JPH09169628A - Skin preparation for external use - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a skin preparation for external use, having melanogenesis suppressing action and effective against pigmentation, stain, freckle, chloasma, etc., after sun burn by using a specific compound obtained by extracting from a plant, etc., of the family Zingiberaceae, etc., as an active ingredient. SOLUTION: This skin preparation for external use is obtained by using a compound represented by the formula (R<1> and R<2> are each H or methyl). The compound of the formula is obtained by immersing Lempuyang which is a plant of the genus Zingiber of the family Zingiberaceae into a solvent or heating the plant under reflux together with the extracting solvent, filtering the mixture, concentrating the solution and purifying the concentrate by a silica gel column chromatography. The blend amount of the compound of the formula is preferably 0.001-20.0wt.%, especially preferably 0.1-7.0wt.%. The skin preparation for external use is preferably prepared into a form such as cream, ointment, gel, lotion, emulsion, stick, pack or solution. The skin preparation for external use is excellent also in safety.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an external preparation for skin which has an inhibitory action on melanin production and is effective for preventing and improving pigmentation, spots, freckles, liver spots, etc. after sunburn.

[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 satisfactory in terms of safety.

[0004]

[Means for Solving the Problems] In view of such circumstances,
As a result of intensive studies, the present inventors have recognized that a specific compound exerts a whitening effect more than hydroquinone and has high safety, and have completed the present invention.

That is, the present invention is an external preparation for skin characterized by containing a compound represented by the following general formula (1).

[0006]

Embedded image

(In the formula, R ¹ and R ² each represent a hydrogen atom or a methyl group.) The constitution of the present invention will be described in detail below. The compound of the general formula (1) according to the present invention is a known substance. However, it has never been used for a specific purpose.

The compound of the present invention can be produced by chemical synthesis, but it is usually obtained by isolation from a plant extract.

To isolate the compound from plant extracts,
Ginger (Zingiberaceae) Family Zingiber
Lempuyang, a genus plant, scientific name:
Zingiber aromaticum Mal.). As an extraction method, whole plants such as leaves of the above plants, stems including rhizomes, fruits, etc. are immersed or heated under reflux with an extraction solvent, and then filtered and concentrated. The extraction solvent used in the present invention is not particularly limited as long as it is a solvent usually used for extraction. In particular, an organic solvent such as alcohols such as methanol and ethanol, aqueous alcohols, acetone, and ethyl acetate is used alone or in combination. Can be. The compound of the present invention can be obtained by purifying the above extract by, for example, silica gel column chromatography. Examples of the elution solvent at this time include benzene-acetone.

The external preparation for skin of the present invention contains the compound of the general formula (1) thus obtained, and its content is 0.001 to 20.0% by weight based on the total amount of the external preparation for skin, preferably Is 0.01 to 10.0% by weight, particularly preferably 0.1.
It is 1 to 7.0% by weight. If it is less than 0.001% by weight, the skin whitening effect is poor, and if it exceeds 20.0% by weight, the effect cannot be expected to increase.

The external preparation for skin of the present invention can be prepared in various forms by a conventional method, but in general, cream, ointment, gel, lotion, emulsion, stick, pack, organic It is preferable that the solution form a solvent.

The external preparation for skin of the present invention contains, in addition to the above-mentioned essential components, components usually used in external preparations for skin such as cosmetics and pharmaceuticals, for example, other whitening agents, moisturizers, antioxidants and oily ingredients. , UV absorber, surfactant, thickener,
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.

[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 the examples, the test methods and the results of the melanin suppressing effect, tyrosinase activity inhibiting effect, and whitening effect of the compound of the present invention will be described.

Test Method and Results 1. Preparation of Sample (1) Compound A of the present invention (in the general formula (1), R ¹ = H, R ² =
Preparation of Compounds of Methyl Group) Lempuyan's rhizome 500
g in methanol (7.5 l) at room temperature for 5 days,
The extract was concentrated to obtain 24.9 g of a methanol extract.
Partition the extract between ethyl acetate and water (11:11),
The ethyl acetate phase was concentrated to obtain 21.0 g of extract. This extract was purified by silica gel column chromatography (elution solvent; benzene: acetone = 6: 1) to obtain 755 mg of the desired product. The following experiment was performed using this.

(2) Compound B of the present invention (in the general formula (1), R ¹
= Methyl group, R ² = H) Preparation of compound of Lempuyang rhizome 500
g in methanol (7.5 l) at room temperature for 5 days,
The extract was concentrated to obtain 24.9 g of a methanol extract.
Partition the extract between ethyl acetate and water (11:11),
The ethyl acetate phase was concentrated to obtain 21.0 g of extract. This extract was purified by silica gel column chromatography (elution solvent; benzene: acetone = 6: 1) to obtain 760 mg of the desired product. The following experiment was performed using this.

2. Cell culture method B16 melanoma cultured cells derived from mice were used. 1
0% FBS and theophylline (0.09 mg / ml)
The cells were cultured in an Eagle MEM medium containing C. in a CO ₂ incubator (95% air, 5% carbon dioxide) at 37 ° C. After 24 hours of culturing, the sample solution was added so that the final concentration (concentration of extracted dry matter) was 10 ^-3 to 10 ^-5 % by weight, culturing was continued for another 3 days, and the melanin production amount was visually sensed by the following method. The determination and the tyrosinase activity inhibitory effect were measured.

3. Visual measurement of melanin amount A diffusion plate was placed on the lid of the well plate, and the intracellular melanin amount was observed with an inverted microscope, and compared with the case of a sample (reference) to which the compound of the present invention 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 a mussel extract (Lamiaceae, Odorikosou Subfamily) extract and hydroquinone, which are 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)

4. 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 ratio of the absorbance difference of the sample to which the compound of the present invention was added to the absorbance difference between the time of 0 minute and the time of 60 minutes in the case of the sample to which the compound of the present invention was not added (control) was defined as a tyrosinase activity rate (%). Table 1 shows the results. Further, as a reference example, the same test as above was carried out on an ethanol extract of mussel and hydroquinone which are already known to have a tyrosinase activity inhibitory action. Table 1 also shows the results. In addition,-in a table | surface means that the significant difference was not recognized within 5% of the risk ratio compared with the control.

[0021]

[Table 1] ─────────────────────────────────── Test Melanin production Visual evaluation Tyrosinase activity rate (% ) ──────── ─────────── ──────────── Concentration (wt%) 10 ^-5 10 ^-4 10 ^-3 10 ^-5 10 ^-4 10 ^-3 ─────────────────────────────────── Compound of the present invention A ○ ○ ○ 91 85 4 Compound B of the present invention × ○ ○ 90 82 7 mussel extract × × × − − − Hydroquinone × × ○ 98 92 60 ─────────────────────── ─────────────

5. Whitening effect test [Test method] Each of the 64 subjects exposed to the sunlight in the summer for 4 hours (2 hours per day for 2 days) was subjected to the sunlight for 5 days from the day 5 days after the day when the skin was exposed to the sunlight. Was applied once each morning and evening for 4 weeks. The panel was divided into 8 groups, and 8 groups were prepared. (Alcohol phase) 95% Ethyl alcohol 55.0% by weight Polyoxyethylene (25 mol) hydrogenated castor oil ether 2.0 Antioxidants / preservatives Appropriate amount Fragrance Appropriate amount Drug (described in Table 2) Amount described 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] ──────────────────────────────────────────────────────────────── ─────────────── Addition- × Hydroquinone 1.0 △ Compound A of the present invention 0.1 ○ Compound A of the present invention 1.0 ○ Compound A of the present invention 10.0 ◎ Compound B of the present invention 0.1 ○ Compound B of the present invention 1.0 1.0 ○ Compound B of the present invention 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 Compound A of the present invention 0.01 ( In the general formula (1), R ¹ = H, R ² = methyl group) Caustic potassium 0.2 Sodium bisulfite 0.01 Preservative proper amount Perfume proper amount Ion-exchanged water Residual (production method) Ion-exchanged water with propylene glycol and compound A Add caustic potash to dissolve, heat and 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 water phase, and after the addition is completed, the temperature is maintained for a while to cause a reaction. Then, homogenize with a homomixer and stir well at 30 ° C.
Cool down to

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 Compound B of the present invention 0.05 (in the general formula (1), R ¹ = methyl group, R ² = H) sodium bisulfite 0.03 ethyl Paraben 0.3 Fragrance Suitable 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 Compound A of the present invention 0.05 (in the general formula (1), R ¹ = H, R ² = methyl group) Compound B 0.05 of the present invention (general formula ( In 1), R ¹ = methyl group, R ² = H) 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 heated to dissolve. 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 wt% Cetyl alcohol 1.5 Vaseline 5.0 Liquid paraffin 10.0 Polyoxyethylene (10 mol) Monooleate ester 2.0 Polyethylene glycol 1500 3. 0 triethanolamine 1.0 carboxyvinyl polymer 0.05 (trade name: Carbopol 941, BFGoodrich Chemical company) Compound A of the present invention A 0.01 (in the general formula (1), R ¹ = H, R ² = methyl) Group) Sodium hydrogen sulfite 0.01 Ethylparaben 0.3 Perfume Suitable amount Ion-exchanged water Residue (production method) A carboxyvinyl polymer is dissolved in a small amount of ion-exchanged water (phase A). 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 Compound B of the present invention 10.0 (in the general formula (1), R ¹ = methyl group, R ² = H) sodium bisulfite 0.01 ethylparaben 0 ３ Perfume A suitable amount Ion-exchanged water Residual (production method) Add propylene glycol to the 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% by weight 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 Compound A of the present invention 7.0 (in the general formula (1), R ¹ = H, R ² = methyl group) 2-hydroxy-4-methoxy Benzophenone Sodium sulfonate 0.05 Ethylenediaminetetraacetate ・ 3 sodium ・ 2 water 0.05 Methylparaben 0.2 Perfume Suitable amount Ion exchange water Residual (production method) Carbopol 940 is uniformly dissolved in ion exchange water, while 95% ethanol Compound A, polyoxyethylene (50 mol) oleyl alcohol A It was dissolved Le, 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 Compound of the Invention B 1.5 (in the general formula (1), R ¹ = methyl group, R ² = H) methylparaben 0.15 (B phase) potassium hydroxide 0.1 (C phase) glycerin 5.0 dipropylene glycol 10. 0 Sodium bisulfite 0.03 Carboxyvinyl polymer 0.2 (Brand name: Carbopol 940, BFGoodrich Chemical company) Purified water Residue (Production method) Phases A and C are uniformly dissolved, and A is added to phase C
Add phases and solubilize. Next, after adding the phase B, filling is performed.

Example 8 Pack (formulation) (Phase A) Dipropylene glycol 5.0 wt% Polyoxyethylene (60 mol) hydrogenated castor oil 5.0 (Phase B) Compound A 0.01 of the present invention (general formula) (1), R ¹ = H, R ² = methyl group) Olive oil 5.0 Tocopherol acetate 0.2 Ethylparaben 0.2 Perfume 0.2 (Phase C) Sodium hydrogen sulfite 0.03 Polyvinyl alcohol 13.0 ( Degree of saponification 90, degree of polymerization 2,000) Ethanol 7.0 Purified water Residual (production method) Phases A, B, and C are uniformly dissolved, and A
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% by weight 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 Compound B 1.0 of the present invention (in the general formula (1), R ¹ = methyl group, R ² = H) preservative Proper amount Perfume Proper amount (Manufacturing method) Talc to black iron oxide powder components are thoroughly mixed with a blender, and squalane to isocetyl octoate oil component, bengle ethanol extract, preservative, and fragrance are added and kneaded well. Fill and mold.

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 bottles Compound A 1.5 of the Invention (in the general formula (1), R ¹ = H, R ² = methyl group) sorbitan sesquioleate ester 3.0 preservative appropriate amount perfume appropriate amount (production method) After heating and stirring the aqueous phase, sufficient Then, the powder portion which has been mixed and pulverized is added to the mixture and homomixed. 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.

The external preparations for skin obtained in Examples 1 to 10 were all effective in the whitening effect test.

[0038]

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 has an excellent whitening effect and also has excellent safety.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location // A61K 35/78 A61K 35/78 C C07D 311/62 C07D 311/62 (72) Inventor Yokokawa Yoshihiro, Shiseido Daiichi Research Center, Inc. 1050 Shinba-cho, Kohoku-ku, Yokohama-shi, Kanagawa

Claims (3)

[Claims] 1. An external preparation for skin comprising a compound represented by the following general formula (1). Embedded image (In the formula, R ¹ and R ² each represent a hydrogen atom or a methyl group.) 2. The external preparation for skin according to claim 1, wherein the compounding amount of the compound represented by the formula (1) is 0.001 to 20.0% by weight. 3. The external preparation for skin according to claim 1, which is an external preparation for whitening skin.