JP7519753B2 - Compositions containing D-chiro-inositol - Google Patents

Description

The present invention relates to a composition 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 one hydrogen atom on each carbon of the cyclohexane is replaced with a hydroxyl group, and is known as a vitamin-like substance. Inositol exists in nine stereoisomers, depending on the combination of the configuration of the hydroxyl groups.

Patent Document 1 discloses a hair growth agent containing inositol as an active ingredient. As in Patent Document 1, the term "inositol" used in the prior art generally means a stereoisomer of myo-inositol (cis-1,2,3,5-trans-4,6-cyclohexanehexaol) as an additive for drugs, quasi-drugs, cosmetics, etc. (see, for example, Non-Patent Documents 1 to 3).
Furthermore, the present inventors have found that, among the stereoisomers of inositol, chiro-inositol is a compound useful as a hair growth agent (see Patent Document 2).

JP 2006-28026 A International Publication No. 2017/188393

Quasi-drug Raw Materials Standards 2006 Integrated Edition, Yakuji Nipposha, p. 318 Pharmaceutical Additives Standards 2003, Yakuji Nipposha, pp. 101-102 Pharmaceutical Additives Encyclopedia 2000, Yakuji Nipposha, p. 26

Here, the present inventors have found that, among the stereoisomers of inositol, D-chiro-inositol is a compound that is water-soluble among the isomers of inositol.
However, in the course of continuing research into compositions containing D-chiro-inositol in order to make the most of these properties of D-chiro-inositol, it was discovered that, among the stereoisomers of inositol, D-chiro-inositol is the one that tends to form precipitates more easily in aqueous solutions. In particular, D-chiro-inositol has very low solubility in solvents other than water, and tends to form precipitates more easily when an aqueous solution with a water ratio below a certain value is placed in a low-temperature environment.

The present invention therefore aims to provide a composition capable of inhibiting the precipitation of D-chiro-inositol.

As a result of extensive research to solve the above problems, the inventors discovered that a composition containing D-chiro-inositol can suppress the precipitation of D-chiro-inositol even in low-temperature environments by adjusting the water ratio to a predetermined value or higher, and thus completed the present invention.

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

The present invention provides a composition that can inhibit the precipitation of D-chiro-inositol even in a low-temperature environment.

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

The composition of the present invention contains D-chiro-inositol and water.

D-chiro-inositol is not particularly limited, but examples include naturally occurring products extracted from buckwheat, beans, citrus fruits, etc., products extracted by purifying legumes using fermentation methods, chemically synthesized products, and commercially available products. The method of extraction is not particularly limited, and any 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, even more preferably 0.05 to 15% by mass, even more preferably 1 to 10% by mass, and even more preferably 3 to 7% by mass.

In this specification, "mass %" refers to the mass percentage of a component contained in a composition relative to the mass of the entire composition.
In addition, in this 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. Examples of the external preparation include preparations for cracks and chapped skin, preparations for heat rash and sores, preparations for corns and calluses, preparations for dryness and roughness, preparations for wrinkles and age spots, moisturizers, hair dyes, hair growth agents, shampoos, rinses, conditioners, lotions, creams, milky lotions, hand creams, medicated soaps, and packs.
By containing D-chiro-inositol, the composition of the present invention can have a vitamin-like effect and hair growth activity, and may be used as a hair growth agent.
Specifically, the hair growth activity is activity relating to hair shaft growth promotion, hair growth, hair loss prevention, etc., and is preferably activity relating to hair shaft growth promotion and hair growth.

The composition of the present invention may further contain an organic acid or a salt thereof. Although not particularly limited, the composition of the present invention preferably contains an organic acid and a salt of an organic acid.
By including an organic acid or a salt thereof, it tends to be possible to improve the feel when used in a preparation containing the composition of the present invention, even when the preparation further includes a solvent other than water, for example, a monoalcohol having 1 to 3 carbon atoms. The reason for this effect is presumed to be that the organic acid or a salt thereof exerts a chelating effect, which functions to alleviate the irritation contributed by a solvent other than water, for example, a monoalcohol having 1 to 3 carbon atoms (however, the reason is not limited to this).

The organic acid refers to an organic compound that exhibits acidity in water by itself.
The organic acid is not particularly limited as long as it is an organic compound that exhibits acidity, and examples thereof include monocarboxylic acids, polycarboxylic acids, and organic sulfonic acids. Among these, polycarboxylic acids are preferred from the viewpoint of obtaining a good feeling of use. Meanwhile, in the present invention, among these, monocarboxylic acids and organic sulfonic acids are preferred, and organic sulfonic acids are more preferred, from the viewpoint of suppressing the precipitation of D-chiro-inositol.

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

The organic acid or its salt may be used alone or in combination of two or more. When two or more types are used in combination, the combination may be two or more organic acids, two or more salts of organic acids, or two or more organic acids and salts of organic acids.
When an organic acid and a salt of an organic acid are used, the organic acid and the organic acid of the salt of the organic acid may be the same or different, but it is preferable to use the organic acid and the salt of the organic acid in combination.

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 mass%, preferably 0.01 to 3 mass%, more preferably 0.03 to 1 mass%, and even more preferably 0.05 to 1 mass%.

The composition of the present invention may further comprise a surfactant.
The inclusion of a surfactant tends to make it possible to suppress precipitation of D-chiro-inositol in an aqueous solution containing D-chiro-inositol. Furthermore, the inclusion of a surfactant in the composition of the present invention tends to make it possible to improve the feel when used in a preparation containing the composition of the present invention. The reason for this effect is presumed to be that the surfactant improves the solubility of D-chiro-inositol in an aqueous solution (however, the reason is not limited to this).

The surfactant is not particularly limited, but includes nonionic surfactants, cationic surfactants, anionic surfactants, and amphoteric surfactants. Among these, nonionic surfactants are preferred from the viewpoint of obtaining a good feeling of use, particularly from the viewpoint of excellent penetration into pores.
The surfactant may be used alone or in combination of two or more kinds.

The HLB value of the surfactant is not particularly limited, but is preferably 2 to 17, more preferably 6 to 17, and even more preferably 12 to 17. The use of a surfactant with an HLB value in this range tends to reduce the precipitation of D-chiro-inositol. HLB is an abbreviation for hydrophile-lipophile balance, and is one of the indicators of the effect of a surfactant, with a higher HLB value indicating higher hydrophilicity. The HLB value in the present invention refers to a value calculated by the Davies formula: HLB = 7 + Σ (number of hydrophilic groups) - Σ (number of lipophilic groups) (hereinafter, the same applies when simply referring to "HLB value"). In addition, when two or more surfactants are contained, the HLB value is the weighted average of the HLB values of each surfactant.

The nonionic surfactant refers to a surfactant that does not exhibit ionic properties 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 ester of oleic acid and diglycerin. Among these, polyoxyethylene hydrogenated castor oil and polyoxyethylene polyoxypropylene alkyl ether are preferred from the viewpoints of suppressing precipitation of D-chiro-inositol, obtaining a good feeling of use, and particularly from the viewpoint of excellent penetration into pores.

The cationic surfactant and the anionic surfactant refer to surfactants that become cations and anions, respectively, when dissociated in an aqueous solution, and the amphoteric surfactant refers to a surfactant that becomes either a cation, an anion, or a zwitterion in an aqueous solution depending on the pH of the aqueous solution.
The cationic surfactant is not particularly limited, but examples thereof include alkyl dimethyl amines, alkyl trimethyl ammonium salts, and dialkyl dimethyl ammonium salts.
The anionic surfactant is not particularly limited, but examples thereof include fatty acid salts and alkyl sulfate salts.
Examples of amphoteric surfactants include, but are not limited to, alkylamino fatty acid salts, alkyl betaines, and alkyl amine oxides.

The content of the surfactant in the composition of the present invention is not particularly limited, but is usually 0.1 to 10% by mass, preferably 0.5 to 7% by mass, and more preferably 1 to 5% by mass.

The water content in the composition of the present invention is not particularly limited as long as it is in the range of 40% by mass or more, but is preferably 70% by mass or less, and more preferably 50% by mass or less.
By having the proportion of water within the above range, it is possible to suppress the precipitation of D-chiro-inositol even in a low-temperature environment, and in particular, even when the composition of the present invention contains an organic acid or a salt thereof, it is possible to suppress the precipitation of D-chiro-inositol. In particular, it is presumed that the cause of such an effect is that, since D-chiro-inositol is water-soluble, the water content of 40% by mass or more functions to alleviate the precipitation of D-chiro-inositol in a low-temperature environment, and in particular, the organic acid or a salt thereof exerts a chelating effect to promote the precipitation of D-chiro-inositol (however, the cause is not limited to this). In addition, it is possible to improve the feeling of use in a preparation containing the composition of the present invention, and also to exhibit excellent permeability into pores.

Examples of water include pure water such as ion-exchanged water, ultrafiltered water, reverse osmosis water, and distilled water, as well as ultrapure water, which has had as many ionic impurities removed as possible.

The composition of the present invention may further comprise a monoalcohol and/or a polyhydric alcohol having 1 to 3 carbon atoms.
By including a polyhydric alcohol, it tends to be possible to inhibit precipitation of D-chiro-inositol in an aqueous solution containing D-chiro-inositol.
By including a monoalcohol and/or a polyhydric alcohol having 1 to 3 carbon atoms, it tends to be possible to obtain a composition having antibacterial properties and moisturizing properties.

The monoalcohol having 1 to 3 carbon atoms includes methanol, ethanol, n-propanol, and isopropanol, with ethanol and isopropanol being preferred, and ethanol being more preferred.
The polyhydric alcohol means an alcohol having two or more hydroxyl groups in the molecule.
The polyhydric alcohol is not particularly limited, but examples thereof include 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-butanediol, 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.
The monohydric alcohols and polyhydric alcohols having 1 to 3 carbon atoms may each independently be used alone or in combination of two or more kinds.

The content of the monoalcohol having 1 to 3 carbon atoms in the composition of the present invention is not particularly limited, but it is possible to set the content of the monoalcohol having 1 to 3 carbon atoms high.
The content of the monoalcohol having 1 to 3 carbon atoms in the composition of the present invention is usually 80% by mass or less, may be 60% by mass or less, may be 30 to 60% by mass, may be 30 to 50% by mass, or may be 30 to 40% by mass.

The content of polyhydric alcohol in the composition of the present invention is not particularly limited, but is usually 0.1% by mass or more, preferably 0.5% by mass or more, more preferably 0.5 to 30% by mass, even more preferably 0.5 to 20% by mass, and even more preferably 0.5 to 15% by mass.

The compositions of the present invention may further comprise a monoterpene.
By including a monoterpene, a refreshing feeling is imparted and an excellent composition tends to be obtained by suppressing the precipitation of D-chiro-inositol.

The monoterpene is not particularly limited, and examples thereof include monoterpene hydrocarbons such as limonene, pinene, and camphor; monoterpene alcohols such as citronellol, geraniol, linalool, menthol, terpineol, and borneol; monoterpene aldehydes such as citronellal, citral, and safranal; and monoterpene ketones such as menthone, carbomenthone, and ionone. Monoterpene alcohols are preferred, and menthol is more preferred. These monoterpenes may be any of d-, l-, and dl-isomers. In particular, menthol is preferably l-menthol or d-menthol, and more preferably l-menthol. A mixture of l-menthol and d-menthol may be used.
The monoterpenes may be used alone or in combination of two or more.

The content of monoterpene in the composition of the present invention is not particularly limited, but is preferably 0.01 to 10% by mass, more preferably 0.05 to 2% by mass, even more preferably 0.1 to 1.0% by mass, and even more preferably 0.7 to 1.0% by mass, because it not only provides a refreshing sensation, but also inhibits the precipitation of D-chiro-inositol, inhibits dripping and irritation (tingling sensation) of the resulting composition, and is excellent in inhibiting separation of the monoterpene itself.

The composition of the present invention may further contain additives that are generally acceptable for use in drugs, quasi-drugs, cosmetics, and the like.
The additives are not particularly limited, but examples thereof include excipients, stabilizers, odorants, bases, dispersants, diluents, emulsifiers, transdermal absorption enhancers, preservatives, colorants, oils (oils and fats, mineral oils, etc.), thickeners, polymers, film-forming agents, UV absorbers, cell activators, antioxidants, preservatives, cooling agents, deodorants, pigments, dyes, fragrances, sugars, amino acids, vitamins, organic acids, organic amines, and plant extracts.

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 in which the components are mixed is not particularly limited.
The mixing conditions are not particularly limited, and the composition of the present invention can be prepared according to a conventionally known method.

When the composition of the present invention is used as an external preparation, it can be used as a medicine, a quasi-drug, a cosmetic, etc. For example, it can be used as an external preparation for skin, an external preparation for hair, and an external preparation for scalp, and more specifically, it can be used as a medicine for skin, a medicine for hair, and a medicine for scalp, a quasi-drug for skin, a quasi-drug for hair, and a quasi-drug for scalp, as well as a cosmetic for skin, a cosmetic for hair, and a cosmetic for scalp. More specifically, it can be in the form of an ointment, a cataplasm, a liniment, a lotion, an external liquid, a dusting agent, a cream, a gel, an emulsion, a hair tonic, or a hairspray.
In this specification, "external preparations for hair" and "external preparations for scalp" may be used in the same or different forms and methods of application as external preparations, but differ mainly in whether the site of direct action is the hair or the scalp. In addition, "external preparations for skin" is a concept that includes "external preparations for scalp" and means an external preparation that acts directly on the skin, not limited to the scalp.

The method of the present invention includes a step of administering the composition of the present invention to a subject. The amount of D-chiro-inositol administered to a subject per administration is not particularly limited, but is preferably 0.005 to 200 mg, more preferably 0.05 to 100 mg, and even more preferably 0.5 to 10 mg.

The number of times the composition of the present invention is administered 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 even more preferably 1 to 2 times per day.

The subjects to which the composition of the present invention is administered are not particularly limited, but examples include humans, livestock, pets, and other animals.

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, Ltd., hereinafter abbreviated as "DCI")
[Organic acid or its salt]
Citric acid (Showa Kako Co., Ltd.)
Sodium citrate (manufactured by Showa Kako Co., Ltd., hereafter abbreviated as "Na citrate")
Sodium edetate (manufactured by Junsei Chemical Co., Ltd.; hereafter abbreviated as "Na edetate")
[Surfactant]
HCO-10 (polyoxyethylene (10) hydrogenated castor oil, HLB value: 6.5, manufactured by Nikko Chemicals Co., Ltd.)
HCO-20 (polyoxyethylene (20) hydrogenated castor oil, HLB value: 10.5, manufactured by Nikko Chemicals Co., Ltd.)
HCO-40 (Polyoxyethylene (40) hydrogenated castor oil, HLB value: 12.5, manufactured by Nikko Chemicals Co., Ltd.)
HCO-50 (Polyoxyethylene (50) hydrogenated castor oil, HLB value: 13.5, manufactured by Nikko Chemicals Co., Ltd.)
HCO-60 (polyoxyethylene (60) hydrogenated castor oil, HLB value: 14, manufactured by Nikko Chemicals Co., Ltd.)
PPG-8 Ceteth-20 (addition polymerization of ethylene oxide and propylene oxide to cetanol, HLB value: 12.5, manufactured by Nikko Chemicals Co., Ltd., hereinafter abbreviated as "PBC44")
PPG-4 Ceteth-20 (Polyoxyethylene polyoxypropylene cetyl ether, HLB value: 16.5, manufactured by Nikko Chemicals Co., Ltd., hereinafter abbreviated as "PBC34")
Polysorbate 80 (polyoxyethylene sorbitan oleate, HLB value: 15, manufactured by Nikko Chemicals Co., Ltd.)
Glyceryl oleate (monoester of oleic acid and glycerin, HLB value: 2.5, manufactured by Nikko Chemicals Co., Ltd.)
Polyglyceryl-2 oleate (ester of oleic acid and diglycerin, HLB value: 5.5, manufactured by Nikko Chemicals Co., Ltd.)
[Monoalcohols having 1 to 3 carbon atoms]
Ethanol (manufactured by Wako Pure Chemical Industries, Ltd., hereafter abbreviated as "EtOH")
[Polyhydric alcohol]
Propylene glycol (Wako Pure Chemical Industries, Ltd.)
1,3-Butylene glycol (Wako Pure Chemical Industries, Ltd.)
Glycerin (Wako Pure Chemical Industries, Ltd.)
[Monoterpene]
l-Menthol (manufactured by Wako Pure Chemical Industries, Ltd.; hereinafter abbreviated as "l-menthol")
[water]
purified water

Example 1
DCI and an organic acid and/or a salt thereof were dissolved in purified water so that each component had the composition shown in Table 1 below, a solution of EtOH and a surfactant was added, and the remaining volume was diluted with EtOH and mixed to prepare each composition as a formulation.

A. Formulation Stability Test The resulting formulations were evaluated for DCI precipitation in each composition by the following method.
Three lots of each formulation were prepared, and DCI precipitation was induced by a low-temperature cycle (incubation at 5°C for 12 hours, followed by incubation at -20°C for 12 hours, repeated for 14 days), and the precipitation was evaluated visually based on the following criteria. The evaluation results are shown in Table 1 (N=3).
No crystal precipitation was observed in any lot. "◎"
Even in 1 lot, slight crystal precipitation was observed (Good).
Even in one lot, a small amount of crystals were observed (△).
Even in one lot, a large amount of crystals was observed (X).

B. Test of Usability The resulting preparations were evaluated for usability (penetration into pores) when applied to the preparations of each composition by the following method.
Three lots of each formulation were prepared and used to prepare a coloring formulation with 0.25% Coomassie Brilliant Blue R-250 (CBB R-250, Tokyo Chemical Industry Co., Ltd.). The hair on the back of C57BL/6 mice was then trimmed to 1 mm length with clippers, and the coloring formulation was applied to the mice. After application, the coloring formulation was quickly wiped off, and the skin from the applied area was sampled and raw sections were prepared. The raw sections were observed under an optical microscope, and the depth of pigment penetration into the hair follicles was evaluated based on the following criteria.
<Usage>
・Penetration into hair pores: The pigment is confirmed to reach more than 3/4 of the depth of the hair root, giving it a rating of "◎".
"○" indicates that the pigment has reached 2/4 to 3/4 of the depth of the hair root
"△" indicates that the pigment has reached 1/4 to 2/4 of the depth of the hair root.
"X" indicates that the dye has not reached more than 1/4 of the hair root

From the results in Table 1, it can be determined that DCI precipitation can be effectively suppressed by ensuring that the water content in DCI-containing formulations is 40% by mass or more.

Claims (13)

D-chiro-inositol and water;
The water content is 40% by mass or more.
A composition (excluding hair growth agents which are external preparations containing 0.001 to 20 % by weight of D-chiro-inositol based on the total weight ). The composition according to claim 1, wherein the content of D-chiro-inositol is 0.001 to 20% by mass. The composition according to claim 1 or 2, further comprising an organic acid and/or a salt thereof. Contains organic acids,
The composition according to claim 3, wherein the organic acid is a monocarboxylic acid or a polycarboxylic acid. Contains polycarboxylic acid,
The composition according to claim 4, wherein the polycarboxylic acid is citric acid or edetic acid. Contains salts of organic acids,
The composition according to any one of claims 2 to 5, wherein the salt is one or more selected from the group consisting of sodium salts, potassium salts, calcium salts, and magnesium salts. The composition according to any one of claims 2 to 6, comprising an organic acid and a salt of the organic acid. The composition according to any one of claims 1 to 7, further comprising a surfactant. The composition according to claim 8, wherein the surfactant comprises a nonionic surfactant. The composition according to claim 9, wherein the nonionic surfactant comprises polyoxyethylene hydrogenated castor oil or polyoxyethylene polyoxypropylene alkyl ether. D-chiro-inositol and water;
The content of D-chiro-inositol is 1 to 10% by mass,
The water content is 40% by mass or more,
Further comprising citric acid and salts of citric acid and a surfactant,
A composition (excluding hair growth agents which are external preparations containing 0.01 to 10% by weight of D-chiro-inositol and 45 to 49.995% by weight of water). An external preparation comprising the composition according to any one of claims 1 to 11 . An external preparation for the scalp comprising the composition according to any one of claims 1 to 11 .