JPH08133944A - Skin external agent for beautifully whitening - Google Patents

Abstract

PURPOSE: To obtain a safe and stable skin external agent for beautifully whitening the skin, inhibiting the tyrosinase biosynthesis of melanocyte to prevent the production of melanin, exhibiting an excellent beautifully whitening action and low in skin irritability by compounding an α-hydroxy acid compound. CONSTITUTION: This skin external agent for beautifully whitening the skin contains 0.001-10wt.% of one or more of the phosphatidyl ester and lysophosphatidyl ester of an α-hydroxy acid of formula I [A is group of formula II, etc.; B is group of formula III, etc.; (R1 , R2 are both fatty acid residues; R3 is H, an alkyl, etc.; X is an acyloxy, an amide); M is H, an alkali metal, etc.,] or its derivative. The conversion of the α-hydroxy acid, etc., into the phosphatidyl ester or lysophosphatidyl ester remarkably enhances the percutaneous permeability and cell membrane permeability of the acid, etc., and improves the tyrosinase biosynthesis-inhibiting action in the same compounding amount. The skin external agent exhibits an effective chromatodermatosis-improving effect in a small amount.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a whitening skin external preparation for improving pigmentation due to dark skin, dark spots, freckles, or sunburn. More specifically, by blending one or more selected from phosphatidyl ester and lysophosphatidyl ester of α-hydroxy acid or its derivative, and inhibiting melanin production by inhibiting tyrosinase biosynthesis of melanocytes, The present invention relates to a skin whitening external preparation that exhibits an effective whitening effect, is low in skin irritation, and is safe and stable.

[0002]

2. Description of the Related Art Conventionally, for the purpose of improving skin color darkness, stains, freckles, or pigmentation due to sunburn,
Development of a skin whitening external preparation was promoted, and ascorbic acid,
Glutathione, colloidal sulfur, etc. have been used as active ingredients. There are also examples in which extracts of various medicinal plants, plant-derived gallic acid, geraniin and the like are used. Recently, effective whitening ingredients such as hydroquinone glycosides such as kojic acid and arbutin have been isolated and incorporated into external skin preparations.

On the other hand, it has long been reported that α-hydroxy acids such as glycolic acid and lactic acid have an action of inhibiting tyrosinase biosynthesis of melanocytes and suppressing melanin production.

[0004] However, ascorbic acid is easily oxidized and is unstable, and glutathione and colloidal sulfur have a disadvantage that they give off a peculiar offensive odor and precipitate. In addition, conventional medicinal plant extracts have problems that the whitening effect is insufficient and that the quality is not constant.
Further, kojic acid and the like also have a problem in stability, and some of the other whitening components cause side effects due to continuous use.

On the other hand, α-hydroxy acids have excellent melanin production-inhibiting action, but since they have low lipophilicity, they have low transdermal permeability and cell membrane permeability, and in order to exert an effective whitening effect. It was necessary to blend a fairly high concentration into the external preparation base. Therefore, the pH of the external preparation is lowered to affect the stability of the preparation, or the skin is irritated, so that it is difficult to obtain a preferable whitening skin external preparation.

[0006]

DISCLOSURE OF THE INVENTION The present invention solves the above problems and provides a skin whitening external preparation which is safe and stable without causing skin irritation and side effects and exerts a very excellent whitening effect. The purpose is to That is, it is possible to increase the percutaneous and cell membrane permeability of α-hydroxy acid or its derivative having an excellent whitening effect, and to reach an effective concentration of melanocytes present in the basal layer of the epidermis.

[0007]

In the present invention, α-
In order to enhance the transdermal and cell membrane permeability of hydroxy acid and its derivatives, we tried to use phosphatidyl group or lysophosphatidyl group, which is a cell membrane constituent, as a carrier. As a result, it was found that by using α-hydroxy acid or the like as a phosphatidyl ester or a lysophosphatidyl ester, the transdermal permeability of these is significantly increased, and the tyrosinase biosynthesis inhibitory action at the same blending amount is surprisingly improved. Therefore, the compounding amount of the phosphatidyl ester such as α-hydroxy acid and lysophosphatidyl ester with respect to the skin external preparation base may be small, the influence on the formulation stability of the external preparation is small, and the safety such as the occurrence of skin irritation is improved. There is no problem.

The phosphatidyl ester of α-hydroxy acid or its derivative is a phospholipase D derived from a microorganism using phosphatidylcholine, soybean lecithin or the like as a substrate.
It can be efficiently obtained by the phosphatidyl group transfer reaction by.

For example, glycolic acid, glyceric acid,
The phosphatidyl ester of gluconic acid can be produced by the method described in JP-A-60-41494, and the phosphatidyl ester of lactic acid can be produced by the method described in JP-A-59-187786. That is, it can be produced by transferring a phosphatidic acid residue of a phospholipid to a hydroxyl group of α-hydroxy acid or a derivative thereof with phospholipase D.

The phospholipids used in the above reaction include those derived from plants or animals such as soybean and egg yolk lecithin,
A phospholipid derived from a microorganism or a synthetic phospholipid can be used, and a phospholipid hardened by hydrogenation may be used. The phospholipase D may be of any origin as long as it has the ability to transfer a phosphatidic acid residue to α-hydroxy acid or the like.

The specific transfer reaction is carried out by dissolving phospholipid in an organic solvent such as ether, adding an aqueous solution of α-hydroxy acid and phospholipase D, and mixing them. At this time, by adding a metal salt such as sodium salt, potassium salt, calcium salt or magnesium salt to the reaction solution,
A salt of the phosphatidyl ester is obtained depending on the metal salt added. After the reaction, the phosphatidyl ester is recovered from the solution by the method described in the above publication and, if necessary, purified to obtain the desired phosphatidyl ester such as α-hydroxy acid.

Further, the lysophosphatidyl ester such as α-hydroxy acid is hydrolyzed to the above-mentioned phosphatidyl ester such as α-hydroxy acid with phospholipase A1 or A2 to hydrolyze the fatty acid at the α-position or β-position of the phosphatidyl group. It can be prepared by

Regarding the transdermal permeability and tyrosinase biosynthesis inhibitory action of phosphatidyl ester and lysophosphatidyl ester of α-hydroxy acid or its derivative used in the present invention, an example of using lactic acid as α-hydroxy acid is shown below. .

Percutaneous permeability is determined by labeling phosphatidyl lactic acid, lysophosphatidyl lactic acid, and lactic acid for comparison with tritium, and adding them to a percutaneous permeation cell, and permeating the guinea pig skin piece of the cell to obtain a solution under the skin piece. The radioactivity eluted in was measured with a scintillation counter,
The ratio of the radioactivity eluted through the skin pieces was calculated and evaluated. The results are shown in Fig. 1.

From FIG. 1, it is recognized that the transdermal permeability of phosphatidyl lactic acid and lysophosphatidyl lactic acid is significantly improved as compared with lactic acid. After 24 hours, phosphatidyl lactic acid was observed to elute 4.2 times that of lactic acid, and lysophosphatidyl lactic acid was observed to elute 4.0 times that of lactic acid.

The tyrosinase biosynthesis inhibitory effect was evaluated as follows. An ethanol solution of phosphatidyl lactic acid and lysophosphatidyl lactic acid and an aqueous lactic acid solution were added to a suspension of mouse B16 melanoma cells (the number of cells was about 50,000), and the cells were cultured for 3 days, and then tyrosinase in the cells was cultured by the following method. The activity was measured. That is, 1
0.5 ml of 1.0 wt% dopa aqueous solution and 0.5 m of cultured cell fluid in 2 ml of 15/15 M phosphate buffer (pH 6.8)
l were mixed and incubated at 37 ° C. for 1 hour,
Absorbance (As) at 405 nm was measured. As a control, only the solvent ethanol or purified water was added in the same manner and the cells were cultured. Similarly, the cultured cell solution and the dopa aqueous solution were incubated to measure the absorbance (Ab), and the tyrosinase biosynthesis inhibition rate was calculated by It was Phosphatidyl lactic acid,
The final doses of lysophosphatidyl lactic acid and lactic acid were varied within the range of 1.0 mM to 80 mM, and the dose response was determined and shown in FIG.

[Equation 1]

In FIG. 2, when phosphatidyl lactic acid and lysophosphatidyl lactic acid were added, the 50% inhibitory concentrations (ID50) were 5.4 mM and 6.5 mM, respectively, whereas the ID50 when lactic acid was added was 24. 0.0 m
It was M. Therefore, when the same concentration is added, the inhibition rate of tyrosinase biosynthesis is significantly improved by using phosphatidyl ester or lysophosphatidyl ester.

The external whitening agent for whitening according to the present invention can be in the form of lotion, gel, emulsion, ointment and the like. In addition, softening lotion, astringent lotion, lotion such as wash lotion, emollient cream, moisture cream, massage cream, cleansing cream,
Creams such as make-up cream, emollient emulsions, moisturizing emulsions, nourishing emulsions, emulsions such as cleansing emulsions, jelly packs, peel-off packs,
It can also be provided as a whitening cosmetic in various formulations such as packs such as powder packs and face wash. The amount of the phosphatidyl ester of α-hydroxy acid or its derivative to be blended is preferably 0.001 to 10% by weight.

[0019]

When the external preparation for whitening skin according to the present invention is continuously applied to the skin, the active ingredient, phosphatidyl ester or lysophosphatidyl ester of α-hydroxy acid or its derivative, is rapidly percutaneously absorbed and melanin biosynthesis occurs. It reaches the basal layer of the epidermis where melanocytes are distributed, effectively inhibits tyrosinase biosynthesis, and consequently exerts an effective melanin production suppressing action. Therefore, it is possible to improve the pigment deposition due to spots, freckles, or sunburn, and to prevent the pigment deposition due to sunlight and ultraviolet rays. In addition, since the phosphatidyl ester or lysophosphatidyl ester of α-hydroxy acid or a derivative thereof exhibits an effective action with a small amount of compounding, the desired above-mentioned effects can be exhibited even if only a small amount is compounded, and the influence on the stability of the preparation is also exerted. There are few safety problems such as skin irritation.

[0020]

EXAMPLES The present invention will be described in more detail with reference to Examples. First, production examples of phosphatidyl ester and lysophosphatidyl ester of α-hydroxy acid used in the present invention are shown. Regarding other phosphatidyl or lysophosphatidyl derivatives of α-hydroxy acid,
It can be prepared in the same manner as in the following production example.

[Production Example 1] 20 g of egg yolk lecithin (Kewpie Co., Ltd.) was dissolved in 100 ml of diethyl ether, and 4.0 g of sodium chloride, 20 g of α-hydroxy acid, and phospholipase derived from the genus Actinomadura. D (Meito Sangyo Co., Ltd.) 1,000
Dissolve the unit in 100 ml of purified water and add it at 30 ° C for 24 hours.
The enzyme reaction was carried out for a time. After the reaction was completed, the ether layer was recovered, ether was removed, and 20 g of total phospholipid after the transfer reaction
Was recovered. This phospholipid was analyzed by the phospholipid composition analysis method 5.3.3.1-86 of the standard oil and fat analysis test method (edited by Japan Oil Chemistry Association). As a result, 80% by weight of phosphatidylglycolic acid newly generated by the transfer reaction and phosphatidylglyceric acid were generated. Is 50 wt% and phosphatidyl gluconic acid is 5
0% by weight and 40% by weight of phosphatidyl lactic acid were contained.

[Production Example 2] 10 g of the phosphatidyl glycolic acid obtained in Production Example 1 above was redissolved in 50 ml of ether, and 10 ml of an aqueous solution of phospholipase A2 (manufactured by Novo Nordisk Bioindustry Co., Ltd.) was added, and the mixture was heated to 30 ° C. For 24 hours to hydrolyze the β-position fatty acid of phospholipid. After the reaction is completed, the ether layer is collected,
The ether was removed to recover 8.2 g of total phospholipid. This phospholipid is used as a standard oil and fat analysis test method (edited by Japan Oil Chemistry Association)
As a result of analysis by the phospholipid composition analysis method 5.3.3.1-86 of
It contained 70% by weight of lysophosphatidyl glycolic acid newly formed by the hydrolysis reaction.

Next, Table 1 shows the formulations of Examples 1 to 5 as the whitening cream according to the present invention. These are shown in Table 1.
Medium (1) to (8) were dissolved by heating at 75 ° C, and (9) to (11) and (13) heated and dissolved at 75 ° C were added to this to emulsify, and the mixture was cooled at 50 ° C at (12). ) Is added, and it cools to room temperature, and it prepares.

[Table 1]

Examples 6 to 10 are whitening ointments. The prescription is shown in Table 2. These are obtained by mixing and dissolving the oil phase components (1) to (5) in Table 2 to make them uniform and heating to 75 ° C.
(6) is dissolved in (7), heated to 75 ° C., added to the mixture, emulsified, and cooled to prepare.

[Table 2]

Examples 11 to 15 are whitening emulsions. The prescription is shown in Table 3. In Table 3, (1) to (7) in Table 3 were heated and melted at 75 ° C, and (8) to (11) and (13) heated and melted at 75 ° C were added to emulsify and cool. It is prepared by adding (12) at 50 ° C. and further cooling to room temperature.

[Table 3]

Examples 16 to 20 are whitening lotions.
The prescription is shown in Table 4. These are prepared by mixing, dissolving and homogenizing the components (1) to (10) in Table 4.

[Table 4]

The whitening effect of the above examples was evaluated by a usage test. At that time, α blended in each Example
-Phosphatidyl ester such as hydroxy acid or lysophosphatidyl ester is converted into α-hydroxy acid,
A substitute for α-hydroxy acid ester or α-hydroxy acid amide was used as a comparative example. In the use test, pigmentation such as spots, freckles, and sunburn was clearly observed.
20 female panelists in their 50s were set as one group, and each sample of Examples and Comparative Examples was blindly used for each group. The use of the sample was continued for 2 months by applying an appropriate amount to the face after washing twice each day in the morning and at night. The whitening effect was evaluated by observing the degree of facial pigmentation after the use test. The results are shown in Tables 5-8.

In Table 5, in the group used in Example 1 containing 1.00% by weight of phosphatidylglycolic acid, improvement in pigmentation symptoms was observed in all panelists. In Comparative Example 1 containing glycolic acid, the number of panelists in which a clear improvement was recognized was only half. Glyceric acid,
In the use groups of Comparative Examples 2 to 5 containing citric acid, malic acid diethyl ester and citric acid monoamide, these α-
Although the whitening effect of hydroxy acids is considerably inferior, the improvement effect of the pigmentation symptom was clearly recognized to be improved in the groups using Examples 2 to 5 in which the hydroxy acids were blended as the phosphatidyl ester.

[Table 5]

The same tendency was observed in Table 6, and in the groups using Examples 6, 7 and 10 in which the phosphatidyl ester of lactic acid, ethyl glycolate and cholesteryl glycolate was added, improvement was observed in all panelists. In Comparative Example 10 in which cholesteryl glycolate was blended, a good improvement was observed because it had considerably good transdermal permeability, but the whitening effect was further enhanced by using the phosphatidyl ester. Example 9 containing phosphatidyl lactic acid, phosphatidyl citrate amide and phosphatidyl lactic acid propyl ester
The use group showed a clear improvement at 85% of panelists. Further, also in the use group of Example 8 containing phosphatidyl gluconic acid, Comparative Example 8 containing gluconic acid
A marked improvement in pigmentation was observed as compared with the use group.

[Table 6]

Also in Table 7, it is recognized that the whitening effect of each α-hydroxy acid is improved by using the phosphatidyl ester. In all of the groups used in the examples, the symptoms were improved in all the panelists, and no panelists did not find any change in the symptoms. In particular, Example 11 in which 0.50% by weight of phosphatidylglycolic acid and 0.30% by weight of phosphatidyl lactic acid methyl ester were mixed.
In the group using Example 12 in which 0.80% by weight of 1-acyl lysophosphatidyl lactic acid was blended, almost all panelists recognized improvement.

[Table 7]

In Table 8 as well, it is 65 in the use group of each example.
% Or more of the panelists had a clear improvement, and no panelists whose symptoms were not alleviated. On the other hand, in the group using the comparative examples in which α-hydroxy acids were not used as the phosphatidyl ester or the lysophosphatidyl ester, the panelists in which the clear improvement was observed were 35%.
There were some panelists who did not show any improvement in symptoms, as shown below.

[Table 8]

No panelists complained of skin irritation such as pain and itch or skin disorder such as allergic reaction in any of the groups used in the above-mentioned use period. In addition, deterioration of the emulsified state and sedimentation of the blended components,
No alteration was observed.

[0033]

INDUSTRIAL APPLICABILITY As described above in detail, according to the present invention, it is possible to provide a whitening skin external preparation capable of improving a very excellent pigmentation symptom by blending a small amount of a whitening component. In the external preparation for whitening skin according to the present invention, the active ingredient α-hydroxy acids can reach the melanocytes of the basal layer of the epidermis, which are the target cells, satisfactorily, and exhibit excellent melanin production-inhibiting action at a low concentration. Therefore, there is no risk of skin irritation or sensitization, and the stability of the preparation is not adversely affected.

[Brief description of drawings]

FIG. 1 is a diagram showing a comparison of transdermal permeability of phosphatidyl lactic acid, 1-acyl lysophosphatidyl lactic acid and lactic acid.

FIG. 2 is a diagram showing a comparison of tyrosinase biosynthesis inhibitory effects of phosphatidyl lactic acid, 1-acyl lysophosphatidyl lactic acid and lactic acid.

[Explanation of symbols]

 1 Phosphatidyl lactic acid 21-Acyl lysophosphatidyl lactic acid 3 Lactic acid

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical indication location A61K 38/00 ADA (72) Inventor Akira Tsunoda 1-27-5 (72) Musashidai, Fussa-shi, Tokyo ) Inventor Sumitaka Kokusei 7026-3 Taniho, National City of Tokyo

Claims (3)

[Claims] 1. An external preparation for whitening skin, comprising one or more selected from a phosphatidyl ester and a lysophosphatidyl ester of an α-hydroxy acid represented by the general formula (1) or a derivative thereof. . Embedded image 2. An α-hydroxy acid is glycolic acid in which B is a compound of formula (2) in general formula (1), lactic acid in which B is a compound of formula (3) in general formula (1), and In (1), B is selected from glyceric acid, which is a compound of formula (4), and in general formula (1), B is selected from gluconic acid, which is a compound of formula (5). A skin external preparation for whitening as described. Embedded image Embedded image [Chemical 4] Embedded image 3. The whitening skin external preparation according to claim 1 or 2, wherein the whitening skin external preparation is a whitening cosmetic composition.