JP2022165922A - solid composition - Google Patents

Abstract

To provide a solid composition that contains a vitamin B12 and a specific vitamin, the solid composition less prone to a degradation of vitamins over time and having high storage stability.SOLUTION: A solid composition contains (A) at least one selected from vitamin B1, vitamin B2, vitamin B6, and ascorbic acid or salt thereof, (B) vitamin B12, and (C) taurine.SELECTED DRAWING: None

Description

TECHNICAL FIELD The present invention relates to a stable composition in a vitamin-containing composition in which a decrease in the content of vitamins is suppressed.

Currently, pharmaceuticals, quasi-drugs, health foods, etc. containing multiple vitamins are on the market. These contain different vitamins, etc., depending on the purpose, and are extremely useful in that they allow you to take the necessary active ingredients more easily than taking multiple types of drugs, quasi-drugs, health foods, etc. individually. Useful.

In formulating a pharmaceutical composition, the stability of ingredients is very important. After the ingredients are formulated, they become unstable over time under various environmental conditions (e.g., under high or low temperatures, under exposure, under high humidity, etc.), and when their contents are greatly reduced, the ingredients become unstable. There is a concern that the desired effects may not be achieved. In particular, pharmaceutical compositions that require strict dosage control of ingredients require a higher degree of formulation stability.

It is known that water-soluble vitamins are generally unstable under the influence of environmental factors such as heat and light, and tend to cause a decrease in content.

Vitamin B1s are known to promote metabolism of carbohydrates, have the effect of maintaining normal nerve and muscle functions, and are effective in recovering from fatigue and relieving stress (Patent Document 1).

Vitamin B2 is a component of nutritional supplements when intake from food is insufficient, such as wasting disease, and vitamin B2 deficiency or metabolic disorder such as angular stomatitis, stomatitis, acute/chronic eczema, and conjunctivitis are involved. It is used as a component of prophylactic and therapeutic agents for diseases presumed to be (Patent Document 2)

In addition, vitamin B6 is a component involved in protein metabolism as a coenzyme for amino acid decarboxylase and aminotransferase in vivo. , hair restorer, health food, etc. (Patent Document 3).

Vitamin B12s are involved in many metabolic systems in vivo, and play an important role in normal growth, hematopoiesis, myriene sheath formation of nerve tissue, and the like. It is also known to have pharmacological actions such as improving eyestrain and asthenopia, and is often added to multivitamins and eye drops.

However, it is widely known that these B vitamins, such as vitamin B1, vitamin B2, vitamin B6 and vitamin B12, have many stability problems. Various methods have been studied to achieve this. For example, when vitamin B1s are mixed with tocopherol succinate at the same time, one of them may be coated with a coating agent for stabilization, or by blending starch and calcium hydrogen phosphate together with vitamins B1s. A method capable of suppressing the degradation of vitamin B1s over time has been disclosed (Patent Documents 4 and 5).

Also, ascorbic acid or a salt thereof is a water-soluble vitamin and is widely known to be unstable to heat and light. Therefore, various methods for stabilizing ascorbic acid or salts thereof have been investigated. For example, a method of stabilizing ascorbic acid by coating it with a hydrophobic heat-meltable lipid has been disclosed (Patent Document 6).

However, there are many cases where conventional methods cannot be used due to restrictions on formulation formulation and formulation design.

JP 2018-104393 JP-A-11-199486 JP 2015-196655 A JP-A-5-271072 JP-A-9-268127 Japanese Patent Application Laid-Open No. 2001-128644

The present inventors have found that when at least one selected from the group consisting of vitamins B1, B2, B6, and ascorbic acid or salts thereof and at least one selected from the group of vitamins B12 are added at the same time, the contents of various vitamins decrease over time. found to do. An object of the present invention is to provide a solid composition containing vitamin B12s and specific vitamins, which can inhibit decomposition of the vitamins over time and has excellent storage stability.

The inventors of the present invention conducted various studies to solve the above problems, and as a result, surprisingly, the addition of taurine, which is one of amino acids, suppresses the decrease in the content of vitamins due to changes over time. and completed the present invention.

That is, the present invention
(1) characterized by containing at least one selected from (A) vitamin B1, vitamin B2, vitamin B6, and ascorbic acid or a salt thereof, (B) vitamin B12, and (C) taurine a solid composition that
(2) The solid composition according to (1), which further contains (D) a low-substituted hydroxypropylcellulose,
(3) (A) The solid composition according to (1) or (2), wherein the vitamin B1 is thiamine or a salt thereof;
(4) The solid composition according to any one of (1) to (3), wherein (A) vitamin B2 is riboflavin or a salt thereof;
(5) (A) The solid composition according to any one of (1) to (4), wherein the vitamin B6 is pyridoxine or a salt thereof;
(6) The solid composition according to any one of (1) to (5), wherein (B) the vitamin B12 is cyanocobalamin or mecobalamin;
(7) The solid composition according to any one of (1) to (6), wherein (C) taurine is synthetic taurine or marine product-derived taurine;
(8) The solid composition according to any one of (1) to (7), wherein (C) taurine is 30 to 90% by mass relative to the total mass of the composition;
(9) The solid composition according to any one of (1) to (8), which is a tablet, granule, powder or capsule;
is.

INDUSTRIAL APPLICABILITY According to the present invention, it has become possible to provide a solid composition in which a decrease in the content of vitamins is suppressed.

In the present invention, "vitamin B1" refers to vitamin B1 or a derivative thereof or a salt thereof, including thiamine itself and derivatives thereof (bistiamine, thiamine disulfide, dicetiamine, fursultiamine, octotiamine, sicotiamine, bisive Thiamine, bisbentiamine, prosultiamine, benfotiamine, thiamine diphosphate, etc.) and salts thereof (inorganic acid salts such as nitrates, hydrochlorides, sulfates, etc.) are also included, and these alone or two More than one species can be used in combination. Among these, in the present invention, thiamine hydrochloride, thiamine nitrate (thiamine nitrate), bistiamine nitrate, thiamine disulfide, thiamine dicetyl sulfate, disetiamine hydrochloride, fursultiamine hydrochloride, octotiamine, sicotiamine, bisivutiamine, Bisbentiamine, fursultiamine, prosultiamine, benfotiamine are preferred, thiamine nitrate (thiamine nitrate), fursultiamine hydrochloride, benfotiamine are more preferred, fursultiamine hydrochloride, thiamine nitrate (thiamine nitrate) is more preferred, and thiamine nitrate (thiamine nitrate) is particularly preferred. These vitamin B1s are known compounds, and commercially available ones may be used, or they may be produced by known methods.

The blending ratio of vitamin B1s and taurine in the present invention is, from the effect of the stability of vitamins B1s, vitamin B1s (the total amount when multiple vitamins B1s are included; hereinafter the same), 1 part by mass of taurine is preferably 4 to 300 parts by mass, more preferably 20 to 200 parts by mass, even more preferably 20 to 150 parts by mass, and particularly preferably 20 to 100 parts by mass.

The blending ratio of vitamin B1s and low-substituted hydroxypropyl cellulose in the present invention is 0.5 to 50 parts by mass of low-substituted hydroxypropyl cellulose for 1 part by mass of vitamin B1s from the effect of the stability of vitamin B1s. 1 to 20 parts by mass, more preferably 1 to 10 parts by mass, and particularly preferably 2 to 10 parts by mass.

The daily intake of vitamin B1s in the present invention is not particularly limited, and can be adjusted as appropriate according to the intended use of the composition. For example, in the case of a composition for oral administration, the daily amount of vitamin B1s is preferably 0.1 to 300 mg, more preferably 1 to 100 mg, even more preferably 1 to 25 mg.

In the composition of the present invention, from the viewpoint that the stability of the composition can be sufficiently maintained, vitamin B1s are preferably contained in an amount of 0.01 to 30% by mass relative to the total mass of the composition, and 0.1 The content is more preferably up to 20 mass %, more preferably 0.1 to 10 mass %, and particularly preferably 0.8 to 5 mass %.

In the present invention, "vitamin B2" means vitamin B2 or a derivative thereof or a salt thereof, and in addition to riboflavin itself, derivatives thereof (riboflavin phosphate, riboflavin butyrate, flavin adenine dinucleotide, etc.) and salts thereof ( alkali metal salts such as sodium salts) are also included, and in the present invention, these can be used alone or in combination of two or more. Among these, in the present invention, flavin adenine dinucleotide sodium, riboflavin, riboflavin sodium phosphate, and riboflavin butyrate are preferred, and riboflavin is particularly preferred. These vitamin B2s are known compounds, and commercially available ones may be used, or they may be produced by known methods.

The blending ratio of vitamin B2s and taurine in the present invention is, from the effect of the stability of vitamins B2s, vitamin B2s (the total amount if multiple vitamins B2 are included; hereinafter the same), 1 part by mass of taurine is preferably 4 to 750 parts by mass, more preferably 20 to 500 parts by mass, still more preferably 20 to 300 parts by mass, and particularly preferably 40 to 250 parts by mass.

In the present invention, the blending ratio of vitamin B2s and low-substituted hydroxypropyl cellulose is 0.5 to 50 parts by mass of low-substituted hydroxypropyl cellulose for 1 part by mass of vitamin B2s from the effect of the stability of vitamin B2s. Parts by mass are preferable, 1 to 40 parts by mass are more preferable, 1 to 50 parts by mass are even more preferable, and 8 to 50 parts by mass are particularly preferable.

The daily intake of B2 vitamins in the present invention is not particularly limited, and can be adjusted as appropriate according to the intended use of the composition. For example, in the case of a composition for oral administration, the daily amount of vitamin B2s is preferably 0.1 to 100 mg, more preferably 0.5 to 45 mg, still more preferably 1 to 45 mg, and particularly preferably 2 to 15 mg.

In the present invention, from the viewpoint that the stability of the composition can be sufficiently maintained, vitamin B2s are preferably contained in an amount of 0.01 to 30% by mass, preferably 0.01 to 20% by mass, relative to the total mass of the composition. %, more preferably 0.05 to 10% by mass, and particularly preferably 0.1 to 2.5% by mass.

In the present invention, "vitamin B6" refers to vitamin B6, derivatives thereof, or salts thereof, including pyridoxine, pyridoxamine, pyridoxal itself, derivatives thereof (pyridoxal phosphate, etc.) and salts thereof (calcium salts, etc.). alkaline earth metal salts of; inorganic acid salts such as hydrochlorides) are also included, and in the present invention, these can be used alone or in combination of two or more. Among these, in the present invention, pyridoxine hydrochloride and pyridoxal phosphate are preferred, and pyridoxine hydrochloride is particularly preferred. These vitamin B6s are known compounds, and commercially available ones may be used, or they may be produced by known methods.

The blending ratio of vitamin B6 and taurine in the present invention is, from the effect of the stability of vitamin B6, vitamin B6 (the total amount when multiple vitamin B6 is included; hereinafter the same), taurine per 1 part by mass is preferably 4 to 750 parts by mass, more preferably 20 to 400 parts by mass, still more preferably 20 to 250 parts by mass, and particularly preferably 25 to 250 parts by mass.

In the present invention, the blending ratio of vitamin B6 and low-substituted hydroxypropyl cellulose is 0.5 to 50 parts by mass of low-substituted hydroxypropyl cellulose for 1 part by mass of vitamin B6 from the effect of the stability of vitamin B6. Parts by weight are preferred, 1 to 50 parts by weight are more preferred, and 10 to 50 parts by weight are even more preferred.

The daily intake of vitamin B6 in the present invention is not particularly limited, and can be appropriately adjusted according to the intended use of the composition. For example, in the case of a composition for oral administration, the amount of vitamin B6s per day is preferably 0.1-100 mg, more preferably 0.5-50 mg, even more preferably 1-50 mg, and particularly preferably 1-10 mg.

In the present invention, from the viewpoint that the stability of the composition can be sufficiently maintained, vitamin B6s are preferably contained in an amount of 0.01 to 30% by mass, preferably 0.1 to 20% by mass, relative to the total mass of the composition. %, more preferably 0.1 to 10% by mass, and particularly preferably 0.3 to 1.8% by mass.

In the present invention, "ascorbic acid or a salt thereof" includes not only ascorbic acid itself, but also salts thereof (alkaline earth metal salts such as calcium salts; alkali metal salts such as sodium salts, etc.). can be used alone or in combination of two or more. Among these, in the present invention, ascorbic acid and calcium ascorbate are preferred, and calcium ascorbate is particularly preferred. These ascorbic acids or salts thereof are known compounds, and commercially available ones may be used, or they may be produced by known methods.

The blending ratio of ascorbic acid or a salt thereof and taurine in the present invention is ascorbic acid or a salt thereof (when a plurality of ascorbic acids or salts thereof is included, the total amount; hereinafter the same) from the effect of the stability of ascorbic acid or a salt thereof. , Taurine is preferably 0.2 to 30 parts by mass, more preferably 0.3 to 20 parts by mass, even more preferably 1 to 15 parts by mass, and particularly preferably 1 to 10 parts by mass.

In the present invention, in the blending ratio of ascorbic acid or a salt thereof and low-substituted hydroxypropylcellulose, low-substituted hydroxypropylcellulose is added to 1 part by mass of ascorbic acid or a salt thereof from the stability effect of ascorbic acid or a salt thereof. is preferably 0.1 to 40 parts by mass, more preferably 0.1 to 30 parts by mass, still more preferably 0.1 to 10 parts by mass, and particularly preferably 0.2 to 2.5.

The daily intake of ascorbic acid or a salt thereof in the present invention is not particularly limited, and can be adjusted as appropriate according to the intended use of the composition. For example, in the case of a composition for oral administration, the daily dose of ascorbic acid or its salt is preferably 1-2,000 mg, more preferably 10-1,000 mg, and even more preferably 50-700 mg.

In the present invention, from the viewpoint that the stability of the composition can be sufficiently maintained, ascorbic acid or a salt thereof is preferably contained in an amount of 1 to 60% by mass, preferably 5 to 60% by mass, based on the total mass of the composition. It is more preferable to contain it, more preferably 5 to 50% by mass.

In the present invention, "vitamin B12" refers to vitamin B12 or derivatives thereof or salts thereof, including cyanocobalamin, hydroxocobalamin itself, derivatives thereof (mecobalamin, deoxyadenosylcobalamin, etc.) and salts thereof (hydrochloric acid Inorganic acid salts such as salts; Organic acid salts such as acetates, etc.) are also included, and in the present invention, these can be used alone or in combination of two or more. Vitamin B12s commonly have a choline ring structure containing cobalt in the center of the molecule. In the present invention, hydroxocobalamin hydrochloride, hydroxocobalamin acetate, cyanocobalamin, mecobalamin and hydroxocobalamin are preferred, cyanocobalamin and mecobalamin are more preferred, and cyanocobalamin is particularly preferred. These vitamin B12s are known compounds, and commercially available ones may be used, or they may be produced by known methods.

The blending ratio of vitamin B12s and taurine in the present invention is, from the effect of the stability of vitamins B12s, vitamin B12s (the total amount when multiple vitamins B12 are included; hereinafter the same), 1 part by mass of taurine is preferably 30 to 150,000 parts by mass, more preferably 100 to 150,000 parts by mass, still more preferably 2,500 to 50,000 parts by mass, and particularly preferably 5,000 to 25,000 parts by mass.

The blending ratio of vitamin B12s and low-substituted hydroxypropyl cellulose in the present invention is 0.2 to 20 parts by mass of low-substituted hydroxypropyl cellulose for 1 part by mass of vitamin B12s from the effect of the stability of vitamin B12s. 000 parts by mass is preferable, 0.6 to 15,000 parts by mass is more preferable, 15 to 5,000 parts by mass is even more preferable, and 500 to 5,000 parts by mass is particularly preferable.

The daily intake of vitamin B12s in the present invention is not particularly limited, and can be appropriately adjusted according to the intended use of the composition. For example, in the case of a composition for oral administration, the amount of vitamin B12s per day is preferably 1-5,000 μg, more preferably 1-1,500 μg, even more preferably 1-60 μg.

In the present invention, from the viewpoint of sufficiently maintaining the stability of the composition, vitamin B12s are preferably contained in an amount of 0.0001 to 5% by mass, and 0.001 to 1.5% by mass, based on the total mass of the composition. It is more preferably contained in an amount of 5% by mass, and even more preferably in an amount of 0.001 to 0.06% by mass.

Taurine used in the present invention is taurine in compliance with the Japanese Pharmacopoeia or food additives, and synthetic taurine, or extracts from marine products such as squid containing taurine, octopus, and oysters (extracts derived from marine products). I can give Synthetic taurine (synthetic product) or marine product-derived taurine is preferred, and synthetic taurine is more preferred. Taurine derived from bovine bile is not preferred. Taurine can be produced by a known method, or can be commercially available.

Taurine in the present invention is preferably contained in an amount of 20 to 98% by mass, more preferably 30 to 98% by mass, even more preferably 40 to 96% by mass, based on the total mass of the composition.

The low-substituted hydroxypropyl cellulose used in the present invention is a cellulose having a very small amount of hydroxypropoxy groups in the cellulose skeleton, and from the viewpoint of producing a solid composition, the hydroxypropoxy group content is 5 to 16% by mass. One is preferable, the content of hydroxypropoxy group is more preferably 7 to 14% by mass, and the content of hydroxypropoxy group is more preferably 8 to 11% by mass. Although not particularly limited, low-substituted hydroxypropyl cellulose conforming to the Japanese Pharmacopoeia or food additives is preferred, and low-substituted hydroxypropyl cellulose conforming to the Japanese Pharmacopoeia is more preferred. Low-substituted hydroxypropyl cellulose can be produced by a known method, or commercially available products can be used.
In the present invention, the particle form of the low-substituted hydroxypropylcellulose is not particularly limited, but fine powder or fibrous form is more preferable, and fibrous form is more preferable.

In the present invention, the low-substituted hydroxypropyl cellulose is preferably contained in an amount of 1 to 30% by mass, more preferably 1 to 20% by mass, and more preferably 3 to 20% by mass with respect to the total mass of the composition. is more preferred.

The solid composition of the present invention is not particularly limited, and examples thereof include pharmaceuticals, quasi-drugs, foods, and the like. Pharmaceuticals and quasi-drugs are preferred.

The solid composition of the present invention is generally not particularly limited as long as it is in the dosage form prescribed in the Japanese Pharmacopoeia's General Rules for Pharmaceutical Preparation, but preferably tablets, powders, fine granules, granules, pills, and capsules. be. Tablets defined in the General Rules for Pharmaceutical Preparations of the Japanese Pharmacopoeia include orally disintegrating tablets, chewable tablets, effervescent tablets, dispersible tablets and dissolving tablets, film-coated tablets, sugar-coated tablets, laminated tablets and the like. In addition, the tablet can be provided with a score line, a mark for improving identification, or an engraving. Furthermore, the tablet of the present formulation may be a round tablet, an irregularly shaped tablet, or a mini-tablet.

In the solid composition of the present invention, other commonly used active ingredients, excipients, disintegrants, binders, fluidizing agents, lubricants, Acidulants, sweeteners, corrigents, cooling agents, coloring agents, foaming agents, surfactants, plasticizers, fragrances, coating agents and the like can be added.

Other active ingredients that can be incorporated into the solid composition of the present invention include, for example, antipyretic analgesics, antihistamines, antitussives, bronchodilators, expectorants, sedative hypnotics, vitamins, amino acids, anti-inflammatory agents, and gastric mucosa protectors. medicines, herbal medicines, herbal medicines, caffeines, etc., and may contain one or more selected from the group consisting of these.

Examples of excipients that can be incorporated into the solid composition of the present invention include lactose, starches, crystalline cellulose, sucrose, sugar alcohols, calcium hydrogen phosphates, and the like. Propylcellulose, sodium starch glycolate, crospovidone, carmellose, carmellose sodium, carmellose calcium, pregelatinized starch, etc. Binders include hydroxypropylcellulose, hypromellose, gelatin, pregelatinized starch, polyvinylpyrrolidone, pullulan. Examples of fluidizing agents include light anhydrous silicic acid and hydrous silicon dioxide, and examples of lubricants include sucrose fatty acid esters, hydrogenated oils, stearic acid, magnesium stearate, and calcium stearate. be done.

The tablet of the present invention can be produced by a conventional tablet production method. That is, the present formulation is produced by mixing the active pharmaceutical ingredient and the excipients as described above in a suitable mixer such as a mixer to produce a mixed powder for tablets, and then directly compressing the mixed powder into tablets, or , a method of compressing granules into tablets, or the like. Granules can be produced by a dry granulation method (slug method, roller compactor method) or a wet granulation method, preferably a wet granulation method. As a granulating apparatus, a roller compactor, stirring granulation method, fluid bed granulation method, extrusion granulation method, tumbling granulation method, spray granulation method, or the like may be used. As a machine for compressing the mixed powder for tablets or the granules of the mixed powder, a single-punch tableting machine, a rotary tableting machine, or the like can be used.

EXAMPLES The present invention will be described in more detail below with reference to examples and comparative examples, but the present invention is not limited to these examples.

(Preparation of solid composition)
(Examples 1 to 10, Comparative Examples 1 to 6)
After each raw material component was weighed according to the composition shown in Table 1, it was uniformly mixed. The mixture was added with a suitable amount of a mixture of water and ethanol, kneaded in a mortar, granulated, and then sufficiently dried. Thereafter, the whole amount was passed through a sieve (710 μm mesh size) to obtain granules, which were then compressed to obtain tablets.

Stability test (content change)
Regarding the obtained tablets, the contents of thiamine nitrate, riboflavin, pyridoxine hydrochloride and cyanocobalamin were measured at the start of the test and after storage at 65°C for 1 day, and the residual ratio was calculated.
Table 2 shows the results.

As shown in Table 2, in Comparative Example 1 containing only low-substituted hydroxypropyl cellulose without taurine, and in Comparative Examples 2 to 5 containing no taurine, all residual rates of B vitamins were 90% or less. On the other hand, in Example 1 containing only taurine, it was found that the survival rate of vitamin B group was dramatically improved as compared with Comparative Examples 1-3.
In addition, Examples 2 to 8, in which both taurine and low-substituted hydroxypropyl cellulose were blended, exhibited a residual rate of 90% or more for the vitamin B group, demonstrating that the residual rate was further improved.
The residual ratio of cyanocobalamin in Comparative Example 6 containing calcium ascorbate was 80% or less. In Examples 9 and 10, in which both taurine and low-substituted hydroxypropyl cellulose were blended, the residual ratio of cyanocobalamin was 90% or more, demonstrating a dramatic improvement in the residual ratio of cyanocobalamin.

According to the present invention, it is possible to provide a solid composition containing vitamins and taurine and having excellent storage stability.

Claims (9)

A solid composition characterized by containing (A) at least one selected from vitamin B1, vitamin B2, vitamin B6, and ascorbic acid or a salt thereof, (B) vitamin B12, and (C) taurine. thing. 2. The solid composition according to claim 1, further comprising (D) low-substituted hydroxypropylcellulose. 3. The solid composition according to claim 1 or 2, wherein (A) vitamin B1 is thiamine or a salt thereof. 3. The solid composition according to claim 1 or 2, wherein (A) vitamin B2 is riboflavin or a salt thereof. 3. The solid composition according to claim 1, wherein (A) vitamin B6 is pyridoxine or a salt thereof. 3. The solid composition according to claim 1, wherein (B) the vitamin B12 is cyanocobalamin or mecobalamin. 3. The solid composition according to claim 1 or 2, wherein (C) taurine is synthetic taurine or marine product-derived taurine. 3. The solid composition according to claim 1, wherein (C) taurine is 30 to 90% by weight relative to the total weight of the composition. 3. The solid composition according to claim 1 or 2, which is a tablet, granule, powder or capsule.