JPS6222963B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a stable, non-irritating external skin bleaching agent that bleaches skin pigments when applied externally. 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, it has been proposed to mix steroids with hydroquinone preparations to eliminate skin irritation.
It has achieved some success. However, with such preparations, side effects of steroids such as skin atrophy occur when used externally for a long period of time, and even when steroids are used together, the concentration of hydroquinone is limited to about 5%. It is difficult to further increase the Furthermore, hydroquinone is a substance that is easily oxidized, and oxidation causes the topical preparation to turn black, which not only impairs its commercial value, but also because its oxidation products are severely irritating to the skin, increasing side effects and reducing 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 inventor found that the fatty acid ester of hydroquinone is sufficiently stable even without a special stabilizer, and when tested for skin irritation on guinea pigs, it showed almost no irritation and showed extremely good skin irritation. They discovered that it has a decolorizing effect and completed the present invention. That is, the present invention uses the formula: [wherein, X and Y are the same or different,
Each of COR and R means a linear or branched saturated aliphatic hydrocarbon group having 1 to 5 carbon atoms. The present invention provides an external skin bleaching agent, in which the fatty acid ester of hydroquinone used as an active ingredient is non-irritating and stable.
Because of its high concentration, no special stabilizers or steroids are required, and long-term use is possible.Also, the concentration of the active ingredient can be extremely high, and it exhibits an excellent skin bleaching effect. Next, the results of testing the depigmentation effect, skin irritation, and stability of the hydroquinone fatty acid ester of formula [] will be shown. (1) Depigmentation effect test Cultured pigment cells isolated from B16 mouse melanoma were cultured at 37°C for 24 hours in Eagle's MEM liquid medium supplemented with 10% fetal bovine serum in a 6 cm diameter culture dish. Next, hydroquinone fatty acid ester was added to the culture solution at a concentration of 1 μg/ml, and the culture was 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 criteria for evaluation were that no melanin deposition was observed at all, and + and ++ were used depending on the degree of melanin deposition. The results are shown in Table 1. The results are also shown when hydroquinone or ascorbic acid was used instead of the fatty acid ester of hydroquinone as a test compound, and when these were not used at all as a control.

[Table] As is clear from these results, hydroquinone fatty acid ester completely suppresses the melanin pigment production ability of cultured pigment cells at the same concentration as hydroquinone. (2) Skin irritation test Hair was removed from the backs of guinea pigs, ointments containing various concentrations of hydroquinone dibutyrate were applied once a day for 3 days, and skin irritation was determined visually according to the following criteria. did. −: No change. +: Erythema occurs. ++: Produces more than + stimulation. The results are shown in Table 2. The results are also shown when hydroquinone was used as a test compound in place of these fatty acid esters of hydroquinone, and as a control when they were not used at all.

[Table] As is clear from these results, hydroquinone fatty acid esters exhibit almost no skin irritation. (3) Stability test-1 Hydroquinone fatty acid ester was dissolved in a 70% ethanol aqueous solution to a concentration of about 1mM, and the pH was adjusted to 12 with 0.1N sodium hydroxide.
The temperature was maintained at 50°C, and the absorbance at 420 nm was measured over time to test the degree of coloration due to oxidation of the fatty acid ester of hydroquinone. The results are shown in the attached Figure 1. The results obtained when hydroquinone was used instead of the fatty acid ester of hydroquinone are also shown. Figure 1 is a graph showing the change in optical density of each sample solution over time (minutes), with curve 1
shows the case of hydroquinone diacetate.
Hydroquinone dipropionate, hydroquinone dibutyrate, and hydroquinone divalerate all show results as shown in curve 2. Curve 3 is for hydroquinone. As is clear from this graph, hydroquinone is rapidly oxidized and becomes colored.
However, fatty acid esters of hydroquinone are extremely stable in ethanol-water systems. (4) Stability test-2 Hydroquinone dibutyrate was added to pharmacopoeial water-absorbing ointments at various concentrations, left to stand at room temperature, and the degree of coloration over time was visually determined according to the following criteria. ○: No coloring. △: Extremely colored. ×: Extremely colored. The results are shown in Table 3. The results are also shown when hydroquinone or hydroquinone and ascorbic acid were used as the test compound instead of the fatty acid ester of hydroquinone.

[Table] As is clear from these 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 diacetate, hydroquinone dipropionate, hydroquinone dibutyrate, and hydroquinone divalerate. These hydroquinone fatty acid esters may be used alone or in combination of two or more, and are usually blended in a skin bleaching agent in an amount of 0.01 to 50% (by weight, the same hereinafter), preferably 0.5 to 20%. The external skin bleaching agent of the present invention can be made into various dosage forms used in ordinary pharmaceuticals, quasi-drugs, and cosmetics according to conventional methods, and other ingredients are not particularly limited. Any commonly used material 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, post-sunburn pigmentation, Lille melasma, and the like. Next, the present invention will be explained in more detail with reference to Examples and Reference Examples. Example 1 A cream was manufactured by a conventional method according to the following recipe. 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 divalerate 5.00 Fragrance Appropriate amount Preservative Appropriate amount Purified water 18.70 Example 2 A lotion was produced by a conventional method according to the following recipe. Ingredients % Ethanol 10.00 Polyvinylpyrrolidone 0.05 Oleyl alcohol 0.10 Polyoxyethylene sorbitan monolaurate
1.20 Propylene glycol 5.00 Hydroquinone dibutyrate 0.10 Flavor Appropriate amount Preservative Appropriate amount Purified water 83.55 Example 3 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 dipropionate 10.00 Flavor 0.49 Example 4 A milk lotion was produced by a conventional method according to the following recipe. Ingredients % Stearic acid 1.70 Cetanol 0.50 Lanolin 2.00 Oleyl oleate 2.00 Squalane 3.00 Liquid paraffin 8.00 Hydroquinone divalerate 0.50 Emulsifier 2.60 Triethanolamine 1.00 Propylene glycol 4.00 Fragrance Appropriate amount Preservative Appropriate amount Purified water 74.90 Example 5 The following prescription Pasta was produced according to the conventional method. Ingredients % Polyoxyethylene sorbitan distearate
15.00 Polyoxyethylene sorbitan monooleate
2.00 Microcrystalline cellulose (Avicel) 1.00 Glycerin 10.00 Hydroxyethylcellulose 4.00 Hydroquinone diacetate 20.00 Preservative Appropriate amount Purified water 48.00 Reference example 1 110g of hydroquinone and 80g of sodium hydroxide
in 400 ml of water, and cooled on ice at 0°C.
A solution of 157 g of acetyl chloride in 157 g of tetrahydrofuran was added dropwise. Leave the reaction mixture overnight. Pour the reaction mixture into 1 portion of water, collect the resulting crystals, and dissolve 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. Points 121-122.5
℃. Reference Example 2 In the same manner as in Reference Example 1, 55 g of hydroquinone and 92.52 g of propionyl chloride are reacted to obtain 105 g of hydroquinone bibropionate. Melting point 112-114℃. Reference Example 3 55 g of hydroquinone was dissolved in a solution of 40 g of sodium hydroxide in 300 ml of water, and the solution was heated to 3 to 6 ml of water.
100 g of butyryl chloride is added dropwise while maintaining the temperature at °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. Remove the solvent from the extract and dissolve the residue in 300 ml of ethanol. Add 80 ml of water and recrystallize to obtain 108 g of hydroquinone dibutyrate. Melting point 42-43℃. Reference example 4 45.6g of hydroquinone and 33.2g of sodium hydroxide
g in solution in 332 ml of water, and this was heated to a temperature of 3.
Add 10 g of valeryl chloride dropwise while maintaining the temperature at ~6°C. Incubate at 15°C for 1 hour. After the reaction, the reaction mixture is extracted with benzene, and the benzene extract is washed with dilute sodium hydroxide to remove unreacted hydroquinone. The solvent is removed from the extract and the residue is distilled under reduced pressure to obtain 40 g of crude crystals. This is recrystallized from ethanol to obtain 36 g of hydroquinone divalerate. Boiling point 155-157℃/1mm
Hg.

[Brief explanation of the drawing]

FIG. 1 is a graph showing changes in optical density at 420 nm with respect to time (minutes) for each sample solution in stability test-1. 〓〓〓〓

Claims (1)

[Claims] 1. As an active ingredient, the formula: [wherein, X and Y are the same or different,
Each of COR and R means a linear or branched saturated aliphatic hydrocarbon group having 1 to 5 carbon atoms. agent. 2 Hydroquinone difatty acid ester from 0.01 to
The external skin bleaching agent according to item 1 above, containing 50% by weight.