JPH022848B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a novel cosmetic, and more particularly to a cosmetic that prevents darkening of the skin, which is a so-called whitening cosmetic that contains at least one or two or more of ursolic acid, its salts, or ursolic acid derivatives. . It has been known that ursolic acid, which is one of the ursan triterpenoids, is widely distributed in the waxy coating of fruits and leaves of apples, cherries, etc. As a result of intensive research on various ursolic acids including ursolic acids, we found that when these are blended into a cosmetic base and applied to the skin, this substance has an effect that was completely unknown until now, namely, a significant skin darkening due to inhibition of tyrosinase activity. We have discovered an effect that prevents this from occurring. Generally, when the skin is irradiated with ultraviolet rays from sunlight, melanin is significantly produced due to the activation of tyrosinase in the skin, and the skin tends to darken. Substances that have been added to cosmetics to prevent skin darkening caused by sunburn include:
Various natural products such as ascorbic acids, hydrogen peroxide, glutathione, colloidal sulfur, etc. have been known for some time, but ascorbic acids are easily oxidized and unstable in systems containing a lot of water such as wet products, causing discoloration and discoloration. It tends to cause odor. Due to the characteristics of hydrogen peroxide, it is difficult to say that it is sufficient in terms of safety, storage, and stability. Glutathione and colloidal sulfur are avoided in cosmetics because they emit a strange odor. Moreover, there are almost no natural products whose effects have been confirmed, and like the above-mentioned substances, their effect on preventing skin darkening is not fully satisfactory. In any case, there are no examples of applying the tyrosinase inhibitory effect of triterpenoid compounds such as ursolic acids according to the present invention. That is, the main purpose of the present invention is to achieve extremely excellent effects that cannot be obtained with the above-mentioned known skin tanning prevention substances by incorporating ursolic acid, its salts, or various ursolic acid derivatives into a cosmetic base. The object of the present invention is to provide a novel cosmetic material that has the following properties. The ursolic acid, its base salt, or ursolic acid derivatives applied to the present invention are those represented by the following general formula (), in which the hydroxyl group at the 3-position is unsubstituted or substituted with various acyl groups, and the 28-position hydroxyl group is unsubstituted or substituted with various acyl groups. The carboxyl group is unsubstituted, substituted with a base, or esterified with various alkyl groups. General formula () (In the formula, R ₁ is a hydrogen atom or Na, K, NH ₄ , H ₂ N
(CH ₃ ) ₂ , Ca, Mg or a straight chain, branched alcohol alkyl residue, R ₂ is a hydrogen atom or a straight chain,
Indicates that it is a branched fatty acid acyl residue. ) Specific examples of ursolic acid represented by the above general formula () and its salts include ursolic acid, sodium ursolic acid, potassium ursolic acid, ammonium ursolic acid, dimethylammonium ursolic acid, calcium ursolic acid, magnesium ursolic acid, etc. On the other hand, specific examples of acylursolic acid and its ester derivatives, which are ursolic acid derivatives, include butanoylursolic acid, sodium butanoylursolic acid, octanoylursolic acid, uraloylursolic acid, ammonium lauroylursolic acid, and palmitoylursole. acid, magnesium palmitoylursolic acid, 2-ethylhexanoylursolic acid, hexyldecanoylursolic acid, octanoylursolic acid ethyl ester,
Palmitoylursolic acid ethyl ester, 2-
Examples include ethylhexanoylursolic acid-2-ethylhexyl ester, 2-hexyldecanoylursolic acid octyldodecyl ester, dilauroylursolic acid cetyl ester, dibutanoylursolic acid-2-hexyldecyl ester, and ursolic acid alkyl ester. Specific examples of derivatives include ursolic acid ethyl ester, ursolic acid 2-ethylhexyl ester,
Examples include octidodecyl ursolic acid ester, cetyl ursolic acid ester, and 2-hexyldecyl ursolic acid ester. The acyl group represented by R ₂ in the general formula () has 2 or more carbon atoms.
20. Those in which the alkyl group represented by R ₁ has 1 to 20 carbon atoms are listed from the viewpoint of stability and ease of handling in cosmetics, and these are selected as appropriate depending on the type of cosmetic preparation. It is something that There are various methods for synthesizing acyl ursolic acid and its alkyl ester derivatives that can be applied to the present invention. The method of obtaining the desired product by reacting chloride is advantageous, and in the case of acyl ursolic acid alkyl ester derivatives, first, ursolic acid is reacted with a chlorinating agent such as thionyl chloride in an appropriate solvent such as chloroform in the presence of a base such as triethylamine, and It is equally advantageous to generate a chloride such as ursole, react it with a desired alcohol such as ethanol or cetanol in the presence of a base such as triethylamine to form an alkyl ursolic acid ester, and obtain the desired product by following the above-mentioned method for acylation. . Next, examples of synthesis of acyl ursolic acid and its alkyl ester derivatives will be shown. Synthesis example 1 Butanoyl ursolic acid 45.7 g of ursolic acid was mixed with 200 g of tetrahydrofuran.
ml and added 32 g of triethylamine, 12 g of butyric acid chloride was added dropwise under ice cooling and reacted with stirring for 1 hour. After stirring at room temperature for 2 hours, unreacted butyric acid chloride and triethylamine were dissolved in ethanol and 2% After each treatment with hydrochloric acid, the reaction product was extracted with ethyl acetate, and the extraction solvent was distilled off to obtain a crude reaction product. For purification, use a column and elute with hexane/ether (98/2) solvent to obtain white crystals of butanoylursolic acid (34.2%).
get g. The yield was 65%. Synthesis example 2 Ethyl octanoylursolic acid 45.7g of ursolic acid and 10.1g of triethylamine
Separately, 11.9 g of freshly distilled thionyl chloride dissolved in 30 ml of chloroform was added dropwise to a mixed solution of 100 ml of chloroform, and stirred and reacted for 1 hour, without removing the ursolic acid chloride produced. ethanol 32
A solution of 10.1 g of triethylamine dissolved in 30 ml of chloroform was further added dropwise under ice cooling and reacted for 3 hours. The triethylamine hydrochloride formed was separated and distilled off at below 40°C. Then, the obtained ethyl ursolic acid was mixed with benzene.
Dissolve in 200ml and add 32g of triethylamine
36 g of octylic acid chloride was added dropwise to the mixed solution under ice cooling, and the mixture was stirred and reacted for 1 hour.
After stirring at room temperature for 2 hours, the reaction was stopped, unreacted triethylamine was treated with 2% hydrochloric acid, the reaction product was extracted with ethyl acetate, and the extraction solvent was distilled off to obtain a crude reaction product. Purification was carried out using a column and eluting with a hexane/ether (98/2) solvent to obtain 36 g of octanoylursolic acid ethyl ester as a colorless liquid. Yield 59%. Synthesis Example 3 2-ethylhexanoylursolic acid-2-ethylhexyl ester 45.7g of ursolic acid and 10.1g of triethylamine
Separately, 11.9 g of freshly distilled thionyl chloride dissolved in 30 ml of benzene was added dropwise to a mixture of 100 ml of benzene while cooling on ice.
The reaction was stirred for hours, and a mixture of 12 g of 2-ethylhexyl alcohol and 10.1 g of triethylamine dissolved in 30 ml of benzene was added dropwise under ice cooling without taking out the ursolic acid chloride produced.
After reacting for an hour, the triethylamine hydrochloride produced is separated and the solvent is distilled off at 40°C or below. Next, the obtained ursolic acid-2-ethylhexyl ester was dissolved in 200 ml of benzene, and 32 g of triethylamine was further added to the mixture. 36 g of 2-ethylhexanoic acid chloride was added dropwise under ice cooling, and the reaction was stirred for 1 hour. After stirring at room temperature for 2 hours and refluxing at the boiling point of benzene for 1 hour, the reaction was stopped, unreacted triethylamine was treated with 2% hydrochloric acid, the reaction product was extracted with ethyl acetate, and the extraction solvent was distilled off. A crude reaction product was obtained. Purification using a column with hexane/ether (98/2)
Elution with a solvent yields 30 g of 2-ethylhexanoylursolic acid-2-ethylhexyl ester as a colorless liquid. Yield: 49% The amounts of ursolic acid, its salts and its derivatives to be blended into the cosmetic composition of the present invention are 0.01 to 5% by weight, preferably 0.1 to 1% by weight, based on the total weight. If it is less than 0.01% by weight, even if the cosmetic of the present invention is applied to the skin, the amount of transdermal absorption will not be the required amount to exhibit the effect of preventing skin darkening, and if it is less than 5% by weight.
Exceeding the amount should be avoided in view of the effects on the skin. When the above-mentioned ursolic acid, its salts or ursolic acid derivatives are incorporated into a cosmetic base, they may be used alone or in combination, or together with other reducing skin darkening inhibiting substances. The tyrosinase inhibitory effect of ursolic acid and butanoylursolic acid, one of the ursolic acid derivatives, was studied by Harding-Putsey.
Using the enzyme tyrosinase extracted from mouse melanoma (Passay), its yeast activity was determined by photometry, which measures the absorbance of Doperchrome at 475 nm. After incubating guinea pig skin homogenate with 3 x 10 ^-5 mol of the test substance ursolic acid and ursolic acid derivatives, the reaction solution was compared with the skin homogenate and the doperchrome reaction was observed. It showed an lag period of 12 minutes, whereas the lag period of skin homogenate alone was approximately 2 minutes. Furthermore, the reaction rate after the induction period was inhibited by 50% of the initial reaction rate of the skin homogenate alone. These results demonstrated that ursolic acid and ursolic acid derivatives inhibit tyrosinase activity and reduce the production of dopachrome. As detailed above, the present invention relates to cosmetics for preventing skin darkening that are effectively formulated with highly bioactive ursolic acid, its salts, and its various ursolic acid derivatives, and which are conventionally known. The present invention provides a so-called whitening cosmetic that has superior efficacy and stability compared to known substances such as various ascorbic acids, hydrogen peroxide, glutathione, and colloidal sulfur, especially glutathione, which inhibits tyrosinase activity. In addition, ursolic acid and its derivatives, which are the active ingredients of the cosmetics of the present invention, are extremely stable and do not undergo changes over time such as discoloration, odor, or decomposition and inactivation even when made into formulations, so they can be used in various cosmetics. It is extremely advantageous in that it can be stably and easily blended. Next, an oil-in-water emulsion type cream shown in Example 5 containing 1.0% butanoylursolic acid cetyl ester A as an ursolic acid derivative and ascorbic acid distearate B were added to the ursolic acid derivative in Example 5. The results of the thermal stability observation over time of creams with the same formulation after being left at 40°C are shown below. Figure 1 shows the residual rate of the active ingredient [A or B] over time, Table 1 shows the degree of odor change, and Table 2 shows the degree of discoloration.

【table】

【table】

[Table] As shown in the results of Figure 1, Table 1 and Table 2,
Ursolic acid derivative A according to the present invention does not decompose and lose its activity even after 4 weeks and has high stability (residual rate), whereas the conventional product ascorbic acid distearate B shows significant decomposition and deactivation. It is clear that this results in odor and discoloration. Incidentally, similar observations were made using glutathione instead of ascorbic acid distearate, but almost the same results were obtained. Furthermore, the cream of the present invention containing 1% of the above A and the conventional cream containing ascorbic acid distearate without containing this substance were statistically equivalent to each other.
When a group of 100 women used it continuously for one month, the former cream of the present invention was proven to be clearly more effective in improving dark spots and freckles than the conventional control cream. (See Table-3)

[Table] In addition to the above, we conducted use tests on the skin whitening effect, eliminating spots and freckles, beautifying the skin, etc. using cosmetics containing the cosmetics according to the present invention and the above-mentioned known substances. It was also demonstrated that the effects of the cosmetics of the present invention were extremely excellent. Next, examples of the cosmetics of the present invention will be shown. The blending ratio is in parts by weight. Example 1 Lotion ethanol 10.0 Propylene glycol 5.0 Polyoxyethylene (50) Hydrogenated castor oil 0.5 Citric acid 0.015 Sodium citrate 0.1 Methylparaben 0.05 Ursolic acid butyl ester 1.0 Fragrance Appropriate amount of water 83.0 Example 2 Cosmetic oil Squalane 47.5 Castor oil 49.9 Stearoylursolic acid butyl ester 1.0 Butylated hydroxytoluene 0.01 Fragrance Appropriate amount Example 3 Packaging polyvinyl alcohol 20.0 Ethanol 20.0 Butanoylursolic acid 1.0 Glycerin 5.0 Fragrance Appropriate amount Water 53.5 Example 4 Two-layer type lotion A Ethanol 1,3-butyl glycol 15.0 4.0 B Liquid paraffin myristate isopropyl lauroyl ursolic acid ethyl ester 5.0 1.0 0.5 C Fragrance methylparaben water Appropriate amount 0.1 74.4 Example 5 Cream stearic acid 8.0 Gaylow 4.0 Setanol 4.0 Lanolin 2.0 Isopropyl myristate 6.0 Squalane 7.0 Olive oil 2.0 Polyoxy monostearate ethylene sorbitan
5.0 Sorbitan monostearate 1.0 Propylene glycol 5.0 Butylparaben 0.1 Methylparaben 0.1 Butylated hydroxytoluene 0.05 Fragrance Appropriate amount of water 54.5 Butanoylursolic acid cetyl ester 1.0 Example 6 Lotion ethanol 7.0 Propylene glycol 5.0 Polyoxyethylene (50) hydrogenated castor oil 0.5 Citric acid 0.02 Sodium citrate 0.1 Methylparaben 0.05 δ-tocopherol 0.2 Ursolic acid 0.1 Sodium ursolic acid 0.2 Fragrance 0.4 Water 87.0 Example 7 Lotion ethanol 10.0 Glycerin 5.0 Propylene glycol 4.0 Oleyl alcohol 0.1 Ammonium ursolic acid 0.1 Magnesium ursolic acid 0 .05 Polyoxy Ethylene (20) Sorbitan Monolaurate 1.5 Polyoxyethylene (20) Lauryl Ether 0.5 Methylparaben 0.05 Fragrance 0.3 Water 78.4

[Brief explanation of drawings]

Figure 1 shows the residual rate of the active ingredient.
A is butanoylursolic acid cetyl ester, B
is ascorbic acid distearate.

Claims (1)

[Claims] 1 General formula () (In the formula, R ₁ is a hydrogen atom or Na, K, NH ₄ , H ₂ N
(CH ₃ ) ₂ , Ca, Mg or a straight chain, branched alcohol alkyl residue, R ₂ is a hydrogen atom or a straight chain,
Indicates that it is a branched fatty acid acyl residue. ) A cosmetic comprising at least one or two or more of ursolic acid, its salts, or ursolic acid derivatives.