JPH1017486A - Raw material for antiandrogenic agent and composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prepare a raw material for an antiandrogenic agent and composition, available from Cymbopogon flexuosus (D.C.) Stapf and having excellent inhibiting effects on activities of 5 α-reductases. SOLUTION: This raw material for an antiandrogenic agent is an essential oil or an extract of at least one site of a leaf, a terrestrial stem or a root of Cymbopogon flexuosus (D.C.) Stapf. The raw material is preferably obtained by carrying out the separation and purification according to a column chromatography with any one of a packing selected from an aromatic synthetic adsorbent, silica gel and alumina. Water or ethanol is preferably used as a solvent when using the extract which is the raw material from the viewpoint of safety for human bodies. Thereby, the antiandrogenic agent having effects equal to or higher than those of well-known 1-carboxylic acids is obtained and prevention of alopecia, treatment, etc., of benign prostatic hyperplasia are considered as possible.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a raw material of an antiandrogen and an antiandrogen composition,
The present invention relates to a raw material of an antiandrogen and an antiandrogen composition which inhibits the activity of 5α-reductase, which is a reductase that metabolizes testosterone, a male hormone, to dihydrotestosterone, an active male hormone. In addition, the anti-androgen agent raw material or the anti-androgen agent composition according to the present invention may belong to any of pharmaceuticals, quasi-drugs, and cosmetics in the Pharmaceutical Affairs Law.

[0002]

2. Description of the Related Art Dihydrotestosterone (hereinafter referred to as DHT)
Is an active androgen produced by metabolizing testosterone, a male hormone, by 5α-reductase, a reductase, and this reduction reaction is one of metabolic reactions in the human body. Testosterone is mainly produced in Leydig cells of the testes or in the adrenal cortex, seminiferous tubules, liver, prostate and skeletal muscle. Testosterone's mechanism of action is complex, acting not only as a natural hormone, but also as a prohormone. That is, 5 which is a reductase
It is reduced to DHT by α-reductase, and aromatized to estradiol. One of the hormonal actions of the active androgen, DHT, is to inhibit the supply of nutrients to hair mother cells and promote hair loss. In addition, as another effect, benign prostatic hyperplasia (hereinafter referred to as BPT), which is androgen-dependent,
Has the effect of strongly stimulating. Also, as another effect,
It is said that it has the effect of promoting acne. From these viewpoints, it is considered that by inhibiting the activity of reductase 5α-reductase, which metabolizes testosterone to DHT, it is possible to prevent alopecia, treat BPT, and treat acne. In the treatment of BPT, reductase 5α
-Administration of inhibitors of reductase activity has recently been introduced.

Hitherto, as a synthetic substance having a chemical property which inhibits the activity of reductase 5α-reductase, 2-methyl-5-isopropenylcyclohexen-3-one (hereinafter referred to as l-carvone, , Tokyo Chemical Industry Co., Ltd.).

[0004]

However, cosmetics containing l-carvone have a problem that when the content of l-carvone is low, the effect of inhibiting the activity of 5α-reductase is significantly reduced. For this reason, there has been a demand in the industry for the development of anti-androgenic agent raw materials and anti-androgenic agent compositions having an excellent 5α-reductase activity inhibiting effect. In view of the above circumstances, the present invention provides an antiandrogenic agent raw material and an antiandrogenic agent composition having an excellent effect of inhibiting the activity of 5α-reductase.

[0005]

According to the first aspect of the present invention,
Lemongrass (Cymbopogon flexuou)
s (DC) Staps) comprising an essential oil or extract of at least one site of leaves, aboveground stems and roots. The invention according to claim 2 is obtained by further fractionating and purifying the anti-androgenic agent raw material according to claim 1 by column chromatography using any one of an aromatic synthetic adsorbent, silica gel, and alumina. To a raw material for an antiandrogen. The invention according to claim 3 relates to an anti-androgen composition comprising the anti-androgen drug raw material according to claim 1 or 2.

[0006]

Embodiments of the present invention will be described below. As apparent from the examples described later, the inventor of the present invention used lemongrass (Cymbopogon fle).
5α excellent in xuous (DC) Staps
-It has been found that there is an effect of inhibiting the activity of reductase. Lemongrass (Cymbopogon flexu)
oos (DC) Staps is a perennial herbaceous plant belonging to the genus Calkaya, which is native to the Indian subcontinent and is one of the perfume plants. The leaves are broad, linear, whitish pale green on both sides, and usually do not flower. Also,
It contains essential oils that emit a lemon-like aroma in the whole plant.

In the present invention, lemongrass (Cy
mbopogon flexuous (DC)
A solvent is added to at least one site of the leaves, ground stems and roots of the staples (Staps), and after immersion, the extract of lemongrass is collected to obtain the antiandrogenic agent raw material according to the present invention.

[0008] Further, the solvent may be distilled off from the anti-androgen agent raw material to obtain the anti-androgen agent raw material according to the present invention.

As a solvent to be used, in addition to water, polar organic solvents such as methanol, ethanol, isopropyl alcohol, n-propyl alcohol, isobutanol, n-hexanol, methyl amyl alcohol,
1-8 carbon atoms such as ethylbutanol and n-octanol
Monohydric alcohol or carbon number of ethylene glycol, propylene glycol, 1,3-butylene glycol, hexylene glycol, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether, etc. 2-6 polyhydric alcohols or derivatives thereof, ketones having 3 to 6 carbon atoms such as acetone, methyl acetone, ethyl methyl ketone, isobutyl methyl ketone, methyl-n-propyl ketone, or carbons such as ethyl acetate and isopropyl acetate Ester of number 4 to 5, or C4 to C4 of ethyl ether, isopropyl ether, n-butyl ether, etc.
8 ethers. As the non-polar organic solvent, petroleum ether, or an aliphatic hydrocarbon having 4 to 8 carbon atoms such as n-butane, n-pentane, n-hexane, n-octane, or carbon tetrachloride, chloroform, Carbon number 1 such as dichloroethane and trichloroethylene
And aliphatic hydrocarbons having 6 to 7 carbon atoms such as benzene and toluene.

[0010] Among the above-mentioned organic solvents, water and ethanol are particularly preferably used. The reason is that it has safety to the human body, and can be used as a raw material for an antiandrogenic agent without performing a solvent distillation operation.

In the present invention, the lemongrass (Cymbopogon flexuous) (D.
C. ) At least one site of the leaves, above-ground stems and roots of the Staps) may be immersed in water, heated, and then subjected to steam distillation to obtain an essential oil, which may be used as a raw material for the antiandrogenic agent according to the present invention.

[0012] The separated material obtained by further fractionating the anti-androgen drug raw material obtained as described above by column chromatography or a concentrate thereof may be used as the anti-androgen drug raw material. The reason for fractionation is to efficiently remove inactive substances.

As the fractionation method, all commonly used fractionation methods are suitably used.

The most preferred example of the fractionation method is column chromatography.

When column chromatography is used, any adsorbent to be packed is preferably used as long as the adsorbate can be easily eluted.

Specific examples of the adsorbent include aromatic synthetic adsorbents such as Diaion HP-20, Diaion HP-21, Diaion HP-30, and Diaion H.
P-40, Diaion HP-50, Diaion SP
-800, Diaion SP-825, Diaion S
P-850, DIAION SP-875, DIAION SP-205, DIAION SP-206, DIAION SP-207 (all manufactured by Mitsubishi Kasei Kogyo Co., Ltd.), as well as silica gel, alumina and the like. .

The fractionation by column chromatography
The adsorbent as described above may be filled in a column, and the column may be filled with the extract obtained in the first embodiment or the extract obtained in the first embodiment in chloroform, ethanol, or the like. The solution dissolved in the organic solvent is passed through, and lemongrass (Cymbopogonf) is passed through.
The hair-growth component adsorbed on the above-mentioned adsorbent may be eluted by adsorbing the hair-growth component of Lexous (DC) Staps) and then flowing an appropriate solvent.

As a solvent used for elution, an organic solvent,
A solution in which one of a mixture of an organic solvent and a mixture of an organic solvent and water is mixed at a predetermined ratio is used. Examples of the polar organic solvent include monohydric alcohols having 1 to 8 carbon atoms such as methanol, ethanol, isopropyl alcohol, n-propyl alcohol, isobutanol, n-hexanol, methyl amyl alcohol, 2-ethylbutanol, and n-octanol, or , Ethylene glycol, propylene glycol, 1,3-butylene glycol, hexylene glycol, ethylene glycol monomethyl ether,
Polyhydric alcohols having 2 to 6 carbon atoms such as ethylene glycol monoethyl ether, propylene glycol monomethyl ether, propylene glycol monoethyl ether or derivatives thereof, acetone, methyl acetone, ethyl methyl ketone, isobutyl methyl ketone, methyl-n-
C3-C6 ketones such as propyl ketone, or
Ester having 4 to 5 carbon atoms such as ethyl acetate and isopropyl acetate, or ether having 4 to 8 carbon atoms such as ethyl ether, isopropyl ether and n-butyl ether;
Alternatively, hexane, heptane, octane, etc.
8 hydrocarbons and the like.

The fraction obtained by fractionation according to the above method is used as a raw material of the antiandrogen agent of the present invention.

Further, lemongrass (Cymbopogon fle) obtained by distilling off the solvent from the above-mentioned fractionated solution.
The fractionation part of the Xuous (DC) Staps) extract may be used as the raw material of the antiandrogen agent of the present invention.

When using Diaion HP-20 as a filler, a water-ethanol mixture or a water-methanol mixture is preferably used as a solvent. Further, when ethanol is used as the polar organic solvent, ethanol is safe for the human body, so that it can be suitably used as an antiandrogen agent raw material without distilling off the solvent from the fractionated solution.

Furthermore, in the present invention, as a hair growth and hair growth component, specifically, vitamin E and its derivatives, assembly extract, garlic extract, cepharanthin, carpronium chloride, acetylcholine, and other blood circulation promoters, chili tincture, canthalis Local stimulants such as tincture, ginger tincture, vanylamide nonylate, keratolytic agents such as salicylic acid, resorcinol and lactic acid, metabolic activators such as placenta extract, pentadecanoic acid glyceride, pantothenyl ethyl ether, biotin, hinokitiol, allantoin, and glycyrrhizin Acids, anti-inflammatory agents such as glycyrrhetinic acid, bactericides such as isopropylmethylphenol, triclosan, zinc pyrithione, hinokitiol, menthol, refreshing agents such as camphor, and other female hormones may be appropriately combined. Iga, is not particularly limited. In the present invention, in addition to the above, other components which are usual, such as alcohol, polyhydric alcohol, water-soluble polymer, antioxidant, p
H adjuster, UV inhibitor, sequestering agent, thickener,
Surfactants, purified water, fragrances, preservatives, antibacterial agents, oil agents, higher fatty acids, fatty acid esters, humectants, cooling agents, ordinary cosmetic ingredients such as pigments, or hormones, vitamins, amino acids, astringents and Animal and plant extracts including crude drug components such as placenta extract, elastin, collagen, mucopolysaccharide, aloe extract, loofah water, royal jelly, birch, carrot extract, chamomile extract, licorice extract, salvia extract, altea extract, and yarrow extract Special blending components such as components may be arbitrarily blended as appropriate according to the purpose. Further, the final form of the antiandrogenic agent in the present invention may be a cosmetic product applied to healthy skin for the purpose of beauty, or a specific use purpose such as alleviation of spots, freckles, and recovery of skin after sunburn. It may be a medicated cosmetic (quasi-drug) possessed or a medicament for treating spots and the like, and any form may be arbitrarily adopted. When preparing these dosage forms, ascorbic acid and its derivatives known as whitening agents, sulfur preparations, glutathione and the like, or moisturizing agents, ultraviolet absorbers, vitamins and the like, commonly used known additives are added to this formulation. They can be used in combination as appropriate within a range that does not impair the invention.

[0023]

Next, embodiments of the present invention will be described in detail with reference to tables. (Example 1) Lemongrass (Cymbopogon f)
Lemongrass (Cymbopogon flexuous) (D.C. Staps) in ethanol at a volume ratio 7 times that of the whole plant.
C. ) Staps) was sealed at room temperature and immersed for 7 days, and then ethanol was removed to obtain a lemongrass extract.

(Example 2) Extract obtained in Example 1
About 0g, 300cc of Diaion HP
By column chromatography using -20, 75
After performing elution with a 90% aqueous ethanol solution, a 90% aqueous ethanol solution was obtained, and the 90% aqueous ethanol solution was distilled off to remove chlorophyll.
mbopogon flexuous (DC)
(Staps) extract 3.3 g was obtained. Example 3 Lemongrass (Cymbopogon f)
Lexous (DC) Staps) was immersed in water and heated to obtain an essential oil produced by steam distillation.

Comparative Example 1 l-Carbon was used as Comparative Example 1.

(Test Method) As a testosterone-5α-reductase solution, 900 g of rat liver homogenate was used.
0 × g supernatant fraction (hereinafter, referred to as S-9) was used. Further, 1 mg / ml β-N was added to 1.5 ml of a 0.576 mg / ml testosterone-propylene glycol solution.
A solution (hereinafter, referred to as solution A) to which 5.0 ml of an ADPH / 5 mM-Tris-HCl buffer (sometimes required to be prepared) was added was prepared.

For Example 1, 6.3 mg of extract
The sample solution was prepared by adding ethanol having a purity of 99% so that the total volume was 0.25 ml. This sample solution was added to the above solution A, and S-9 was added 1.0 m
l was used as a reaction solution. At this time, the weight% of the extract
Is 0.08% in the reaction solution. For Example 2,
A sample solution was prepared by adding 6.3 mg of extract to ethanol having a purity of 99% so that the total amount was 0.25 ml. This sample solution is added to the above solution A,
Further, 1.0 ml of S-9 was added to obtain a reaction solution. At this time, the weight% of the extract was 0.08% in the reaction solution.
It is.

For Example 3, the essential oils 50, 25, 1
2.5, 6.3, 3.1 mg, total volume 0.25 ml
The sample solution was prepared by adding ethanol having a purity of 99% so that Each of these sample solutions was added to the above-mentioned solution A, and 1.0 ml of S-9 was further added thereto to obtain a reaction solution. At this time, the weight% of the essential oil was 0.64, 0.32, 0.16, 0.08,
0.03%.

For Comparative Example 1, 1-carvone 50,
25, 12.5, 6.3, 3.1 mg with a total amount of 0.2
A sample solution was prepared by adding ethanol having a purity of 99% to a volume of 5 ml. These sample solutions are
Each was added to the above-mentioned solution A, and S-9 was added to 1.
The reaction solution was added in an amount of 0 ml each. At this time, the weight% of l-carvone was 0.64, 0.32, 0.1% in the reaction solution.
16, 0.08, 0.03%

The above reaction solution was sufficiently stirred and stirred at 37 ° C.
And incubate for 30 minutes. Thereafter, 5.0 ml of dichloromethane was added as a reaction terminator to stop the reaction, and 0.1 ml of a progesterone-ethanol solution having a concentration of 5.0 mg / ml was added as an internal standard substance, followed by sufficient stirring. After stirring, the dichloromethane layer was separated and concentrated, and then testosterone remaining in the sample, DHT as a reaction product, and androstanediol were quantitatively analyzed using gas chromatography. The conditions for the quantitative analysis by gas chromatography were as follows: DB-17 was used for the column, and the column temperature was from 200 ° C to 280 ° C. The detection was performed using FID.

Based on the above test, 5α-reductor
The inhibition rate of an enzyme reaction that metabolizes testosterone into DHT using ze as a catalyst was calculated. Calculations were performed as described below. From the peak area of each component in the gas chromatography, the amount of the compound of each component was determined.
Testosterone catalyzed by 5α-reductase was converted to DH
The inhibition rate of the enzymatic reaction metabolizing to T was defined.

(Equation 1) From this definition, the higher the inhibitory effect of the enzyme reaction upon sample addition, the higher the inhibition rate.

The above test results are shown in (Table 1) and (Table 2).

[Table 1]

[Table 2]

The anti-androgen composition according to the present invention is shown below. (Example 4) Hair restorer (%) Ethanol extract of lemongrass (Example 1) 10.0 Tocopherol acetate 0.1 Pantothenyl alcohol 0.2 Nicotinamide 0.1 Hinokitiol 0.05 Polyoxyethylene (EO60) ) Hardened castor oil 0.3 Perfume 0.1 Glycerin 0.1 Ethanol 55.0 Purified water 34.05 Total 100.00 (Example 5) Aerosol hair growth agent (%) Stock solution Lemongrass essential oil (Example 2) 0 .3 Polyoxyethylene (EO60) hydrogenated castor oil 0.2 dipotassium glycyrrhizinate 0.1 assembly extract 0.5 1,3-butanediol 1.0 ethanol 65.0 fragrance 0.2 purified water 32.7 total 100. 0 propellant LPG (20 ℃, 1.5kg / cm 2) 86.2 nitrogen 13.8 total 100.0 stock 97.11 propellants 2. 9 Total 100.00

As is clear from Table 1, the lemongrass (Cymbopogon fle) according to the first aspect of the present invention is evident.
An extract of whole plant of Xuous (DC) Staps) and the lemongrass (Cymbo) of the invention according to claim 2.
pogon flexuous (DC) Stap
Regarding the extract obtained by fractionating the whole plant extract of s) by column chromatography, when the content is 0.08% in the reaction solution by weight%, reductase 5α superior to l-carvone is used. -Has an inhibitory effect on the activity of reductase. As is clear from Table 2, the lemongrass (Cymbopogon flexuou) according to the first aspect of the present invention is described.
s (DC) Staps), the whole plant essential oil inhibits the activity of reductase 5α-reductase to the same extent as l-carvone when the content is high, and the content in the reaction system Is low, it has an effect of inhibiting the activity of reductase 5α-reductase which is relatively superior to l-carvone.

──────────────────────────────────────────────────続 き Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI Technical display location A61K 7/06 A61K 7/06 (72) Inventor Nobunori Fujiwara 5 Junjikencho, Chuo-ku, Osaka-shi No. 12 Inside Mandom Central Research Institute Co., Ltd. (72) Inventor Osamu Nakaguchi 5-12, Junkencho, Chuo-ku, Osaka City Inside Mandom Central Research Institute

Claims (3)

[Claims] 1. Lemongrass (Cymbopogon)
A raw material for an antiandrogen, comprising an essential oil or an extract of at least one part of a flexuous (DC Staps) leaf, an aboveground stem, or a root. 2. The anti-androgenic agent raw material according to claim 1, which is further obtained by fractionating and purifying it by column chromatography using any one of an aromatic synthetic adsorbent, silica gel and alumina. Characteristic anti-androgenic agent raw material. 3. An antiandrogenic agent composition comprising the antiandrogenic agent raw material according to claim 1 or 2.