JP7397563B2 - solid preparation - Google Patents

Description

The present invention relates to a solid preparation that can suppress the decomposition of vitamin B1 over time and has excellent preparation stability. The present invention also relates to a method for stabilizing vitamin B1 in solid preparations.

Vitamin B1 has the effect of maintaining normal nerve and muscle functions by promoting the metabolism of carbohydrates, and is known to be effective in recovering from fatigue and relieving stress, and is used in foods, medicines, etc. Widely used. However, vitamin B1s have low storage stability, and preparations containing vitamins B1s have the disadvantage that the content of vitamins B1s decreases over time.

Conventionally, various studies have been made on formulation techniques for stabilizing vitamin B1 in solid preparations. For example, Patent Document 1 discloses that in a preparation containing tocopherol succinate or its salt and vitamin B1, the vitamin B1 can be stabilized by coating at least one of them with a coating agent. has been done. Further, Patent Document 2 discloses that decomposition of the vitamin B1 derivative over time can be suppressed by blending starch and calcium hydrogen phosphate together with the vitamin B1 derivative in a solid preparation. Furthermore, Patent Document 3 discloses that the content of vitamin B1s can be reduced by combining tocopherol succinate or its salt, vitamin B1s, and a basic inorganic compound with a specific volume of about 3 ml/g or more. It has been disclosed that it is possible to suppress Further, Patent Document 4 discloses that vitamin B1 can be stabilized by blending an amino sugar such as glucosamine in a ratio of 0.1 part by weight or more to 1 part by weight of vitamin B1. ing.

However, conventional drug formulation techniques have limitations on drug formulations, and therefore may not be able to respond to recent diversification of drug formulations. Therefore, it is desired to develop a new formulation technology that can stabilize vitamin B1 in solid preparations.

Japanese Patent Application Publication No. 5-271072 Japanese Patent Application Publication No. 9-268127 Japanese Patent Application Publication No. 2000-247879 Japanese Patent Application Publication No. 2002-145780

An object of the present invention is to provide a solid preparation that can suppress the decomposition of vitamin B1 over time and has excellent preparation stability.

The present inventor conducted intensive studies to solve the above problems and found that a solid preparation containing dicarboxylic acid that does not have an alcoholic hydroxyl group together with vitamin B1 suppresses the decomposition of vitamin B1 over time. It was found that the formulation has excellent stability. The present invention was completed through further studies based on this knowledge.

That is, the present invention provides the inventions of the following aspects.
Item 1. A solid preparation containing vitamin B1 and a dicarboxylic acid that does not have an alcoholic hydroxyl group.
Item 2. Item 2. The solid preparation according to Item 1, wherein the dicarboxylic acid is succinic acid.
Item 3. Item 2. The solid preparation according to Item 1, wherein the vitamin B1 is thiamine hydrochloride.
Item 4. Any of items 1 to 3, in which 1.9 g of the solid preparation is added to 8.1 g of purified water and mixed, and the pH of the solution in which the solid preparation is dissolved becomes 3.0 to 6.0 at 25°C. The solid preparation described in .
Item 5. Item 5. The solid preparation according to any one of Items 1 to 4, which contains the dicarboxylic acid in a ratio of 0.3 to 3,500 parts by weight per 100 parts by weight of vitamin B1.
Item 6. Item 6. The solid preparation according to any one of Items 1 to 5, containing 0.001 to 10% by weight of the dicarboxylic acid.
Section 7. Item 7. The pharmaceutical composition according to any one of Items 1 to 6, which is a tablet.
Section 8. A stabilizer for vitamin B1 in solid preparations, which contains a dicarboxylic acid having no alcoholic hydroxyl group as an active ingredient.
Item 9. A method for stabilizing vitamin B1, which comprises adding a dicarboxylic acid having no alcoholic hydroxyl group to a solid preparation together with vitamin B1.

According to the present invention, since decomposition of vitamin B1s over time can be suppressed, it is possible to provide a solid preparation containing vitamin B1s with excellent formulation stability.

1. Solid Preparation The solid preparation of the present invention is characterized by containing vitamin B1 and a dicarboxylic acid having no alcoholic hydroxyl group. Hereinafter, the solid of the present invention will be explained in detail.

Vitamin B1 The solid preparation of the present invention contains vitamin B1. Vitamin B1 has the disadvantage that it decomposes over time and its content decreases, but in the present invention, this disadvantage is overcome by using a dicarboxylic acid that does not have an alcoholic hydroxyl group, and vitamin B1 can be stabilized.

In the present invention, "vitamin B1" refers to vitamin B1 and its derivatives. The type of vitamin B1 used in the present invention is not particularly limited as long as it is pharmaceutically acceptable, and examples thereof include thiamine, thiamine hydrochloride, thiamine nitrate, and the like. The type of vitamin B1 derivative used in the present invention is not particularly limited as long as it is pharmaceutically acceptable, but examples include octothiamine, fursultiamine, cicotiamine hydrochloride, dicethiamine hydrochloride, fursultiamine hydrochloride. , bisthiamine nitrate, thiamine disulfide, thiamine lauryl sulfate, thiamine cetyl sulfate, thiamine dicetyl sulfate, bisbutythiamine, bisbenchiamine, benfotiamine, dibenzoylthiamine, dibenzoylthiamine hydrochloride, bisbutyamine, Thiaminenaphthalene-1,5-disulfonate, thiaminenaphthalene-1,5-disulfonate, thiamine thiocyanate, thiamine disulfide nitrate, thiamine propyl disulfide (TPD), thiamine tetrahydrofurphylyl disulfide (TTFD), thiamine- 8-Methyl-6-acetyl dihydrothioctate disulfide (TATD), O,S-dibenzoylthiamine (DBT), O,S-dicarboethoxythiamine hydrochloride (DCET), S-benzoylthiamine-O-monophosphate (BTMP), O-benzoylthiamine disulfide (BTDS), and the like.

In the present invention, as vitamin B1, one type may be selected from vitamin B1 and its derivatives and used alone, or two or more types may be used in combination.

Among these vitamin B1s, vitamin B1 is preferred, and thiamine hydrochloride is more preferred.

In the solid preparation of the present invention, the content of vitamin B1 may be appropriately set depending on the type of vitamin B1 used, dosage form, purpose, daily dose, etc., but for example, 0.001 -95% by weight, preferably 0.01-0.5% by weight, more preferably 0.1-0.5% by weight.

In the solid preparation of the present invention, the daily dosage of vitamin B1 may be appropriately set depending on the type of vitamin B1 used, dosage form, purpose, administration form, etc., but for example, 0.002 -2200 mg/day, preferably 0.02-50 mg/day, more preferably 0.2-12 mg/day.

Dicarboxylic acid having no alcoholic hydroxyl group The solid preparation of the present invention contains a dicarboxylic acid having no alcoholic hydroxyl group in order to suppress the decomposition of vitamin B1 over time.

The dicarboxylic acid used in the present invention is not particularly limited as long as it is edible, has two carboxyl groups, and has no alcoholic hydroxyl group.

The dicarboxylic acid used in the present invention has, for example, 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, and more preferably 4 carbon atoms.

Furthermore, the dicarboxylic acid used in the present invention may have a structure in which two carboxyl groups are connected by a saturated or unsaturated hydrocarbon, or two carboxyl groups are connected by an aromatic hydrocarbon. It is also possible to have a structure in which Further, when the dicarboxylic acid has a structure in which two carboxyl groups are connected by a saturated or unsaturated hydrocarbon, the hydrocarbon may be linear or branched, but is preferably is linear. From the viewpoint of more effectively suppressing the decomposition of vitamin B1 over time, preferably a dicarboxylic acid in which two carboxyl groups are linked by a saturated or unsaturated hydrocarbon, more preferably two carboxyl groups. Mention may be made of dicarboxylic acids in which the groups are linked by saturated hydrocarbons.

Specifically, dicarboxylic acids used in the present invention include oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid, phthalic acid, isophthalic acid, and terephthalic acid. etc. Among these dicarboxylic acids, from the viewpoint of more effectively suppressing the decomposition of vitamin B1 over time, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, more preferably malonic acid, Mention may be made of succinic acid and glutaric acid, particularly preferably succinic acid.

In the solid preparation of the present invention, the content of the dicarboxylic acid may be appropriately set depending on the content of vitamin B1, etc., and may be, for example, 0.001 to 10% by weight. From the viewpoint of more effectively suppressing the decomposition of vitamin B1 over time, the content of the dicarboxylic acid in the solid preparation of the present invention is preferably 0.5 to 8% by weight, more preferably 1 to 5% by weight. Weight % may be mentioned.

In the solid preparation of the present invention, the ratio of the dicarboxylic acid to vitamin B1 is not particularly limited, and may be appropriately set within a range that satisfies the content of vitamin B1 and the dicarboxylic acid described above. From the viewpoint of more effectively suppressing the decomposition of vitamin B1 types over time, the dicarboxylic acid is contained in an amount of 0.3 to 3500 parts by weight, preferably 150 to 3000 parts by weight, more preferably 100 parts by weight of the total amount of vitamin B1 types. The ratio is 300 to 1,700 parts by weight.

Vitamin B2 The solid preparation of the present invention may contain vitamin B2, if necessary.

In the present invention, "vitamin B2" refers to vitamin B2 and its derivatives. The type of vitamin B2 used in the present invention is not particularly limited as long as it is pharmaceutically acceptable, but examples include riboflavin, flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate. , riboflavin 5'-sodium phosphate, riboflavin tetranicotinate, and salts thereof (alkali metal salts such as sodium salts, etc.). These vitamin B2 types may be used alone or in combination of two or more.

When the solid preparation of the present invention contains vitamin B2, the content is not particularly limited and may be set as appropriate depending on the physiological function or pharmacological effect to be imparted, but for example, 0.00001 to 95 Weight%, preferably 0.00001 to 20% by weight, more preferably 0.00001 to 2% by weight.

Vitamin B5 The solid preparation of the present invention may contain vitamin B5, if necessary.

In the present invention, "vitamin B5" refers to vitamin B5, provitamin B5, and derivatives thereof. The type of vitamin B5 used in the present invention is not particularly limited as long as it is pharmaceutically acceptable, but examples include pantothenic acid, pantothenic acid salts (alkali metal salts such as sodium salts; calcium salts, etc.). alkaline metal salts, etc.), pantethine, pantetheine, panthenol, pantothenyl ethyl ether, acetyl pantothenyl ethyl ether, and the like. These vitamin B5s may be used alone or in combination of two or more.

When the solid preparation of the present invention contains vitamin B5, the content is not particularly limited and may be set as appropriate depending on the physiological function or pharmacological effect to be imparted, but for example, 0.00001 to 95 Weight%, preferably 0.00001 to 20% by weight, more preferably 0.00001 to 2% by weight.

Crude drug powder The solid preparation of the present invention may contain crude drug powder, if necessary. The type of crude drug powder used in the solid preparation of the present invention is not particularly limited and may be selected as appropriate depending on the physiological function or pharmacological effect to be imparted to the solid preparation. , Eucommia end, Boksoku end, Akamegashiwa end, Aspergilla end, Konzurango end, Ephedra end, Turmeric end, Scutellariae end, Oriental end, Onji end, Licorice end, Peony end, Safflower end, Sanshin end, Masinin end, Yokuinin end, Borei end, end of kakkon, end of touki, end of chimpi, end of sage, end of fennel, end of age, end of corydalis, end of valerian, end of rhubarb, end of radish, end of gentian, end of gennoshoko, end of red ginseng, end of kobushi, end of gogo, end of gomish, The end of Saiko, the end of Aspera, the end of Sojutsu, the end of Aloe, the end of Sankirai, the end of Sanshishi, the end of Botanpi, the end of Sansho, the end of Senega, the end of Sanyaku, the end of Digitalis, the end of Saishin, the end of Ipecac, the end of Tragacanth, the end of Shuksha, the end of Gingerbread, Senkyu end, Senna end, Bellflower end, Kujin end, Soyou end, Taksha end, Chikusetsu ginseng end, Clove end, Chorei end, Chili pepper end, Tonin end, Nigaki end, Carrot end, Sandalwood end, Ryokyo end, Bukryo end , Bowie powder, Ryutan powder, Amacha powder, Opium powder, Nantenjitsu powder, Kyonin powder, Shazenshi powder, Fritillary powder, Saishin powder, Souhakuhi powder, Hange powder, Daisan powder, Kouka powder, Saffron powder, Mokutsu powder, Lennik powder, etc. . These crude drug powders may be used alone or in combination of two or more.

When the solid preparation of the present invention contains crude drug powder, the content is not particularly limited and may be set as appropriate depending on the physiological function or pharmacological effect to be imparted, but for example, 4 to 95% by weight, Preferably it is 30 to 95% by weight, more preferably 50 to 80% by weight.

Other Contained Components The solid preparation of the present invention may contain nutritional components and pharmacological components in addition to the components described above. Such nutritional and pharmacological ingredients are not particularly limited as long as they can be used in food and medicine, but include, for example, antacids, stomachic agents, digestive agents, intestinal regulation agents, antispasmodics, mucosal repair agents, anti-inflammatory agents, Astringents, antiemetics, antitussives, expectorants, anti-inflammatory enzymes, sedative-hypnotics, antihistamines, caffeine, cardiac diuretics, antibacterial agents, vasoconstrictors, vasodilators, local anesthetics, herbal medicines, herbal medicine extract powder, Examples include amino acids, vitamins other than the above (vitamin B6, vitamin B7, vitamin B12, folic acid, etc.), menthol, and the like. These nutritional components and pharmacological components may be used alone or in combination of two or more. Further, the content of these components may be appropriately set depending on the types of components used.

In addition to the above-mentioned components, the solid preparation of the present invention may contain other additives necessary for formulation, etc., to the extent that they do not impede the effects of the present invention. Examples of such additives include excipients, flow agents, lubricants, disintegrants, binders, acidulants, sweeteners, flavors, colorants, and the like.

Specifically, such additives include sugars such as lactose, glucose, maltose, sucrose, and sucrose; sugar alcohols such as mannitol, sorbitol, xylitol, trehalose, and erythritol; corn starch, potato starch, wheat starch, Starch and its derivatives such as rice starch, dextrin, carboxymethyl starch; Cellulose and its derivatives such as cellulose, crystalline cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, carboxy methyl cellulose; gum arabic, dextran, pullulan, light silicic anhydride, hydrated Examples include silicon dioxide, synthetic aluminum silicate, magnesium aluminate metasilicate, calcium phosphate, calcium carbonate, calcium sulfate, crospovidone, croscarmellose sodium, carmellose calcium, calcium stearate, magnesium stearate, and the like. These additives may be used alone or in combination of two or more. Moreover, the content of these additives may be appropriately set depending on the type of additives used, the dosage form of the solid preparation, etc.

Characteristics of Solid Preparation As a preferred embodiment of the present invention, 1.9 g of the solid preparation of the present invention is added and mixed to 8.1 g of purified water, and the solid preparation of the present invention is dissolved in the liquid at 25°C. The pH is 3.0 to 6.0, preferably 3.0 to 5.0, more preferably 4.0 to 5.0, particularly preferably 4.0 to 4.7. By satisfying such characteristics, decomposition over time can be suppressed even more effectively.

Dosage form The dosage form of the solid preparation of the present invention is not particularly limited as long as it is solid, but examples include tablets, pills, capsules (soft capsules, hard capsules), powders, granules ( (including dry syrup). Among these dosage forms, tablets are preferred.

Applications The solid preparation of the present invention may be used as an internal medicine, or as a food with health claims such as a food for specified health uses, a food with nutritional claims, and a food with functional claims.

The solid preparation of the present invention can exert effects such as recovery from fatigue, stress relief, and normalization of nerve function due to vitamin B1, so it can be used for nutritional supplementation as well as recovery from fatigue, stress relief, and normalization of nerve function. It can be used for purposes such as.

Manufacturing method The solid preparation of the present invention is prepared using vitamin B1, a dicarboxylic acid having no alcoholic hydroxyl group, and other pharmacological components, bases, and additives added as necessary. It can be manufactured by formulating it into a mold according to a conventional formulation method.

2. Stabilizers for vitamin B1s and methods for stabilizing vitamin B1s As mentioned above, dicarboxylic acids that do not have alcoholic hydroxyl groups can inhibit the decomposition of vitamin B1s over time in solid preparations. can. Therefore, the present invention further provides a stabilizer for vitamin B1 contained in a solid preparation, which contains a dicarboxylic acid having no alcoholic hydroxyl group as an active ingredient. The present invention also provides a method for stabilizing vitamin B1, which comprises adding a dicarboxylic acid having no alcoholic hydroxyl group together with vitamin B1 to a solid preparation.

The stabilizer is used as an additive for dicarboxylic acids that do not have alcoholic hydroxyl groups, and the stabilization method uses dicarboxylic acids that do not have alcoholic hydroxyl groups to form solid preparations. This method suppresses the decomposition of vitamin B1 over time.

In the above-mentioned stabilizer and stabilization method, the types and amounts of the components used, the dosage form of the solid preparation, etc. are as shown in the column of "1. Solid preparation" above.

EXAMPLES The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited thereto.

Test example 1
Tablets having the composition shown in Table 1 (190 mg per tablet, recommended daily intake of 12 tablets) were prepared according to a conventional method. Immediately after production, 80 tablets each were placed in an aluminum laminate bag, sealed with a heat seal, and stored at 50° C. 60% for one week.

The content of thiamine hydrochloride in each tablet before and after storage was measured, and the residual rate of thiamine hydrochloride was calculated from the content of thiamine hydrochloride before and after storage. The content of thiamine hydrochloride in each tablet was measured by the following method. The tablets were placed in an aqueous solution containing 1 mol/L of hydrochloric acid to obtain an extract of thiamine hydrochloride. Next, the obtained extract was adjusted to pH 4.5, and a Takadiastase solution and an acetate buffer (pH 4.5) were added thereto to perform volumetric and enzymatic decomposition. Thereafter, after filtration with filter paper and purification with a cation exchange column, thiamine hydrochloride was quantified using high performance liquid chromatography (fluorescence spectrophotometer).

In addition, 1.9 g of each tablet immediately after manufacture was dissolved in 8.1 g of purified water, and the pH at 25° C. was measured.

The results obtained are shown in Table 1. As is clear from Table 1, when citric acid anhydride (anhydride of tricarboxylic acid having an alcoholic hydroxyl group) and malic acid (dicarboxylic acid having an alcoholic hydroxyl group) were blended with thiamine hydrochloride (Comparative Examples 2 to 4) ), the residual rate of thiamine hydrochloride was comparable to the case without carboxylic acid (Comparative Example 1). On the other hand, tablets containing succinic acid (dicarboxylic acid without an alcoholic hydroxyl group) together with thiamine hydrochloride (Examples 1 to 3) had a higher concentration than those containing no carboxylic acid (Comparative Example 1). As a result, the residual rate of thiamine hydrochloride was significantly improved.

Formulation Example Tablets having the compositions shown in Tables 2 to 4 (190 mg per tablet, recommended daily intake of 12 tablets) were prepared according to a conventional method. When the resulting tablets were evaluated for the residual rate of thiamine hydrochloride or thiamine nitrate in the same manner as in Test Example 1, all tablets had a high residual rate of thiamine hydrochloride or thiamine nitrate.

Claims (8)

at least one type of vitamin B1 selected from the group consisting of thiamine hydrochloride and thiamine nitrate, and
Containing at least one dicarboxylic acid selected from the group consisting of succinic acid and malonic acid ,
The dicarboxylic acid is 150 to 3000 parts by weight per 100 parts by weight of the total amount of vitamin B1,
A solid preparation in which the vitamin B1 group and the dicarboxylic acid coexist so that they can directly interact without being physically isolated. The solid preparation according to claim 1, wherein the dicarboxylic acid is succinic acid. The solid preparation according to claim 1, wherein the vitamin B1 is thiamine hydrochloride. Any one of claims 1 to 3, wherein 1.9 g of the solid preparation is added to 8.1 g of purified water and mixed, and the pH of the liquid in which the solid preparation is dissolved becomes 3.0 to 6.0 at 25°C. A solid preparation as described in Crab. The solid preparation according to any one of claims 1 to 4 , which is a tablet. The solid preparation according to any one of claims 1 to 5 , which does not contain ubidecarenone. A stabilizer for vitamin B1 in a solid preparation,
The vitamin B1 type is at least one selected from the group consisting of thiamine hydrochloride and thiamine nitrate,
at least one dicarboxylic acid selected from the group consisting of succinic acid and malonic acid as an active ingredient,
The dicarboxylic acid is blended so as to fill 150 to 3000 parts by weight per 100 parts by weight of the total amount of the vitamin B1 types, and the dicarboxylic acid is not physically separated from the vitamin B1 types in the solid preparation. Said stabilizer is formulated for direct interaction. A solid preparation is blended with at least one type of vitamin B1 selected from the group consisting of thiamine hydrochloride and thiamine nitrate, and at least one dicarboxylic acid selected from the group consisting of succinic acid and malonic acid ,
The dicarboxylic acid is blended so as to fill 150 to 3000 parts by weight per 100 parts by weight of the total amount of vitamin B1,
A method for stabilizing vitamin B1s, in which the vitamin B1s and the dicarboxylic acid coexist in a solid preparation so that they can directly interact without being physically isolated.