JP2004002482A - Pharmaceutical preparation containing aminosugar - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a pharmaceutical preparation containing stabilized vitamin B1, and to provide a solid preparation containing glucosaminoglycans such as chondroitin sulfate and having improved disintegration. <P>SOLUTION: The vitamin B1 is stabilized by making a pharmaceutical preparation containing the vitamin B1 include aminosugars (glucosamine or the like), wherein the use of the aminosugars is a sufficient amount to stabilize the vitamin B1 e.g. ≥0.1 pt. wt. based on 1 pt. wt. vitamin B1. The disintegration of the solid preparation containing glucosaminoglycanes (hyaluronic acid, chondroitin or their salts) is improved by compounding the aminosugars in the preparation, wherein the use of the aminosugars is ≥0.1 pt. wt. based on 1 pt. wt. glycosaminoglycanes, and the solid prepartation suppresses gel mass formation of the glucosaminoglycane to improve disintegration even when pH is fluctuated. <P>COPYRIGHT: (C)2004,JPO

Description

The present invention relates to a preparation in which vitamin B1 is stabilized, particularly a preparation in which vitamin B1 is stabilized and disintegration is improved (particularly, a solid preparation).

数 多 く Many pharmaceutical preparations containing vitamin B1 are commercially available. This vitamin B1 has a problem in stability, and its content decreases during storage due to environmental factors such as heat, pH, light, and moisture, as well as in the form of formulation and various coexisting components in the formulation. Stability needs to be considered.

Particularly, when vitamins are blended in high units, a method of stabilizing by blending a stabilizer such as an antioxidant is known. However, it is not preferable from the viewpoint of safety. In addition, in the case of improving by formulation design such as a two-layer tablet, a laminated tablet, and a coating technique, there is a disadvantage that a manufacturing process is complicated.

In order to stabilize vitamin B1 in a solid preparation, JP-A-5-27072 (Patent Document 1) discloses that at least one component contains a succinic acid ester of tocopherol or a salt thereof and a vitamin B1 or ascorbic acid. Which are coated with a coating agent. JP-A-2000-247879 (Patent Document 2) discloses a vitamin preparation containing a succinic acid ester of tocopherol or a salt thereof, vitamins B1 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 a liquid preparation, JP-A-5-255069 (Patent Document 4) discloses that a group of vitamins containing at least one of the 13 essential vitamins includes at least one selected from leucine, isoleucine, methionine, and valine. An intravenous vitamin formulation containing one 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 mixed with vitamin B2. Furthermore, Japanese Patent Application Laid-Open No. Hei 9-12458 (Patent Document 6) proposes a method in which fat is contained in a vitamin B1-containing liquid preparation in the form of an emulsion or the like.

On the other hand, sodium chondroitin sulfate is effective for arthritis and the like, and a number of drugs containing sodium chondroitin sulfate are commercially available. For example, Japanese Patent Publication No. 9-503197 (Patent Document 7) discloses a composition for treating connective tissues of humans and animals, which contains glycosaminoglycans such as chondroitin and amino sugars such as glucosamine. ing. JP-A-2000-53569 (Patent Document 8) discloses a composition containing L-carnitines, glucosaminoglycan, and an excipient as a composition suitable for prevention and treatment of joint disorders. ing. This document also discloses a composition containing L-carnitines, chondroitin sulfate, and glucosamine. Furthermore, Japanese Patent Application Laid-Open No. 2000-139408 (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 if necessary, a saccharide and an excipient. Confectionery).

グ ル コ Glucosaminoglycan such as chondroitin sulfate is a kind of high molecular polysaccharide and forms a hydrogel mass in water. In particular, when the concentration of glucosaminoglycan is high, a hydrogel mass is easily formed. The formation of a hydrogel mass is likely to be promoted, especially in a low pH environment, and the formed hydrogel mass is poorly soluble and blocks water from entering the interior of the mass. Thus, if the dosed formulation forms a hydrogel with water in the gastrointestinal tract, it impedes the penetration of water into the solid formulation, resulting in a delayed disintegration time and impedes release of the active ingredient. Therefore, it is necessary to consider the disintegration characteristics in designing a solid preparation.

Further, it is known that the internal environment in the stomach fluctuates greatly due to external or internal factors such as individual differences and the contents of meals, and the stomach pH of a healthy person fluctuates in the range of 1.2 to 6.8. ing. Therefore, it is necessary to take care to suppress the gelation of sodium chondroitin sulfate and promote its disintegration under any internal environment.
JP-A-5-27072 JP 2000-247879 A JP-A-9-268127 JP-A-5-255069 JP-A-6-145056 JP-A-9-12458 Japanese Patent Publication No. 9-503197 JP-A-2000-53569 JP 2000-139408 A

Therefore, 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 for improving the disintegration of the solid preparation. .

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

The present inventors have conducted intensive studies to achieve the above object. As a result, when an amino sugar such as glucosamine is used, vitamin B1 can be stabilized in a preparation, and vitamin B1 remains over a long period of time, and chondroitin sulfate The present invention has been found to be able to remarkably suppress the formation of gels due to glycosaminoglycans, promote disintegration in the gastrointestinal tract, and stably release the active ingredient, thereby completing the present invention.

That is, the preparation of the present invention is a preparation containing vitamins B1 and is effective in stabilizing the vitamins B1 in an amount of, for example, 0.1 parts by weight or more based on 1 part by weight of the vitamins B1. Contains amino sugars (such as glucosamine). Further, the preparation of the present invention is a preparation containing vitamin B1 and an amino sugar, and the content of vitamin B1 is 0.001 to 30% by weight based on the whole. Such a preparation of the present invention may be a liquid preparation, but since it can improve disintegration by amino sugars, it is advantageously applied to a solid preparation when it contains glycosaminoglycans that easily form a gel. You. That is, the preparation of the present invention may be a solid preparation further containing glycosaminoglycans (such as hyaluronic acid, chondroitin and salts thereof).

The present invention also includes a method of stabilizing vitamin B1 by incorporating an amino sugar into a preparation containing vitamin B1. Furthermore, the present invention also includes a method for improving the disintegration of a solid preparation by incorporating an amino sugar into a solid preparation containing glycosaminoglycans.

In the present invention, vitamin B1 can be effectively stabilized by amino sugars. Further, even with a solid preparation containing glucosaminoglycan such as chondroitin sulfate, formation of a hydrogel mass can be suppressed, and disintegration can be improved. In particular, the disintegration dependence of pH is small, and the disintegration of the solid preparation can be effectively improved even if the pH fluctuates.

ビ タ ミ ン Vitamin B1 contained in the preparation of the present invention includes thiamine, thiamine derivatives and salts thereof, and the thiamine derivatives may be disulfide type, acyl type and the like. Examples of the thiamine derivative include bisthiamine, thiamine disulfide (TDS), thiamine dicetyl sulfate, benfotiamine (BTMP), prosultiamine (TPD), fursultiamine (TTFD), bisbenthamine (BTDS), Sicotiamine (CCT), octiamine (TATD), alitiamine, thiamine propyl disulfide, thiamine tetrahydrofurfuryl disulfide (TPFD), dicetiamine (DCET), bisbutiamine, bisibutiamine (DBT), thiamine monophosphate disulfide, thiamine pyrophosphate, sicotiamine , Thiamine ethyl disulfide, thiamine propyl disulfide and the like. Examples of the thiamine salts include physiologically acceptable salts, for example, hydrochlorides such as thiamine hydrochloride, thiamine nitrate, bisthiamine nitrate, disetiamine hydrochloride, and fursultiamine hydrochloride, and nitrates. These vitamins B1 can be used alone or in combination of two or more.

の う ち Among these vitamins B1, thiamine, thiamine disulfide, benfotiamine, fursultiamine, bisbenthamine, dicetiamine, thiamine ethyl disulfide, and thiamine propyl disulfide are preferable from the viewpoint of stability. In particular, bisbenthamine, fursultiamine and thiamine are preferred from the viewpoint of stability and absorbability.

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

Note that vitamins B1 may be used in combination with other vitamins. Other vitamins include, for example, water-soluble vitamins [vitamin B2 (riboflavins such as sodium flavin adenine dinucleotide, riboflavin, sodium riboflavin phosphate, riboflavin butyrate), and vitamin B6 (vitamin B6, pyridoxine, pyridoxal, etc.). Pyridoxine, physiologically acceptable salts (hydrochlorides such as pyridoxine hydrochloride, corresponding acetates, phosphates such as pyridoxal phosphate, etc.)), vitamin B12 (vitamin B12, mecobalamin, cyanocobalamin, hydroxocobalamin, Vitamin Bs and Cs (ascorbic acid, calcium ascorbate) such as cobalamins such as methylcobalamin or their physiologically acceptable salts (eg, hydrochloride, acetate such as hydroxocobalamin acetate); , Sodium ascorbate, etc.), nicotinic acids (nicotinic acid, nicotinic acid amide, etc.), pantothenic acids (panthenol, pantothenic acid or a salt thereof, etc.), biotin, folic acid, etc., fat-soluble vitamins [vitamin A (retinol acetate, etc.) , Retinol palmitate, vitamin A oil), vitamin Ds (ergocalciferol, cholecalciferol, etc.), vitamin Es (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 can be usually used in combination with water-soluble vitamins (such as vitamin B) such as vitamin B6 and vitamin B12.

In the present invention, there is an advantage that vitamin B6 and / or vitamin B12 can be blended. That is, it is known that the stability of vitamin B6 or vitamin B12 decreases when they coexist with vitamin B1. Therefore, it is necessary to devise a formulation such as a two-layer tablet by avoiding the contact of each component, which complicates the manufacturing process. In the present invention, vitamin B1 is stabilized, and more stable combination with vitamin B6 or vitamin B12 becomes possible. In addition, pyridoxine is preferable among the vitamin B6, and cyanocobalamin or hydroxocobalamin is preferable among the vitamin B12.

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, and more preferably about 100/0 to 50/50. May be selected from the range.

ビ タ ミ ン And by combining with amino sugars, vitamin B1 can be effectively stabilized. Examples of the amino sugars include sialic acid, muramic acid, glucosamines (eg, glucosamine, etc.) and salts thereof (eg, glucosamine salts (physiologically acceptable salts such as hydrochloride, sulfate, etc., eg, glucosamine hydrochloride, glucosamine) Inorganic acid salts such as sulfates and glucosamine phosphates)] and derivatives [eg, glucosamine derivatives (eg, N-acetylglucosamine, N-methyl-L-glucosamine)] and the like. The amino sugar may be in D, L or DL form. 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, or the like by enzymatic or hydrolysis treatment, and a commercially available product can also be used.

The amount of amino sugars such as glucosamine can be selected from a wide range of about 1 to 99.9% by weight based on the whole preparation (particularly a solid preparation), and usually 5 to 99.9% by weight (for example, 7.5). -99.9% by weight), preferably 10-90% by weight, more preferably about 10-80% by weight. Usually, it is about 10 to 60% by weight. The content of the amino sugar in the solution is, for example, about 0.001 to 10 W / V%, preferably about 0.01 to 10 W / V%, and more preferably about 0.01 to 5 W / V%.

The ratio of the amino sugar to the vitamin B1 may be an amount effective for stabilizing the vitamin B1. For example, the amino sugar is 0.1 part by weight or more (for example, 0.1 part by weight) per 1 part by weight of the vitamin B1. To 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), and particularly about 2 to 50 parts by weight. You can choose from a range.

Amino sugars can function as stabilizers for vitamin B1s, and vitamin B1s can be effectively stabilized by incorporating amino sugars. Therefore, the present invention also includes a method of stabilizing vitamin B1 by incorporating an amino sugar into a preparation containing vitamin B1.

As described above, since vitamin B1 can be stabilized by combination with an amino sugar, the present invention is applied to various preparations containing vitamin B1 as an active ingredient (bioactive ingredient or pharmacologically active ingredient), for example, liquid preparations. When used in combination with glycosaminoglycans, they are usually used in the form of a solid preparation. That is, the amino sugar functions as a disintegrant and promotes the disintegration of a solid preparation containing glycosaminoglycans. Therefore, the present invention provides not only a composition (or a solid preparation or a composition for a solid preparation) in which amino sugars and glycosaminoglycans are combined, but also glycosaminoglycans regardless of the presence or absence of vitamin B1s. A method for improving the disintegration of the 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). These glycosaminoglycans can be used as an active ingredient (bioactive ingredient or pharmacologically active ingredient) of the preparation. Glycosaminoglycans are a series of acidic polysaccharides including amino sugars, and include, for example, hyaluronic acid, chondroitin, jaruronic acid, heparan, keratan or salts thereof. Examples of the salts of glycosaminoglycans include alkali metal salts (eg, 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, and keratan sulfate II. The sulfated glucosaminoglycan may be a metal salt such as sodium, potassium, calcium, magnesium, iron, manganese or the like, 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). Particularly, chondroitin or chondroitin sulfate or a salt thereof is preferable.

Chondroitin or a salt thereof can be obtained from animal cartilage or natural products such as collagen, and commercially available products can also be used. Not only purified chondroitin, but also chondroitin or a salt thereof can be used as an animal cartilage powder, extract or extract. The salts may be any physiologically acceptable salts such as hydrochloride and sulfate. Purified chondroitin or chondroitin sulfate or a salt thereof is more preferable in view of safety and absorbability.

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

The amount of amino sugars (such as glucosamine) to be used with respect to glycosaminoglycans (such as chondroitin sulfate) is not particularly limited as long as the amount does not impair the disintegration of the solid preparation, particularly an effective amount that can improve the disintegration. It can be selected from a wide range of about 0.01 to 100 parts by weight per 1 part by weight of glycosaminoglycans. The amount of the amino sugar used is, for example, 0.1 part by weight or more (for example, 0.1 to 50 parts by weight), preferably 0.2 part by weight or more (for example, 1 part by weight of glycosaminoglycans). 0.2 to 30 parts by weight), more preferably about 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 may contain other physiologically active ingredients and pharmacologically active ingredients such as analgesics for joints and muscles (analgesic antipyretics such as acetaminophen, ibuprofen, salicylic acid derivatives, mefenamic acid, anti-inflammatory agents, antihistamines, etc.). , Aminoethyl sulfonic acid, γ-oryzanol, crude drug ingredients (processed garlic, carrot, yoquinin, etc.), inorganic salts (equivalent mixture of potassium and magnesium aspartate, calcium glycerophosphate, calcium gluconate, precipitated calcium carbonate, calcium lactate, anhydrous phosphorus) Calcium hydrogen oxide, calcium hydrogen phosphate, etc., caffeine (caffeine, anhydrous caffeine, etc.), amino acid or its salt (L-cysteine, L-cysteine hydrochloride, etc.), glucuronolactone, glucuronic acid, minerals, etc. May contain .

Further, the dosage form of the preparation of the present invention is not particularly limited, and may be a liquid preparation (suspension, emulsion, syrup, injection, etc.) or a solid preparation (powder, fine granule, granule, pill, capsule) , Tablets, etc.), and solid preparations include not only pharmaceutical preparations, but also confectionery agents (candys, gummy agents, nougat agents, etc.). In addition, since the vitamin B1 can be stabilized even in the liquid preparation containing glycosaminoglycans, the liquid preparation may contain glycosaminoglycans, but it utilizes the disintegration promoting action of amino sugars. For this purpose, the preparation containing glycosaminoglycans is preferably a solid preparation.

製 剤 The preparation of the present invention can be prepared by a conventional method by adding a conventional carrier component according to the form of the preparation as long as stability and the like are not impaired. In the solid preparation, as the carrier component or additive, for example, excipients (sugar alcohols such as D-sorbitol, D-mannitol, xylitol, sugars such as glucose, sucrose, lactose, fructose, crystalline cellulose, carmellose sodium, Disintegrator (low substitution degree) calcium hydrogen phosphate, wheat starch, rice starch, corn starch, potato starch, dextrin, β-cyclodextrin, light silicic anhydride, titanium oxide, magnesium aluminate metasilicate, talc, kaolin, etc. Hydroxypropylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, hydroxypropyl starch, partially pregelatinized starch, etc .; binders (methylcellulose, ethylcellulose, hydroxypropylcell) Cellulose, cellulose derivatives such as hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, acrylic acid polymers, 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, polyvinylacetal diethylaminoacetate, aminoalkyl methacrylate copolymer, hydroxypropylmethylcellulose acetate succinate, methacrylic acid Coloring agents (turmeric extract, riboflavin, titanium oxide, carotene solution, etc.); Flavoring agents (aspartame, ascorbic acid, stevia, menthol, licorice crude extract, single syrup, etc.); Surfactant (polyoxyethylene cured castor Glycerin monostearate, sorbitan monostearate, sorbitan monolaurate, polyoxyethylene polyoxypropylene, polysorbates, sodium lauryl sulfate, macrogol, sucrose fatty acid ester, etc.); plasticizers (triethyl citrate, polyethylene glycol, Sweeteners (natural or synthetic sweeteners such as sucrose, mannitol, aspartame); flavorants (such as menthol); adsorbents, preservatives, wetting agents, and antistatic agents.

In liquid solutions, water or alcohol-containing water can be usually used as a carrier component, and can be formulated using conventional components. Examples of the additional component of the liquid agent include a pH adjuster (citric acid, malic acid, sodium hydrogen phosphate, dipotassium phosphate, etc.), a cooling agent (l-menthol, peppermint water, etc.), the surfactant, and a surfactant. Turbidity agents (kaolin, carmellose sodium, xanthan gum, methylcellulose, tragacanth, etc.), defoamers (dimethylpolysiloxane, silicone defoamer, etc.), thickeners (xanthan gum, tragacanth, methylcellulose, dextrin, etc.), solubilizer (Ethanol, sucrose fatty acid ester, macrogol, etc.), the above-mentioned antioxidants, coloring agents, sweeteners, flavoring agents and the like.

製 剤 The preparation of the present invention can be obtained as it is or by appropriately applying a conventional method in the art. For example, a tablet can be prepared by mixing a powdered active ingredient and a pharmaceutically acceptable carrier component (excipient, etc.) and compression-molding the confectionery tablet, such as a candy (candy). It may be prepared by injection. Further, among solid preparations, granules such as granules can be obtained by various granulation methods (extrusion granulation method, pulverization granulation method, dry compaction granulation method, fluidized bed granulation method, tumbling granulation method, high-speed granulation method). Tablets may be prepared by an appropriate combination of the above granulation methods and tableting methods (wet tableting method, direct tableting method) and the like. Furthermore, capsules can be prepared by filling powders and granules (powder, granules, etc.) in capsules (soft or hard capsules) by a conventional method. The preferred dosage form of the solid preparation of the present invention is a tablet (for example, a chewable tablet in the mouth). Tablets may be sugar-coated to give sugar-coated tablets. Further, the tablet may be a single-layer tablet or a laminated tablet such as a two-layer tablet.

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

According to the present invention, vitamin B1 can be stabilized by amino sugars such as glucosamine. Therefore, the present invention is applicable to preparations containing various vitamin B1s. Furthermore, the formation of gels due to glycosaminoglycans such as chondroitin sulfate can be remarkably suppressed by amino sugars, and disintegration can be improved. Therefore, the present invention is advantageously applied to solid preparations containing glycosaminoglycans. The solid preparation of the present invention is effective for promoting disintegration in the gastrointestinal tract and for stably releasing the active ingredient, without being affected by fluctuations in pH. For example, even if the pH fluctuates in the range of about 1 to 10 (for example, about 1 to 7), the solid preparation is efficiently disintegrated. Particularly, the disintegration in a low pH range (for example, about 1 to 4) can be greatly improved. Therefore, even if the intragastric pH varies in the range of 1.2 to 6.8, it is suitable for use as a pharmaceutical.

The formulation of the present invention is suitable for oral administration, and can be administered one or more times a day. The dose of the preparation per adult per day is, for example, about 1 to 300 mg, preferably 5 to 150 mg, more preferably 5 to 100 mg, particularly about 5 to 30 mg of free vitamin B1. When vitamin B6 is added, the daily dose of vitamin B6 in adult is, for example, 1 to 300 mg, preferably 10 to 100 mg in terms of free vitamin B6. The daily dose of vitamin B12 for adults is, for example, about 10 to 3000 µg, preferably about 50 to 1500 µg, in terms of free vitamin B12.

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

Furthermore, the dose 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 to 1 day per adult per day. It is about 1.7 g.

The preparation of the present invention is used as a pharmaceutical preparation (for example, a pharmaceutical preparation which is effective for the prevention and treatment of joint disorders such as arthralgia and arthritis, the treatment of myalgia, etc., utilizing the activities of vitamins B1 and chondroitins). It can be used as a confectionary 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 the mixture is stirred and granulated. The dried and sized granulated powder is mixed with an equal mixture of potassium-magnesium L-aspartate, sodium chondroitin sulfate, croscarmellose sodium, light anhydrous silicic acid, and magnesium stearate, and stirred until uniform. The mixture was tableted with a rotary tableting machine to obtain circular tablets (8.5 mm in diameter, 270 mg in weight, and 5 kg in hardness (measured with a digital hardness meter)). The prescription of the tablet is shown below.

[Tablet prescription] ("parts" indicates "parts by weight"; the same applies hereinafter)
Thiamine nitrate 1.25 parts Equivalent mixture of potassium and magnesium L-aspartate 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 5.5 parts Croscarmellose sodium 6.0 parts Light anhydrous silicic acid 1.0 parts Total 100 parts

Example 2
Granules (1 packet = 1500 mg) were produced using the following formulation according to the Japanese Pharmacopoeia, General Rules for Preparations "Granules".
Mixing ratio (parts)
Thiamine hydrochloride 0.6 part Sodium chondroitin sulfate 17.8 parts Glucosamine hydrochloride 22.2 parts Riboflavin butyrate 0.3 part Pyridoxine hydrochloride 0.3 part Hydroxypropyl cellulose 2.4 parts Crystalline cellulose 24.4 parts Mannitol 31.8 parts Menthol 0.2 parts Total 100 parts

Example 3 (vitamin B1, vitamin B6 and vitamin B12-containing preparation)
Tablets (1 tablet = 280 mg) were produced using the following tablet formulation according to the Japanese Pharmacopoeia, General Rules for Preparation “Tablets”.
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 (Vitamin B1 and Vitamin E-containing preparation)
Tablets (1 tablet = 270 mg) were produced using the following tablet formulation according to the Japanese Pharmacopoeia, General Rules for Preparation “Tablets”.
Mixing ratio (parts)
Thiamine nitrate 1.2 parts Chondroitin sodium sulfate 20.6 parts Glucosamine hydrochloride 20.6 parts d-α-tocopherol acetate 0.5 parts Hydroxypropyl cellulose 3.0 parts Crystalline cellulose 28.8 parts Mannitol 24.7 parts Fragrances 0. 1 part Magnesium stearate 0.5 part Total 100 parts

Example 5 (Vitamin B1 and hyaluronic acid-containing preparation)
Tablets (1 tablet = 500 mg) were produced using the following tablet formulation according to the Japanese Pharmacopoeia, General Rules for Preparation “Tablets”.
Mixing ratio (parts)
Thiamine hydrochloride 0.8 part 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 part Total 100 parts

Example 6
Tablets (1 tablet = 350 mg) were produced using the following tablet formulation according to the Japanese Pharmacopoeia, General Rules for Preparation “Tablets”.
Mixing ratio (parts)
Thiamine nitrate 0.1 part Sodium chondroitin 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 sodium chondroitin sulfate (manufactured by Seikagaku Corporation), 50 parts by weight of glucosamine hydrochloride (manufactured by Yaizu Suisan Co., Ltd.), and 0.5 part by weight of magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.) By mixing, a mixture of the tablet components was prepared. Using a rotary tableting machine, the mixture was used to obtain circular tablets (diameter 8.5 mm, weight 270 mg, hardness 5 kg (measured with a digital hardness meter)) as in Example 1.

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

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

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

(4) Each tablet and each test solution were put into a glass tester, and while the temperature of the test solution was kept at 37 ° C. ± 2 ° C., 29-32 reciprocations per minute, and an up-and-down motion with an amplitude of 53-57 mm were performed smoothly. Then, the time until the residue of the tablet was not recognized in the tester was measured.

錠 剤 All tablets tended to have a longer disintegration time due to a decrease in pH, but in Example 1 containing glucosamine, the disintegration was high at any pH. In Comparative Examples 1 and 2, the disintegration time at a particularly low pH is slow, and the formation of a hydrogel mass of sodium chondroitin sulfate cannot be suppressed. Table 1 shows the results.

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 part by weight of magnesium stearate (manufactured by Taihei Chemical Industry Co., Ltd.) are uniformly mixed. Thus, a mixture of tablet components was prepared. Using a rotary tableting machine, the mixture was used to obtain circular tablets (diameter 8.5 mm, weight 270 mg, hardness 5 kg (measured with a digital hardness tester)) as in Example 2.

錠 剤 The tablets of Example 2 and Comparative Example 2 were put 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 ratio (the residual amount of thiamine nitrate in the tablet / the initial amount of thiamine nitrate in the tablet) ) Was 99.8%, whereas that of Comparative Example 3 was 95.3%.

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

Claims (8)

(4) A preparation containing vitamin B1 containing at least 0.1 part by weight of an amino sugar per 1 part by weight of vitamin B1. (4) A preparation containing a vitamin B1 and an amino sugar, wherein the content of the vitamin B1 is 0.001 to 30% by weight based on the whole. 3. The preparation according to claim 1, wherein the amino sugar is glucosamine. 製 剤 The preparation according to claim 1 or 2, which is a solid preparation further containing glycosaminoglycans. 5. The preparation according to claim 4, wherein the glycosaminoglycans are at least one selected from hyaluronic acid, chondroitin, and salts thereof. 5. The preparation according to claim 4, wherein the amount of the amino sugar is 0.1 part by weight or more based on 1 part by weight of the glycosaminoglycans. 方法 A method of stabilizing vitamin B1 by blending amino sugars with a preparation containing vitamin B1. (4) A method for improving the disintegration of a solid preparation by incorporating an amino sugar into a solid preparation containing glycosaminoglycans.