JPH08157360A - Suppressing agent for melanin production and skin external agent - Google Patents

Abstract

PURPOSE: To obtain a suppressing agent for melanin production excellent in beatifying effect and in the prevention and improvement of pigmentation, and having stability and safety by compounding a compound having a reduced β-ionone ring-containing nonane as a partial structure as an active component, and obtain a skin external agent by compounding the suppressing agent. CONSTITUTION: This suppressing agent for melanin production contains a compound selected from among 3,7-dimethyl-9-(2,2,6-trimethyl-1-yl-cyclohexane)-1- nonanol of formula I; 3,7-dimethyl-9-(2,2,6-trimethyl-1-yl-6-cyclohexene)-1-nonanol of formula II; 3,7-dimethyl-9-(2,2,6-trimethyl-1-yl-cyclohexane)nonanoic acid of formula III; and 3,7-dimethyl-9-(2,2,6-trimethyl-1-yl-6-cyclohexene)nonanoic acid of formula IV. The objective skin external agent is obtained by compounding at least one kind of the melanin-suppressing agents in an amount of 0.001-10wt.% on the basis of the total amount. Especially, for the purpose of the prevention or improvement of aggravation of spots, freckles and dark skin caused by sunburn, it is preferably compound in an amount of >=0.1wt.%.

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 comprising a compound containing reduced β-ionone ring-containing nonane as a partial structure, and this as an active ingredient. It is intended to provide an external preparation for skin having an excellent whitening effect.

[0002]

2. Description of the Related Art Pigmentation after freckles and sunburn is a marked increase in melanin production due to the activation of pigment cells in the skin, which is one of the troubles of the middle-aged and old-aged skin. There is. In general, melanin is changed from tyrosine to dopa and dopa to dopaquinone by the action of the enzyme tyrosinase biosynthesized in pigment cells, and then an intermediate such as 5,6-dihydroxyindophenol is formed. It is supposed to be formed through.

Therefore, in order to prevent or improve color blackness, it is possible to inhibit the melanin production process or to bleach already produced melanin. Based on such an idea, various whitening components have been conventionally proposed. For example, a sulfur compound typified by glutathione is one that inhibits thyrodinase activity and suppresses melanin production. In addition, hydrogen peroxide, hydroquinone, vitamin C, etc. have been used as the ones that lightly bleach the produced melanin.

[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 whitening effect, but has a problem in safety such as causing irreversible white spots and rashes.

As described above, the conventionally used whitening ingredients are not truly practically satisfactory in any of the effects, stability and safety. The present invention has been made in view of such circumstances, and has a melanin production inhibitor and a sufficient effect of improving and treating skin pigmentation,
Another object of the present invention is to provide an external preparation for skin which 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 a specific reduction β-
A compound containing a nonone-containing nonone as a partial structure was found to have a strong inhibitory effect on melanin production in living pigment cells, and further compounded in a base at a certain concentration or higher and used as a skin external preparation. Then, they found that they exhibited an excellent whitening effect on the skin, and completed the present invention.

That is, the present invention relates to 3,7-dimethyl-
9- (2,2,6-trimethyl-1-yl-cyclohexane) -1-nonanol, 3,7-dimethyl-9-
(2,2,6-Trimethyl-1-yl-6-cyclohexene) -1-nonanol, 3,7-dimethyl-9-
(2,2,6-Trimethyl-1-yl-cyclohexane) nonanoic acid, 3,7-dimethyl-9- (2,2,6-
A melanin production inhibitor comprising a compound selected from trimethyl-1-yl-6-cyclohexene) nonanoic acid.

In the present invention, one or two or more of these melanin production inhibitors are used as an active ingredient and the total amount is 0.0
The external preparation for skin is characterized by containing 0.1 to 10% by weight.

The present invention will be described in detail below. <1> Melanin Production Inhibitor The melanin production inhibitor of the present invention is 3,7-dimethyl-9- (2,2,6-trimethyl-1-yl-cyclohexane) -1 represented by the following structural formula. -Nonanol, 3,7-dimethyl-9- (2,2,6-trimethyl-1-yl-6-cyclohexene) -1-nonanol of Chemical formula 2,
3,7-Dimethyl-9- (2,2,6-trimethyl-1-yl-cyclohexane) nonanoic acid of Chemical formula 3, and 3,7-dimethyl-9- (2,2,6-trimethyl-chemical formula 4) 1
-Yl-6-cyclohexene) nonanoic acid and the like.

[0010]

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[0011]

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[0012]

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[0013]

[Chemical 4]

The compound of the present invention can be synthesized from retinoic acid in the following synthetic steps. The synthesis method will be described below.

1) Catalytic hydrogenation of retinoic acid in methanol in the presence of palladium-carbon (5%) and hydrogen for 24 hours and purification by column chromatography to obtain 3,7-dimethyl-9- (2,2,6-Trimethyl-1-yl-6-cyclohexene) nonanoic acid was obtained.

2) 3,7-dimethyl-9-of the above chemical formula 4
(2,2,6-Trimethyl-1-yl-6-cyclohexene) nonanoic acid was hydrogenated in acetic acid in the presence of a platinum catalyst to give 3,7-dimethyl-9- (2,2,6 -Trimethyl-1-yl-cyclohexane) nonanoic acid was obtained.

3) 3,7-dimethyl-9-of the above chemical formula 4
(2,2,6-Trimethyl-1-yl-6-cyclohexene) nonanoic acid is reduced with lithium aluminum hydride in ethyl ether to give 3,7-dimethyl-9
-(2,2,6-Trimethyl-1-yl-6-cyclohexene) -1-nonanol was obtained.

4) 3,7-dimethyl-9-of the above chemical formula 3
(2,2,6-Trimethyl-1-yl-cyclohexane) nonanoic acid is reduced with lithium aluminum hydride in ethyl ether to give 3,7-dimethyl-9-
(2,2,6-Trimethyl-1-yl-cyclohexane) -1-nonanol was obtained.

<2> External preparation for skin The external preparation for skin of the present invention generally comprises one or more of the above-mentioned melanin production inhibitors in an amount of 0.001 to 0.001 based on the total amount of the external preparation.
10% by weight, preferably 0.01 to 10% by weight, and more preferably 0.1 to 5% by weight. Among the external preparations for the skin, in particular spots due to sunburn, freckles, and dark black For the purpose of preventing and improving exacerbation, the blending amount is preferably 0.1% by weight or more.

The compounding amount of the above compound is 0.001% by weight.
If the amount is less, the whitening effect based on the melanin production inhibitory effect will be reduced, and even if the amount exceeds 10% by weight, the effect will reach the ceiling, so it is preferable to blend within the above range.

The external preparation for skin of the present invention contains, in addition to the above-mentioned active ingredients, various ingredients generally used in pharmaceuticals, cosmetics and the like, that is, an aqueous ingredient, an oily ingredient, a powder ingredient, a surfactant (as an emulsifier), and 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),
Examples thereof include lower alcohols (lower alcohols such as ethanol, propanol and isopropanol). Examples of oily components 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, wax, carnauba wax, candelilla wax, etc., natural or synthetic oils (squalane, liquid paraffin, lanolin or its derivatives, olive oil, camellia oil, cottonseed oil, oleyl) Alcohol, castor oil, petrolatum, adipic acid diethoxyethyl ester,
Silicon oil, fluorine oil and the like).

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, and propylene glycol monostearate.

Examples of moisturizers 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,
Veegum, synthetic hectorite and the like can be mentioned.

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),
Examples thereof include thioglycolic acid, thiolactic acid and thioglycerin.

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

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,
Examples include fine particle iron oxide.

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 agents can be used alone or in admixture of two or more. The external preparation for skin of the present invention may contain one or two or more kinds of whitening components (or whitening agents) other than the compound containing the terpene ketone as a partial structure. As other whitening ingredients,
Examples thereof include pantethein-S-sulfonic acid, isoferric acid, ascorbic acid and magnesium phosphate thereof, arbutin, kojic acid, linoleic acid, tranexamic acid, esculin, vitamin A acid, retinol and the like.

The dosage form of the external preparation for skin of the present invention is not particularly limited, and it is usually used in medicines, quasi drugs, cosmetics and the like, such as ointments, creams, emulsions, lotions and packs. , A bath agent and the like.

[0034]

The action of the compound group containing the reduced β-ionone ring-containing nonane used as a partial structure in the present invention will be described below based on experimental examples. The compound containing the reduced β-ionone ring-containing nonane as a partial structure used in the following experimental examples and examples was obtained as described above.

(1) Inhibitory action of melanin production on pigment cells 5 × 10 ⁴ B-16 melanoma cells were seeded in a plastic culture flask (75 cm ² ) and in an Eagle MEM medium containing 10% serum. In the presence of 5% carbon dioxide, 3
The culture was carried out at a temperature of 7 ° C. Two days later, a test sample of a compound containing a reduced β-ionone ring-containing nonane as a partial structure was added to the medium at concentrations of 5, 10, 15, and 20 μM, and the cells were further cultured for 4 days.

After the completion of the culture, the medium is removed and washed with a phosphate buffered saline solution (hereinafter referred to as PBS), the cells are 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 once with PBS, a certain amount of PBS
Was added, and the cells were mixed by flushing, a fixed amount of the cell suspension was taken, and the number of cells was counted with a Coulter counter. The remaining suspension was centrifuged again and the whiteness of the sediment was visually observed. The results are shown in Table 1 according to 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 ++: Clearly whiter than solvent control

[0038]

[Table 1]

Then, 1N sodium hydroxide was added to the precipitate to dissolve it by heating, and 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 prepared in advance using synthetic melanin. The melanin amount was calculated as the amount per 10 ⁴ cells. The results are shown in Table 2. The inhibition rate in the table was calculated by the following formula. Inhibition rate (%) = [(melanin amount of control product-melanin amount of test sample added product)] x 100 / (melanin amount of control product)

[0040]

[Table 2]

As is clear from these results, all of the compounds according to the present invention containing the reduced β-ionone ring-containing nonane as a partial structure were compared with the solvent control (control),
It was shown that it has the effect of whitening pigment cells and the effect of significantly suppressing melanin production in pigment cells.

(2) Inhibitory action of pigmentation by ultraviolet rays The back skin of brown guinea pigs (7 animals) was shaved and shaved with an electric hair clipper and a shaver, and this site was 1.5 × 1.5c.
A black cloth with a total of 6 left and right m irradiation windows is covered, and the FL20S / E30 lamp is used as a light source from above this cloth.
Ultraviolet rays of mW / cm ² / sec were 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 in which a predetermined amount of a compound containing a reduced β-ionone ring-containing nonane as a partial structure was dissolved in ethanol as a solvent was continuously applied once a day for a total of 20 days. In addition, the same experiment was conducted using ethanol as a control. On the 21st day from the start of the experiment, the degree of pigmentation in the treated area was visually determined according to the following criteria. The results are shown in Table 3 as an average value.

0: no pigmentation 0.5: weak pigmentation with unclear boundary 1: weak pigmentation with clear boundary 2: moderate pigmentation with clear boundary 3: clear boundary with strong intensity With pigmentation

[0044]

[Table 3]

As shown in Table 3, the reduction β according to the present invention
-The compound containing a nonone-ring-containing nonane as a partial structure,
When both were applied to the skin after UV irradiation, the melanin pigment deposition by UV was clearly suppressed at a concentration of 0.5% as compared with the case where the solvent control was applied.

As shown above, the reduction β according to the present invention
-The compound containing a nonone-ring-containing nonane as a partial structure,
It has an effect of suppressing melanin production and an effect of suppressing pigmentation after ultraviolet irradiation. 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.

[0047]

EXAMPLES Examples of the present invention will be described below. In addition, the compounding quantity in an Example is a weight part.

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 3,7-Dimethyl-9- (2,2,6-trimethyl 0.5-1-yl-cyclohexane) -1-nonanol B Propylene glycol 10.0 Purified water 58.34

(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 obtained above and a comparative cream (in the cream of Example 1, 3,7-dimethyl-9- (2,2,6-trimethyl-1- (Il-cyclohexane) -1-nonanol was replaced with water), and the statistically equivalent color of 40 people,
The pigmentation-improving effect of the actual use was evaluated by continuously applying it to a female group suffering from spots and freckles for 3 months. The results are shown in Table 4.
Shown in

[0051]

[Table 4]

As is clear from this result, the product of the present invention containing 3,7-dimethyl-9- (2,2,6-trimethyl-1-yl-cyclohexane) -1-nonanol does not contain this compound. It was confirmed that the comparative product had a remarkably effective pigmentation improving effect. No unfavorable reaction on the skin was observed at the application site of the product of the present invention.

Example 2. 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 3,7-Dimethyl-9- (2,2,6-trimethyl 3.0-1-yl-6-cyclohexene) nonanoic acid 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.

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 3,7-Dimethyl-9- (2,2,6-trimethyl 1.0-1-yl-cyclohexane) nonanoic acid B 1,3-butylene glycol 3.0 propylene glycol 7.0 caustic potash 0.2 Purified water 77.44

(Production method) 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. 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 3,7-Dimethyl-9- (2,2,6-trimethyl 0.1-1-yl-6-cyclohexene) -1-nonanol B 1,3-butylene glycol 3.0 propylene glycol 7.0 Caustic potash 0.2 Purified water 78.34

(Production Method) 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 5. Lotion A POE (20) sorbitan monolaurate 1.5 POE (20) lauryl ester 0.5 ethanol 10.0 γ-tocopherol 0.02 3,7-dimethyl-9- (2,2,6-trimethyl 0 .5-1-yl-6-cyclohexene) -1-nonanol B glycerin 5.0 propylene glycol 4.0 citric acid 0.15 sodium citrate 0.1 purified water 78.23

(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 6. Lotion A POE (20) sorbitan monolaurate 1.5 POE (20) lauryl ester 0.5 ethanol 10.0 γ-tocopherol 0.02 3,7-dimethyl-9- (2,2,6-trimethyl 0 .001-1-yl-cyclohexane) -1-nonanol B glycerin 5.0 propylene glycol 4.0 citric acid 0.15 sodium citrate 0.1 purified water 78.729

(Production method) The respective 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 7. 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 3,7-Dimethyl-9- (2,2,6-trimethyl 1.5-1-yl-cyclohexane) nonanoic acid 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 7, the actual use test of the pigmentation improving effect was conducted, and the same results as in Example 1 were obtained.

[0066]

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

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI Technical indication location A61K 9/107 S 9/70 386 31/20 ADA 9455-4C (72) Inventor Yukiko Yokoyama Kanagawa 560 Kashio-cho, Totsuka-ku, Yokohama Pola Chemical Industry Co., Ltd.In the Totsuka Laboratory (72) Inventor Susumu Nozawa 560 Kashio-cho, Totsuka-ku, Yokohama-shi, Kanagawa Pola Chemical Industry Co., Ltd.Totsuka Research Institute (72) Inventor Takayuki Katagiri Yokohama, Kanagawa 560 Kashio-cho, Totsuka-ku Pola Chemical Industry Co., Ltd.In the Totsuka Laboratory (72) Inventor Akihiro Tada 560 Kashio-cho, Totsuka-ku, Yokohama City, Kanagawa Prefecture In the Totsuka Laboratory (72) Inventor Hiroyuki Nakano Totsuka-ku, Yokohama-shi, Kanagawa Prefecture 560 Kashiocho Pola Chemical Industry Co., Ltd. Totsuka Research Center

Claims (2)

[Claims] 1. 3,7-Dimethyl-9- (2,2,6-
Trimethyl-1-yl-cyclohexane) -1-nonanol, 3,7-dimethyl-9- (2,2,6-trimethyl-1-yl-6-cyclohexene) -1-nonanol, 3,7-dimethyl-9. -(2,2,6-Trimethyl-1-yl-cyclohexane) nonanoic acid, 3,7-dimethyl-9- (2,2,6-trimethyl-1-yl-6-
A melanin production inhibitor comprising a compound selected from cyclohexene) nonanoic acid. 2. The melanin production inhibitor according to claim 1,
A skin external preparation characterized by containing 0.001 to 10% by weight of one kind or two or more kinds with respect to the total amount.