JPH0925209A - Skin preparation for external use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a skin preparation for external use suppressing generation of melanin and effective for preventing and improving of chromatosis after sunburn, spot, freckle, chloasma, etc., by mixing a specific compound obtained by extracting from a plant such as family Equisetales. SOLUTION: Lutein expressed by the formula is used as an active component. This preparation is especially useful as a skin preparation for external use for whitening. A mixing amount of lutein is 0.005-20.0wt.% based on whole amount of the preparation for external use. The lutein of the formula is obtained by, e.g. extracting a plant such as Cola-de-Caballo (family Equisetales) in an organic solvent, dividing with ethyl acetate and water, and purifying the ethyl acetate phase by silica gel column chromatography, etc. The skin preparation for external use is used as, e.g. an ointment, cream, a latex, lotion, a pack or a bathing agent.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an external preparation for the skin, which is effective for the prevention and improvement of pigmentation, spots, freckles, chloasma, etc. after sunburn by suppressing the production of melanin by blending a specific compound. .

[0002]

2. Description of the Related Art Although there are some unclear points about the mechanism of the occurrence of skin spots and the like, melanin pigments are generally formed due to hormonal abnormalities and stimulation of ultraviolet rays from sunlight. It is believed to be abnormally deposited within. This melanin pigment, which causes skin coloring, is produced in melanin-producing granules (melanosomes) in melanocytes (melanocytes) between the epidermis and dermis,
The generated melanin diffuses into adjacent cells by the osmotic effect. The biochemical reaction in this melanocyte is presumed to be as follows. That is, tyrosine, which is an essential amino acid, is converted into dopaquinone by the action of the enzyme tyrosinase, and the process in which it is converted to black melanin via a red pigment and a colorless pigment by an enzymatic or non-enzymatic oxidative action is a melanin pigment production process. Therefore, suppressing the action of tyrosinase, which is the first step of the reaction, is important for suppressing melanin production.

[0003]

However, compounds that suppress the tyrosinase action, except for hydroquinone, have very slow onset of their effects, so that the effect of improving skin pigmentation is not sufficient. On the other hand, although hydroquinone is recognized as having an effect, its use is generally restricted because of its sensitizing properties. Therefore, in order to improve its safety, attempts have been made to use higher fatty acid monoesters or alkyl monoethers (JP-A-58-154507), but the esters are decomposed by a hydrolase in the body. Therefore, it is not always safe, and ethers have not been sufficiently satisfied in terms of safety.

[0004]

Therefore, as a result of investigating the melanin production inhibitory effect of various substances to solve these problems, the present inventors have found that lutein represented by the following formula (1) produces melanin. They found that they have an inhibitory action and a tyrosinase inhibitory action, and completed the present invention. There has been no report on the melanin production inhibitory effect of lutein, and its application to a whitening agent has never been known. The present inventors have completed the present invention based on the above findings.

That is, the present invention uses the formula (1):

[0006]

Embedded image

A skin external preparation characterized by containing lutein represented by: The external preparation of the present invention is preferably a skin whitening external preparation.

Hereinafter, the configuration of the present invention will be described in detail. The lutein represented by the above formula (1) used in the present invention is
For example, it can be obtained by extracting a plant such as Cola de Caballo (Equisetum) with an organic solvent, partitioning it with ethyl acetate and water, and purifying the ethyl acetate phase by silica gel column chromatography or the like.

Any solvent can be used as the extraction solvent as long as it is a solvent usually used for extraction. In particular, alcohols such as methanol and ethanol, hydrous alcohols, organic solvents such as acetone and ethyl acetate can be used alone or in combination. .

The content of lutein in the present invention is 0.005 to 20.0% by weight, preferably 0.01 to 10.0% by weight, based on the total amount of the external preparation. If the amount is less than 0.005% by weight, the effect of the present invention is not sufficiently exhibited, and 2
If it exceeds 0.0% by weight, it is not preferable because it is difficult to formulate the preparation. Further, even if the content is 10.0% by weight or more, the effect is not so much improved.

[0011] In addition to the above essential components, the skin external preparation of the present invention contains components usually used in skin external preparations such as cosmetics and pharmaceuticals, for example, other whitening agents, humectants, antioxidants, and oily components. , UV absorbers, surfactants, thickeners,
Alcohols, powder components, coloring materials, aqueous components, water, various skin nutrients and the like can be appropriately blended as necessary.

In addition, sequestering agents such as disodium edetate, trisodium edetate, sodium citrate, sodium polyphosphate, sodium metaphosphate, gluconic acid, caffeine, tannin, verapamil, tranexamic acid and its derivatives, licorice extraction Substance, glabridin, hot water extract of fruits of fire thorns, various crude drugs, tocopherol acetate,
Drugs such as glycyrrhizic acid and its derivatives or salts thereof, vitamin C, magnesium ascorbate phosphate,
Other whitening agents such as ascorbic acid glucoside, arbutin, kojic acid, glucose, fructose, mannose,
Sugars such as sucrose and trehalose can also be appropriately blended.

The external preparation for skin of the present invention may be any ointment, cream, emulsion, lotion, pack, bath agent or the like as long as it is a conventional external preparation for skin, and its form is not particularly limited.

[0014]

Next, the present invention will be described in more detail by way of examples. Note that the present invention is not limited by this. The compounding amount is% by weight. Prior to Examples, test methods and results of the melanin suppressing effect, tyrosinase activity inhibiting effect and whitening effect of the plant extract of the present invention will be described.

Production of lutein Cola de Caballo (Eguisetum giganteum), dry weight 1 kg
Was extracted with methanol (10 l) for 1 week at room temperature to obtain a methanol extract (53.7 g). This methanol extract was distributed between ethyl acetate and water (1 l: l), and the ethyl acetate phase was concentrated to obtain an extract (13.8 g). This extract was subjected to silica gel chromatography (elution solvent:
Fractionation with hexane-ethyl acetate (2: 1) was carried out, followed by purification by reversed-phase silica gel chromatography (elution solvent: methanol-water (10: 1)) to give lutein (336 m).
g) was obtained. The following experiment was conducted using the obtained lutein.

Test Method and Results 1. Cell culture method B16 melanoma cultured cells derived from mice were used. 1
0% FBS and theophylline (0.09 mg / ml)
Was cultured in a CO2 incubator (95% air, 5% carbon dioxide) at 37 ° C. in an Eagle MEM medium containing After 24 hours of culturing, the sample solution containing lutein (DMSO solution) had a sample concentration of 10-4 to 10-6% by weight.
And the culture was continued for another 3 days, and the visual evaluation of melanin production amount and the tyrosinase activity inhibitory effect were measured by the following methods.

2. Visual measurement of melanin amount A diffuser plate was placed on the lid of the plate of the well, and the intracellular melanin amount was observed with an inverted microscope, and compared with the case of the sample (reference) to which lutein was not added. The results are shown in Table 1.

In addition, as a reference example, the same test as above was carried out on an extract of Kaigai (Lamiaceae, Odorikosou subfamily), which is already known to have a melanin production inhibitory action. Table 1 also shows the results.

<Judgment Criteria> 白: White (melanin content) Δ: Slightly white (melanin content) ×: Standard (melanin content)

3. Measurement of tyrosinase activity Before measurement, the medium in the wells is removed and washed twice with 100 μl of PBS. 45 μl of 1% Triton-X in each well
(Rohm and Haas product name, surfactant) containing PBS is added. Shake the plate for 1 minute, break the cell membrane well, and use a microplate reader for 475n.
The absorbance at m was measured, and this was taken as the absorbance at 0 minutes. Then, 5 μl of 10 mM L-DOPA solution was quickly added, and the mixture was transferred to an incubator at 37 ° C. and reacted for 60 minutes. The plate was shaken for 1 minute, and the absorbance (475 nm) at 60 minutes was measured. The tyrosinase activity inhibition rate (%) was defined as the decrease in the absorbance difference of the lutein-added sample with respect to the absorbance difference between the 0-minute and 60-minute samples in the case where the lutein was not added (control). Table 1 shows the results. Further, as a reference example, the same test as above was carried out on an ethanol extract of mussel, which is already known to have a tyrosinase activity inhibitory action. Table 1 also shows the results. In the table, "toxic" means that cytotoxicity was observed, and "-" means that no significant difference was observed within a risk rate of 5% as compared with the control.

[0021]

[Table 1] ──────────────────────────────────── Test melanin production Visual evaluation Tyrosinase activity inhibition rate (%) ─────── ───────────── ───────────── Concentration (wt%) 10 ^-6 10 ^-5 10 ^-4 10 ^-3 10 ^-6 10 ^-5 10 ^-4 10 ^-3 ──────────────────────────────────── ─ Lutein × ○ ○ ○ 21 23 23 20 Kaigai extract × × × × − − − − ────────────────────────────── ───────

4. Whitening test [Test method] 40 subjects exposed to sunlight in summer for 4 hours (2 hours per day for 2 days) each sample from 5 days after the day of sun exposure to the skin of the upper arm inner skin Was applied once each morning and evening for 4 weeks. The panel was divided into 8 groups, and 5 groups were prepared, and the tests were conducted according to the formulations shown below. (Alcohol phase) 95% Ethyl alcohol 55.0% by weight Polyoxyethylene (25 mol) hydrogenated castor oil ether 2.0 Antioxidant / preservative proper amount Fragrance proper amount drug (listed in Table 2) (water phase) glycerin 5.0 Sodium hexametaphosphate Suitable amount Ion-exchanged water Residue <Production method> An aqueous phase and an alcohol phase are prepared, respectively, and then both are mixed and solubilized.

[Evaluation Method] The lightening effect after use was judged based on the following judgment criteria. <Judgment criteria> ：: When the ratio showing significant effect and effectiveness among the subjects is 80% or more 割 合: The ratio showing significant effect and effectiveness among the subjects is 50% or more
Less than 80% △: The proportion of the test subjects showing excellent and effective is 30% or more
When less than 50% x: When the ratio of markedly effective or effective among the subjects is less than 30%

Samples having the blending composition described in the above test method were prepared and the whitening effect was compared using the agents shown in Table 2.
The results are shown in Table 2.

[0025]

[Table 2] ─────────────────────────── Drugs Compounding amount (% by weight) Effect ────────── ────────────────── Additive- × Hydroquinone 1.0 △ Lutein 0.1 ○ Lutein 1.0 ○ Lutein 10.0 ◎ ─ ──────── ────────────────────

As is clear from Table 2, the effect after exposure to sunlight is recognized that the addition of the compound of the present invention prevents the deposition of excess melanin pigment and prevents darkening. Was given.

Example 1 Cream (Formulation) Stearic acid 5.0% by weight Stearyl alcohol 4.0 Isopropyl myristate 18.0 Glycerin monostearate 3.0 Propylene glycol 10.0 Lutein 0.01 Caustic potassium 0.2 Sulfite Sodium hydrogen 0.01 Preservative Suitable amount Fragrance Suitable amount Ion-exchanged water Residual (production method) Propylene glycol, lutein methanol extract and caustic potash are added to ion-exchanged water and dissolved, and heated to 70 ° C (water phase). The other components are mixed, melted by heating and kept at 70 ° C. (oil phase). The oil phase is gradually added to the water phase, and after the addition is completed, the temperature is maintained for a while to cause a reaction. Then, it is uniformly emulsified with a homomixer and cooled to 30 ° C. with thorough stirring.

Example 2 Cream (formulation) Stearic acid 2.0% by weight Stearyl alcohol 7.0 Hydrogenated lanolin 2.0 Squalane 5.0 2-Octyldodecyl alcohol 6.0 Polyoxyethylene (25 mol) cetyl alcohol ether 3.0 Glycerin monostearate 2.0 Propylene glycol 5.0 Lutein 0.05 Sodium hydrogen sulfite 0.03 Ethylparaben 0.3 Perfume proper amount Ion-exchanged water Residual (production method) Add propylene glycol to ion-exchanged water,
Heat and maintain at 70 ° C. (aqueous phase). The other components are mixed, melted by heating and kept at 70 ° C. (oil phase). The oil phase is added to the aqueous phase to carry out preliminary emulsification, and the mixture is uniformly emulsified with a homomixer and then cooled to 30 ° C. with thorough stirring.

Example 3 Cream (formulation) Solid paraffin 5.0% by weight Beeswax 10.0 Vaseline 15.0 Liquid paraffin 41.0 Glycerin monostearate 2.0 Polyoxyethylene (20 mol) sorbitan monolaurate 2 0.0 Soap powder 0.1 Borax 0.2 Lutein 0.1 Sodium bisulfite 0.03 Ethylparaben 0.3 Perfume proper amount Ion-exchanged water Residual (production method) Soap powder and borax are added to ion-exchanged water and dissolved by heating. Keep at 70 ° C (aqueous phase). The other components are mixed, melted by heating and kept at 70 ° C. (oil phase). The oil phase is gradually added to the aqueous phase while stirring to carry out the reaction. After the reaction is completed, the mixture is uniformly emulsified with a homomixer, and after emulsification, the mixture is cooled to 30 ° C. with thorough stirring.

Example 4 Emulsion (formulation) Stearic acid 2.5% by weight Cetyl alcohol 1.5 Vaseline 5.0 Liquid paraffin 10.0 Polyoxyethylene (10 mol) monooleate 2.0 Polyethylene glycol 1500 3. 0 Triethanolamine 1.0 Carboxyvinyl polymer 0.05 (Brand name: Carbopol 941, BFGoodrich Chemical company) Lutein 0.01 Sodium hydrogen sulfite 0.01 Ethylparaben 0.3 Perfume Suitable amount Ion-exchanged water Residual (manufacturing method) Small amount The carboxyvinyl polymer is dissolved in the ion-exchanged water of (A phase). Polyethylene glycol 1500 and triethanolamine are added to the remaining ion-exchanged water, dissolved by heating, and kept at 70 ° C. (aqueous phase). The other components are mixed, melted by heating and kept at 70 ° C. (oil phase). The oil phase is added to the water phase to perform preliminary emulsification, the phase A is added, and the mixture is uniformly emulsified with a homomixer. After the emulsification, the mixture is cooled to 30 ° C. while stirring well.

Example 5 Emulsion (Formulation) Microcrystalline wax 1.0% by weight Beeswax 2.0 Lanolin 20.0 Liquid paraffin 10.0 Squalane 5.0 Sorbitan sesquioleate 4.0 Polyoxyethylene (20 mol) ) Sorbitan monooleate 1.0 Propylene glycol 7.0 Lutein 10.0 Sodium bisulfite 0.01 Ethylparaben 0.3 Perfume Suitable amount Ion-exchanged water Residue (production method) Add propylene glycol to ion-exchanged water,
Heat and maintain at 70 ° C. (aqueous phase). The other components are mixed, heated and melted and kept at 70 ° C. (oil phase). While stirring the oil phase, the aqueous phase is gradually added thereto, and the mixture is uniformly emulsified with a homomixer. After emulsification, cool to 30 ° C with good stirring.

Example 6 Jelly (formulation) 95% ethyl alcohol 10.0 wt% dipropylene glycol 15.0 polyoxyethylene (50 mol) oleyl alcohol ether 2.0 carboxyvinyl polymer 1.0 (trade name: Carbopol) 940, BFGoodrich Chemical company) Caustic soda 0.15 L-Arginine 0.1 Lutein 7.0 Sodium 2-hydroxy-4-methoxybenzophenone sulfonate 0.05 Ethylenediaminetetraacetate ・ 3 sodium ・ diwater 0.05 Methylparaben 0.2 Fragrance A suitable amount Ion-exchanged water Residual (production method) Carbopol 940 is uniformly dissolved in ion-exchanged water, while lutein and polyoxyethylene (50 mol) oleyl alcohol ether are dissolved in 95% ethanol and added to the aqueous phase. Next, after adding other components, the mixture is neutralized with caustic soda and L-arginine to increase the viscosity.

Example 7 Beauty Serum (Formulation) (Phase A) Ethyl Alcohol (95%) 10.0% by Weight Polyoxyethylene (20 mol) Octyldodecanol 1.0 Pantotenyl Ethyl Ether 0.1 Lutein 1.5 Methylparaben 0.15 (Phase B) Potassium hydroxide 0.1 (Phase C) Glycerin 5.0 Dipropylene glycol 10.0 Sodium hydrogen sulfite 0.03 Carboxyvinyl polymer 0.2 (trade name: Carbopol 940, BFGoodrich Chemical company) Purified water Residual (manufacturing method) Dissolve Phases A and C uniformly,
Add phases and solubilize. Next, after adding the phase B, filling is performed.

Example 8 Pack (formulation) (Phase A) 5.0% by weight dipropylene glycol Polyoxyethylene (60 mol) hydrogenated castor oil 5.0 (Phase B) Lutein 0.01 Olive oil 5.0 Tocopherol acetate 0 .2 Ethyl paraben 0.2 Perfume 0.2 (Phase C) Sodium hydrogen sulfite 0.03 Polyvinyl alcohol 13.0 (Saponification degree 90, degree of polymerization 2,000) Ethanol 7.0 Purified water Residual (production method) Phase A , Phase B, and phase C are uniformly dissolved,
Add phase B to phase and solubilize. Next, this is added to the C phase and then filled.

Example 9 Solid Foundation (Formulation) Talc 43.1 wt% Kaolin 15.0 Sericite 10.0 Zinc white 7.0 Titanium dioxide 3.8 Yellow iron oxide 2.9 Black iron oxide 0.2 Squalane 8 0.0 isostearic acid 4.0 POE sorbitan monooleate 3.0 isocetyl octanoate 2.0 lutein 1.0 preservative appropriate amount perfume appropriate amount (manufacturing process) Talc to black iron oxide powder components are mixed sufficiently with a blender. Squalane-isocetyl octoate oil component, eleus, preservative, and fragrance are added and kneaded well, then filled into a container and molded.

Example 10 Emulsion type foundation (cream type) (Formulation) (Powder part) Titanium dioxide 10.3% by weight Sericite 5.4 Kaolin 3.0 Yellow iron oxide 0.8 Bengala 0.3 Black iron oxide 0.2 (oil phase) decamethylcyclopentasiloxane 11.5 liquid paraffin 4.5 polyoxyethylene-modified dimethylpolysiloxane 4.0 (water phase) purified water 50.0 1,3-butylene glycol 4.5 lutein 1.5 Sorbitan sesquioleate 3.0 Preservative proper amount Perfume proper amount (Manufacturing method) After heating and stirring the aqueous phase, a powder portion thoroughly mixed and pulverized is added and treated with a homomixer. Further, the oil phase mixed by heating is added, and the mixture is treated with a homomixer. Then, a fragrance is added with stirring, and the mixture is cooled to room temperature.

[0037]

Industrial Applicability As described above, the external preparation for skin of the present invention has a melanin production inhibitory action and a tyrosinase activity inhibitory action, and it causes lightening of pigmentation, stains, freckles, melasma etc. after sunburn. It is an external preparation for skin that has excellent whitening effect and safety.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/045 ADS A61K 31/045 ADS AED AED C07C 35/21 9155-4H C07C 35/21 C12N 9 / 99 C12N 9/99 (72) Inventor Seiichi Yoshida 1050 Shinba-cho, Kohoku-ku, Yokohama-shi, Kanagawa Inside Shiseido Daiichi Research Center (72) Inventor Tadao Fukuhara 1050 Nibachi-cho, Kohoku-ku, Yokohama-shi, Kanagawa Shiseido Daiichi Research Center

Claims (2)

[Claims] (1) Formula (1): An external preparation for skin characterized by containing lutein represented by 2. The external preparation for skin according to claim 1, which is an external preparation for whitening skin.