JP2008308429A - Stable external preparation for skin - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an emulsion form external preparation for skin, which contains a hydroquinone glycoside and/or an ascorbic acid derivative, and a non-ionic surfactant, and has improved high temperature storage stability. <P>SOLUTION: This emulsion form external preparation for the skin comprises (1) one or more compounds selected from hydroquinone glycosides and their salts, ascorbic acid derivatives and their salts, (2) a nonionic surfactant, and (3) a compound represented by general formula (1) and/or its salt. 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 a group having aromatic property. <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.

  Hydroquinone glycosides such as arbutin, ascorbic acid glycosides such as ascorbic acid-2-glucoside, and ascorbic acid mineral esters such as ascorbic acid phosphate stabilize unstable hydroquinone and ascorbic acid, It is a useful whitening material that can be used. Other ingredients are useful in practical cosmetic preparations such as lotions, milky lotions, creams, etc. without any practical problems. When exposed to extreme high temperatures, such as when left inside, sometimes emulsified or partially separated from the water phase due to micelle association or coalescence. There were cases, and a response to such a situation was desired. As a factor of such high temperature destabilization, for example, an interaction between these materials and a nonionic surfactant under high temperature has been pointed out (for example, Patent Document 1, Patent Document 2, Patent Document). 3). It is said that this is also due to the fact that the hydrophilic portion of the nonionic surfactant becomes hydrophobic in a high temperature range. Since it is considered that the micelles become larger by associating or uniting in this manner, it is considered to affect the percutaneous absorption of the active ingredient (see, for example, Non-Patent Document 1) and should be avoided.

  Further, among the compounds represented by the general formula (1), as in 2,6-di-tert-butyl-4- (2′-thenoyl) phenol, it has an antioxidant action and suppression of prostaglandins. It is known that there are those having anti-inflammatory action, anti-allergic action, anti-rheumatic action, etc. as a mechanism (for example, Patent Document 4, Patent Document 5, Patent Document 6, Patent Document 7, Non-Patent Document 2). , See Non-Patent Document 3). It is also known that the compound has a whitening effect (Japanese Patent Application No. 2006-036842).

  However, in a skin external preparation in an emulsified form containing a hydroquinone glycoside or ascorbic acid derivative and a nonionic surfactant, the compound represented by the general formula (1) is allowed to coexist, thereby causing extreme high-temperature storage conditions. It has not been known that the stability of the emulsified skin external preparation below is improved.

JP 2006-117534 A JP 2006-8709 A JP 2000-256173 A JP-A-53-141265 JP 63-008380 A JP 63-502281 A Japanese Translation of National Publication No. 06-501919 Luppi B., et al, Drug Deli. 2002; 9 (3): 147-52 Agents and Action, Vol.12, No.5, 674-683, (1982) Bioorganic & Medicinal Chemistry, Vol.11, 4207-4216, (2003)

  The present invention has been made in view of such a situation, and in an emulsified skin external preparation containing a hydroquinone glycoside or an ascorbic acid derivative, the skin in an emulsified form that is stable even under extreme high-temperature storage conditions It is an object to provide an external preparation.

  In view of such a situation, the present inventors include a hydroquinone glycoside and an ascorbic acid derivative, and in the skin external preparation in an emulsified form emulsified with a nonionic surfactant, the general formula (1) By coexisting the compounds represented, it has been found that a skin emulsification agent in a stable emulsified form can be obtained even under extremely high temperature storage conditions, and the present invention has been completed. That is, the present invention is as follows.

(1) 1) One or more selected from hydroquinone glycosides and salts thereof, ascorbic acid derivatives and salts thereof, 2) nonionic surfactants, and 3) the following general formula ( A skin external preparation in an emulsified form containing the compound represented by 1) and / or a salt thereof.

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。）
（２） 前記一般式（１）で表される化合物が、次に示す、一般式（２）又は一般式（３）で表される化合物であることを特徴とする、（１）に記載の乳化形態の皮膚外用剤。

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) An emulsified external skin 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 An emulsified external skin preparation.
(4) The hydroquinone glycoside and salt thereof, the ascorbic acid derivative and salt thereof are selected from hydroquinone glucoside, hydroquinone maltoside, ascorbic acid phosphate ester salt, and ascorbic acid glucoside, The skin external preparation in the emulsified form according to any one of 1) to (3).
(5) The nonionic surfactant has a polyoxyethylene group as a hydrophilic group, and has an acyl group or alkyl group having 12 to 24 carbon atoms as a lipophilic group, (1)-(4) The skin external preparation of the emulsified form in any one.
(6) The emulsified external preparation for skin according to any one of (1) to (5), which contains only a nonionic surfactant as a surfactant.
(7) 1) The sum of the content of one or more selected from hydroquinone glycosides and salts thereof, ascorbic acid derivatives and salts thereof, and the content of the compound represented by the general formula (1) The skin external preparation in the emulsified form according to any one of (1) to (6), wherein the ratio of the sum to the sum is 10: 1 to 2: 1 in terms of mass ratio.
(8) The emulsified external preparation for skin according to any one of (1) to (7), wherein the preparation is for melanin production suppression.

  ADVANTAGE OF THE INVENTION According to this invention, even if it contains hydroquinone glycoside and its salt, an ascorbic acid derivative, and its salt, the skin external preparation of the emulsified form excellent in high temperature storage stability can be provided.

(1) Hydroquinone glycoside and its salt, ascorbic acid derivative and salt thereof, which are essential components of the skin external preparation of the present invention The skin external preparation of the present invention comprises hydroquinone glycoside and its salt And an ascorbic acid derivative and a salt thereof. Hydroquinone glycoside is a compound in which sugar is glycosidically bonded to hydroquinone. Examples of the sugar include monosaccharides such as glucose, mannose and galactose, disaccharides such as maltose, lactose and cellobiose, and trisaccharides such as maltotriose. Among these, it is preferable to use arbutin which is a glucoside. This is because arbutin is relatively excellent in stability and is easily available because there are commercial products. As the ascorbic acid derivative, a derivative of the hydroxyl group at the 2-position of ascorbic acid is excellent in stability, and it is preferable to use a compound derivatized at this position. As such a compound, a 2-glycoside form of ascorbic acid can be mentioned. Among such compounds, ascorbic acid-2-glucoside, which is a glucoside, is relatively stable and preferred because it is commercially available. As another ascorbic acid derivative, an ascorbic acid-2-phosphate ester in which the hydroxyl group at the 2-position of ascorbic acid is phosphorylated is relatively stable, and there are commercially available products, which are preferable.

  Such hydroquinone glycosides and ascorbic acid derivatives 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) Compound represented by general formula (1) which is an essential component of the external preparation for skin of the present invention The skin external preparation of the present invention is a compound represented by general formula (1) and / or a salt thereof. It is characterized by containing. 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 replacing the thiophene and thiophenecarboxylic acid with furan and furancarboxylic acid, a compound represented by the general formula (2) in which X is an oxygen atom 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.

(3) Nonionic surfactant which is an essential component of the skin external preparation of the emulsified form of the present invention The skin external preparation of the emulsified form of the present invention is composed of hydroquinone glycoside and its salt, alcorbic acid derivative and its salt. It is characterized by containing a nonionic surfactant together with one or more selected. Examples of the lipophilic group of the nonionic surfactant include saturated, unsaturated, branched acyclic aliphatic hydrocarbon groups, sterol groups such as acyl groups and phytosterols. Examples of the hydrophilic group include residues of polyhydric alcohols such as polyoxyethylene residues, polyglycerin residues and sorbitan residues, and saccharide residues such as sucrose residues and polysaccharides. Examples of the bond between the lipophilic group and the hydrophilic group include an ester bond, an ether bond, and a glycoside bond.
Examples of such nonionic surfactants include sorbitan fatty acid esters such as sorbitan monostearate and sorbitan sesquioleate, glycerin fatty acids such as glyceryl monostearate, and propylene glycol fatty acid esters such as propylene glycol monostearate. , Polyoxyethylene (POE) hydrogenated castor oil derivative, glycerin alkyl ether, POE sorbitan monolaurate, POE sorbitan monooleate, POE sorbitan fatty acid esters such as polyoxyethylene sorbitan monostearate, POE-sorbite monolaurate, etc. POE sorbite fatty acid esters, POE glycerol fatty acid esters such as POE-glycerol monoisostearate, POE monolaurate, POE monooleate, PO POE fatty acid esters such as distearate, POE cetyl ether, POE alkyl ethers such as POE2-octyldodecyl ether, POE alkylphenyl ethers such as POE nonylphenyl ether, Pluronics®, POE / POP2-decyltetradecyl Nonionic surfactants such as POE / POP alkyl ethers such as ether, Tetronic (registered trademark), POE castor oil, POE castor oil such as POE hydrogenated castor oil, hardened castor oil derivatives, sucrose fatty acid ester, alkyl glucoside, etc. Examples include agents.
Among these, a compound having a polyoxyethylene group (POE) as a hydrophilic group and a saturated, unsaturated, branched acyl group or alkyl group having 12 to 24 carbon atoms as a lipophilic group is preferable. The added mole number of the polyoxyethylene group is preferably 2 to 60 although it depends on the structure of the lipophilic group. In the skin external preparation in the emulsified form containing hydroquinone glycoside and ascorbic acid derivative, the effect of the present invention is most obtained when such a nonionic surfactant having a polyoxyethylene group is used. It is easy.

(4) Skin external preparation of the emulsified form of the present invention The skin external preparation of the emulsified form of the present invention is 1) one or more selected from hydroquinone glycosides and salts thereof, ascorbic acid derivatives and salts thereof. And 2) a nonionic surfactant and 3) a compound represented by the above general formula (1) and / or a salt thereof as essential components. In the skin external preparation of the emulsified form of the present invention, the hydroquinone glycoside and its salt, or the ascorbic acid derivative and its salt may contain only one kind, or may contain two or more kinds. The compound represented by the general formula (1) and / or a salt thereof may contain one kind or two or more kinds.

  The present invention relates to a skin external preparation in an emulsified form using a nonionic surfactant as an emulsifier, containing a hydroquinone glycoside and a salt thereof, an ascorbic acid derivative and a salt thereof, and the extreme high-temperature storage conditions The present invention relates to a technique for obtaining a stable external preparation for skin even when exposed to water. Here, in the skin external preparation of the emulsifier type containing hydroquinone glycoside and / or its salt, ascorbic acid derivative and / or its salt, the stabilization effect by making the compound represented by General formula (1) coexist. Is remarkable when the surfactant to be used is a nonionic surfactant, and more remarkable when the surfactant to be used is a nonionic surfactant having a polyoxyethylene group. It becomes more prominent when it consists only of nonionic surfactant which has, and is preferable.

  The preferred content of hydroquinone glycoside and / or salt thereof, ascorbic acid derivative and / or salt thereof in the emulsified external skin preparation of the present invention is a content suitable for the purpose of blending in these external skin preparations. Specifically, for example, if the purpose of blending is whitening, the total amount thereof is 0.1% by mass or more, preferably 0.2% by mass or more, more preferably, based on the total amount of the external preparation for skin. It is 0.5 mass% or more. On the other hand, the upper limit is 10% by mass or less, preferably 8% by mass or less, more preferably 6% by mass or less. This is because if the content is too low, the effect for the purpose of blending such as a sufficient whitening effect cannot be exhibited. On the other hand, if the content is too much, the effect for the purpose of blending will reach its peak, and the degree of freedom of formulation may be impaired.

  In the skin external preparation of the emulsified form of the present invention, the compound represented by the general formula (1) or a salt thereof may contain only one species or may contain two or more species in combination. The preferable content of the compound represented by the general formula (1) in the external preparation for skin of the present invention is 0.01% by mass or more, preferably 0.05% by mass or more, and more preferably based on the total amount of the external preparation for skin. Is 0.1% by mass or more. On the other hand, the upper limit is 3% by mass or less, preferably 2% by mass or less, and more preferably 1% by mass or less. This is because even if the content is too low or too high, it is difficult to obtain the effect of maintaining the surface activity of the nonionic surfactant in the high temperature range of the present invention.

  The sum of the content of hydroquinone glycoside and / or its salt, ascorbic acid derivative and / or its salt and the content of the compound represented by the general formula (1) in the skin external preparation of the emulsified form of the present invention The ratio to the sum is preferably 10: 1 to 1: 1 by mass ratio. This is because the effects of the present invention can be best exhibited when used in this range.

  Further, in the skin external preparation of the emulsified form of the present invention, various components generally used in pharmaceuticals, cosmetics and the like, that is, fats and oils, waxes, hydrocarbons, as long as the stability of the dosage form is not hindered. , Fatty acids, higher alcohols, esters, oils, aqueous components, powder components, humectants, thickeners, surfactants, powders, colorants, fragrances, pH adjusters, chelating agents, preservatives, vitamins , Other whitening agents, anti-inflammatory agents and the like.

  Specific examples of the fats and waxes include macadamia nut oil, avocado oil, corn oil, olive oil, rapeseed oil, sesame oil, castor oil, safflower oil, cottonseed oil, jojoba oil, coconut oil, palm oil, liquid lanolin, Oils such as hardened coconut oil, hardened oil, mole, hardened castor oil, beeswax, candelilla wax, carnauba wax, ibotarou, lanolin, reduced lanolin, hard lanolin, jojoba wax, waxes, liquid paraffin, squalane, pristane, ozokerite, paraffin, Examples include hydrocarbons such as ceresin, petrolatum, and microcrystalline wax, and examples of fatty acids include higher fatty acids such as oleic acid, isostearic acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, and undecylenic acid. High-class Cole includes cetyl alcohol, stearyl alcohol, isostearyl alcohol, behenyl alcohol, octyldodecanol, myristyl alcohol, cetostearyl alcohol, and esters include cetyl isooctanoate, isopropyl myristate, hexyldecyl isostearate, adipine Diisopropyl acid, di-2-ethylhexyl sebacate, cetyl lactate, diisostearyl malate, ethylene glycol di-2-ethylhexanoate, neopentyl glycol dicaprate, glycerin di-2-heptylundecanoate, tri-2-ethyl Glycerin hexanoate, tri-2-ethylhexanoic acid trimethylolpropane, triisostearic acid trimethylolpropane, tetra-2-ethylhexanoic acid pe Synthetic ester oils such as tan erythritol, dimerlinolate dimerlinoleate, dimerlinoleic acid (phytosteryl / isostearyl / cetyl / stearyl / behenyl), N-lauroylglutamic acid (phytosteryl / 2-octyldodecyl), etc. As the oil agent, chain polysiloxane such as dimethylpolysiloxane, methylphenylpolysiloxane, diphenylpolysiloxane, cyclic polysiloxane such as octamethylcyclotetrasiloxane, decamethylcyclopentasiloxane, dodecamethylcyclohexanesiloxane, amino-modified polysiloxane, Examples thereof include silicone oils such as polyether-modified polysiloxane, alkyl-modified polysiloxane, and modified polysiloxane such as fluorine-modified polysiloxane.

  As the humectant, glycerin, diglycerin, 1,3-butanediol, propylene glycol, dipropylene glycol, isoprene glycol, 1,2-pentanediol, 2,4-hexylene glycol, 1,2-hexanediol, 1 , 2-octanediol, polyethylene glycol, erythritol, sorbitol, xylitol, maltitol, polyhydric alcohols, sodium pyrrolidonecarboxylate, lactic acid, sodium lactate, etc., and thickeners include guar gum, quince seed, carrageenan , Galactan, gum arabic, pectin, mannan, starch, curdlan, methylcellulose, hydroxyethylcellulose, methylhydroxypropylcellulose, chondroitin sulfate, dermatan sulfate, glycogen, Paran 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, chitosan, carboxymethyl Examples include chitin, agar, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene glycol, and bentonite.

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.

  Moreover, since the compound represented by the general formula (1) has an excellent melanin production inhibitory action, it is also a preferred form to be used as a skin external preparation for melanin production inhibition or whitening.

  The skin external preparation of the emulsified form of the present invention can be produced in the same manner as the preparation of skin external preparations such as ordinary 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 arbutin substituted with water was produced as Comparative Example 1-2. Further, a compound in which both the compound (1) and arbutin were substituted with water was produced as Comparative Example 1-3.
(A)
Sorbitan POE (20) lauryl ester 2.0% by mass
POE (2) lauryl ether 2.0 mass%
2-Ethylhexanoic acid triglyceride 8.0 mass%
Methylphenylpolysiloxane 1.0 mass%
Methylparaben 0.3 mass%
δ-Tocopherol 1.0% by mass
Compound (1) 0.5% by mass
(B)
Arbutin 3.0 mass%
Citric acid 0.1% by mass
Sodium citrate 0.1% by mass
Xanthan gum 0.1% by mass
1,3-butanediol 10.0% by mass
Sodium hydroxide 0.1% by mass
Purified water 71.8% by mass

<Test Example 1> High temperature storage test 1 of the external preparation for skin according to 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 thermostatic chamber at 60 ° C. for 2 weeks. Two weeks later, the contents of each stored sample were observed.
Three cases were judged according to the following criteria, and the average was calculated. The results are shown in Table 1.
0: No separation (separation cannot be confirmed even if the container is tilted)
1: Slight separation (inclined container can confirm separation state)
2: Separation (separation status can be confirmed without tilting the container)
3: Clear separation (the state of separation can be clearly confirmed without tilting the container)

  From the results in Table 1, it can be seen that in Comparative Example 1-3 containing neither arbutin nor compound (1), slight separation was observed, but the dosage form was relatively stable. Further, although slight separation was observed in Comparative Example 1-2 containing only compound (1), compound (1) does not significantly affect the stability of the dosage form under high temperature storage conditions. I understand. Here, in Comparative Example 1-1 containing only arbutin, clear separation was observed after high-temperature storage, indicating that arbutin impairs the stability of the dosage form. On the other hand, the cream of Example 1 containing arbutin and compound (1) was found to be stable in dosage form even after high temperature storage. That is, in Example 1, it was found that the stability of the dosage form was ensured while containing arbutin.

  In the formulation of Example 1, arbutin was substituted with ascorbic acid-2-glucoside to produce the cream of Example 2. In Example 2, the compound (1) substituted with water was produced as Comparative Example 2.

  The cream of Example 3 was prepared by substituting arbutin with ascorbic acid-2-phosphate sodium salt in the formulation of Example 1. In Example 3, the compound (1) substituted with water was produced as Comparative Example 3.

<Test Example 2> High-temperature storage test 2 of the external preparation for skin according to the present invention
Each sample of Example 2, Comparative Example 2, Example 3, and Comparative Example 3 was put in a glass storage container, sealed, and stored in a thermostatic chamber at 60 ° C. for 2 weeks. Two weeks later, the state of the contents of each storage sample was observed, and the stability was evaluated in the same manner as in Test Example 1.

  From the results in Table 2, in Comparative Example 2 or Comparative Example 3 containing ascorbic acid-2-glucoside or sodium ascorbic acid-2-phosphate and not containing compound (1), the stability of the dosage form was impaired. You can see that In contrast, in Example 2 or Example 3 containing ascorbic acid-2-glucoside or sodium ascorbic acid-2-phosphate and compound (1), it can be seen that the stability of the dosage form is ensured. .

  The cream of Example 4 was produced by replacing Compound (1) with Compound (2) in the formulation of Example 1.

  The cream of Example 5 was prepared by replacing Compound (1) with Compound (3) in the formulation of Example 1.

  The cream of Example 6 was produced by replacing Compound (1) with Compound (4) in the formulation of Example 1.

  The cream of Example 7 was prepared by replacing Compound (1) with Compound (5) and arbutin with ascorbic acid-2-glucoside in the formulation of Example 1.

  The cream of Example 8 was produced by replacing Compound (1) with Compound (6) in the formulation of Example 7.

  The cream of Example 9 was produced by replacing Compound (1) with Compound (7) in the formulation of Example 7.

  The cream of Example 10 was prepared by replacing Compound (1) with Compound (8) in the formulation of Example 7.

  The cream of Example 11 was prepared by replacing Compound (1) with Compound (9) and arbutin with ascorbic acid-2-phosphate sodium salt in the formulation of Example 1.

  The cream of Example 12 was produced by replacing Compound (1) with Compound (10) in the formulation of Example 11.

  The cream of Example 13 was prepared by replacing Compound (1) with Compound (11) in the formulation of Example 11.

<Test Example 3> High-temperature storage test 3 of the external preparation for skin according to the present invention
Each sample of Examples 4 to 13 and Comparative Examples 4 to 13 was put in a glass storage container, sealed, and stored in a thermostatic chamber at 60 ° C. for 2 weeks. Two weeks later, the stability of the dosage form was evaluated in the same manner as in Test Example 1 for each storage sample.

  From the results of Table 3, with respect to Comparative Example 1-1 containing only arbutin, Examples 4 to 6 containing only arbutin and compound (2) to compound (4), only ascorbic acid-2-glucoside To Comparative Example 3 containing Ascorbic acid-2-glucoside and Examples 7 to 10 containing compounds (5) to (8), Comparative Example 3 containing sodium salt of Ascorbic acid-2-phosphate In contrast, in Examples 11 to 13 containing ascorbyl 2-phosphate sodium salt and compounds (9) to (11), it was found that the stability of the dosage form under high temperature storage conditions was ensured. It was.

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 14. In Example 14, the compound (1) substituted with water was produced as Comparative Example 14.
(A)
Sorbitan POE (20) lauryl ester 2.0% by mass
POE (2) lauryl ether 2.0 mass%
2-Ethylhexanoic acid triglyceride 8.0 mass%
Methylphenylpolysiloxane 1.0 mass%
Methylparaben 0.3 mass%
δ-Tocopherol 1.0% by mass
Compound (1) 0.5% by mass
(B)
Arbutin 0.3% by mass
Citric acid 0.1% by mass
Sodium citrate 0.1% by mass
Xanthan gum 0.2% by mass
1,3-butanediol 10.0% by mass
Sodium hydroxide 0.1% by mass
Purified water 74.4% 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 15. In the formulation of Example 15, a compound (1) substituted with water was produced as Comparative Example 15.
(A)
Sorbitan POE (20) lauryl ester 2.0% by mass
POE (2) lauryl ether 2.0 mass%
2-Ethylhexanoic acid triglyceride 8.0 mass%
Methylphenylpolysiloxane 1.0 mass%
Methylparaben 0.3 mass%
δ-Tocopherol 1.0% by mass
Compound (1) 0.5% by mass
(B)
Arbutin 10.0% by mass
Citric acid 0.1% by mass
Sodium citrate 0.1% by mass
Xanthan gum 0.2% by mass
1,3-butanediol 10.0% by mass
Sodium hydroxide 0.1% by mass
Purified water 64.7% by mass

<Test Example 4> High-temperature storage test 4 of the external preparation for skin according to the present invention
Each sample of Example 14, Comparative Example 14, Example 15, and Comparative Example 15 was put in a glass storage container, sealed, and stored in a thermostatic chamber at 60 ° C. for 2 weeks. Two weeks later, the state of the contents of each storage sample was observed, and the stability was evaluated in the same manner as in Test Example 1.

  From the results of Table 4, in Example 14 where the ratio of the content of arbutin and the compound (1) is 0.3: 0.5, also in Example 15 where the ratio is 10: 0.5, no comparison is made with no compound (1). Compared with Example 14 and Comparative Example 15, it can be seen that the stability of the dosage form during high-temperature storage is ensured. From this result, it can be seen that the content ratio of arbutin to compound (1) in the external preparation for skin is preferably 10: 1 to 1: 1.

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. A compound in which the compound (1) was replaced with water in the formulation of Example 16 was produced as Comparative Example 16.
(A)
Polyglycerin (10) monooleate 2.0% by mass
Sorbitan monolaurate 2.0% by mass
2-Ethylhexanoic acid triglyceride 8.0 mass%
Methylphenylpolysiloxane 1.0 mass%
Methylparaben 0.3 mass%
δ-Tocopherol 1.0% by mass
Compound (1) 0.5% by mass
(B)
Arbutin 3.0 mass%
Citric acid 0.1% by mass
Sodium citrate 0.1% by mass
Xanthan gum 0.2% by mass
1,3-butanediol 10.0% by mass
Sodium hydroxide 0.1% by mass
Purified water 71.7% 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 compound (1) substituted with water was produced as Comparative Example 17.
(A)
Sorbitan POE (20) lauryl ester 2.0% by mass
Sucrose laurate 2.0% by mass
2-Ethylhexanoic acid triglyceride 8.0 mass%
Methylphenylpolysiloxane 1.0 mass%
Methylparaben 0.3 mass%
δ-Tocopherol 1.0% by mass
Compound (1) 0.5% by mass
(B)
Arbutin 3.0 mass%
Citric acid 0.1% by mass
Sodium citrate 0.1% by mass
Xanthan gum 0.2% by mass
1,3-butanediol 10.0% by mass
Sodium hydroxide 0.1% by mass
Purified water 71.7% by mass

<Test Example 5> High-temperature storage test 5 of the external preparation for skin according to the present invention
Each sample of Example 16, Comparative Example 16, Example 17, and Comparative Example 17 was put in a glass storage container, sealed, and stored in a thermostatic chamber at 60 ° C. for 2 weeks. Two weeks later, the state of the contents of each storage sample was observed, and the stability was evaluated in the same manner as in Test Example 1.

  From the results of Comparative Example 16 and Comparative Example 17 in Table 5, even in a dosage form using a nonionic surfactant other than the surfactant having a polyoxyethylene group, the stability of the dosage form is inhibited by containing arbutin. The effect was recognized. Also in this case, the stabilizing effect by addition of compound (1) was recognized.

<Test Example 6> Melanin production inhibition test of skin preparation for external use of emulsified form of the present invention Four sites of 1.5 cm × 1.5 cm are set on the inner part of the forearm of 10 subjects, and one of the four sites The cream produced in Example 1, Comparative Example 1-1 at another site, Comparative Example 1-2 at another site, and the cream of Comparative Example 1-3 at the other site. Was applied three times a day for one week. 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 6.

  As shown in Table 6, after 7 days of ultraviolet irradiation, the cream application sites of Example 1, Comparative Example 1-1, Comparative Example 1-2, and Comparative Example 1-3 all had an L value (less than the ultraviolet non-irradiated site). Brightness) was down. 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 containing only arbutin and the cream of Comparative Example 1-2 containing only compound (1), the cream of Example 1 containing both arbutin and compound (1) was not irradiated. It can be seen that the ΔL value indicating the difference between the values is small, and the brightness is remarkably recovered. Compared with Comparative Example 1-1 and Comparative Example 1-2, it was found that the cream of Example 1 was excellent in the action of remarkably improving pigmentation due to the synergistic effect of arbutin and compound (1). This proves that percutaneous absorption of the active ingredient is appropriately secured in a stable preparation.

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

Claims (8)

1) One or more selected from hydroquinone glycosides and salts thereof, ascorbic acid derivatives and salts thereof, 2) nonionic surfactants, and 3) the following general formula (1) A skin external preparation in an emulsified form containing the represented compound and / or a salt thereof.

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 emulsified form 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): Skin external preparation.

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 of the emulsified form of description. The hydroquinone glycoside and salt thereof, the ascorbic acid derivative and salt thereof are selected from hydroquinone glucoside, hydroquinone maltoside, ascorbic acid phosphate ester salt, and ascorbic acid glucoside. 3. The external preparation for skin according to any one of 3 above. The nonionic surfactant is one having a polyoxyethylene group as a hydrophilic group and having an acyl group or an alkyl group having 12 to 24 carbon atoms as a lipophilic group. The skin external preparation of the emulsified form of any one of -4. The emulsified external preparation for skin according to any one of claims 1 to 5, comprising only a nonionic surfactant as the surfactant. 1) The sum of the content of one or more selected from hydroquinone glycosides and salts thereof, ascorbic acid derivatives and salts thereof, and the sum of the contents of compounds represented by the general formula (1) The skin external preparation in an emulsified form according to any one of claims 1 to 6, characterized in that the ratio is 10: 1 to 1: 1 by mass ratio. It is for melanin production suppression, The skin external preparation of the emulsified form of any one of Claims 1-7 characterized by the above-mentioned.