JP5971833B2 - Testosterone-5α-reductase inhibitor - Google Patents

Description

The present invention relates to a novel testosterone-5α-reductase (hereinafter abbreviated as 5α-reductase) inhibitor, hair restorer, acne treatment agent and prostate disease treatment agent.

Conventionally, the cause of male pattern alopecia has been proposed as (1) hormone imbalance theory, (2) genetic theory, (3) blood circulation failure theory, (4) nutrition theory, etc. It has long been suggested that the male hormone testosterone plays an important role in the outbreak. That is, testosterone biosynthesized by testicles is converted to dihydrotestosterone by 5α-reductase present in hair follicles, sebaceous glands and the like in the head. This dihydrotestosterone significantly reduces the activity of adenyl cyclase resulting in a decrease in intracellular cyclic AMP levels. As a result, it is considered that male pattern baldness progresses by inducing a decrease in energy production around hair and hair and suppression of protein synthesis.

Further, dihydrotestosterone produced from testosterone by 5α-reductase is considered to be involved in acne generation and exacerbation (see Non-Patent Document 1). Furthermore, it is known that when the production of dihydrotestosterone increases, prostate diseases such as prostatic hypertrophy and prostate cancer develop, and it is possible to suppress or inhibit the production of dihydrotestosterone by a drug having a 5α-reductase inhibitory action. If possible, it is believed that prostate disease can be prevented and treated.

J. et al. Steroid Biochemistry, 11, 609 (1979)

Accordingly, it has been desired to develop effective drugs for these diseases, particularly effective drugs based on the suppression of dihydrotestosterone production.

As a result of intensive studies aimed at solving the above problems, the present inventors have found that an extract of rice bran cherry has an excellent 5α-reductase inhibitory action. Furthermore, the present inventors have found that a drug containing the extract is safe and stable and is excellent in a hair-growth effect and an acne improvement effect, and has completed the present invention.

The extract of the rice crabs used in the present invention is a plant belonging to the genus Comebaceae genus, the plant of the genus Combataceae (scientific name: Arcterica nana) (also known as: Hamazakura), plants, stems, leaves, branches, branch leaves, roots, seeds, etc. It is extracted from part of the body or whole grass. The extraction method is not particularly limited, and for example, it may be a heat extraction or a room temperature extraction. The plant material may be used raw or dried. Shredding can increase extraction efficiency.

Examples of the solvent to be extracted include water, lower alcohols (methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, 2-butanol, etc.), liquid polyhydric alcohols (1,3-butylene glycol, propylene glycol). , Glycerin, etc.), ketones (acetone, methyl ethyl ketone, etc.), acetonitrile, esters (ethyl acetate, butyl acetate, etc.), hydrocarbons (hexane, heptane, liquid paraffin, etc.), ethers (ethyl ether, tetrahydrofuran, propyl ether) Etc.). Preferred are polar solvents such as water, lower alcohols and liquid polyhydric alcohols, and particularly preferred are water, ethanol, 1,3-butylene glycol and propylene glycol. These solvents may be used alone or in combination of two or more.

The extract may be used as it is, or may be used after concentration, dilution and filtration treatment, decolorization with activated carbon, deodorization treatment, or the like, if necessary. Further, the extracted solution may be subjected to a treatment such as concentration to dryness, spray drying, freeze drying, etc., and used as a dried product.

The blending amount of the extract in the total composition of the 5α-reductase inhibitor, hair restorer or acne treatment agent of the present invention may be 0.001 to 10% by weight (hereinafter simply referred to as “%”) as the extracted solid content. Preferably it is 0.01 to 5%. If it is less than 0.001%, the intended effect of the present invention is not sufficient. On the other hand, even if the upper limit is exceeded, an improvement in the effect commensurate with the increase is hardly expected.

In addition to the extract, the hair restorer and acne treatment agent of the present invention are appropriately selected from additives and other agents conventionally used as hair restorers or acne treatment agents as long as the effects of the present invention are not impaired. Can be blended. Examples of additives include antibacterial agents such as hinokitiol, benzalkonium chloride, hexachlorophene and undecylenic acid, refreshing agents such as menthol, higher fatty acids, higher alcohols, surfactants, perfumes, antioxidants, ethanol, purification Water, a humectant, etc. are mentioned. Examples of other drugs that are commonly used as hair restorers include vasodilators such as assembly extract and acetylcholine derivatives, swelltinogen, vitamin E nicotinic acid ester, red pepper tincture, and ginseng. One or more of these can be used. In addition, other drugs commonly used as acne treatments include, for example, steroids such as prednisolone valerate acetate and hydrocortisone acetate, vitamins such as ascorbic acid and pyridoxine hydrochloride, and wound healing agents such as allantoin. These can be used alone or in combination of two or more.

The hair growth agent of the present invention is not limited as long as it is used as an external preparation. For example, hair tonic, hair lotion, hair cream, hair conditioner, hair gel, hair mist, hair foam, shampoo , Rinse and the like. The acne treatment agent is not limited as long as it is used as an external preparation, and examples thereof include ointments, liquids, patches, sprays and the like. In addition, the 5α-reductase inhibitor of the present invention can be applied orally, and examples of the preparation include dosage forms such as tablets, capsules, powders, fine granules, granules, oral liquids and the like.

The extract of the rice bran cherry of the present invention showed an excellent 5α-reductase inhibitory effect, hair growth effect and acne treatment effect. It is also effective in treating prostate diseases.

Next, in order to describe the present invention in detail, examples of producing the extract used in the present invention, formulation examples and experimental examples of the present invention will be given as examples, but the present invention is not limited thereto. In the examples, the part of the amount is part by weight, and% is% by weight.

Production Example 1 Hot Water Extract of Rice Butter Crab 400 mL of purified water is added to 20 g of dried dried whole plant of Arcterica nana, extracted at 95-100 ° C. for 2 hours, filtered, and the filtrate is concentrated and lyophilized As a result, 1.0 g of a hot water extract of rice bran cherry was obtained.

Production Example 2 50% Ethanol Extract of Rice Butter Crab (Arterica nana) Whole plant dry product 20 g was added with 400 mL of 50% ethanol aqueous solution, extracted at room temperature for 7 days, filtered, and the filtrate was concentrated to dryness. 1.5 g of a 50% ethanol extract of rice bran cherry was obtained.

Production Example 3 Ethanol extract of Kumebatsuzakura 1000 mL of ethanol was added to 50 g of dried plant of Arcterica nana, extracted at room temperature for 7 days, filtered, the filtrate was concentrated to dryness, and ethanol extraction of Kumebatsuzakura 1.4 g of product was obtained.

Production Example 4 Extract of 50% 1,3-butylene glycol from Kumebatsuzakura 400 mL of a 50% 1,3-butyleneglycol aqueous solution was added to 20 g of a dry product of whole plant of Kumebatsuzakura (Arterica nana), extracted at room temperature for 7 days, and filtered. As a result, 380 g of 50% 1,3-butylene glycol extract of rice bran cherry was obtained.

Formulation Example 1 Hair Lotion Formulation Formulation (Part)
1. Hot water extract of rice bran cherry (Production Example 1) 0.2
2. Stearic acid 5.0
3. Cetyl alcohol 5.0
4). Liquid paraffin 2.0
5. Glycerin monostearate 1.3
6). Sorbitan monostearate 1.5
7). Polyoxyethylene (10) sorbitan monooleate 0.8
8). Glycerin 6.0
9. Preservative appropriate amount10. [Production method] Components 2 to 7 were heated and dissolved and mixed with purified water to 100. The oil phase was maintained at 70 ° C. Ingredients 1 and 8 to 10 were dissolved by heating and mixed, and kept at 75 ° C. to obtain an aqueous phase. An aqueous phase was added to the oil phase, and the mixture was cooled while stirring to obtain a product.

Formulation Example 2 Hair Tonic Formulation Amount (parts)
1. Ethanol extract of rice bran cherry (Production Example 3) 2.0
2.95% ethanol 60.0
3. Glycerin 2.0
4). [Manufacturing method] Component 1 was dissolved in 2 with purified water to 100, and components 3 and 4 were added and mixed with sufficient stirring to obtain a product.

Comparative Example 1 A conventional product was prepared by replacing component 1 with purified water in conventional hair tonic formulation example 2.

Formulation Example 3 Shampoo Formulation Blending (parts)
1. 50% ethanol extract of rice bran cherry (Production Example 2) 0.1
2. Alkyl sulfate triethanolamine 18.0
3. Lauric acid diethanolamide 3.0
4). Methylcellulose 0.5
5. Perfume appropriate amount 6. [Manufacturing method] in which component 4 is uniformly dissolved in component 6 with purified water 100, components 1 and 2 are added, heated and dissolved at 70 to 75 ° C, component 3 is added, and cooling is in progress. Ingredient 5 was added and cooled to 30 ° C. to obtain a product.

Formulation Example 4 Rinse Formulation Amount (parts)
1. 50% 1,3-butylene glycol extract of rice bran cherry (Production Example 4) 0.1
2. Jojoba oil 0.01
3. Behenyl alcohol 3.0
4.1,3-Butylene glycol 5.0
5. Distearyldimethylammonium chloride (75%) 8.0
6). Citric acid 0.05
7). Perfume appropriate amount 8. [Manufacturing method] Components 1 to 8 were dissolved at 60 ° C., and the total amount was 100 with purified water, stirred and cooled to 30 ° C. to obtain a product.

Formulation Example 5 Acne Treatment Ointment Formulation Blending (parts)
1. Ethanol extract of rice bran cherry (Production Example 3) 1.0
2. 50% 1,3-butylene glycol extract of rice bran cherry (Production Example 4) 1.0
3. Polyoxyethylene cetyl ether (30E.O.) 2.0
4). Glycerol monostearate 10.0
5. Liquid paraffin 5.0
6). Cetanol 6.0
7). Methyl paraoxybenzoate 0.1
8). Propylene glycol 10.0
9. [Manufacturing method] Components 1 and 3 to 6 were heated and dissolved and mixed with purified water to 100. The oil phase was maintained at 70 ° C. Ingredients 2 and 7-9 were dissolved by heating and mixed, and kept at 75 ° C. to obtain an aqueous phase. The aqueous phase was added to the oil phase to emulsify, and the mixture was cooled to 30 ° C. with stirring to obtain a product.

Comparative Example 2 A conventional product was prepared by replacing Component 1 with liquid paraffin and Component 2 with 50% 1,3-butylene glycol in Conventional Ointment Formulation Example 5.

Next, experimental examples will be given to explain the effects of the present invention in detail.

Experimental Example 1 5α-Reductase Activity Inhibition Test Using rat liver microsome-derived 5α-reductase, measurement was performed under the following reaction conditions.
After dissolving testosterone (final concentration 0.49 mM) in DMSO, NADPH (final concentration 0.97 mM) dissolved in 0.1 M Tris-HCl buffer (pH 7.2) was added, and then the sample and 5α- Reductase was added in order and reacted at 37 ° C. for 30 minutes. After the reaction, an equal amount of dichloromethane was added to stop the reaction, and then the dichloromethane layer was extracted. Then, the dichloromethane layer was distilled off under reduced pressure, and after silylation using BSTFA, the reaction amount was measured by a conventional method using a gas chromatography mass spectrometer. The inhibition rate is determined by using purified water instead of the sample as a control, assuming that the control reaction rate is 100% (inhibition rate 0%), and calculating the amount of reaction with the sample added to determine the inhibition rate. It was. The formula is as follows.

Inhibition rate (%) = (1− (b ′ / a ′) / (b / a)) × 100
a: Peak area of testosterone (control)
b: Peak area of dihydrotestosterone (control)
a ′: Testosterone peak area (sample addition)
b ′: Peak area of dihydrotestosterone (sample addition)
These results are summarized in Table 1. As a result, the extract of the rice bran cherry showed an excellent inhibitory activity on 5α-reductase activity.

Experimental example 2 Use test on hair growth effect Using the hair tonic of prescription example 2 and the conventional hair tonic of comparative example 1, a 6 month use test was conducted for 10 male pattern baldness (42 to 53 years old). went. After use, a questionnaire survey was conducted on hair growth, thinning, and hair loss, and a comprehensive determination was made. As a result, the hair restoring agent containing the extract of rice bran cherry showed an excellent hair restoring effect (Table 2). During the test period, there was no skin problem and there was no problem with safety. There was also no problem with the deterioration of the prescription ingredients.

Experimental Example 3 Use Test for Acne Treatment Effect Using the acne treatment ointment of Formulation Example 5 and the conventional ointment of Comparative Example 2 for 15 months (19 to 28 years old) each suffering from acne, a 1 month use test Went. After use, a questionnaire survey was conducted on the effect of acne improvement (prevention and treatment) to make a comprehensive assessment. As a result, the acne treatment ointment containing the extract of rice bran cherry showed an excellent acne improving effect (Table 3). During the test period, there was no skin problem and there was no problem with safety. There was also no problem with the deterioration of the prescription ingredients.

From the above, the extract of rice bran cherry had an excellent 5α-reductase inhibitory action. Moreover, the hair restorer and acne treatment ointment containing this extract exhibited excellent hair growth effects, acne prevention and treatment effects, respectively, and were excellent in safety and stability. Therefore, the 5α-reductase inhibitor of the present invention is effective in preventing or treating male pattern alopecia, acne, prostate disease and the like.

Claims (2)

A testosterone-5α-reductase inhibitor comprising a hot water extract of rice bran cherry. A therapeutic agent for acne comprising a hot water extract of rice bran cherry.