JP7203522B2 - Compositions containing D-chiro-inositol - Google Patents

Description

The present invention relates to compositions containing D-chiro-inositol. The present invention also relates to an external preparation containing the composition.

Inositol (1,2,3,4,5,6-cyclohexanehexaol) has a structure in which each hydrogen atom on each carbon of cyclohexane is substituted with a hydroxyl group, and is known as a vitamin-like active substance. there is Inositol has nine stereoisomers depending on the combination of steric configurations of hydroxy groups.

Patent Document 1 discloses a hair restorer containing inositol as an active ingredient. As in Patent Document 1, "inositol" used in the prior art refers to myo-inositol (cis-1,2,3,5-trans-4 , 6-cyclohexanehexaol) (see, for example, Non-Patent Documents 1-3).
In addition, the present inventors have found that among stereoisomers of inositol, chiro-inositol is a compound useful as a hair restorer (see Patent Document 2).

JP-A-2006-28026 WO2017/188393

Standards for Quasi-drug Ingredients 2006 Integrated Edition, Yakuji Nippo, p. 318 Pharmaceutical Excipients Standards 2003, Yakuji Nippousha, p. 101-102 Pharmaceutical Additives Encyclopedia 2000, Yakuji Nipposha, p. 26

Here, the present inventors have found that among stereoisomers of inositol, D-chiro-inositol is a compound having water solubility among isomers of inositol.
However, while continuing research on compositions containing D-chiro-inositol in order to take advantage of these properties of D-chiro-inositol, D-chiro-inositol is an inositol stereoisomer in an aqueous solution. It was found that they tended to form precipitates. In particular, D-chiro-inositol has very low solubility in solvents other than water, and tends to form precipitates more easily in mixed solutions containing solvents other than water. In particular, D-chiro-inositol tends to form a significant precipitate in a mixed solution containing a solvent other than water when the storage temperature changes.

Accordingly, an object of the present invention is to provide a composition capable of suppressing precipitation of D-chiro-inositol.

The present inventors have made intensive studies to solve the above problems, and found that D-chiro-inositol, an organic acid or a salt thereof, and surfactant The composition containing the agent and the polyhydric alcohol is a composition capable of suppressing the precipitation of D-chiro-inositol by having the concentration of the surfactant and the concentration of the polyhydric alcohol each within a predetermined range. We found a certain thing and came to complete the present invention.

That is, the present invention provides the following inventions.
[1] containing D-chiro-inositol, an organic acid and/or a salt thereof, a surfactant, a monoalcohol having 1 to 3 carbon atoms, a polyhydric alcohol and water,
The content of monoalcohol having 1 to 3 carbon atoms is 40% by mass or more,
The content of the surfactant is 1 to 10% by mass,
A composition having a polyhydric alcohol content of 1 to 10% by mass.
[2] The composition according to [1], wherein the content of D-chiro-inositol is 0.001 to 20% by mass.
[3] containing an organic acid,
The composition according to [1] or [2], wherein the organic acid is monocarboxylic acid or polycarboxylic acid.
[4] containing a polycarboxylic acid,
The composition according to [3], wherein the polycarboxylic acid is citric acid or edetic acid.
[5] containing a salt of an organic acid,
The composition according to any one of [1] to [4], wherein the salt is one or more selected from the group consisting of sodium salts, potassium salts, calcium salts, and magnesium salts.
[6] The composition according to any one of [1] to [5], comprising an organic acid and a salt of the organic acid.
[7] The composition according to any one of [1] to [6], wherein the surfactant contains a nonionic surfactant.
[8] The composition according to any one of [1] to [7], wherein the nonionic surfactant comprises polyoxyethylene hydrogenated castor oil or polyoxyethylene polyoxypropylene alkyl ether.
[9] The composition according to any one of [1] to [8], wherein the monoalcohol having 1 to 3 carbon atoms is ethanol.
[10] An external preparation containing the composition according to any one of [1] to [9].
[11] An external scalp preparation comprising the composition according to any one of [1] to [9].

According to the present invention, a composition capable of suppressing precipitation of D-chiro-inositol is provided.

Hereinafter, the present invention will be clarified by describing the composition of the present invention and specific embodiments thereof. However, the invention is not limited to the specific embodiments described below.

The composition of the present invention comprises D-chiro-inositol, an organic acid or a salt thereof, a surfactant, a monoalcohol having 1 to 3 carbon atoms, a polyhydric alcohol and water.

D-chiro-inositol is not particularly limited, but for example, those extracted from naturally occurring buckwheat, beans, citrus fruits, etc., those purified and extracted from leguminous plants by fermentation, those chemically synthesized, and A commercial item is mentioned. Here, the extraction method is not particularly limited, and a known extraction method can be used.

The content of D-chiro-inositol in the composition of the present invention is not particularly limited, but is preferably 0.001 to 20% by mass, more preferably 0.01 to 20% by mass, still more preferably 0 05 to 15% by mass, more preferably 1 to 10% by mass, and even more preferably 3 to 7% by mass.

As used herein, "% by mass" means the percentage by mass of a component contained in the composition with respect to the mass of the entire composition.
In addition, in the present specification, the expression “X to Y” means X or more and Y or less.

The composition of the present invention can be used as an external preparation. External preparations include, for example, cracks and chapped skin, prickly heat and sores, corns and calluses, dry skin and rough skin, wrinkles and blemishes, moisturizers, hair dyes, hair restorers, shampoos, Examples include rinses, conditioners, lotions, creams, milky lotions, hand creams, medicated soaps, packs, and the like.
By containing D-chiro-inositol, the composition of the present invention can obtain a composition imparted with vitamin-like action and hair growth activity, and may be used as a hair restorer.
Specifically, the hair-restoring activity is activity related to promotion of hair shaft growth, hair growth, prevention of hair loss, etc., and preferably activity related to promotion of hair shaft growth and hair growth.

The composition of the present invention contains an organic acid or a salt thereof, and preferably contains an organic acid and a salt of an organic acid.
By containing an organic acid or a salt thereof, even if a solvent other than water, such as a monoalcohol having 1 to 3 carbon atoms, is further contained, it is possible to improve the usability of the formulation containing the composition of the present invention. becomes. It is surmised that the reason why such an effect is produced is that the organic acid or its salt exerts a chelating action and functions to alleviate the irritation caused by a solvent other than water, such as a monoalcohol having 1 to 3 carbon atoms. (However, the factors are not limited to this.)

An organic acid means an organic compound that shows acidity in water by itself.
The organic acid is not particularly limited as long as it is an organic compound exhibiting acidity, and examples thereof include monocarboxylic acids, polyvalent carboxylic acids, and organic sulfonic acids. Among these, polyvalent carboxylic acids are preferred from the viewpoint of obtaining a good feel during use. On the other hand, among these, in the present invention, monocarboxylic acids and organic sulfonic acids are preferable, and organic sulfonic acids are more preferable, from the viewpoint of suppressing the precipitation of D-chiro-inositol.

A monocarboxylic acid means an organic compound having one carboxylic acid in the molecule, and a polyvalent carboxylic acid means an organic compound having two or more carboxylic acids in the molecule.
Organic sulfonic acid means an organic compound having at least one sulfonic acid in the molecule.
Examples of monocarboxylic acids include, but are not limited to, formic acid, acetic acid, propionic acid, and valeric acid.
Examples of polycarboxylic acids include, but are not limited to, dicarboxylic acids, tricarboxylic acids, tetracarboxylic acids, etc. Examples include citric acid, edetic acid, phthalic acid, isophthalic acid, terephthalic acid, succinic acid, fumaric acid, and maleic acid. Acids, malic acid, and tartaric acid. Among these, citric acid and edetic acid are preferred.
Organic sulfonic acids include, but are not limited to, methanesulfonic acid, benzenesulfonic acid, and taurine.
Examples of salts of organic acids include, but are not particularly limited to, sodium salts, potassium salts, calcium salts, and magnesium salts. Among these, sodium salts are preferred.

An organic acid or its salt may be used individually by 1 type, and may be used in combination of 2 or more type. When two or more are used in combination, it may be a combination of two or more organic acids, or a combination of two or more organic acid salts, or an organic acid and an organic acid salt. The above may be used in combination.
When using an organic acid and a salt of an organic acid, the organic acid and the organic acid of the salt of the organic acid may be the same or different, but the organic acid and the salt of the organic acid are used in combination. is preferred.

The content of the organic acid or its salt in the composition of the present invention is not particularly limited, but is usually 0.001 to 5% by mass, preferably 0.01 to 3% by mass, more preferably 0.03. 1% by mass, more preferably 0.05 to 1% by mass.

The composition of the invention contains a surfactant.
By including a surfactant, it is possible to suppress precipitation of D-chiro-inositol in an aqueous solution containing D-chiro-inositol. In addition, by including a surfactant in the composition of the present invention, it is possible to improve the usability of the formulation containing the composition of the present invention. It is surmised that the reason why such an effect is exhibited is that the surfactant improves the solubility of D-chiro-inositol in an aqueous solution (but the factor is not limited to this).

Surfactants include, but are not limited to, nonionic surfactants, cationic surfactants, anionic surfactants, and amphoteric surfactants. Among these, nonionic surfactants are preferable from the viewpoint of obtaining a good feel during use, particularly from the viewpoint of excellent permeability into pores.
Surfactants may be used alone or in combination of two or more.

The HLB value of the surfactant is not particularly limited, but is preferably 2-17, more preferably 6-17, even more preferably 12-17. By using a surfactant having an HLB value within this range, precipitation of D-chiro-inositol tends to be reduced. HLB is an abbreviation for hydrophilic-lipophile balance, and is one of the indices representing the effects of surfactants. A higher HLB value indicates higher hydrophilicity. The HLB value in the present invention refers to a value calculated by the Davies formula HLB=7+Σ (number of bases of hydrophilic groups)−Σ (number of bases of lipophilic groups). ). Moreover, the HLB value in the case of containing two or more surfactants is the weighted average value of the HLB values of the respective surfactants.

A nonionic surfactant means a surfactant that does not exhibit ionicity in an aqueous solution.
Examples of nonionic surfactants include, but are not limited to, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene alkyl ether, polyoxyethylene sorbitan oleate, monoester of oleic acid and glycerin, and oleic acid and Esters of diglycerin may be mentioned. Among these, polyoxyethylene hydrogenated castor oil and polyoxyethylene poly Oxypropylene alkyl ethers are preferred.

Cationic surfactants and anionic surfactants mean surfactants that become cations and anions when dissociated in an aqueous solution, respectively; means a surfactant that is either cationic, anionic, or zwitterionic, depending on .
Examples of cationic surfactants include, but are not limited to, alkyldimethylamines, alkyltrimethylammonium salts, and dialkyldimethylammonium salts.
Examples of anionic surfactants include, but are not limited to, fatty acid salts and alkyl sulfates.
Examples of amphoteric surfactants include, but are not limited to, alkylamino fatty acid salts, alkylbetaines, and alkylamine oxides.

The content of the surfactant in the composition of the present invention is 1 to 10% by mass, preferably 1 to 7% by mass, more preferably 1 to 5% by mass. When the content of the surfactant is in such a range, it is possible to suppress the precipitation of D-chiro-inositol in the aqueous solution containing D-chiro-inositol, and in the formulation containing the composition of the present invention It is possible to improve usability.

In the composition of the present invention, the content of monoalcohol having 1 to 3 carbon atoms is 40% by mass or more.
Precipitation of D-chiro-inositol by dissolving D-chiro-inositol, an organic acid or a salt thereof, a surfactant, and a polyhydric alcohol in an aqueous monoalcohol solution having 1 to 3 carbon atoms of 40% by mass or more. can be suppressed.

Examples of water include pure water such as ion-exchanged water, ultrafiltrated water, reverse osmosis water, and distilled water, and water from which ionic impurities are removed as much as possible, such as ultrapure water.

The content of monoalcohol having 1 to 3 carbon atoms in the composition of the present invention is within the range of 40% by mass or more, usually 80% by mass or less, preferably 50% by mass or less, more preferably 45% by mass. % or less.

Monoalcohols having 1 to 3 carbon atoms include methanol, ethanol, n-propanol and isopropanol, preferably ethanol and isopropanol, and more preferably ethanol.
Monoalcohols having 1 to 3 carbon atoms may be used singly or in combination of two or more.

The composition of the invention contains a polyhydric alcohol.
By containing a polyhydric alcohol, it is possible to suppress the precipitation of D-chiro-inositol in an aqueous solution containing D-chiro-inositol, and it is possible to improve the usability of a formulation containing the composition of the present invention. becomes. Moreover, by containing a polyhydric alcohol, there is a tendency to obtain a composition imparted with antibacterial properties and moisturizing properties.
Also, by containing a surfactant and a polyhydric alcohol, it is possible to suppress precipitation of D-chiro-inositol in an aqueous solution containing D-chiro-inositol and an organic acid or a salt thereof.

Monoalcohols having 1 to 3 carbon atoms include methanol, ethanol, n-propanol and isopropanol, preferably ethanol and isopropanol, and more preferably ethanol.
A polyhydric alcohol means an alcohol having two or more hydroxyl groups in the molecule.
Examples of polyhydric alcohols include, but are not limited to, glycerin, ethylene glycol, diethylene glycol, triethylene glycol, propylene glycol (1,2-propanediol), dipropylene glycol, trimethylolpropane, 1,3-propylene glycol ( 1,3-propanediol), isobutylene glycol (2-methyl-1,2-propanediol), 1,2-butanediol, 1,3-butylene glycol (1,3-butanediol), 1,4-butane Diol, 2-butene-1,4-diol, 1,2-pentanediol, 1,5-pentanediol, 2-methyl-2,4-pentanediol, 1,2-hexanediol, 1,6-hexanediol , 2-ethyl-1,3-hexanediol, 1,7-heptanediol, and 1,8-octanediol. Among these, glycerin, propylene glycol and 1,3-butylene glycol are preferred.
A polyhydric alcohol may be used individually by 1 type, and may be used in combination of 2 or more type.

The content of polyhydric alcohol in the composition of the present invention is 1 to 10% by mass, preferably 2 to 7% by mass. When the content of the polyhydric alcohol is within such a range, it is possible to suppress the precipitation of D-chiro-inositol in the aqueous solution containing D-chiro-inositol, and in the formulation containing the composition of the present invention It is possible to improve usability.

Compositions of the invention may further comprise a monoterpene.
Containing a monoterpene tends to provide a refreshing feeling and to obtain an excellent composition by suppressing precipitation of D-chiro-inositol.

The monoterpene is not particularly limited, but monoterpene hydrocarbons such as limonene, pinene, and camphor; monoterpene alcohols such as citronellol, geraniol, linalool, menthol, terpineol, and borneol; monoterpenes such as citronellal, citral, and safranal. aldehydes; monoterpene ketones such as menthone, carbomentone, and ionone; Monoterpene alcohols are preferred, and menthol is more preferred. These monoterpenes may be d-, l-, or dl-forms. As menthol, l-menthol and d-menthol are particularly preferable, and l-menthol is more preferable. A mixture of l-menthol and d-menthol may also be used.
A monoterpene may be used individually by 1 type, and may be used in combination of 2 or more type.

The content of monoterpene in the composition of the present invention is not particularly limited, but in addition to imparting a refreshing feeling, it suppresses precipitation of D-chiro-inositol, and suppresses dripping and irritation (tingling sensation) of the resulting composition. , And because it is excellent in suppressing the separation of the monoterpene itself, it is preferably 0.01 to 10% by mass, more preferably 0.05 to 2% by mass, and still more preferably 0.1 to 1.0% by mass. %, and more preferably 0.7 to 1.0% by mass.

The composition of the present invention may further contain additives generally accepted in pharmaceuticals, quasi-drugs, cosmetics and the like.
Examples of additives include, but are not limited to, excipients, stabilizers, flavoring agents, bases, dispersants, diluents, emulsifiers, percutaneous absorption enhancers, preservatives, coloring agents, oils (oils, minerals, oils, etc.), thickeners, polymers, film-forming agents, UV absorbers, cell activators, antioxidants, preservatives, cooling agents, deodorants, pigments, dyes, fragrances, sugars, amino acids, vitamins, Examples include organic acids, organic amines, plant extracts, and the like.

The composition of the present invention is not particularly limited and can be produced by mixing the components included in the present invention. The order of mixing each component is not particularly limited.
Also, the conditions for mixing are not particularly limited, and the composition of the present invention can be obtained according to a conventionally known method.

When the composition of the present invention is used as an external preparation, it can be used as pharmaceuticals, quasi-drugs, cosmetics, or the like. For example, it can be used for external skin preparations, hair preparations, and scalp preparations, more specifically, skin drugs, hair drugs and scalp drugs, skin quasi drugs, and hair It can be used for quasi-drugs, quasi-drugs for scalp, skin cosmetics, hair cosmetics and scalp cosmetics. More specifically, it can be in the form of ointments, poultices, liniments, lotions, liquids for external use, dusting agents, creams, gels, milky lotions, hair tonics, and hair sprays.
As used herein, "external preparation for hair" and "external preparation for scalp" may be the same or different in form and usage as external preparations. It differs in whether it is the skin or the scalp. In addition, "external preparation for skin" is a concept including "external preparation for scalp" and means an external preparation for directly acting on the skin without being limited to the scalp.

The methods of the invention comprise administering the compositions of the invention to a subject. The dose of D-chiro-inositol per administration to a subject is not particularly limited, but is preferably 0.005 to 200 mg, more preferably 0.05 to 100 mg, still more preferably 0.5 to 10 mg.

The frequency of administration of the composition of the present invention to a subject is not particularly limited, but is preferably 1 to 6 times per day, more preferably 1 to 3 times per day, and still more preferably 1 time per day. ~2 times.

Subjects to which the composition of the present invention is administered are not particularly limited, but examples thereof include animals such as humans and domestic animals and pets.

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

The components used in this example are as follows.
[D-chiro-inositol]
D-chiro-inositol (manufactured by Wako Pure Chemical Industries, hereinafter abbreviated as "DCI")
[Organic acid or its salt]
Citric acid (manufactured by Showa Kako Co., Ltd.)
Sodium citrate (manufactured by Showa Kako Co., Ltd., hereinafter abbreviated as "sodium citrate")
Sodium edetate (manufactured by Junsei Chemical Co., Ltd., hereinafter abbreviated as “Na edetate”)
Acetic acid (manufactured by Wako Pure Chemical Industries, Ltd.)
Isophthalic acid (manufactured by Wako Pure Chemical Industries, Ltd.)
Taurine (manufactured by Mitsui Chemicals, Inc.)
[Surfactant]
HCO-10 (polyoxyethylene (10) hydrogenated castor oil, HLB value: 6.5, manufactured by Nikko Chemicals)
HCO-20 (polyoxyethylene (20) hydrogenated castor oil, HLB value: 10.5, manufactured by Nikko Chemicals)
HCO-40 (polyoxyethylene (40) hydrogenated castor oil, HLB value: 12.5, manufactured by Nikko Chemicals)
HCO-50 (polyoxyethylene (50) hydrogenated castor oil, HLB value: 13.5, manufactured by Nikko Chemicals)
HCO-60 (polyoxyethylene (60) hydrogenated castor oil, HLB value: 14, manufactured by Nikko Chemicals)
PPG-8 Ceteth-20 (addition polymerization of ethylene oxide and propylene oxide to cetanol, HLB value: 12.5, manufactured by Nikko Chemicals, hereinafter abbreviated as "PBC44")
PPG-4 Ceteth-20 (polyoxyethylene polyoxypropylene cetyl ether, HLB value: 16.5, manufactured by Nikko Chemicals, hereinafter abbreviated as "PBC34")
Polysorbate 80 (polyoxyethylene sorbitan oleate, HLB value: 15, Nikko Chemicals Co., Ltd.)
Glyceryl oleate (monoester of oleic acid and glycerin, HLB value: 2.5, manufactured by Nikko Chemicals)
Polyglyceryl-2 oleate (ester of oleic acid and diglycerin, HLB value: 5.5, manufactured by Nikko Chemicals)
[Monoalcohol having 1 to 3 carbon atoms]
Ethanol (manufactured by Wako Pure Chemical Industries, Ltd., hereinafter abbreviated as “EtOH”)
[Polyhydric alcohol]
Propylene glycol (manufactured by Wako Pure Chemical Industries, Ltd.)
1,3-butylene glycol (manufactured by Wako Pure Chemical Industries, Ltd.)
Glycerin (manufactured by Wako Pure Chemical Industries, Ltd.)
[Monoterpene]
l-menthol (manufactured by Wako Pure Chemical Industries, Ltd., hereinafter abbreviated as “l-mentol”)
[water]
purified water

Example 1
Dissolve DCI and an organic acid and/or its salt in purified water so that each component has the composition shown in Table 1 below, add a mixed solution of EtOH and a surfactant, and add the remaining volume to purified water. and mixed to prepare each composition as a formulation.

A. Formulation Stability Test The obtained formulations were evaluated for precipitation of DCI in each composition by the following method.
Prepare 3 lots of formulations for each composition, induce precipitation of DCI by low temperature cycle (after 12 hours incubation at 5°C, repeat 12 hours -20°C for 14 days), and visually evaluate based on the following indicators. bottom. The evaluation results are shown in Table 1 (N number is 3).
No precipitation of crystals is observed in all lots "◎"
Even in 1 lot, slight precipitation of crystals was observed "○"
"△" where a small number of crystals were precipitated even in 1 lot
"X" that a large number of crystals were precipitated even in 1 lot

B. Test of feeling in use The obtained preparations were evaluated for feeling in use (permeability into pores) upon application by the following method.
Three lots of formulations were prepared for each composition, and 0.25% Coomassie Brilliant Blue R-250 (CBB R-250, manufactured by Tokyo Kasei Kogyo Co., Ltd.) color formulations were prepared. Next, the hair on the back of the C57BL/6 mouse was clipped to a length of 1 mm with a hair clipper, and then the color preparation was applied. Immediately after the application, the color preparation was wiped off, and the skin of the applied part was collected to prepare a raw section. The prepared raw sections were observed with an optical microscope, and the depth of dye penetration into the hair follicle was evaluated based on the following indices.
<Usage feeling>
・Permeability into pores
"◎" indicates that the pigment has reached the depth of 3/4 or more of the hair root.
"○" indicates that the pigment has reached 2/4 to 3/4 of the hair root.
"△" indicates that the pigment has reached 1/4 to 2/4 of the hair root.
"X" that the pigment has not reached the deep part of 1/4 or more of the hair root

From the results in Table 1, it can be determined that precipitation of DCI can be effectively suppressed by including an organic acid or a salt thereof and a surfactant and a polyhydric alcohol each having a concentration within a predetermined range in the formulation. In addition, it was confirmed that the permeability of DCI-containing formulations into pores was improved by containing an organic acid or a salt thereof, a surfactant and a polyhydric alcohol each having a concentration within a predetermined range. Furthermore, the higher the monoalcohol content, the more the precipitation increases, and although not shown in Table 1, the precipitation tends to increase as the monoalcohol content increases from 40% by mass. Even when the content of monoalcohol was high, the composition of the present invention sufficiently inhibited precipitation and exhibited excellent permeability into pores.

Claims (10)

D-chiro-inositol, an organic acid and / or a salt thereof, a surfactant, a monoalcohol having 1 to 3 carbon atoms, a polyhydric alcohol and water,
The content of D-chiro-inositol is 0.001 to 20% by mass,
The content of monoalcohol having 1 to 3 carbon atoms is 40% by mass or more,
The content of the surfactant is 1 to 10% by mass,
A composition having a polyhydric alcohol content of 1 to 10% by mass. containing organic acids,
A composition according to claim 1 , wherein the organic acid is a monocarboxylic acid or a polycarboxylic acid. containing a polycarboxylic acid,
3. The composition according to claim 2 , wherein the polycarboxylic acid is citric acid or edetic acid. containing salts of organic acids,
The composition according to any one of claims 1 to 3 , wherein the salt is one or more selected from the group consisting of sodium salts, potassium salts, calcium salts and magnesium salts. A composition according to any preceding claim, comprising an organic acid and a salt of an organic acid. A composition according to any preceding claim, wherein the surfactant comprises a nonionic surfactant. A composition according to any preceding claim, wherein the nonionic surfactant comprises polyoxyethylene hydrogenated castor oil or polyoxyethylene polyoxypropylene alkyl ether. The composition according to any one of claims 1 to 7 , wherein the C1-C3 monoalcohol is ethanol. An external preparation containing the composition according to any one of claims 1 to 8 . An external preparation for the scalp comprising the composition according to any one of claims 1 to 8 .