JPH107542A - Skin lotion - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a skin lotion which has actions to prohibit the melanin formation and to inhibit the tyrosinase activity and is effective for prevention and improvement of pigmentation after sun burn, skin spots, freckles and liver spots. SOLUTION: This preparation contains a compound of the formula (n is 1-3; R<1> is an alkyl, an aralkyl; R<2> is an alkyl; R<3> and R<4> are each H, an alkyl or they link to each other to form a cycloalkyl ring together with two carbon atoms on the phenyl) in an amount of 0.001-20wt.%. In addition, usually used additives are properly formulated to prepare cream, ointment, gel, emulsion, stick, pack, solution and the like. The use of the compound of the formula reveals higher skin-lightening effect than that of hydroquinone and can give an external preparation for skin of high 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 produced melanin diffuses to adjacent cells by osmosis. The biochemical reaction in this melanocyte is estimated 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,
It is important to suppress the action of tyrosinase, which is the first step of the reaction, to suppress 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. In order to improve the safety, attempts have been made to use monoesters or alkyl monoethers of higher fatty acids (Japanese Patent Application Laid-Open No. 58-154507), but the esters are decomposed by hydrolytic enzymes in the body. Therefore, it is not always safe, and ethers have not been obtained that are 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

(Wherein, n represents an integer of 1 to 3; R ¹ represents a linear or branched alkyl group or an aralkyl group; R ² represents a linear or branched alkyl group) R ³ and R ⁴ each independently represent a hydrogen atom or a straight-chain or branched alkyl group, or together form two groups on the phenyl group substituted by R ³ and R ⁴ May form a cycloalkyl ring together with the carbon atoms, and the cycloalkyl ring may have a substituent.)

Hereinafter, the configuration of the present invention will be described in detail. The compound of the general formula (1) according to the present invention is a known benzolactam derivative (International Publication Number: WO 95/09160, International Application Number: PCT / JP94 / 01561). However, nothing is known about the whitening effect of these compounds,
In addition, there is no example applicable to a skin external preparation.

An example of the method for producing the benzolactam derivative of the present invention is represented by the general formula (1), wherein n = 1; R ¹ = −.
_{CH (CH 3) 2; R} 2 = -CH 3; R 3 = -n-C 10 H 21;
The compound of R ⁴ ＝ H is shown in the scheme, but the compound of the present invention and the production method thereof are not limited to these production methods. The reaction conditions in the scheme are as follows.

[0010] _{a) CH 3 CONHCH (COOC 2} H 5) 2, NaH / DMF b) C 9 H 19 P + Ph 3 Br -, n-BuLi / THF c) HCl / AcOH; d) SOCl 2 / C 2 H ₅ OH; e) Boc ₂ O / CH ₂ Cl ₂ ; f)
LiBH ₄ / THF g) H ₂ , Pd-C / C ₂ H ₅ OH; h) HCOOH, AcOH; i) BH ₃ / THF j) Triflate of benzyl DL-α-hydroxyisovalerate, 2,6- Lutidine / CH ₂ Cl ₂ k) N-hydroxysuccinimide, DCC / CH ₃ CN l) CF ₃ COOH / CH ₂ Cl ₂ ; m) aq.NaHCO ₃ / CH ₃ COOC ₂ H ₅

[0011]

Embedded image

General formula (1) in the skin external preparation of the present invention
The compounding amount of the compound is 0.001-2 in the total amount of the external preparation for skin.
It is 0.0% by weight, preferably 0.01 to 7.0% by weight. If it is less than 0.001% by weight, the skin whitening effect is poor,
If the content exceeds 20.0% by weight, the effect cannot be enhanced.

The external preparation for skin of the present invention can be prepared into various forms by a conventional method. Generally, creams, ointments, gels, emulsions, sticks, packs, solutions with organic solvents are used. It is preferable to make the shape.

Further, in addition to the above-mentioned components, the skin external preparation of the present invention contains components usually used in skin external preparations such as cosmetics and pharmaceuticals, such as humectants, antioxidants, oily components, ultraviolet absorbers, Activators, thickeners, alcohols, powder components, coloring agents, aqueous components, water, various skin nutrition agents, and the like can be appropriately compounded 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 derivatives thereof, licorice extract, glabridine , Hot water extract of fire thorn fruit, various crude drugs, drugs such as tocopherol acetate, glycyrrhizic acid and its derivatives or salts thereof, vitamin C, magnesium ascorbate phosphate, glucoside ascorbate,
Other whitening agents such as arbutin and kojic acid, and sugars such as glucose, fructose, mannose, sucrose, trehalose and the like can also be appropriately compounded.

[0015]

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, a test method for the melanin inhibitory effect and tyrosinase activity inhibitory effect of the compound of the present invention and the results thereof will be described.

1. Preparation of Sample The following compound was synthesized according to the method described in International Publication Number: WO 95/09160, and used as a sample. Compound 1: n = 1; R ¹ = -CH (CH ₃ ) ₂ ; R ² = -CH ₃ ; R ³ = -n-C
₁₀ H ₂₁ ; R ⁴ = H ((±) -epi-BL-V8-310, racemic) Compound 2: n = 1; R ¹ = -CH (CH ₃ ) ₂ ; R ² = -CH ₃ ; R ³ = -N-C
₁₀ H ₂₁ ; R ⁴ = H ((−)-BL-V8-310, optically active) Compound 3: n = 1; R ¹ = -CH (CH ₃ ) ₂ ; R ² = -CH ₃ ; R ³ = H; R ⁴ = −n−C
₁₀ H ₂₁ ((−)-BL-V8-210, optically active) Compound 4: n = 1; R ¹ = -CH (CH ₃ ) ₂ ; R ² = -CH ₃ ; R ^{3 to} R ⁴ = -C (CH ₃ ) ₂
CH ₂ CH ₂ C (CH ₃ ) _2- : ((±) -BL-V8-23T, racemic) Compound 5: n = 1; R ¹ = -CH (CH ₃ ) ₂ ; R ² = -CH ₃ ; R ^{3 to} R ⁴ = -C (CH ₃ ) ₂
CH ₂ CH ₂ C (CH ₃ ) _2- : ((±) -epi-BL-V8-23T, racemic)

2. 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 CO ₂ incubator (95% air, 5% carbon dioxide) at 37 ° C. in an Eagle MEM medium containing After 24 hours of culture, the sample solution is adjusted to a final concentration of 10 ^-5.
It was added to a 10 ^-8 wt%, further continued for 3 days of culture was determined visual determination and tyrosinase activity inhibition effect of melanin production amount by the following method.

3. Visual determination of the amount of melanin A diffusion plate was placed on the lid of the well plate, and the amount of melanin in the cells was observed with an inverted microscope, and compared with the case of the 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 described above was conducted for hydroquinone, which is already known to have a melanin production inhibitory action. Table 1 also shows the results. In the table, "nt" indicates that the test was not performed.

<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. Thereafter, 5 μl of a 10 mM L-DOPA solution was quickly added, and the mixture was transferred to a 37 ° C. incubator 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 0 minute and 60 minutes in the case of the sample (control) to which the compound of the present invention was not added was defined as the tyrosinase activity rate (%). Table 1 shows the results. In addition, as a reference example, a test similar to the above was performed on hydroquinone, which is already known to have a tyrosinase activity inhibitory effect. 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. In addition, nt indicates that the test was not performed.

[0021]

[Table 1] 評 価 Melanin production visual evaluation Tyrosinase activity rate (%) Test concentration (M) ──────────── ──────────── 10 ^-8 10 ^-7 10 ^-6 10 ^-5 10 ^-8 10 ^-7 10 ^-6 10 ^-5 ─────────────────────────────────── Hydroquinone × × × × − − − 98 ─── ──────────────────────────────── Compound 1 (±) epi-310 × × × ○ 91 89 87 81 Compound 2 (−)-310 × △ ○ nt 76 − 44 nt Compound 3 (−) -210 × × Δ nt 85 88 76 nt Compound 4 (±) -23T × × × ○ − − − − Compound 5 (±) epi- 23T × × × △ − − − − ────────────────────────────────────

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 1 0.01 Caustic potash 0.2 Sodium bisulfite 0.01 Preservatives Appropriate amount Fragrance Appropriate amount Ion-exchanged water residue (Preparation method) Add propylene glycol, compound 1 and potassium hydroxide to ion-exchanged water, dissolve and heat to 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, emulsify uniformly 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 2 0.05 Sodium bisulfite 0.03 Ethyl paraben 0.3 Perfume Appropriate amount Ion-exchanged water Residue (Production method) Add propylene glycol to ion-exchanged water and dissolve And heat to 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 gradually added to the water phase to carry out preliminary emulsification, and after uniform emulsification with a homomixer, the mixture is cooled to 30 ° C. while stirring well.

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 3 0.05 Compound 4 0.05 Sodium bisulfite 0.03 Ethyl paraben 0.3 Perfume Appropriate amount Ion-exchange water residue (Preparation method) Soap powder and borax in ion-exchange water Add, dissolve, 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 gradually added to the aqueous phase to carry out the reaction. After completion of the reaction, the mixture is uniformly emulsified with a homomixer, and cooled to 30 ° C. while stirring well after emulsification.

Example 4 Emulsion (Formulation) 2.5% by weight of stearic acid Cetyl alcohol 1.5 Vaseline 5.0 Liquid paraffin 10.0 Polyoxyethylene (10 mol) monooleate 2.0 Polyethylene glycol 1500 0 Triethanolamine 1.0 Carboxyvinyl polymer 0.05 (Product name: Carbopol 941, BFGoodrich chemical company) Compound 5 0.01 Sodium bisulfite 0.01 Ethylparaben 0.3 Perfume Appropriate amount Ion-exchanged water Residue (Preparation method) The 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, heated and melted and kept at 70 ° C. (oil phase). The oil phase is added to the water phase, pre-emulsification is performed, 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 1 1.0 Sodium bisulfite 0.01 Ethylparaben 0.3 Perfume Appropriate amount Ion-exchanged water Residue (Production method) Propylene glycol is added to ion-exchanged water.
Heat and maintain at 70 ° C. (aqueous phase). The other components are mixed and melted by heating, 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 (Product name: Carbopol) 941, BFGoodrich chemical company) Caustic soda 0.15 L-arginine 0.1 Compound 2 3.0 Sodium 2-hydroxy-4-methoxybenzophenonesulfonate 0.05 Ethylenediaminetetraacetate trisodium dihydrate 0.05 Methylparaben 0.2 Perfume Appropriate amount Ion-exchange water Residue (Preparation method) Uniformly dissolve the carboxyvinyl polymer in ion-exchange water, while dissolving Compound 2, polyoxyethylene (50 mol) oleyl alcohol ether in 95% ethanol, To be added. Next, after adding other components, the mixture is neutralized with caustic soda and L-arginine to increase the viscosity.

Example 7 Essence (Formulation) (A phase) 95% ethyl alcohol 10.0% by weight Polyoxyethylene (50 mol) octyldodecanol 1.0 Pantothenyl ethyl ether 0.1 Compound 3 7.0 Methyl paraben 0.15 (Phase B) Potassium hydroxide 0.1 (Phase C) Glycerin 5.0 Dipropylene glycol 10.0 Sodium bisulfite 0.03 Carboxyvinyl polymer 0.2 (Product name: Carbopol 941, BFGoodrich chemical company) Purified water residue (Preparation method) Dissolve A phase and C phase uniformly, and add A to C phase
Add phases and solubilize. Next, after adding the phase B, filling is performed.

Example 8 Pack (Formulation) (A phase) Dipropylene glycol 5.0% by weight Polyoxyethylene (60 mol) castor oil 5.0 (B phase) Compound 3 0.01 Olive oil 5.0 Tocopherol acetate 0 0.2 Ethylparaben 0.2 Fragrance 0.2 (Phase C) Sodium bisulfite 0.03 Polyvinyl alcohol (degree of saponification 90, degree of polymerization 2,000) 13.0 Ethanol 7.0 Purified water Residue (Preparation method) Phase A, B Phase and phase C are uniformly dissolved,
Add phase B to phase and solubilize. Next, this is added to the C phase, and then filling is performed.

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 octoate 2.0 Compound 5 1.0 Preservatives Appropriate amount Perfume Appropriate amount (Preparation method) Powdery components of talc to black iron oxide are sufficiently mixed in a blender. After adding oily components of squalane to isocetyl octanoate, compound 5, preservative, and flavor, the mixture was kneaded well, and filled and molded into a container.

Example 10 Emulsion type foundation (cream type) (Prescription) (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 (aqueous phase) purified water 50.0 1,3-butylene glycol 4.5 compound 3 1.5 Sorbitan sesquioleate 3.0 Preservatives Appropriate amount Flavors Appropriate amount (Preparation method) After heating and stirring the aqueous phase, a well-mixed and pulverized powder portion was added and treated with a homomixer. Further, the oil phase mixed by heating was added thereto, and the mixture was subjected to a homomixer treatment. Then, a fragrance was added with stirring, and the mixture was cooled to room temperature.

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

[0033]

As described above, the external preparation for skin of the present invention comprises
It has a melanin production inhibitory effect and a tyrosinase activity inhibitory effect, and has pigmentation, spots, freckles,
It has excellent effects on lightening of white spots and whitening, and also has excellent safety.

 ────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Koichi Shuto 5-9-18 Takaido, Suginami-ku, Tokyo

Claims (3)

[Claims] 1. An external preparation for skin comprising a compound represented by the following general formula (1). Embedded image (Wherein, n represents an integer of 1 to 3; R ¹ represents a linear or branched alkyl group or an aralkyl group;
² represents a linear or branched alkyl group; R ³ and R ⁴ each independently represent a hydrogen atom or a linear or branched alkyl group, or ^A cycloalkyl ring may be formed together with two carbon atoms on the phenyl group substituted by ³ and R ⁴ , and the cycloalkyl ring may have a substituent. ) 2. The external preparation for skin according to claim 1, wherein the compounding amount of the compound represented by the general 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 skin whitening.