JP2009249316A - Lanost-8-ene derivative and skin care preparation for external use comprising the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a lanost-8-ene derivative exhibiting excellent beautifying and whitening effects and to provide a skin care preparation for external use that comprises the same and can prevent and treat a spot and a freckle. <P>SOLUTION: The lanost-8-ene derivative exhibits particularly excellent melanin formation-inhibiting effects. The skin care preparation for external use comprising the same can prevent or ameliorate pigmentation on the skin such as a spot, a freckle and sunburn. These can be applied to a cosmetic, a quasi-drug, a pharmaceutical and the like. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

The present invention relates to an external preparation for skin having a remarkably high whitening effect.

In general, skin pigmentation observed in spots, buckwheat, sunburn, and the like is caused by excessive production of melanin pigment by melanin-producing cells present in the skin. In the treatment of this pigmentation, a treatment using hydroquinone externally has been performed.

However, although hydroquinone is recognized to have an effect of preventing pigmentation, since it is allergic, its use is generally restricted, and the formulation is unstable and has a problem. Thus, an ingredient and a preparation with a high effect on prevention and treatment of pigmentation have been desired.

On the other hand, in the general formula (1) of the present invention, CH—OH is a known substance (Non-Patent Document 1). However, it has never been known that such derivatives have a whitening effect.

R. B. Clayton et al, Journal of Biol. Chem. , 218, 305-320 (1956)

In view of such conventional problems, the present invention aims to provide a substance and an external preparation for skin which are excellent in whitening effect and can prevent and treat spots and freckles.

As a result of intensive studies to obtain a skin external preparation having a high safety and an excellent whitening effect, the present inventors have found that a lanoster-8-ene derivative represented by the following general formula (1) is remarkable. It was found that the whitening effect was exhibited.

Moreover, it discovered that the lanosta-8-ene derivative represented by following General formula (2) was a novel substance.

That is, this invention provides the skin external preparation and the whitening agent characterized by containing the lanosta-8-ene derivative represented by General formula (1). (Substituent A in the formula represents C═O or CH—OH.)

In addition, the present invention provides a lanoster-8-ene derivative represented by the general formula (2).

In the present invention, a whitening effect is found in a lanosta-8-ene derivative, and this is used as a skin external preparation. As described above, the lanosta-8-ene derivative of the present invention suppresses melanin production, and has an excellent whitening effect to prevent and treat spots and freckles. Effective as an ingredient.

Next, details of the present invention will be described.
[1] With respect to the substituent A in the general formula (1), the substituent A represents C═O or CH—OH.

[2] Method for Synthesizing Lanost-8-ene Derivative The lanoster-8-ene derivative of the present invention can be synthesized from lanosterol or its oxide by various known diolation methods. For example, there are a method using osmium tetroxide, potassium osmate and potassium permanganate, and a method using a sharpless asymmetric diol formation method.

The lanoster-8-ene derivative represented by the general formula (2) can be produced by preparing lanosterone obtained by oxidizing the ketone portion of lanosterol by a known method, and then using the above-mentioned diolation method. .

The lanost-8-ene derivative represented by the general formula (1) of the present invention can be used alone or in combination of two or more.

The external preparation for skin of the present invention is a blend of a lanosta-8-ene derivative represented by the general formula (1), and the blending amount is 0.0001 to 20% by weight as the lanosta-8-ene derivative. Preferably, 0.001 to 5 weight% can be mix | blended. If the concentration is less than 0.0001%, it is difficult to obtain a sufficient effect. If the concentration exceeds 20% by weight, the enhancement of the effect may not be observed, which is uneconomical.

In the external preparation for skin of the present invention, components used in normal cosmetics, quasi drugs, pharmaceuticals and the like can be appropriately blended as necessary. For example, materials such as whitening agents, moisturizers, oily ingredients, ultraviolet absorbers, preservatives, antioxidants, water, alcohols, surfactants, chelating agents, thickeners, powders, coloring materials, and fragrances are appropriately used. Can be blended.

The skin external preparation of the present invention can enhance the whitening effect by combining with other known whitening agents and antioxidants. For example, ascorbic acid, ascorbic acid derivatives (magnesium ascorbyl phosphate, ascorbic acid glucoside, ascorbic acid phosphate fatty acid ester, etc.), kojic acid, kojic acid derivatives, arbutin, placenta extract, vitamin E, vitamin E derivatives, glycyrrhizic acid, Glycyrrhetinic acid, glycyrrhizic acid derivative, tea extract, tannin, licorice extract, grabrizine, larvae (beneficient) extract, aloe (aloe andnogensis, yellow aloe vera, aloe vera, etc.) extract, fukitan popo extract, garlic mushroom (red ganoderma) , Black reishi etc.) extract, mulberry white skin extract and the like can be blended.

The skin external preparation of the present invention is used for lotions, creams, emulsions, gels, ointments, packs, aerosols, poultices, pastes, plasters, cleaning agents, foundations, lipsticks, soaps, bath preparations, etc. However, it is not limited to these. Moreover, the skin external preparation of this invention contains a pharmaceutical, a quasi-drug, and cosmetics.

The lanosta-8-ene derivative of the present invention showed an excellent melanin production inhibitory effect, and a skin external preparation containing these showed an excellent whitening effect.

Next, in order to describe the present invention in detail, examples of production of compounds used in the present invention, formulation examples and experimental examples will be given as examples, but the present invention is not limited thereto. The compounding amount shown in the formulation example indicates% by weight. Further, MS shown below is mass spectrometry, EI is electron impact method, and 1H-NMR is nuclear magnetic resonance analysis of hydrogen nucleus.

Production Example 1 Synthesis of Lanost-8-ene Derivative (Compound 1)

Lanosterol 1.0 g was dissolved in a mixture of 150 mL of acetone and 20 mL of water, 2.3 g of N-methylmorpholine-N-oxide and 0.1 g of osmium tetroxide were added, and the mixture was reacted at room temperature for 24 hours. After the reaction, the solvent was removed and the mixture was extracted with ethyl acetate and water. The ethyl acetate layer was dried over sodium sulfate and filtered, and then the filtrate was concentrated. This was purified by silica gel column chromatography using an elution solvent of hexane: ethyl acetate = 1: 1 to obtain 0.85 g of Compound 1.
MS (EI, m / z) 460 (M +), 445 (M-CH3) +, 427, 409, etc. 1H-NMR (CD3OD, δ) 3.10 to 3.23 (2H, m), 2.06 ( 5H, m), 0.9 to 1.9 (19H, m), 0.75 (3H, d, J = 6.3 Hz), 0.80 (3H, s), 0.91 (3H, s) 0.95 (3H, s), 0.98 (3H, s), 1.01 (3H, s), 1.12 (3H, s), 1.16 (3H, s)

Production Example 2 Synthesis of Lanost-8-ene Derivative (Compound 2)

1.0 g of lanosterol was dissolved in 100 mL of acetone, and 1.5 mL of Jones reagent was added and allowed to react for 1 hour under ice cooling. After the reaction, the solvent was removed and the mixture was extracted with ethyl acetate and water. The ethyl acetate layer was dried over sodium sulfate and filtered, and then the filtrate was concentrated. Diolization was performed in the same manner as in Production Example 1, and the residue was purified by silica gel column chromatography using an elution solvent of hexane: ethyl acetate = 2: 1 to obtain 0.51 g of Compound 2.
MS (EI, m / z) 458 (M +), 443 (M-CH3) +, 425, 407, etc. 1H-NMR (CD3OD, δ) 3.14 to 3.23 (1H, m), 2.47 to 2.71 (2H, m), 2.06 (5H, m), 0.88 to 2.04 (19H, m), 0.75 (3H, d, J = 6.3 Hz), 0.80 ( 3H, s), 0.91 (3H, s), 0.95 (3H, d), 0.98 (3H, s), 1.01 (3H, s), 1.12 (3H, s), 1.16 (3H, s)

Formulation Example 1 Lotion [Prescription] Compound 1 0.001 part 2.1,3-butylene glycol 8.0 parts 2.0 parts of glycerin 4. Xanthan gum 0.02 part 5. Citric acid 0.01 part 6. 6. Sodium citrate 0.1 part Ethanol 5.0 parts 8. 8. Methyl paraoxybenzoate 0.1 part 9. Polyoxyethylene hydrogenated castor oil (40E.O.) 0.1 part10. Perfume proper amount11. Bring the total amount to 100 with purified water.
[Production Method] Components 1 to 6 and 11 and components 7 to 10 are uniformly dissolved, and both are mixed and filtered to obtain a product.

Formulation Example 2 Cream [Prescription] Compound 1 1.0 part2. Squalane 5.5 parts 3. Olive oil 3.0 parts 4. Stearic acid 2.0 parts 5. Beeswax 2.0 parts 6. 6. Octyldodecyl myristate 3.5 parts Polyoxyethylene cetyl ether (20E.O.) 3.0 parts 8. Behenyl alcohol 1.5 parts 9. Glyceryl monostearate 2.5 parts 10.1,3-butylene glycol 8.5 parts11. Methyl paraoxybenzoate 0.2 part 12. Ethyl paraoxybenzoate 0.05 part13. Fragrance 0.1 part14. Bring the total amount to 100 with purified water.
[Manufacturing method] Components 1 to 9 are heated and dissolved and mixed, and kept at 70 ° C to obtain an oil phase. Ingredients 10-12 and 14 are heated and dissolved and mixed, and kept at 75 ° C. to form an aqueous phase. Add the water phase to the oil phase, cool while stirring, add component 13 at 45 ° C, and further cool to 30 ° C to make the product.

Comparative Example 1 A conventional cream was prepared by replacing Compound 1 with squalane in Conventional Cream Formulation Example 2.

Formulation Example 3 Emulsion [Prescription] Compound 1 0.05 parts Compound 2 0.05 parts 3. Squalane 5.0 parts 4. Olive oil 5.0 parts 5. Jojoba oil 5.0 parts 6. Cetanol 1.5 parts 7. Glyceryl monostearate 2.0 parts 8. Polyoxyethylene cetyl ether (20E.O.) 3.0 parts 9. Polyoxyethylene sorbitan monooleate (20EO) 2.0 parts10. Propylene glycol 1.0 part11. Glycerin 2.0 parts 12. Methyl paraoxybenzoate 0.2 part13. Fragrance 0.1 part14. Bring the total amount to 100 with purified water.
[Manufacturing method] Components 1 to 9 are heated and dissolved and mixed, and kept at 70 ° C to obtain an oil phase. Ingredients 10-12 and 14 are heated and dissolved and mixed, and kept at 75 ° C. to form an aqueous phase. The aqueous phase is added to the oil phase to emulsify, and the mixture is cooled while stirring. The component 13 is added at 45 ° C., and further cooled to 30 ° C. to obtain a product.

Formulation Example 4 Gel [Prescription] Compound 1 0.05 parts Compound 2 0.05 parts 3. Ethanol 5.0 parts 4. 4. Methyl paraoxybenzoate 0.1 part 5. Polyoxyethylene hydrogenated castor oil (60 EO) 0.1 part Perfume appropriate amount 7.1,3-butylene glycol 5.0 parts 8. Glycerin 5.0 parts 9. Xanthan gum 0.1 part10. Carboxyvinyl polymer 0.2 part11. Potassium hydroxide 0.2 part 12. Bring the total amount to 100 with purified water.
[Production method] Components 1 to 6 and components 7 to 12 are uniformly dissolved, mixed and filtered to obtain a product.

Formulation Example 5 Ointment [Prescription] Compound 1 5.0 parts 2. 2.0 parts of polyoxyethylene cetyl ether (30E.O.) 3. Glycerol monostearate 10.0 parts 4. Liquid paraffin 5.0 parts 5. Cetanol 6.0 parts 6. 6. Methyl paraoxybenzoate 0.1 part Propylene glycol 10.0 parts 8. Bring the total amount to 100 with purified water.
[Manufacturing method] Components 1 to 5 are dissolved by heating and mixed, and kept at 70 ° C to obtain an oil phase. It heat-dissolves and mixes with the components 6-8, and it maintains at 75 degreeC and makes it an aqueous phase. The aqueous phase is added to the oil phase to emulsify, and the mixture is cooled to 30 ° C. with stirring to obtain a product.

Formulation Example 6 Pack [Prescription] Compound 1 1.0 part2. Compound 2 1.0 part3. Polyvinyl alcohol 12.0 parts 4. Ethanol 5.0 parts 5.1,3-butylene glycol 8.0 parts 6. 6. Methyl paraoxybenzoate 0.2 part Polyoxyethylene hydrogenated castor oil (20E.O.) 0.5 part 8. Citric acid 0.1 part 9. Sodium citrate 0.3 part10. Perfume proper amount11. Bring the total amount to 100 with purified water.
[Production Method] Components 1 to 11 are uniformly dissolved to obtain a product.

Formulation Example 7 Foundation [Prescription] Compound 2 0.2 parts Stearic acid 2.4 parts 3. Polyoxyethylene sorbitan monostearate (20E.O.) 1.0 part 4. Polyoxyethylene cetyl ether (20E.O.) 2.0 parts 5. Cetanol 1.0 part 6. 6. Purified lanolin 2.0 parts Liquid paraffin 3.0 parts 8. 6. Isopropyl myristate 6.5 parts 9. Butyl paraoxybenzoate 0.1 part10. Sodium carboxymethylcellulose 0.1 part11. Bentonite 0.5 part12. Propylene glycol 4.0 parts13. Triethanolamine 1.1 parts14. Methyl paraoxybenzoate 0.2 part15. Titanium dioxide 8.0 parts 16. Talc 4.0 part 17. Bengala 1.0 part 18. Yellow iron oxide 2.0 parts 19. Perfume proper amount20. Bring the total amount to 100 with purified water.
[Production Method] Components 1 to 9 are heated and dissolved, and kept at 80 ° C. to obtain an oil phase. Swell component 10 well with component 20, then add components 11-14 and mix uniformly. To this, components 15 to 18 pulverized and mixed with a pulverizer are added, and the mixture is stirred with a homomixer and kept at 75 ° C. to obtain an aqueous phase. The oily phase is added to the aqueous phase with stirring, cooled, and component 19 is added at 45 ° C, and cooled to 30 ° C with stirring to give a product.

Formulation Example 8 Bath preparation [prescription] Compound 1 0.005 part Sodium bicarbonate 50.0 parts 3. Yellow 202 No. 4 Perfume appropriate amount 5. Bring the total amount to 100 with sodium sulfate.
[Production method] Components 1 to 5 are uniformly mixed to obtain a product.

Experimental Example 1 Inhibition test of melanin production using B16 mouse melanoma B16 mouse melanoma in the logarithmic growth phase was seeded with 3 × 10 4 cells in φ60 mm dish, and Eagles'MEM (containing 10% FCS) containing the test substance was contained. In addition, the cells were cultured at 37 ° C. under 5% CO 2 conditions. After culturing for 5 days, the cells were detached from the dish, and the cells were sonicated, 4N-NaOH was added and treated at 60 ° C. for 2 hours, and OD475 nm was measured with a spectrophotometer. In addition, the cell disruption solution after sonication is subjected to protein quantification by Lowry's method (J. Biol. Chem. 1951, 193, 265-275), and the amount of melanin per protein amount is compared. It was used as an index. As test substances, compounds 1 and 2 were used, and arbutin was used as a comparative compound, which is known to have a melanin production inhibitory effect.

As a result, as shown in Table 1, compounds 1 and 2 showed an excellent melanin production inhibitory effect.

Experimental Example 2 Clinical Example For 4 patients with sunburn inflammation and pigmentation, the cream shown in Formulation Example 2 was applied to the affected area twice a day and observed for 2 months. At the same time, the conventional cream of Comparative Example 1 was tested in the same manner. Judgment of the effect was made into four stages:-: unchanged, +: faint, ++: almost disappeared, +++: completely disappeared. In skin findings, abnormalities such as deterioration and inflammation were observed.

As a result, as shown in Table 2, in the cream of Formulation Example 2, the effect was recognized in 3 cases out of 4 cases. On the other hand, as shown in Table 3, the effect was not recognized in the conventional cream of Comparative Example 1. In addition, no skin abnormality was observed in any cream.

When other usage examples were similarly tested for use, they showed excellent whitening effects.

The lanosta-8-ene derivative of the present invention exhibited an excellent melanin production inhibitory effect, and a skin external preparation containing these exhibited an excellent whitening effect. These can be applied to cosmetics, quasi drugs, pharmaceuticals and the like.

Claims (3)

A skin external preparation characterized by containing a lanoster-8-ene derivative represented by the general formula (1). (Substituent A in the formula represents C═O or CH—OH.)

A whitening agent comprising a lanosta-8-ene derivative represented by the general formula (1). (Substituent A in the formula represents C═O or CH—OH.)

A lanosta-8-ene derivative represented by the general formula (2).