JP2003104849A - TESTOSTERONE-5alpha-REDUCTASE INHIBITOR - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a testosterone-5α-reductase inhibitor containing an extract of Nostoc flagelliforme and a hair grower. SOLUTION: This testosterone-5α-reductase inhibitor comprises an extract of Nostoc flagelliforme. This hair grower comprises an extract of Nostoc flagelliforme. The Nostoc flagelliforme is a terrestrial alga of the genus Nostoc. Nostoc commune Vauch. var. flagelliforme, Nostoc commune Vauch., etc., may be cited as the Nostoc flagelliforme.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel testosterone-5α-reductase (hereinafter abbreviated as 5α-reductase) inhibitor and a hair-growing agent.

[0002]

2. Description of the Related Art Conventionally, the causes of androgenetic alopecia have been as follows: (1) hormone imbalance theory, (2) genetic theory,
Although (3) blood circulation failure theory and (4) nutrition theory have been proposed, it has long been suggested that the male hormone testosterone plays an important role in hair development. That is, testosterone biosynthesized in the testes
In the head, it is converted to dihydrotestosterone by 5α-reductase existing in hair follicles, sebaceous glands, and the like. This dihydrotestosterone significantly reduces the activity of adenyl cyclase, resulting in a decrease in intracellular cyclic AMP level, and as a result, a decrease in energy production around hair and hair and a suppression of protein synthesis. Is considered to cause androgenetic alopecia.

Further, dihydrotestosterone produced from testosterone by 5α-reductase is considered to be involved in the generation and exacerbation of acne and the enlargement of the prostate [J. Steroid Biochemis
try, 11, 609 (1979)].

[0004]

However, an effective drug against these diseases, particularly an effective drug based on the inhibition of dihydrotestosterone production has not been found, and its development has been desired.

[0005]

In view of the above-mentioned circumstances, the present inventors have succeeded in inhibiting 5α-reductase inhibition of overproduction of dihydrotestosterone, which causes androgenetic alopecia, the development and exacerbation of acne, and prostatic hypertrophy. As a result of conducting sincerity research to find out an agent, it was found that the extract of hairy vegetables meets the purpose, and the present invention was completed.

That is, the present invention relates to a 5α-reductase inhibitor and a hair-growing agent containing an extract obtained from hairy vegetables as an active ingredient.

The hairy vegetables used in the present invention are terrestrial algae belonging to the genus Nostoc, Nostoc, belonging to the blue-green alga, Nostoc.
commune Vouch. var. flag
lliforme and Nostoc commune V
auch. And so on. In recent years, it has been noted that it is effective in preventing and treating adult diseases such as cardiovascular diseases and cancer. Also, since it is used for Chinese cuisine, it is possible to use a commercial product.

The hairy vegetable extract used in the present invention can be extracted by, for example, shredding commercially available dried hairy vegetables. The preparation method is not particularly limited, and may be, for example, one extracted by heating or one extracted at room temperature.

As the solvent to be extracted, for example, water, lower monohydric alcohols (methanol, ethanol, 1-propanol, 1-propanol, 1-butanol, 2-butanol, etc.), liquid polyhydric alcohol (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) , Propyl ether, etc.). Water, lower monohydric alcohols and liquid polyhydric alcohols are preferable, and water, ethanol, 1,3-butylene glycol and propylene glycol are particularly preferable. Supercritical extraction using carbon dioxide or the like can also be used. These solvents may be used alone or in combination of two or more.

These extracts may be used as they are as the extracted solvent, or may be subjected to treatments such as concentration, dilution and filtration, if necessary. Furthermore, the extracted solution may be subjected to treatments such as concentration to dryness, spray drying, freeze drying, and the like, to be used as a dried product.

The extract of the present invention comprises 5α-reductase.
5α in mammals, especially humans, due to its inhibitory effect
-Useful for treating and preventing diseases caused by overproduction of dihydrotestosterone by reductase. Such diseases include, for example, alopecia including androgenetic alopecia, acne and benign prostatic hyperplasia.

When the extract according to the present invention is used for the above purpose, it is usually administered systemically or locally, orally or transdermally. Dosage depends on age, weight, symptoms, therapeutic effect,
Although it depends on the administration method and treatment time, in the case of treatment or prevention of benign prostatic hyperplasia, it is usually 1 m / adult per adult
g to 1 g, preferably 1 in the range of 20 mg to 200 mg
It is orally administered once to several times a day. For treatment and prevention of alopecia and acne, usually 10μ per adult per administration
It is transdermally administered once to several times a day in the range of g to 50 mg, preferably 100 μg to 5 mg. Of course, as described above, since the dose varies depending on various conditions, a dose smaller than the above range may be sufficient in some cases, or a dose exceeding the range may be necessary in some cases.

The solid preparation for oral administration according to the present invention includes tablets, pills, powders, granules, capsules and the like. For such solid preparations, in addition to the extract as the active ingredient, for example, lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, inert dilution of magnesium aluminometasilicate, etc. Agents, lubricants such as magnesium stearate, and disintegrants such as fibrin calcium gluconate. The tablets or pills may be coated with a film of a gastric solvent such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, phthalate or an enteric substance, if necessary.

Liquid preparations for oral administration include emulsions, solutions, suspensions, syrups and elixirs. Such liquid preparations include, in addition to the active ingredient and inert diluent, auxiliary agents such as wetting agents and suspending agents,
Sweetening agents, flavoring agents, aromatic agents, preservatives and the like may be contained. Other formulations for oral administration include sprays and the like.

Typical preparations for transdermal administration in the present invention include creams, emulsions, lotions, hair tonics, sprays, packs, solutions, ointments, emulsions, coatings such as suspensions, and rectal administration. Examples include suppositories for administration, pessaries for vaginal administration and the like. In particular, as a preparation for the treatment and prevention of alopecia, lotion, hair tonic,
Sprays and solutions are preferred. These formulations include, in addition to the active ingredient, water, a lower alcohol such as ethanol,
Higher alcohols such as cetanol, polyhydric alcohols such as polyethylene glycol and propylene glycol, celluloses such as hydroxypropyl cellulose, oils and waxes of animal and vegetable origin, hydrocarbons such as petrolatum, silicones, surfactants. , Zinc oxide, etc. can be added.

[0016]

EXAMPLES In order to explain the present invention in detail, production examples of extracts used in the present invention, prescription examples of the present invention and experimental examples will be given below, but the present invention is not limited thereto. is not. The parts of the compounding amounts shown in the examples are parts by weight, and
Means% by weight.

Production Example-1 To 100 g of shredded hair vegetables, 1 kg of purified water was added,
It was extracted at 100 ° C. for 2 hours. The obtained extract was concentrated under reduced pressure and freeze-dried to obtain 10 g of a hot water extract of hairy vegetables.

Production Example-2 To 100 g of shredded hair vegetables, 500 g of purified water and 500 g of 1,3-butylene glycol were added, and the mixture was extracted at room temperature for 2 weeks. After extraction, the mixture was filtered to obtain 950 g of a 1,3-butylene glycol extract of hairy vegetables.

Production Example-3 To 100 g of hair vegetables, 1 kg of ethanol was added, and the mixture was allowed to stand at room temperature for 2 hours.
It was extracted for a week. The obtained extract was concentrated under reduced pressure to obtain 5 g of a paste-like extract.

Example-1 Lotion Formulation Amount 1. Hot water extract of hair vegetables (Production Example-1) 0.1 part 2.1,3-butylene glycol 8.0 3. Glycerin 2.0 4. Xanthan gum 0.02 5. Citric acid 0.01 6. Sodium citrate 0.1 7. Ethanol 5.0 8. Methyl paraoxybenzoate 0.1 9. Polyoxyethylene hydrogenated castor oil (40 EO) 0.1 10. Perfume proper amount 11. [Production method] Components 1 to 6 and 11 and components 7 to 10 each having a total amount of 100 with purified water are uniformly dissolved, and both are mixed and filtered to obtain a product.

Comparative Example-1 Conventional Lotion A conventional lotion was prepared by replacing the hot water extract of hairy vegetables with purified water in Example-1.

Example-2 Cream Formulation Amount 1. Hot water extract of hair vegetables (Production Example-1) 0.05 part 2. Squalane 5.5 3. Olive oil 3.0 4. Stearic acid 2.0 5. Beeswax 2.0 6. Octyldodecyl myristate 3.5 7. Polyoxyethylene cetyl ether (20 EO) 3.0 8. Behenyl alcohol 1.5 9. Glycerin monostearate 2.5 10. Fragrance 0.1 11.1, 3-butylene glycol 8.5 12. Ethyl paraoxybenzoate 0.05 13. Methyl paraoxybenzoate 0.2 14. [Manufacturing method] The total amount is 100 with purified water. Components 2 to 9 are dissolved by heating and mixed, and the mixture is heated to 70 ° C.
Keep it in the oil phase. Ingredients 1 and 11 to 14 are dissolved by heating and mixed, and the mixture is kept at 75 ° C to form an aqueous phase. Add the water phase to the oil phase to emulsify, cool with stirring and mix at 1
0 is added, and the product is further cooled to 30 ° C. to obtain a product.

Example-3 Emulsion formulation Formulation amount 1. 1. Ethanol extract of hair vegetables (Production Example-3) 0.5 part 2. Squalane 5.0 3. Olive oil 5.0 4. Jojoba oil 5.0 5. Cetanol 1.5 6. Glycerin monostearate 2.0 7. Polyoxyethylene cetyl ether (20 EO) 3.0 8. Polyoxyethylene sorbitan monooleate (20EO) 2.0 9. Perfume 0.1 10. Propylene glycol 1.0 11. Glycerin 2.0 12. Methyl paraoxybenzoate 0.2 13. The total amount is 100 with purified water [Production method] Components 2 to 8 are dissolved by heating and mixed, and the mixture is heated to 70 ° C.
Keep it in the oil phase. Ingredients 1 and 10 to 13 are dissolved by heating and mixed, and the mixture is kept at 75 ° C to form an aqueous phase. Add the water phase to the oil phase to emulsify, cool with stirring and mix at 9
Is added, and the product is further cooled to 30 ° C.

Example-4 Hair Tonic Formulation Amount 1. Ethanol 60.0 parts 2. 1,3-Butylene glycol extract of hair vegetables (Production Example-2) 2.0 3. Glycerin 2.0 4. [Manufacturing method] The total amount is 100 with purified water [Production method] The 1,3-butylene glycol extract of hairy vegetables is dissolved in ethanol, glycerin and purified water are added, and the mixture is sufficiently stirred and mixed to obtain a product.

[0025]   Example-5 Pack Prescription amount 1. Hot water extract of hair vegetables (Production Example-1) 0.1 part 2. Polyvinyl alcohol 12.0 3. Ethanol 5.0 4.1,3-butylene glycol 8.0 5. Methyl paraoxybenzoate 0.2 6. Polyoxyethylene hydrogenated castor oil (20EO) 0.5 7. Citric acid 0.1 8. Sodium citrate 0.3 9. Fragrance suitable amount 10. Adjust the total volume to 100 with purified water [Production method] Components 1 to 10 are uniformly dissolved to obtain a product.

[0026]

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

Experimental Example-1 Inhibitory effect on 5α-reductase 5α- extracted from the liver of SD male rat (7 weeks old).
It measured using reductase on condition of the following reaction systems.

(Reaction conditions) Testosterone (0.6 μ
M) was dissolved in 10 drops of propylene glycol, 5 mL of Tris-HCl buffer (pH 7.2) was added, and then,
NADPH (5 mg) and 5α-reductase solution (2 mL) are sequentially added, and the mixture is reacted at 37 ° C for 30 minutes. After the reaction, methylene chloride is added to stop the reaction, and the whole is extracted with 50 mL of methylene chloride. Then, the methylene chloride layer is distilled off under reduced pressure, and the reaction amount is measured by gas chromatography. The addition of the extract according to the present invention to the reaction system is performed after dropping testosterone. (Gas chromatography conditions: column OV-17 (3 mmφ, 2
m); column temperature 250 ° C .; detector; FID)

Inhibition rate: The inhibition rate is calculated by considering the reaction rate (control) without addition of the extract as 100% (inhibition rate of 0%) and calculating the decrease in the reaction rate with the addition of the extract. The formula is as follows. Since dihydrotestosterone is further metabolized to produce androstanediol, the peak area (amount) of the 5α-reductase metabolite was calculated by including androstanediol. Inhibition rate (%) = (b / a−b ′ / a ′) / (b / a) ×
100 a: Control (peak area of testosterone) b: Control (peak area of dihydrotestosterone and androstanediol) a ′: Peak area of testosterone (addition of extract) b ′: Peak area of dihydrotestosterone and androstanediol (extraction Added)

The results are summarized in Table 1.

[0031]

[Table 1]

Experimental Example-2 Hair growth effect Hattori et al. [J. Dermatology, 10,
45-54 (1983)], C3H 45 days after birth.
The back hair of the mouse was cut with a hair clipper, this portion was divided into two, and 1 mL of the lotion of Example-1 was used on one side and 1 mL of the conventional lotion containing no extract of the present invention (Comparative Example-1) on the other side. It was applied once a day. The comparison was made based on the number of days required until hair growth was observed in each part. As a result, Example-1 was compared with the period until hair growth of the lotion containing no extract according to the present invention was observed.
Lotion has shortened that period. In addition, similar effects were observed in the other examples.

Experimental Example-3 Toxicity Each mouse extract was subjected to an acute toxicity test by oral administration in mice, and no death was observed even if 2,000 mg / kg was administered.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61P 43/00 111 A61P 43/00 111 (72) Inventor Tomonori Katata 2-7 Torimicho, Nishi-ku, Nagoya-shi Japan Menard Cosmetics Research Institute F-term (reference) 4C083 AA082 AA111 AA112 AA122 AC022 AC072 AC102 AC122 AC182 AC242 AC302 AC352 AC422 AC432 AC482 AD112 AD352 CC04 CC05 CC07 CC37 DD23 DD31 EE09 EE14 EE22 4C088 AA12 AC01 BA08 CA03 MA20 ZA19 ZA89 ZA20

Claims (2)

[Claims] 1. A testosterone-5α-reductase inhibitor, which comprises a hairy vegetable extract. 2. A hair restorer comprising a hairy vegetable extract.