparation including glycosaminoglycans (hyaluronic acid, chondroitin or salts thereof). The amount of amino sugars to be used is at least 0.1 pt.wt. based on 1 pt.wt. of glycosaminoglycans. The solid preparation, even when a pH fluctuates, suppresses formation of a mass of gel of a glycosaminoglycan to improve disintegrability.

Description

  The present invention relates to a preparation in which vitamin B1s are stabilized, and particularly to a preparation (especially a solid preparation) in which vitamin B1s are stabilized and disintegration is improved.

  Many pharmaceutical preparations containing vitamin B1 are commercially available. This vitamin B1 has a problem in stability, and its content is reduced during storage due to environmental factors such as heat, pH, light, moisture, etc., formulation forms, and various coexisting components in the formulation. It is necessary to consider stability.

  In particular, when vitamins are blended in a high unit, a method of stabilizing by blending a stabilizer such as an antioxidant is known. However, it is not preferable from the viewpoint of safety. Moreover, when improving by formulation design, such as a bilayer tablet, a laminated tablet, and a coating technique, there exists a demerit of complicating a manufacturing process.

In order to stabilize vitamin B1 in a solid preparation, JP-A-5-271072 (Patent Document 1) contains tocopherol succinate or a salt thereof, vitamin B1 or ascorbic acid, and at least one component A vitamin preparation coated with a coating is disclosed. Japanese Unexamined Patent Publication No. 2000-247879 (patent document 2) discloses a vitamin preparation containing a succinic acid ester of tocopherol or a salt thereof, vitamin B1s, and a specific basic inorganic compound. JP-A-9-268127 (Patent Document 3) discloses a solid preparation containing a vitamin B1 derivative, starch and calcium hydrogen phosphate.

  In order to stabilize vitamins in liquids, JP-A-5-255069 (Patent Document 4) describes at least one selected from leucine, isoleucine, methionine and valine in a vitamin group containing at least one of 13 essential vitamins. An intravenous vitamin preparation containing one kind is disclosed. Japanese Patent Application Laid-Open No. 6-145056 (Patent Document 5) discloses a liquid preparation containing vitamin Bs in which a specific amount of vitamin B6 is blended with vitamin B2. Furthermore, Japanese Patent Application Laid-Open No. 9-12458 (Patent Document 6) proposes a method in which a vitamin B1-containing liquid preparation contains fat in the form of an emulsion or the like.

  On the other hand, sodium chondroitin sulfate is effective for arthritis and the like, and many pharmaceuticals containing sodium chondroitin sulfate are also commercially available. For example, Japanese translation of PCT publication No. 9-503197 (Patent Document 7) discloses a composition for treating connective tissues of humans and animals, which contains a glycosaminoglycan such as chondroitin and an amino sugar such as glucosamine. ing. JP 2000-53569 A (Patent Document 8) discloses a composition containing L-carnitine, glucosaminoglycan and an excipient as a composition suitable for prevention and treatment of joint disorders. ing. This document also discloses a composition containing L-carnitine, chondroitin sulfate and glucosamine. Furthermore, JP 2000-139408 A (Patent Document 9) discloses a food (tablet) containing glucosamine or a salt thereof, a taste improving agent such as an organic acid, fruit juice or salt, and a saccharide and an excipient as necessary. Confectionery etc.) are disclosed.

  Glucosaminoglycans such as chondroitin sulfate are a type of high molecular polysaccharide and form a hydrogel mass in water. In particular, when the concentration of glucosaminoglycan is high, a hydrogel mass is easily generated. The formation of hydrogel lumps is likely to be promoted particularly in low pH environments, and the formed hydrogel lumps are sparingly soluble and block the penetration of water into the lumps. For this reason, when the formulation taken contains water in the gastrointestinal tract to form a hydrogel, the penetration of water into the solid formulation is hindered, resulting in a delay in disintegration time and inhibiting the release of the active ingredient. Therefore, it is necessary to consider the disintegration characteristics when designing a solid preparation.

  Furthermore, it is known that the internal environment of the stomach varies greatly due to external or internal factors such as individual differences and meal contents, and the gastric pH of healthy persons varies within a range of 1.2 to 6.8. ing. Therefore, it is also necessary to consider that gelation of sodium chondroitin sulfate is suppressed and disintegration is promoted under any internal environment.

Japanese Patent Laid-Open No. 5-271072 JP 2000-247879 A JP-A-9-268127 JP-A-5-255069 JP-A-6-145056 Japanese Patent Laid-Open No. 9-12458 Japanese National Patent Publication No. 9-503197 JP 2000-53569 A JP 2000-139408 A

  Accordingly, an object of the present invention is to provide a preparation capable of effectively stabilizing vitamin B1 and a method for stabilizing vitamin B1.

  Another object of the present invention is to provide a solid preparation capable of suppressing the formation of a hydrogel mass even in a solid preparation containing glucosaminoglycans such as chondroitin sulfate and a method capable of improving the disintegration property of the solid preparation. .

  Still another object of the present invention is to provide a method capable of suppressing the gel formation of glucosaminoglycans and improving the disintegration property of a solid preparation even when the pH varies.

  As a result of intensive studies to achieve the above-mentioned problems, the present inventor has been able to stabilize vitamin B1 in the preparation by using aminosaccharides such as glucosamine, and the vitamin B1 remains for a long period of time, and chondroitin sulfate. The present inventors have found that the production of gels by glycosaminoglycans such as the above can be remarkably suppressed, promote disintegration in the gastrointestinal tract, and are effective in stably releasing active ingredients, thereby completing the present invention.

  That is, the preparation of the present invention is a preparation containing vitamin B1, and is an amount effective for stabilizing vitamin B1, for example, 0.1 part by weight or more with respect to 1 part by weight of vitamin B1. Contains amino sugars (such as glucosamine). Moreover, the formulation of this invention is a formulation containing vitamin B1 and aminosaccharides, Comprising: Content of vitamin B1 is 0.001-30 weight% with respect to the whole. Such a preparation of the present invention may be a liquid preparation, but can be advantageously applied to a solid preparation when it contains glycosaminoglycans that easily form a gel because the disintegration can be improved by aminosaccharides. The That is, the preparation of the present invention may be a solid preparation further containing glycosaminoglycans (hyaluronic acid, chondroitin and salts thereof).

  The present invention also includes a method of stabilizing vitamin B1 compounds by adding amino sugars to a preparation containing vitamin B1 compounds. Furthermore, this invention also includes the method of mix | blending an amino saccharide | sugar with the solid formulation containing glycosaminoglycans, and improving the disintegration property of a solid formulation.

That is, the present invention provides the following.
Item 1. A preparation containing vitamin B1 and containing at least 0.1 part by weight of an amino sugar relative to 1 part by weight of vitamin B1.
Item 2. A preparation containing vitamin B1 and an amino sugar, wherein the content of vitamin B1 is 0.001 to 30% by weight based on the whole.
Item 3. Item 3. The preparation according to Item 1 or 2, wherein the amino sugar is glucosamine.
Item 4. Item 3. The preparation according to Item 1 or 2, which is a solid preparation containing glycosaminoglycans.
Item 5. Item 5. The preparation according to Item 4, wherein the glycosaminoglycan is at least one selected from hyaluronic acid, chondroitin, and salts thereof.
Item 6. Item 5. The preparation according to Item 4, comprising an amino sugar in a proportion of 0.1 part by weight or more per 1 part by weight of glycosaminoglycan.
Item 7. A method of stabilizing vitamin B1 by blending an amino sugar with a preparation containing vitamin B1.
Item 8. A method for improving the disintegration property of a solid preparation by adding an amino sugar to a solid preparation containing glycosaminoglycans.

  In the present invention, vitamin B1 can be effectively stabilized by amino sugars. Moreover, even if it is a solid formulation containing glucosaminoglycans, such as chondroitin sulfate, formation of a hydrogel lump can be suppressed and disintegration can be improved. In particular, the disintegration dependence due to pH is small, and even if the pH varies, the disintegration property of the solid preparation can be effectively improved.

  The vitamin B1 contained in the preparation of the present invention includes thiamine, thiamine derivatives and salts thereof, and the thiamine derivative may be disulfide type, acyl type and the like. Examples of thiamine derivatives include bis-thiamine, thiamine disulfide (TDS), thiamine dicetyl sulfate, benfotiamine (BTMP), prosultiamine (TPD), fursultiamine (TTFD), bisbenchamine (BTDS), Chicothiamine (CCT), Octothiamine (TATD), Alithyamine, Thiaminepropyl disulfide, Thiaminetetrahydrofurfuryl disulfide (TPFD), Dicetiamine (DCET), Bisbutiamine, Bisbutiamine (DBT), Thiamine monophosphate disulfide, Thiamine pyrophosphate, Chicotiamine And thiamine ethyl disulfide and thiamine propyl disulfide. Examples of thiamine salts include physiologically acceptable salts, for example, hydrochlorides such as thiamine hydrochloride, thiamine nitrate, bisthiamine nitrate, dicetiamine hydrochloride, and fursultiamine hydrochloride, and nitrates. These vitamin B1s can be used alone or in combination of two or more.

  Of these vitamin B1 compounds, thiamine, thiamine disulfide, benfotiamine, fursultiamine, bisbenchamine, dicetiamine, thiamineethyl disulfide, and thiaminepropyl disulfide are preferable from the viewpoint of stability. In particular, bisbenchamine, fursultiamine, and thiamine are preferable from the viewpoint of stability and absorbability.

  The amount of vitamin B1 compounded is, for example, 0.001 to 30% by weight, preferably 0.01 to 20% by weight, more preferably about 0.1 to 10% by weight, based on the whole preparation (particularly solid preparation). It can be selected from the range, and is usually about 0.1 to 5% by weight. In the liquid preparation, the content of vitamin B1 is usually preferably about 0.0002 to 0.03 W / V% with respect to the whole.

  Vitamin B1 may be used in combination with other vitamins. Other vitamins include, for example, water-soluble vitamins [vitamin B2 (riboflavins such as flavin adenine dinucleotide sodium, riboflavin, sodium riboflavin phosphate, riboflavin butyrate), vitamin B6 (vitamin B6, pyridoxine, pyridoxal, etc. Pyridoxines, physiologically acceptable salts (hydrochlorides such as pyridoxine hydrochloride, corresponding acetates, phosphates such as pyridoxal phosphate), vitamin B12 (vitamin B12, mecobalamin, cyanocobalamin, hydroxocobalamin, Vitamin Bs such as cobalamins such as methylcobalamin, or physiologically acceptable salts thereof (hydrochloride, acetates such as hydroxocobalamin acetate), vitamin Cs (ascorbic acid, calcium ascorbate) , Sodium ascorbate, etc.), nicotinic acids (nicotinic acid, nicotinic acid amide, etc.), pantothenic acids (pantenol, pantothenic acid or its salts, etc.), biotin, folic acid, etc.], fat-soluble vitamins [vitamin A (retinol acetate) , Retinol palmitate, vitamin A oil, etc.), vitamin D (ergocalciferol, cholecalciferol, etc.), vitamin E (liver oil, strong liver oil, d-α-tocopherol acetate, dl-α-tocopherol acetate, d- α-tocopherol, dl-α-tocopherol, etc.), vitamin K, etc.) These vitamins can also be used alone or in combination of two or more.Vitamin B1 is usually a water-soluble vitamin (vitamin B), for example, vitamin B6 and vitamin B12 Only together can be used.

  In this invention, there exists an advantage which can mix | blend vitamin B6 and / or vitamin B12. That is, it is known that the stability of vitamin B6 or vitamin B12 decreases when coexisting with vitamin B1. Therefore, it is necessary to devise a formulation such as making a bilayer tablet by avoiding contact of each component, resulting in a complicated manufacturing process. In the present invention, vitamin B1 is stabilized, and a more stable blending with vitamin B6 or vitamin B12 is possible. Pyridoxine is preferable among the vitamin B6 types, and cyanocobalamin or hydroxocobalamin is preferable among the vitamin B12 types.

  The ratio (weight ratio) between vitamin B1 and other vitamins is the former / the latter = 100/0 to 20/80, preferably 100/0 to 30/70, more preferably about 100/0 to 50/50. You may select from the range.

  And vitamin B1 class can be effectively stabilized by combining with amino saccharides. Examples of amino sugars include sialic acid, muramic acid, glucosamine [for example, glucosamine], and salts thereof [for example, physiologically acceptable salts such as glucosamine salts (hydrochloride, sulfate, etc., for example, glucosamine hydrochloride, glucosamine). Examples thereof include inorganic acid salts such as sulfates and glucosamine phosphates], and derivatives [for example, glucosamine derivatives (N-acetylglucosamine, N-methyl-L-glucosamine, etc.)] and the like. The amino sugar may be D, L or DL. These amino sugars can be used alone or in combination of two or more. A preferred amino sugar is glucosamine or a salt thereof (such as glucosamine hydrochloride).

  Note that glucosamine or a salt thereof, which is a typical amino sugar, can be obtained by purifying shrimp, crab, squid and the like by enzyme or hydrolysis treatment, and commercially available products can also be used.

  The compounding quantity of aminosaccharides, such as glucosamine, can be selected from the wide range of about 1-99.9 weight% with respect to the whole preparation (especially solid preparation), and is normally 5-99.9 weight% (for example, 7.5 ˜99.9 wt%), preferably 10 to 90 wt%, more preferably about 10 to 80 wt%. Usually, it is about 10 to 60% by weight. Content of the amino saccharide in a liquid agent is 0.001-10 W / V%, for example, Preferably it is 0.01-10 W / V%, More preferably, it is about 0.01-5 W / V%.

  The ratio of the amino saccharide to the vitamin B1 may be an amount effective for stabilizing the vitamin B1. For example, 0.1 part by weight or more of the amino saccharide with respect to 1 part by weight of the vitamin B1 (for example, 0.1% ~ 1000 parts by weight), preferably 0.5 parts by weight or more (for example, 1 to 500 parts by weight), more preferably 1 part by weight or more (for example, 1 to 100 parts by weight), particularly about 2 to 50 parts by weight. You can select from a range.

  Aminosaccharides can function as a stabilizer for vitamin B1s, and vitamin B1s can be effectively stabilized by adding aminosaccharides. Therefore, the present invention also includes a method of stabilizing vitamin B1 compounds by adding amino sugars to a preparation containing vitamin B1 compounds.

  Thus, since vitamin B1 can be stabilized by a combination with an amino sugar, the present invention is applied to various preparations having vitamin B1 as an active ingredient (a physiologically active ingredient or a pharmacologically active ingredient), for example, liquid preparations. However, when used in combination with glycosaminoglycans, it is usually used in the form of a solid preparation. That is, the amino sugar functions as a disintegrant and promotes the disintegration property of the solid preparation containing glycosaminoglycans. Therefore, the present invention is not limited to the combination of amino sugars and glycosaminoglycans (or solid preparations or compositions for solid preparations), regardless of the presence or absence of vitamin B1. A method for improving the disintegration property of a solid preparation by incorporating an amino sugar such as glucosamine into the contained solid preparation is also included.

  As described above, the solid preparation of the present invention may further contain glycosaminoglycans (mucopolysaccharide or acidic mucopolysaccharide). This glycosaminoglycan can be used as an active ingredient (a physiologically active ingredient or a pharmacologically active ingredient) of a preparation. Glycosaminoglycans are a series of acidic polysaccharides including amino sugars, and include, for example, hyaluronic acid, chondroitin, jalluronic acid, heparan, keratan, or salts thereof. As salts of glycosaminoglycans, alkali metal salts (sodium salts such as sodium hyaluronate), sulfated glucosaminoglycans (chondroitin sulfate A (chondroitin 4-sulfate), chondroitin sulfate B (dermatan sulfate), chondroitin Examples thereof include chondroitin sulfate such as sulfate C (chondroitin 6-sulfate), heparin, heparan sulfate, keratan sulfate I, keratan sulfate II, and the like. The sulfated glucosaminoglycan may be a metal salt such as sodium, potassium, calcium, magnesium, iron, manganese, or a salt such as ammonium salt. These glycosaminoglycans can be used alone or in combination of two or more.

  Preferred glycosaminoglycans include hyaluronic acid or a salt thereof (such as sodium hyaluronate), chondroitin or chondroitin sulfate or a salt thereof (such as a metal salt of chondroitin sulfate). In particular, chondroitin or chondroitin sulfate or a salt thereof is preferable.

  Chondroitin or a salt thereof can be obtained from natural products such as animal cartilage or collagen, and commercially available products can also be used. In addition to purified chondroitin, it can also be used as animal cartilage powder or extract / extract containing chondroitin or a salt thereof. The salts may be physiologically acceptable salts such as hydrochlorides and sulfates. Purified chondroitin or chondroitin sulfate or a salt thereof is more preferable in terms of safety and absorbability.

  The blending amount of glycosaminoglycans such as chondroitin sulfate can be selected from a wide range of about 0.5 to 90% by weight with respect to the whole solid preparation. For example, the blending amount of glycosaminoglycans is 1 to 90. % By weight, preferably 5 to 80% by weight, more preferably about 10 to 70% by weight, usually 10 to 60% by weight, more preferably about 10 to 50% by weight.

  The amount of amino sugar (such as glucosamine) used for glycosaminoglycans (such as chondroitin sulfate) is not particularly limited as long as it is an amount that does not impair the disintegration property of the solid preparation, particularly an effective amount that can improve disintegration. It can be selected from a wide range of about 0.01 to 100 parts by weight with respect to 1 part by weight of glycosaminoglycans. The amount of aminosaccharide used is, for example, 0.1 parts by weight or more (for example, 0.1 to 50 parts by weight), preferably 0.2 parts by weight or more (for example, 1 part by weight of glycosaminoglycans). 0.2 to 30 parts by weight), more preferably 0.3 parts by weight or more (particularly 0.3 to 10 parts by weight, usually 0.5 to 5 parts by weight).

  If necessary, the preparation of the present invention contains other physiologically active ingredients and pharmacologically active ingredients such as joint and muscle analgesics (analgesic antipyretic agents such as acetaminophen, ibuprofen, salicylic acid derivatives, mefenamic acid, anti-inflammatory agents, antihistamines, etc.) , Aminoethyl sulfonic acid, γ-oryzanol, herbal medicine ingredients (processed potato, carrot, yokuinin, etc.), inorganic salts (mixture of equal amounts of potassium aspartate and magnesium, calcium glycerophosphate, calcium gluconate, precipitated calcium carbonate, calcium lactate, anhydrous phosphorus Calcium oxyhydrogen, calcium hydrogen phosphate, etc.), caffeine (caffeine, anhydrous caffeine, etc.), amino acids or salts thereof (such as L-cysteine, L-cysteine hydrochloride), glucuronolactone, glucuronic acid, minerals, etc. May contain

  Furthermore, the dosage form of the preparation of the present invention is not particularly limited, and is a liquid preparation (suspension, emulsion, syrup, injection, etc.) or solid preparation (powder, fine granules, granules, pills, capsules). The solid preparation includes not only a pharmaceutical preparation but also a confectionery agent (candy (candy), gummi, nougat agent, etc.). In addition, even if it is the liquid agent containing glycosaminoglycans, since vitamin B1 can be stabilized, the liquid agent may contain glycosaminoglycans, but utilizes the disintegration promoting action of aminosaccharides. For this purpose, the preparation containing glycosaminoglycans is preferably a solid preparation.

  The preparation of the present invention can be prepared by a conventional method by adding a conventional carrier component depending on the form of the preparation as long as the stability and the like are not impaired. In solid preparations, carrier components or additives include, for example, excipients (sugar alcohols such as D-sorbitol, D-mannitol, xylitol, sugars such as glucose, sucrose, lactose, fructose, crystalline cellulose, carmellose sodium, Calcium hydrogen phosphate, wheat starch, rice starch, corn starch, potato starch, dextrin, β-cyclodextrin, light anhydrous silicic acid, titanium oxide, magnesium aluminate metasilicate, talc, kaolin, etc .; disintegrant (low substitution degree) Hydroxypropylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, hydroxypropyl starch, partially pregelatinized starch, etc .; binder (methylcellulose, ethylcellulose, hydroxypropyl cell) Cellulose derivatives such as cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, acrylic polymer, gelatin, gum arabic, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol alginate, etc.); Agents (stearic acid, magnesium stearate, calcium stearate, polyoxyl stearate, cetanol, talc, hydrogenated oil, sucrose fatty acid ester, dimethylpolysiloxane, beeswax, beeswax etc.); antioxidants (dibutylhydroxytoluene (BHT), Propyl gallate, butylhydroxyanisole (BHA), tocopherol, citric acid, etc.); coating agent (hydroxypropylmethylcellulose, Hydroxypropylcellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer, hydroxypropylmethylcellulose acetate succinate, methacrylic acid Copolymer, polyvinyl acetate diethylaminoacetate, shellac, etc.); colorant (turmeric extract, riboflavin, titanium oxide, carotene solution, etc.); taste-masking agent (aspartame, ascorbic acid, stevia, menthol, licorice crude extract, simple syrup, etc.) Surfactant (Polyoxyethylene Cured Castor Glyceryl monostearate, sorbitan monostearate, sorbitan monolaurate, polyoxyethylene polyoxypropylene, polysorbates, sodium lauryl sulfate, macrogol, sucrose fatty acid ester, etc .; plasticizer (triethyl citrate, polyethylene glycol, Triacetin, cetanol, etc.); sweeteners (natural or synthetic sweeteners such as sucrose, mannitol, aspartame); flavoring agents (menthol, etc.); adsorbents, preservatives, wetting agents, antistatic agents and the like.

  In liquid preparations, water or alcohol-containing water can be usually used as a carrier component, and can be formulated using conventional components. Examples of the additive component of the liquid agent include a pH adjuster (citric acid, malic acid, sodium hydrogen phosphate, dipotassium phosphate, etc.), a cooling agent (l-menthol, mint water, etc.), the surfactant, Turbidizing agents (kaolin, carmellose sodium, xanthan gum, methylcellulose, tragacanth, etc.), antifoaming agents (dimethylpolysiloxane, silicon antifoaming agents, etc.), thickeners (xanthan gum, tragacanth, methylcellulose, dextrin, etc.), solubilizing agents (Ethanol, sucrose fatty acid ester, macrogol, etc.), the above antioxidants, colorants, sweeteners, flavoring agents and the like.

  The preparation of the present invention can be obtained by applying a conventional method in the art as it is or appropriately. For example, if it is a tablet, it can be prepared by mixing and compressing a powdered active ingredient and a pharmaceutically acceptable carrier component (excipient, etc.). You may prepare by the method of inject | pouring. Further, among solid preparations, granules such as granules are available in various granulation methods (extrusion granulation method, pulverization granulation method, dry compaction granulation method, fluidized bed granulation method, rolling granulation method, high speed granulation method, The tablet may be prepared by appropriately combining the above granulation method, tableting method (wet tableting method, direct tableting method) and the like. Furthermore, the capsule can be prepared by filling a capsule (soft or hard capsule) with a powder (powder, granule, etc.) by a conventional method. A preferable dosage form of the solid preparation of the present invention is a tablet (for example, a chewable tablet in the mouth). The tablets may be sugar-coated to give sugar-coated tablets. Furthermore, the tablet may be a monolayer tablet or a laminated tablet such as a bilayer tablet.

  The liquid preparation can be prepared by dissolving or dispersing each component in an aqueous medium as a carrier component (purified water, ethanol-containing purified water, etc.), filtering or sterilizing as necessary, filling a predetermined container, and sterilizing. .

  In the present invention, vitamin B1 can be stabilized by an amino sugar such as glucosamine. Therefore, the present invention can be applied to preparations containing various vitamin B1s. Furthermore, the formation of gels by glycosaminoglycans such as chondroitin sulfate can be remarkably suppressed by aminosaccharides, and disintegration can be improved. Therefore, the present invention is advantageously applied to solid preparations containing glycosaminoglycans. In addition, the solid preparation of the present invention is effective for accelerating disintegration in the digestive tract and stably releasing active ingredients without being affected by pH fluctuations. For example, even if the pH varies in the range of about 1 to 10 (for example, about 1 to 7), the solid preparation disintegrates efficiently. Particularly, the disintegration property in a low pH range (for example, about 1 to 4) can be greatly improved. Therefore, even if the gastric pH varies within the range of 1.2 to 6.8, it is suitable for use as a pharmaceutical product.

  The formulations of the present invention are suitable for oral administration and can be administered one or more times per day. The dose of the preparation per day for an adult is, for example, about 1 to 300 mg, preferably 5 to 150 mg, more preferably 5 to 100 mg, particularly 5 to 30 mg as free vitamin B1s. When blending vitamin B6, the dose of vitamin B6 per day for an adult is, for example, 1 to 300 mg, preferably 10 to 100 mg in terms of free vitamin B6. Moreover, the dose of vitamin B12 per day for an adult is, for example, about 10 to 3000 μg, preferably about 50 to 1500 μg in terms of free vitamin B12.

  The dose of aminosaccharides such as glucosamine (in terms of free amino sugar) is, for example, about 50 to 3000 mg, preferably 100 to 2500 mg, more preferably 300 to 2000 mg, particularly about 500 to 1500 mg per day for an adult.

  Furthermore, the dosage of glycosaminoglycans such as chondroitin (as free glycosaminoglycans) is, for example, 0.01 to 5 g, preferably 0.05 to 2 g, more preferably 0.1 per day per adult. It is about -1.7g.

  The preparation of the present invention is used as a pharmaceutical preparation (for example, a pharmaceutical preparation effective for the prevention and treatment of joint disorders such as arthritis and arthritis, and the treatment of muscle pain using the activities of vitamin B1 and chondroitin). It can be used as a confectionery tablet or health supplement.

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

Example 1
Hydroxypropyl cellulose dissolved in purified water is added to a mixed powder obtained by mixing thiamine nitrate, glucosamine hydrochloride and crystalline cellulose until uniform, and granulated with stirring. To a granulated powder that has been dried and sized, a mixture of an equal amount of potassium L-aspartate / magnesium, sodium chondroitin sulfate, croscarmellose sodium, light anhydrous silicic acid, and magnesium stearate is mixed and stirred until uniform. The mixture was tableted with a rotary tableting machine to obtain a circular tablet (diameter 8.5 mm, weight 270 mg, hardness 5 kg (measured with a digital hardness meter)). The tablet formulation is shown below.

[Tablet prescription] ("Part" indicates "part by weight". The same applies hereinafter)
Thiamine nitrate 1.25 parts L-aspartate potassium / magnesium equivalent mixture 8.3 parts Sodium chondroitin sulfate 33.3 parts Glucosamine hydrochloride 41.7 parts Hydroxypropyl cellulose 1.62 parts Crystalline cellulose 5.33 parts Magnesium stearate 1 .5 parts croscarmellose sodium 6.0 parts light anhydrous silicic acid 1.0 part total 100 parts

Example 2
A granule (1 capsule = 1500 mg) was produced according to the Japanese Pharmacopoeia according to the general formulation “Granule”.
Mixing ratio (parts)
Thiamine hydrochloride 0.6 parts Sodium chondroitin sulfate 17.8 parts Glucosamine hydrochloride 22.2 parts Riboflavin butyrate 0.3 parts Pyridoxine hydrochloride 0.3 parts Hydroxypropyl cellulose 2.4 parts Crystalline cellulose 24.4 parts Mannitol 31.8 parts Menthol 0.2 parts Total 100 parts

Example 3 (formulation containing vitamin B1, vitamin B6 and vitamin B12)
A tablet (1 tablet = 280 mg) was produced using the following tablet formulation according to the Japanese Pharmacopoeia, General Formula “Tablet”.
Mixing ratio (parts)
Fursultiamine hydrochloride 4.0 parts Sodium chondroitin sulfate 23.8 parts Glucosamine hydrochloride 35.7 parts Pyridoxine hydrochloride 4.0 parts Hydroxocobalamin 0.06 parts Hydroxypropyl cellulose 0.7 parts Crystalline cellulose 31.24 parts Magnesium stearate 0 .5 copies total 100 copies

Example 4 (Preparation containing vitamin B1 and vitamin E)
A tablet (1 tablet = 270 mg) was produced using the following tablet prescription according to the Japanese Pharmacopoeia, General Rules for Tablets “Tablet”.
Mixing ratio (parts)
Thiamine nitrate 1.2 parts Sodium chondroitin sulfate 20.6 parts Glucosamine hydrochloride 20.6 parts Acetic acid d-α-tocopherol 0.5 parts Hydroxypropylcellulose 3.0 parts Crystalline cellulose 28.8 parts Mannitol 24.7 parts Fragrance 0. 1 part Magnesium stearate 0.5 part Total 100 parts

Example 5 (vitamin B1 and hyaluronic acid-containing preparation)
A tablet (1 tablet = 500 mg) was produced using the following tablet prescription according to the Japanese Pharmacopoeia, General Formula “Tablet”.
Mixing ratio (parts)
Thiamine hydrochloride 0.8 parts Hyaluronic acid 15 parts Glucosamine hydrochloride 30 parts Hydroxypropyl cellulose 3 parts Crystalline cellulose 17.3 parts Lactose 33.5 parts Magnesium stearate 0.5 parts Total 100 parts

Example 6
A tablet (1 tablet = 350 mg) was produced using the following tablet formulation according to the Japanese Pharmacopoeia, General Rules for Tablets “Tablet”.
Mixing ratio (parts)
Thiamine nitrate 0.1 part Chondroitin sodium sulfate 19.0 parts Glucosamine sulfate 9.5 parts Hydroxypropyl cellulose 2.0 parts Mannitol 68.9 parts Magnesium stearate 0.5 parts Total 100 parts

Test example 1
50 parts by weight of chondroitin sulfate (manufactured by Seikagaku Corporation), 50 parts by weight of glucosamine hydrochloride (manufactured by Yaizu Suisan Co., Ltd.), 0.5 part by weight of magnesium stearate (manufactured by Taihei Chemical Sangyo Co., Ltd.) Mix to prepare a mixture of tablet ingredients. A circular tablet (diameter: 8.5 mm, weight: 270 mg, hardness: 5 kg (measured with a digital hardness meter)) as in Example 1 was obtained from the mixture using a rotary tableting machine.

  On the other hand, as a comparative example, in place of 50 parts by weight of glucosamine hydrochloride, comparison was made in the same manner as above except that 50 parts by weight of crystalline cellulose (manufactured by Asahi Kasei Co., Ltd.) or 50 parts by weight of lactose (manufactured by DMV Co., Ltd.) was used. Tablets of Example 1 (crystalline cellulose) and Comparative Example 2 (lactose) were obtained.

  According to the disintegration test method (general test method Japanese Pharmacopoeia 13th revision), the disintegration property of the obtained tablets with respect to the test solution was tested. The taken solid preparation needs to be dissolved in the test solution or dispersed to a small particle state so that the solid preparation can be quickly disintegrated in the stomach and the drug can be eluted.

  As the test solution, assuming a gastric pH of a healthy person, pH = 1.2 test solution adjusted with sodium chloride and hydrochloric acid (corresponding to the first solution of the Japanese Pharmacopoeia Disintegration Test Method), adjusted with acetate buffer PH = 4.5 test solution, pH = 6.8 test solution adjusted with potassium dihydrogen phosphate and sodium hydroxide (corresponding to the second solution of the Japanese Pharmacopoeia disintegration test method) was prepared.

  Each tablet and each test solution was placed in a glass tester and smoothly moved up and down 29-32 reciprocations per minute with an amplitude of 53-57 mm while maintaining the temperature of the test solution at 37 ° C. ± 2 ° C. And the time until the residue of a tablet was not recognized in a test device was measured.

  In any tablet, the disintegration time tended to be longer due to a decrease in pH, but in Example 1 containing glucosamine, disintegration is high at any pH. In Comparative Examples 1 and 2, the disintegration time is particularly slow at a low pH, and the formation of a hydrogel mass of sodium chondroitin sulfate cannot be suppressed. The results are shown in Table 1.

Test example 2
3 parts by weight of thiamine nitrate (manufactured by Takeda Pharmaceutical Co., Ltd.), 100 parts by weight of glucosamine hydrochloride (manufactured by Yaizu Suisan Co., Ltd.), and 0.5 parts by weight of magnesium stearate (manufactured by Taihei Chemical Industrial Co., Ltd.) are mixed uniformly. A mixture of tablet ingredients was prepared. A circular tablet (diameter: 8.5 mm, weight: 270 mg, hardness: 5 kg (measured with a digital hardness meter)) was obtained from the mixture using a rotary tableting machine.

  The tablets of Example 2 and Comparative Example 2 were placed in a glass bottle and stored at 50 ° C. under light shielding for 2 weeks. Thereafter, the residual amount of thiamine nitrate in the tablet was measured by a high performance liquid chromatography (HPLC) method according to a conventional method. In Example 2, the residual rate (the residual amount of thiamine nitrate in the tablet / the initial amount of thiamine nitrate in the tablet) ) Was 99.8%, whereas in Comparative Example 3, it was 95.3%.

  Further, the tablet of Example 2 was placed in a glass bottle, stored at 40 ° C. for 1 month, 3 months, and 6 months under light shielding. Similarly, the residual ratio of thiamine nitrate was measured, and 100% remained after 1 and 3 months. Even after 6 months, the residual rate was as high as 99.9%. Therefore, glucosamine has been shown to be effective for long-term stabilization of thiamine nitrate.

Claims (1)

A preparation containing vitamin B1 and containing at least 0.1 part by weight of amino sugar relative to 1 part by weight of vitamin B1 [provided that vitamin B1, amino sugar, and glycosamino A preparation containing glycans, containing 1 to 100 parts by weight of an amino sugar relative to 1 part by weight of vitamin B1, and 10 to 50 parts by weight of glycosaminoglycan relative to the whole preparation %, 10 to 80% by weight of amino sugar, and 0.1 to 10% by weight of vitamin B1, and 0.5 to 5 parts by weight of amino sugar with respect to 1 part by weight of glycosaminoglycan Except in the case of tablets containing at a ratio of] .