JPH02108614A - Agent for external application - Google Patents

Abstract

PURPOSE:To provide an external agent repressing erythema and chromatosis caused by UV light, having a high activity for preventing blotch and freckle caused by sunburn and preventing the coloration of the external agent when used by using both kojic acid or a derivative thereof and a specific UV light- absorbing substance. CONSTITUTION:One kind or more of UV light-absorbing substances selected from dibenzoylmethane carboxylic acid derivatives, polyvalent metal salts thereof, poly aluminum hydroxide salt thereof, carbamoyldibenzoylmethane derivatives, isocoumarin derivatives, benzylideneaniline derivatives and dibenzylidenecyclopentenone derivatives is compounded with an external agent containing the known kojic acid or a derivative thereof as a melamine production-inhibiting agent in an amount of 0.01-5.0wt.% based on the whole amount of an external agent to provide the external agent having the above- mentioned effects without giving any damage to the skins of people when used.

Description

Detailed Description of the Invention [Field of Industrial Application] The present invention uses kojic acid or a kojic acid derivative as an active ingredient, which suppresses skin erythema 1 pigmentation caused by ultraviolet rays and prevents coloring of external preparations during use. This topic relates to external preparations for use in medicine.

[Conventional technology]

Kojic acid and kojic acid derivatives are known as substances that suppress the production of melanin in human skin.

Further, skin liniments containing these substances as active ingredients are also known. For example, skin-whitening cosmetics containing kojic acid as a whitening ingredient (JP-A-53-3538, JP-A-56-18)
569), skin-lightening cosmetics containing aliphatic carboxylic acid diesters of kojic acid, aliphatic carboxylic acid monoesters of kojic acid as whitening ingredients (Japanese Patent Publication No. 6160801, Japanese Patent Publication No. 60-9722), Skin-lightening cosmetics containing esters of aromatic carboxylic acids such as cinnamic acid and benzoic acid as skin-whitening ingredients (Japanese Patent Publication No. 10005/1983); Ointment for suppressing melanin production containing kojic acid as an active ingredient (Japanese Patent Publication No. 1983-10005);
1-10447), 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 formulated as a cosmetic or external skin preparation and applied to the skin, it has an excellent fair skin and melanin production inhibiting effect and does not cause any damage to the skin. Known as a 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 discolored.

[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 pigment staining caused by ultraviolet rays, enhances the effect of preventing stains 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, kojic acid was developed.

External preparations containing kojic acid derivatives as active ingredients include dibenzoylmethanecarboxylic acid derivatives, polyvalent metal salts thereof, polyaluminum hydroxide salts thereof, carbamoyldibenzoylmethane derivatives, isocoumarin derivatives, benzylideneaniline derivatives, and dibenzylidenecyclopene. By incorporating an ultraviolet absorbing substance made of a tenono derivative, we discovered that when applied to the skin, there was no erythema or pigmentation on the skin even after irradiation with ultraviolet rays, and that it also prevented discoloration during use. Completed the invention.

Kojic acid and kojic acid derivatives, which are the active ingredients of the external preparation of the present invention, are substances known as substances that suppress the production of melanin. Examples of kojic acid derivatives include monofatty acid esters of kojic acid, such as kojic acid monopalmitate, kojic acid monobutyrate, kojic acid monocaprylate 1, kojic acid monostearate (disclosed in JP-A-56-77272), and kojic acid monofatty acid esters. Difatty acid esters, such as kojic acid dipalmitate, kojic acid dibutyrate, kojic acid dioleate, kojic acid distearate (JP-A-59-7
776), kojic acid monocinnamoate.

Kojic acid monobenzoate (JP-A-59-3320
(disclosed in Publication No. 7), etc.

The external preparations of the present invention include cosmetics such as creams, lotions, and pack powders, as well as emulsions and lotions.

The term is used to include quasi-drugs used externally such as liniments and ointments. Each of these preparations is made into an external preparation by formulating the above-mentioned active ingredients with a formulation base commonly used for each preparation by a conventional method.

The dibenzoylmethanecarboxylic acid derivative of the ultraviolet absorbing substance used to prevent coloring of the external preparation containing kojic acid and kojic acid derivatives of the present invention has the general formula [wherein X is a hydrogen atom, a -valent metal cation, an organic cation] , a straight or branched aliphatic hydrocarbon group having 1 to 24 carbon atoms or a polyoxine alkylene (2 or 3 carbon atoms) oxide group, n Y's and m 2's each being the same or different, a hydroxyl group , represents a linear or branched aliphatic hydrocarbon group having 1 to 24 carbon atoms, an alkoxy group having 1 to 24 carbon atoms, or a polyoxyalkylene (2 or 3 carbon atoms) oxide group, and m and n are each 0 to 24. is an integer of 3] and is disclosed in JP-A-60-190708.

The polyvalent metal salt of the compound of formula (1) has the general formula [where Z and Y have the same meanings as in the above formula (1), n and l represent an integer of 0 to 3, and M is an aluminum atom. , a zinc atom, a calcium atom, a magnesium atom, a barium atom, a strontium atom, or a zirconium atom, m represents the valence of M], and is a compound represented by JP-A-62-240610
It is disclosed in the publication No.

The polyaluminum hydroxide salt of the compound of formula (1) has the general formula [wherein Y, Z, m, and n have the same meanings as in formula (1), and 1
is a number from -1 to 3] and is a compound represented by
It is disclosed in the publication No.-240611.

The carbamoyldibenzoylmethane derivative has the general formula [wherein R represents an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a methylenedioxy group, or a phenoxy group, and n represents an integer of 1 to 2] ] and is disclosed in JP-A-63-51318.

The benzylideneaniline derivative has the general formula [wherein Z, Y, m, and n have the same meanings as in formula (1), and R1
R2 are the same or different and each represents a straight or branched aliphatic hydrocarbon group having 1 to 24 carbon atoms] and is disclosed in Jikai@62-56418.

It is a compound represented by [wherein R and n have the same meanings as in formula (5)] and is disclosed in JP-A-63-51319.

The dibenzylidene thalopentenone derivative has the general formula [wherein R represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a methylenedioxy group, or a phenoxy group, and n is 0 to is an integer of 2] and is disclosed in JP-A-63-51320.

The ultraviolet absorber used in the external preparation of the present invention includes dibenzoylmethanecarboxylic acid derivatives such as sodium dibenzoylmethane-2-carboxylate, sodium 4'-methoxydibenzoylmethane-2-carboxylate, and sodium 3'-methoxydibenzoylmethane-2-carboxylate.
-hydroxy-4゜methoxydibenzoylmethane-2-
carboxylic acid.

3', 4° -bis(polyoxyethyleneoxy)°dibenzoylmethane-3-sodium carboxylate, 4'-
Potassium methoxy-3'-polyoxyethyleneoxy-dibenzoylmethane-4-carboxylate and the like are exemplified as water-soluble ones. Also, 4′-methoxy-4-methyldibenzoylmethane-2-carboxylic acid instearyl ester, 2′-4°-dimethoxydibenzoylmethane-
4-carboxylic acid stearyl ester, 3°,4°-bis(polyoxypropyleneoxy)-dibenzoylmethane-2-carboxylic acid methyl ester, 4°-palmityldibenzoylmethane-4-carboxylic acid isopropyl ester, 3' , 4'-dimethoxydibenzoylmethane-2
- Carboxylic acid oleyl ester and the like are mentioned as fat-soluble ones. And preferred ones are 3', 4'-
It is sodium bis(polyoxypropyleneoxy)-dibenzoylmethane-3-carboxylate.

Examples of polyvalent metal salts of dibenzoylmethanecarboxylic acid derivatives include magnesium 4'-methoxydibenzoylmethane-2-carboxylate, zinc 4°-methoxydibenzoylmethane-2-carboxylate, and 4-medoxydibenzoylmethane-2-carboxylate. Examples include aluminum carboxylate, calcium 4-methoxydibenzoylmethane-2-carboxylate, and barium 4'-methoxydibenzoylmethane-2-carboxylate. A preferred one is zinc 4'-methoxydibenzoylmethane-2-carboxylate.

Examples of the dibenzoylmethanecarboxylic acid derivative polyaluminum hydroxide salt include [4°-methoxydibenzoylmethane-2-carboxylic acid] Alx (OH) s .

[4°-Methoxydibenzoylmethane-2-carboxylic acid) A17(OH)2. (Dibenzoylmethane-2
-carboxylic acid]Agz(on)s, C4'-methyldibenzoylmethane-2-carboxylic acid) Affz(
OH)s, C4'-ethoxydibenzoylmethane-2-carboxylic acid] #z(O)l)s, C4'-methoxydibenzoylmethane-2-carboxylic acid) #, (OH)S
, C4'-methoxydibenzoylmethane-4-carboxylic acid) Alt (DH) s, and the like. And the preferred one is [4゛-methquinbenzoylmethane-2
-carboxylic acid) A3(OH)2.

As a carbamoyldibenzoylmethane derivative, 4°-
Methoxy-2-(N,N-diethylcabamoyl)dibenzoylmethane, 3″,4°-dimethoxy-2-(N,
N-dibutylcarbamoyl)dibenzoylmethane, 4'
-Ethoxy-2-(N.

N-dimethylcarbamoyl)dibenzoylmethane.

Examples include 2°14′-dimethoxy-2-(N,N-dibutylcarbamoyl)dibenzoylmethane. A preferred one is 4'-ethoxy-2-(N.

N-dimethylcarbamoyl)dibenzoylmethane.

Isocoumarin derivatives include 3-(4°-methoxyphenyl)isocoumarin, 3-(4°-ethoxyphenyl)
Examples include isocoumarin, 3-(3°, 4′-methylenedioxyphenyl) isocoumarin, and a preferred one is 3-(4′-methoxyphenyl) isocoumarin.

As a benzylideneaniline derivative, 4-acetyl-4
゛ -Ethoxybenzylideneaniline, 4-acetyl-4
°-Methoquinbenzylideneaniline, 4-acetyl-3
and 4'-methylenedioxybenzylideneaniline, and a preferred one is 4'-acetyl-4'-methoxybenzylideneaniline.

Examples of dibenzylidenecyclopentenone derivatives include dibenzylidenecyclopentenone, di(p-isopropylbenzylidene)cyclobentenone, and di(p-methquinbenzylidene)cyclobentenone.

Examples include di(p-ethylbenzylidene)cyclobentenone, and a preferred one is dibenzylidenecyclopentenone.

In the present invention, 0.0% of this substance is added to the total amount of the external preparation. O
By blending 1 to 5.0% (weight) of kojic acid and kojic acid derivatives, it can sufficiently suppress skin erythema and pigmentation caused by ultraviolet rays, enhance the effect of preventing spots and freckles caused by sunburn, and is suitable for external use when used. can prevent coloring.

In the external preparation of the X invention, in addition to the above ultraviolet absorbing substance,
Known ultraviolet absorbers, such as 2-hydroquine-4-methoxybenzophene, 2-hydroquine-4-methoxybenzophene-5-sulfonic acid.

Benzophenone compounds such as 2.2', 4.4'-tetrahydroxybenzophenone, phenyl salicylate, ethyl paraaminobenzoate, ethyl urocanate,
UV absorbing substances such as 2-(2-hydroquine-5-methylphenyl)benzotriazole, isopropyl paramethoxycinnamate, 2-ethylhexyl paramethoxycinnamate,
aloe extract.

Scutellariae extract, avatar, T-oryzanol.

The effects of the present invention can also be enhanced by appropriately adding UV-absorbing substances such as soybean oil and other plant components.

Furthermore, anionic substances such as sodium N-lauroyl-thi-glutamate and sodium dl-pyrrolidonecarboxylate; cationic substances such as stearyltomethylammonium chloride and cetyltomethylammonium chloride;
Nicotinic acid amide.

Antioxidants such as nicotinic acid and natural vitamin E 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 l (Lotion) Polyoxyethylene hydrogenated castor oil (60E, O,) 1.
0Og, ethanol 15.00g, ethyl roseoxybenzoate 0.10g, citric acid 0.10g,
Sodium citrate OJOg, 1.3-butylene glycol 4.00 g.

Edetate disodium 0.01g, kojic acid 0.50
g.

Sodium 3°,4°-bis(polyoxyethyleneoxy)-dibenzoylmethane-3-carboxylate (n=3)
Add purified water to 0.50 g to make 100 g, stir evenly, and dissolve to obtain a lotion.

Example 2 (Cream pack) Polyethylene glycol monostearate (40E, 0
．． ) 2.00 g 1 Self-emulsifying glycerin monostearate 5.00 g, stearic acid 5.00 g, behenyl alcohol 0.50 g, Swaran 15.0
0 g of cetyl octoate, 5.00 g of cetyl octoate, and 20 g of ethyl paraoxybenzoate Q were heated and dissolved. Separately 1
．． 3-butylene glycol 5.00 g, C4'-methquine dibenzoylmethane-2-carboxylic acid) #(OH)
z 1.00 g and purified water 52.29 g are heated and mixed. The latter solution is added to the former solution, emulsified, stirred, and then cooled. To this, 0.01 g of edetate disodium
, add 1.0 Og of kojic acid and 8.00 g of purified water,
Stir to mix and cool to obtain a cream pack.

Example 3 (Emulsion) Polyoxyethylene sorbitan monostearate (20
B, 0. ) 1.00 g, polyoxyethylene sorbitol tetraoleate (60B, 0.) 0.50 g
, lipophilic glyceryl monostearate 1.00 g,
Stearic acid 0.50 g, behenyl alcohol 0.
50 g, avocado oil 4.00 g,) glyceryl rioctanoate 4.00 g and ethyl paraoxybenzoate 0
．． Heat and dissolve 20 g. Separately, 1.3-butylene glycol 5.00 g, xanthan gum 0.14 g
, 1.00 g of zinc 4°-methoxydibenzoylmethane-2-carboxylate and 73.15 g of purified water are heated and mixed. The latter solution is added to the former solution, emulsified, stirred, and then cooled. Add to this 0.01 g of edetate disodium
, 1.00 g of kojic acid and purified water8. Add OOg,
After stirring and mixing, the mixture is cooled to obtain a milky lotion.

Example 4 (Rireem) Polyethylene glycol monostearate (40ε, 0
．． >2.00 g, self-emulsifying glyceryl monostearate 5.00 g, stearic acid 5.00 g,
Behenyl alcohol 1.00 g, liquid paraffin 1
0.00 g, glyceryl trioctanoate 10.
00 g and 0.20 g of ethyl paraoxybenzoate were heated and dissolved. Separately, 1.3 butylene glycol5.
00 g and 52.29 g of purified water are heated and mixed. The latter solution is added to the former solution, emulsified, stirred, and then cooled. To this, 0.01 g of disodium edetate, 1.00 g of kojic acid, 4'-ethoxy-2-(N,N-
dimethylcarbamoyl)dibenzoylmethane 0.50
g and 8.00 g of purified water were added, stirred and mixed, and then cooled to obtain cream.

Example 5 (Rime) Same as Example 4 except that 0.50 g of dibenzylidenecyclopentenone was used instead of 4'-ethoxy-2-(N,N-dimethylcarbamoyl)dibenzoylmethane. and get the cream.

Example 6 (lime) Instead of 4°-ethoxy-2-(N,N-dimethylcarbamoyl)dibenzoylmethane in Example 4, 3-(4'
A cream is obtained in the same manner as in Example 4, except that 0.50 g of -methoxyphenyl)isocoumarin is used.

Example 7 (lime) Instead of 4°-ethoxy-2(N,N-dimethylcarbamoyl)dibenzoylmethane in Example 4, 4-acetyl-
A cream is obtained in the same manner as in Example 4, except that 0.50 g of 4''-methoxybenzylideneaniline is used.

Example 8 (mousse) N-methacryloylethyl-N,N-dimethylammonium/α-N-methylcarboquine betaine/butyl methacrylate copolymer (30%) 3.50 g, polyoxyethylene cetyl ether (10ε, 0.)0,. 1
5 g, polyoxyethylene cetyl ether (2B,
0. ) 0.15 g, ethanol 13.00 g, edetate disodium 0.01 g, 4°-methoxy-3
-Purified water was added to potassium polyoxyethyleneoxy-dibenzoylmethane-4-carboxylate (n=4>0.50 g to make a total amount of 100 g, and the mixture was stirred and dissolved 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, stearin 15.00
g, behenyl alcohol 1.00 g, liquid paraffin 10.00 g.

10.00 g of glyceryl trioctanoate and 0.20 g of ethyl roseoxybenzoate are heated and dissolved. Separately, add 5.00 g of 1,3-butylene glycol to 5.5 g of purified water.
Add 9.79g, warm and mix. The latter solution is added to the former solution, emulsified, stirred, and cooled. Add to this 0.01 g of edetate (dis)IJum and 2.00 g of purified water.
Cream obtained by adding and stirring and mixing (control) b
) Cream containing 1 g of kojic acid in sample Ha) (control).

C) Cream containing 0.5 g of 4'-methoxydibenzoylmethane-2-carboxylic acid in test sample b) (external preparation of the present invention) d) Test sample b) containing 4'-methoxydibenzoylmethane-2-carboxylic acid Cream containing 1.0 g of zinc 2-carboxylate (
External preparation of the present invention).

e) Addition of 4°-methoxy-2-(N) to test sample b).

N-dimethylcarbamoyl)dibenzoylmethane 0.5
f) Cream (external preparation of the present invention) containing 21.0 g of [4'-methoxybenzoylmethane-2-carboxylic acid E Al(0)1] in test sample b) (external preparation of the present invention) g) 3-(4'-methoxyphenyl) in test sample b)
Cream containing 0.5 g of isocoumarin (external preparation of the present invention) h) Cream containing 0.5 g of 4-acetyl-4'-methoxybenzylideneaniline in sample b) (external preparation of the present invention).

i) Dibenzylidenecyclopentenone 0 in test sample b)
．． Cream containing 5 g (external preparation of the present invention) Test Example 1 Coloring test of cream The above test samples a), b), c), d), e).

Put f), g), h), and i) into a plastic petri dish, and place ultraviolet rays (FL2O3-BLB lamp (Tokyo Shibaura Electric)
g&)] was irradiated (25 J/c port 2).

Immediately after irradiation, the degree of coloration of each sample cream was observed with the naked eye, and the coloring degree of each sample cream was observed with the naked eye. uZ-1001DP
The color difference (ΔE) before and after irradiation with ultraviolet rays was measured.

The results were as shown in Table 1.

(Hereafter, this page margin) Table 1 As mentioned above, sample C) of the product of the present invention Sample d).

Sample e), sample f), sample g), sample h) and sample i)
It is clear that coloring is significantly prevented.

Test Example 2 Erythema and Pigmentation Suppression Test Nine 2×2C11 sites were placed on the upper backs of test subjects (46 healthy male volunteers).

Aluminum foil was set on the upper back so that ultraviolet rays could be irradiated only on the test area, and a FL2O3-BLB lamp manufactured by Tokyo Shibaura Electric ■ and FL203-E-3 were applied from a distance of 10 cm.
0 lamps each at the same time 0.8 Xl0-'erg/c
Irradiation was carried out three times on consecutive days at II12/times/day. Before irradiation, the test area was thoroughly washed with warm water.

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

Apply g), h), and i) to each area three times a day (morning and afternoon).

3 days and 7.21 days after the start of the test, the degree of pigmentation was compared with control a) and evaluated on a 4-grade scale by visual observation.

The results were as shown in Tables 2 to 40 below.

1) Erythema (after 3 days) Table 2 Sample b) (control) compared to sample a) (control),
Suppressed erythema [obviously pale (++) or better is 71.8
%] is the external preparation of the present invention, Sample C) [Clearly thin (++) or more is 84.8%], Sample d) [Clearly thin (++) [Clearly thin (++)] [Clearly thin (++) [Apparently pale (++)] [Apparently pale (++)] [Apparently pale (++) Moreover, erythema was suppressed.

2) Pigmentation (after 7 days) 80.4% or above 80.4% or above 82.6% above 82.6% 78.3% above 80.4% , sample e), sample f), sample g), sample h), and sample i). (++) or above is 69
．． 6%, 60.8%], but sample C) [obviously thin (+
+) or above 84.8%, 86.9%], sample d) [obviously thin (+10) or above 80.4%, 82.6%].

Sample e) [82.7% clearly thin (++) or above.

84.8%], Sample F Sample rice is clearly thin (++) or above 82.6%, 87.0%], %],) C Sample rice is clearly thin (++) or above 84.8%, 87. 0%], sample h) (
78.2% and 82.6% were clearly thin (++) or above]
,%],)[82.6% are clearly thin (++) or more,
84.8%] were suppressed even more.

Evaluation criteria for the degree of visual coloration in the above tests +++: Noticeably pale ++: Obviously pale +: Slightly pale: No difference Test Example 3 Sun exposure test 5 x 5 cta was applied to the lower part of the shoulder blades of 10 healthy men. Nine parts were established. Sample a), sample b), sample C), sample d), sample e), sample ') sample g of Test Example 1 were added to this part.
), sample h), and sample l) in an amount of about 25 mg each. 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: Location: Fukuoka Prefecture Weather: Clear skies Temperature: 24.0-29.0℃ Ultraviolet intensity: 365r+m 4.05-4.90 mW
/cm”305na+ 0.23~0.39 ml
/cm2ll/between 10:30 and 15:30.

The results of this test are shown in Table 5.

This is an extremely useful external preparation that suppresses the effects of Table 5 and prevents coloring of the external preparation during use.

A change in yellow tone was observed in samples $4a> and b), but samples c), sample d), sample e), and sample f>.

No change was observed in Sample g), Sample h〉, and Sample ]).

〔Effect of the invention〕

Claims (1)

[Claims] 1. External preparations containing kojic acid or kojic acid derivatives include dibenzoylmethanecarboxylic acid derivatives, polyvalent metal salts thereof,
Ultraviolet rays characterized by being blended with one or more ultraviolet absorbing substances consisting of polyaluminum hydroxide salts, carbamoyldibenzoylmethane derivatives, isocoumarin derivatives, benzylideneaniline derivatives and dibenzylidenecyclopentenone derivatives. A topical preparation that suppresses erythema and pigmentation caused by sunburn, enhances the effect of preventing spots and freckles caused by sunburn, and prevents discoloration during use.