JPH09132527A - Suppressant for melanogenesis and dermal preparation for external use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain both suppressant for the melanogenesis and dermal preparation for external use, excellent in beautifying and whitening effects and prevention, improvement and treatment of pigmentation and having high stability and safety. SOLUTION: This suppressant for the melanogenesis comprises a 4-(2,2,6- trimethyl-yl-cyclohexane)-2-butyl cinnamate represented by formula I (R is H, OH or methoxy). The suppressant for the melanogenesis in an amount of 0.01-10wt.% based on the total amount is contained as an active ingredient to prepare the dermal preparation for external use. The compound represented by formula I is prepared by hydrogenating β-ionone in the presence of a palladium carbon and hydrogen in a methanol solvent, providing a tetrahydroionone represented by formula II, then dissolving the resultant compound in isopropyl alcohol, reducing the compound with sodium borohydride, purifying the reduced compound, affording 4-(2,2,6-trimethy1-yl-cyclohexane)-2-butanol and reacting the prepared compound with p-hydroxycinnamic acid by using N,N'- dicyclohexylcarbodiimide (DCC) and dimethylaminopyridine.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a melanin production inhibitor and a skin external preparation, and more specifically, a melanin production inhibitor for preventing skin pigmentation, and an excellent whitening effect as well as an ultraviolet protection effect. An external preparation for skin is provided.

[0002]

2. Description of the Related Art Spots and freckles and pigmentation after tanning are caused by the remarkable enhancement of melanin production due to the activation of pigment cells existing in the skin. I have. Generally, melanin is changed from tyrosine to dopa and dopa to dopaquinone by the action of the enzyme tyrosine which is biosynthesized in pigment cells,
Then, it is supposed to be formed via an intermediate such as 5,6-dihydroxyindophenol.

Therefore, in order to prevent or improve the darkness of the skin, it is considered to inhibit the melanin production process or to bleach already produced melanin. Based on such a concept, various whitening components have been conventionally proposed. For example, a sulfur compound represented by glutathione or hydroquinone is mentioned as a substance that inhibits tyrosine enzyme activity and suppresses melanin production. Further, as a light-color bleaching of the generated melanin,
Hydrogen peroxide, vitamin C, etc. have been used.

[0004]

However, these conventional whitening ingredients are extremely poor in stability in the formulation system and cause discoloration and off-flavor due to decomposition, and their effects at the cell or biological level are still insufficient. there were. Further, hydroquinone has a strong lightening effect, but has a problem in safety such as causing irreversible white spots and rashes.

As described above, the conventionally used whitening ingredients are effective, stable and safe.
Not truly practically satisfactory. The present invention has been made in view of such circumstances, using a melanin production inhibitor, and this melanin production inhibitor as an active ingredient, having sufficient ameliorating and treating effect of skin pigmentation disease, and ultraviolet light It is an object of the present invention to provide a skin external preparation that has a protective effect and can practically satisfy safety and stability.

[0006]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventors have found that cinnamic acid-4- (2,2,6- It was determined that the trimethyl-yl-cyclohexane) -2-butyl ester derivative has a strong inhibitory effect on the melanin production of living pigment cells, and it was further compounded in a base at a certain concentration or higher to give a skin external preparation. It has been found that when used as a composition, it exhibits an excellent whitening effect on the skin, and the present invention has been completed.

That is, the present invention relates to the inhibition of melanin production consisting of a cinnamic acid-4- (2,2,6-trimethyl-yl-cyclohexane) -2-butyl ester derivative represented by the general formula (I) shown below. It is related to agents.

The present invention also relates to a skin external preparation characterized by containing at least one of the melanin production inhibitors as an active ingredient, preferably 0.01 to 10% by weight based on the total amount of the skin external preparation. Is.

[0009]

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(In the formula, R represents hydrogen, a hydroxyl group or a methoxy group.)

Hereinafter, the present invention will be described in detail.

<1> Melanin Production Inhibitor The melanin production inhibitor of the present invention comprises cinnamic acid-4- (2,2,6-trimethyl-yl-) represented by the general formula (I).
It consists of a cyclohexane) -2-butyl ester derivative. Specifically, cinnamic acid-4- (2,2,6-trimethyl-yl-cyclohexane) -2-butyl ester (hereinafter abbreviated as CA-TMCHB), p-hydroxycinnamic acid-4- (2,2). 2,6-Trimethyl-yl-cyclohexane) -2-butyl ester (hereinafter, pHCA-TM
CHB), p-methoxycinnamic acid-4- (2,2)
2,6-trimethyl-yl-cyclohexane) -2-butyl ester (hereinafter abbreviated as pMCA-TMCHB) and the like.

These compounds according to the present invention can be synthesized from β-ionone and a cinnamic acid derivative. The synthesis method will be described below by taking pHCA-TMCHB as an example.

Β-Ionone was hydrogenated in a methanol solvent in the presence of palladium carbon and hydrogen to obtain tetrahydroionone (compound of formula 3).

Next, the obtained tetrahydroionone was dissolved in isopropyl alcohol, reduced at room temperature with sodium borohydride, and further purified by silica gel column chromatography to give 4- (2,2,6-trimethyl-). Il-cyclohexane) -2-butanol (compound of formula 4)
I got

Then, the compound of Chemical formula 4 was reacted with p-hydroxycinnamic acid at room temperature for 2 hours using N, N'-dicyclohexylcarbodiimide (DCC) and separated and purified by silica gel column chromatography. The target pHCA-TMCHB (compound of Chemical formula 5) was obtained.

[0017]

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[0018]

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[0019]

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Other compounds can also be produced according to the above method by replacing p-hydroxycinnamic acid with cinnamic acid or p-methoxycinnamic acid.

<2> External preparation for skin The external preparation for skin of the present invention includes the above-mentioned cinnamic acid-4- (2,2,2).
One or more melanin production inhibitors consisting of 6-trimethyl-yl-cyclohexane) -2-butyl ester derivative are preferably 0.01 to 10% by weight, more preferably 0.05 to 10% by weight based on the total amount of the external preparation. %, Particularly preferably 0.1 to 5% by weight. Among the external preparations for skin, the content is preferably 0.1% by weight or more particularly for those for the purpose of preventing and improving spots, freckles and darkening of the skin due to sunburn.

When the content is less than 0.01% by weight, the whitening effect based on the melanin production inhibitory effect is lowered,
Further, even if the amount exceeds 10% by weight, the effect reaches a plateau, so that the content is preferably within the above range.

In the external preparation for skin of the present invention, in addition to the above-mentioned active ingredients, various ingredients generally used in pharmaceuticals, cosmetics, etc., that is, an aqueous ingredient, an oily ingredient, a powder ingredient, a surfactant (as an emulsifier), a moisturizing agent Agents, thickeners, coloring agents, fragrances, antioxidants, pH adjusters, chelating agents, preservatives, or agents such as ultraviolet ray protective agents and anti-inflammatory agents can be blended alone or in combination of two or more.

Examples of the aqueous component include water (purified water),
Lower alcohols (ethanol, propanol, isopropanol) and the like.

Examples of the oily component include higher fatty acids (stearic acid, palmitic acid, myristic acid, lauric acid, and their esters), higher alcohols (cetanol, lanolin alcohol, stearyl alcohol, cetostearyl alcohol, etc.) and Waxes (solid paraffin, microcrystalline wax, ceresin wax, polyethylene wax, beeswax, wood wax, carnauba wax, candelilla wax, etc.), natural or synthetic oil substances (squalane, liquid paraffin, lanolin or its derivatives, olive oil, camellia oil, Cottonseed oil, oleyl alcohol, castor oil, petrolatum, adipic acid diethoxyethyl ester, silicone oil, fluorine oil, etc.)
Is mentioned.

Examples of the powder component include aluminum powder, titanium oxide powder, zinc oxide powder, iron oxide powder, acrylic powder, silica beads, talc and sericite.

Examples of the surfactant include polyoxyethylene monooleate, polyoxyethylene cetyl ether, aluminum stearate, octyldodecanol, new oil type glyceryl monostearate, propylene glycol monostearate and the like.

Examples of moisturizing agents include glycerin, propylene glycol, 1,3-butylene glycol, dipropylene glycol, ethylene glycol, 1,4-butylene glycol, diglycerin, triglycerin, sorbit and its derivatives, polyethylene glycol and the like. Polyhydric alcohols: glucose, maltose, maltitol, sucrose, fructose, threitol, erythritol, sorbit, starch-degrading sugar, hyaluronic acid, chondroitin sulfate, hydrolyzed collagen, carboxymethyl chitin and the like.

Examples of the thickener include carboxyvinyl polymer, CP jelly, carboxymethyl cellulose,
Carrageenan, sodium alginate, bentonite,
Vegum, synthetic hectorite and the like.

Examples of antioxidants include dibutylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), sodium tocopherol pyrosulfite, sodium bisulfate, tocopherol acetate, vitamin E and rosemary extract. .

Examples of the pH adjusting agent include citric acid, lactic acid, tartaric acid, phosphoric acid and the like. Examples of the chelating agent include EDTA (ethylenediaminetetraacetic acid),
Thioglycolic acid, thiolactic acid, thioglycerin and the like.

Examples of preservatives include methyl, ethyl, propyl and butyl esters of p-oxybenzoic acid (called methylparaben, ethylparaben, propylparaben and butylparaben, respectively), o-phenylphenol, dehydroacetic acid and Its salt, p-cresol,
m-cresol, o-chloro-m-xylenol and the like.

Examples of the ultraviolet protective agent include ascorbic acid or its derivative, isoferulic acid or its salt, oxybenzone or its derivative, p-aminobenzoic acid or its derivative, urocanic acid or its derivative, kojic acid, dibenzoylmethane or its derivative. Derivatives, p-methoxycinnamic acid or its derivatives, fine particle titanium oxide, fine particle zinc oxide,
Fine particle iron oxide and the like.

Examples of the anti-inflammatory agent include glycyrrhetinic acid or its derivative, glycyrrhizic acid or its derivative, bisabolol, geraniin, horse chestnut extract, aloe extract and the like.

Each of these components or drugs can be used alone or in combination of two or more.

The external preparation for skin of the present invention includes the above-mentioned cinnamic acid-4.
-(2,2,6-Trimethyl-yl-cyclohexane)
One or two or more kinds of whitening components (or whitening agents) other than the 2-butyl ester derivative may be blended. Other whitening ingredients include, for example, pantetheine-S-sulfonic acid, isoferric acid, ascorbic acid and its magnesium phosphate salts, arbutin, kojic acid, linoleic acid, tranexamic acid, esculin, vitamin A acid, retinol and the like.

There is no particular limitation on the form of the external preparation for skin of the present invention, and those usually used for pharmaceuticals, quasi-drugs, cosmetics, etc., for example, ointments, creams, emulsions, lotions, packs And bath preparations.

[0038]

BEST MODE FOR CARRYING OUT THE INVENTION The action of the cinnamic acid-4- (2,2,6-trimethyl-yl-cyclohexane) -2-butyl ester derivative used in the present invention will be described below based on experimental examples. To do.

(1) Inhibition of melanin production on pigment cells 5 × 10 ⁴ B-16 melanoma cells were seeded in a plastic culture flask (75 cm ² ), and cultured in an Eagle MEM medium containing 10% serum. In the presence of 5% carbon dioxide, 3
The cells were cultured at a temperature of 7 ° C. After 2 days, the test sample was added so as to have a concentration of 5, 10, 15, 20 μM in the medium,
It was further cultured for 4 days.

After completion of the culture, the medium was removed and washed with a phosphate buffered saline solution (hereinafter referred to as PBS), and then the cells were detached from the flask using trypsin and EDTA-containing medium and centrifuged from the cell suspension. The cells were collected by. After washing the obtained cells twice with PBS, a fixed amount of PBS is added.
Was added thereto, and the cells were mixed by flushing. An aliquot of the cell suspension was taken, and the number of cells was counted using a Coulter counter. The remaining suspension was centrifuged again, and the whiteness of the sediment was visually observed. Table 1 shows the results based on the following criteria.
Shown in The number of cells (%) in the table represents the number of cells (%) when the number of cells when a solvent is used instead of the test sample (solvent target) is 100.

−: Equivalent to solvent control +: slightly whiter than solvent control ++: clearer white than solvent control

[0042]

[Table 1]

Thereafter, 1N sodium hydroxide was further added to the precipitate to dissolve it by heating. After cooling, chloroform was added and the mixture was centrifuged again. The absorbance of the obtained supernatant was measured at 400 nm, and the amount of melanin was determined from a calibration curve previously prepared using synthetic melanin. The amount of melanin was determined as an amount per 10 ⁴ cells. Table 2 shows the results. In addition, the suppression rate in the table was obtained by the following equation. Inhibition rate (%) = [(melanin amount of control product−melanin amount of test sample added product)] × 100 / (melanin amount of control product)

[0044]

[Table 2]

As is clear from these results, all the cinnamic acid-4- (2,2,6-trimethyl-yl-cyclohexane) -2-butyl ester derivatives were compared with the solvent control (control) in comparison with the dye. It was shown to have a whitening effect on the cells and also an effect to remarkably suppress melanin production in pigment cells.

(2) Inhibition of pigmentation by ultraviolet rays (animal test) The back skin of brown guinea pigs (7 animals) was shaved and shaved with an electric clipper and a shaver, and this area was 1.5 × 1. .5cm
Cover the irradiation window of 4 with a black cloth having a total of 4 on the left and right, and use the FL20S / E30 lamp as a light source for 1 m from the top of this cloth.
Ultraviolet light of W / cm ² / sec was irradiated for 4 minutes and 20 seconds.
This operation was performed once a day for 3 consecutive days. From the day after the end of irradiation, 20 μl of a test solution prepared by dissolving a predetermined amount of test sample using ethanol as a solvent was added once a day for a total of 20
It was applied continuously for days. In addition, an experiment was similarly performed using only ethanol as a control. On the 21st day from the start of the experiment, the degree of pigmentation of the treated part was determined by visual observation according to the following criteria. The results are shown in Table 3 as an average value.

0: No pigmentation 0.5: Weak pigmentation with indistinct borders 1: Weak pigmentation with definite borders 2: Moderate pigmentation with definite borders 3: Definite borderline intensity With pigmentation

[0048]

[Table 3]

As shown in Table 3, cinnamic acid-4- (2,2
All of the 2,6-trimethyl-yl-cyclohexane) -2-butyl ester derivatives, when applied to the skin after UV irradiation, cause deposition of melanin pigment by UV at a concentration of 3% as compared with the case of applying a solvent control. Obviously suppressed.

(3) UV protection effect On the inside of the upper arm of 10 humans aged 20 to 35,
Four sites of A, B, C, and D having an area of 1.5 × 1.5 cm are set, and 3% CA-TMCHB (solvent is 7
0% ethanol aqueous solution), B site 3% pMCA-
TMCHB (solvent is 70% ethanol aqueous solution), C site is coated with 3% pHCA-TMCHB (solvent is 70% ethanol aqueous solution), and D site is coated with only 10 μl of solvent (70% ethanol aqueous solution) and left for 15 minutes. did. Then, cover the area other than the application area with a black cloth having an irradiation window of the same size as the application area, and apply FL20S.E 30 from the top of this cloth.
Using the lamp as a light source, 1 mW / cm ² / sec of ultraviolet rays was applied to the application site for 2 minutes and 30 seconds.

On the 14th day after the start of the experiment, the degree of pigmentation in the treated area was evaluated by visual observation according to the following criteria. The results are shown in Table 4 as an average value.

0: No pigmentation 0.5: Weak pigmentation with indistinct borders 1: Weak pigmentation with definite borders 2: Moderate pigmentation with definite borders 3: Definite intensity With pigmentation

[0053]

[Table 4]

As shown in Table 4, cinnamic acid-4- (2,
When the 2,6-trimethyl-yl-cyclohexane) -2-butyl ester derivative was applied to the skin before UV irradiation, the melanin pigment was deposited by UV at a concentration of 3% as compared with the case where the solvent control was applied. Was clearly suppressed.

As indicated above, cinnamic acid-4 of the present invention
-(2,2,6-Trimethyl-yl-cyclohexane)
The 2-butyl ester derivative has an action of suppressing melanin production, an action of suppressing pigmentation after ultraviolet irradiation, and an ultraviolet protective action. As a result, a mixture of this in a certain proportion or more in a skin external preparation base brings an excellent whitening effect on the skin, and not only local pigmentation diseases such as spots, freckles, and dark skin due to sunburn, It can be used for prevention, improvement and treatment of systemic pigmentation such as Addison's disease. Moreover, since the compound is excellent in safety and stability, it can be used continuously for a long period of time.

[0056]

Embodiments of the present invention will be described below. The amounts in the examples are parts by weight.

Example 1. Oil-in-water cream A POE (30) Cetyl ether 2.0 Glycerin monostearate 10.0 Liquid paraffin 10.0 Vaseline 4.0 Cetanol 5.0 γ-tocopherol 0.05 BHT 0.01 Butyl Paraben 0.1 CA-TMCHB 3.0 B Propylene glycol 10.0 Purified water 55.84

(Production Method) The components A and B are dissolved at 80 ° C. with stirring. These are added and stirred to emulsify, and then cooled.

<Actual use test of pigmentation improving effect> The cream of the present invention obtained in the above Example 1 and the cream of the comparative product (the cream of Example 1 in which CA-TMCHB was replaced with liquid paraffin) were used. , A statistically equivalent group of 40 females suffering from dark-black, spots and freckles were used for 3 months, and the effect of improving pigmentation by actual use was evaluated.
Table 5 shows the results.

[0060]

[Table 5]

As is clear from this result, CA-TM
It was confirmed that the product of the present invention containing CHB has a markedly more effective pigmentation improving effect than the comparative product not containing this compound. Incidentally, no unfavorable reaction on the skin was observed at the application site of the product of the present invention.

Example 2. Emulsion A Synthetic Geiro 2.5 Cetanol 1.0 Squalane 4.0 Stearic acid 1.0 POE (25) monostearate 2.2 Glycerin monostearate 0.5 Butylparaben 0.1 γ-tocopherol 0.05 BHT 0.01 pHCA-TMCHB 0.5 B 1,3-butylene glycol 3.0 propylene glycol 7.0 caustic potash 0.2 purified water 77.94

(Production method) The components A and B are dissolved at 70 ° C. with stirring. The component A is added to the component B to carry out preliminary emulsification, uniformly emulsify with a homomixer, and after emulsification, cool to 30 ° C. with stirring.

Example 3. Emulsion A Synthetic Gairow 2.5 Cetanol 1.0 Squalane 4.0 Stearic Acid 1.0 POE (25) Monostearate 2.2 Glycerin Monostearate 0.5 Butylparaben 0.1 γ-Tocopherol 0.05 BHT 0.01 pMCA-TMCHB 1.0 B 1,3-butylene glycol 3.0 propylene glycol 7.0 caustic potash 0.2 purified water 77.44

(Production Method) The components A and B are dissolved at 70 ° C. with stirring. The component A is added to the component B to carry out preliminary emulsification, uniformly emulsify with a homomixer, and after emulsification, cool to 30 ° C. with stirring.

Example 4. Lotion A POE (20) sorbitan monolaurate ester 1.5 POE (20) lauryl ester 0.5 ethanol 10.0 γ-tocopherol 0.02 pMCA-TMCHB 0. O5B Glycerin 5.0 Propylene glycol 4.0 Citric acid 0.15 Sodium citrate 0.1 Purified water 78.68

(Manufacturing method) The components of A are combined and dissolved at room temperature. On the other hand, each component of B also dissolves at room temperature,
Solubilize in addition to the ingredients.

Example 5. Lotion A POE (20) sorbitan monolaurate 1.5 POE (20) lauryl ester 0.5 ethanol 10.0 γ-tocopherol 0.02 pHCA-TMCHB 0.01 B glycerin 5.0 propylene glycol 4.0 Quen Acid 0.15 Sodium citrate 0.1 Purified water 78.72

(Production method) The components of A are combined and dissolved at room temperature. On the other hand, each component of B also dissolves at room temperature,
Solubilize in addition to the ingredients.

Example 6. Packing material A Polyvinyl alcohol 15.0 Purified water 40.0 B Ethanol 4.0 1,3-Butylene glycol 4.0 Polyoxyethylene (8) Polyoxypropylene glycol (55) 3.0 Bisaborole 0.5 Tocopherol 0.02 CA-TMCHB 1.5 Purified water 31.98

(Production Method) The component A is dispersed and dissolved at room temperature. The component B is added to this and uniformly dissolved.

In addition, also in Examples 2 to 6, a practical use test for the effect of improving pigmentation was conducted, and the same results as in Example 1 were obtained.

[0073]

According to the present invention, it is possible to provide a melanin production inhibitor and a skin external preparation which are excellent in whitening effect, high in stability and safety. The skin external preparation of the present invention,
It can be used for prevention, improvement and treatment of not only local pigmentation such as spots, freckles and sunburn, but also systemic pigmentation such as Addison's disease.

Claims (3)

[Claims] 1. A melanin production inhibitor comprising a cinnamic acid-4- (2,2,6-trimethyl-yl-cyclohexane) -2-butyl ester derivative represented by the following general formula (I): Embedded image (In the formula, R represents hydrogen, a hydroxyl group or a methoxy group.) 2. A skin external preparation containing at least one kind of the melanin production inhibitor according to claim 1. 3. The external preparation for skin according to claim 2, wherein the content of the melanin production inhibitor according to claim 1 is 0.01 to 10% by weight based on the total amount.