JPH0648940A - Composition for external preparations and external preparation containing the same - Google Patents

Abstract

PURPOSE:To provide a composition which contains a high concentration of gamma-oryzanol and keeps high stability during the storage for a long period of time without deposition of gamma-oryzanol crystals. CONSTITUTION:A composition for external use containing (a) one or more than 2 mixture consisting of liquid aliphatic carboxylic acid esters of 13 to 42 carbon atoms and a liquid phthalic acid diesters of 12 to 16 carbon atoms, (b) an acylated collagen hydrolyzate, (c) gamma-oryzanol and (d) when needed, crotamiton and a preparation for external use containing the composition. The ointment, cream, lotion, solution and other preparations are effective as a gamma- oryzanol-containing preparation for external use.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a composition for external application of .gamma.-oryzanol having a high concentration of .gamma.-oryzanol and good storage stability, and an external preparation containing the same.

[0002]

BACKGROUND OF THE INVENTION γ-Oryzanol is a white to slightly yellowish hardly soluble crystal or crystalline powder obtained by extraction and purification from rice bran oil, and is used by oral administration, for example, for the treatment of menopausal disorders. , Is also considered to be effective against diseases in which secretion of sebum is considered to be reduced, such as atopic dermatitis, senile xerosis, ichthyosis vulgaris, etc., and application to these diseases as an external preparation is desired. By the way. However, since γ-oryzanol has low solubility in the base used in the external preparation, it is generally difficult to obtain an external preparation containing γ-oryzanol in a high concentration and having good storage stability.

Conventionally, in order to solve this problem, a method of dissolving γ-oryzanol in a composition composed of a liquid higher alcohol, a liquid higher fatty acid ester and a solid fatty acid ester (JP-A-56-16409), egg yolk oil or Method of dissolving in lanolin or lanolin derivative
6-161315), N-lauroyl-L-glutamic acid-2-octyldodecyl diester (hereinafter LG-O
Represented by D. )) (Japanese Patent Application Laid-Open No. 57-4262)
Γ-oryzanol solubilization methods such as 1) have been proposed.

However, even with these methods,
When the concentration of γ-oryzanol is high (for example, 8 to 10% by weight), crystals of γ-oryzanol are precipitated when stored for a long period of time, and it is difficult to obtain an external preparation having good storage stability.

Acylated hydrolyzed collagen is a condensate of a polypeptide obtained by hydrolyzing a collagen protein and a fatty acid. For example, a polypeptide obtained by hydrolyzing a collagen protein and isostearic acid, undecylenic acid, myristin A solution of a condensate of an acid or a coconut oil fatty acid or a salt thereof is known (standard for quasi drug raw materials,
Supervised by the Examination Division, Pharmaceutical Affairs Bureau, Ministry of Health and Welfare, June 15, 1991, published by Yakuji Nippo, pages 178-179, 190, 776, 813). But,
It is not known to be useful for solubilizing γ-oryzanol and preventing crystal precipitation.

In addition, crotamiton (chemical name Crotonyl-N-et
It is already known that hyl-o-toluidine) is useful, for example, for solubilizing ketoprofen or indomethacin and preventing crystal precipitation, and ketoprofen-containing cream (JP-A-61-238723) or indomethacin external cream (special Kai 59-116212) has been proposed. However, it is not known that they are useful for solubilizing γ-oryzanol having different physicochemical properties from these drugs and preventing crystal precipitation.

[0007]

DISCLOSURE OF THE INVENTION The object of the present invention is γ-
An object is to provide a stable external preparation composition of γ-oryzanol which contains oryzanol in a high concentration and does not precipitate crystals upon storage, and an external preparation containing the same.

[0008]

In order to achieve the above object, the inventors of the present invention have studied various bases, and as a result, (a) a liquid aliphatic carboxylic acid ester having 13 to 42 carbon atoms and 1 carbon atom.
2 to 42 liquid aliphatic dicarboxylic acid diester and 12 to 16 carbon liquid phthalic acid diester, 1 or 2 or more mixtures selected from the group, and (b) a base comprising acylated hydrolyzed collagen Is more useful for solubilization and storage stability of γ-oryzanol than conventional bases, and by adding crotamiton, a larger amount of γ-oryzanol can be obtained.
The present inventors have completed the present invention by discovering that oryzanol can be solubilized, and that a stable external preparation composition in which crystals do not precipitate even when stored for a long period of time can be obtained.

The liquid aliphatic carboxylic acid ester having 13 to 42 carbon atoms in the present invention is a room temperature obtained from an aliphatic carboxylic acid having a linear or branched chain and an aliphatic alcohol having a linear or branched chain. And a liquid ester,
It means that the total number of carbon atoms constituting the ester is 13 to 42.

Examples of these esters include eicosanyl propionate, isodecyl pivalate, isostearyl pivalate, isocetyl octanoate, cetyl caprylate, isobutyl pelargonate, isodecyl isononanoate, hexyldecyl dimethyloctanoate, hexyl laurate, myristin. Isopropyl acetate, butyl myristate, isocetyl myristate, octyldecyl myristate, isostearyl myristate, isopropyl palmitate, isostearyl palmitate, butyl stearate, isocetyl stearate, isopropyl isostearate, hexyldecyl isostearate, decyl oleate , Octyldodecyl ricinoleate, Isopropyl linoleate, Isostearyl erucate, Octyldodecyl erucate And the like can be given.

The liquid aliphatic dicarboxylic acid diester having 12 to 42 carbon atoms in the present invention is a room temperature obtained from an aliphatic dicarboxylic acid having a straight chain or a branched chain and an aliphatic alcohol having a straight chain or a branched chain. And a liquid diester, wherein the total number of carbon atoms constituting the diester is 12 to 4
It means 2 things. Examples of these diesters include diisopropyl adipate, diisobutyl adipate, dioctyl adipate, di (2-heptylundecyl) adipate, diethyl sebacate, and diisopropyl sebacate.

The liquid phthalic acid diester having 12 to 16 carbon atoms in the present invention is a diester which is liquid at room temperature and is obtained from phthalic acid and an aliphatic alcohol having a straight chain or a branched chain, and constitutes the diester. The total number of carbons used is 1
2 to 16 are meant. Examples of these phthalic acid diesters include diethyl phthalate and dibutyl phthalate.

In the present invention, the acylated hydrolyzed collagen is a peptide or peptide mixture (average molecular weight of less than 1000) obtained by hydrolyzing collagen protein with acid, alkali, enzyme or a combination thereof.
And a condensate of a C10 to C25 linear or branched aliphatic carboxylic acid, or a mixture of these condensates.

These acylated hydrolyzed collagens are known (standard for quasi-drug raw materials, supervised by the Ministry of Health, Labor and Welfare Pharmaceutical Affairs Bureau Examination Division, June 15, 1991, published by Yakuji Nippo, pages 178-179, 190.
Pp. 776, 813) or according to a known method for producing acylated hydrolyzed collagen.

Specific examples of the acylated hydrolyzed collagen include myristoyl hydrolyzed collagen, palmitoyl hydrolyzed collagen, stearoyl hydrolyzed collagen, isostearoyl hydrolyzed collagen, oleoyl hydrolyzed collagen, and undecylenoyl hydrolyzed. Examples thereof include degraded collagen, hydrolyzed lauroylated collagen, and a condensate of coconut oil fatty acid and hydrolyzed collagen.

The external preparation composition of the present invention has 13 to 4 carbon atoms.
2 liquid aliphatic carboxylic acid ester having 12 to 42 carbon atoms
Of liquid aliphatic dicarboxylic acid diester and carbon number 12
~ 16 of liquid phthalic acid diester, and a mixture of one or more kinds (hereinafter simply referred to as esters) selected from the group consisting of liquid phthalic acid diester and acylated hydrolyzed collagen with γ-
Add oryzanol, and if necessary, crotamiton,
For example, it can be easily produced by heating to 80 to 90 ° C. to dissolve γ-oryzanol and then cooling to room temperature.

The amount of the ester used relative to the acylated hydrolyzed collagen is usually 1 to 10 parts by weight, preferably 2 to 5 parts by weight, based on 1 part by weight of the acylated hydrolyzed collagen.

The amount of crotamiton added is usually 0.1 to 4 parts by weight per 1 part by weight of acylated hydrolyzed collagen.

The amount of γ-oryzanol used is usually 1 to 10% by weight based on the total amount of the external preparation composition of the present invention when crotamiton is not added, and the external preparation composition of the present invention is added when crotamiton is added. It is 1 to 20% by weight based on the total amount of the product.

Although the composition of the present invention can be used as it is as an external preparation, it is an emulsifier (eg, a surfactant such as polyoxyethylene lauryl ether) or an emulsion stabilizer (eg, alginic acid) which is usually used in the production of pharmaceuticals or cosmetics. Propylene glycol, carboxyvinyl polymer, etc.), wetting agent (eg, glycerin, propylene glycol, sodium dl-pyrrolidone carboxylate liquid, etc.), preservative (eg, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, paraoxybenzoic acid) Butyl or the like) or other additives, and if necessary, crude drug extracts (perilla extract, carrot extract, dio extract, etc.) and various ointments, lotions, W / O type creams, O / W type creams, etc. Use external preparations such as liquids It can be.

[0021]

EFFECT OF THE INVENTION γ-Oryzanol has a higher solubility in the mixture of the ester used in the present invention and the acylated hydrolyzed collagen than in the known base, and the solution is crystalline even if stored for a long period of time. Is stable without precipitation (see Test Example below). Therefore, the composition of the present invention and various external preparations produced by adding pharmaceutical or cosmetic raw materials to the composition of the present invention are useful as therapeutic agents for skin diseases or cosmetics.

The effects of the present invention will be described below with reference to test examples. In the following, percentages mean% by weight unless otherwise specified. [Test Example 1] Comparison of Solubility of γ-Oryzanol in Various Bases 1. Test composition Composition of Examples 1-14 and composition of Comparative Examples 1-8 1. Test Method After the test composition was prepared, the presence or absence of crystal precipitation when stored at 5 ° C. for 1 month was observed with the naked eye or a microscope. 3. Test results: Table 1 shows + when the crystals were precipitated and − when the crystals were not precipitated. In Table 1, in the column of composition
Represents the following. : Γ-oryzanol -1): Isopropyl isostearate -2): Hexyldecyl isostearate: Isostearoylated hydrolyzed collagen: Crotamiton -1): Myristyl lactate -2): Propylene glycol monostearate: LG-OD

[0023]

[Table 1] As shown in Table 1, the composition of the present invention contains γ-oryzanol in a high concentration and is excellent in storage stability as compared with the conventional composition of Comparative Example.

[Test Example 2] Comparison of storage stability (crystal precipitation) of petrolatum ointment 1. Test formulation Formulation of Comparative Example 9 and Example 15. Test method After the test preparation was stored at room temperature for 1 week, the presence or absence of crystal precipitation was observed with a microscope (magnification: 200 times) to compare storage stability. 3. Test Results FIG. 1 shows a photomicrograph of the formulation of Example 15 stored at room temperature for 1 week, and FIG. 2 shows a photomicrograph of the formulation of Comparative Example 9 similarly stored.

No crystal precipitation of γ-oryzanol was observed in the preparation of Example 15, but crystal precipitation was observed in the preparation of Comparative Example 9.

[0026]

EXAMPLES The present invention will be described in more detail below with reference to examples and comparative examples. Example 1 6 g of γ-oryzanol was added to a mixture of 47 g of isostearoylated hydrolyzed collagen and 47 g of isopropyl isostearate, and the mixture was heated with stirring at 90 ° C. and then cooled to room temperature to prepare a γ-oryzanol-containing composition. Examples 2 to 3 γ-oryzanol-containing compositions of Examples 2 to 3 were prepared in the same manner as in Example 1 except that the amounts of γ-oryzanol, hydrolyzed isostearoylated collagen and isopropyl isostearate were changed. Γ in each example
-The amount of oryzanol, isostearoylated hydrolyzed collagen and isopropyl isostearate used in Table 2
Shown in.

[0027]

[Table 2] Example 4 6 g of γ-oryzanol is 25% isostearoylated hydrolyzed collagen-hexyl decyl isostearate solution [trade name Promoise E-118 (HI); Seiwa Kasei Co., Ltd.] 9
In addition to 4 g, the mixture was heated with stirring at 90 ° C. and then cooled to room temperature to prepare a γ-oryzanol-containing composition.

Examples 5-6 γ-oryzanol, 25% isostearoylated hydrolyzed collagen-hexyl decyl isostearate solution (trade name: Promois E-118 (HI); Seiwa Kasei Co., Ltd.) except that the amount used is changed. In the same manner as in Example 4, γ-oryzanol-containing compositions of Examples 5 to 6 were prepared. Table 3 shows the amounts of γ-oryzanol and 25% isostearoylated hydrolyzed collagen-hexyldecyl isostearate solution [trade name Promoise E-118 (HI); SEIWA KASEI CO., LTD.] Used in each example.

[0029]

[Table 3]

Example 7 25 g of 6 g of γ-oryzanol and 10 g of crotamiton
% Isostearoylated hydrolyzed collagen-hexyldecyl isostearate solution (trade name Promois E-118 (H.
I.); Seiwakasei Co., Ltd.] 84 g was added, and the mixture was heated with stirring at 90 ° C. and then cooled to room temperature to prepare a γ-oryzanol-containing composition. Examples 8 to 14 Except that the amount of [gamma] -oryzanol, crotamiton and 25% isostearoylated hydrolyzed collagen-hexyldecyl isostearate solution (trade name Promoise E-118 (HI); Sawa Kasei Co., Ltd.) was changed. The γ-oryzanol-containing compositions of Examples 8 to 14 were prepared in the same manner as in Example 7. The amounts of γ-oryzanol, crotamiton, and 25% isostearoylated hydrolyzed collagen-hexyldecyl isostearate solution [trade name Promoise E-118 (HI); Naruwa Kasei Co., Ltd.] used in each example are shown in Table 4.
Shown in.

[0031]

[Table 4]

Example 15 Vaseline ointment ; (formulation) γ-oryzanol 5 g Vaseline 50 g 25% isostearoylated hydrolyzed collagen-hexyldecyl isostearate solution [trade name Promois E-118 (HI); Suwakasei Co., Ltd.] 45 g (Production method) After dissolving γ-oryzanol at 80 ° C. in 25% isostearoylated hydrolyzed collagen-hexyldecyl isostearate solution (trade name: Promois E-118 (HI); Seiwa Kasei Co., Ltd.), further vaseline Was added, mixed and stirred, and cooled to room temperature to obtain 5% γ-oryzanol-containing petrolatum ointment.

Example 16 Lotion ; (Formulation) Component [A]: γ-Oryzanol 1 g Isostearoylated hydrolyzed collagen 2.9 g Isopropyl stearate 8.6 g Cetanol 4 g Beeswax 1 g Stearic acid 2 g Silicone oil 0.5 g Polyoxyethylene (23) Lauryl ether 3.8 g Ethyl paraoxybenzoate 0.1 g Butyl paraoxybenzoate 0.1 g [B] component: Carboxyvinyl polymer (1.5% aqueous solution) 5 g Propylene glycol 5 g Sodium edetate 0.1 g Triethanolamine 0.6 g Purified water 65.3 g (Production method) After dissolving isostearoylated hydrolyzed collagen in isopropyl isostearate, the mixture is heated to 80 ° C., γ-oryzanol is added, and then other [A] components are added. In addition They were uniformly dissolved to obtain a solution of [A] component. Next, add [B] component excluding triethanolamine to 8 parts.
After being heated to 5 ° C. and dissolved, it was added to the solution of the component [A] and sufficiently stirred to emulsify. Then cool to around 60 ° C,
Triethanolamine was added, mixed evenly, and gradually cooled to obtain a lotion containing 1% γ-oryzanol.

Example 17 W / O type cream ; (formulation) [A] component: γ-oryzanol 4 g 25% isostearoylated hydrolyzed collagen-hexyldecyl isostearate solution [trade name Promoise E-118 (HI); Wakasei Co., Ltd.] 36 g Cetanol 6 g Beeswax 12 g Ethyl paraoxybenzoate 0.1 g Butyl paraoxybenzoate 0.1 g [B] component: Borax 0.5 g Propylene glycol 2 g Purified water 39.3 g (Production method) γ-oryzanol Is dissolved in 25% isostearoylated hydrolyzed collagen-hexyldecyl isostearate solution [trade name Promoise E-118 (HI); SEIWA KASEI CO., LTD.] At 80 ° C, and then the other [A] components are added to homogenize To obtain a solution of the component [A]. Next, the [B] component is heated to 85 ° C. and dissolved to prepare a solution of the [B] component,
The mixture was added to the solution of the component [A] and sufficiently stirred to emulsify. After emulsification, the mixture was gradually cooled and mixed uniformly to obtain a W / O type cream containing 4% γ-oryzanol.

Example 18 O / W type cream (containing 3% γ-oryzanol ); (formulation) [A] component: γ-oryzanol 3 g 25% isostearoylated hydrolyzed collagen-hexyldecyl isostearate solution [trade name Promoise] E-118 (HI); Seiwa Kasei Co., Ltd.] 13.5 g Hexyldecyl isostearate 13.5 g Cetanol 2 g Beeswax 4 g Stearic acid 8 g Silicon oil 0.5 g Polyoxyethylene (23) lauryl ether 5 g Paraoxyethyl benzoate 0 .1 g Butyl paraoxybenzoate 0.1 g [B] component: Propylene glycol 6 g Glycerin 4 g Sodium edetate 0.1 g Triethanolamine 0.25 g Purified water 39.95 g (Production method) γ-oryzanol, 25% isostearoylated hydrolyzate Degraded collagen- Sosutearin hexyldecyl solution [trade name Promois E-118 (HI); Seiwa Kasei Co.] and 80 ° C. isostearic acid hexyl decyl
After being mixed and dissolved in (1), the other [A] component was added and uniformly dissolved to obtain a solution of the [A] component. Then, add [B] component to 8
A solution of the component [B] is prepared by heating at 5 ° C. to dissolve,
The mixture was added to the solution of the component [A] and sufficiently stirred to emulsify. After the emulsification, the mixture was gradually cooled and mixed uniformly to obtain an O / W type cream containing 3% γ-oryzanol.

Example 19 O / W type cream (containing 1% γ-oryzanol ); (formulation) Component [A]: γ-oryzanol 1 g 25% isostearoylated hydrolyzed collagen-hexyldecyl isostearate solution [trade name: Promoise] E-118 (HI); Seiwa Kasei Co., Ltd.] 10 g polyoxyethylene (23) lauryl ether 4 g sorbitan trioleate 1 g cetanol 8 g paraffin wax 1.5 g stearic acid 5 g silicon oil 0.5 g paraoxybenzoic acid methyl 0.1 g Propyl paraoxybenzoate 0.1 g [B] component: Propylene glycol 3 g Propylene glycol alginate 0.5 g Carboxyvinyl polymer 0.25 g Sodium edetate 0.1 g Purified water 60.95 g Triethanolamine 1 g dl-Pyrrolidone Carboxylic acid Aqueous sodium (50%) 3 g

(Production Method) The component [A] was uniformly mixed and dissolved at 80 ° C., and then the solution of the component [B] kept at 85 ° C. was added with sufficient stirring to emulsify. After cooling to around 70 ° C., triethanolamine was added and mixed uniformly, and then an aqueous solution of sodium dl-pyrrolidonecarboxylate (50
%) And gradually cooled with stirring to obtain the desired cream.

Example 20 O / W type cream (containing crotamiton ): (formulation) [A] component: γ-oryzanol 4.5 g 25% isostearoylated hydrolyzed collagen-hexyldecyl isostearate solution [trade name Promoise E- 118 (HI); Seiwakasei Co., Ltd.] 13.5 g Hexyldecyl isostearate 2 g Crotamiton 10 g Cetanol 2 g Beeswax 4 g Stearic acid 8 g Silicon oil 0.5 g Polyoxyethylene (23) lauryl ether 5 g Carboxyvinyl polymer 0.2 g Paraoxy Ethyl benzoate 0.1 g Butyl paraoxybenzoate 0.1 g [B] component: Propylene glycol 6 g Glycerin 4 g Sodium edetate 0.1 g Triethanolamine 2 g Purified water 38 g

(Production Method) γ-Oryzanol, 25% Isostearoylated Hydrolyzed Collagen-Hexyldecyl Isostearate Solution [Brand name Promois E-118 (HI);
Seiwa Kasei Co., Ltd.), hexyldecyl isostearate and crotamiton were mixed and dissolved at 80 ° C., and then other [A]
The components were added and dissolved uniformly to obtain a solution of the component [A]. Next, the solution of the component [B] prepared by heating and dissolving the component [B] at 85 ° C. was added to the solution of the component [A], and sufficiently stirred to emulsify. After emulsification, cool slowly and mix evenly,
An O / W type cream containing 4.5% γ-oryzanol was obtained.

Example 21 Cream containing crude drug extract ; (formulation) [A] component: γ-oryzanol 1 g 25% isostearoylated hydrolyzed collagen-hexyldecyl isostearate solution [trade name Promois E-118 (HI); Kasei Co., Ltd.] 10 g polyoxyethylene (23) lauryl ether 4 g sorbitan trioleate 1 g cetanol 8 g paraffin wax 1.5 g stearic acid 5 g silicon oil 0.5 g methyl paraoxybenzoate 0.1 g propyl paraoxybenzoate 0.1 g [B ] Ingredients: Perilla extract 5 g Carrot extract 1 g Sioux extract 1 g Propylene glycol 3 g Propylene glycol alginate 0.5 g Carboxyvinyl polymer 0.25 g Sodium edetate 0.1 g Purified water 53.95 g Trieta Ruamin 1 g dl-pyrrolidone carboxylic acid sodium aqueous solution (50%) 3 g (manufacturing method) was prepared in the same manner as in Example 19, to obtain a herbal extract combination γ- oryzanol cream.

Comparative Examples 1 to 6 According to the description in JP-B-59-23292, the γ-oryzanol-containing compositions of Comparative Examples 1 to 6 shown in Table 5 were prepared.

[0042]

[Table 5] Comparative Examples 7 to 8 According to the description in JP-B-1-40806, the γ-oryzanol-containing compositions of Comparative Examples 7 to 8 shown in Table 6 were prepared.

[0043]

[Table 6]

Comparative Example 9 Vaseline ointment ; (Formulation) γ-oryzanol 5 g Vaseline 50 g Hexyldecyl isostearate 33.75 g Propylene glycol monostearate 11.25 g (Production method) γ-oryzanol was dissolved in hexyldecyl isostearate at 80 ° C. After that, propylene glycol monostearate was added, and vaseline was further added, mixed and stirred, and cooled to room temperature to obtain 5% γ-oryzanol-containing vaseline ointment.

[Brief description of drawings]

FIG. 1 shows a micrograph taken at 200 × magnification after the formulation of Example 15 was stored at room temperature for 1 week.

FIG. 2 shows that the preparation of Comparative Example 9 was stored at room temperature for 1 week,
A micrograph taken at 200 times magnification is shown.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location A61K 31/165 8413-4C 47/14 G 7433-4C J 7433-4C 47/42 J 7433-4C

Claims (4)

[Claims] 1. A selected from the group consisting of (a) liquid aliphatic carboxylic acid ester having 13 to 42 carbon atoms, liquid aliphatic dicarboxylic acid diester having 12 to 42 carbon atoms, and liquid phthalic acid diester having 12 to 16 carbon atoms. One kind or a mixture of two or more kinds, (b) acylated hydrolyzed collagen and
(C) An external preparation composition comprising γ-oryzanol. 2. A selected from the group consisting of (a) liquid aliphatic carboxylic acid ester having 13 to 42 carbon atoms, liquid aliphatic dicarboxylic acid diester having 12 to 42 carbon atoms, and liquid phthalic acid diester having 12 to 16 carbon atoms. One kind or a mixture of two or more kinds, (b) acylated hydrolyzed collagen, (c) γ
An external preparation composition comprising oryzanol and (d) crotamiton. 3. A liquid aliphatic carboxylic acid ester having 13 to 42 carbon atoms, a liquid aliphatic dicarboxylic acid diester having 12 to 42 carbon atoms and a liquid phthalic acid diester having 12 to 16 carbon atoms. One kind or a mixture of two or more kinds, (b) acylated hydrolyzed collagen and
(C) An external preparation containing an external preparation composition comprising γ-oryzanol. 4. A liquid aliphatic carboxylic acid ester having 13 to 42 carbon atoms, a liquid aliphatic dicarboxylic acid diester having 12 to 42 carbon atoms, and a liquid phthalic acid diester having 12 to 16 carbon atoms. One kind or a mixture of two or more kinds, (b) acylated hydrolyzed collagen, (c) γ
An external preparation containing an external preparation composition comprising oryzanol and (d) crotamiton.