JPS63216812A - Skin drug for external use - Google Patents

Abstract

PURPOSE:To obtain a skin drug for external use, containing a specific amide derivative, capable of enhancing moisture holding power of keratinous layers and exhibiting excellent improving and preventive effects on roughening of the skin. CONSTITUTION:A skin drug for external use obtained by containing a compound expressed by formula I (R<1> is 10-26C hydrocarbon group; R<2> is 9-25C hydrocar bon group; n is 3-6), e.g. N-(2-hydroxyl-3-hexadecyloxypropyl)-N-3-hydroxy propylhexadacanamide, in an amount of 0.001-50wt.%, preferably 0.1-20wt.% based on the total composition. Effects are further increased by additionally blending 0.01-20wt.% preferably 0.1-5wt.% surfactant, particularly nonionic surfactant. The compound expressed by formula I is prepared by reacting a glycidyl ether expressed by formula II with an amino-alcohol expressed by formula III and then selectively acylating the amino group of the resultant compound expressed by formula IV.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to an external skin preparation, and more particularly to an external skin preparation that can improve the moisture retention capacity of the stratum corneum and improve rough skin.

[Conventional technology]

It has been known that moisture in the stratum corneum is important for moisturizing the skin and making it soft. The retention of moisture is said to be due to water-soluble components contained in the stratum corneum, such as free amino acids, organic acids, urea, or inorganic ions, and these substances may be used alone or in combination in medicated skin preparations. Alternatively, it is used in cosmetics to improve or prevent rough skin.

In addition, many other moisturizing substances that have a high affinity for water have been developed and are used for similar purposes.

[Problem that the invention seeks to solve]

However, when these moisturizing substances are applied to the skin, their action is to supply moisture to the stratum corneum on the stratum corneum, and the effect is temporary.
It did not fundamentally improve the water retention ability of the stratum corneum and essentially prevent or cure rough skin.

[Means for solving problems]

Under these circumstances, the present inventors conducted intensive research to solve the above problems, and found that the following general formula (I) % formula % (wherein R1 is carbon 10 to 26 linear or branched saturated or unsaturated hydrocarbon groups R2 has 9 to 26 carbon atoms
The amide derivative represented by 25 linear or branched saturated or unsaturated hydrocarbon groups, where n is a number from 3 to 6) has the effect of fundamentally improving the water retention ability of the stratum corneum; The inventors have also discovered that the effect of this amide derivative can be further enhanced by using a surfactant in combination, and have completed the present invention.

That is, the present invention provides an external skin preparation containing the amide derivative represented by the formula (I), and an external skin preparation containing the amide derivative represented by the formula (I) and a surfactant.

The amide derivative represented by formula (I) used in the present invention is produced, for example, according to the reaction formula shown below.

(CH2) n0H R2COOCH3(”) R2-C-N-CH.

(CHz )nOCOR” C (where R1, R2 and n are the same as above), that is,
Amide derivatives can be obtained by selectively acylating the amine group of compound (II) obtained from glycisol ether and amino alcohol, or by acylating the compound (It) and then selectively hydrolyzing the ester group. (I
) is manufactured.

The reaction between glycysol ether and amino alcohol is a reaction between glycysol ether and 3-amino-1-7' lono9ol, 4-amino-1-butanol, 5-amino-1-pentanol, or 6-amino-1 -Hexanol without solvent or methanol, ethanol, Solono Q-nol,
In a lower alcoholic medium such as isozorono Q-nol, 25~
This is carried out by stirring at 150°C for several tens of minutes to 5 hours.

In order to acylate only the amino group of compound (II), for example, long-chain fatty acid methyl ester and compound (If) are reacted at normal pressure in the presence of a base such as alkali hydroxide or alkali carbonate.
The reaction is carried out under a reduced pressure of 0.01 Torr at 25 to 150°C for several tens of minutes to 5 hours.

Non-selective acylation of compound (I1)' is carried out, for example, by reacting a long-chain fatty acid halide with compound (I1) in the presence of pyridine, a tertiary amine, or the like. Selective hydrolysis of the ester group of the obtained amide-ester is carried out by a conventional method using a base such as an alkali hydroxide or an alkali carbonate.

The amount of the amide derivative (I) thus obtained to be incorporated into the skin external preparation of the present invention is not particularly limited, but in the case of an emulsion type skin external preparation, it is usually 0.001 to 50% by weight of C based on the total composition.
(hereinafter simply indicated by H), particularly preferably 0.1 to 20%,
In the case of oily skin preparations based on liquid hydrocarbons such as maasqualene, the amount is preferably 1 to 50%, particularly 5 to 25%.

As the surfactant to be incorporated into the external skin preparation of the present invention, nonionic surfactants, anionic surfactants, and amphoteric surfactants can also be used, but nonionic surfactants are particularly preferred. be.

What are some examples of nonionic surfactants? Lioxyethylene alkyl ether,? Lyoxyethylene alkyl phenyl ether,? Lioxyethylene fat F [ester, sorbitan fatty acid ester, ? Examples include lyoxyethylenelupitan fatty acid ester, fatty acid monoglyceride, and glyceryl ether. Among them, the following general formula (
I) Glyceryl ether represented by % formula %) (wherein R represents an alkyl group having 8 to 24 carbon atoms), in which R represents the following formula 1, p
represents an integer of 4 to 10, q represents an integer of 5 to 11, p+Q
= 11 to 17, with p = 7 and q = 3 as vertices) is particularly preferred.

The amount of surfactant to be blended is preferably 0.01 to 2%, particularly 0.1 to 5% of the total composition.

The external skin preparation of the present invention can be broadly classified into external skin preparations for riding and cosmetics in terms of its usage form.

Examples of medicated skin external preparations include various ointments containing medicinal ingredients. The ointment may be one based on an oily base, or one based on an oil/water or water/oil type emulsion base. There are no particular restrictions on the oily base, such as vegetable oil, animal oil,
Examples include synthetic oils, fatty acids, natural or synthetic glycerides, and the like.

There are no particular limitations on the medicinal ingredients, and for example, anti-inflammatory agents, anti-pruritic agents, sterilizing agents, astringents, emollients, hormonal agents, etc. may be used as appropriate.

When used as a cosmetic, in addition to the above-mentioned essential ingredients, oils, moisturizers, ultraviolet absorbers, alcohols, chelating agents, pH adjusters, preservatives, thickeners, and thickeners that are commonly used as cosmetic ingredients should be added. Agents, dyes, fragrances, etc. can be blended in any combination.

Cosmetics can be used in various forms, such as water/oil, oil/water type emulsified cosmetics, creams, cosmetic emulsions, lotions, oil-based cosmetics, lipsticks, foundations, skin cleansers, hair tonics, 1i hair preparations, and hair tonics. , skin cosmetics such as hair growth agents.

[Effect]

Although the details of the mechanism of action of the amide derivative represented by formula (I) in the skin external preparation of the present invention have not been completely elucidated,
It is thought that this rebuilds the lipid membrane between corneocytes and exerts the water retention function of the stratum corneum.

〔Effect of the invention〕

Since the skin external preparation of the present invention contains the amide derivative (I) having such an effect, it can exhibit excellent anti-aging and preventive effects against rough skin.

〔Example〕

Next, an example will be given and explained.

Reference Example I N-(2-hydroxy-3-hexadecyloxyzolobyl)-N-3-hydroxyzolobyl hexadecanamide [In formula (I), R1=Cl8H33, R''=C15
HH, n = 3] (Ia).

3-Amino-1 into a 200d4 Turow flask equipped with a stirrer, addition funnel, thermometer, reflux condenser and N2 inlet.
- Delono Q Nord 25. Of (0,333mol
) and ethanol 509 gold case, 80 under N2 atmosphere
Hexadecyl glycisol ether 10. Of (0,034mot) with ethanol 30? A solution dissolved in water was added dropwise over 2 hours. After the dropwise addition was completed, the mixture was further heated and stirred for 30 minutes under the same conditions, and then the distillation apparatus 'i! c, ethanol and unreacted 3-
Amino-1-7' lono9nol was distilled off under reduced pressure to give a pale yellow solid (Ha) of 12.5? I got it. '147f (equivalent to 0,020mat) of the obtained crude product (Ila) was taken, 0.056r'i of potassium hydroxide was added, and 8
Methyl hexadecanoate 5.42F (0,020 mot) was added dropwise thereto over 1 hour while heating and stirring at 0° C./20 Torr. After the dropwise addition was completed, the mixture was further heated and stirred for 1 hour under the same conditions to obtain a pale yellow crude product 12.2F.

This was done once from Hexa 7120F and 100 methanol?
By recrystallizing once from
Ia) 9.18F was obtained (total yield 75%).

m, p, 82.4-83.4℃ IR (Standard 1) 3250, 2920, 2854, 160
5゜1470.1119”H-NMRO,87(t,6H)1.1-2.0(m
, 56H) 2.42(t, 2H) 3.2=4.4(m,
13H) Elemental analysis Actual value (theoretical value) Cnia 4.67% (74,57%) H: 12.73% (I2, 68%) N: 2.21% (2,29%) Reference example 2 N -(2-Hydroxy-3-hexadecyloxyprobyl)-N-6-hydroxyhexylhexadecanamide [In formula (I), R1: C16H33, R2=C15
Synthesis of H31, n = 6) (Ib).

58.0 ml of 6-amino-1-hexanol in a 200 ml 4 flask equipped with a stirrer, addition funnel, thermometer, reflux condenser and N2 inlet. (0,50mo
t) and 150 t of ethanol, and while heating and stirring at 80°C under N2 atmosphere, 15.t of hexadecyl glycisol ether was added. O? A solution of (0,050 mot) dissolved in ethanol 502 was added dropwise over 1 hour.

After the dropwise addition was completed, the mixture was further heated and stirred for 30 minutes under the same conditions, and then a distillation apparatus was attached, and ethanol and unreacted 6-amino-1-hexanol were distilled off under reduced pressure to obtain a pale yellow solid (Ilb) 15. I got 8F. Of the obtained crude product, 8.3 F (0,020 mot phase) was taken, dissolved in 200 ml of methylene chloride, and 4.8 F (0,0
06mot). Hexadecanoyl chloride 16. under water cooling. FM' (0.06 mot) was added dropwise over about 30 minutes, and after the addition was completed, the mixture was stirred at room temperature for 1 hour. The reaction product was washed with water to remove bilicin hydrochloride, and the solvent was distilled off to obtain amide-ester (l[1b) 22.6F.

Subsequently, this was dissolved in 95% ethanol aqueous solution 4009, and 2.24f (0.04at) of potassium hydroxide was added.
was added, and the mixture was heated and stirred at 50'C for 1 hour. The target compound (Ib) was obtained as a colorless powder by extracting the chloroform-soluble material from the reaction product and purifying it by silica gel flash column chromatography.9. Of (0,0138m
ot) was obtained (total yield 52.4%).

m-p-78,8-79.8℃ IR(d')3334,2920,2854,1623
゜1467.1113 "H-NFdRO, 87 (t, 6H) 1.2 ~ 1.9 (
m, 62H) 2.41 (t, 2H) 3.1 to 4.3 (
m, 13H) Elemental analysis Actual value (theoretical value) Cnia 5.33% (75,28%) H: 12.83% (I2, 79%) N: 2.09% (2,14%) Example 1 Compound Ia-1i obtained according to Reference Examples 1 and 2 and the same
using vaseline/compound (Ia ml1) = 3/
The skin conductance and skin roughness of a mixture c (inventive product 1) and vaseline (comparative product 1) of 1 (ff1t ratio) were evaluated by the following method. The results are shown in Table 1.

(Test method) Ten women between the ages of 20 and 50 who suffer from rough skin on their cheeks during the winter were used as subjects, and two different topical skin preparations were applied to their left and right cheeks.
Apply weekly. The next day after the two-week application was completed, the following tests were conducted.

(I) Skin conductance After washing the face with warm water at 37°C and resting in a room with a temperature of 20°C and a humidity of 40% for 20 minutes, the water content of the stratum corneum was measured using a skin conductance meter (manufactured by IBS). . As for the conductance value, the smaller the value, the more rough the skin becomes, and when it is less than 5, the skin becomes severely rough. On the other hand, if this value is 20 or more, skin roughness is hardly observed.

(2) Skin roughness score Skin roughness was observed with the naked eye and judged according to the following criteria: 1, and the score is shown as an average value.

Table 1 Example 2 Reference Example 1.2 and Compounds 1a-1i Obtained Accordingly
A skin external preparation (emulsified cosmetic) having the composition shown in Group 2 below was prepared using the following, and its effect on improving rough skin was evaluated in the same manner as in Example 1. The results are shown in Table 3.

Claims (1)

[Claims] 1. The following general formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, R^1 is a linear or branched saturated or straight chain having 10 to 26 carbon atoms. An amide derivative represented by an unsaturated hydrocarbon group, R^2 is a linear or branched saturated or unsaturated hydrocarbon group having 9 to 25 carbon atoms, and n is a number from 3 to 6). Contains external skin preparations. 2. The following general formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R^1 is a straight chain or branched chain saturated or unsaturated hydrocarbon group having 10 to 26 carbon atoms. , R^2 is a linear or branched saturated or unsaturated hydrocarbon group having 9 to 25 carbon atoms, and n is a number of 3 to 6) and a surfactant. External skin preparation.