JP2009137879A - Skin-whitening agent and skin-whitening cosmetic containing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a skin-whitening agent having excellent skin-whitening effects, melanogenesis inhibitor, tyrosinase production inhibitor and tyrosinase decomposition accelerator, and further a skin-whitening cosmetic exhibiting excellent skin-whitening effects for the skin. <P>SOLUTION: This skin-whitening agent is obtained by finding out that an ester of retinol with a 18-22C fatty acid having a number of ≥2 of unsaturated bonds in its molecular structure has skin-whitening effects, and the skin-whitening cosmetic blended with them exhibits safe and excellent skin-whitening effects for the skin such as the prevention and improvement of pigmentation after sun burn, spots, freckles and chloasma, etc. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention provides a skin lightening agent, a melanin production inhibitor, a tyrosinase production inhibitor, a tyrosinase degradation accelerator, and a skin whitening agent for preventing and improving pigmentation / stain / freckle / liver patches after sunburn. The present invention relates to a whitening cosmetic that exhibits an effect.

  Pigmentation such as skin spots and freckles is a result of increased production of excessive melanin caused by ultraviolet rays and other stimuli, and is a serious cosmetic problem. Melanin is considered to be formed through several stages of reaction after tyrosine, an essential amino acid, is enzymatically oxidized by tyrosinase in melanocytes. Therefore, controlling tyrosinase, which is the first stage of the reaction, is important in suppressing the production of melanin and the occurrence of skin stains and freckles. Arbutin, kojic acid, and the like are known as substances that inhibit the activity of tyrosinase, and are widely used as active ingredients of whitening agents.

  Linoleic acid with two or more unsaturated bonds in the molecule is also known to act on tyrosinase to suppress the production of melanin in cultured melanoma cells and promote the disappearance of pigmentation formed on the skin. Yes. This melanin production inhibitory action is considered to be related to the tyrosinase degradation promoting action. However, since linoleic acid cannot be said to have a sufficient effect even when used alone, vitamin E acetate, Use in combination with active ingredients such as inflammatory agents, ultraviolet absorbers and / or ultraviolet scattering agents, 2-hydroxy-4-methoxybenzophenone, ascorbic acid, and linoleic acid, which is a derivative of linoleic acid (see Patent Documents 2 to 6) Methods such as using vitamin C esters have been found. (See Patent Document 7)

  On the other hand, retinol (vitamin A alcohol), like other vitamins A, promotes the differentiation of epidermal cells, removes the old stratum corneum of the epidermis, and has the effect of softening the skin and the singlet oxygen scavenging effect. ing. However, since retinol is easily oxidized in the air, it is easily oxidized and unstable by heat and light, and itself is irritating, retinol derivatives such as retinol palmitate are usually used. ing. (See Patent Document 8)

As for esters of retinol and fatty acids having two or more unsaturated bonds in the molecule, retinyl linoleate, retinyl linolenate, retinyl arachidonate, and the like have been reported. They promote skin radiance without causing inflammation, and are useful for treating aging phenomena such as wrinkles, and skin diseases such as acne, vesicular and lesional papules, actinic keratosis, and oily skin. It has been found to be. However, it is not known that an ester of retinol and a fatty acid having 18 to 22 carbon atoms and having 2 or more unsaturated bonds in the molecular structure exhibits an extremely excellent whitening effect.
JP 63-284109 A JP-A-1-93520 JP-A-1-186809 Japanese Unexamined Patent Publication No. 1-186810 JP-A-3-209305 Japanese Patent Laid-Open No. 1-186811 JP-A-1-85907 JP 58-208207 A JP 10-45533 A J. et al. Soc. Cosmet. Chem. Japan. , 33, 3, 1999

  The present invention provides a whitening agent having an excellent whitening effect, a melanin production inhibitor, a tyrosinase production inhibitor, a tyrosinase degradation accelerator, and a whitening cosmetic that exhibits an excellent whitening effect on the skin. It is in.

  The present inventors have intensively studied to provide a whitening cosmetic that exhibits a satisfactory whitening effect. As a result, an ester of retinol and a fatty acid having 18 to 22 carbon atoms and a number of unsaturated bonds in the molecular structure of 2 or more has a whitening effect, and a whitening cosmetic compounded with these has pigmentation after sunburn. -The present invention was completed by finding that it exhibits a safe and excellent whitening effect on the skin, such as prevention and improvement of spots, freckles, and liver spots.

  Test for evaluating tyrosinase production using human melanocytes and esterification of retinol with fatty acids having 18 to 22 carbon atoms and unsaturated bonds in the molecular structure of 2 or more, tyrosinase degradation promotion test, melanin production inhibition test using 3D skin model When a whitening test was performed on pigmentation induced by ultraviolet irradiation, the effect was remarkable in all cases. By blending these components, a whitening cosmetic that exhibits an excellent whitening effect on the skin, such as prevention and improvement of pigmentation, stains, freckles, liver spots and the like after sunburn is obtained.

  Esters of retinol and fatty acids having 18 to 22 carbon atoms and two or more unsaturated bonds in the molecular structure used in the present invention can be synthesized by known methods.

  Typical examples of fatty acids used in the synthesis of esters of the present invention with esters of retinol and fatty acids having 18 to 22 carbon atoms and 2 or more unsaturated bonds in the molecular structure include linoleic acid, linoelaidic acid, α- Eleostearic acid, β-eleostearic acid, linolenic acid, linolenic acid, linolenic elaidic acid, pseudoeleosteric acid, α-parinaric acid, β-parinaric acid, arachidonic acid, docosadienoic acid, eicosapentaenoic acid, docosahexaenoic acid Tetracosadenoic acid and the like, and one or more of these are used. Linoleic acid and linolenic acid are preferably used, and linoleic acid is more preferable.

  Therefore, it is preferable to use retinyl linoleate and retinyl linolenate, more preferably linole, as an ester of retinol used in the present invention and a fatty acid having 18 to 22 carbon atoms and 2 or more unsaturated bonds in the molecular structure. Acid retinyl is preferred. What is marketed can also be used for retinyl linoleate, for example, the retinol linoleate of Pingtung Chemical Co., Ltd. can be used.

  The amount of ester of retinol and an ester of fatty acid having 18 to 22 carbon atoms and 2 or more unsaturated bonds in the molecular structure to whitening cosmetics varies depending on the application, dosage form, compounding purpose, etc., and is particularly limited Although it is not, generally 0.001-20.0 mass% is preferable in whitening cosmetics, More preferably, it is 0.01-10.0 mass%.

  In the present invention, L-ascorbic acid, sodium L-ascorbate, L-as the existing whitening agents, together with an ester of retinol with a fatty acid having 18 to 22 carbon atoms and 2 or more unsaturated bonds in the molecular structure. Synthetic whitening by blending sodium ascorbate-2-phosphate, magnesium L-ascorbate-2-phosphate, glucoside L-ascorbate, ascorbyl tetrahexyldecanoate, kojic acid, cysteine, arbutin, glutathione, etc. There may be an effect.

  The blending amount of the whitening agent is preferably 0.001 to 5% by mass, more preferably 0.01 to 2% by mass in the whitening cosmetic.

  The whitening agent of the present invention and the whitening cosmetic composition containing the same comprise, as an essential component, an ester of retinol and an ester of a fatty acid having 18 to 22 carbon atoms and 2 or more unsaturated bonds in the molecular structure. In addition, the components blended in the skin whitening cosmetics such as cosmetics and quasi-drugs can be blended within the range that does not impair the skin.

  For example, oils and fats, esters, hydrocarbons, waxes, silicone oil phase components, fatty acids, lower alcohols, higher alcohols, polyhydric alcohols, surfactants, water-soluble polymers, fragrances, Can be used in combination with water, various solvents, etc., and further, anti-aging agent, moisturizer, hair restorer, hair growth agent, percutaneous absorption enhancer, ultraviolet absorber, cell activator, anti-inflammatory agent, other physiologically active ingredients An antiseptic and fungicidal agent can be blended.

  The whitening agent of this invention and the whitening cosmetics containing this can be applied suitably for a pharmaceutical composition, cosmetics, etc. The use form of the whitening cosmetic is optional, and examples thereof include lotion, lotion, emulsion, cream, pack, ointment, dispersion, solid, mousse, patch and the like. The base of the whitening cosmetic may be a known external base and is not particularly limited.

  EXAMPLES The present invention will be specifically described below with reference to examples, but the technical scope of the present invention is not limited to these examples.

1. Melanin production inhibition test

1-1. Method B16 mouse melanoma strain F0 (B16F0) was seeded in a 6-well plate with Dulbecco's modified MEM (DMEM / 5) containing 5% calf serum (FBS). After 24 hours of culture, the sample was replaced with DMEM / 5 containing a sample having a predetermined concentration. After continuous culture for 1 week, a cell pellet was prepared, and the color tone of the cell pellet was scored by visual judgment (5-level score: 1 white-5 black).
Next, the amount of melanin produced was measured by an alkali solubilization method. The cell pellet was washed with 5% trichloroacetic acid, ethanol / diethyl ether solution and diethyl ether, and then 1N sodium hydroxide was added and dissolved by heating (100 ° C., 5 minutes). Absorbance at 430 nm was measured using a microplate reader. The amount of melanin was calculated from a calibration curve prepared using synthetic melanin (manufactured by Sigma) as a standard product. At the same time, the amount of protein was quantified. The amount of melanin per unit protein amount was calculated by dividing the amount of melanin by the amount of protein in all cells, and the difference from the control was evaluated.

1-2. Sample Retinyl linoleate, Retinyl linolenate, Linoleic acid

1-3. Results Whitening of the cell color and a decrease in the amount of melanin production were observed by retinyl linoleate treatment and retinyl linolenate treatment (Table 1). Therefore, retinyl linoleate treatment and retinyl linolenate have an inhibitory effect on melanin production.

2. Tyrosinase production inhibition test

2-1. Method The inhibitory effect of retinyl linoleate on tyrosinase production was evaluated by detecting tyrosinase protein using Western blot.
Normal human melanocytes were seeded in 90 mm dishes using Medium 254 (manufactured by Kurabo Industries). After overnight culture, the medium was replaced with a test medium containing a predetermined concentration of sample. After 48 hours of continuous culture in the sample-containing medium, the total protein of the cells was extracted with a RIPA buffer. At this time, the protein concentration was measured and used as an index of the number of cells. The protein concentration of each sample-treated cell was adjusted to 10 μg / mL, and SDS-PAGE was performed using a 7.5% acrylamide gel. After the electrophoretic protein was transferred to a PVDF membrane, immunostaining was performed. The primary antibody reaction used was an anti-tyrosinase antibody, and the secondary antibody reaction used horseradish-derived peroxidase-labeled anti-mouse IgG antibody. The density of the detected band was semi-quantified by image analysis.

2-2. Sample Retinyl linoleate, Retinyl linolenate, Linoleic acid

2-3. Results Tyrosinase production was significantly suppressed by treatment with retinyl linoleate and retinyl linolenate (Table 2). Therefore, the melanin production inhibitory action by the retinyl linoleate treatment and the retinyl linolenate treatment is expected to be due to the tyrosinase production inhibitory action.

3. Tyrosinase degradation acceleration test

3-1. Method The inhibitory effect of retinyl linoleate on tyrosinase production was evaluated by detecting tyrosinase protein using Western blot.

  Normal human melanocytes were seeded in 90 mm dishes using Medium 254 (manufactured by Kurabo Industries). 24 hours after sowing, the medium was replaced with a test medium containing a predetermined concentration of the sample and the protein synthesis inhibitor cycloheximide (CHX). After continuous culture in the sample-containing medium for 8 hours, the total protein of the cells was extracted with a RIPA buffer. At this time, the protein concentration was measured and used as an index of the number of cells. The protein concentration of each sample-treated cell was adjusted to 10 μg / mL, and SDS-PAGE was performed using a 7.5% acrylamide gel. After the electrophoretic protein was transferred to a PVDF membrane, immunostaining was performed. The primary antibody reaction used was an anti-tyrosinase antibody, and the secondary antibody reaction used horseradish-derived peroxidase-labeled anti-mouse IgG antibody. The density of the detected band was semi-quantified by image analysis.

3-2. Sample Retinyl linoleate, Retinyl linolenate, Linoleic acid

3-3. Results The promotion of tyrosinase degradation was significantly suppressed by the retinyl linoleate treatment and the retinyl linolenate treatment (Table 3). Therefore, the melanin production inhibitory effect by retinyl linoleate treatment and retinyl linolenate treatment is expected to be due to tyrosinase degradation promoting action.

4). Whitening effect test

4-1. Method Preparation of pigmentation by UV irradiation The test site is the inner left upper arm that is not easily exposed to sunlight in daily life. Irradiation with ultraviolet rays corresponding to 5 MED was performed to produce pigmentation with a diameter of 1 cm. As a light source, a multiport solar UV simulator model 601 (Solar Light Co. Inc.) is used with a wavelength range of 300 to 400 nm and a peak wavelength of 356 nm, and the irradiation intensity is measured using a multi-function measurement system model PMA2100 (Solar Light Co. Inc.). It was measured.

4-2. Test preparation A test preparation having the following formulation is used. A test preparation was obtained according to a conventional method for preparing an oil-in-water emulsion composition.

4-3. Application method and application period About 20 mg of the test preparation was applied twice a day in the morning and evening for 3 weeks to 2 × 2 cm ² including each ultraviolet irradiation site.

4-4. Skin color measurement and evaluation On the day of observation, the test site was measured using a spectrocolorimeter CR-13 (Minolta). L * was used as a colorimetric parameter, and pigmentation was evaluated using a ΔL * value (= L * value before ultraviolet irradiation−L * value after ultraviolet irradiation).
The whitening effect was evaluated according to the following criteria.
×: ΔL * value is the same as the control value Δ: ΔL * value is (control value -1.0) or more ○: ΔL * value is less than (control value -1.0)

5-5. Results From the results in Table 5, it can be seen that the retinyl linoleate of the present invention has a whitening effect superior to arbutin.

  Examples of whitening cosmetics containing the compound according to the present invention will be given below. A compounding quantity represents the mass%. The whitening cosmetics obtained in Examples 5 to 13 were all effective in the whitening effect test.

Cream 1
(Prescription) Mass%
Oil phase Retinyl linoleate 0.5
Squalane 3.0
Behenyl alcohol 4.0
Vaseline 3.0
Liquid paraffin 15.0
Aqueous phase POE (20) sorbitan monostearate
3.0
1,3-butylene glycol 3.0
Preservative Appropriate amount Fragrance Appropriate amount Purified water The remainder (preparation method)
The oil-in-water emulsion composition was prepared according to a conventional method.

Essence (Prescription) Mass%
Retinyl linolenate 0.1
Squalane 1.0
Behenyl alcohol 4.0
Vaseline 3.0
Liquid paraffin 15.0
Decaglyceryl monolaurate 1.0
Monostearic acid POE (20) sorbitan
3.0
Xanthan gum 0.1
1,3-butylene glycol 10.0
Preservative Appropriate amount Fragrance Appropriate amount Purified water The remainder (preparation method)
The oil-in-water emulsion composition was prepared according to a conventional method.

Lotion (Prescription) Mass%
Retinyl linoleate 0.01
Squalane 0.2
Decaglyceryl monolaurate 2.0
Sodium hyaluronate 0.2
1,3-butylene glycol 3.0
Ethyl alcohol 10.0
Preservative Appropriate amount Perfume Appropriate amount Purified water The remainder
All ingredients were mixed and prepared at 50 ° C. until uniform.

Cream 2 (emollient type)
(Prescription) Mass%
Oil phase Retinyl linoleate 1.0
Squalane 10.0
Isocetyl myristate 6.0
Glyceryl tri-2-ethylhexanoate 3.0
Macadamia nut oil 1.0
Dimethylpolysiloxane (6cs) 0.2
Cetanol 5.0
POE (20) cetyl ether 1.0
Tetraoleic acid POE (40) Sorbit
0.5
Glyceryl monostearate 1.0
Aqueous phase Hydrogenated soybean lecithin 0.2
1,3-butylene glycol 5.0
Xanthan gum 0.1
Sodium hyaluronate 0.01
Citric acid 0.1
Sodium citrate 0.4
Preservative Appropriate amount Purified water The remainder (preparation method)
It was prepared according to a conventional method for producing an oil-in-water emulsion composition.

Beauty oil (prescription) Weight%
Retinyl linoleate 3.0
Isocetyl myristate 10.0
Jojoba oil 5.0
Natural vitamin E 0.1
The remaining squalane (preparation method)
All ingredients were mixed and prepared at 50 ° C. until uniform.

Skin lotion (prescription)
Oil phase Retinyl linoleate 0.1
Tri (caprylic acid / capric acid) glyceryl
0.1
POP (4) POE (20) cetyl ether
0.6
Aqueous phase Propylene glycol 10.0
Sodium hyaluronate 0.1
Preservative Appropriate amount Purified water The remainder (preparation method)
It was prepared according to a conventional method for producing an oil-in-water emulsion composition.

Emulsion (prescription) mass%
Oil phase Retinyl linoleate 0.6
Eicosapentaenoic acid retinyl 0.2
Docosahexaenoic acid retinyl 0.2
d-δ-tocopherol 0.1
Squalane 5.0
Cetyl 2-ethylhexanoate 5.0
Dimethylpolysiloxane (100 mPa · s)
0.5
Cetyl palmitate 0.5
Behenyl alcohol 1.5
Stearic acid 0.5
Lipophilic glyceryl monostearate
1.0
Monostearic acid POE (20) sorbitan
1.0
Tetraoleic acid POE (40) sorbitan
1.5
Aqueous phase Propylene glycol 7.0
Xanthan gum 0.1
Preservative Appropriate amount Purified water The remainder (preparation method)
It was prepared according to a conventional method for producing an oil-in-water emulsion composition.

Cream 3 (water-in-oil emollient type)
(Prescription) Mass%
Oil phase Retinyl linoleate 0.5
Retinyl linolenate 0.5
Dimethicone copolyol 0.5
Decamethylcyclopentasiloxane 5.0
Tri (Capryl / Capric Acid) Glyceryl
15.0
Beeswax 2.0
Decaglyceryl pentahydroxy acid 2.0
Isostearic acid 1.0
Aqueous phase Glycerin 4.5
Sodium hyaluronate 0.01
Preservative Appropriate amount Purified water The remainder (preparation method)
An emulsified composition was prepared according to a conventional method for emulsifying water-in-oil emulsified compositions.

Sunscreen cream (prescription)
Oil phase Retinyl tetracosadenoate 0.5
Liquid paraffin 7.0
Decamethylcyclopentasiloxane 3.0
Cetyl alcohol 4.0
Condensed ricinoleic acid hexaglyceryl 0.5
POE (20) cetyl ether 1.0
Octyl paramethoxycinnamate 7.0
Powder phase Titanium oxide 3.0
Aqueous phase Sodium cetyl sulfate 1.0
Stearoyl methyl taurine sodium 0.3
1,3-butylene glycol 5.0
Xanthan gum 0.3
Preservative Appropriate amount Purified water The remainder (preparation method)
After the powder phase was added to the oil phase, an emulsion composition was prepared according to a conventional method for emulsifying water-in-oil emulsion compositions.

  Formulated with esters of retinol, which has been used as a conventional skin softener, active oxygen scavenger, and anti-aging agent, with fatty acids having 18 to 22 carbon atoms and two or more unsaturated bonds in the molecular structure, and / or a combination thereof. By applying the whitening cosmetic to the skin, it is possible to obtain a whitening cosmetic having an excellent whitening effect on the skin, such as prevention and improvement of pigmentation, stains, freckles and liver spots after sunburn.

Claims (6)

A whitening agent comprising, as an active ingredient, an ester of retinol and an ester of a fatty acid having 18 to 24 carbon atoms and 2 or more unsaturated bonds in the molecular structure. 2. A whitening agent, wherein the fatty acid according to claim 1 is selected from linoleic acid, linolenic acid, eicosapentaenoic acid, docosahexaenoic acid, and tetracosadenoic acid. The melanin production inhibitor which uses the ester of any one of Claim 1 or 2 as an active ingredient. The tyrosinase production inhibitor which uses the ester of any one of Claim 1 or 2 as an active ingredient. A tyrosinase degradation promoting system comprising the ester according to claim 1 or 2 as an active ingredient. Whitening cosmetics characterized by mix | blending 1 type (s) or 2 or more types of ester of any one of Claims 1-5.