JP2016027035A - Composition for skin external application, cosmetics and method for preventing discoloration of composition for skin external application - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a composition for skin external application and others that sufficiently prevent the discoloration resulting from an antioxidant that discolors with time.SOLUTION: A composition for skin external application comprises a lipid peptide represented by the formula (1) and/or a pharmacologically acceptable salt thereof, a polyhydric alcohol and/or a glycol ether, and an antioxidant that discolors with time. In the formula, R-Reach represent a predetermined group, and m is an integer of 1 to 3.SELECTED DRAWING: None

Description

  The present invention relates to a skin external composition, a cosmetic, and a method for suppressing discoloration of the skin external composition.

  Cosmetics that cleanse, beautify, enhance appeal, change appearance, or keep skin or hair healthy by blending various active ingredients into various external compositions such as cosmetics In addition to the basic action, it is possible to give the composition various functions.

  Among various active ingredients, antioxidants typified by vitamin C (ascorbic acid) are components that can extend the expiration date of the composition by antioxidant action, such as removal of active oxygen generated by ultraviolet rays, etc. Since it has a useful effect on the skin, it has been widely used in conventional cosmetics. In addition, for example, there are antioxidants having useful actions other than the antioxidant action, such as vitamin C having a collagen production promoting action.

  However, some antioxidants discolor over time. For example, vitamin C is discolored by being decomposed by heat or light. This discoloration is particularly problematic when trying to formulate it in large quantities to increase the effectiveness of the antioxidant.

  If the ascorbic acid is dissolved in a raw material other than glycerin, the ascorbic acid becomes unstable, and the amount of the ascorbic acid cannot be increased, so that it may precipitate in cosmetics (see Patent Document 1). ).

  Both the problem of discoloration and the problem of precipitation described above are fatal problems in products such as cosmetics where appearance is important.

  Regarding the stability of vitamin C, Patent Document 2 describes that vitamin C can be stably solubilized by blending low molecular weight betaine and glycol ethers such as ethoxydiglycol into vitamin C. ing. However, solubilization and discoloration are completely different issues.

  Patent Document 3 discloses a cosmetic containing a low molecular weight lipid peptide represented by the following formula.

  In the examples of this document, cosmetics containing ascorbic acid 2-glucoside, glycerin and palmitoylglycylhistidine (free form) are prepared. However, ascorbic acid 2-glucoside is a substance that is different from an antioxidant that changes color over time, and in this document, the low-molecular-weight lipid peptide is an antioxidant that colors over time, such as vitamin C. There is no disclosure or suggestion of using it to prevent the resulting discoloration.

JP 2006-111554 A JP 2005-225865 A WO2011 / 052613 Publication

  When the present inventors examined the problem of the discoloration of the antioxidant, it was found that vitamin C was solved to some extent by adding a large amount of glycol ethers. However, when glycol ethers are blended in a large amount, they have a high moisturizing power, so that the feeling of use may be impaired depending on the usage situation.

  On the other hand, if, for example, the blending amount of glycol ethers is reduced and other components such as water are increased in order to ensure a good feeling of use, the problem of the discoloration of the antioxidant that discolors over time cannot be solved.

  In view of such problems, the present invention provides a composition for external use for skin, in which discoloration derived from an antioxidant that changes color over time (hereinafter also referred to as a time-varying antioxidant) is sufficiently suppressed. With the goal.

  Desirably, an object of the present invention is to provide an external composition for skin, etc. in which discoloration derived therefrom is sufficiently suppressed while a large amount of a time-varying antioxidant is blended.

  More desirably, the present invention has an object to provide a composition for external use on skin, in which discoloration derived from a time-varying antioxidant is sufficiently suppressed while the blending amount of glycol ethers or the like is reduced.

  As a result of intensive studies to solve the above problems, the present inventors have used polyhydric alcohol and / or glycol ethers together with a predetermined lipid peptide and / or a pharmaceutically acceptable salt thereof, It has been found that discoloration derived from a time-varying antioxidant can be sufficiently suppressed, and the present invention has been completed.

  That is, the gist of the present invention is as follows.

  <1> Skin containing a lipid peptide represented by the following formula (1) and / or a pharmaceutically acceptable salt thereof, a polyhydric alcohol and / or glycol ether, and an antioxidant that changes color over time. Topical composition:

Wherein R ¹ represents an aliphatic group having 9 to 23 carbon atoms, and R ² and R ³ are each independently a hydrogen atom, a methyl group, an ethyl group, or a branched chain having 1 to 3 carbon atoms. Represents an alkyl group having 3 to 7 carbon atoms, a phenylmethyl group, a phenylethyl group, or a — (CH ₂ ) _n —X group, and at least one of R ^{2 and} R ³ is — (CH ₂ ) _n- X group, wherein n is an integer of 1 to 4, and X is an amino group, a guanidino group, a carbamoyl group, or a 5-membered or 6-membered ring group that may have 1 to 3 nitrogen atoms Or, it represents a condensed ring group composed of a 5-membered ring and a 6-membered ring, m is an integer of 1 to 3, and when m is 2 or more, a plurality of R ² may be the same or different from each other.

<2> The external composition for skin according to <1>, wherein in formula (1), R ² represents a hydrogen atom, a methyl group, an i-propyl group, an i-butyl group, or a sec-butyl group.

<3> In the formula (1), R ¹ represents an aliphatic group having 13 to 17 carbon atoms, R ² represents a hydrogen atom, a methyl group, or an i-propyl group, and R ³ represents 4-aminobutyl. The external composition for skin according to <1> or <2>, which represents a group, a 4-imidazolmethyl group, or a 3-methylindole group.

  <4> The external composition for skin according to any one of <1> to <3>, wherein the antioxidant that changes color over time is water-soluble or oil-soluble.

  <5> The external composition for skin according to any one of <1> to <4>, wherein the content of the antioxidant that changes color with time in the external composition for skin is 3 to 30% by weight.

  <6> The external composition for skin according to any one of <1> to <5>, wherein the content of the polyhydric alcohol and / or glycol ether in the external composition for skin is 5 to 90% by weight.

  <7> The polyhydric alcohol and / or glycol ether is at least one selected from the group consisting of ethoxydiglycol, dipropylene glycol, 1,3-butylene glycol, propylene glycol and glycerin, <1> to <1. 6> The composition for external use in skin.

  <8> Any one of <1> to <7>, wherein the antioxidant that changes color with time is at least one selected from the group consisting of vitamin C, hydroquinone, arbutin, astaxanthin, dibutylhydroxytoluene, and coenzyme Q10. The composition for external application to skin.

  <9> A cosmetic comprising the external composition for skin according to any one of <1> to <8>.

  <10> A composition for external use containing an antioxidant that changes color over time, a lipid peptide represented by the following formula (1) and / or a pharmaceutically acceptable salt thereof, a polyhydric alcohol and / or glycol: A method for suppressing discoloration of a composition for external use of skin, which comprises an ether

Wherein R ¹ represents an aliphatic group having 9 to 23 carbon atoms, and R ² and R ³ are each independently a hydrogen atom, a methyl group, an ethyl group, or a branched chain having 1 to 3 carbon atoms. Represents an alkyl group having 3 to 7 carbon atoms, a phenylmethyl group, a phenylethyl group, or a — (CH ₂ ) _n —X group, and at least one of R ^{2 and} R ³ is — (CH ₂ ) _n- X group, wherein n is an integer of 1 to 4, and X is an amino group, a guanidino group, a carbamoyl group, or a 5-membered or 6-membered ring group that may have 1 to 3 nitrogen atoms Or, it represents a condensed ring group composed of a 5-membered ring and a 6-membered ring, m is an integer of 1 to 3, and when m is 2 or more, a plurality of R ² may be the same or different from each other.

  ADVANTAGE OF THE INVENTION According to this invention, the skin external composition etc. in which the discoloration derived from a time-dependent discoloration antioxidant was fully suppressed are provided.

It is a figure which shows (DELTA) E * ab increase rate of the composition of Examples 1-3 and Comparative Examples 1-3 after a storage at 40 degreeC in an Example. In an Example, it is a figure which shows (DELTA) E * ab increase rate of the composition of Examples 1-3 and Comparative Examples 1-3 after storage at 50 degreeC. In an Example, it is a figure which shows (DELTA) E * ab increase rate of the composition of Examples 1-3 and Comparative Examples 1-3 after storage at 60 degreeC. It is a figure which shows (DELTA) E * ab increase rate of the composition of Example 4 and the comparative example 4 after storage at various temperatures in an Example. It is a figure which shows (DELTA) E * ab increase rate of the composition of Example 5 and the comparative example 5 after storage at various temperatures in an Example. It is a figure which shows (DELTA) E * ab increase rate of the composition of Examples 6-9 and Comparative Examples 6-9 after storage in various temperatures in an Example. It is a figure which shows (DELTA) E * ab increase rate of the composition of Example 10 and the comparative example 10 after storage at various temperatures in an Example. In an Example, it is a figure which shows (DELTA) E * ab increase rate of the composition of the comparative examples 3 and 11 after storage at 60 degreeC.

  Hereinafter, the external composition for skin and the cosmetics of the present invention will be described in detail.

[Skin external composition]
The composition for external use of the skin of the present invention has an anti-lipid composition and / or a pharmaceutically acceptable salt thereof represented by the above formula (1), a polyhydric alcohol and / or glycol ether, and an anti-coloring property that changes with time. And an oxidizing agent. Hereinafter, these essential components and other components that can be contained in the composition will be described.

<Lipid peptide and / or pharmaceutically acceptable salt thereof>
The lipid peptide used in the present invention is a compound composed of a lipid portion of R ¹ CO represented by the following formula (1) and a peptide portion on the right side in the formula (1).

  This compound has high biocompatibility and safety, and when applied, it stretches on the surface of the skin and hair, and is familiar to the skin and hair, and there is no stickiness and no kinking after application. In the case of a dosage form such as liquid or sol which has been improved, it has been developed as a gelling agent capable of providing a cosmetic without dripping at the time of application. Recently, the present inventors have examined the present compound and found that the present compound has a function of suppressing discoloration derived from a time-varying antioxidant due to a synergistic action with a polyhydric alcohol or a glycol ether. It was.

(About R ¹ )
In the formula (1), R ¹ represents an aliphatic group having 9 to 23 carbon atoms, and preferably an aliphatic group having 13 to 17 carbon atoms.

Examples of the lipid moiety composed of R ¹ and the adjacent carbonyl group include a decoyl group, a dodecoyl group, an undecoyl group, a lauroyl group, a dodecylcarbonyl group, a myristoyl group, a tetradecylcarbonyl group, a palmitoyl group, a margaroyl group, and oleoyl. Group, elidoyl group, linoleoyl group, stearoyl group, baccenoyl group, octadecylcarbonyl group, arachidonoyl group, icosanoyl group, behenoyl group, elcoyl group, docosylcarbonyl group, lignocelloyl group, nerbonoyl group, etc., preferably Examples include myristoyl group, tetradecylcarbonyl group, palmitoyl group, margaroyl group, oleoyl group, eridoyl group, linoleoyl group, stearoyl group, and vaccenoyl group.

Among these, a palmitoyl group is particularly preferable as R ¹ CO from the viewpoint of the ease of production of lipid peptides and the effect of suppressing discoloration derived from a time-varying antioxidant.

(About R ² and R ³ )
In the above formula (1), R ² and R ³ are each independently a hydrogen atom, a methyl group, an ethyl group, or an alkyl group having 3 to 7 carbon atoms which may have a branched chain having 1 to 3 carbon atoms, It represents a phenylmethyl group, a phenylethyl group, or a — (CH ₂ ) _n —X group, and at least one of R ² or R ³ represents a — (CH ₂ ) _n —X group.

  In the alkyl group having 3 to 7 carbon atoms, the number of carbon atoms includes the number of branched carbon atoms that the alkyl group may have.

In addition, with respect to the — (CH ₂ ) _n —X group, n is an integer of 1 to 4, and X is an amino group, a guanidino group, a carbamoyl group, or a 5-membered cyclic group that may have 1 to 3 nitrogen atoms. Alternatively, it represents a 6-membered ring group or a condensed ring group composed of a 5-membered ring and a 6-membered ring. When a plurality of R ² and R ³ are — (CH ₂ ) _n —X groups, the plurality of n are independent from each other, and the plurality of X are also independent from each other.

From the viewpoint of the effect of suppressing discoloration derived from the time-varying antioxidant, R ² is preferably a hydrogen atom, a methyl group, an ethyl group, or the number of carbon atoms that can have a branched chain having 1 to 3 carbon atoms. Represents 3 to 7 alkyl groups; Therefore, R ² is preferably a hydrogen atom, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, an n-butyl group, an i-butyl group, a sec-butyl group, or a tert-butyl group, More preferred is a hydrogen atom, methyl group, i-propyl group, i-butyl group, or sec-butyl group, even more preferred is a hydrogen atom, methyl group, or i-propyl group, and most preferred is hydrogen. Is an atom.

From the viewpoint of the effect of suppressing discoloration derived from the time-varying antioxidant, R ³ preferably represents a hydrogen atom, a methyl group, or a — (CH ₂ ) _n —X group, and n represents an integer of 1 to 4. , X represents an amino group, a guanidino group, a carbamoyl group, or a 5-membered ring group or a 6-membered ring group which can have 1 to 3 nitrogen atoms, or a condensed ring group composed of a 5-membered ring and a 6-membered ring.

From the same viewpoint, R ³ is preferably a — (CH ₂ ) _n —X group, and X is preferably an amino group, guanidino group, carbamoyl group, pyrrole group, imidazole group, pyrazole group or indole group. Accordingly, the — (CH ₂ ) _n —X group is preferably an aminomethyl group, 2-aminoethyl group, 3-aminopropyl group, 4-aminobutyl group, carbamoylmethyl group, 2-carbamoylethyl group, 3- Carbamoylpropyl group, 2-guanidinoethyl group, 3-guanidinopropyl group, pyrrolemethyl group, 4-imidazolemethyl group, pyrazolemethyl group or 3-indolemethyl group, more preferably 4-aminobutyl group, carbamoylmethyl group , Carbamoylethyl group, 3-carbamoylpropyl group, 4-imidazolemethyl group or 3-indolemethyl group, more preferably 4-aminobutyl group, 4-imidazolemethyl group or 3-methylindole group, and more More preferred is a 4-imidazolemethyl group.

(About m)
In the formula (1), the number m of repeating units derived from amino acids constituting the peptide structure is an integer of 1 to 3. When m is 2 or more, a plurality of R ² are independent of each other. Further, m is preferably 1 from the viewpoint of the effect of suppressing discoloration derived from the time-varying antioxidant.

(Lipid peptide)
The compound useful in the present invention as the lipid peptide described above is a compound formed from the following lipid part and peptide part. The abbreviations of amino acids are asparagine (Asn), alanine (Ala), glutamine (Gln), glycine (Gly), valine (Val), histidine (His), lysine (Lys), and leucine (Leu). : Myristoyl-Gly-His, myristoyl-Gly-Lys, myristoyl-Gly-Asn, myristoyl-Gly-Gln, myristoyl-Gly-Gly-His, myristoyl-Gly-Gly-Lys, myristoyl-Gly-Gly-Asn, -Gly-Gly-Gln, Myristoyl-Gly-Gly-Gly-His, Myristoyl-Gly-Gly-Gly-Lys, Myristoyl-Gly-Gly-Gly-Asn, Myristoyl-Gly-Gly-Gly-Gln, Myristoyl-Aln -His, Myristoyl-Ala-Lys, Myristoyl-Ala-Asn, Myristoyl-Ala-Gln, Myristoyl-Ala-Ala-His, Myristoyl-Ala-Ala-Lys, Myristoyl Ala-Ala-Asn, Myristoyl-Ala-Ala-Gln, Myristoyl-Ala-Ala-Ala-His, Myristoyl-Ala-Ala-Ala-Lys, Myristoyl-Ala-Ala-Ala-Asn, Myristoyl-Ala-Ala- Ala-Gln, Myristoyl-Val-His, Myristoyl-Val-Lys, Myristoyl-Val-Asn, Myristoyl-Val-Gln, Myristoyl-Val-Val-His, Myristoyl-Val-Val-Lys, Myristoyl-Val-Val- Asn, Myristoyl-Val-Val-Gln, Myristoyl-Val-Val-Val-His, Myristoyl-Val-Val-Val-Lys, Myristoyl-Val-Val-Val-Asn, Myristo Le-Val-Val-Val-Gln, Myristoyl-Leu-His, Myristoyl-Leu-Lys, Myristoyl-Leu-Asn, Myristoyl-Leu-Gln, Myristoyl-Leu-Leu-His, Myristoyl-Leu-Leu-Lys, Myristoyl-Leu-Leu-Asn, Myristoyl-Leu-Leu-Leu-His, Myristoyl-Leu-Leu-Leu-Asn, Myristoyl-Leu-Leu-Leu-Asn, Myristoyl-Leu-Leu-Asn Leu-Leu-Gln;
Palmitoyl Gly-His, Palmitoyl Gly-Lys, Palmitoyl Gly-Asn, Palmitoyl Gly-Gln, Palmitoyl Gly-Gly-His, Palmitoyl Gly-Gly-Lys, Palmitoyl Gly-Gly-Gly-Gyl -Gly-Gly-His, Palmitoyl Gly-Gly-Gly-Lys, Palmitoyl Gly-Gly-Gly-Asn, Palmitoyl Gly-Gly-Gly-Gln, Palmitoyl Ala-His, Palmitoyl Ala-Lys, Palmitoyl Alys Ala-Gln, Palmitoyl Ala-Ala-His, Palmitoyl Ala-Ala-Lys, Palmitoyl Ala-Ala-Asn, Palmitoyl A a-Ala-Gln, Palmitoyl Ala-Ala-Ala-His, Palmitoyl Ala-Ala-Ala-Lys, Palmitoyl Ala-Ala-Ala-Asn, Palmitoyl Ala-Ala-Ala-Gln, Palmitoyl Val-His, Palmitoyl Val- Lys, Palmitoyl Val-Asn, Palmitoyl Val-Gln, Palmitoyl Val-Val-His, Palmitoyl Val-Val-Lys, Palmitoyl Val-Val-Asn, Palmitoyl Val-Val-Gln, Palmitoyl Val-Val-Val-His Val-Val-Val-Lys, Palmitoyl Val-Val-Val-Asn, Palmitoyl Val-Val-Val-Gln, Palmitoyl Leu-His, Palmito Leu-Lys, Palmitoyl Leu-Asn, Palmitoyl Leu-Gln, Palmitoyl Leu-Leu-His, Palmitoyl Leu-Leu-Lys, Palmitoyl Leu-Leu-Asn, Palmitoyl Leu-Leu-Leu-Lil His, Palmitoyl Leu-Leu-Leu-Lys, Palmitoyl Leu-Leu-Leu-Asn, Palmitoyl Leu-Leu-Leu-Gln;
Stearoyl Gly-His, Stearoyl Gly-Lys, Stearoyl Gly-Asn, Stearoyl Gly-Gln, Stearoyl Gly-Gly-His, Stearoyl Gly-Gly-Lys, Stearoyl Gly-Gly-Asn, Stearoyl Gly-Gly-Gly-Gly-Gly-Gly-Gyl -Gly-Gly-His, stearoyl Gly-Gly-Gly-Lys, stearoyl Gly-Gly-Gly-Asn, stearoyl Gly-Gly-Gly-Gln, stearoyl Ala-His, stearoyl Ala-Lys, stearoyl Ala-Asyl Ala-Gln, stearoyl Ala-Ala-His, stearoyl Ala-Ala-Lys, stearoyl Ala-Ala-Asn, stearoyl A a-Ala-Gln, stearoyl Ala-Ala-Ala-His, stearoyl Ala-Ala-Ala-Lys, stearoyl Ala-Ala-Ala-Asn, stearoyl Ala-Ala-Ala-Gln, stearoyl Val-His, stearoyl Val- Lys, stearoyl Val-Asn, stearoyl Val-Gln, stearoyl Val-Val-His, stearoyl Val-Val-Lys, stearoyl Val-Val-Asn, stearoyl Val-Val-Gln, stearoyl Val-Val-Val-His, stearoyl Val-Val-Val-Lys, Stearoyl Val-Val-Val-Asn, Stearoyl Val-Val-Val-Gln, Stearoyl Leu-His, Stearo Leu-Lys, stearoyl Leu-Asn, stearoyl Leu-Gln, stearoyl Leu-Leu-His, stearoyl Leu-Leu-Lys, stearoyl Leu-Leu-Asn, stearoyl Leu-Leu-Gle, stearoyl Leu-Leu-Leu-Leu-LuLeu His, stearoyl Leu-Leu-Leu-Lys, stearoyl Leu-Leu-Leu-Asn, stearoyl Leu-Leu-Leu-Gln.

  Among these, myristoyl-Gly-His, myristoyl-Gly-Gly-His, myristoyl-Gly-Gly-His, palmitoyl-Gly-His, palmitoyl-Gly-Gly-His, palmitoyl-Gly-Gly -Gly-His, stearoyl-Gly-His, stearoyl-Gly-Gly-His, stearoyl-Gly-Gly-Gly-His. Of these, palmitoyl-Gly-His is most preferable.

(Pharmaceutically acceptable salt of lipid peptide)
The composition for external use of the skin of the present invention contains the lipid peptide described above and / or a pharmaceutically acceptable salt thereof. Examples of the salt include a lithium salt, a salt corresponding to the carboxyl group of the lipid peptide, When the alkali metal salt and alkaline earth metal salt such as sodium salt, potassium salt, calcium salt and the like are a group having a nitrogen atom such as a group having an imidazole structure, for example, R ³ is a hydrochloride corresponding to it. And inorganic acid salts and organic acid salts such as acetate, sulfate, carbonate, phosphate, citrate and succinate.

(Method for producing lipid peptide and pharmaceutically acceptable salt thereof)
The production method of the lipid peptide and the pharmaceutically acceptable salt thereof described above is known. For example, by peptide solid phase synthesis, amino acids are formed in the direction from the C-terminal to the N-terminal of the amino acids constituting the lipid peptide. Ligating and reacting the N-terminus of the amino acid at the terminal position with respect to the solid phase with a fatty acid (eg, myristic acid, palmitic acid, stearic acid) as a lipid moiety, and if necessary, of the salt It can manufacture by setting it as a form.

  In addition, by starting with fatty acids and reacting them with amino acids by the liquid phase method, the amino acids are linked in the direction from the N-terminus to the C-terminus of the amino acids, and if necessary, in the form of a salt Lipid peptides and pharmaceutically acceptable salts thereof can be prepared.

(Contents of lipid peptides and pharmaceutically acceptable salts thereof)
The composition for external use of the skin of the present invention contains the lipid peptide and / or a pharmaceutically acceptable salt thereof described above, and the content thereof is generally 0. 0% in the entire composition for external use of the skin (100% by weight). From the viewpoint of the effect of suppressing discoloration derived from the time-varying antioxidant, it is preferably from 0.001 to 8% by weight, more preferably from 0.01 to 5% by weight. Most preferably, it is 0.5 to 5% by weight. In particular, when the content of the lipid peptide and its pharmaceutically acceptable salt is 0.5 to 5% by weight, the discoloration suppressing effect is remarkable, and the gelation state by the component is very good. Become.

  In the present invention, lipid peptides and / or pharmaceutically acceptable salts thereof may be used singly or in combination of two or more.

<Polyhydric alcohol and / or glycol ethers>
The skin external composition of the present invention contains a polyhydric alcohol and / or glycol ether, and conventionally known components corresponding to these can be used in the present invention without any particular limitation.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that polyhydric alcohol in addition to glycol ethers can be used in combination with the lipid peptide and / or pharmaceutically acceptable salt thereof over time. It has been found that the discoloration derived from the discoloration antioxidant can be sufficiently suppressed.

As said polyhydric alcohol, C2-C6 and a C2-C4 polyhydric alcohol can be used, for example. Specifically, for example, ethylene glycol, propylene glycol, 1,3-propanediol (trimethylene glycol), 1,2-butylene glycol, 1,3-butylene glycol, 2,3-butylene glycol, 1,4- Butanediol (tetramethylene glycol), 2-butene-1,4-diol, 1,5-pentanediol (pentamethylene glycol), 1,2-pentanediol, isoprene glycol (isopentyldiol), hexylene glycol, diethylene glycol And dihydric alcohols such as dipropylene glycol;
And trihydric alcohols such as glycerin and trimethylolpropane; and tetrahydric alcohols such as diglycerin, pentaerythritol, and 1,2,6-hexanetriol.

  Among these, 1,3-butylene glycol and 1,2-pentane are used from the viewpoint of the effect of suppressing discoloration derived from a time-varying antioxidant by the combined use with a lipid peptide and / or a pharmaceutically acceptable salt thereof. Diol, dipropylene glycol, propylene glycol and glycerin are preferable, and 1,3-butylene glycol, 1,2-pentanediol, dipropylene glycol and propylene glycol are more preferable.

  Examples of the glycol ethers include diethylene glycol monomethyl ether, diethylene glycol monoethyl ether (ethoxydiglycol), diethylene glycol monopropyl ether, diethylene glycol monobutyl ether, diethylene glycol monoisobutyl ether, diethylene glycol dimethyl ether, ethylene glycol monobutyl ether, ethylene glycol monomethyl ether, ethylene glycol. Monoethyl ether, triethylene glycol monobutyl ether, tetraethylene glycol monobutyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, propylene glycol monopropyl ether, dipropylene glycol monomethyl ether, Propylene glycol monoethyl ether, dipropylene glycol monopropyl ether and the like.

Among these, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether (ethoxydiethyl ether) are preferred from the viewpoint of suppressing the discoloration derived from the time-varying antioxidant due to the combined use with lipid peptides and / or pharmaceutically acceptable salts thereof. Glycol), diethylene glycol monopropyl ether, diethylene glycol monobutyl ether, diethylene glycol monoisobutyl ether, diethylene glycol dimethyl ether, ethylene glycol monobutyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, triethylene glycol monobutyl ether, tetraethylene glycol monobutyl ether, propylene glycol Monomethyl ether, propylene glycol Bruno ethyl ether, propylene glycol monopropyl ether, dipropylene glycol monomethyl ether, dipropylene glycol monoethyl ether, dipropylene glycol monopropyl ether,
More preferably, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether (ethoxydiglycol), diethylene glycol monopropyl ether, ethylene glycol monobutyl ether, triethylene glycol monobutyl ether, tetraethylene glycol monobutyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether , Propylene glycol monopropyl ether, dipropylene glycol monomethyl ether, dipropylene glycol monoethyl ether, dipropylene glycol monopropyl ether,
More preferred is diethylene glycol monoethyl ether (ethoxydiglycol).

  The polyhydric alcohols and / or glycol ethers described above are ethoxydiglycol from the viewpoint of the effect of suppressing discoloration derived from a time-varying antioxidant due to the combined use with a lipid peptide and / or a pharmaceutically acceptable salt thereof. 1,3-butylene glycol, dipropylene glycol, propylene glycol and glycerin are more preferable, and ethoxydiglycol is particularly preferable.

  The content of the polyhydric alcohol and / or glycol ether described above in the external composition for skin of the present invention is not particularly limited, but the content is usually the external composition for skin of the present invention (100 wt. %) In total is 4% by weight or more, preferably 5% by weight or more, more preferably 10% by weight or more, and still more preferably 20% by weight or more. Moreover, the said content in the whole skin external composition of this invention (100 weight%) is 90 weight% or less normally in total, 85 weight% or less is preferable, and 80 weight% or less is more preferable.

  In the present invention, the combination of polyhydric alcohol and / or glycol ether and lipid peptide and / or pharmaceutically acceptable salt thereof is derived from the time-varying antioxidant even if the former compounding amount is reduced. It is possible to sufficiently suppress discoloration.

  Therefore, in this invention, when it mix | blends abundantly, the compounding quantity of glycol ethers which may impair the usability | use_condition of the composition for external use for skin can be restrained low. Specifically, the content of glycol ethers in the external composition for skin (100% by weight) of the present invention can be preferably 60% by weight or less, more preferably 55% by weight or less. Even more preferably, it can be 50% by weight or less. If it is such a range, the favorable use feeling of the composition for external skin can be ensured, suppressing the discoloration derived from a time-dependent discoloration antioxidant. In addition, the lower limit of content of glycol ethers is the same as the above.

<Antioxidant that changes color over time>
The composition for external use of the skin of the present invention contains an antioxidant that changes color with time (time-changing antioxidant), and is excellent in antioxidant properties. This time-varying antioxidant is a component that changes color due to deterioration due to heat or light, etc., but in the present invention, the predetermined lipid peptide described above and / or a pharmaceutically acceptable salt thereof, a polyhydric alcohol, and The discoloration is sufficiently suppressed by the combined use with glycol ethers.

  The time-discoloring antioxidant is not particularly limited as long as it is an antioxidant that changes color due to deterioration due to some cause as described above. Further, “discoloration” means that the color changes, and includes fading. Moreover, such a discoloration appears as a change in the color of the appearance of the entire skin external composition, and can be confirmed with the naked eye, and can also be confirmed as a predetermined parameter change as in the examples described later.

  The time-varying antioxidant may be water-soluble or oil-soluble. Examples of water-soluble color-changing antioxidants include vitamin C (ascorbic acid), hydroquinone and arbutin. Examples of oil-soluble time-varying antioxidants include astaxanthin, dibutylhydroxytoluene, and coenzyme Q10. Among these, water-soluble ones are low in toxicity, and water-soluble time-varying antioxidants are preferable.

  The content of the time-varying antioxidant in the external composition for skin of the present invention is not particularly limited, but lipid peptides and / or pharmaceutically acceptable salts thereof, polyhydric alcohols and / or glycol ethers, Since the discoloration-suppressing effect by the combined use is extremely high, in the present invention, a high-concentration composition for external skin can be obtained by blending a large amount of a time-varying antioxidant to enhance its function.

  Specifically, the content of the time-varying antioxidant in the external composition for skin (100% by weight) of the present invention is usually 0.1% by weight or more, preferably 3% by weight or more, preferably 5% by weight. % Or more is more preferable, and 10% by weight or more is even more preferable. In addition, the total content of the composition for external skin (100% by weight) of the present invention is preferably 30% by weight or less, more preferably 25% by weight or less, and even more preferably 20% by weight or less.

  Also, some time-varying antioxidant derivatives do not change over time. In the composition for external use of the skin of the present invention, the time-varying antioxidant may be formulated as such a derivative and may be derived from the derivative. In this case, the derivative liberates a time-varying anti-oxidant, for example, after a certain period of time, or is converted into it.

And in the present invention,
(1) A time-varying antioxidant produced by the liberation or conversion alone, or (2) a time-changing antioxidant produced by the liberation or conversion, and a time-varying antioxidant mixed separately. Is the sum,
It should be present in an amount that causes the topical skin composition to discolor over time.

  In the external composition for skin of the present invention, the above-described discoloration is sufficiently suppressed because the lipid peptide and / or pharmaceutically acceptable salt thereof described above and a polyhydric alcohol and / or glycol ether are blended. Is done.

<Other ingredients>
The composition for external use of the skin of the present invention contains the lipid peptide and / or pharmaceutically acceptable salt thereof described above, a polyhydric alcohol and / or glycol ether, and a time-varying antioxidant, and various others. Antibacterial ingredients, anti-inflammatory ingredients, anti-inflammatory analgesic ingredients, antipruritic ingredients, vitamins, local anesthetic ingredients, moisturizing ingredients, whitening ingredients, anti-aging ingredients other than time-varying antioxidants, anti-aging ingredients, keratin softness Ingredients, cell activation ingredients, blood circulation promoting ingredients, ingredients that prevent and / or repair DNA damage, UV absorbing ingredients, UV scattering ingredients, cleaning ingredients, astringent ingredients, hair growth ingredients, antihistamine ingredients, antiseptic ingredients, etc. Other components may be included as long as the effects of the present invention are not impaired. In addition, although the substance applicable to a time-varying antioxidant in the other component is also mentioned, these are a time-varying antioxidant and also show various actions as other components.

  In addition, these other components may be used individually by 1 type, or may be used in combination of 2 or more type, and the compounding quantity is suitably selected from the range well-known to those skilled in the art. Moreover, what corresponds to the following several components, and the thing applicable also to the base and support | carrier mentioned later show an effect | action as the various various components in this invention. In addition, when the quantity which functions as various components is not mix | blended, the effect | action as all applicable components may not be show | played.

  Examples of the antibacterial component include terbinafine and its salt, butenafine and its salt, sulconazole nitrate, luliconazole, miconazole, amorolfine hydrochloride, clotrimazole, ketoconazole, bifonazole, neticoconate hydrochloride, lanonaconazole, riranaphthate, efinaconazole, chlorhexidine chloride, Benzalkonium, Acrinol, Ethanol, Benzethonium chloride, Cresol, Gluconic acid and its derivatives, Popidone iodine, Potassium iodide, Iodine, Isopropylmethylphenol, Triclosan, Triclosan, Photosensitizer 101, Photosensitizer 201, Paraben, Phenoxyethanol, And alkyldiaminoglycine hydrochloride and the like. Among these, terbinafine and its salts, butenafine and its salts, benzalkonium chloride, benzethonium chloride, gluconic acid and its derivatives, isopropylmethylphenol, triclocarban, triclosan, photosensitizer 101, photosensitizer 201, paraben, phenoxyethanol And terbinafine and its salts, butenafine and its salts, benzalkonium chloride, gluconic acid and its derivatives, benzethonium chloride, and isopropylmethylphenol.

  Examples of the anti-inflammatory component include a component derived from a plant (for example, Comfrey); allantoin, calamine, glycyrrhizic acid or a derivative thereof, glycyrrhetinic acid or a derivative thereof, zinc oxide, guaiazulene, pyridoxine hydrochloride, and turpentine oil. It is done. Among these, Comfrey leaf extract, allantoin, dipotassium glycyrrhizinate, and stearyl glycyrrhetinate are preferable.

  Examples of the anti-inflammatory analgesic component include: indomethacin; felbinac; ibuprofen; ibuprofen piconol; bufexamac; butyl flufenamate; bendazac; piroxicam; ketoprofen and the like.

  Examples of the antipruritic component include crotamiton; chlorpheniramine; chlorpheniramine maleate; diphenhydramine; diphenhydramine hydrochloride; diphenhydramine salicylate; nonyl acid vanillyl amide; mequitazine; camphor; thymol; eugenol: polyoxyethylene lauryl ether;

Examples of the vitamins include retinol, retinol derivatives (eg, retinol acetate, retinol palmitate), retinal, retinoic acid, methyl retinoic acid, ethyl retinoic acid, retinol retinoic acid, d-δ-tocopheryl retinoate, α- Vitamin A such as tocopheryl retinoate and β-tocopheryl retinoate;
provitamins A such as β-carotene, α-carotene, γ-carotene, δ-carotene, lycopene, zeaxanthin, cryptoxanthin, and echinone;
vitamin E such as α-tocopherol, β-tocopherol, dl-α-tocopherol succinate, dl-α-tocopherol calcium succinate, δ-tocopherol, and tocopherol nicotinate;
Vitamin B2s such as riboflavin, flavin mononucleotide, flavin adenine dinucleotide, riboflavin butyrate, riboflavin tetrabutyrate, sodium riboflavin 5′-phosphate, and riboflavin tetranicotinate;
Nicotinic acids such as methyl nicotinate, nicotinic acid, and nicotinamide;
Ascorbyl stearate, L-ascorbyl dipalmitate, ascorbyl tetraisopalmitate (ascorbyl tetra-2-hexyldecanoate), sodium ascorbate, dehydroascorbic acid, sodium ascorbate phosphate, magnesium ascorbate phosphate, and ascorbic acid Vitamin Cs such as glucoside;
Vitamin Ds such as methyl hesperidin, ergocalciferol, and cholecalciferol;
Vitamin Ks such as phylloquinone and farnoquinone;
Dibenzoyl thiamine, dibenzoyl thiamine hydrochloride, thiamine hydrochloride, thiamine cetyl hydrochloride, thiamine thiocyanate, thiamine lauryl hydrochloride, thiamine nitrate, thiamine monophosphate, thiamine lysine salt, thiamine triphosphate, thiamine monophosphate Vitamins B1 such as phosphate, thiamine monophosphate, thiamine diphosphate, thiamine diphosphate hydrochloride, thiamine triphosphate, and thiamine triphosphate monophosphate;
Vitamin B6s such as pyridoxine hydrochloride, pyridoxine acetate, pyridoxal hydrochloride, 5'-pyridoxal phosphate, and pyridoxamine hydrochloride;
Vitamins B12 such as cyanocobalamin, hydroxocobalamin, and deoxyadenosylcobalamin;
Folic acids such as folic acid and pteroylglutamic acid;
Pantothenic acids, such as pantothenic acid, calcium pantothenate, pantothenyl alcohol (panthenol), D-pantethein, D-panthetin, coenzyme A, and pantothenyl ethyl ether;
And biotins such as biotin and biocytin; and vitamin-like agents such as carnitine, ferulic acid, α-lipoic acid, orotic acid, and γ-oryzanol.

  Among these, vitamin Cs such as sodium ascorbate phosphate, magnesium ascorbate phosphate, and ascorbyl tetraisopalmitate (ascorbyl tetra-2-hexyldecanoate) are preferable.

  Examples of the local anesthetic component include lidocaine, lidocaine hydrochloride, dibucaine, dibucaine hydrochloride, ethyl aminobenzoate, eucalyptus oil, eugenol, chlorobutanol and the like.

  Examples of the moisturizing component include components derived from plants (for example, lavender, rhododendron, chigaya); amino acids such as alanine, serine, leucine, isoleucine, threonine, glycine, proline, hydroxyproline, glucosamine, and theanine, and the like Derivatives; Proteins such as collagen, gelatin, and elastin, peptides, or hydrolysates thereof; sugar alcohols such as sorbitol; phospholipids such as lecithin and hydrogenated lecithin; hyaluronic acid, sodium hyaluronate, acetyl hyaluron Mucopolysaccharides such as acids, sodium acetyl hyaluronate, heparin, and chondroitin; NMF-derived components such as lactic acid, sodium pyrrolidonecarboxylate, and urea; polyglutamic acid; MPC polymers (eg , LIPIDURE (registered trademark), etc.) polymers having a phospholipid polar group; polyoxypropylene methylglucoside; trimethylglycine (betaine); hydroxyethylurea; acrylic acid / acrylamide / dimethyldiallylammonium chloride copolymer; and sorbitol Etc.

  Among these, lavender oil, rhododendron extract, chigaya root extract, hydrolyzed collagen, hydrolyzed elastin, MPC polymer, trimethylglycine (betaine), hydroxyethylurea, acrylic acid / acrylamide / dimethyldiallylammonium chloride copolymer, hydrogenated Lecithin, hyaluronic acid, sodium hyaluronate, acetyl hyaluronic acid, sodium acetyl hyaluronate, and sorbitol are preferred.

  Examples of the whitening component include arbutin, hydroquinone, kojic acid, ellagic acid, phytic acid, 4-n-butylresorcinol, chamomile extract, ascorbic acid or a derivative thereof, vitamin E or a derivative thereof, pantothenic acid or a derivative thereof, tranexam Examples include acids and plant components having a whitening effect (for example, plant extracts such as grapefruit extract, hamamelis extract, Iris root extract and aloe extract; seaweed-derived components such as brown algae extract and caraft comb extract; essential oil). Among these, arbutin, hydroquinone, kojic acid, and tranexamic acid are preferable.

  Examples of antioxidant components other than the time-varying antioxidant include components derived from plants (eg, grapes, ginseng, and comfrey); proanthocyanidins, tocopherols and derivatives thereof, ascorbic acid derivatives, hesperidin, glucosyl Examples include hesperidin, ergothioneine, sodium bisulfite, erythorbic acid and salts thereof, flavonoids, glutathione, glutathione peroxidase, glutathione-S-transferase, catalase, superoxide dismutase, thioredoxin, taurine, thiotaurine, and hypotaurine.

  Among these, grape seed extract, grape leaf extract, ginseng extract, comfrey leaf extract, proanthocyanidins, tocopherol and its derivatives (particularly δ-tocopherol and α-tocopherol), ascorbic acid derivatives (particularly ascorbic acid phosphate) Sodium ester, magnesium ascorbate phosphate, and ascorbyl tetraisopalmitate (ascorbyl tetra-2-hexyldecanoate), hesperidin, glucosyl hesperidin, and ergothioneine are preferred.

  Examples of the anti-aging component include hydrolyzed soy protein, retinoid (retinol and derivatives thereof, retinoic acid, retinal, etc.), pangamic acid, kinetin, ursolic acid, turmeric extract, sphingosine derivative, silicon, silicic acid, N- Examples include methyl-L-serine and mevalonolactone. Among these, artemia extract, hydrolyzed soy protein, retinol, retinol acetate, and retinol palmitate are preferable.

  Examples of the keratin soft component include lanolin, urea, phytic acid, lactic acid, lactate, glycolic acid, malic acid, and citric acid. Among these, lactic acid, sodium lactate, glycolic acid, and phytic acid are preferable.

  Examples of the cell activation component include components derived from plants (for example, bilberry); amino acids such as γ-aminobutyric acid and ε-aminoproic acid; retinol and derivatives thereof, thiamine, riboflavin, pyridoxine hydrochloride, and pantothene. Vitamins such as acids; α-hydroxy acids such as glycolic acid and lactic acid; tannins, flavonoids, saponins, allantoin, and photosensitizer 301. Among these, bilberry leaf extract, retinol, retinol acetate, and retinol palmitate are preferable.

  Examples of the blood circulation promoting component include plants (e.g., ginseng, ashitaba, arnica, ginkgo, fennel, entomop, dutch oak, chamomile, roman chamomile, carrot, gentian, burdock, rice, hawthorn, shitake, hawthorn, cherries, Senkyu, assembly, thyme, clove, chimpi, spruce, spruce, spruce, carrot, garlic, butcher bloom, grapes, buttons, maronier, melissa, yuzu, yokuinin, rosemary, rosehip, chimpi, spruce, spruce, peach, apricot , Walnuts, or corn); tocopherol nicotinate, glucosyl hesperidin, and hesperidin.

  Among these, ginseng extract, tocopherol nicotinate, glucosyl hesperidin, and hesperidin are preferable.

  Examples of the component having an action of preventing and / or repairing DNA damage include, for example, a component derived from an animal (for example, Artemia); a component derived from a plant (for example, cat's claw); and DNA, DNA salt, RNA, And nucleic acid components such as RNA salts. Among these, artemia extract and DNA-Na are preferable.

  Examples of the ultraviolet ray absorbing component include 2-methoxyhexyl paramethoxycinnamate, 2- [4- (diethylamino) -2-hydroxybenzoyl] benzoic acid hexyl ester, 2,4,6-tris [4- (2- Ethylhexyloxycarbonyl) anilino] -1,3,5-triazine, dimethoxybenzylidene oxoimidazolidinepropionate 2-ethylhexyl, and 2,4-bis-[{4- (2-ethylhexyloxy) -2-hydroxy} -phenyl ] -6- (4-methoxyphenyl) -1,3,5-triazine and the like.

  Among these, 2-methoxyhexyl paramethoxycinnamate, 2- [4- (diethylamino) -2-hydroxybenzoyl] benzoic acid hexyl ester, and 2,4,6-tris [4- (2-ethylhexyloxycarbonyl) Anilino] -1,3,5-triazine is preferred.

  Examples of the ultraviolet scattering component include inorganic compounds such as zinc oxide, titanium oxide, iron oxide, cerium oxide, zirconium oxide, titanium silicate, zinc silicate, anhydrous silicic acid, cerium silicate, and hydrous silicate. These inorganic compounds are coated with inorganic powders such as hydrous silicic acid, aluminum hydroxide, mica, or talc, and these inorganic compounds are compounded with resin powders such as polyamide, polyethylene, polyester, polystyrene, or nylon. And those obtained by treating or coating these inorganic compounds with a silicone oil or a fatty acid aluminum salt.

  Among these, inorganic compounds such as zinc oxide, titanium oxide, and iron oxide, these inorganic compounds treated or coated with inorganic powders such as aluminum hydroxide, hydrous silicic acid, mica, or talc, or silicone oil Is preferred.

Examples of the cleaning component include polyoxyalkylene alkyl (or alkenyl) ether sulfate, alkyl (or alkenyl) sulfate, higher fatty acid salt, ether carboxylate, amide ether carboxylate, alkyl phosphate ester salt, N Anionic surfactants such as acyl amino acid salts, polyoxyalkylene fatty acid amide ether sulfates, acylated isethionates, and acylated taurates;
Nonionic surfactants such as amine oxides, glycerin fatty acid esters, sorbitan fatty acid esters, alkyl saccharides, polyoxyalkylene alkyl ethers, fatty acid alkanolamides, and polyoxyalkylene hydrogenated castor oil;
Cationic surfactants such as mono- or di-long-chain alkyl quaternary ammonium salts having a linear or branched long-chain alkyl group, to which an alkylene oxide may be added; and carbobetaines, sulfobetaines, imidazoles Examples include amphoteric surfactants such as nium betaine and amide betaine.

  Among these, anionic surfactants, nonionic surfactants, and amphoteric surfactants are preferable. Anionic surfactants include higher fatty acid salts (particularly salts of higher fatty acids such as palmitic acid, lauric acid, myristic acid and stearic acid), and N-acyl amino acid salts (particularly sodium N-lauroyl aspartate, water). Potassium oxide / N-coconut oil fatty acid potassium acylglutamate, coconut oil fatty acid acylglycine sodium, and myristoyl glutamic acid) are preferred. Among the nonionic surfactants, fatty acid alkanolamides (particularly, coconut oil fatty acid diethanolamide and coconut oil fatty acid monoethanolamide) and amine oxides (particularly, coconut oil alkyldimethylamine oxide and lauryldimethylamine oxide) are preferred. Amphoteric surfactants include imidazolinium betaines (particularly 2-alkyl-N-carboxymethyl-N-hydroxyethyl imidazolium betaine and N-coconut oil fatty acid acyl-N-carboxymethoxyethyl-N-carboxymethylethylenediamine). Sodium) is preferred.

  Examples of the astringent component include metal salts such as alum, chlorohydroxyaluminum, aluminum chloride, allantoin aluminum salt, zinc sulfate, and potassium aluminum sulfate; and organic acids such as tannic acid, citric acid, lactic acid, and succinic acid. Can be mentioned. Among these, alum, chlorohydroxyaluminum, aluminum chloride, allantoin aluminum salt, aluminum potassium sulfate, and tannic acid are preferable.

  Examples of the hair-restoring ingredients include procyanidins, dipotassium glycyrrhizinate, capronium chloride, cephalanthin, menthol, hinokitiol, L-hydroxyproline, acetylhydroxyproline, fucoidan, capsicum tincture, cephalanthin, sultianin, symphunginicin, flavonosteroid, minoxidil, FGF 10, Enmiso extract (extract), assembly extract (extract), beetle extract (extract), amachazuru extract (extract), hypericum extract (extract), gentian extract (extract), sage extract (extract) , Peppermint extract (extract), hop extract (extract), yokuinin extract (extract), persimmon leaf extract (extract), ginger extract (extract), carrot extract (extract), bo Schima wallichii extract (extract), moutan bark extract (extract), and the like Jiyu extract (extract).

  Examples of the antihistamine component include ethanolamine compounds such as diphenhydramine, diphenhydramine hydrochloride and dimenhydrinate; propylamine compounds such as chlorpheniramine maleate; phenothiazine compounds such as promethazine hydrochloride; piperazine compounds such as hydroxyzine; In addition to piperidine compounds such as cyproheptadine hydrochloride, epinastine hydrochloride, loratadine, and fexofenadine hydrochloride are exemplified. In addition to the hydrochloride, pharmaceutically acceptable salts of the respective compounds can also be used. Among these, diphenhydramine, diphenhydramine hydrochloride, and chlorpheniramine maleate are preferable.

  Examples of the antiseptic component include benzoic acid, sodium benzoate, dehydroacetic acid, sodium dehydroacetate, isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, butyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, benzyl paraoxybenzoate, Examples include methyl paraoxybenzoate and phenoxyethanol. Among these, methyl paraoxybenzoate, propyl paraoxybenzoate, and phenoxyethanol are preferable.

<Properties>
The composition for external use of the skin of the present invention is the above-described lipid peptide and / or pharmaceutically acceptable salt thereof, polyhydric alcohol and / or glycol ether, time-varying antioxidant, and if necessary, the above-mentioned. Other components, bases, carriers, additives and the like described later.

  The lipid peptide and / or a pharmaceutically acceptable salt thereof is an excellent gelling agent, and a predetermined viscosity can be imparted to the external composition for skin of the present invention by blending this component. Thereby, dripping at the time of application | coating of the said composition can be prevented, and the usability | use_condition of a composition can be improved.

<Formulation form of external composition for skin>
The composition for external use of the skin of the present invention comprises the essential components and the other components described above, a base or carrier usually used for pharmaceuticals, quasi drugs, or cosmetics, and additions described later as necessary. It can be mixed with an agent according to a conventional method to form a composition for external use on the skin in the form of pharmaceutical, quasi-drug or cosmetic preparation.

  Examples of the base or carrier include hydrocarbons such as liquid paraffin, squalane, petrolatum, gelled hydrocarbon (such as plastic base), ozokerite, α-olefin oligomer, and light liquid paraffin; methyl polysiloxane, highly polymerized methyl polysiloxane, cyclic Silicone, alkyl-modified silicone, amino-modified silicone, polyether-modified silicone, polyglycerin-modified silicone, silicone-alkyl chain co-modified polyether-modified silicone, silicone-alkyl chain co-modified polyglycerin-modified silicone, polyether-modified branched silicone, polyglycerin Silicone oils such as modified branched silicone, acrylic silicone, phenyl-modified silicone, and silicone resin; oils and fats such as coconut oil, olive oil, rice bran oil, and shea butter; jojoba Waxes such as beeswax, candelilla wax, lanolin; higher alcohols such as cetanol, cetostearyl alcohol, stearyl alcohol, behenyl alcohol, octyldodecanol, isostearyl alcohol, phytosterol, cholesterol; ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc. Cellulose derivatives of: polyvinyl pyrrolidone; carrageenan; polyvinyl butyrate; polyethylene glycol; dioxane; butylene glycol adipate polyester; diisopropyl adipate, isopropyl myristate, octyldodecyl myristate, isopropyl palmitate, cetyl palmitate, isononyl isononanoate, tetranoate 2-Ethylhexanoic acid pentaeryth Examples include esters such as lit; polysaccharides such as dextrin and maltodextrin; vinyl polymers such as carboxyvinyl polymer and alkyl-modified carboxyvinyl polymer; lower alcohols such as ethanol and isopropanol; water and the like.

  When the composition for external use of the skin of the present invention contains a polyhydric alcohol, the polyhydric alcohol may also serve as a base or carrier.

  When the external composition for skin of the present invention contains a base or carrier other than water, the base or carrier is preferably a higher alcohol, hydrocarbon, oil, ester, silicone oil, wax, and higher alcohol, ester. Oil and silicone oil are more preferable. Among these components, cetanol, cetostearyl alcohol, stearyl alcohol, behenyl alcohol, glyceryl tri-2-ethylhexanoate, dimethicone, cyclomethicone, polyether-modified silicone, and polyglycerin-modified silicone are more preferable.

  When the composition for external skin of the present invention contains water, its content in the composition for external skin (100% by weight) of the present invention is preferably 3% by weight or more, more preferably 5% by weight or more, and 10% by weight. The above is even more preferable. The total content (100% by weight) of the external composition for skin of the present invention is preferably 50% by weight or less, more preferably 40% by weight or less, and even more preferably 20% by weight or less.

  The bases or carriers described above can be used singly or in combination of two or more, and the amount used thereof is appropriately selected from a range known to those skilled in the art.

<Form>
The form of the composition for external use in skin of a pharmaceutical preparation is not particularly limited. For example, an ointment, liquid, suspension, emulsifier (emulsion and cream), gel, liniment, lotion, aerosol, tape and poultice Etc. These preparations can be manufactured according to the method described in the 16th revised Japanese Pharmacopoeia General Rules for Preparations.

  The form of the composition for external use on the skin of a quasi-drug or a cosmetic preparation is not particularly limited. For example, lotion, cosmetic liquid, emulsion, cream, gel, ointment, spray, hand cream, body lotion, body cream, Examples include lip balm and sunscreen. These preparations can be manufactured according to a conventional method.

<Additives>
In the composition for external use of the skin of the present invention, known additives added to pharmaceuticals, quasi drugs, or cosmetics, for example, surfactants, stabilizers, discoloration over time, as long as the effects of the present invention are not impaired. Antioxidants other than antioxidants, colorants, pearlescent agents, dispersants, chelating agents, pH adjusters, preservatives, thickeners, irritation reducing agents, and the like can be added. In addition, although the substance corresponding to a time-varying antioxidant is mentioned in the following additives, it is a time-varying antioxidant and also exhibits an action as an additive.

  These additives can be used alone or in combination of two or more. Further, the following additives that correspond to a plurality of components exhibit the action as the corresponding plurality of components, but may not have a plurality of actions in a predetermined case.

  Examples of the surfactant include amines such as stearylamine and oleylamine; silicones such as polyoxyethylene / methylpolysiloxane copolymer, lauryl PEG-9 polydimethylsiloxyethyl dimethicone, and PEG-9 polydimethylsiloxyethyl dimethicone. And surface active agents.

  Examples of the stabilizer include magnesium sulfate, sodium polyacrylate, dibutylhydroxytoluene, butylhydroxyanisole and the like.

  Examples of the antioxidant other than the time-varying antioxidant include butylhydroxyanisole, sorbic acid, sodium sulfite, erythorbic acid, L-cysteine hydrochloride and the like.

  Examples of the colorant include inorganic pigments and natural pigments.

  Examples of the pearl luster imparting agent include ethylene glycol distearate, ethylene glycol monostearate, and triethylene glycol distearate.

  Examples of the dispersant include sodium pyrophosphate, sodium hexametaphosphate, polyvinyl alcohol, polyvinyl pyrrolidone, methyl vinyl ether / maleic anhydride crosslinked copolymer, and organic acid.

  Examples of the chelating agent include EDTA · disodium salt and EDTA · calcium disodium salt.

  Examples of the pH adjuster include inorganic acids (hydrochloric acid, sulfuric acid, etc.), organic acids (lactic acid, sodium lactate, citric acid, sodium citrate, succinic acid, sodium succinate, etc.), inorganic bases (potassium hydroxide, water, etc.). Sodium oxide), organic bases (triethanolamine, diisopropanolamine, triisopropanolamine, etc.).

  Examples of the preservative include benzoic acid, sodium benzoate, dehydroacetic acid, sodium dehydroacetate, isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, butyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, and paraoxybenzoic acid. Examples include benzyl, methyl paraoxybenzoate, and phenoxyethanol.

  Examples of the thickener include cellulose-based thickeners such as methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxyethylcellulose, guar gum, pectin, pullulan, gelatin, locust bean Gum, carrageenan, agar, xanthan gum, polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, alkyl methacrylate copolymer, polyethylene glycol, bentonite, alginic acid, propylene glycol alginate, macrogol, sodium chondroitin sulfate, hyaluronic acid, hyaluronic acid Sodium, (hydroxyethyl acrylate / Acryloyl dimethyl taurine Na) copolymer, and the like (ammonium acryloyldimethyltaurate / vinylpyrrolidone) copolymer.

  Examples of the irritation reducing agent include licorice extract, sodium alginate, gum arabic, polyvinylpyrrolidone, licorice extract, sodium alginate and the like.

<Method for preparing external composition for skin>
The preparation method of the external composition for skin of the present invention is not particularly limited. In addition to the essential components, other components and various components necessary for producing a normal external composition for skin (the above-mentioned base or carrier, addition) Can be produced by a conventional method by appropriately selecting and blending agents. The form of the manufactured skin external composition of the present invention is as described above.

  In the composition for external use of the skin of the present invention, the combination of the lipid peptide represented by the above formula (1) and / or a pharmaceutically acceptable salt thereof with a polyhydric alcohol and / or glycol ethers, Discoloration derived from the discoloration antioxidant is suppressed. Therefore, according to another aspect of the present invention, a lipid peptide represented by the above formula (1) and / or a pharmaceutically acceptable salt thereof is provided in a composition for external use containing an antioxidant that changes color over time. And polyhydric alcohol and / or glycol ethers can be regarded as a method for inhibiting discoloration of a composition for external use on skin.

  In the discoloration suppressing method, “the lipid peptide represented by the formula (1) and / or a pharmaceutically acceptable salt thereof and a polyhydric alcohol and / or glycol ethers are blended” The blending method (order and conditions) of this component and the time-varying antioxidant are not particularly limited. As a result of the implementation of the method for inhibiting discoloration, in the composition for external use on skin, a time-varying antioxidant, a lipid peptide and / or a pharmaceutically acceptable salt thereof, and a polyhydric alcohol and / or glycol ethers coexist. Just do it. For example, these three components (and other components as necessary) may be blended (mixed) at the same time, or these components may be blended sequentially in any order.

[Cosmetics]
The composition for external use of the skin of the present invention contains a lipid peptide and / or a pharmaceutically acceptable salt thereof that imparts a predetermined viscosity to enhance the feeling of use of the composition, and discoloration due to a time-varying antioxidant is suppressed. Therefore, the appearance of the composition can be kept constant, and various cosmetic ingredients can be included, so that it can be suitably used as a cosmetic.

  As the cosmetic preparation form of the present invention, among those listed as the preparation form of the external composition for skin of the present invention, in addition to those corresponding to the cosmetic preparation form, conventionally known as a cosmetic preparation form is known. These various types can be employed without any particular limitation.

  EXAMPLES Hereinafter, although an Example demonstrates this invention in detail, this invention is not limited by these. The unit of the numerical value is% by weight unless otherwise specified.

[Examples 1-3 and Comparative Examples 1-3]
<Method for preparing compositions of Examples 1 to 3 and Comparative Examples 1 to 3>
As shown in Table 1 below, 0.5% of palmitoyl-Gly-His (hereinafter also referred to as Pal-GH) is contained, and the final concentration of ascorbic acid (VC) is 3%, 10%, and 20%. The compositions of Examples 1, 2, and 3 were prepared.

  Further, as Comparative Examples 1, 2, and 3, as shown in Table 2 below, final compositions of ascorbic acid were 3%, 10%, and 20%, and compositions containing no palmitoyl-Gly-His were prepared.

  20 ml each of the compositions of Examples and Comparative Examples were filled into glass bottles, and initial ΔE * ab (0) was determined with a color difference meter (SPECTROPHOTOMETERCM-5 manufactured by Konica Minolta). At this time, purified water was used as a reference color. ΔE * ab is represented by the following formula and serves as an index representing the degree of coloring of the composition of the example or the comparative example.

  The L * value (ΔL *) is a value related to lightness, the a * value (Δa *) is a value related to bidirectional between red and green, and the b * value (Δb *) is related to bidirectional between yellow and blue. is there. The compositions of the above Examples and Comparative Examples were stored (light-shielded) at 40 ° C., 50 ° C., and 60 ° C., respectively, taken out after 4 days, and ΔE * ab (4) was determined using the color difference meter.

And the increase rate of (DELTA) E * ab by having stored at the said temperature for 4 days was calculated | required with the following formula | equation. In the formula, (D65) indicates that a D65 light source was used.
ΔE * ab (D65) increase rate = ΔE * ab (D65) (4) / ΔE * ab (D65) (1)

  The results are shown in FIGS. The ΔE * ab increase rate indicates that the lower the value, the smaller the degree of coloring. 1-3, the composition of the Example containing a predetermined lipid peptide and a polyhydric alcohol and / or glycol ether includes the case of a high concentration compared with the composition of the comparative example which does not contain a lipid peptide. It can be seen that various concentrations of vitamin C can be stably contained without discoloration.

[Examples 4 and 5 and Comparative Examples 4 and 5]
In the same manner as in Examples 1 to 3 and Comparative Examples 1 to 3, compositions having the compositions described in Tables 3 and 4 below were prepared.

* PG is propylene glycol. same as below.

  In the same manner as in Examples 1 to 3 and Comparative Examples 1 to 3, the obtained compositions were stored (light-shielded) at 50 ° C. and 60 ° C. and stored for 4 days when taken out after 4 days. ΔE * ab increase rate was calculated.

  The results are shown in FIGS. 4 and 5, the composition of the example containing the predetermined lipid peptide and the polyhydric alcohol and / or glycol ethers has a high concentration of 20% by weight as compared with the composition of the comparative example not containing the lipid peptide. It can be seen that the vitamin C can be stably contained without discoloration.

[Examples 6-9 and Comparative Examples 6-9]
In the same manner as in Examples 1 to 3 and Comparative Examples 1 to 3, compositions having the compositions described in Tables 5 and 6 below were prepared.

  In the same manner as in Examples 1 to 3 and Comparative Examples 1 to 3, the obtained compositions were stored (light-shielded) at 50 ° C. and 60 ° C. and stored for 4 days when taken out after 4 days. ΔE * ab increase rate was calculated.

  The results are shown in FIG. As shown in FIG. 6, the composition of the example containing a predetermined lipid peptide and polyalcohols and / or glycol ethers of various concentrations is 10% by weight as compared with the composition of the comparative example not containing the lipid peptide. It can be seen that vitamin C at a high concentration of% can be stably contained without discoloration.

[Example 10 and Comparative Example 10]
In the same manner as in Examples 1 to 3 and Comparative Examples 1 to 3, compositions having the compositions shown in Table 7 below were prepared.

  In the same manner as in Examples 1 to 3 and Comparative Examples 1 to 3, the obtained compositions were stored (light-shielded) at 40 ° C. and 50 ° C. and stored for 4 days when taken out after 4 days. ΔE * ab increase rate was calculated.

  The results are shown in FIG. From FIG. 7, it can be seen that also for hydroquinone, which is an antioxidant that changes color over time, discoloration can be suppressed by combining a predetermined lipid peptide with a polyhydric alcohol and / or glycol ether. Further, FIG. 7 shows that the composition of the comparative example not containing the lipid peptide cannot suppress the discoloration of hydroquinone.

[Comparative Example 11]
In the same manner as in Examples 1 to 3 and Comparative Examples 1 to 3, compositions having the compositions described in Table 8 below were prepared. In addition, the composition of Comparative Example 3 was prepared again.

  In the same manner as in Examples 1 to 3 and Comparative Examples 1 to 3, the obtained compositions were stored at 60 ° C. (light-shielded) and ΔE * ab was stored for 4 days when taken out after 4 days. The rate of increase was determined.

  The results are shown in FIG. FIG. 8 shows that ascorbic acid glucoside is not an antioxidant that changes color over time, and no color change occurs even after storage at 60 ° C. for 4 days.

[Prescription example]
Hereinafter, formulation examples of the external composition for skin of the present invention will be shown.

Claims (10)

A composition for external use of skin comprising a lipid peptide represented by the following formula (1) and / or a pharmaceutically acceptable salt thereof, a polyhydric alcohol and / or glycol ethers, and an antioxidant that changes color over time. :

Wherein R ¹ represents an aliphatic group having 9 to 23 carbon atoms, and R ² and R ³ are each independently a hydrogen atom, a methyl group, an ethyl group, or a branched chain having 1 to 3 carbon atoms. Represents an alkyl group having 3 to 7 carbon atoms, a phenylmethyl group, a phenylethyl group, or a — (CH ₂ ) _n —X group, and at least one of R ^{2 and} R ³ is — (CH ₂ ) _n- X group, wherein n is an integer of 1 to 4, and X is an amino group, a guanidino group, a carbamoyl group, or a 5-membered or 6-membered ring group that may have 1 to 3 nitrogen atoms Or, it represents a condensed ring group composed of a 5-membered ring and a 6-membered ring, m is an integer of 1 to 3, and when m is 2 or more, a plurality of R ² may be the same or different from each other. The external composition for skin according to claim 1, wherein R ² in the formula (1) represents a hydrogen atom, a methyl group, an i-propyl group, an i-butyl group, or a sec-butyl group. In the formula (1), R ¹ represents an aliphatic group having 13 to 17 carbon atoms, R ² represents a hydrogen atom, a methyl group, or an i-propyl group, R ³ represents a 4-aminobutyl group, 4 The external composition for skin according to claim 1 or 2, which represents -imidazolemethyl group or 3-methylindole group.   The external composition for skin according to any one of claims 1 to 3, wherein the antioxidant that changes color with time is water-soluble or oil-soluble.   The external composition for skin according to any one of claims 1 to 4, wherein the content of the antioxidant that changes color with time in the external composition for skin is 3 to 30% by weight.   The external composition for skin according to any one of claims 1 to 5, wherein the content of the polyhydric alcohol and / or glycol ether in the external composition for skin is 5 to 90% by weight.   The polyhydric alcohol and / or glycol ether is at least one selected from the group consisting of ethoxydiglycol, 1,3-butylene glycol, dipropylene glycol, propylene glycol and glycerin. The composition for external application to skin.   The skin external application according to any one of claims 1 to 7, wherein the antioxidant that changes color with time is at least one selected from the group consisting of vitamin C, hydroquinone, arbutin, astaxanthin, dibutylhydroxytoluene, and coenzyme Q10. Composition.   Cosmetics containing the external composition for skin in any one of Claims 1-8. A composition for external use containing an antioxidant that changes color over time, a lipid peptide represented by the following formula (1) and / or a pharmaceutically acceptable salt thereof, a polyhydric alcohol and / or glycol ethers: A method for inhibiting discoloration of an external composition for skin comprising:

Wherein R ¹ represents an aliphatic group having 9 to 23 carbon atoms, and R ² and R ³ are each independently a hydrogen atom, a methyl group, an ethyl group, or a branched chain having 1 to 3 carbon atoms. Represents an alkyl group having 3 to 7 carbon atoms, a phenylmethyl group, a phenylethyl group, or a — (CH ₂ ) _n —X group, and at least one of R ^{2 and} R ³ is — (CH ₂ ) _n- X group, wherein n is an integer of 1 to 4, and X is an amino group, a guanidino group, a carbamoyl group, or a 5-membered or 6-membered ring group that may have 1 to 3 nitrogen atoms Or, it represents a condensed ring group composed of a 5-membered ring and a 6-membered ring, m is an integer of 1 to 3, and when m is 2 or more, a plurality of R ² may be the same or different from each other.