JPH02200622A - External agent for suppressing melanogenesis - Google Patents

Abstract

PURPOSE:To obtain a melanogenesis-suppressing external drug effective in suppressing the erythema and pigmentation of skin caused by ultraviolet ray and the melanization of skin caused by sunburn by compounding an ultraviolet absorbing substance to kojic acid or a kojic acid derivative. CONSTITUTION:An external drug containing kojic acid or a kojic acid derivative is compounded with 0.001-5.0wt.% (based on the total amount of the external drug) of an ultraviolet absorbing substance consisting of p-aminobenzoic acid compound, salicylic acid compound, methoxycinnamic acid compound and benzophenone compound. The compounded product is further compounded properly with other ultraviolet absorbing substance, anionic substance, cationic substance, antioxidant, pH-modifier, etc., to obtain the objective agent. It can be used in the form of cosmetic such as cream, face lotion, pack or powder and an external agent such as emulsion, lotion, liniment or ointment.

Description

[Detailed Description of the Invention] [Field of Industrial Application] The present invention suppresses erythema on the skin caused by ultraviolet rays, enhances the effect of preventing melanin deposition on the skin such as spots and freckles caused by sunburn, and further The present invention relates to an external preparation containing kojic acid or a kojic acid derivative as an active ingredient, which prevents coloring of the external preparation during use.

[Conventional technology]

Kojic acid and kojic acid derivatives are known as substances that suppress the production of melanin in human skin. And q
Skin liniments containing these substances as active ingredients are also known. For example, skin-lightening cosmetics containing kojic acid as a whitening ingredient (JP-A-53-3538 and JP-A-56-18569), aliphatic carboxylic acid diesters of kojic acid, and aliphatic carboxylic acid monoesters of kojic acid for skin whitening. Whitening cosmetics as ingredients (Japanese Patent Publication No. 61-60801, Japanese Patent Publication No. 60-60-
No. 9722), skin-lightening cosmetics containing esters of aromatic carboxylic acids such as cinnamic acid and benzoic acid as whitening ingredients (Japanese Patent Publication No. 10005/1983), melanin production suppressing products containing kojic acid as an active ingredient Ointment (Tokuko Sho 61-104
Publication No. 47), etc.

In addition, in order to prevent kojic acid from changing over time and causing discoloration, cosmetics are known in which kojic acid is blended with a 2-hydroxybenzophenone compound (Japanese Unexamined Patent Publication No. 62-1
08804) [Problems to be Solved by the Invention] As mentioned above, kojic acid and kojic acid derivatives are extremely excellent substances that suppress the production of melanin.

When this substance is manufactured into cosmetics or external skin preparations containing this substance as its main ingredient and applied to the skin, it has the effect of fairing skin and inhibiting melanin production, and it does not cause any damage to the skin. It is known and useful as a skin liniment.

However, even if pigmentation such as melasma is improved by the action of kojic acid, the pigmentation that has been cured may return to its original state due to the effects of ultraviolet rays when exposed to direct sunlight.

It has also been pointed out that if these external preparations are applied to the skin and exposed to strong direct sunlight outdoors, they may become colored.

The present invention uses kojic acid and kojic acid derivatives that eliminate various harmful effects caused by kojic acid and kojic acid derivatives, prevent discoloration during use, and do not cause any damage to human skin when used as an external preparation. The object of the present invention is to provide an external preparation containing a derivative as an active ingredient.

[Means to solve the problem]

The present inventor has discovered that a topical preparation containing kojic acid or a kojic acid derivative suppresses erythema 1 pigmentation caused by ultraviolet rays, enhances the effect of preventing spots and freckles caused by sunburn, and prevents discoloration during use. As a result of research aimed at obtaining a topical preparation containing kojic acid and kojic acid derivatives as active ingredients, which does not cause any damage to human skin when used, we have developed a topical preparation containing kojic acid and kojic acid derivatives as an active ingredient. When a UV-absorbing substance consisting of a para-aminobenzoic acid compound, a salicylic acid compound, a methoxycinnamic acid compound, and a benzophenone compound is applied to the skin, it causes erythema and pigmentation on the skin even after irradiation with ultraviolet rays. The present invention was completed by discovering that there is no deposition and also preventing coloring during use.

The present invention provides a topical preparation containing kojic acid or a kojic acid derivative containing one or more ultraviolet absorbing substances consisting of a paraaminobenzoic acid compound, a salicylic acid compound, a methoxycinnamic acid compound, and a benzophenone compound. This is a melanin production inhibiting topical agent.

Kojic acid, which is the active ingredient of the external preparation of the present invention, is a 5-oxy-2-
Oxymethyl-T-pyrone.

Kojic acid derivatives include monofatty acid esters of kojic acid, such as kojic acid monopalmitate, kojic acid monobutyrate, kojic acid monocaprylate, kojic acid monostearate (see Japanese Patent Publication No. 58-22152), and kojic acid difatty acids. Esters such as kojic acid dipalmitate, kojic acid dibutyrate, kojic acid dioleate, kojic acid distearate (see Japanese Patent Publication No. 58-22151), kojic acid monocinnamoate, kojic acid monobenzoate (see Japanese Patent Publication No. 60-10005) ) etc. are included.

The external preparation of the present invention can be used for the purpose of suppressing melanin production and preventing melanin deposition on the skin.In addition to cosmetics such as lotions, packs, and powders, the external preparations include emulsions and lotions. It can be formulated into various forms for external use, such as liniments, ointments, and other quasi-drugs used for external use. A preparation for external use is prepared by adding appropriate agents, pigments, fragrances, antioxidants, preservatives, sequestering agents, etc., and formulating it by a conventional method.

The para-aminobenzoic acid compounds used as ultraviolet absorbing substances to prevent discoloration of external preparations containing kojic acid and kojic acid derivatives of the present invention include ethyl para-aminobenzoate, glyceryl para-aminobenzoate, amyl para-dimethylaminobenzoate, and para-aminobenzoic acid-based compounds. Octyl dimethylaminobenzoate, para-aminobenzoate 8i12. Examples include ethyl 1-C bis(hydroxypropyl) 1-aminobenzoic acid and para-aminobenzoic acid-bound allantoin. Preferred is octyl valadimethylaminobenzoate.

A salicylic acid compound is phenyl salicylate.

Edylene glycol salicylate, octyl salicylate,
Examples include dipropylene glycol salicylate, myristyl salicylate, acetamidophenyl salicylate, diphenhydramine salicylate, methyl salicylate, homomenthyl salicylate, and triethanolamine salicylate. Preferred is octyl salicylate.

Metkin cinnamic acid compounds include cinoxate, methyl diisopropyl cinnamate, isopropyl baramethoxy cinnamate,
Examples include ethyl paramethoxycinnamate, potassium paramethoxycinnamate, sodium paramethoxycinnamate, octyl methquine cinnamate, and jetanolamine 4-methoxycinnamate. Preferred is octyl methoxycinnamate.

A benzophenone compound is oxybenzone.

Oxybenzone sulfonic acid, dihydroxydimethoxybenzophenone, sodium dihydroxydimethoxybenzophenone sulfonate, dihydroxybenzophenone,
Tetrahydroxybenzophenone Sodium hydroxymethoxybenzophenone sulfonate, p-hydroxybenzophenone.

Examples include p-methoxybenzophenone, dioxybenzophenone, 2-ethylhexyl 4-phenylbenzophenone-2carboxylate, polyvalent metal salts of benzophenone derivatives, and benzophenone derivatives using benzophenones as ferulate salts. Preferred is tetrahydroxybenzophenone.

In the present invention, each of the above ultraviolet absorbing substances or two
By incorporating 0.001 to 5.0% (by weight) of kojic acid or more to the total amount of the external preparation, erythema and pigmentation of the skin caused by ultraviolet rays of kojic acid kojic acid derivatives can be sufficiently suppressed.
It enhances the effect of preventing spots and freckles caused by sunburn, and can prevent discoloration of external preparations during use.

In addition to the above-mentioned ultraviolet absorbing substances, the external preparation of the present invention contains! −(
2-Hydroxy-5-methylphenyl)-benzotriazole, 2-(2°-hydroxy5-1-octylphenyl)-benzotriazole, oxybenzotriazole, urocanic acid ethyl urocanate, methyl anthranilate, menthyl anthranilate, 3 -(4-methylbenzilitine)camphor, (-(4-)limethylaminobenzylidene)camphor methosulfate, 2-phenylbenzimidazole-5-sulfonic acid 3.4-dimethylphenylglyoxalate sodium, 5- (3,3
-dimethyl-2-norbornylidene)-3-pentene-
2-one, cicaroyl trioleate, Lawson and 3%
Mixture with dihydroxyacetone 12-cyano-3,3
°-2-ethylhexyl diphenyl acrylate, red petrolatum N-(hydroxystyl)benzamide, 2-phenacylthiazoline derivative, α-dehydroamino acid derivative, furan derivative, chalcone derivative, 5-(
UV absorbers such as octyl 3,4-dimethoxy)benzyl 3-hydantoinpropionate, UV absorbers of plant ingredients such as aloe extract, scutellariae extract, shea butter, T-oryzanol, and soybean oil are appropriately added to this product. It is also possible to enhance the effects of the invention.

Furthermore, anionic substances such as sodium N-lauroyl-L-glutamate and sodium dl-pyrrolidonecarboxylate; cationic substances such as stearyltrimethylammonium chloride and cetyltrimethylammonium chloride;
Nicotinic acid amide Nicotinic acid, natural vitamin E, hydrogen sulfite) Antioxidants such as IJium, monosodium L-glutamate, potassium sodium tartrate, sodium alginate, monosodium L-aspartate, etc.
A pH adjusting agent can also be added.

Next, examples of the present invention and test examples for suppressing skin erythema and pigmentation caused by ultraviolet rays and preventing discoloration of external preparations will be shown.

〔Example〕

Example 1 (Lotion) Polyoxyethylene hydrogenated castor oil (60E, o, >1.
00g1 ethanol 15.00 g, ethyl paraoxybenzoate 0.10 g, citric acid 0.10 g,
Sodium citrate 0.30 g, 1.3-butylene glycol 4.00 g.

Edetate disodium 0.01 g, kojic acid 0.5
Add purified water to 0g and 0.50g of tetrahydroxybenzophenone to make 100g, stir evenly, and dissolve to obtain a lotion.

Example 2 (Cream pack) Polyethylene glycol monostearate (40B, 0
．． ) 2,00 g, self-emulsifying glyceryl monostearate 5,00 g, stearic acid 5.00 g
, behenyl alcohol 0.50 g, squalane 15
．． 00 g, cetyl octoate, 5.00 g, ethyl paraoxybenzoate, 0.20 g, and octyl paradimethylaminobenzoate, 2.00 g, were dissolved by heating.

Separately, 5.00 g of 1.3-butylene glycol and 49.29 g of purified water are heated and mixed. Add the latter solution to the former solution and emulsify 1. Stir and cool. To this, edetate disodium 0.01 g, kojic acid 1.00 g
g and 10.00 g of purified water were added, stirred and mixed, and cooled to obtain a cream pack.

Example 3 (Emulsion) Polyoxyethylene sorbitan monostearate (20
E, 0. > 1.00 g, polyoxyethylene sorbitol tetraoleate (60B, 0.) 0.5
0 g, lipophilic glyceryl monostearate 1.00 g
, stearic acid 0.50 g, behenyl alcohol 0.50 g, avocado oil 4. OOg, ) 4.00 g of glyceryl rioctanoate, 0.20 g of ethyl nozuraoxybenzoate and 1.00 g of octyl salicylate are heated and dissolved. Separately 1.3-butylene glycol5.
00 g, xanthus gum 0.14 g and purified water 73
．． Mix 15g with heating. The latter solution is added to the former solution, emulsified, stirred, and then cooled. To this were added 0.01 g of disodium edetate, 1.00 g of kojic acid, and 8.00 g of purified water, stirred and mixed, and then cooled to obtain a milky lotion.

Example 4 (Rireem) Polyethylene glycol monostearate (40ε, 0
．． ) 2.00 g, self-emulsifying glyceryl monostearate 5.00 g, stearin! 15.00 g, behenyl alcohol 1.00 g, liquid paraffin 10
．． 00 g, glyceryl trioctanoate 10.00 g
Then, 0.20 g of ethyl paraoxybenzoate and 2.00 g of octyl methoxycinnamate were heated and dissolved. Separately, 5.00 g of 1.3-butylene glycol and 50.79 g of purified water are added, heated, and mixed. The latter solution is added to the former solution, emulsified, stirred, and then cooled. to this,
Disodium edetate 0.01 g, kojic acid 1.
Dog and 8.00 g of purified water are added, stirred and mixed, and then cooled to obtain cream.

Example 5 (Mousse) 3.50 g of N-methacryloylethyl-N,N-dimethylammonium/α-N-methylcarboxybetaine/butyl methacrylate copolymer (30%).

Polyoxyethylene cetyl ether (10B, O,)0
．． 15g, polyoxyethylene cetyl ether (2E,
O, >0, 15 g, ethanol 13.00 g, edetate disodium 0.01 g and kojic acid 1.00 g
and 4-methoxy 4"-hexanoyloxychalcone 2
．． Add purified water to OOg to bring the total amount to 100g, and stir and dissolve uniformly.

This liquid is dispensed into a pressure-resistant container, filled with dichlorodifluoromethane and liquefied petroleum gas under pressure, and an injection device is attached to the container and sealed to obtain a mousse.

Test Example Test Sample a) Polyethylene glycol monostearate (40E
,,0,) 2.00 g, self-emulsifying glyceryl monostearate 5.00 g, stearic acid 5.00
g, behenyl alcohol 1. tlJ g, liquid paraffin 10.00 g.

10.00 g of glyceryl triofucinate and 0.20 g of ethyl paraoxybenzoate are heated and dissolved. Separately, add 59 g of purified water to 5.00 g of 1,3-butylene glycol.
．． Add 79g, warm and mix. Add the latter solution to the former solution, emulsify 1, stir, and cool. A cream (control) was obtained by adding 0.01 g of disodium edetate and 2.00 g of purified water and stirring and mixing.

b) Cream containing 91g of Koji in test sample a) (
control).

C) Tetrahydroxybenzophenone 0 in test sample b)
．． d) A cream containing 2.0 g of octyl p-dimethylaminobenzoate in sample b) (external preparation of the present invention).

e) Cream containing 1.0 g of octyl salicylate in test sample b) (external preparation of the present invention) f) Test sample b) containing 2.0 g of octyl methoxycinnamate. Cream containing Og (external preparation of the present invention) g) Test sample b) 4-methoxy-4°
- Cream-1 containing 2.0 g of hexanoyloxychalcone (external preparation of the present invention) Test Example 1 Coloring test of cream The above test samples a), b), c), d), and e).

f) and g> in a plastic Petri dish, and exposed to ultraviolet light [J
L2O3-BLB lamp (manufactured by Tokyo Shibaura Electric (6))] was irradiated (25 J/cm2).

The degree of coloration of each sample cream immediately after irradiation was observed with the naked eye, and the color difference (ΔE) before and after UV irradiation was measured using a pigment meter (Model Z-1001DP manufactured by Nippon Denshoku Industries).

The results were as shown in Table 1.

(Hereafter, this page margin) table ■ As described above, samples c) and d) of the products of the present invention.

It is clear that coloring is significantly prevented in samples #Je), f), and g).

Test Example 2 Erythema and Pigmentation Suppression Test Seven 2 x 2 cm sites were placed on the upper backs of test subjects (46 healthy male volunteers).

Aluminum foil was placed on the upper back so that ultraviolet rays could only be applied to the test area, and a Tokyo Shibaura Electric FL2O5-BLB lamp and FL2O3-E were applied from a distance of 1 cm.
-2 each of 30 lamps at the same time 0.8 Xl0-'er
Irradiation was performed three times on consecutive days at a dose of g/cm2/dose/8. Before irradiation, the test area was thoroughly washed with warm water.

Each test sample a), b), c), d), e), f).

g) was applied to each site three times a day (morning, noon, and night), and the erythema was observed 3 days after the start of the test, and the degree of pigmentation was compared with control a) after 7.21 days. ,
Evaluation was made on a four-level scale.

The results were as shown in Tables 2 to 4 below.

(Hereinafter, the margin of this page) 1) Erythema (after 3 days) Table 2 Sample b) (control) suppressed erythema compared to sample a><control) [Clearly pale (10+) or higher is 71
．． 8%] is the external preparation of the present invention, Sample C) [89.2% is clearly thin (++) or more], Sample D is 76.0% is clearly thin (10) or more], Sample e) [78.3% of rice grains are obviously thin (10+) or more], Sample f 76.0% of rice grains are clearly thin (10+) or more], %], ) [Clearly thin (++) 91.3%] suppressed erythema more than the control.

2) After 7 days and 21 days of pigmentation, sample b) suppressed the induction of pigmentation more than sample a) [Clearly lighter (++) or higher is 69
．． 6%, 60.9%], sample c) C clearly thin (10+) or more 89.2%, 91.3%], sample d) [obviously thin (++) or more 76.1% , 783%] Sample e
) [Clearly thin (→-+) or more is 8014%.

82.6%], sample f) C clearly thin (++) or above 78.3%, 82.6%], sample g) [obviously thin (++) or above 93.5%, 95.6% ] suppressed pigmentation more than the control.

Evaluation criteria for the degree of visual coloration in the above tests ++12 Noticeably thin 10+: Obviously pale+: Slightly pale: No difference Test Example 3 Sun exposure test 10 healthy men At the bottom of the page 5 x 5 Seven am sites were provided. Sample a) of Test Example 1, sample b
), sample C), sample d), sample C), sample f).

About 25 mg of sample g> was applied to each sample. The upper body of the back including each test site was exposed to direct sunlight for 5 hours.

Changes in color of each test sample were observed over time.

The conditions at this time were as follows: Location: Fukuoka Prefecture Weather: Clear skies Temperature: 25.0 to 29.0℃ Ultraviolet intensity: 365 nm 4.25 to 4.95 rnU
cm'305nm O,26~0,41 +nW/c
m2 exposure time was 10:30 to 15:30.

The results of this test are shown in Table 5.

In Table 5 b), a change in color tone was observed in the applied external preparation, but no change was observed in Sample C), Sample d>Sample e), Sample f), and Sample G), which are the external preparations of the present invention. I was not able to admit.

〔Effect of the invention〕

The present invention is a melanin production suppressing topical preparation that suppresses erythema and pigmentation of the skin caused by ultraviolet rays, and has an enhanced effect of preventing melanin deposition on the skin such as spots and freckles caused by sunburn. This is an extremely useful topical agent that prevents.

Claims (1)

[Claims] 1. A topical preparation containing kojic acid or a kojic acid derivative containing one or more ultraviolet absorbing substances consisting of para-aminobenzoic acid compounds, salicylic acid compounds, methoxycinnamic acid compounds, and benzophenone compounds. A melanin production suppressing topical agent characterized by: