JPS58154507A - Skin bleaching agent for external use - Google Patents

Abstract

PURPOSE:To provide a stable and non-irritant skin-bleaching agent for external use, containing a fatty acid ester of hydroquinone as an active component, and exhibiting excellent effects to the bleaching of moth patch, freckle, chromatosis caused by inflammation, chromatosis caused by sunburn, Riehl's melanosis, etc. CONSTITUTION:The titled bleaching agent contains 0.01-50wt% (preferably 0.5- 20wt%) of the compound of formula (X and Y are H or OCOR; R is straight- chain or branched-chain saturated or unsaturated aliphatic hydrocarbon group; at least one of X and Y is OCOR). Hydroquinone has various problems such as skin irritation, easy oxidizability, and strong irritation of the oxidation product to the skin, etc. By converting hydroquinone to fatty acid ester, the irritancy is eliminated and the safety is improved, and consequently, the agent can be made to be applicable for a long period, and the concentration of the active component can also be increased.

Description

[Detailed description of the invention] This invention relates to a regular, non-irritating external skin bleaching agent.

Many melanin production inhibitors have been found in hydroquinone and many of its derivatives, which are thought to be effective for skin bleaching, but only hydroquinone has been found to be actually usable for the purpose of skin bleaching.

On the other hand, external skin bleaching agents such as ointments containing hydroquinone have been used locally for a long time, but they have problems with side effects such as skin irritation.

In recent years, in order to eliminate skin irritation caused by hydroquinone preparations, it has been proposed to mix them with steroids, and this has achieved some success. However, with such preparations, steroid side effects such as skin atrophy occur due to long-term topical use, and even when steroids are used in combination, the concentration of hydroquinone is limited to approximately 5%. It is difficult to increase.

Furthermore, hydroquinone is a substance that is easily oxidized, and oxidation causes the topical preparation to turn black, which not only reduces its commercial value, but also because its oxidation products have severe irritation to the skin, which increases side effects and reduces its commercial value. This will result in a loss. In order to suppress this oxidation, it has been proposed to incorporate a stabilizer such as ascorbic acid, but this is not satisfactory.

Surprisingly, the present inventors have found that the fatty acid ester of hydroquinone is sufficiently stable even without special stabilizers, shows almost no irritation when tested for skin irritation on guinea pigs, and It was discovered that this compound has an extremely good skin bleaching effect, leading to the completion of the present invention.

That is, the present invention provides, as an active ingredient, the formula: [wherein X
and Y are the same or different, and each is hydrogen or 0
COR,R is a straight or branched saturated or unsaturated aliphatic hydrocarbon group having 1 to 20 carbon atoms, provided that at least one of 7, X and Y is 0COR. The topical skin bleaching agent of the present invention is formulated with fatty acid esters, and since the external skin bleaching agent of the present invention has a high quality when used as an active ingredient and L2, it does not require special stabilizers or steroids. It can be used for a long period of time, and the concentration of the active ingredient can be made extremely high, and it exhibits an excellent skin bleaching effect.

The depigmentation effect, skin irritation, and stability of the fatty acid ester of hydroquinone of the formula [■] were tested and the results are presented.

(1) Tax pigment action test Cultured pigment cells isolated from B16 mouse melanoma were placed in a 6-diameter culture dish in Eagle ME supplemented with 10% fetal bovine serum.
M liquid medium? and cultured at 37°C for 24 hours. Next, 1μ of the fatty acid ester of hydroquinone was added to the culture solution.
The cells were added at a concentration of f/ml and further cultured at 37°C for 3 days. After culturing, the cells were fixed with 10% neutral formalin, subjected to DOPA reaction, and the degree of melanin deposition was determined under a microscope. The evaluation criteria were - and L- for no melanin deposition, and + and square depending on the degree of melanin deposition. All results are shown in Table 1. In addition, the results are also shown when no-hydroquinone or ascorbic acid was used instead of the JAW fatty acid ester of no-hydroquinone as a test compound, and when these were not used at all as a control.

Table 1 As is clear from the results, the fatty acid ester of no-hydroquinone completely suppresses the melanin pigment production ability of cultured melanocytes at the same concentration as no-hydroquinone.

(2) Skin irritation test The hair on the backs of guinea pigs was removed7, and ointments containing various concentrations of no-hydroquinone monopalmitate or no-hydroquinone dibutyrate were applied once a day for 3 days to test for skin irritation. was determined visually according to the following criteria.

1: No change.

+: Erythema occurs.

-H- Produces more than 20 stimuli.

The results are shown in Table 2. Table 2 also shows the results when hydroquinone was used in place of these fatty acid esters of hydroquinone as a test compound, and when they were not used at all as a control. Fatty acid esters show almost no skin irritation).

(3) Stability test-1 In a 70% ethanol aqueous solution]
c Dissolve fatty acid ester of hydroquinone, 0, IN
The pH was adjusted to 12 with sodium hydroxide, maintained at 50°C, and the absorbance at 420 nm was measured over time to test the degree of coloration due to oxidation of hydroquinone fatty acid ester. The results are shown in the attached Figure 1. The results are also shown when hydroquinone was used instead of the fatty acid ester of hydroquinone.

Figure 1 is a graph showing the change in optical density of each sample solution over time (0 min), where curve 1 is hydroquinone monopalmitate, curves 2.3 and 5 are hydroquinone monopalmitate and hydroquinone monolaure, respectively. Both hydroquinone dibutyrate and hydroquinone divalerate show results as shown in curve 4. As is clear from this graph, hydroquinone is rapidly oxidized and becomes colored, whereas hydroquinone fatty acid ester Extremely stable in ethanol-water systems.

(4) Stability test-2 Hydroquinone monopalmitate or hydroquinone divaleretate was added to local water-absorbing soft-h using various electrical processes.
The product was left at room temperature, and the degree of coloration over time was visually determined according to the following criteria.

○: No coloring.

/＼: Mild coloring.

×: Extremely colored.

The results are shown in Table 3. The results are also shown when hydroquinone or hydroquinone and ascorbic acid was used as the test compound instead of the fatty acid ester of hydroquinone.

Table 3 As is clear from the results, hydroquinone fatty acid esters are extremely stable in ointments.

Thus, the fatty acid ester of hydroquinone represented by the formula [■] can be obtained by a known esterification method, for example, by reacting hydroquinone with a fatty acid chloride to esterify it. Preferred examples of hydroquinone fatty acid esters of formula [■] include hydroquinone monoacetate, hydroquinone monoprobi-A-1, hydroquinone-D quinone monophylate, hydroquinone monovaler-1,
Hydroquinone monotunobrylate, hydroquinone 1 nostearate, hydroquinone monolaurate, hydroquinone monomyristate, hydroquinone monolaurate, hydroquinone 1 nostearate, hydroquinone 1 nostearate, hydroquinone monostearate ．．
Hydroquinone dibutyrate, hydroquinone dibutyrate, hydroquinone dibutyrate, hydroquinone dibutyrate, hydroquinone dibutyrate, and hydroquinone dibutyrate.

These fatty acid esters of hydroquinone can be used alone,
Two or more types may be used in combination, and usually 001 in the skin remover.
~50% C market weight, same as below), (Il"tL<1., 05-20% blended).

The external skin brightening agent of the present invention can be made into various net shapes used in ordinary pharmaceuticals, quasi-drugs, and cosmetics according to conventional methods, and other ingredients are not particularly limited.
Any of those commonly used for sunra may be used.

When applied externally, the skin bleaching agent of the present invention exhibits excellent effects on depigmentation of melasma, sparrow spots, post-inflammatory hyperpigmentation, pigmentation after sunburn, and Lille melasma.

Next, the present invention will be explained in more detail with reference to Examples and Reference Examples.

Example 1 A cream was prepared by a conventional method according to the following recipe.

Ingredients Liquid paraffin 41.00 Vaseline 15.00 Beeswax 10.00 Solid paraffin 600 Glycerin monostearate 2.00 Polyoxyethylene vine and tan monooleate 2
．． 00 stearic acid 0.
10 Borax 0.20 Hydroquinone Monostearate 5.0
0 Fragrances Appropriate amount of preservatives Appropriate Rectangular purified water
18.70 Example 2 A cream was manufactured by a conventional method according to the following recipe.

Ingredients Liquid paraffin 41. OO Vaseline 15.00 Beeswax 10.00 Solid Paraffin 6.00 Glycerin Monostearate 1/2600 Polyokine Ethylene Rubitan Monooleate
200 stearic acid 0.1
0 Borax 0.20 Hydroquinone Monoacetate 5.00
Flavorings Appropriate amount Preservatives Appropriate amount Ice making
18.70 Example 3 In the formulation of Example 2, a cream was prepared using the same amount of idroquinone monovalerate in place of idroginone monoacetate.

Example 4 A lotion was prepared according to the following recipe in a conventional manner.

Ingredients Thiethanol 10. OO
Polyvinylpyrrolidone 0.05 Oleyl alcohol 0.10 Polyquine ethylene sorbitan monolaurate 1
．． 20 Propylene Glycol 5.0
0 Hydroquinone monopalmitate 0
．． 10Fragrance, appropriate amount of preservative, appropriate amount of purified water
88.55 Example 5 A lotion was manufactured by a conventional method according to the following recipe.

Ingredients Thiethanol 10.00 Polyvinylpyrrolidone 0.05 Oleyl Alcohol 0.10 Polyoxyethylene Sorbitan Monolaurate 1.
20 Propylene Glycol 5.00
Hydroquinone monoundecanoate 0.
10Fragrance, appropriate amount of preservative, appropriate amount of purified water
83.55 Example 6 A lotion was obtained using the same amount of hydroquinone monomyristate in the formulation of Example 5 instead of hydroquinone monoundecanoate.

Example 7 A pack was manufactured by a conventional method according to the following recipe.

Ingredients Thikaolin 65.00 Starch 19.00 Propylene glycol 5.00 Calcium citrate o, oi Uric acid
050 Hydroquinone monopalmitate 10
．． 00 Perfume 0.49 Example 8 A pack was manufactured by a conventional method according to the following recipe.

Chikaorin 65.00 Starch 1900 Propylene glycol 5.00 Calcium acetate 001 Uric acid
0.50 Hydroquinone monoisostearate 10.0
0 fragrance 0.49 Example 9 A pack was obtained using the same amount of hydroquinone monocabrilate in the formulation of Example 8 instead of hydroquinone monoisostearate.

Example 10 A milk lotion was produced by a conventional method according to the following recipe.

Ingredients Stearic acid 1.70 Cetol 0.50 Lanolin 2.00 Oleyl oleate 2.00 Squalane
300 liquid paraffin
8.00 Hydroquinone monostearate 0.50 Emulsifier
2.60 Triethanolamine 1.00 Propylene Glycol
4.00 Fragrance, appropriate amount of preservative.

Purified water 74.90 Example 11 A milk lotion was produced by a conventional method according to the following recipe.

Ingredients: stearic acid 1.70 cetanol 0.50 lanolin 200 oleyl oleate) 2.00 squalane
3.00 liquid paraffin
8.00 Hydroquinone Monopropione) 0.50 Emulsifier
2.60 Triethanolamine 1.00 Propylene Glycol 4.00 Flavor Appropriate amount Preservative Appropriate amount Purified water
74.90 Example 12 Pasta was produced by a conventional method according to the following recipe.O Ingredient: Thipolyoxyethylene sorbitan dinutearate
15.00 Polyoxyethylene sorbitan monooleate 2.00 Microcrystalline cellulose (Avicel)
1.00 Glycerin 10.0
0 hydroxyethyl cellulose 4.
00 Hydroquinone monolaurate 2
0. OO preservative suitable
Quantity wood ＾ Seisui 48.00
Example 13 Pasta was produced in a conventional manner according to the recipe.

Ingredients: Polyoquinoethylene sorbitane distearate)
15.00 Polyethylene rubitan monooleate 2.00 Microcrystalline cellulose C Avicel) 1゜00 Glycerin
10.00 Hydroquine Ethyl Cellulose
4.00 Hydroquinone Monobutyre)
20.00 Preservatives
Appropriate amount of purified water
48.00 Example 14 A cream was produced in a conventional manner according to the following formulation.

Ingredients Liquid paraffin 41.00 Vaseline 15.00 Beeswax 10.00 Solid paraffin 6.00 Glycerin monostearate) 2.00 Polyoxyethylene sorbitan monooleate
2.00 Stearic acid 0
．． 10 borax 0.20
hydroquinone divaler) 5
．． 00 Fragrance Appropriate amount Preservative Appropriate amount Purified water
18.70 Example 15 A lotion was manufactured by a conventional method according to the following recipe.

Ingredients Thiethanol 10.00 Polyvinylpyrrolidone 0.05 Oleyl Alcohol 0.10 Polyoxyethylene rubitan monolaurate 1.
20 Propylene Glycol 5.0
0 Hydrogynone Diptyre)
0.10Fragrance Appropriate amount Preservative Appropriate amount Purified water
88.55 Example 16 A pack was manufactured by a conventional method according to the following recipe.

Ingredients Kaolin 65.00 Starch 19.00 Propylene glycol 5.00 Calcium acetate 0.01 Uric acid
0.50 Hydroquinone dipropione) 10
．． 00 Fragrance 0.49 Example 7 A milk lotion was produced by a conventional method according to the following recipe.

Ingredients Tistearic acid 1.70 Cetol 0.50 Lanolin 2.00 Oleyl oleate 2.00 Squalane
3.00 liquid paraffin
8.00 Hytroquinone Divalerate 0.50 Emulsifier 2.60 Triethanolamine 1.00 Propylene Glycol 4.00 Fragrance
Appropriate amount of preservative Appropriate amount of purified water 74.90 Example 1
8 Pasta was produced in a conventional manner according to the following recipe.

Ingredients Thipolyoxyethylene sorbitan distearate
15.00 Polyoxyethylene sorbitan monooleate 2.00 Microcrystalline cellulose C Avicel)
1.00 glycerin
10. OO Hydroxyethylcellulose
4.00 Hydroquinone diacetate)
20.00 Preservatives
Appropriate amount of purified water
48.00 Reference Example 1 Hydroquinone 55f was dissolved in 200 g of 10% sodium hydroxide aqueous solution, and 50 gf of tetrahydrofuran was added to this.
Add. A solution of 13.7 g of palmitic acid chloride in tetrahydrofuran is added dropwise to this mixed solution over about 1 hour while cooling the mixture to 0 to 5° C. for reaction. 2 hours at the same temperature
After stirring at room temperature for 1 hour, the reaction mixture was poured into diluted sulfuric acid and extracted with ethyl acetate. After washing with water, concentrate under reduced pressure.
Purify the concentrate by gel column chromatography 1
,,． 4-Hydroxyphenylno2lumitate 10gf
C, +7). Melting point: 905-91.5°C, Rf in silica gel thin layer chromatography = 0.76 (developing solvent: chloroform-acetone-2=1).

Reference example 2 Hydroquinone 440 fl'r Sodium hydroxide 16
1600 s+ of 0f water is dissolved in a medium solution, and a tetrahydrofuran solution of 346 g of acetyl chloride is added dropwise to this at 0° C. while cooling with water. Further, stir for 1 hour at 0°C [7
, and then allowed to react at room temperature for 2 hours. The reaction mixture was extracted with ethyl acetate [7, washed with a small amount of water. Ethyl acetate is removed and distilled under reduced pressure to obtain hydroquinone monoacetate 188f. Boiling point 144-147℃/41118
g, silica gel thin layer chromatography C developing solvent: chloroform-ethyl acetate-3:1, detection: ultraviolet lamp.

Rf=0.85° in ) Reference Example 3 In the same manner as in Reference Example 2, hydroquinone and lyl chloride were reacted and extracted with ethyl acetate.

Wash the ethyl acetate extract with water to remove ethyl acetate. The residue is thoroughly washed with water to remove unreacted hydroquinone, and then distilled under reduced pressure to obtain hydroquinone monovalerate. Boiling point 163-166℃/111110
g, silica gel thin layer chromatography (developing solvent;
Chloroform-ethyl acetate = 3:1. Detection: Ultraviolet light-)
Rf = Q in VC, 71° Reference Example 4 In the same manner as Reference Example 2, no-hydroquinone and n-undecanoyl chloride (prepared by chlorinating n-undecanoic acid with thionyl chloride) were reacted, and ethyl acetate was added. Extract with Wash the ethyl acetate extract with water (7) and concentrate. Dissolve the concentrate in n-hexane and cool. The precipitated crystals were further recrystallized from n-hexane to obtain the entire hydroquinone monoundecanoate. Melting point 72-74°C, Rf in silica gel thin layer chromatography (developing solvent: chloroform-ethyl acetate = 3:], detection: ultraviolet lamp)
=0.60°Reference Example 5 In the same manner as in Reference Example 2, hydroquinone and instearoyl chloride (prepared by chlorinating isostearic acid with thionyl chloride) are reacted, and extracted with ethyl acetate. Wash the ethyl acetate extract with water to remove ethyl acetate. The entire residue was thoroughly washed with water to remove unreacted hydroquinone, and
Concentrate under reduced pressure (l gmHg) on a water bath at 0.degree. C. to obtain hydroquinone monoisostearate. Silica gel thin layer chromatography (developing solvent: chloroform-ethyl acetate-3=1, detection: ultraviolet lamp) Rf in vc
20.48° Reference Example 6 Hydroquinone 4401 Sodium hydroxide 80g Water 2
000 ml bath solution dissolve. 18℃ under vigorous stirring
The following is a solution of n-caproyl chloride 6481 in tetrahydrofuran 600 Me. After dropping, stir for 1 hour and leave at room temperature overnight. This is filtered and the furnace liquid is extracted with ethyl acetate. Wash the extract with water to remove ethyl acetate. The residue is dissolved in ethyl acetate and washed with water to remove unreacted hydroquinone. Removal of ethyl acetate yields 36 g of hydroquinone monocaprylate. Melting point 64-65.5°C.

Reference Example 7 In the same manner as in Example 6, hydroquinone and propionyl chloride were reacted and extracted with ethyl acetate. The ethyl bipartite extract was thoroughly washed with water j7. Remove solvent. The residue is distilled under reduced pressure to obtain hydroquinone mono/propionate. Boiling point 140-142° 5℃/3ymHg, melting point 68-
74℃.

Reference Example 8 Similarly to Reference Example 6, hydroquinone and butyryl chloride are reacted and extracted with ethyl acetate.

Wash the ethyl acetate extract thoroughly with water to remove the solvent. The residue is distilled under reduced pressure to obtain hydroquinone monobutyrate. Boiling point 150-b Hg.

Reference Example 9 Hydroquinone 55f was mixed with 20 g of sodium hydroxide and 3
A solution containing 123 g of myristoyl chloride and 150 g of tetrahydrofuran was added dropwise to the solution under water cooling. The formed precipitate was removed, and the filtrate was extracted with ethyl acetate. The extract was thoroughly washed with water to remove unreacted hydroquinone, yielding 2 y of hydroquinone monomyristate. Melting point 75-78°C.

Reference Example 10 110 g of hydroquinone was dissolved in a solution of 80 g of sodium hydroxide in 400 txl of water, and 157 g of acetylchloride and 15 g of tetrahydrofuran were added to the solution at 0°C under cooling with water.
Add 7g of the solution dropwise. Leave the reaction mixture overnight. The reaction mixture was poured into 1/2 volume of water, and the resulting crystals were separated and dissolved in chloroform.

This solution is washed with dilute sodium hydroxide solution to remove unreacted hydroquinone. After removing the solvent, the residue is recrystallized from water-ethanol to obtain 175 g of hydroquinone diacetate. MLa 121-122.5°C.

Reference Example 11 In the same manner as in Reference Example 10, 55 g of hydroquinone and 92.52 f of propionyl chloride are reacted to obtain 105 g of hydroquinone dipropionate. Melting point 11
2-114℃0 Meeting 4 examples] 2 Hydroquinone 55f 40g of sodium hydroxide 3
00ml solution, and 100g of butyryl chloride is added dropwise to this while maintaining the temperature at 3-6°C].

React at 10-13°C for 4 hours. After the reaction, the reaction mixture is extracted with benzene and the extract is washed with dilute sodium hydroxide solution.

The solvent was removed from the extract, and the remaining Fk was dissolved in ethanol 300%.
Dissolve in rd. Add 80s+ti of water and recrystallize to obtain 108g of hydroquinone dibutyrate. Melting point 42~
43℃.

Reference example] 3 Hydroquinone 45.69 to sodium hydroxide 33.2
Valeryl chloride] (1'
drip. React at 15°C for 1 hour.

After the reaction, the reaction mixture is extracted with benzene, and the benzene extract is diluted with hydroxide) and washed with +1 um to remove unreacted hydroquinone. The solvent is removed from the extract 7, and the residue is distilled under reduced pressure to obtain crude crystals 401. This is recrystallized from ethanol to obtain 36 g of hydroquinone divalerate. Boiling point 155-157℃/】Igo

[Brief explanation of the drawing]

FIG. 1 is a graph showing the change in optical density at 4200 m for each sample solution in Stability Test-1 over time (0 minutes). Patent Applicant: Sunstar Co., Ltd. Representative Patent Attorney Aoyama Sho &■'-2 people

Claims (2)

[Claims] (1) As a J-effective component, the formula: [In the formula, X and V are the same or different, and each is hydrogen or 0COR= 1. A skin depigmenting agent for external use, characterized in that it contains a fatty acid ester of hydroquinone represented by a saturated aliphatic hydrocarbon group, provided that at least one of X and Y (equal to 0 COR). (2) Fatty acid ester of hydroquinone ff1O,0
The external skin bleaching agent according to item (1) above, which is formulated in an amount of 1 to 50% by weight.