JP7047997B2 - Composition - Google Patents

Description

The present invention relates to a composition containing an active ingredient of an anti-aging cosmetic in a chemically stable manner.

Wrinkle formation is a typical symptom of the skin aging phenomenon due to aging. Wrinkles are broadly classified into shallow wrinkles formed on the skin surface that can be improved by moisturizing and deep wrinkles caused by exposure to ultraviolet rays and accumulation of physical stimuli, and it is very difficult to prevent or improve the latter deep wrinkles. Further, various wrinkle improving agents have been developed up to now (see, for example, Non-Patent Document 1). As such a wrinkle improving agent, one containing retinoic acid as an active ingredient is famous. Tretinoin acid is approved as a therapeutic drug for wrinkles and acne in the United States, but it is not approved in Japan due to safety issues such as skin irritation. Further, as other wrinkle improving agents, collagen production promoters (see, for example, Patent Document 1), hyaluronic acid production promoters (see, for example, Patent Document 2) and the like have been reported. However, it is difficult to say that all of the above-mentioned wrinkle improving agents have obtained sufficient effects, and effective means have not yet been established.

An elastase inhibitor is a wrinkle improving agent having a mechanism of action different from that of the wrinkle improving agent. Elastin, one of the structural proteins present in skin tissue, builds a cross-linked structure and maintains the elasticity of the tissue. It is known that skin irritation such as exposure to ultraviolet rays denatures and disintegrates elastin by overexpressing and activating elastase, an elastin-degrading enzyme, causing a decrease in skin firmness and elasticity, and promoting wrinkle formation. .. The elastase inhibitor exerts a preventive or ameliorating effect on wrinkle formation by inhibiting the above-mentioned elastin-degrading enzyme. On the other hand, structural analysis of elastin-degrading enzymes and substrates and structural activity correlation studies are underway, but it is difficult to achieve high enzyme inhibitory activity and selectivity by small organic molecules, and peptides are used as components with high enzyme inhibitory activity. And its derivatives (see, for example, Patent Document 3).
As an elastase inhibitor of such a peptide derivative, a peptide derivative such as WS7622A mono or dissulfate ester is known (see, for example, Patent Document 4), and its application to ischemic diseases due to such pharmacological action has been achieved. There is. Further, it is known that the compound represented by the following general formula (1) has a leukocyte elastase inhibitory action similar to WS7622A, and a skin aging preventive or therapeutic action (see, for example, Patent Document 5) has been reported. There is.

[式中、Ｒ_１は、カルボキシル基により置換された炭素数１～４の直鎖若しくは分岐のアルキル基、又は炭素数１～４のアルキル鎖を有するカルボン酸エステル基により置換された炭素数１～４の直鎖若しくは分岐のアルキル基を表し、Ｒ_２及びＲ_３は、それぞれ独立に、炭素数１～４の直鎖又は分岐のアルキル基を表す。]

[In the formula, R ₁ has 1 to 4 carbon atoms substituted with a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group, or a carboxylic acid ester group having an alkyl chain with 1 to 4 carbon atoms. Represents a linear or branched alkyl group of to 4, and R ₂ and R ₃ independently represent a linear or branched alkyl group having 1 to 4 carbon atoms. ]

Japanese Unexamined Patent Publication No. 2002-255847 Japanese Unexamined Patent Publication No. 2004-123637 International Publication No. 2001/40263 International Publication No. 1998/27998 International Publication No. 1999/43352

Development technology for anti-aging, whitening and moisturizing cosmetics, CMC Publishing, supervised by Masato Suzuki, Chapter 2 Anti-aging anti-wrinkle) Functional cosmetics

Since the peptide bonds contained in the compound represented by the general formula (1) are susceptible to hydrolysis, the present inventors try to include the compound in a composition for skin anti-aging. , Found that there is a problem of its chemical stability.
The present invention has been made under such circumstances, and the compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof can be chemically stable and chemically stable. An object of the present invention is to provide a method for uniformly solubilizing. Furthermore, it is an object of the present invention to provide a solubilized form of a solubilized external preparation for skin containing the above compound and having an excellent feeling of use.

In view of such a situation, the present inventors have made diligent efforts, and as a result, if an alcohol having 2 to 9 carbon atoms is used, the compound represented by the general formula (1), an isomer thereof and / or them are used. It was conceived that the pharmacologically acceptable salt of the above compound can be uniformly solubilized while suppressing the decomposition of the compound. Further, when a specific oil agent is contained in such a solubilized composition, a compound represented by the following general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof, which is excellent in usability, is excellent in usability. Is dissolved in an alcohol having 2 to 9 carbon atoms to suppress the decomposition of the compound and prepare a composition having a uniform solubilized form. Further, they have also found that by further containing a specific oil agent in the composition, the feeling of use when used as an external preparation for skin can be improved, and the present invention has been completed.

[式中、Ｒ_１は、カルボキシル基により置換された炭素数１～４の直鎖若しくは分岐のアルキル基、又は炭素数１～４のアルキル鎖を有するカルボン酸エステル基により置換された炭素数１～４の直鎖若しくは分岐のアルキル基を表し、Ｒ_２及びＲ_３は、それぞれ独立
に、炭素数１～４の直鎖又は分岐のアルキル基を表す。]
［２］さらに、水酸基を０～２個有する油剤を含有する、［１］に記載の組成物。
［３］前記アルコールと前記油剤との含有量の質量比が１０：９０～１００：０である、［１］又は［２］に記載の組成物。
［４］実質的に水を含有しない、［１］～［３］のいずれかに記載の組成物。
［５］皮膚外用剤である、［１］～［４］のいずれかに記載の組成物。 That is, the present invention is as follows.
[1] A composition containing a compound represented by the following general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof, and an alcohol having 2 to 9 carbon atoms.

[In the formula, R ₁ has 1 to 4 carbon atoms substituted with a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group, or a carboxylic acid ester group having an alkyl chain with 1 to 4 carbon atoms. Represents a linear or branched alkyl group of to 4, and R ₂ and R ₃ independently represent a linear or branched alkyl group having 1 to 4 carbon atoms. ]
[2] The composition according to [1], further containing an oil agent having 0 to 2 hydroxyl groups.
[3] The composition according to [1] or [2], wherein the mass ratio of the content of the alcohol and the oil is 10:90 to 100: 0.
[4] The composition according to any one of [1] to [3], which does not contain substantially water.
[5] The composition according to any one of [1] to [4], which is an external preparation for skin.

According to the present invention, the hydrolysis of the compound represented by the general formula (1), its isomer and / or a pharmacologically acceptable salt thereof is suppressed, which is chemically stable and uniform. A solubilized form of the composition can be provided. Further, by further containing a specific oil agent in the composition, it is possible to improve the feeling of use when it is used as an external skin preparation.

The composition of the present invention is characterized by containing a compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof, and an alcohol having 2 to 9 carbon atoms. And.

The compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof can be produced, for example, by the method described in JP-A-04-297446.
Since the compound represented by the general formula (1) is an optically active compound having a plurality of asymmetric carbon atoms in its molecular structure, enantiomers and diastereomers are present as its isomers. Further, as the compound represented by the general formula (1) of the present invention, there are a racemate, an enantiomer, a diastereomer, and a compound in which the isomer is mixed at an arbitrary ratio.

Speaking of the compound represented by the general formula (1) of the present invention, in the formula, R ₁ is a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group or an alkyl group having 1 to 4 carbon atoms. Represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxylic acid ester group having an alkyl chain of 1 to 4, and R ₂ and R ₃ are independently linear or branched having 1 to 4 carbon atoms, respectively. Represents the alkyl group of.
Specific examples of preferred _R1 are carboxymethyl group, carboxyethyl group, carboxypropyl group, carboxybutyl group, methoxycarbonylmethyl group, methoxycarbonylethyl group, methoxycarbonylpropyl group, methoxycarbonylbutyl group, and the like. Ethoxycarbonylmethyl group, ethoxycarbonylethyl group, ethoxycarbonylpropyl group, ethoxycarbonylbutyl group, propyloxycarbonylmethyl group, propyloxycarbonylethyl group, propyloxycarbonylpropyl group, propyloxycarbonylbutyl group, butyloxycarbonylmethyl group, Butyloxycarbonylethyl group, butyloxycarbonylpropyl group, butyloxycarbonylbutyl group and the like can be preferably exemplified, and more preferably, carboxymethyl group can be exemplified.
The R ₂ and R ₃ are independent of each other, and specific preferred ones are methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group and tert-. A butyl group and the like can be preferably exemplified, and more preferably, an isopropyl group can be preferably exemplified.

The compound represented by the general formula (1) has a human leukocyte elastase inhibitory activity and is expected to have a therapeutic effect on cerebral ischemic diseases such as cerebral infarction. Further, for example, as described in the pamphlet of International Publication No. 1999/43352, it has a preventive or therapeutic effect on skin aging. In addition, the compound represented by the general formula (1) of the present invention has actions such as the formation of elastic fibers in the papillary line of the dermis, the formation of fine collagen fibers in the dermis region immediately below the epidermis, and the increase in the thickness of the epidermis. However, such an action exerts a preventive or ameliorating effect on wrinkle formation.

The compound represented by the general formula (1) is preferably a compound represented by the following general formula (2).

Regarding the compound represented by the general formula (2) of the present invention, in the formula, R ₄ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group, and R ₅ and R ₆ each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms. The R ₄ represents a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group, and specific preferred examples of the R ₄ are a carboxymethyl group and a 1-carboxyethyl group. 2-carboxyethyl group, 1-carboxypropyl group, 2-carboxypropyl group, 3-carboxypropyl group, 1-carboxybutyl group, 2-carboxybutyl group, 3-carboxybutyl group, 4-carboxybutyl group and the like are preferable. And more preferably, a carboxymethyl group can be preferably exemplified.

The R ₅ and R ₆ each independently represent a linear or branched alkyl group having 1 to 4 carbon atoms, and specific preferred ones with respect to the R ₅ and R ₆ are a methyl group and an ethyl group. N-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group and the like can be preferably exemplified, and more preferably, an isopropyl group can be preferably exemplified. Further, as the compound represented by the general formula (2), 3-[[4- (carboxymethylaminocarbonyl) phenylcarbonyl] -valyl-prolyl] amino-1,1,1-trifluoro-4-methyl -2-oxopentane, N- [4-[[(carboxymethyl) amino] carbonyl] benzoyl] -L-alanyl-N- [3,3,3-trifluoro-1- (1-methyl) -2- Oxopropyl] -L-proline amide, N- [4-[[(carboxyethyl) amino] carbonyl] benzoyl] -L-alanyl-N- [3,3,3-trifluoro-1- (1-methyl) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxypropyl) amino] carbonyl] benzoyl] -L-alanyl-N- [3,3,3-trifluoro-1- (1) -Methyl) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxybutyl) amino] carbonyl] benzoyl] -L-alanyl-N- [3,
3,3-Trifluoro-1- (1-methyl) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxymethyl) amino] carbonyl] benzoyl] -L-alanyl-N- [3,3,3-trifluoro-1- (1-ethyl) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxyethyl) amino] carbonyl] benzoyl] -L-alanyl -N- [3,3,3-trifluoro-1- (1-ethyl) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxypropyl) amino] carbonyl] benzoyl]- L-alanyl-N- [3,3,3-trifluoro-1- (1-ethyl) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxybutyl) amino] carbonyl] Benzoyl] -L-alanyl-N- [3,3,3-trifluoro-1- (1-ethyl) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxymethyl) amino ] Carbonyl] benzoyl] -L-alanyl-N- [3,3,3-trifluoro-1- (1-methylethyl) -2-oxopropyl] -L-proline amide, N- [4-[[( Carboxyethyl) amino] carbonyl] benzoyl] -L-alanyl-N- [3,3,3-trifluoro-1- (1-methylethyl) -2-oxopropyl] -L-proline amide, N- [4 -[[(Carboxypropyl) amino] carbonyl] benzoyl] -L-alanyl-N- [3,3,3-trifluoro-1- (1-methylethyl) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxybutyl) amino] carbonyl] benzoyl] -L-alanyl-N- [3,3,3-trifluoro-1- (1-methylethyl) -2-oxopropyl] -L -Proline amide, N- [4-[[(carboxymethyl) amino] carbonyl] benzoyl] -L-valyl-N- [3,3,3-trifluoro-1- (1-methyl) -2-oxopropyl] ] -L-Prolinamide, N- [4-[[(carboxyethyl) amino] carbonyl] benzoyl] -L-Valyl-N- [3,3,3-trifluoro-1- (1-methyl) -2 -Oxopropyl] -L-proline amide, N- [4-[[(carboxypropyl) amino] carbonyl] benzoyl] -L-valyl-N- [3,3,3-trifluoro-1- (1-methyl) ) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxybutyl) amino] carbonyl] benzoyl] -L-valyl-N- [3,3,3-trifluoro-1- (1) -Methyl) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxymethyl) amino] carbonyl] benzoyl] -L-valyl-N- [3,3,3-trifluoro-1 -(1-Ethyl) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxyethyl) amino] carbonyl] benzoyl] -L-valyl-N- [3,3,3-tri Fluoro-1- (1-ethyl) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxypropyl) amino] carbonyl] benzoyl] -L-valyl-N- [3,3 3-Trifluoro-1- (1-ethyl) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxybutyl) amino] carbonyl] benzoyl] -L-valyl-N- [3 , 3,3-Trifluoro-1- (1-ethyl) -2-oxopropyl] -L-proline amide, N- [4-[[(carboxymethyl) amino] carbonyl] benzoyl] -L-valyl-N -[3,3,3-trifluoro-1- (1-methylethyl) -2-oxopropyl] -L-proline amide (3 (RS) -N- [4-[[(carboxymethyl) amino] carbonyl ] Benzoyl] -L-Valyl-N- [3,3,3-trifluoro-1- (1-methylethyl) -2-oxopropyl] -L-proline amide), N- [4-[[(carboxy) Ethyl) amino] carbonyl] benzoyl] -L-valyl-N- [3,3,3-trifluoro-1- (1-methylethyl) -2-oxopropyl] -L-proline amide, N- [4- [[(Carboxypropyl) amino] carbonyl] benzoyl] -L-valyl-N- [3,3,3-trifluoro-1- (1-methylethyl) -2-oxopropyl] -L-proline amide, N -[4-[[(carboxybutyl) amino] carbonyl] benzoyl] -L-valyl-N- [3,3,3-trifluoro-1- (1-methylethyl) -2-oxopropyl] -L- Proline amide can be preferably exemplified.

Among the compounds represented by the general formula (2), 3-[[4- (carboxymethylaminocarbonyl) phenylcarbonyl] -valyl-prolyl] amino-1,1,1-trifluoro-
4-Methyl-2-oxopentane is more preferably mentioned, and more preferably 3 (RS)-[[4- (carboxymethylaminocarbonyl) phenylcarbonyl] -L-valyl-L represented by the following formula (3). -Prolyl] Amino-1,1,1-trifluoro-4-methyl-2-oxopentane. The compounds contained in the composition of the present invention include the above-mentioned 3 (RS)-[[4- (carboxymethylaminocarbonyl) phenylcarbonyl] -L-valyl-L-prolyl] amino-1,1,1-. A sodium salt of trifluoro-4-methyl-2-oxopentane (hereinafter, also referred to as “KSK32”) is particularly preferable.
In another nomenclature, KSK32 is N- [4-[[(carboxymethyl) amino] carbonyl] benzoyl] -L-valyl-N- [(RS) -3,3,3-trifluoro-1. -(1-Methylethyl) -2-oxopropyl] -L-proline amide, but the same compound.

In the present invention, the compound represented by the general formula (1) can be contained in the composition as it is, but it is treated with a pharmacologically acceptable acid or base to be converted into a salt form and used as a salt. It is also possible to use it. Inorganic acid salts such as hydrochlorides, sulfates, nitrates, phosphates, carbonates; maleate, fumarate, oxalate, citrate, lactate, tartrate, methanesulfonate, para Organic acid salts such as toluene sulfonates and benzene sulfonates; alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as calcium salts and magnesium salts; triethylamine salts, triethanolamine salts, ammonium salts, Examples thereof include organic amine salts such as monoethanolamine salts and piperidine salts, and basic amino acid salts such as lysine salts and arginates.
In addition, the composition of the present invention contains one or more selected from the compounds represented by the general formula (1), their isomers and / or pharmaceutically acceptable salts thereof. be able to.

The content of the compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof in the composition of the present invention is not particularly limited, but is based on the entire composition. It is preferably 0.01 to 10% by mass, more preferably 0.1 to 5% by mass. By containing the compound in such a range, the compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof can easily exert the wrinkle formation preventing or improving effect. ..
It will be possible to fully demonstrate it.

The composition of the present invention comprises solubilizing an alcohol having 2 to 9 carbon atoms with a compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof. It is a thing.
The alcohol is not particularly limited, and is, for example, a monohydric alcohol such as ethanol, 1-propanol, 2-propanol, butyl alcohol, pentanol, hexanol, and heptanol (including structural isomers thereof), glycerin, and diglycerin. , 1,
Polyhydric alcohols such as 3-propanediol, 1,2-hexanediol, ethylene glycol, diethylene glycol, propylene glycol, dipropylene glycol, 1,2-pentanediol, 1,3-butylene glycol, cyclohexyl glycerin and ethylhexyl glycerin are preferred. Can be mentioned. Of these, ethanol is more preferable as the monohydric alcohol, glycerin and 1,2-pentanediol are more preferable as the polyhydric alcohol, and ethanol is particularly preferable.

Since the peptide bond of the compound represented by the general formula (1), its isomer and / or a pharmacologically acceptable salt thereof is easily cleaved by hydrolysis, the composition containing the compound over time. Therefore, there is a problem that the content of the compound is reduced. In response to this problem, the present invention can solubilize the compound and chemically stably blend it into the composition by using the above-mentioned specific alcohol as a solvent.

The content of the alcohol in the composition of the present invention is preferably 10% by mass or more, more preferably 20% by mass or more, still more preferably 30% by mass or more with respect to the entire composition. Within such a range, it becomes easy to uniformly solubilize the compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof.

It is not prevented that the composition of the present invention contains an alcohol other than the alcohol having 2 to 9 carbon atoms, but the content thereof is preferably 20% by mass or less, preferably 10% by mass or less, based on the entire composition. More preferably, 5% by mass or less is further preferable. This is because when an alcohol other than the alcohol having 2 to 9 carbon atoms coexists in an amount of a certain amount or more, the compound represented by the general formula (1), its isomer and / or a pharmacologically acceptable salt thereof. This is because the solubilization of the compound is not hindered, but these are easily hydrolyzed, and the residual amount of the compound in the composition may decrease over time.
Here, examples of alcohols other than alcohols having 2 to 9 carbon atoms include, but are not limited to, monohydric alcohols such as cetyl alcohol and phenoxyethanol, and polyhydric alcohols such as polyethylene glycol and dipropylene glycol.

The compositions of the present invention are usually substantially free of water. Here, "substantially free" means that the content thereof is preferably 1% by mass or less, more preferably 0.5% by mass or less, and further preferably 0.1 by mass with respect to the entire composition. It means that it is mass% or less.
The presence of water in the composition facilitates the hydrolysis of the compounds represented by the general formula (1), their isomers and / or pharmaceutically acceptable salts thereof, and is added to the composition over time. This is because the residual amount of the compound may decrease.

In the composition of the present invention, the residual amount of the compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof in the composition over time is It is expensive. Specifically, for example, the content of the compound after storage at 60 ° C. for 2 weeks is preferably 60% or more, more preferably more than the content of the compound after storage at 5 ° C. for 2 weeks. It is 80% or more, more preferably 90% or more.

Since the composition of the present invention is in a solubilized form, it is usually transparent. In the present specification, transparency can be visually determined qualitatively, and quantitatively, the visible light transmittance (wavelength 600 nm, optical path length 1 cm) measured by a spectrophotometer at 25 ° C. is controlled. When the distilled water of the above is 100, it may be in the range of 70 to 100.

In the composition of the present invention, as described above, the compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof may exert a preventive or ameliorating effect on wrinkle formation. .. In addition, the chemical stability and dispersion stability of the compound in the composition of the present invention with time are excellent. Therefore, the composition of the present invention can be suitably used for external skin preparations, more preferably applied to cosmetics, and particularly preferably applied to anti-aging cosmetics. Here, cosmetics include quasi-drugs.

When the composition of the present invention is used as an external preparation for skin, it is preferable to further contain an oil agent having 0 to 2 hydroxyl groups. Here, the number of hydroxyl groups means the number per molecule. Further, the oil agent is not particularly limited, but an oil agent selected from the group consisting of hydrocarbons, silicones and esters is more preferable.
The composition containing the compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof is sticky, slimy, squeaky, etc. when applied on the skin. Where an unfavorable feel may occur, the feeling of use can be improved / improved by using the above-mentioned oil agent in combination.

The hydrocarbon is not particularly limited, but is preferable from the viewpoint of the chemical stability of the compound represented by the general formula (1), its isomer and / or a pharmacologically acceptable salt thereof. For example, paraffin, isoparaffin, liquid paraffin, α-olefin oligomer, squalane, isododecane, isohexadecane and the like are preferably mentioned.

The silicone is not particularly limited, but those having no or even one hydroxyl group are the compounds represented by the general formula (1), their isomers and / or their pharmacology. It is preferable from the viewpoint of the chemical stability of the salt which is acceptable. For example, polysiloxane, dimethylpolysiloxane, decamethylcyclopentasiloxane, methylpolysiloxane, diphenyldimethicone, dimethiconols and the like are preferably mentioned. Further, it may or may not have a side chain, and may or may not be crosslinked. Further, although not particularly limited, those having a viscosity at 20 ° C. of 1000 cs or less are preferable, more preferably 100 cs or less, still more preferably 10 cs or less.

The ester having 0 to 2 hydroxyl groups is not particularly limited, but a triester of a fatty acid having 6 to 18 carbon atoms and glycerin is preferable, more preferably 6 to 12 carbon atoms, and further preferably 6 to 8 carbon atoms. Is. For example, glyceryl tri2ethylhexanoate, glyceryl triisostearate, cetyl 2-ethylhexenoate, tricapryl-glyceryl caprate, ethylene glycol distearate and the like are preferable.

In the present invention, the oil agent having 0 to 2 hydroxyl groups is usually compatible with alcohols having 2 to 9 carbon atoms, thereby realizing a composition in a solubilized form.
The alcohol having 2 to 9 carbon atoms and the above-mentioned oil agent can be arbitrarily combined, but as a preferable combination, for example, when ethanol, 1,2-pentanediol, or glycerin is used as the alcohol having 2 to 9 carbon atoms, Examples of the oil agent include glyceryl tri2-ethylhexanoate or glyceryl tricaprylcaprate, and more preferably, a combination of ethanol and glyceryl tri2-ethylhexanoate can be mentioned.

The content of the oil agent in the composition of the present invention is preferably 1% by mass or more, more preferably 5% by mass or more, and in such a range, the feeling of use when the composition is used as an external skin preparation. It becomes easy to improve. Further, the upper limit is preferably 90% or less, more preferably 80% or less, still more preferably 70% or less. It becomes easy to uniformly solubilize in such a range.

Further, in the composition of the present invention, the mass ratio of the content of the alcohol having 2 to 9 carbon atoms to the oil agent is preferably 10:90 to 100: 0, more preferably 20:80 to 100: 0, and 30: 70 to 100: 0 is more preferable. In such a range, the feeling of use when the composition is used as an external preparation for skin is improved, and the solubilized form of the composition is easily stabilized.

It is not prevented that the composition of the present invention contains an oil agent having 3 or more hydroxyl groups, but the content thereof is preferably 40% by mass or less, more preferably 20% by mass or less, based on the entire composition. It is more preferably 10% by mass or less. This is because when an oil having a hydroxyl group coexists in an amount of a certain amount or more, the solubilization of the compound represented by the general formula (1), its isomer and / or a pharmacologically acceptable salt thereof is hindered. However, these are easily hydrolyzed, and the residual amount of the compound in the composition may decrease over time.
Here, examples of the oil agent having three or more hydroxyl groups include, but are not limited to, an ester of a fatty acid and polyglycerin, an ester of a fatty acid and a monosaccharide, and an ester of a fatty acid and a polysaccharide.

Since the composition of the present invention is usually in a solubilized form as described above, it can be suitably used as a dosage form for external skin preparations such as lotions and essences that take advantage of its transparent appearance.
Further, the composition of the present invention may be used to produce a composition having a dosage form other than the solubilized form. For example, a compound represented by the general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof solubilized with the alcohol having 2 to 9 carbon atoms is suitable for surface activity. The agent and the oily component may be combined to form an emulsified form, or a dosage form such as a milky lotion or a cream may be used as an external skin preparation. Further, the composition of the present invention may be combined with an insoluble component such as powder to form a dosage form in a dispersed form or a time-to-use dispersion mode.

In the composition of the present invention, in addition to the above-mentioned components, any component used in ordinary skin external preparations can be arbitrarily contained as long as the effect of the present invention is not impaired. Examples of such an optional component include various active ingredients, powders, surfactants, thickeners, ultraviolet absorbers and the like.

Examples of the active ingredient include a whitening ingredient, other wrinkle improving ingredients, an anti-inflammatory ingredient, an animal and plant-derived extract, and the like.
The whitening ingredient is not particularly limited as long as it is generally used in cosmetics. For example, 4-n-butylresorcinol, ascorbic acid glucoside, 3-О-ethylascorbic acid, tranexamic acid, arbutin, ellagic acid, kodiic acid, linoleic acid, nicotinic acid amide, 5,5'-dipropylbiphenyl-2, Examples thereof include 2'-diol, 5'-disodium adenylate, cetyl tranexamic acid, potassium 4-methoxysalicylic acid salt, hydroquinone, pantothenic acid and the like.

The other wrinkle-improving ingredients are not particularly limited as long as they are generally used in cosmetics. For example, nicotinic acid amide, vitamin A or a derivative thereof (retinol, retinal, retinoic acid, retinoin, isotretinoin, tocopherol retinoate, retinol palmitate, retinol acetate, etc.), ursolic acid benzyl ester, ursolic acid phosphate ester, bethuric acid. Examples thereof include benzyl ester and benzylic acid phosphate ester.

The animal and plant-derived extracts are not particularly limited as long as they are generally used in cosmetics. For example, akebi extract, asunaro extract, asparagus extract, avocado extract, amacha extract, almond extract, arnica extract, aloe extract, aronia extract, apricot extract, ginkgo extract, indokino extract, uikyo extract, udo extract, agetsu extract, elephant kogi extract. , Enmeisou extract, Ogon extract, Oubaku extract, Ouren extract, Otaneninjin extract, Otogirisou extract, Odorikosou extract, Orange extract, Kakyoku extract, Kakkon extract, Chamomile extract, Carrot extract, Kawarayomogi extract, Kanzo extract, Kiwi extract, Cucumber extract, Guava extract, Kujin extract, Kuchinashi extract, Kumazasa extract, Clara extract, Walnut extract, Grapefruit extract, Black rice extract, Chlorella extract, Kwa extract, Keiketto extract, Gettoyo extract, Gentiana extract, Gennoshoco extract, Tea extract, Gobo extract, Rice extract, Fermented rice extract, fermented rice bran extract, rice germ oil, kokemomo extract, salvia extract, sabonsou extract, sasa extract, sanzashi extract, sansha extract, sansho extract, shiitake extract, dioe extract, shikon extract, shiso extract, shinanoki extract, shimotsukesou extract, shakuyaku Extract, ginger extract, ginger root extract, white birch extract, sugina extract, stevia extract, stevia fermented product, ginger extract, ginger extract, ginger extract, ginger extract, ginger extract, sage extract, zenia oyster extract, senkyu Extract, Senburi extract, Souhakuhi extract, Daiou extract, Soybean extract, Taiso extract, Thyme extract, Dandelion extract, Tea extract, Chouji extract, Chinpi extract, Jincha extract, Togarashi extract, Touki extract, Tokinsenka extract, Tounin extract, Tohi extract, Dokudami extract , Tomato extract, Natto extract, Carrot extract, Garlic extract, Novara extract, Hibiscus extract, Bakumondou extract, Hass extract, Parsley extract, Birch extract, Hamamelis extract, Hikiokoshi extract, Hinoki extract, Biwa extract, Fukitanpopo extract, Fukinotou extract, Bukuryo extract , Butcher Bloom Extract, Grape Extract, Grape Seed Extract, Hechima Extract, Benibana Extract, Peppermint Extract, Bo Daiju extract, button extract, hop extract, pine extract, mayonara extract, marronnier extract, mizubasho extract, mukuroji extract, melissa extract, mozuku extract, peach extract, yagurumagiku extract, eucalyptus extract, yukinoshita extract, yuzu extract, lily extract, yokunin extract, yomogi extract, lavender Extracts such as extract, green tea extract, apple extract, louisbos tea extract, reishi extract, lettuce extract, lemon extract, lotus extract, lotus extract, rose extract, rosemary extract, Roman chamomile extract, royal jelly extract, and crackle extract are preferable. Can be mentioned.

Examples of the anti-inflammatory component include clarinone, glabridin, glycyrrhizinic acid, glycyrrhetinic acid, pantothenyl alcohol and the like, preferably glycyrrhizinic acid and its salt, alkyl glycyrrhetinate and its salt, and glycyrrhetinic acid and its salt.

As the powders, the surface may be treated, and the surface may be treated with powders such as silica (silicic anhydride), mica, talc, kaolin, synthetic mica, calcium carbonate, magnesium carbonate, aluminum oxide, barium sulfate, etc. May be treated, red iron oxide, black iron oxide, cobalt oxide, ultramarine, dark blue, titanium oxide, zinc oxide inorganic pigments, surface may be treated, mica titanium, fish phosphorus foil, Pearl agents such as bismuth oxychloride, red 202, red 228, red 226, yellow 4, blue 404, yellow 5, red 505, red 230, red 223, which may be raked. No., Orange No. 201, Red No. 213, Yellow No. 204, Yellow No. 203, Blue No. 1, Green No. 201, Purple No. 201, Red No. 204 and other organic pigments, polyester powder, polyamide powder, polyethylene powder, polymethacrylic Examples thereof include organic powders such as methyl acid, nylon powder, and organopolysiloxane elastomer.

Examples of the surfactant include fatty acid sequens (sodium laurate, sodium palmitate, etc.), anionic surfactants such as potassium lauryl sulfate and triethanolamine alkyl sulfate ether, stearyltrimethylammonium chloride, benzalconium chloride, and laurylamine oxide. Cationic surfactants such as, betaine-based surfactants (alkylbetaine, amide betaine, sulfobetaine, etc.), imidazoline-based amphoteric surfactants (2-cocoyl-2-imidazolinium hydroxyside-1-carboxyethyroxy 2) (Sodium salt, etc.), amphoteric surfactants such as acylmethyltaurine,
Solbitan fatty acid esters (sorbitan monostearate, sorbitan sesquioleate, etc.), glycerin fatty acid esters (glyceryl monostearate, etc.), propylene glycol fatty acid esters (propylene glycol monostearate, etc.), hardened castor oil derivative, glycerin alkyl Ether, POE sorbitan fatty acid esters (POE sorbitan monooleate, monostearate polyoxyethylene sorbitan, etc.), POE sorbit fatty acid esters (POE-Sorbit monolaurate, etc.), POE glycerin fatty acid esters (POE-glycerin monoiso) Stearetes, etc.), POE fatty acid esters (polyethylene glycol monooleate, POE distearate, etc.), POE alkyl ethers (POE2-octyldodecyl ether, etc.), POE alkylphenyl ethers (POE nonylphenyl ether, etc.), pluronic types, POE / POP alkyl ethers (POE / POP2-decyltetradecyl ethers, etc.), Tetronics, POE castor oil / hardened castor oil derivatives (POE castor oil, POE cured castor oil, etc.), sucrose fatty acid esters, alkyl glucosides, etc. Non-ionic surfactants, etc. may be mentioned.

As thickeners, guar gum, quince seed, carrageenan, galactan, arabic gum, pectin, mannan, starch, xanthan gum, curdlan, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylhydroxypropylcellulose, chondroitin sulfate, dermatane sulfate, glycogen, Heparan sulphate, hyaluronic acid, sodium hyaluronate, tragant gum, keratane sulphate, chondroitin, mucoitin sulphate, hydroxyethyl guar gum, carboxymethyl guar gum, dextran, keratosulfuric acid, locust bean gum, succinoglucan, caronic acid, chitin, chitosan, carboxymethyl Examples thereof include chitin, agar, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, alkyl-modified carboxyvinyl polymer, sodium polyacrylate, polyethylene glycol, bentonite and the like.

Examples of UV absorbers include paraaminobenzoic acid-based UV absorbers, anthranylic acid-based UV absorbers, salicylic acid-based UV absorbers, cinnamic acid-based UV absorbers, benzophenone-based UV absorbers, sugar-based UV absorbers, 2- (2). Examples thereof include UV absorbers such as'-hydroxy-5'-t-octylphenyl) benzotriazole and 4-methoxy-4'-t-butyldibenzoylmethane.

The composition of the present invention can be produced by treating the essential component, preferable component, arbitrary component and the like according to a conventional method.

Hereinafter, the present invention will be described in more detail with reference to examples, but it goes without saying that the present invention is not limited to such examples.

<Manufacturing example>
The compositions of Examples and Comparative Examples were prepared according to the formulations shown in Table 1 below. That is, all the components were mixed under stirring to obtain a composition in a solubilized form, which was subjected to each test described later.

<Test example>
(1) Evaluation of Decomposition Stability of KSK32 The content of KSK32 after storing each prepared composition at 60 ° C. for 2 weeks was measured, and the content of KSK32 after storing at 5 ° C. for 2 weeks was set to 100. The rate of time (residual rate) was calculated. When the residual rate is 95% or more, the stability against decomposition is ◎, when it is less than 95% and 80% or more, the stability is ○, when it is less than 80% and 60% or more, the stability is Δ, and when it is less than 60%. The stability was evaluated as x. The results are also shown in Table 1.
The content of KSK32 was measured by measuring about 0.5 g of the composition by performing high performance liquid chromatography (HPLC) using a sample solution diluted to 50 mL in the mobile phase.
HPLC conditions are: column; reverse phase column (3.0 × 100 mm), column temperature; room temperature, mobile phase; anionic sulfonic acid type surfactant aqueous solution / THF 25%, pH; 3, flow rate; 0.4 mL / min., Detection; 240 nm).

(2) Evaluation of solubilized state (transparency) After each prepared composition was allowed to stand at room temperature for 1 day, the appearance of the composition was visually observed, and when it was transparent, the dispersion stability was ◎, and it was almost transparent. In some cases, it was evaluated as ◯, in the case of slight cloudiness, it was evaluated as Δ, and in the case of turbidity, it was evaluated as ×. The results are also shown in Table 1.

(3) Evaluation of usability Ten skilled evaluators took an appropriate amount of each prepared composition, evaluated the degree of stickiness when applied to the back of the hand, and the smoothness of the back skin on a four-point scale, and took the average. rice field. The criteria for the 4-grade evaluation were 4 points for good results, 3 points for stickiness or smoothness, 2 points for slightly sticky or lacking smoothness, and 1 point for stickiness or roughness. The results are also shown in Table 1.

The present invention can be applied to external skin preparations such as cosmetics.

Claims (5)

A composition comprising a compound represented by the following general formula (1), an isomer thereof and / or a pharmacologically acceptable salt thereof, and an alcohol having 2 to 9 carbon atoms, wherein the alcohol contains ethanol. thing.

[In the formula, R ₁ has 1 to 4 carbon atoms substituted with a linear or branched alkyl group having 1 to 4 carbon atoms substituted with a carboxyl group, or a carboxylic acid ester group having an alkyl chain with 1 to 4 carbon atoms. Represents a linear or branched alkyl group of to 4, and R ₂ and R ₃ independently represent a linear or branched alkyl group having 1 to 4 carbon atoms. ] The composition according to claim 1, further comprising an oil agent having 0 to 2 hydroxyl groups. The composition according to claim 1 or 2, wherein the mass ratio of the content of the alcohol and the oil is 10:90 to 100: 0. The composition according to any one of claims 1 to 3, wherein the content of water is 1% by mass or less with respect to the entire composition. The composition according to any one of claims 1 to 4, which is an external preparation for skin.