JP2023095834A - Composition for internal use - Google Patents

Abstract

To provide a composition for internal use that suppresses discoloration during storage and contains vitamins B1, vitamins C and vitamins D.SOLUTION: A composition for internal use contains vitamins A, vitamins B1, vitamins C, vitamins D and vitamins E.SELECTED DRAWING: None

Description

The present invention relates to an internal composition containing vitamins.

Vitamin _B1 is known to be taken into the body and act as a coenzyme for enzymes involved in glucose metabolism and branched-chain amino acid metabolism, playing an important role in carbohydrate metabolism. Vitamin _B1 deficiency increases the risk of neuritis, damage to brain tissue, beriberi and Wernicke-Korsakoff syndrome. Modern people tend to take in a lot of carbohydrates, so they tend to be deficient in vitamin _B1 .

Vitamin C is taken into the body and contributes to the synthesis of collagen in the skin and cells, and also contributes to cell protection by eliminating active oxygen due to its antioxidant action. A lack of vitamin C results in insufficient collagen production in blood vessels, leading to increased hemorrhage and an increased risk of scurvy. In recent years, various studies have revealed that antioxidant effects are related to anti-aging, etc., and the need for vitamin C supplementation is increasing.

Vitamin Ds are taken into the body and metabolized to α,25-dihydroxyvitamin D, which regulates various gene expressions through binding with vitamin D receptors and regulates the absorption of calcium and phosphorus in the intestinal tract and liver. Facilitate. Vitamin D deficiency results in hypocalcemia, which increases the risk of osteoporosis and fracture through accelerated bone resorption. Further deficiency can result in bone mineralization disorders (rickets, osteomalacia). Vitamin D intake is recommended to prevent the decline in bone density due to aging, but in recent years, the amount of vitamin D synthesized in the body has decreased due to lifestyle habits that avoid exposure to sunlight, and there is a tendency to become deficient in vitamin D. It is in.

As described above, in order to deal with the increasing risk of insufficient vitamin B ₁ , vitamin C and vitamin D in recent years, there is a need for an internal composition for supplementing vitamin B ₁ , vitamin C and vitamin D. rising.

“Dietary Reference Intakes for Japanese (2020 Edition)” Review Committee Report, Ministry of Health, Labor and Welfare, January 21, 2020, URL: https://www.mhlw.go.jp/stf/newpage_08517.html

Under the circumstances as described above, the present inventors prepared an oral composition containing vitamin _B1 , vitamin C and vitamin D, and found that the composition discolored during storage, resulting in uneven color. and deterioration of color tone.

Accordingly, an object of the present invention is to provide a composition for internal use containing vitamin _B1 , vitamin C, and vitamin D, in which discoloration during storage is suppressed.

As a result of intensive studies, the present inventors have found that a composition for internal use in which discoloration during storage is suppressed by coexisting vitamins A and E in addition to vitamin _B1 , vitamin C and vitamin D. The inventors have found that a product can be obtained, and have completed the present invention.

Specifically, the present invention provides the following compositions for internal use.
Section 1.
A composition for internal use containing vitamins A, ₁ vitamin B, vitamins C, vitamins D and vitamins E.
Section 2.
Item 2. The composition for internal use according to Item 1, wherein the vitamin A is at least one selected from the group consisting of retinol, retinol derivatives and salts thereof.
Item 3.
Item 3. The composition for internal use according to item 1 or 2, wherein the vitamin _B1 is at least one selected from the group consisting of thiamine, derivatives thereof, and salts thereof.
Section 4.
Item 4. The composition for internal use according to any one of Items 1 to 3, wherein the vitamin C is at least one selected from the group consisting of ascorbic acid and salts thereof.
Item 5.
Item 5. The composition for internal use according to any one of Items 1 to 4, wherein the vitamin D is at least one selected from the group consisting of ergocalciferol and cholecalciferol.
Item 6.
Item 6. The composition for internal use according to any one of Items 1 to 5, wherein the vitamin E is at least one selected from the group consisting of tocopherol, derivatives thereof, and salts thereof.
Item 7.
Item 7. The composition for internal use according to any one of Items 1 to 6, which suppresses discoloration caused by a combination of vitamin _B1 , vitamin C and vitamin D.
Item 8.
Item 8. The composition for internal use according to any one of Items 1 to 7, further comprising a hydrophobic dispersion medium.

Moreover, this invention provides the following discoloration inhibitor.
Item 9.
A discoloration inhibitor for a composition containing vitamins A and E, and containing vitamins _B1 , vitamins C and D.

Furthermore, the present invention provides the following method for suppressing discoloration.
Item 10.
A composition containing vitamin B ₁ , vitamin C and vitamin D,
A method for suppressing discoloration of the composition, comprising allowing vitamins A and E to coexist.

Since the composition for internal use of the present invention contains vitamin A, vitamin _B1 , vitamin C, vitamin D and vitamin E, discoloration during storage is suppressed.

As used herein, "vitamins" include the following vitamins A, vitamin _B1 , vitamins C, vitamins D, vitamins E, and other vitamins.

As used herein, "salts" of vitamins are not particularly limited as long as they are pharmaceutically, pharmacologically (pharmaceutical) or physiologically acceptable. Specifically, there are alkali metal salts, salts with inorganic bases such as alkaline earth metal salts, and basic salts such as salts with organic bases. and salt. In addition, ammonia, methylamine, dimethylamine, trimethylamine, dicyclohexylamine, tris(hydroxymethyl)aminomethane, N,N-bis(hydroxyethyl)piperazine, 2-amino-2-methyl-1-propanol, ethanolamine, N -Amine salts such as methylglucamine and L-glucamine; and salts with basic amino acids such as lysine, δ-hydroxylysine and arginine. Furthermore, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid; acid, oxalic acid, succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid, lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinic acid, salicylic acid, gluconic acid, salts with organic acids such as palmitic acid; Salts with acidic amino acids such as aspartic acid and glutamic acid may also be used. The above "salt" includes solvates and hydrates of salts.

[Composition for internal use]
The composition for internal use of the present invention contains vitamin A, vitamin _B1 , vitamin C, vitamin D and vitamin E.

(Vitamin A)
Examples of vitamin A include retinol, retinol derivatives (esterified vitamin A such as retinol acetate and retinol palmitate), and salts thereof.

Vitamin A may be either isolated from natural products such as animals, plants, or microorganisms, or chemically synthesized. In addition, vitamin A is vitamin A oil (synthetic ester-type vitamin A listed as "vitamin A oil" in the Japanese Pharmacopoeia diluted by adding vegetable oil, and 30,000 vitamin A units per 1 g ( IU) or above), natural oils extracted and refined from animals (eg, cod liver oil, strong cod liver oil), or vitamin A dissolved in vegetable oil or the like may be used.

All of these vitamins A may be used singly or in any combination of two or more.

The vitamin A used in the present invention is any one selected from the group consisting of vitamin A oil, retinol acetate, and retinol palmitate, either alone or in combination of two or more, from the viewpoint of remarkably exhibiting the effects of the present invention. A combination is preferred.

The total content of vitamin A in the composition for internal use of the present invention is not particularly limited, and is appropriately set according to the type and content of other compounding ingredients, formulation form, method of use, and the like. The total content of vitamin A is preferably 100 IU/g or more, more preferably 200 IU/g or more, still more preferably 500 IU/g or more, relative to the total amount of the composition for internal use, from the viewpoint of significantly exhibiting the effects of the present invention. g or more. In addition, the total content of vitamin A is preferably 50,000 IU/g or less, more preferably 30,000 IU/g or less, relative to the total amount of the composition for internal use, from the viewpoint of significantly exhibiting the effects of the present invention. and more preferably 20,000 IU/g or less.

The total content of vitamin A in the composition for internal use of the present invention is preferably 100 to 50,000 IU/g, more preferably 200 to 30,000 IU/g, further preferably 200 to 30,000 IU/g, based on the total amount of the composition for internal use. is 500-20,000 IU/g.

In this specification, the vitamin A unit of each component of vitamin A is determined by the method described in the 18th revision of the Japanese Pharmacopoeia (June 7, 2021 Ministry of Health, Labor and Welfare Notification No. 220).

The total content of vitamin A in the composition for internal use of the present invention is preferably 0.005% by mass or more, more preferably 0.01% by mass or more, and still more preferably 0% by mass, relative to the total amount of the composition for internal use. 0.05% by mass or more, for example, 0.1% by mass or more, and for example, 20% by mass or less, preferably 10% by mass or less, more preferably 5% by mass or less, and still more preferably 3% by mass. or less, and may be, for example, 2% by mass or less.
The total content of vitamin A in the composition for internal use of the present invention is preferably 0.005 to 10% by mass, more preferably 0.01 to 5% by mass, and still more preferably, relative to the total amount of the composition for internal use. is 0.05 to 2% by mass. The total content of vitamin A in the composition for internal use of the present invention may be, for example, 0.01 to 20% by mass, 0.05 to 10% by mass, or 0.1 to 5% by mass.

(Vitamin B ₁ type)
Vitamin _B1 includes, for example, thiamine, thiamine derivatives (e.g., thiamine disulfide, thiamine dicetyl, octotiamine, sicotiamine, cetotiamine, bis-butiamine, bis-bentiamine, fursultiamine, prosultiamine, benfotiamine, etc. ) or salts thereof.

Vitamin _B1 may be either isolated from natural products such as animals, plants, or microorganisms, or chemically synthesized.

All of these vitamin _B1s may be used singly or in any combination of two or more.

The vitamin _B1 used in the present invention includes thiamine chloride hydrochloride, thiamine disulfide, thiamine disulfide nitrate, thiamine dicetyl sulfate, thiamine nitrate, and octotiamine, from the viewpoint of exhibiting the effects of the present invention remarkably. , sicotiamine, cetotiamine hydrochloride hydrate, bisivetiamine, bisbentiamine, fursultiamine, fursultiamine hydrochloride, prosultiamine and benfotiamine any one selected from the group consisting of single or two or more I prefer the combination of
Any selected from the group consisting of thiamine chloride hydrochloride, thiamine dicetyl sulfate, thiamine nitrate, octotiamine, sicotiamine, cetotiamine hydrochloride hydrate, bisivetiamine, bisbentiamine, prosultiamine and benfotiamine It is more preferable to use one kind alone or a combination of two or more kinds.

The total content of vitamin _B1 in the composition for internal use of the present invention is not particularly limited, and is appropriately set according to the type and content of other compounding ingredients, formulation form, method of use, and the like. From the viewpoint of significantly exhibiting the effects of the present invention, the total content of vitamin _B1 is an amount determined by the method described in the Japanese Pharmacopoeia below with respect to the total amount of the composition for internal use, preferably 0.005% by mass or more, more preferably 0.01% by mass or more, more preferably 0.03% by mass or more, for example, 0.1% by mass or more, 0.5% by mass or more, 1% by mass or more, Alternatively, it may be 2% by mass or more. In addition, from the viewpoint of significantly exhibiting the effects of the present invention, the total content of vitamin _B1 is an amount determined by the method described in the Japanese Pharmacopoeia below with respect to the total amount of the composition for internal use, For example, it can be 70% by mass or less, or 50% by mass or less, preferably 30% by mass or less, more preferably 20% by mass or less, and even more preferably 12.5% by mass or less.

The total content of vitamin _B1 in the composition for internal use of the present invention is the amount determined by the method described in the Japanese Pharmacopoeia below, preferably 0.005, based on the total amount of the composition for internal use. ~30% by mass, more preferably 0.01 to 20% by mass, still more preferably 0.03 to 12.5% by mass. For example, the total content of vitamin _B1 in the composition for internal use of the present invention is 0.005 to 70% by mass, 0.01 to 50% by mass, 0.1 to It may be 30% by mass, or 1 to 20% by mass.

In the composition for internal use of the present invention, the ratio (M _B1 /M _A ) of the total content M _B1 (mg) of vitamins B ₁ to the total content M _A (IU) of vitamins A is preferably 0.5. 00001-1 mg/IU, more preferably 0.00005-0.05 mg/IU, more preferably 0.00025-0.0125 mg/IU.

In this specification, the content of each component of vitamin _B1 class is determined by the method described in the Japanese Pharmacopoeia 18th edition, thiamine disulfide nitrate is thiamine disulfide, thiamine dicetyl sulfate is thiamine Nitrides or thiamine chloride hydrochloride, cetotiamine hydrochloride hydrate, bisbentiamine and benfotiamine are converted to thiamine chloride hydrochloride, fursultiamine hydrochloride is converted to fursultiamine, and other B vitamins Class ₁ is the content of the substance itself.

(Vitamin C)
Vitamin Cs include, for example, ascorbic acid and salts of ascorbic acid.

Vitamin C may be either isolated from natural products such as animals, plants, or microorganisms, or chemically synthesized.

All of these vitamin Cs may be used singly or in any combination of two or more.

As the vitamin C used in the present invention, any one selected from the group consisting of ascorbic acid, calcium ascorbate and sodium ascorbate, either alone or in combination of two or more, is selected from the viewpoint of exhibiting the effects of the present invention remarkably. At least one selected from the group consisting of ascorbic acid and calcium ascorbate is preferred, and calcium ascorbate is more preferred.

The total content of vitamin Cs in the composition for internal use of the present invention is not particularly limited, and is appropriately set according to the type and content of other compounding ingredients, formulation form, method of use, and the like. From the viewpoint of exhibiting the effects of the present invention remarkably, the total content of vitamin Cs is preferably 0.1% by mass or more, more preferably 0.1% by mass, in terms of ascorbic acid, relative to the total amount of the composition for internal use. It is 5% by mass or more, more preferably 1.25% by mass or more, particularly preferably 5.5% by mass or more, and may be, for example, 6% by mass or more, or 7% by mass or more. In addition, from the viewpoint of significantly exhibiting the effects of the present invention, the total content of vitamin Cs is preferably 95% by mass or less, more preferably 93% by mass, in terms of ascorbic acid, relative to the total amount of the composition for internal use. %, more preferably 90% by mass or less, for example, 80% by mass or less, 70% by mass or less, 60% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, or 20% by mass or less can be

The total content of vitamin C in the composition for internal use of the present invention is preferably 0.1 to 95% by mass, more preferably 0.5 to 95% by mass, in terms of ascorbic acid, relative to the total amount of the composition for internal use. 93% by mass, more preferably 1.25 to 90% by mass, particularly preferably 5.5 to 90% by mass. In addition, the total content of vitamin C in the composition for internal use of the present invention is 2 to 70% by mass, 2 to 30% by mass, 2 to 20% by mass, 3 to 60% by mass, relative to the total amount of the composition for internal use. % by weight, 6 to 50% by weight, 6 to 40% by weight, or 6 to 20% by weight.

In the composition for internal use of the present invention, the ratio (M _C /M _A ) of the total vitamin C content M _C (mg) to the total vitamin A content M _A (IU) is preferably 0.5. 0001-10 mg/IU, more preferably 0.001-1 mg/IU, more preferably 0.0125-0.25 mg/IU.

In this specification, the content of each component of vitamin C is determined by the method described in the Japanese Pharmacopoeia 18th Edition, and the salt of ascorbic acid is the amount converted to ascorbic acid.

(Vitamin Ds)
D vitamins include, for example, ergocalciferol (vitamin _D2 ), cholecalciferol (vitamin _D3 ), or combinations thereof.

Vitamin D may be either isolated from natural products such as animals, plants, or microorganisms, or chemically synthesized.

The total content of vitamin D in the composition for internal use of the present invention is not particularly limited, and is appropriately set according to the type and content of other compounding ingredients, formulation form, method of use, and the like. The total content of vitamin Ds is preferably 0.00005% by mass or more, more preferably 0.0001% by mass or more, and further preferably It is preferably 0.000125% by mass or more, and may be, for example, 0.0005% by mass or more, or 0.0008% by mass or more.
In addition, the total content of vitamin Ds can be, for example, 1% by mass or less or 0.5% by mass or less with respect to the total amount of the composition for internal use, from the viewpoint of significantly exhibiting the effects of the present invention. , preferably 0.1% by mass or less, more preferably 0.05% by mass or less, and even more preferably 0.03% by mass or less.

The total content of vitamin D in the composition for internal use of the present invention is preferably 0.00005 to 0.1% by mass, more preferably 0.0001 to 0.05% by mass, relative to the total amount of the composition for internal use. %, more preferably 0.000125 to 0.03% by mass, for example, 0.0005% to 0.05% by mass, or 0.0008% to 0.1% by mass.

In the composition for internal use of the present invention, the ratio (M _D /M _A ) of the total vitamin D content M _D (μg) to the total vitamin A content M _A (IU) is preferably 0.00. 0001 to 0.05 μg/IU, more preferably 0.0005 to 0.01 μg/IU, still more preferably 0.00125 to 0.005 μg/IU.

In this specification, the content of each component of vitamin D is determined by the method described in the Japanese Pharmacopoeia 18th Edition.

(Vitamin E)
Examples of vitamin E include tocopherol (dl-α-tocopherol), d-α-tocopherol, tocopherol derivatives (e.g., ester-type vitamin E such as tocopherol succinate and tocopherol acetate), and salts thereof. be done.

Vitamin E may be either isolated from natural products such as animals, plants, or microorganisms, or chemically synthesized.

All of these vitamin E may be used singly or in any combination of two or more.

Vitamin E used in the present invention includes tocopherol, d-α-tocopherol, d-α-tocopherol succinate, dl-α-tocopherol succinate, and d-α acetate, from the viewpoint of exhibiting the effects of the present invention remarkably. - Any one or a combination of two or more selected from the group consisting of tocopherol, tocopherol succinate calcium and tocopherol acetate is preferable.

The total content of vitamin E in the composition for internal use of the present invention is not particularly limited, and is appropriately set according to the type and content of other compounding ingredients, formulation form, method of use, and the like. The total content of vitamin E is preferably 0.05% by mass or more in terms of dl-α-tocopherol succinate with respect to the total amount of the composition for internal use, from the viewpoint of significantly exhibiting the effects of the present invention. It is more preferably 0.1% by mass or more, still more preferably 0.25% by mass or more, and may be, for example, 1% by mass or more, 3% by mass or more, 5% by mass or more, or 10% by mass or more. In addition, from the viewpoint of significantly exhibiting the effects of the present invention, the total content of vitamin Ds is preferably 70% by mass or less, more preferably 60% by mass or less, and even more preferably It is 50% by mass or less, and may be, for example, 40% by mass or less, 30% by mass or less, or 20% by mass or less.

The total content of vitamin E in the composition for internal use of the present invention is preferably 0.05 to 70% by mass, more preferably 0.05 to 70% by mass, in terms of dl-α-tocopherol succinate, based on the total amount of the composition for internal use. is 0.1 to 60% by mass, more preferably 0.25 to 50% by mass, and may be, for example, 1 to 40% by mass, 5 to 30% by mass, or 10 to 20% by mass.

The ratio (M _E /M _A ) of the total content M _E (mg) of vitamin E in the composition for internal use of the present invention to the total content (IU) of vitamin A is preferably 0.00001 to 10 mg. /IU, more preferably 0.0001-0.5 mg/IU, more preferably 0.0025-0.05 mg/IU.

In this specification, the content of each component of vitamin E is determined by the method described in the 18th revision of the Japanese Pharmacopoeia, and is the amount converted to dl-α-tocopherol succinate.

(other vitamins)
The composition for internal use of the present invention contains other vitamins such as vitamin _B2 [riboflavin, riboflavin derivatives (riboflavin phosphate, riboflavin ester such as riboflavin butyrate, flavin adenine dinucleotide, etc.) or salts thereof (riboflavin Sodium phosphate, flavin adenine dinucleotide sodium, etc.)]; Vitamin _B6 [pyridoxine, pyridoxal, pyridoxamine or derivatives thereof (pyridoxal phosphate, etc.), or salts thereof (pyridoxine hydrochloride, pyridoxal phosphate water hydrates, etc.), etc.]; Vitamin _B12 [cyanocobalamin, mecobalamin (methylcobalamin), hydroxocobalamin, or salts thereof (hydroxocobalamin hydrochloride, hydroxocobalamin acetate, etc.), etc.]; niacin (nicotinic acid, nicotinic acid amide, etc.) ); pantothenic acids [pantothenic acid, panthenol, or salts thereof (calcium pantothenate, sodium pantothenate, etc.)]; biotin; folic acid; any one of vitamin K (phytonadione, menadione, menacione, etc.) They may be contained singly or in combination of two or more, or one or more of them may not be contained.

The content of vitamin _B2 in the composition for internal use of the present invention is preferably less than 10% by mass in terms of the following conversion amount with respect to the total amount of the composition for internal use, from the viewpoint of significantly exhibiting the effects of the present invention. , more preferably less than 5% by mass, more preferably less than 1% by mass. Further, it is even more preferable that the composition for internal use of the present invention does not substantially contain vitamin _B2 , and it is particularly preferable that it does not contain vitamin _B2 .
The content of vitamin _B6 in the composition for internal use of the present invention is preferably less than 10% by mass in terms of the following conversion amount with respect to the total amount of the composition for internal use, from the viewpoint of significantly exhibiting the effects of the present invention. , more preferably less than 5% by mass, more preferably less than 1% by mass. Further, it is more preferable that the composition for internal use of the present invention does not substantially contain vitamin _B6 , and it is particularly preferable that it does not contain vitamin _B6 .

When the composition for internal use of the present invention contains vitamin _B2 or vitamin _B6 , it is preferable that the vitamin _B2 or vitamin _B6 is added for purposes other than nutritional enhancement or active pharmaceutical ingredients.
When the composition for internal use of the present invention contains vitamin _B2 or vitamin _B6 , for example, vitamin _B2 or vitamin _B6 can be blended as an additive such as a coloring agent.

In this specification, the content of each component of vitamin _B2 and vitamin _B6 is determined by the method described in the Japanese Pharmacopoeia 18th Edition, and flavin adenine dinucleotide sodium is flavin adenine dinucleotide, Riboflavin sodium phosphate is the amount converted to riboflavin, and other components are the content itself.

In the composition for internal use containing the above contents of vitamin _B2 and vitamin _B6 , there is little yellow coloring, which is the original color of vitamin _B2 and vitamin _B6 , so there is no change in appearance due to discoloration. However, according to the configuration of the present invention, even in such a case, it is preferable in that the change in appearance can be suppressed. However, the mechanism of action that brings about the effects of the present invention is not limited to this.

From the viewpoint of exhibiting the effects of the present invention remarkably, the composition for internal use of the present invention does not substantially contain vitamin _B2 and vitamin _B6 , or more preferably does not contain them.
In addition to vitamin _B2 and vitamin _B6 , the composition for internal use of the present invention includes at least one selected from the group consisting of vitamin _B12 , niacin, pantothenic acids, biotin, folic acid and vitamin K. may be substantially free or free of
It may be substantially free or free of all other vitamins.

(calcium)
The composition for internal use of the present invention may further contain calcium in addition to the above vitamins. Examples of calcium include calcium salts, among which calcium glycerophosphate, calcium gluconate hydrate, precipitated calcium carbonate, calcium lactate hydrate, anhydrous calcium hydrogen phosphate, and calcium hydrogen phosphate hydrate are preferred. At least one selected from the group is included.

(dosage form, additive)
The composition for internal use of the present invention is orally ingested or administered, and is preferably a pharmaceutical. The dosage forms include tablets (including intraorally rapidly disintegrating tablets, chewable tablets, effervescent tablets, jelly drops, etc.), lozenges, granules, pills, dry syrups, powders (including fine granules). ), solid formulations such as capsules (including hard capsules and soft capsules), liquid formulations, suspensions, emulsions, syrups, elixirs, limonades, tinctures, extracts, jellies, gels agents, liposome agents, and the like. Among them, solid preparations are preferred, capsules are more preferred, and soft capsules are even more preferred, from the viewpoints of further exerting the effects of the present invention and versatility.

In addition, the composition for internal use of the present invention may contain suitable additives according to its dosage form. Examples of such additives include solid preparations (e.g., tablets, capsules, powders, etc.), excipients (e.g., sucrose, lactose, crystalline cellulose, light anhydrous silicic acid, etc.), binders [gelatin , purified gelatin, carmellose or its salts, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, starch (wheat starch, corn starch, potato starch, etc.), pregelatinized starch, dextrin, cyclodextrin, carboxymethyl starch, hydroxypropyl starch, hydroxyethyl starch, partially pregelatinized starch, etc.], lubricants (e.g., sucrose fatty acid ester, magnesium stearate, talc, etc.), disintegrants (e.g., low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, etc.), foaming agents (eg, sodium hydrogen carbonate, etc.), fluidizing agents (eg, sodium metasilicate aluminate, light anhydrous silicic acid, etc.), and the like. Pharmaceutical uses of these additives may be other than those described above. Additives for liquid preparations (e.g., syrups, liquids, suspensions, soft capsules, liquid contents of hard capsules, etc.) include hydrophobic dispersion media (e.g., olive oil, corn oil, vegetable oils such as soybean oil, sesame oil, cottonseed oil; , polysorbate 80, hydrogenated castor oil, glycerin fatty acid ester, sorbitan sesquioleate, etc.), suspending agent (e.g. white beeswax, various surfactants, soybean lecithin, etc.), dispersant, emulsifier, stabilizer, buffering agent , solubilizers, pH adjusters, antiseptics (preservatives) and the like. In any case, these compositions may optionally contain antioxidants, sweeteners, sour agents, coloring agents, flavoring agents, flavoring agents, and the like.

The "hydrophobic dispersion medium" used when the composition for internal use of the present invention is made into a liquid preparation is not particularly limited as long as it is liquid at 50°C (preferably 37°C, more preferably 20°C). , a hydrophobic dispersion medium that is usually used for filling solutions for soft capsules can be used. Examples of such hydrophobic dispersion media include esters of fatty acids and polyhydric alcohols [e.g., propylene glycol fatty acid esters, sucrose fatty acid esters, sorbitan fatty acid esters and fatty acid triglycerides (e.g., long-chain fatty acid triglycerides)]. , medium-chain fatty acid triglycerides)], polyethylene glycols (e.g., polyethylene glycol and methoxypolyethylene glycol), animal and vegetable oils (e.g., olive oil, corn oil, soybean oil, sesame oil, cottonseed oil, wheat germ oil, safflower oil, hydrogenated oil) ), polyhydric alcohols (eg, glycerin), and the like.

The hydrophobic dispersion medium is preferably fatty acid triglycerides or animal and vegetable oils, more preferably fatty acid triglycerides or vegetable oils, and still more preferably medium chain fatty acid triglycerides, sesame oil, corn oil, olive oil, soybean oil or safflower oil. , more preferably medium-chain fatty acid triglycerides, sesame oil, or corn oil. Here, the "medium-chain fatty acid" in the "medium-chain fatty acid triglyceride" includes, for example, fatty acids having 6 to 12 carbon atoms (eg, caproic acid, caprylic acid, capric acid or lauric acid).

Examples of the "medium-chain fatty acid triglyceride" used in the present invention include ODO (trade name, manufactured by Nisshin Oillio Group Co., Ltd.), Coconard (trade name, manufactured by Kao Corporation), and Panacet (trade name, manufactured by Nisshin OilliO Group). (manufactured by Oil Co., Ltd.). Examples of "sesame oil" include Japanese Pharmacopoeia sesame oil (trade name, manufactured by Kaneda Corporation). Examples of "corn oil" include corn oil (trade name, Okamura essential oil), corn oil (trade name, Kaneda), and eclipse corn salad oil (trade name, Nihon Shokuhin Kako). As "soybean oil", for example, "soybean oil" standardized in the Japanese Pharmacopoeia 18th Edition can be used.

The hydrophobic dispersion medium is preferably a transparent liquid, and may be used alone or in combination of two or more. When a hydrophobic dispersion medium is contained, the content of the hydrophobic dispersion medium in the composition for internal use of the present invention is, for example, 1 to 99% by mass, preferably 30 to 99% by mass, more preferably 40%. It is up to 99% by mass, more preferably 40 to 97% by mass. The "content of the hydrophobic dispersion medium" means the content of the hydrophobic dispersion medium contained in the composition for internal use of the present invention. means

The hydrophobic dispersion medium preferably has an L ^* value in the L ^* a ^* b ^* color space (CIE 1976) of 95 to 105, more preferably 98 to 102, from the viewpoint of significantly exhibiting the effects of the present invention. is more preferred, and 99-101 is even more preferred.
The hydrophobic dispersion medium preferably has an a ^* value of 4 or less in the L ^* a ^* b ^* color space (CIE 1976) measured with water as a blank, from the viewpoint of significantly exhibiting the effects of the present invention. It is more preferably 3 or less, and even more preferably 2 or less.
The hydrophobic dispersion medium preferably has a b ^* value of 4 or less in the L ^* a ^* b ^* color space (CIE 1976) measured with water as a blank, from the viewpoint of significantly exhibiting the effects of the present invention. It is more preferably 3 or less, and even more preferably 2 or less.
Here, the L ^* value, a ^* value and b ^* value are measured using purified water as a reference, which are obtained by the methods described in the examples of the present specification.

When the L ^* value, a ^* value, or b ^* value of the hydrophobic dispersion medium is within the above numerical range, the appearance is likely to change due to discoloration. This is preferable in that changes can be suppressed. However, the mechanism of action that brings about the effects of the present invention is not limited to this.

In addition, the composition for internal use of the present invention does not substantially contain any one or two or more of the above additives, or may not contain them.

(Containers/packaging and accommodation mode)
The container or package for the composition for internal use of the present invention is not particularly limited as long as it can contain the composition for internal use. ), it is preferable in terms of reducing the influence on the appearance due to discoloration.

The composition for internal use of the present invention, when the composition for internal use is a solid preparation, is stored in a manner in which differences in storage conditions between solid preparations are likely to occur (for example, when solid preparations are not individually packaged). It is preferable in that the influence on the appearance due to discoloration can be reduced. Examples of the individual packaging of the solid preparation include PTP packaging, SP packaging, pillow packaging, and stick packaging.

(Production method)
Depending on the dosage form, the composition for internal use of the present invention contains vitamins A, ₁ vitamin B, vitamins C, vitamins D and E, as well as other vitamins and additives used as desired. is obtained by formulating by a conventional method.

In the manufacturing process of the composition for internal use of the present invention, the order of mixing vitamins A, vitamin _B1 , vitamins C, vitamins D and vitamins E, the combination at the time of mixing, etc. are not particularly limited. These ingredients may coexist in the internally obtained composition.

(Application)
Uses of the composition for internal use of the present invention include uses based on the respective effects or efficacy of vitamins A, vitamin _B1 , vitamins C, vitamins D, and vitamins E.

Uses of the composition for internal use of the present invention are preferably alleviation of dryness of the eyes; prevention or amelioration of night blindness (black eyes, difficulty seeing in dark places), poor development of bone teeth or rickets; pregnancy and lactation supplementation of vitamins during a period of illness or when physical strength decreases during or after illness; and supplementation of vitamins during a period of growth or old age.

(Dosage and dosage)
The internal use composition of the present invention is not particularly limited in administration timing, and is preferably orally administered or ingested, for example, 1 to 3 times a day.

The dosage of the composition for internal use of the present invention _is not particularly limited. Preferably, the dose is 3 to 500 mg, vitamin D is 2.5 to 10 μg, and vitamin E is 1.6 to 100 mg. The composition for internal use of the present invention is preferably administered or taken at a dose between the upper limit and the lower limit in Table 1 for each age.

(effect)
As shown in the examples, the composition for internal use of the present invention contains vitamins A and E to suppress discoloration due to the combination of vitamin _B1 , vitamin C and vitamin D. be able to. Here, heat is an example of a cause of discoloration.

In addition, when vitamin A, vitamin _B1 , vitamin C, vitamin D and vitamin E are mixed as in the composition for internal use of the present invention, vitamin C and vitamin D and vitamin A and/or The dispersion stability of the powder is improved as compared with the case where vitamin E is mixed, and the formulation can be made more uniform.

[Discoloration inhibitor]
The discoloration inhibitor of the present invention is a discoloration inhibitor for compositions containing vitamins A and E, vitamins _B1 , vitamins C and vitamins D.

Regarding the types and contents of vitamins A, vitamin _B1 , vitamins C, vitamins D and vitamin E in the discoloration inhibitor, types and contents of other components, aspects of the composition, etc. Conforms to the content described in the section [Composition for internal use].

[Method for suppressing discoloration]
The present invention includes a method for suppressing discoloration of a composition comprising vitamins _B1 , vitamins C and D, and adding vitamins A and E to the composition.

The present invention also includes a method for suppressing discoloration of a composition, comprising adding vitamin E to a composition containing vitamin _B1 , vitamin C and vitamin D.

Regarding the types and contents of vitamins A, vitamin _B1 , vitamins C, vitamins D and vitamin E, types and contents of other ingredients, aspects of the composition, etc. in each of the above methods, see [ Compositions for internal use].

[Method for improving dispersion stability of powder]
Furthermore, the present invention provides a powder-containing composition containing vitamins C and D, and vitamins A and/or vitamins E, in which vitamin _B1 is allowed to coexist. including ways to improve sexuality.

The powder is produced by the coexistence of vitamins C and D and vitamins A and/or E, and is not particularly limited as long as it contains at least one of these vitamins. , vitamin C or vitamin D, and more preferably vitamin C.

Regarding the types and contents of vitamins A, vitamin _B1 , vitamins C, vitamins D and vitamin E, types and contents of other ingredients, aspects of the composition, etc. in each of the above methods, see [ Compositions for internal use].

Next, the present invention will be described in detail with reference to examples and test examples, but the present invention is not limited to the following examples and test examples. In addition, the unit of the amount of each component in the table is % by mass unless otherwise specified.

[raw materials used]
In the test examples below, Riken A Palmitate 1000 (manufactured by Riken Vitamin Co., Ltd., 1,000,000 IU/g as vitamin A) was used as vitamin A oil, and Japanese Pharmacopoeia sesame oil (manufactured by Kaneda Corporation) was used as sesame oil.

[Test Example 1. Confirmation test 1 of discoloration suppressing effect of internal use composition]
(1) Each component was mixed according to the formulation in Table 2, sealed in a 50 mL glass bottle, and the mixture was covered and stirred with a vortex to prepare about 5 mL of an internal composition. Color differences were measured using a spectrophotometer. After that, the lid was put on again to make it a sealed state, and it was stored in a 50° C. constant temperature bath for one week.
(2) The discoloration of the sample was determined by a spectrophotometer CM-5 (manufactured by Konica Minolta Co., Ltd.) at 25 ° C., L ^* a ^* b ^* color space (CIE 1976) when using CIE standard light source D65 It was evaluated by measuring lightness L ^* , chromaticity a ^* and b ^* indicating hue and saturation. Using a spectrophotometer preliminarily calibrated against purified water, L ^* , a ^* and b ^* were measured before and after storage, and each value after storage was subtracted from each value before storage. ΔL ^* , Δa ^* and Δb ^* were calculated. Then, the color difference ΔE ^* was calculated by the following formula.
ΔE ^* = [(ΔL ^* ) ² + (Δa ^* ) ² + (Δb ^* ) ² ] ^1/2
(3) For ΔE ^* , ΔL ^* , and Δb ^* , the change suppression rate of each sample of Reference Example and Example relative to Comparative Example 1-1 was calculated. The greater the change suppression rate of ΔE ^* , ΔL ^* , or Δb ^* of each sample, the more suppressed the increase in ΔE ^* , ΔL ^* , or Δb ^* of that sample compared to Comparative Example 1-1. .
<Calculation formula for ΔE ^* change suppression rate, ΔL ^* change suppression rate, Δb ^* change suppression rate>
ΔE ^* change suppression rate (%) =
[(ΔE ^* of Comparative Example 1-1−ΔE ^* of each sample)/ΔE ^* of Comparative Example 1-1]×100
ΔL ^* change suppression rate (%) =
[(ΔL ^* of Comparative Example 1-1−ΔL ^* of each sample)/ΔL ^* of Comparative Example 1-1]×100
Δb ^* change suppression rate (%) =
[(Δb ^* of Comparative Example 1-1−Δb ^* of each sample)/Δb ^* of Comparative Example 1-1]×100

The results are shown in Table 2. In addition to vitamin B ₁ , vitamin C and vitamin D, further inclusion of vitamin E slightly inhibited discoloration (Reference Example 1-1). On the other hand, the discoloration was not suppressed even when vitamin A was added (Reference Example 1-2). Surprisingly, however, in Example 1-1 containing both vitamins A and E, discoloration was remarkably suppressed as compared with the case where each vitamin was contained alone. When the same storage test was performed for sesame oil alone, ΔE ^* , ΔL ^* , and Δb ^* were 0.09, 0.02, and 0.09, respectively (L ^* , a ^* , and b ^* before storage were 100.09, -0.29, and 1.23), respectively, and no discoloration due to storage was observed.

[Test Example 2. Examination test of dispersion stability of powder in internal use composition]
A composition for internal use having the composition shown in Table 3 below was prepared by mixing and allowed to stand. Visual observation after standing for 20 minutes indicates that the dispersion stability of the powder is poor when precipitation of the powder is observed (×), and the dispersion stability of the powder is good when no precipitation of the powder is observed ( 0).

The results are shown in Table 3. It was found that combinations of vitamins C and D with vitamins A and/or E have poor powder dispersion stability. On the other hand, in the examples of the present invention, the dispersion stability of the powder was good.

[Test Example 3. Confirmation test 2 of discoloration suppression effect of internal use composition]
Each component was mixed according to the formulation in Table 4, and the storage test and the measurement by the spectrophotometer were performed in the same procedure except that the temperature was changed to 60°C for 1 week under the storage conditions of procedure (1) in Test Example 1. Comparative Example 1 Using Comparative Example 3 instead of -1, the ΔE ^* change suppression rate and the ΔL ^* change suppression rate were calculated.

The results are shown in Table 4. Example 3, which contains ascorbic acid instead of calcium ascorbate in Example 1-1, exhibits high ΔE ^* change inhibition rate and ΔL ^* change inhibition rate, and contains vitamins B ₁ , C, and D. As compared with Comparative Example 3, discoloration was significantly suppressed.

Claims (10)

A composition for internal use containing vitamins A, ₁ vitamin B, vitamins C, vitamins D and vitamins E. 2. The composition for internal use according to claim 1, wherein said vitamin A is at least one selected from the group consisting of retinol, retinol derivatives and salts thereof. 2. The composition for internal use according to claim 1, wherein said vitamin _B1 is at least one selected from the group consisting of thiamine, derivatives thereof, and salts thereof. 2. The composition for internal use according to claim 1, wherein said vitamin C is at least one selected from the group consisting of ascorbic acid and salts thereof. 2. The composition for internal use according to claim 1, wherein said vitamin D is at least one selected from the group consisting of ergocalciferol and cholecalciferol. 2. The composition for internal use according to claim 1, wherein said vitamin E is at least one selected from the group consisting of tocopherol, derivatives thereof, and salts thereof. The composition for internal use according to any one of claims 1 to 6, which suppresses discoloration due to a combination of vitamin _B1 , vitamin C and vitamin D. The composition for internal use according to any one of claims 1 to 6, further comprising a hydrophobic dispersion medium. A discoloration inhibitor for a composition containing vitamins A and E, and containing vitamins _B1 , vitamins C and D. A composition containing vitamin B ₁ , vitamin C and vitamin D,
A method for suppressing discoloration of the composition, comprising allowing vitamins A and E to coexist.