JP2008308425A - Stable external preparation for skin - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an external preparation for skin, which contains a compound represented by general formula (1) and has the formulation being improved in stability. <P>SOLUTION: This external preparation for the skin comprises (1) a compound represented by general formula (1) and/or its salt, and (2) one or more compounds selected from compounds each having at least three conjugated double bonds which are liquid at 25°C at 1 atm. Therein, in the general formula (1), R<SB>1</SB>, R<SB>2</SB>are each independently a 3-6C alkyl; R<SB>3</SB>is H, a 1-4C acyl, or a 1-4C alkyl; R<SB>4</SB>is an aromatic group. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to an external preparation for skin, and more particularly to an external preparation for skin in an emulsified form.

  Spots, buckwheat, and pigmentation after sunburn in the skin are a state in which melanin production is remarkably enhanced by activation of pigment cells (melanocytes) existing in the skin. For the purpose of preventing or improving these skin pigment troubles, external preparations for skin (especially whitening agents) containing ascorbic acids, hydrogen peroxide, colloidal sulfur, glutathione, hydroquinone or catechol are known (for example, non-patented) Reference 1 and Non-Patent Document 2). However, these whitening agents may have problems in terms of whitening effect, stability and safety, or may be effective only for symptoms with limited effects. Therefore, it can be said that these effects are not sufficient. In addition, there are various whitening features such as tyrosinase inhibitory effect, degradation of tyrosinase-related proteins, and inhibition of melanin transport by suppressing the extension of melanocyte dendrites. However, there are cases where a single inhibition does not have a sufficient effect, and in addition, it is considered that there is a chemical structure suitable for each. From such a viewpoint, the present inventors have found a compound group represented by the general formula (1) as a compound having a new mother nucleus structure having a whitening effect. The compound represented by the general formula (1) includes a known compound. For example, if it is 2,6-di-tert-butyl-4- (2′-thenoyl) phenol, in addition to the whitening effect, It is known that it has an anti-inflammatory action, an anti-allergic action and an anti-rheumatic action based on the anti-oxidant action and suppression of prostaglandin (for example, Patent Document 1, Patent Document 2, Patent Document 3, Patent (Refer to Literature 4, Non-Patent Literature 3, and Non-Patent Literature 4).

  Although it is a compound represented by General formula (1) which has such an effect | action, there exists a subject about the formulation. That is, the compound represented by the general formula (1) is derived from an aromatic ketone structure in which two aromatic groups are connected by a ketone group, and therefore has good crystallinity and strong aromaticity. This is because the compatibility with other oil component is poor and there is a problem of reprecipitation of crystals, or the surfactant is consumed for the compatibility, and the emulsification characteristics over time may be impaired. In addition, in order to form the compatible system, the type of surfactant tends to be specified and limited. Furthermore, it is already known that the emulsified state affects the percutaneous absorption of the active ingredient (see, for example, Non-Patent Document 5). It can be said that development of means for alleviating the limitation of such formulation is desired for the external preparation for skin containing the compound represented by the general formula (1).

  On the other hand, in a skin external preparation, it is selected from a compound represented by the following general formula (1) and / or a salt thereof and a compound having at least three conjugated double bonds that is liquid at 1 atm and 25 ° C. No attempt has been made to formulate a combination of one or two or more, and such a combination of components improves the compatibility of the compound represented by the general formula (1) in the oil phase, and the emulsification characteristics. Was not known to be stable at all.

JP-A-53-141265 JP 63-008380 A JP 63-502281 A Japanese Translation of National Publication No. 06-501919 George N, Ziakas et al, Bioorganic & Medicinal Chemistry, 14, 5616-5624 (2006) Shaukath Ara. Khanum et al, Bioorganic & Medicinal Chemistry Letters, 14, 5351-5355 (2004) Agents and Action, Vol.12, No.5, 674-683, (1982) Bioorganic & Medicinal Chemistry, Vol.11, 4207-4216, (2003) Luppi B., et al, Drug Deli. 2002; 9 (3): 147-52

  This invention is made | formed in view of such a condition, and makes it a subject to provide the formulation suitable for this compound in order to ensure the usefulness of the compound represented by postscript General formula (1). .

  In view of such a situation, the present inventors sought for a preparation suitable for such a compound in order to ensure the usefulness of the compound represented by the general formula (1), The formulation to be sought can be obtained by including in the emulsifier form one or more selected from compounds having at least three conjugated double bonds that are liquid at 1 atm and 25 ° C. The headline and invention were completed. That is, the present invention is as follows.

(1) 1) Selected from the compound represented by the following general formula (1) and / or a salt thereof, and 2) a compound having at least 3 conjugated double bonds that is liquid at 1 atm and 25 ° C. An external preparation for skin containing 1 type or 2 types or more.

一般式（１）
（但し、式中Ｒ_１、Ｒ_２はそれぞれ独立に炭素数３〜６のアルキル基を表し、Ｒ_３は水素原子、炭素数１〜４のアシル基又は炭素数１〜４のアルキル基を表し、Ｒ_４は芳香族性を有する基を表す。）

General formula (1)
(However, wherein _R 1, _{R 2} each independently represent an alkyl group having 3 to 6 carbon atoms, _{R 3} represents a hydrogen atom, an acyl group or an alkyl group having 1 to 4 carbon atoms having 1 to 4 carbon atoms , R ₄ represents a group having aromaticity.)

(2) The compound represented by the general formula (1) is a compound represented by the following general formula (2) or general formula (3), described in (1) Skin external preparation.

一般式（２）
（但し、式中Ｒ_１及びＲ_２は一般式（１）と同じ基を表し、Ｒ_５は水素原子、水酸基、炭素数１〜４のアルキル基、炭素数１〜４のアシルオキシ基又は炭素数１〜４のアルキルオキシ基を表し、Ｘは酸素原子、硫黄原子又は−ＮＨ−を表す。）

General formula (2)
(However, in the formula, R ₁ and R ₂ represent the same group as in general formula (1), and R ₅ is a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 4 carbon atoms, an acyloxy group having 1 to 4 carbon atoms, or a carbon number. 1-4 represents an alkyloxy group, and X represents an oxygen atom, a sulfur atom or —NH—.)

一般式（３）
（但し、式中Ｒ_６は、水素原子、アルキル基、アルケニル基、フェニル基、アルキルオキシ基、水酸基、メルカプト基、トリフルオロメチル基、アミノ基、アルキルアミノ基、ニトロ基、シアノ基、ホルミル基、カルボキシル基、アルキルアミド基、スルフェニル基、スルホニル基又はハロゲン原子を表す。）

General formula (3)
(In the formula, R ₆ is a hydrogen atom, an alkyl group, an alkenyl group, a phenyl group, an alkyloxy group, a hydroxyl group, a mercapto group, a trifluoromethyl group, an amino group, an alkylamino group, a nitro group, a cyano group, or a formyl group. Represents a carboxyl group, an alkylamide group, a sulfenyl group, a sulfonyl group or a halogen atom.)

(3) The compound represented by the general formula (1) is 2,6-di-tert-butyl-4- (2′-thenoyl) phenol, 3,5-di-tert-butyl-4-hydroxybenzophenone. 3,5-di-tert-butyl-4-hydroxy-4′-fluorobenzophenone, 3,5-di-tert-butyl-4-hydroxy-4′-chlorobenzophenone, 3,5-di-tert-butyl -4-hydroxy-4'-methylbenzophenone, 3,5-di-tert-butyl-4-hydroxy-4'-methoxybenzophenone, 3,5-di-tert-butyl-4-hydroxy-2 ', 4' , 6'-trimethylbenzophenone, 3,5-di-tert-butyl-4,4'-dihydroxybenzophenone, 3,3 ', 5,5'-tetra-tert-butyl-4,4'- (1) or (2), characterized in that it is selected from hydroxybenzophenone and (3,5-di-tert-butyl-4-hydroxyphenyl) -2-naphthalenylmethanone Skin external preparation.
(4) The compound having at least three conjugated double bonds that is liquid at 1 atm and 25 ° C. is α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, vitamin E nicotinic acid ester, acetic acid. Tocopherol, vitamin D ₂ , vitamin D ₃ , retinol, retinal, retinoic acid, 4-methoxycinnamic acid or its derivative, aminobenzoic acid or its derivative, phenoxyethanol, phenethyl alcohol, methyl cinnamate, lyial, anisole, cyclamenaldehyde , Dimethylbenzyl carvinyl acetate, isopentyl salicylate, benzyl salicylate, phenylacetic acid, styryl acetate, 2-isobutyl-3-methoxypyrazine, vanillin and jasminal, (1)-(3) The external preparation for skin according to any one of (1) to (3).
(5) The sum of the contents of the compound represented by the general formula (1) and the sum of the contents of the compound having at least three conjugated double bonds that are liquid at 1 atm and 25 ° C. The skin external preparation according to any one of (1) to (4), wherein the ratio is 1: 1 to 1:10 by mass ratio.
(6) Sum of the sum of the contents of the compound represented by the general formula (1) and the sum of the contents of the compound having at least three conjugated double bonds, which is liquid at 1 atm and 25 ° C. And a component (oil agent component) other than the compound represented by the general formula (1) in the oil phase and the compound having at least three conjugated double bonds, which is liquid at 1 atm and 25 ° C. The skin external preparation according to any one of (1) to (5), characterized in that the ratio of the total to the total is 1: 2 to 1:50 by mass ratio.
(7) The oil component is composed only of components that are liquid at 1 atm and 25 ° C. except for the compound represented by the general formula (1) and salts thereof, (1) to (1) 6) The external preparation for skin according to any one of the above.
(8) The external preparation for skin according to any one of (1) to (7), which is for suppressing melanin production.
(9) The external preparation for skin according to any one of (1) to (8), which is in an emulsifier form.

  ADVANTAGE OF THE INVENTION According to this invention, the formulation suitable for this compound which ensured the usefulness of the compound represented by General formula (1) can be provided.

(1) Compound represented by general formula (1) which is an essential constituent of the external preparation for skin of the present invention The external preparation for skin of the present invention contains the compound represented by general formula (1) and / or a salt thereof. It is characterized by that. In the general formula (1), R ₁ and R ₂ are each independently an alkyl group having 3 to 6 carbon atoms, more preferably a branched structure, such as a 1-methylethyl group, 1-methylpropyl group, 2 -Represents an alkyl group such as a methylpropyl group, a tert-butyl group, an amyl group, particularly preferably a tert-butyl group, and R ₃ represents 1 to C carbon atoms such as a hydrogen atom, a formyl group, an acetyl group, a propanoyl group, and a butanoyl group. 4 represents an acyl group of 4 or an alkyl group having 1 to 4 carbon atoms such as a methyl group, an ethyl group, a propyl group or a butyl group, and R ₄ is aromatic, more preferably an aromatic having 5 to 15 carbon atoms. Represents a group having R ₄ may be composed only of an aromatic group, or may have an aliphatic group interposed. The aromatic group may be a hydrocarbon or a heteroaromatic group having a hetero atom such as an oxygen atom, a sulfur atom, or a nitrogen atom. Depending on the type of the aromatic group, the compound represented by the general formula (1), which is an essential component of the external preparation for skin of the present invention, is represented by the compound represented by the general formula (2) and the general formula (3). It is divided roughly into the compound to be made.

In the general formula (2), R ₁ and R ₂ represent the same group as in the general formula (1), and R ₅ represents a hydrogen atom, a hydroxyl group, a methyl group, an ethyl group, a propyl group, an iso-propyl group, n-butyl. An alkyl group having 1 to 4 carbon atoms such as a group, sec-butyl group or tert-butyl group, more preferably an acyl group having 1 to 4 carbon atoms such as a methyl group, a formyl group, an acetyl group, a propanoyl group or a butanoyl group; More preferably, it represents an acetyl group or an alkyloxy group such as a methoxy group, an ethoxy group, a propyloxy group, or a butyloxy group, more preferably a hydrogen atom, X represents an oxygen atom, a sulfur atom, or —NH—, and more Preferably it represents a sulfur atom. Of these compounds represented by the general formula (2), 2,6-di-tert-butyl-4- (2′-thenoyl) phenol is particularly preferable. The compound represented by the general formula (2) can be used in the free form of the skin external preparation of the present invention, but can also be used as a salt using an alkali or the like. For example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, organic amine salts such as ammonium salt, triethanolamine salt and triethylamine salt, basic such as lysine salt and arginine salt Preferred examples include amino acid salts.

２，６−ジ−ｔｅｒｔ−ブチル−４−（２‘−テノイル）フェノール（化合物（１））

2,6-di-tert-butyl-4- (2′-thenoyl) phenol (compound (1))

  Moreover, these compounds can be manufactured by arbitrary methods, for example, can be manufactured by the method outlined in the following scheme 1 or 2, but are not limited to these methods. Of course, depending on the type of substituent and the like, the production method can be appropriately changed to a form suitable for the purpose.

スキーム１

Scheme 1

The reaction in Scheme 1 will be briefly described.
By treating 3,5-di-alkyl-4-hydroxybenzoic acid with thionyl chloride by a conventional method, acid chloride of 3,5-di-alkyl-4-hydroxybenzoic acid (A) And This acid chloride (A) is treated with a Lewis acid such as aluminum chloride or titanium tetrachloride in a suitable solvent such as carbon disulfide. Subsequently, the compound of General formula (2) can be obtained by adding thiophene (B) and making it Friedel-Craft reaction.

As 3,5-di-alkyl-4-hydroxybenzoic acid, for example, 3,5-di-tert-butyl-4-hydroxybenzoic acid commercially available from Sigma-Aldrich can be used. . As the compound (B), an unsubstituted product in which R ₅ is a hydrogen atom, or a substituted product such as methylthiophene or methoxythiophene can be used. Here, when thiophene is used as the compound (B) (X = S), the compound represented by the general formula (2) is obtained, and 3,5-di-tert- When an acid chloride of butyl-4-hydroxybenzoic acid is used, 2,6-di-tert-butyl-4- (2′-thenoyl) phenol (compound (1)) is obtained.

スキーム２

Scheme 2

The reaction in Scheme 2 will be briefly described.
The thiophenecarboxylic acid is treated with thionyl chloride by a conventional method to obtain an acid chloride form (C) of thiophenecarboxylic acid. This acid chloride (C) is treated with a Lewis acid such as aluminum chloride or titanium tetrachloride in a suitable solvent such as carbon disulfide. Subsequently, the compound of General formula (2) can be obtained by adding 2, 6- dialkylphenol (D) and carrying out Friedel-Craft reaction. In order to obtain the compound (C), 2-thiophenecarboxylic acid, 3-methyl-2-thiophenecarboxylic acid or 5-methyl-2-thiophenecarboxylic acid, in which R ₅ is a hydrogen atom, commercially available from Sigma-Aldrich, is used. An acid or the like can be used. Here, when an acid chloride of 2-thiophenecarboxylic acid is used as the compound (C) (X = S), a compound represented by the general formula (2) is obtained. As 2,6-dialkylphenol (D), 2,6-di-tert-butyl-phenol, 2,6-di-isopropylphenol and the like commercially available from Sigma-Aldrich can be used. When acid chloride of 2-thiophenecarboxylic acid is used as compound (C) and 2,6-di-tert-butyl-phenol is used as compound (D), 2,6-di-tert-butyl-4- ( 2'-thenoyl) phenol (compound (1)) is obtained.

  By substituting the thiophene or thiophenecarboxylic acid with furan or furancarboxylic acid, X is an oxygen atom, and when substituting with pyrrole or pyrrolecarboxylic acid, X is —NH—. Can be produced.

In the general formula (3), R ₆ is a hydrogen atom, a methyl group, an ethyl group, a propyl group, an iso-propyl group, an n-butyl group, a sec-butyl group, a tert-butyl group or the like, more preferably a methyl group. Group, vinyl group, propenyl group, alkenyl group such as n-butenyl group, more preferably propenyl group, methoxy group, ethoxy group, propyloxy group, alkyloxy group such as butyloxy group, more preferably methoxy group, hydroxyl group, mercapto Group, trifluoromethyl group, amino group, methylamino group, ethylamino group, propylamino group, iso-propylamino group, n-butylamino group, sec-butylamino group, tert-butylamino group and other alkylamino groups , More preferably tert-butylamino group, nitro group, cyano group, carbonyl , Carboxyl group, methylamide group, sulfenyl group, a sulfonyl group or a halogen atom, more preferably a chlorine atom. Specific examples of the compound represented by the general formula (3) include 3,5-di-tert-butyl-4-hydroxybenzophenone and 3,5-di-tert-butyl-4- Hydroxy-4′-fluorobenzophenone, 3,5-di-tert-butyl-4-hydroxy-4′-chlorobenzophenone, 3,5-di-tert-butyl-4-hydroxy-4′-methylbenzophenone, 3, 5-di-tert-butyl-4-hydroxy-4′-methoxybenzophenone, 3,5-di-tert-butyl-4-hydroxy-2 ′, 4 ′, 6′-trimethylbenzophenone, 3,5-di- tert-butyl-4,4′-dihydroxybenzophenone, 3,3 ′, 5,5′-tetra-tert-butyl-4,4′-dihydroxybenzophenone, 3,5-di- ert-butyl-4-hydroxy-4′-phenylbenzophenone, (3,5-di-tert-butyl-4-hydroxyphenyl)-(4′-methoxybiphenyl-4-yl) methanone and (3,5-di Preferred examples include those selected from -tert-butyl-4-hydroxyphenyl) -2-naphthalenylmethanone. Of these, more preferred are 3,5-di-tert-butyl-4-hydroxybenzophenone, 3,5-di-tert-butyl-4-hydroxy-4′-fluorobenzophenone, 3,5-di- tert-butyl-4-hydroxy-4'-chlorobenzophenone, 3,5-di-tert-butyl-4-hydroxy-4'-methylbenzophenone, 3,5-di-tert-butyl-4-hydroxy-4 ' -Methoxybenzophenone, 3,5-di-tert-butyl-4-hydroxy-2 ', 4', 6'-trimethylbenzophenone, 3,5-di-tert-butyl-4,4'-dihydroxybenzophenone, 3, 3 ′, 5,5′-tetra-tert-butyl-4,4′-dihydroxybenzophenone and (3,5-di-tert-butyl-4-hydroxy Is selected from phenyl) -2-naphthalenyl methanone.

  The compound represented by the general formula (3) can be used in the free form of the skin external preparation of the present invention, but can also be used as a salt using an alkali or the like. For example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, organic amine salts such as ammonium salt, triethanolamine salt and triethylamine salt, basic such as lysine salt and arginine salt Preferred examples include amino acid salts.

  In addition, the compound represented by the general formula (3) can be produced by an arbitrary method, for example, by appropriately applying the method outlined in Scheme 1 or 2, It is not limited to these methods.

  For example, in Scheme 1 above, various aromatic hydrocarbons are used instead of (substituted) thiophene, and this is reacted with an acid chloride of 3,5-di-tert-butyl-4-benzoic acid. It is possible to manufacture by. Moreover, in the said scheme 2, instead of thiophenecarboxylic acid, using (substituted) benzoic acid, this is made into an acid chloride body, This is manufactured by making it react with 3, 5- di-tert- butylphenol. Is possible.

(2) The compound having at least three conjugated double bonds, which is liquid at 1 atm and 25 ° C., which is an essential component of the external preparation for skin of the present invention, has the general formula (1) And a compound having at least three conjugated double bonds, which is liquid at 1 atm and 25 ° C. As such a compound, any compound having at least three conjugated double bonds that is liquid at 1 atm and 25 ° C. can be used, and preferred compounds include the following. . α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, vitamin E nicotinate, tocopherol acetate, vitamin D ₂ , vitamin D ₃ , retinol, retinal, retinoic acid, p-methoxycinnamic acid, p-methoxycinnamic Acid ethyl ester, p-methoxycinnamic acid or its derivatives such as p-methoxycinnamic acid-2 ethylhexyl ester, p-aminobenzoic acid-2 ethylhexyl ester, N, N-dimethyl-p-aminobenzoic acid-2 ethylhexyl ester P-aminobenzoic acid or its derivatives, such as phenoxyethanol, phenethyl alcohol, methyl cinnamate, lilyal, anisole, cyclamenaldehyde, dimethylbenzylcarbyl acetate, isopentyl salicylate, benzyl salicylate Phenyl acetate, styrallyl, 2-isobutyl-3-methoxy pyrazine, vanillin and Jasumi knurls are preferred. Among these, α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, vitamin E nicotinic acid ester, tocopherol acetate, 4-methoxycinnamic acid-2-ethylhexyl ester, phenoxyethanol are more preferable, δ-tocopherol, 4-methoxycinnamic acid-2 ethylhexyl ester is particularly preferred.

(3) External preparation for skin of the present invention The external preparation for skin of the present invention is a compound represented by the general formula (1) and / or a salt thereof and at least three conjugates which are liquid at 1 atm and 25 ° C. A compound having a double bond is contained as an essential component. In the skin external preparation of the present invention, the compound represented by the general formula (1) and / or a salt thereof may contain only one kind or two or more kinds, and may contain 1 atm and 25 ° C. The liquid compound having at least three conjugated double bonds may contain only one kind or two or more kinds.

  The preferable content of the compound represented by the general formula (1) in the external preparation for skin of the present invention is 0.001% by mass or more, preferably 0.01% by mass or more, more preferably 0.1% by mass or more in total. It is. On the other hand, the upper limit is 3% by mass or less, preferably 1% by mass or less, and more preferably 0.8% by mass or less. The preferred content of the compound having at least three conjugated double bonds that is liquid at 1 atm and 25 ° C. in the external preparation for skin of the present invention is 0.01% by mass or more, preferably 0.1% by mass. As mentioned above, More preferably, it is 0.2 mass% or more. On the other hand, the upper limit is 10% by mass or less, preferably 5% by mass or less, and more preferably 3% by mass or less.

  The sum of the content of the compound represented by the general formula (1) in the external preparation for skin of the present invention and the content of the compound having at least three conjugated double bonds that are liquid at 1 atm and 25 ° C. It is preferable that the ratio to the sum of is 1: 1 to 1:10 by mass ratio. This is because the compound represented by the general formula (1) has high crystallinity and poor solubility in an oil or the like, so that it can be stably dissolved (especially low-temperature solubility), 1 atm, 25 This is because it is preferable that a compound having at least three conjugated double bonds that are liquid at 0 ° C. coexist in this range.

  In order to improve the stability of the dosage form in the external preparation for skin of the present invention, the compound represented by the general formula (1) and at least three conjugated double bonds which are liquid at 1 atm and 25 ° C. By using an oil agent component that is liquid at 1 atm and 25 ° C. together with the compound having the above, the compatibility is further improved, so that it is also preferable to contain such a component.

  Examples of such oil components that are liquid at 1 atm 25 ° C. include, for example, macadamia nut oil, avocado oil, corn oil, olive oil, rapeseed oil, sesame oil, castor oil, safflower oil, cottonseed oil, jojoba oil, palm Oils, vegetable oils such as palm oil, liquid oils such as liquid paraffin and squalane, unsaturated or branched fatty acids such as oleic acid, palmitoleic acid, isostearic acid and isopalmitic acid, oleyl alcohol, isostearyl alcohol, octyldodecanol, jojoba alcohol Unsaturated or branched alcohols such as cetyl isooctanoate, isopropyl myristate, hexyl decyl isostearate, diisopropyl adipate, di-2-ethylhexyl sebacate, cetyl lactate, diisostearyl malate, di-2-ethylhexanoic acid Ester oil such as tylene glycol, 2-ethylhexanoic acid palmityl ester, tri-2-ethylhexanoic acid glycerin, chain polysiloxane such as dimethylpolysiloxane, methylphenylpolysiloxane, diphenylpolysiloxane, octamethylcyclotetrasiloxane, Examples include silicone oils such as cyclic polysiloxanes such as decamethylcyclopentasiloxane and dodecamethylcyclohexanesiloxane, amino-modified polysiloxanes, polyether-modified polysiloxanes, alkyl-modified polysiloxanes, and modified polysiloxanes such as fluorine-modified polysiloxanes. Among these, tri-2-ethylhexanoic acid glycerin, methylphenylpolysiloxane, diphenylpolysiloxane, and isostearic acid are preferable, and tri-2-ethylhexanoic acid glycerin ester is particularly preferable. By using such an oil that is liquid at 1 atm and 25 ° C., the compatibility is improved and the stability of the dosage form is further improved.

  In the external preparation for skin of the present invention, the sum of the contents of the compound represented by the general formula (1) and the compound having at least three conjugated double bonds which are liquid at 1 atm and 25 ° C. Components other than the total sum of the contents, the compound represented by the general formula (1) in the oil phase, and the compound having at least three conjugated double bonds that are liquid at 1 atm and 25 ° C. The ratio of the content of the oil component) to the total content is preferably 1: 2 to 1:50, more preferably 1: 2 to 1:10, and more preferably 1: 2 to 1: 5. More preferably. This is because by using such a composition, the compatibility of the compound represented by the general formula (1) with the oil component is improved and the dosage form is stabilized.

  In the oil phase of the external preparation for skin of the present invention, components other than the compound represented by the general formula (1) and the compound having at least three conjugated double bonds that are liquid at 1 atm and 25 ° C. (oil agent) The component) preferably contains 70% or more of an oil that is liquid at 1 atm and 25 ° C. in the oil phase component in the external preparation for skin excluding the compound represented by the general formula (1), 90 % Or more, more preferably 95% or more, particularly preferably only a liquid oil at 1 atm and 25 ° C.

  That is, in the present invention, it is particularly preferable that the oil phase component is composed only of components that are liquid at 1 atm and 25 ° C., excluding the compound represented by the general formula (1) and salts thereof.

  Here, since the compound represented by the general formula (1) has a property of being easily dissolved in the oil phase, the external preparation for skin of the present invention is preferably in the form of an oily agent or an emulsifier, and preferably in the form of an emulsifier. Is more preferable. This is because various components such as an aqueous component such as a humectant can be contained by adopting an emulsifier form.

  When using the emulsifier form in the external preparation for skin of the present invention, it is preferable to use a high molecular weight emulsifier as at least one emulsifier. This is because the emulsifier of the polymer is easy to orient at the interface and gels the aqueous phase to stabilize the interface film, thereby emulsifying the oil phase containing a highly fluid oil agent as in the present invention at a high concentration. It is because it makes it more stable. The content of such an emulsifier is preferably 0.01% by mass or more, more preferably 0.05% by mass or more, and still more preferably 0.1% by mass or more based on the total amount of the external preparation for skin. Furthermore, the upper limit is preferably 5% by mass or less, more preferably 3% by mass or less, and still more preferably 1% by mass or less. This is because if the amount used is too small, the stabilizing effect of the emulsified particles may be reduced, and if too much, the usability may be impaired due to the thickening effect. Examples of such a material include acrylic acid / alkyl methacrylate copolymers. This is commercially available from Goodrich as “PEMULEN TR-1”, “PEMULEN TR-2”, “Carbopol 1382”, etc., and can be used and is preferable. Furthermore, in order to keep the emulsified particles stable, it is also preferable to increase the viscosity of the aqueous phase by incorporating a water-soluble polymer in the aqueous phase. Examples of such a polymer include carbopol, carboxyvinyl polymer, xanthan gum, carboxymethyl cellulose, hydroxyethyl cellulose, sodium polyacrylate, and the like.

  Further, in the external preparation for skin of the present invention, at least 3 compounds which are liquid at 1 atm and 25 ° C. with the compound represented by the general formula (1) as long as the stability of the dosage form is not hindered. In addition to the compound having a conjugated double bond, various components generally used in pharmaceuticals, cosmetics, etc., that is, fats and oils, waxes, hydrocarbons, fatty acids, higher alcohols, esters, oils, aqueous components, powders Ingredients, humectants, thickeners, surfactants, powders, colorants, fragrances, pH adjusters, chelating agents, preservatives, vitamins, other whitening agents, anti-inflammatory agents, and the like can be included.

  As such components, humectants include glycerin, diglycerin, 1,3-butanediol, propylene glycol, dipropylene glycol, isoprene glycol, 1,2-pentanediol, 2,4-hexylene glycol, 1, Examples include 2-hexanediol, 1,2-octanediol, polyethylene glycol, erythritol, sorbitol, xylitol, maltitol and other polyhydric alcohols, sodium pyrrolidonecarboxylate, lactic acid, sodium lactate and the like. Gua gum, quince seed, carrageenan, galactan, gum arabic, pectin, mannan, starch, curdlan, methylcellulose, hydroxyethylcellulose, methylhydroxypropylcellulose, chondroitin sulfate, dermatan Acid, glycogen, heparan sulfate, hyaluronic acid, sodium hyaluronate, tragacanth gum, keratan sulfate, chondroitin, mucoitin sulfate, hydroxyethyl guar gum, carboxymethyl guar gum, dextran, kerato sulfate, locust bean gum, succinoglucan, caronic acid, chitin, Examples include chitosan, carboxymethyl chitin, agar, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene glycol, and bentonite.

  As surfactants, fatty acid soap (sodium laurate, sodium palmitate, etc.), anionic surfactants such as potassium lauryl sulfate, alkylsulfuric triethanolamine ether, stearyltrimethylammonium chloride, benzalkonium chloride, laurylamine oxide Cationic surfactants such as imidazoline-based amphoteric surfactants (2-cocoyl-2-imidazolinium hydroxide-1-carboxyethyloxy disodium salt, etc.), betaine surfactants (alkyl betaines, amide betaines, Sulfobetaine, etc.), amphoteric surfactants such as acylmethyltaurine, sorbitan fatty acid esters (sorbitan monostearate, sorbitan sesquioleate, etc.), glycerin fatty acids (glyceryl monostearate, etc.), Lopylene glycol fatty acid esters (such as propylene glycol monostearate), hardened castor oil derivatives, glycerin alkyl ether, POE sorbitan fatty acid esters (POE sorbitan monolaurate, POE sorbitan monooleate, polyoxyethylene sorbitan monostearate, etc.) POE sorbite fatty acid esters (such as POE-sorbitol monolaurate), POE glycerin fatty acid esters (such as POE-glycerin monoisostearate), POE fatty acid esters (such as POE monolaurate, POE monooleate, POE distearate), POE alkyl ethers (POE cetyl ether, POE2-octyldodecyl ether, etc.), POE alkyl phenyl ethers (POE nonylphenyl ether) ), Pluronic (registered trademark), POE / POP alkyl ethers (POE / POP2-decyltetradecyl ether, etc.), Tetronic (registered trademark), POE castor oil / hardened castor oil derivative (POE castor oil, POE cured) Nonionic surfactants such as castor oil, sucrose fatty acid esters, alkyl glucosides, and the like.

Examples of vitamins include vitamin B ₁ , vitamin B ₂ , vitamin B ₃ , vitamin B ₆ , vitamin B ₁₂ and other vitamin B groups, ubiquinones, folic acids, pantothenic acid, panthetin, coenzyme Q10, and the like.

  As the inorganic pigment, the surface may be treated, mica, talc, kaolin, synthetic mica, calcium carbonate, magnesium carbonate, anhydrous silicic acid (silica), aluminum oxide, barium sulfate, bengara, yellow iron oxide, black oxide Examples thereof include iron, cobalt oxide, ultramarine, bitumen, titanium oxide, and zinc oxide. As organic powders, the surface may be treated, polyethylene powder, polymethyl methacrylate, nylon powder, organopolysiloxane elastomer. Examples of the pearl agent may include mica titanium, fish phosphorus foil, bismuth oxychloride, etc. whose surface may be treated, and examples of the organic pigment include red 202 which may be raked. No., Red No. 228, Red No. 226, Yellow No. 4, Blue No. 404, Yellow No. 5, Red No. 505, Red No. 230, Red No. 22 No., No. 201 orange red 213 No., Yellow No. 204, Yellow No. 203, Blue No. 1, Green No. 201, Purple No. 201, Red No. 204, and the like.

  The external preparation for skin of the present invention is intended to improve the stability of the dosage form, and is preferably applied to cosmetics that require a beautiful appearance in the appearance of the dosage form.

  Since the skin external preparation of this invention contains the compound represented by General formula (1), it has an anti-inflammatory effect and is also a preferable form used for the care after sunburn.

  Moreover, since the compound represented by general formula (I) has an excellent melanin production inhibitory effect, it is also a preferred form to be used as a skin external preparation for melanin production inhibition or whitening.

  The external preparation for skin of the present invention can be produced in the same manner as the production of external preparations for skin such as normal cosmetics and quasi drugs.

  Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples, but it goes without saying that the present invention is not limited by these Examples and Test Examples.

<Production Example 1>
Production of 2,6-di-tert-butyl-4- (2′-thenoyl) phenol (compound (1)) 3,5-di-tert-butyl-4-hydroxybenzoic acid 23.2 g and thionyl chloride 60 g After stirring for 1 hour at room temperature, excess thionyl chloride was distilled off under reduced pressure. This was dissolved by adding 300 ml of carbon disulfide, and 13.5 g of aluminum chloride was further added. After stirring for 30 minutes at 40 ° C., 88.2 g of thiophene was added. Next, the reaction solution was poured into 10% hydrochloric acid, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, and fractionated and purified with a silica gel column to obtain compound (1).

<Production Example 2> Production of 3,5-di-tert-butyl-4-hydroxybenzophenone (Compound (2)) 1.45 g of benzoyl chloride and 2.06 g of 2,6-di-tert-butylphenol were added to 12 ml of methylene chloride. After dissolution, 1.40 g of aluminum chloride was added and stirred at room temperature for 40 minutes. The reaction solution was poured into ice water, extracted with dichloromethane, dried over anhydrous sodium sulfate, concentrated, fractionated and purified with a silica gel column to obtain compound (2).

<Production Example 3> Production of 3,5-di-tert-butyl-4-hydroxy-4'-fluorobenzophenone (Compound (3)) Using 4-fluorobenzoyl chloride and 2,6-di-tert-butylphenol, In the same manner as in Production Example 2, compound (3) was obtained.

<Production Example 4> Production of 3,5-di-tert-butyl-4-hydroxy-4'-chlorobenzophenone (Compound (4)) Using 4-chlorobenzoyl chloride and 2,6-di-tert-butylphenol, In the same manner as in Production Example 2, compound (4) was obtained.

<Production Example 5> Production of 3,5-di-tert-butyl-4-hydroxy-4'-methylbenzophenone (Compound (5)) Using 4-methylbenzoyl chloride and 2,6-di-tert-butylphenol, The compound (5) was obtained in the same manner as in Production Example 2.

<Production Example 6> Production of 3,5-di-tert-butyl-4-hydroxy-4'-methoxybenzophenone (Compound (6)) Using 4-methoxybenzoyl chloride and 2,6-di-tert-butylphenol, In the same manner as in Production Example 2, compound (6) was obtained.

<Production Example 7> Production of 3,5-di-tert-butyl-4-hydroxy-2 ', 4', 6'-trimethylbenzophenone (compound (7)) 2,4,6-trimethylbenzoyl chloride and 2, 6-Di-tert-butylphenol was used in the same manner as in Production Example 2 to obtain compound (7).

<Production Example 8> Production of 3,5-di-tert-butyl-4,4'-dihydroxybenzophenone (Compound (8)) 0.34 g of sodium ethanethiolate was added to 3 ml of dimethylformamide under ice cooling. To this, 0.53 g of 3,5-di-tert-butyl-4-hydroxy-4′-methoxybenzophenone produced in Production Example 6 was added, heated under reflux for 4 hours, and further stirred overnight at room temperature. The reaction solution was poured into dilute hydrochloric acid and extracted with methylene chloride. The methylene chloride layer was dried over anhydrous sodium sulfate, concentrated, and fractionated and purified on a silica gel column to obtain compound (8).

<Production Example 9> Production of 3,3 ', 5,5'-tetra-tert-butyl-4,4'-dihydroxybenzophenone (compound (9)) 2,6-di-tert-butylbenzoyl chloride and 2, 6-Di-tert-butylphenol was used in the same manner as in Production Example 2 to obtain compound (9).

<Production Example 10> Production of (3,5-di-tert-butyl-4-hydroxyphenyl) -2-naphthalenylmethanone (Compound (10)) 2-Naphthyl chloride and 2,6-di-tert- The same procedure as in Production Example 2 was performed using butylphenol to obtain compound (10).

<Production Example 11> Production of 3,5-di-tert-butyl-4-hydroxy-4'-phenylbenzophenone (Compound (11)) Using 4-biphenylcarbonyl chloride and 2,6-di-tert-butylphenol, In the same manner as in Production Example 2, compound (11) was obtained.

An oil-in-water cream was prepared according to the formulation shown below. That is, each component of (A) was mixed and heated to 80 ° C. On the other hand, each component of (B) was mixed and heated to 80 ° C. To the mixture of (A), the mixture of (B) was added and stirred to emulsify, and then cooled to 35 ° C. to produce Cream 1. In the formulation of Cream 1 of Example 1, the compound (1) substituted with water was produced as Comparative Example 1-1, and the delta-tocopherol substituted with water was produced as Comparative Example 1-2. A compound in which both the compound (1) and δ-tocopherol were substituted with water was produced as Comparative Example 1-3.
(A)
POE (30) hexyl decyl ether 2.0 mass%
2-Ethylhexanoic acid triglyceride 7.0 mass%
Methylphenylpolysiloxane 1.0 mass%
Methylparaben 0.3 mass%
δ-Tocopherol 1.0% by mass
Compound (1) 0.5% by mass
(B)
“PEMULEN TR-2” (manufactured by BFGoodrich) 0.2% by mass
Carboxyvinyl polymer 0.1% by mass
1,3-butanediol 15.0 mass%
Sodium hydroxide 0.1% by mass
Purified water 72.8% by mass

<Test Example 1> Low-temperature long-term storage test 1 of the external preparation for skin of the present invention
Each sample of Example 1 and Comparative Examples 1 to 3 was put in a glass storage container, sealed, and stored in a temperature-controlled room at 20 ° C., 5 ° C., and −10 ° C. for 6 months. After 6 months, with respect to each storage sample, the content 0.2 was spread on a slide glass, the number of precipitates was counted under a microscope, and the average of 5 cases was calculated.

  From the result of Table 1, in Comparative Example 1-2 containing only the compound (1), no precipitate was observed under 20 ° C. storage conditions. However, there was also a sample in which deposits were observed during storage at 5 ° C. Furthermore, a large number of precipitates were observed during storage at -10 ° C. On the other hand, in Example 1, no precipitate was observed even when stored at −10 ° C., and δ-tocopherol improved the solubility of compound (1) in the dosage form containing compound (1). It was found that the stability of the dosage form was improved.

  The cream of Example 2 was produced by replacing the compound (1) with the compound (2) in the formulation of Example 1. Further, in the cream of Example 2, a product obtained by replacing δ-tocopherol with water was produced as Comparative Example 2.

  The cream of Example 3 was produced by replacing the compound (1) with the compound (3) in the formulation of Example 1. Further, in the cream of Example 3, a product obtained by replacing δ-tocopherol with water was produced as Comparative Example 3.

  The cream of Example 4 was produced by replacing the compound (1) with the compound (4) in the formulation of Example 1. Further, in the cream of Example 4, a product obtained by replacing δ-tocopherol with water was produced as Comparative Example 4.

  The cream of Example 5 was produced by replacing the compound (1) with the compound (5) in the formulation of Example 1. Further, in the cream of Example 5, a product obtained by replacing δ-tocopherol with water was produced as Comparative Example 5.

  The cream of Example 6 was produced by replacing the compound (1) with the compound (6) in the formulation of Example 1. Further, in the cream of Example 6, a product obtained by replacing δ-tocopherol with water was produced as Comparative Example 6.

  The cream of Example 7 was produced by replacing the compound (1) with the compound (7) in the formulation of Example 1. Further, in the cream of Example 7, a product obtained by replacing δ-tocopherol with water was produced as Comparative Example 7.

  The cream of Example 8 was produced by replacing Compound (1) with Compound (8) in the formulation of Example 1. Further, in the cream of Example 8, a product obtained by replacing δ-tocopherol with water was produced as Comparative Example 8.

  The cream of Example 9 was produced by replacing the compound (1) with the compound (9) in the formulation of Example 1. Further, in the cream of Example 9, a product obtained by replacing δ-tocopherol with water was produced as Comparative Example 9.

  The cream of Example 10 was produced by replacing Compound (1) with Compound (10) in the formulation of Example 1. Further, in the cream of Example 10, a product obtained by replacing δ-tocopherol with water was produced as Comparative Example 10.

  The cream of Example 11 was produced by replacing the compound (1) with the compound (11) in the formulation of Example 1. Further, in the cream of Example 11, a product obtained by replacing δ-tocopherol with water was produced as Comparative Example 11.

<Test Example 2> Low-temperature long-term storage test 2 of the external preparation for skin of the present invention
Each sample of Examples 2 to 10 and Comparative Examples 2 to 10 was put in a glass storage container, sealed, and stored in a thermostatic chamber at 20 ° C., 5 ° C., and −10 ° C. for 6 months. After 6 months, 0.2 g of the contents of each stored sample was spread on a slide glass, the number of precipitates was counted under a microscope, and the average of 3 cases was calculated.

  From the results in Table 2, in Comparative Examples 2 to 11 containing only compound (2) to compound (11), almost no precipitate was observed in storage at 20 ° C. However, some deposits were observed during storage at 5 ° C. Furthermore, a large number of precipitates were observed during storage at -10 ° C. On the other hand, in Examples containing δ-tocopherol, no precipitate was observed even at -10 ° C storage, and the solubility of Compound (2) to Compound (11) was improved and the dosage form was stable. I found out.

An oil-in-water cream was prepared according to the formulation shown below. That is, each component of (A) was mixed and heated to 80 ° C. On the other hand, each component of (B) was mixed and heated to 80 ° C. To the mixture of (A), the mixture of (B) was added and stirred to emulsify, and then cooled to 35 ° C. to produce Cream 2. In Example 12, a product obtained by replacing retinol with water was produced as Comparative Example 12.
(A)
POE (30) hexyl decyl ether 2.0 mass%
2-Ethylhexanoic acid triglyceride 7.0 mass%
Methylphenylpolysiloxane 1.0 mass%
Methylparaben 0.3 mass%
Retinol 1.0 mass%
Compound (1) 0.5% by mass
(B)
“PEMULEN TR-2” (manufactured by Goodrich) 0.2% by mass
Xanthan gum 0.1% by mass
1,3-butanediol 15.0 mass%
Sodium hydroxide 0.1% by mass
Purified water 72.8% by mass

  The cream of Example 13 was prepared by replacing the retinol in the formulation of Example 12 with 2-ethylhexyl p-methoxycinnamate.

  The cream of Example 14 was produced by replacing the retinol with tocopherol acetate in the formulation of Example 12.

  The cream of Example 15 was prepared by replacing the retinol with phenoxyethanol in the formulation of Example 12.

<Test Example 3> Long-term low-temperature storage test 3 of the cosmetic of the present invention
Each sample of Examples 12 to 15 and Comparative Example 12 was put in a glass storage container, sealed, and stored in a temperature-controlled room at 20 ° C., 5 ° C., and −10 ° C. for 6 months. Six months later, for each stored sample, the deposits were counted in the same manner as in Test Example 1, and the average of three cases was calculated.

  From the results of Table 3, in addition to the compound (1), in Examples 12 to 15 containing retinol, 2-ethylhexyl p-methoxycinnamate, tocopherol acetate and phenoxyethanol, in addition to storage at 20 ° C. and 5 ° C., Precipitates were not observed even in the products stored at -10 ° C. On the other hand, in Comparative Example 12 in which retinol, 2-ethylhexyl p-methoxycinnamate, tocopherol acetate, phenoxyethanol, and the like did not coexist, there was a sample in which deposits were observed during storage at 5 ° C. Furthermore, a large number of precipitates were observed during storage at -10 ° C. Retinol, 2-ethylhexyl p-methoxycinnamate, tocopherol acetate, and phenoxyethanol also suppressed the formation of precipitates, similar to δ-tocopherol.

An oil-in-water cream was prepared according to the formulation shown below. That is, each component of (A) was mixed and heated to 80 ° C. On the other hand, each component of (B) was mixed and heated to 80 ° C. To the mixture of (A), the mixture of (B) was added and stirred to emulsify, and then cooled to 35 ° C. to produce the cream of Example 16. In the formulation of Example 16, a product obtained by replacing δ-tocopherol with water was produced as Comparative Example 16.
(A)
POE (30) hexyl decyl ether 2.0 mass%
2-Ethylhexanoic acid triglyceride 7.0 mass%
Methylphenylpolysiloxane 1.0 mass%
Methylparaben 0.3 mass%
δ-tocopherol 0.2% by mass
Compound (1) 0.5% by mass
(B)
“PEMULEN TR-2” (manufactured by Goodrich) 0.2% by mass
Carboxyvinyl polymer 0.1% by mass
1,3-butanediol 15.0 mass%
Sodium hydroxide 0.1% by mass
Purified water 73.6% by mass

An oil-in-water cream was prepared according to the formulation shown below. That is, each component of (A) was mixed and heated to 80 ° C. On the other hand, each component of (B) was mixed and heated to 80 ° C. To the mixture of (A), the mixture of (B) was added and stirred to emulsify, and then cooled to 35 ° C. to produce the cream of Example 17. In the formulation of Example 17, a product obtained by replacing δ-tocopherol with water was produced as Comparative Example 17.
(A)
POE (30) hexyl decyl ether 2.0 mass%
2-Ethylhexanoic acid triglyceride 7.0 mass%
Methylphenylpolysiloxane 1.0 mass%
Methylparaben 0.3 mass%
δ-tocopherol 0.5% by mass
Compound (1) 0.5% by mass
(B)
“PEMULEN TR-2” (manufactured by Goodrich) 0.2% by mass
Xanthan gum 0.1% by mass
1,3-butanediol 15.0 mass%
Sodium hydroxide 0.1% by mass
Purified water 73.3% by mass

An oil-in-water cream was prepared according to the formulation shown below. That is, each component of (A) was mixed and heated to 80 ° C. On the other hand, each component of (B) was mixed and heated to 80 ° C. To the mixture of (A), the mixture of (B) was added and stirred to emulsify, and then cooled to 35 ° C. to produce the cream of Example 18. In the formulation of Example 18, a product obtained by substituting δ-tocopherol with water was produced as Comparative Example 18.
(A)
POE (30) hexyl decyl ether 2.0 mass%
2-Ethylhexanoic acid triglyceride 7.0 mass%
Methylphenylpolysiloxane 1.0 mass%
Methylparaben 0.3 mass%
δ-Tocopherol 3.0% by mass
Compound (1) 0.3% by mass
(B)
“PEMULEN TR-2” (manufactured by Goodrich) 0.2% by mass
Xanthan gum 0.1% by mass
1,3-butanediol 15.0 mass%
Sodium hydroxide 0.1% by mass
Purified water 71.0% by mass

An oil-in-water cream was prepared according to the formulation shown below. That is, each component of (A) was mixed and heated to 80 ° C. On the other hand, each component of (B) was mixed and heated to 80 ° C. The cream of Example 19 was manufactured by adding the mixture of (B) to the mixture of (A), stirring and emulsifying, and then cooling to 35 ° C. In Example 19, Comparative Example 19 was prepared by substituting δ-tocopherol and 2-ethylhexyl p-methoxycinnamate with water.
(A)
POE (30) hexyl decyl ether 2.0 mass%
2-Ethylhexanoic acid triglyceride 4.0% by mass
Methylphenylpolysiloxane 0.5% by mass
Methylparaben 0.3 mass%
δ-Tocopherol 1.0% by mass
2-Ethylhexyl p-methoxycinnamate 1.0% by mass
Compound (1) 0.3% by mass
(B)
“PEMULEN TR-2” (manufactured by Goodrich) 0.2% by mass
Xanthan gum 0.1% by mass
1,3-butanediol 15.0 mass%
Sodium hydroxide 0.1% by mass
Purified water 75.5% by mass

An oil-in-water cream was prepared according to the formulation shown below. That is, each component of (A) was mixed and heated to 80 ° C. On the other hand, each component of (B) was mixed and heated to 80 ° C. To the mixture of (A), the mixture of (B) was added and stirred to emulsify, and then cooled to 35 ° C. to produce the cream of Comparative Example 20. In the formulation of Example 20, a product obtained by substituting δ-tocopherol and 2-ethylhexyl p-methoxycinnamate with water was produced as Comparative Example 20.
(A)
POE (30) hexyl decyl ether 2.0 mass%
2-Ethylhexanoic acid triglyceride 2.5% by mass
Methylphenylpolysiloxane 0.5% by mass
Methylparaben 0.3 mass%
δ-Tocopherol 1.0% by mass
2-Ethylhexyl p-methoxycinnamate 1.0% by mass
Compound (1) 0.3% by mass
(B)
“PEMULEN TR-2” (manufactured by Goodrich) 0.2% by mass
Xanthan gum 0.1% by mass
1,3-butanediol 15.0 mass%
Sodium hydroxide 0.1% by mass
Purified water 77.0% by mass

An oil-in-water cream was prepared according to the formulation shown below. That is, each component of (A) was mixed and heated to 80 ° C. On the other hand, each component of (B) was mixed and heated to 80 ° C. The cream of Example 21 was manufactured by adding the mixture of (B) to the mixture of (A), stirring and emulsifying, and then cooling to 35 ° C. In the formulation of Example 21, a product obtained by substituting δ-tocopherol and 2-ethylhexyl p-methoxycinnamate with water was produced as Comparative Example 21.
(A)
POE (30) hexyl decyl ether 2.0 mass%
2-Ethylhexanoic acid triglyceride 5.0% by mass
Methylphenylpolysiloxane 1.0 mass%
Solid paraffin 1.0% by mass
Methylparaben 0.3 mass%
δ-Tocopherol 1.0% by mass
2-Ethylhexyl p-methoxycinnamate 1.0% by mass
Compound (1) 0.3% by mass
(B)
“PEMULEN TR-2” (manufactured by Goodrich) 0.2% by mass
Xanthan gum 0.1% by mass
1,3-butanediol 15.0 mass%
Sodium hydroxide 0.1% by mass
Purified water 73.0% by mass

<Test Example 4> Long-term low-temperature storage test 4 of the cosmetic of the present invention
Each sample of Examples 16 to 21 and Comparative Examples 16 to 21 was put in a glass storage container, sealed, and stored in a temperature-controlled room at 20 ° C., 5 ° C., and −10 ° C. for 6 months. Six months later, for each stored sample, the deposits were counted in the same manner as in Test Example 1, and the average of three cases was calculated.

  From the results of Example 16 to Example 18 in Table 4, it was found that the effect of the present invention could not be sufficiently obtained with a dosage form having less δ-tocopherol than compound (1). Moreover, in Example 20 with little content of 2-ethylhexanoic acid triglyceride and methylphenyl polysiloxane which are oil agents, and Example 21 containing solid fats and oils, the effect of this invention has fallen a little, and 25 degreeC Thus, it was found that the amount ratio of the liquid oil agent and the amount ratio of the solid oil agent at 25 ° C. also affect the effect of the present invention.

<Test Example 5> Melanin production inhibition test of the external preparation for skin of the present invention Four sites of 1.5 cm × 1.5 cm are set on the inner side of the forearm of 10 subjects, and one of the four sites is The cream produced in Example 1 was compared with Comparative Example 1-1 at another site, Example 5 at another site, and the cream of Example 6 at another site for 1 week, 1 day. It was applied 3 times. One week later, light was shielded from areas other than the four set sites, and the set sites were irradiated with ultraviolet rays for 3 consecutive days. The amount of energy of the irradiated ultraviolet rays was an amount equivalent to 1.0 MED (Minimum Erythema Dose) of the subject, which was measured in advance (a total amount equivalent to 3.0 MED). The cream was applied three times a day for 21 consecutive days, including 3 days of UV irradiation. 7 days and 21 days after the first ultraviolet irradiation, with respect to the areas irradiated with ultraviolet rays, 7 days and 21 days after the first ultraviolet irradiation, the three set sites and their adjacent sites (sites that were shielded from light) The brightness (L value) was measured with a color difference meter (Konica Minolta color difference meter CR300). About the measurement result, the average value of L value was computed for every setting site | part of 10 test subjects. Furthermore, the difference (ΔL value: L value of the adjacent part−L value of the ultraviolet irradiation part) of the L part between the set part (ultraviolet irradiation part) after 21 days and the ultraviolet non-irradiated adjacent part was calculated. The results are shown in Table 5.

  As shown in Table 5, after 7 days of ultraviolet irradiation, the L value (brightness) of the cream application sites of Example 1, Comparative Example 1-1, Example 5, and Example 6 was lower than that of the non-ultraviolet irradiation sites. It was. That is, it can be seen that the lightness of the skin is reduced by pigmentation by ultraviolet irradiation. Furthermore, the ΔL values calculated for the difference in L value (lightness) between the set site 21 days after the ultraviolet irradiation and the non-irradiated site were compared for each application site. Compared with the cream of Comparative Example 1-1 not containing compound (1), Example 1 containing compound (1), Example 5 containing compound (5), Example 6 containing compound (6) It can be seen that in the cream No., the ΔL value indicating the difference from the non-irradiated site is small, and the brightness is recovered. That is, it was found that the cream containing the compound (1), the compound (5), and the compound (6) is excellent in the action of remarkably improving pigmentation.

  The present invention can be applied to an external preparation for skin.

Claims (9)

1) A compound selected from the compound represented by the following general formula (1) and / or a salt thereof, and 2) a compound having at least three conjugated double bonds that is liquid at 1 atm and 25 ° C. A topical skin preparation containing two or more species.

General formula (1)
(However, wherein _R 1, _{R 2} each independently represent an alkyl group having 3 to 6 carbon atoms, _{R 3} represents a hydrogen atom, an acyl group or an alkyl group having 1 to 4 carbon atoms having 1 to 4 carbon atoms , R ₄ represents a group having aromaticity.) The skin external preparation according to claim 1, wherein the compound represented by the general formula (1) is a compound represented by the following general formula (2) or general formula (3): .

General formula (2)
(However, in the formula, R ₁ and R ₂ represent the same group as in general formula (1), and R ₅ is a hydrogen atom, a hydroxyl group, an alkyl group having 1 to 4 carbon atoms, an acyloxy group having 1 to 4 carbon atoms, or a carbon number. 1-4 represents an alkyloxy group, and X represents an oxygen atom, a sulfur atom or —NH—.)

General formula (3)
(In the formula, R ₆ is a hydrogen atom, an alkyl group, an alkenyl group, a phenyl group, an alkyloxy group, a hydroxyl group, a mercapto group, a trifluoromethyl group, an amino group, an alkylamino group, a nitro group, a cyano group, or a formyl group. Represents a carboxyl group, an alkylamide group, a sulfenyl group, a sulfonyl group or a halogen atom.) The compound represented by the general formula (1) is 2,6-di-tert-butyl-4- (2′-thenoyl) phenol, 3,5-di-tert-butyl-4-hydroxybenzophenone, 3, 5-di-tert-butyl-4-hydroxy-4′-fluorobenzophenone, 3,5-di-tert-butyl-4-hydroxy-4′-chlorobenzophenone, 3,5-di-tert-butyl-4- Hydroxy-4'-methylbenzophenone, 3,5-di-tert-butyl-4-hydroxy-4'-methoxybenzophenone, 3,5-di-tert-butyl-4-hydroxy-2 ', 4', 6 ' -Trimethylbenzophenone, 3,5-di-tert-butyl-4,4'-dihydroxybenzophenone, 3,3 ', 5,5'-tetra-tert-butyl-4 , 4'-dihydroxybenzophenone and (3,5-di-tert-butyl-4-hydroxyphenyl) -2-naphthalenylmethanone, characterized in that The skin external preparation as described. The compound having at least three conjugated double bonds which is liquid at 1 atm and 25 ° C. is α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, vitamin E nicotinic acid ester, tocopherol acetate, vitamin D ₂ , vitamin D ₃ , retinol, retinal, retinoic acid, 4-methoxycinnamic acid or its derivative, aminobenzoic acid or its derivative, phenoxyethanol, phenethyl alcohol, methyl cinnamate, lilyal, anisole, cyclamenaldehyde, dimethyl acetate Claims characterized in that they are selected from benzyl carvinyl, isopentyl salicylate, benzyl salicylate, phenylacetic acid, styryl acetate, 2-isobutyl-3-methoxypyrazine, vanillin and jasminal. -3 skin external preparation according to any one. The ratio of the sum of the contents of the compound represented by the general formula (1) and the sum of the contents of the compound having at least three conjugated double bonds, which is liquid at 1 atm and 25 ° C., The skin external preparation according to any one of claims 1 to 4, wherein the mass ratio is 1: 1 to 1:10. The sum of the contents of the compounds represented by the general formula (1), the sum of the contents of the compounds having at least three conjugated double bonds that are liquid at 1 atm and 25 ° C., and oil. The sum of the contents of the compound (oil agent component) other than the compound represented by the general formula (1) in the phase and the compound having at least three conjugated double bonds that is liquid at 1 atm and 25 ° C. The skin external preparation according to any one of Claims 1 to 5, wherein the ratio of is a mass ratio of 1: 2 to 1:50. The oil agent component is composed only of a component that is liquid at 1 atm and 25 ° C except for the compound represented by the general formula (1) and a salt thereof. The external preparation for skin according to Item. The external preparation for skin according to any one of claims 1 to 7, which is used for suppressing melanin production. The skin external preparation according to any one of claims 1 to 8, which is in an emulsifier form.