JPH0656643A - Skin preparation for external use - Google Patents

Abstract

PURPOSE:To provide a skin preparation for external use containing a hydroquinone glycoside, a specific betaine derivative and an acylmethyltaurine, exhibiting excellent percutaneous absorbability of the hydroquinone glycoside and having high safety. CONSTITUTION:This preparation for external use contains (A) 0.01-20wt.% of a hydroquinone glycoside, (B) one or more kinds of betaine derivatives of formula I (R1 is 8-24C alkyl), formula II (R2 is 7-23C alkyl), formula III (R3 is 7-23C alkyl) or formula IV (R4 is 8-24C alkyl) and (C) an acylmethyltaurine of formula V (R5 is 7-23C alkyl; M is univalent or bivalent metal, ammonium, alkanolamine or H) as active components. The ratio of C:B is 10:90 to 95:5 and the sum of B and C is 0.01-30wt.%. The agent can be used in the form of cream, ointment, gel, lotion, emulsion, tape, poultice, aerosol, etc.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a skin external preparation.
More specifically, it relates to an external preparation for skin in which a specific betaine derivative and acylmethyltaurine are allowed to act as a transdermal absorption enhancer of hydroquinone glycoside.

[0002]

2. Description of the Related Art Conventionally, as a method for administering a drug, oral administration, subcutaneous administration by injection, intramuscular administration, intravenous administration, rectal administration, oral mucosal administration, and the like have been performed. Widely used. However, in the case of oral administration, it is difficult to control the blood concentration because a large amount of the drug is absorbed in a short time, and the absorbed drug may lose its efficacy due to metabolism in the liver during the first circulation. In the case of irritating drugs, there are many drawbacks such that their administration easily causes side effects such as gastrointestinal disorders.

In recent years, topical preparations for transdermal administration have been developed in order to improve such side effects and drawbacks. However, even in such an external preparation, the transdermal absorbability of the drug is often not obtained, and the purpose is rarely achieved. That is, the outermost layer of the skin is called the stratum corneum of the skin, which originally has a physiological function as a barrier to prevent the invasion of foreign substances from outside the body, so that the drug is simply added to the base conventionally used for external preparations. In many cases, sufficient transdermal absorbability cannot be obtained simply by blending.

In order to improve this, in recent years, it has been generally practiced to incorporate various percutaneous absorption enhancers into the base of external preparations. As such a percutaneous absorption enhancer, dimethylformamide, dimethylsulfoxide, dimethylacetamide, 1-dodecylazacycloheptan-2-one, isopropyl myristate and the like are known.

[0005]

However, even if these percutaneous absorption enhancers are used, sufficient percutaneous absorption of the drug may not be obtained, and especially for hydrophilic drugs such as hydroquinone glycosides. Almost no effective transdermal absorption enhancer has been found. In addition, many of the above-mentioned percutaneous absorption enhancers have strong skin irritation, and by applying a formulation containing this, a percutaneous absorption enhancer that is satisfactory in terms of safety is obtained, such as erythema on the skin. The current situation is that it has not been done.

In view of the above problems, the present inventors have conducted earnest research to develop a percutaneous absorption enhancer which is excellent in the effect of promoting percutaneous absorption of hydroquinone glycosides and which is excellent in safety. It was found that the use of a combination of the betaine derivative of and acylmethyl taurine as a percutaneous absorption enhancer provides excellent percutaneous absorption of hydroquinone glycosides, has low skin irritation, and is excellent in safety. The present invention has been completed.

[0007]

That is, the present invention provides a hydroquinone glycoside and one or more betaine derivatives selected from the general formulas 6, 7, 8 and 9 and the general formula 10. The external preparation for skin is characterized by containing acylmethyl taurine represented by the formula:

[0008]

[Chemical 6]

[In the chemical formula 6, R1 represents a linear or branched alkyl group having 8 to 24 carbon atoms. ]

[0010]

[Chemical 7]

[In the general formula 7, R2 has 7 to 2 carbon atoms.
Represents a linear or branched alkyl group of 3]

[0012]

[Chemical 8]

[In the general formula 8, R3 is 7 to 2 carbon atoms.
Represents a linear or branched alkyl group of 3]

[0014]

[Chemical 9]

[In the general formula 9, R4 is 8 to 2 carbon atoms.
4 represents a straight-chain or branched alkyl group]

[0016]

[Chemical 10] [In the formula 10, R5 represents a linear or branched alkyl group having 7 to 23 carbon atoms, and M represents a monovalent or divalent metal, ammonium, alkanolamine or hydrogen atom. ]

The structure of the present invention will be described in detail below. The betaine derivative used in the present invention includes the following. Alkyldimethylaminoacetic acid represented by the general formula 6. 2-Alkyl-1-carboxymethyl-1-hydroxyethyl-2-imidazoline represented by the general formula 7 (hereinafter abbreviated as imidazolinium betaine). N- (3-acylaminopropyl) -N, N represented by the general formula 8
-Dimethylaminoacetic acid (hereinafter abbreviated as amidobetaine). N-alkyl-N, N-dimethyl-3-amino-2-hydroxypropanesulfonic acid represented by the general formula 9 (hereinafter abbreviated as sulfobetaine). The acylmethyl taurine used in the present invention is represented by the general formula 10.

The following are examples of hydroquinone glycosides whose transdermal absorption can be increased by the transdermal absorption enhancer of the present invention. Hydroquinone glycosides are represented by the following general formula.

[0019]

[Chemical 11]

In the chemical formula 11, R6 represents a pentose sugar residue, a hexose sugar residue, an amino sugar residue, a uronic acid residue or their methyl compounds or acetyl compounds. ]

In the formula, R6 is a 5-carbon sugar residue such as L-arabinose, D-xylose, D-ribose, D-xylulose, D-lyxose, D-ribulose, D-glucose, D-galactose, D-mannose. , D-tagatose, D-fructose, L-sorbose, D-tagatose, D-psicose and other hexose sugar residues, D-glucosamine, D-galactosamine, sialic acid, muramic acid and other amino sugar residues, D- Glucuronic acid, D-galacturonic acid,
The uronic acid residues such as D-mannuronic acid and L-iduronic acid or their methyl compounds and acetyl compounds are shown below.
From the viewpoint of pharmacological effect, stability and safety, R6 is most preferably hydroquinone-β-D-glucoside (general name: arbutin, hereinafter referred to as arbutin) in which D-glucose is β-glycoside-bonded. These drugs
When it is mixed with the percutaneous absorption enhancer of the present invention and applied to the skin, it is quickly absorbed into the skin. If the drug is intended for local action, it penetrates deeply into the skin and exhibits excellent effects.

The above-mentioned hydroquinone glycoside and the acylmethyltaurine and betaine derivatives are used by mixing in a suitable external preparation for skin. As the dosage form of the external preparation for skin, a cream preparation, an ointment preparation, a gel preparation, a lotion preparation, an emulsion, a tape preparation, a poultice preparation, an aerosol preparation and the like are used.

The amount of each component in that case varies depending on the type of hydroquinone glycoside, the type of dosage form, the method of administration, the purpose of administration and the like and cannot be determined unconditionally, but it is generally as follows. The range is a preferable blending amount. That is, the blending amount of hydroquinone glycoside was 0.0
It is 1 to 20% by weight, more preferably 0.1 to 10% by weight.
The amount of the acylmethyltaurine and betaine derivative is in the range of 10:90 to 95: 5, more preferably 30:70 to 90:10, and the total amount of the two compounds is It is 0.01 to 30% by weight, more preferably 0.1 to 20% by weight in the external preparation.

In the external preparation for skin according to the present invention, in addition to the above-mentioned essential constituent components, components generally contained in pharmaceuticals, quasi drugs, cosmetics and the like can be blended. As those ingredients, glycerin, propylene glycol,
Polyhydric alcohols such as 1,3-butanediol, liquid paraffin, squalane, higher alcohols, oils such as higher fatty acids, organic acids such as citric acid and lactic acid, alkalis such as caustic potash and triethanolamine, higher alkyl sulfate ester salts , Anionic surfactants such as higher alkyl ether sulfate ester salts, cationic surfactants such as higher alkyl quaternary ammonium salts and alkyl pyridinium salts, amphoteric surfactants such as higher alkyl dimethylamine oxides, polyoxyethylene alkyl ethers ,
Nonionic surfactants such as sorbitan fatty acid esters and polyglycerin fatty acid esters, drugs such as ascorbic acid derivatives and tocopherol derivatives, ultraviolet absorbers,
Examples include chelating agents, antioxidants, preservatives, thickeners, moisturizers, fragrances, alcohols and the like.

[0025]

EXAMPLES The present invention will be specifically described below with reference to examples and test examples, but the present invention is not limited to these examples.

A liquid formulation having the following composition was prepared. Example 1 (1) Arbutin 1.0% (2) N-lauroyl-N-methyltaurine sodium 0.80 (3) N-lauryl-N, N-dimethylaminoacetic acid 0.20 (4) Purified water Residual production method (4) (1) ), (2), (3) were dissolved and used as a sample.

Comparative Example 1 (1) Arbutin 1.0% (2) N-lauroyl-N-methyltaurine sodium 0.80 (3) Purified water Residual production method Same as in Example 1.

Comparative Example 2 (1) Arbutin 1.0% (2) N-lauryl-N, N-dimethylaminoacetic acid 0.20 (3) Purified water Residual production method Same as in Example 1.

Comparative Example 3 (1) Arbutin 1.0% (2) Purified water Residual production method Same as in Example 1.

Example 2 (1) Arbutin 1.0% (2) N-coconut fatty acid-N-methyltaurine sodium 1.0 (3) N-lauryl-N, N-dimethylaminoacetic acid 0.40 (4) Purified water Residual production method Example Same as 1.

Example 3 (1) Arbutin 1.0% (2) N-lauroyl-N-methyltaurine sodium 1.0 (3) 1-carboxymethyl-1-hydroxyethyl-2-undecyl-2-imidazoline sodium salt 0.40 (un) Decyl imidazolinium betaine) (4) Purified water Residual production method Same as in Example 1.

Example 4 (1) Arbutin 1.0% (2) N-lauroyl-N-methyltaurine sodium 1.0 (3) N- (3-lauroylaminopropyl) -N, N-dimethylaminoacetic acid 0.40 (lauroamidobetaine (4) Purified water Residual production method Same as in Example 1.

Example 5 (1) Arbutin 1.0% (2) N-lauroyl-N-methyltaurine sodium 1.0 (3) N, N-dimethyl-N-lauryl-3-amino-2-hydroxypropanesulfonic acid 0.40 ( Lauryl sulfobetaine) (4) Purified water Residual production method Same as in Example 1.

Skin Permeability Test of Drugs Using Examples 1, 2, 3, 4, 5 and Comparative Examples 1, 2, and 3, the skin permeability test of hydroquinone glycosides was conducted.

Test Method In order to evaluate the effect of promoting percutaneous absorption on hydroquinone glycosides, an in vitro skin permeation test using model skin was carried out. As the model skin, a differentiated epidermal cell membrane obtained by culturing human epidermal cells on a collagen-treated nylon membrane and proliferating and differentiating was used. 50 μl of the drug sample was applied on the surface of the membrane having a diameter of 10 mm and kept at 37 ° C. in a CO 2 incubator. After 24 hours, the culture solution was sampled, and the hydroquinone glycoside that had permeated the membrane was quantified by high performance liquid chromatography. The results were expressed as drug penetration rate (%). The results are shown in Table 1.

[0036]

[Table 1]

As is clear from Table 1, the percutaneous absorption enhancer of the present invention is excellent in the skin permeation promoting effect of hydroquinone glycosides. Particularly, by combining acylmethyltaurine and betaine derivative, each of them was used alone. It can be seen that the effect is much higher than in the case.

Example 6 Emulsion A. Arbutin 5.0 N-lauryl-N, N-dimethylaminoacetic acid 0.5 N-coconut fatty acid-N-methyltaurine magnesium 1.0 Caustic potassium 0.07 Ethanol 5.0 Purified water Appropriate amount B. Vaseline 1.5 Squalane 1.0 Liquid paraffin 5.0 Cetanol 0.5 Polyoxyethylene (25) cetyl ether 2.0 Glyceryl monostearate 2.0 Methyl paraoxybenzoate 0.15 Fragrance C. Carboxyvinyl polymer 0.2 Dipropylene glycol 5.0 Sorbit solution (70%) 5.0 Purified water 100%

Manufacturing method Component C was heated and dissolved at 70 ° C., component B was heated and dissolved at 70 ° C., and the mixture was emulsified with a homomixer. After the emulsification, the mixture is cooled to 30 ° C. with stirring, the one in which the component A is dissolved is added, and the mixture is uniformly mixed.

Comparative Example 4 Emulsion A. Arbutin 5.0 Caustic potassium 0.07 Ethanol 5.0 Purified water Suitable amount B. Vaseline 1.5 Squalane 1.0 Liquid paraffin 5.0 Cetanol 0.5 Polyoxyethylene (25) cetyl ether 2.0 Glyceryl monostearate 2.0 Methyl paraoxybenzoate 0.15 Fragrance C. Carboxyvinyl polymer 0.2 Dipropylene glycol 5.0 Sorbit solution (70%) 5.0 Purified water 100%

Manufacturing method According to Example 6.

Test Method for Whitening Effect All three control emulsions excluding arbutin from Example 6, Comparative Example 4 and Example 6 were applied to a subject suffering from spots, freckles, etc., and the whitening effect was examined. The subjects consisted of 20 women in their 30s to 50s, and one emulsion was 3
Apply about 0.5g to the face twice a day for one month,
At the end of the period, the whitening effect was judged by interviewing the subjects. The judgment was scored according to the following criteria and expressed as an average score. The results are shown in Table 3. 4 Stain and freckles are almost inconspicuous 2 Very thin 1 Slightly thin 0 No change

[0043]

[Table 2] ───────────────────── Score after 3 months ───────────────────── -Example 6 2.1 Comparative Example 4 1.2 Emulsion obtained by removing Arbu 0.5 tin from Example 6 ───────────────────────

As is clear from Table 2, the emulsions of Examples have excellent whitening effect.

Example 7 Cream A. Stearic acid 14.0 Cetanol 3.0 Sorbitan monostearate 2.0 Polyoxyethylene (20) sorbitan monostearate 1.5 Propyl paraoxybenzoate 0.2 Perfume Suitable amount B. Propylene glycol 8.0 Glycerin 2.0 Caustic potassium 0.2 N-lauryl-N-methyltaurine triethanolamine 1.0 Hydroquinone-N-acetyl-β-D-glucosaminide 1.0 N- (3-lauroylaminopropyl) -N, N-dimethylaminoacetic acid 2.0 Purification Amount to make the total amount of water 100% Manufacturing method B ingredients are heated and dissolved at 70 ° C, A ingredients are heated and dissolved at 70 ° C, and the resulting mixture is emulsified with a homomixer. After the emulsification, it is cooled by a heat exchange device to obtain a cream.

Example 8 Emulsion A. Arbutin 3.0 N-lauryl-N, N-dimethylaminoacetic acid 0.5 N-coconut fatty acid-N-methyltaurine magnesium 0.5 Caustic potash 0.07 Ethanol 5.0 Purified water Appropriate amount B. Vaseline 1.5 Squalane 1.0 Liquid paraffin 5.0 Cetanol 0.5 Polyoxyethylene (25) cetyl ether 2.0 Glyceryl monostearate 2.0 Methyl paraoxybenzoate 0.15 Fragrance C. Carboxyvinyl polymer 0.2 Dipropylene glycol 5.0 Sorbit solution (70%) 5.0 Purified water 100%

Example 9 Cream A. Stearic acid 14.0 Cetanol 3.0 Sorbitan monostearate 2.0 Polyoxyethylene (20) sorbitan monostearate 1.5 Propyl paraoxybenzoate 0.2 Perfume Suitable amount B. Propylene glycol 8.0 Glycerin 2.0 Caustic potassium 0.2 N-lauryl-N-methyltaurine triethanolamine 0.6 Arbutin 7.0 N- (3-lauroylaminopropyl) -N, N-dimethylaminoacetic acid 1.4 Purified water 100% total amount Manufacturing method B The component (1) was heated and dissolved at 70 ° C., the component (A) was heated and dissolved at 70 ° C., and the mixture was emulsified with a homomixer. After the emulsification, it is cooled by a heat exchange device to obtain a cream.

[0048]

The external preparation for skin according to the present invention is an external preparation for skin which is excellent in the effect of promoting percutaneous absorption of hydroquinone glycoside and is also excellent in safety.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display area A61K 9/06 G 7329-4C 9/107 R 7329-4C 31/70 ADA 8314-4C 47/18 E 7433-4C 47/20 E 7433-4C 47/22 E 7433-4C (72) Inventor Hideo Nakajima 1050 Shinba-cho, Kohoku-ku, Yokohama-shi, Kanagawa Shiseido Research Center 1

Claims (1)

[Claims] 1. A hydroquinone glycoside, one or more betaine derivatives selected from the general formulas 1, 2, 3, and 4, and an acylmethyltaurine represented by the chemical formula 5. An external preparation for skin characterized by: [Chemical 1] [In Chemical Formula 1, R1 represents a linear or branched alkyl group having 8 to 24 carbon atoms. ] [Chemical 2] [In the chemical formula 2, R 2 represents a linear or branched alkyl group having 7 to 23 carbon atoms. ] [Chemical 3] [In Chemical Formula 3, R3 represents a linear or branched alkyl group having 7 to 23 carbon atoms. ] [Chemical 4] [In the chemical formula 4, R4 represents a linear or branched alkyl group having 8 to 24 carbon atoms. ] [Chemical 5] [In Chemical Formula 5, R5 represents a linear or branched alkyl group having 7 to 23 carbon atoms, M represents a monovalent or divalent metal,
Represents an ammonium, alkanolamine or hydrogen atom. ]