JPH04342535A - Testosterone 5alpha-reductase inhibitor - Google Patents

Abstract

PURPOSE:To provide a testosterone 5alpha-reductase inhibitor containing solvent extract of galenical drug and having remarkable hair-tonic effect and therapeutic effect on acne vulgaris. CONSTITUTION:The objective agent contains the solvent extract of galenical drug selected from ASEN-YAKU (leaf of Uncaria gambir), UIKYOU (fruit of Foeniculum vulgare), ONJI (root of Polygala tenuifolia), KANZOU (root of Glycyrrhiza glabra), KENGOSHI (seed of Pharbitis nil), GOBAISHI (gall of Rhus chinensis), SHAKUYAKU (root of Paeonia albiflora), SHAZENSHI (whole grass of Plantago major), SENSO (secreta of Bufo bufo gargorizans), DAIOU (rhizome of Pheum palmatum), CHOUJI (bud of Syzygium aromatica), BINROUJI (seed of Areca catechu), rosin, KAKKOUAZAMI (Pogostemon cabling, GENNO-SHOKO (leaf of Geranium thunbergii), KAGOSOU (spica of Prunella vulgaris), SAIKO (root of Bupleurum falcatum), INCHIN (whole grass of Artemisia capillaris), EIJITSU (fruit of Rosa multiflora), YOKUININ (seed of Coix laryma-jobi), SOYOU (leaf of Perilla frutescens), NIGAKI (wood of Picrasma ailanthoides), KEIGAI (flower of Schizonepeta tenuifolia), KISASAGE (fruit of Catalpa ovata), SHOUZANI and KANOKOSOU (root of Valeriana fauriei). The extract is used as it is, diluted, concentrated or lyophilized in the form of powder or paste or, as necessary, converting to a proper pharmaceutical preparation. The inhibitor exhibits antiandrogen action caused by the 5alpha-reductase inhibiting effect, is free from undesirable other hormonal effects and has high safety.

Description

[Detailed description of the invention]

The present invention relates to a 5α-reductase inhibitor of testosterone, and more particularly, it relates to a 5α-reductase inhibitor of testosterone, and more specifically, it contains 5α-reductase inhibitors such as Acacia japonica, Fennel, Onji, Licorice, Kengoshi, Gobaishi, Peony, Shazenshi, Senso, Rhubarb, Clove, Areca nut, Rosin, Cuckoo thistle, Gennoshoko ,
Kagosou, Saiko, Inchin, Agetsu, Yokuinin,
The present invention relates to a testosterone 5α-reductase inhibitor containing a solvent-extracted extract of a herbal medicine selected from the group consisting of Japanese soybean, bittern, Japanese snail, Japanese sage, Japanese sage, and valerian.

Conventionally, general skin abnormalities that impair beauty (
In order to prevent or treat hair, skin, etc. disorders, drugs containing fungicides, hormones, antibiotics, or other drugs are used. Since the skin is considered to be a target organ for male hormones (androgens), various anti-androgen agents, ie, drugs containing anti-androgens, have recently been developed.

[0003] It has long been pointed out that male hormones are associated with skin abnormalities, especially male pattern hair loss (male pattern baldness), acne vulgaris (acne), and seborrhea, but recent research has shown that these It has been found that the skin disorders in men are caused more by the metabolites of male hormones than by the male hormones themselves. In other words, this metabolite has a stronger androgenic effect, and in particular, the metabolite of 5α-reductase of testosterone, the main male hormone, dihydrotestosterone (DHT) is the cause of these skin disorders. The results of various studies have revealed that For example, in male pattern baldness, it was found that testosterone is converted to the highly biologically active DHT by 5α-reductase in the hair roots, and that 5α-reductase is more active in areas of hair loss than in areas where hair grows. . This DHT affects the sugar metabolism of hair root cells through the enzyme-impairing action within the follicle, and thereby inhibits hair growth by suppressing energy supply, or
It is thought to induce alopecia by binding to specific receptors within cells and promoting the production of proteins that inhibit hair growth. In any case, it can be said that the first step in the involvement of male hormones in male pattern baldness is the conversion of testosterone to DHT.

On the other hand, acne vulgaris is a skin disorder that is mainly caused by an imbalance of sex hormones during puberty and is manifested by changes in hair follicles and sebaceous gland excretory ducts caused by increased sebum secretion caused by male hormones. The drug is known to be effective. Therefore, it is presumed that DHT, which has high biological activity, is involved in the expression of acne vulgaris, as in male pattern baldness. Skin disorders and DH mentioned above
The correlation with T indicates that substances that inhibit the production of DHT, i.e.
Testosterone 5α-, a metabolic enzyme of testosterone
This suggests the therapeutic utility of substances that inhibit reductase for these skin disorders.

[0005] The present inventors focused on this point and conducted research to find such enzyme inhibitors in order to develop more effective drugs for hair growth and skin care. The present inventors have discovered that a number of extracts of herbal medicines have an inhibitory effect on 5α-reductase, and have completed the present invention. That is, the present invention provides the testosterone 5
Provided are α-reductase inhibitors. The enzyme inhibitor comprising the herbal medicine extract according to the present invention has an anti-androgenic effect due to the 5α-reductase inhibitory effect,
Moreover, unlike general synthetic anti-androgens, it is highly safe and does not exhibit other undesirable hormonal effects, and as described below, it not only exhibits remarkable hair-nourishing effects and acne vulgaris-healing effects, but also It is also effective in treating benign prostatic hyperplasia and hirsutism.

[0006] In this specification, crude drug extracts are
Unless otherwise specified, it refers to crude drug extracts, diluted solutions, concentrated extracts, or dry powders obtained by the methods described below. Typical herbal medicines that can be used for the above purpose include, as mentioned above, acaenium, fennel, onji, licorice, kengoshi, gobaishi, peony, chazenshi, senso, rhubarb, clove, areca nut,
Rosin, Cuckoo thistle, Gennoshouko, Kagosou,
Saiko, Inchin, Eijitsu, Yokuinin, Soyou, Nigaki, Keigai, Kisasage, Jozan, and Valerian, but other herbal medicines may be added if further research is conducted. The herbal medicine extract in the present invention can be used as a 5α-reductase inhibitor as it is, or after being diluted, concentrated, or lyophilized, adjusted to a powder or paste form, and formulated into an appropriate formulation as desired. The daily dose of the 5α-reductase inhibitor according to the present invention is preferably 10 to 15,000 mg/adult when administered orally in terms of powdered extract. The herbal medicine used in the present invention has been used by the general public for various medical purposes for many years, and toxicity is not a problem at least at the above-mentioned dosage.

[0007] 5α consisting of crude drug extract according to the present invention
-The enzyme inhibitory activity of the reductase inhibitor was measured by the following method. (1) Regulation of 5α-reductase The method of Larminat et al. [Steroids 31
129 (1978)]. Specifically, an SD male rat weighing 200 g was buffed and exsanguinated, excess fat was removed from the prostate gland and testicle, and 5 times the amount of homogenization medium [0.32 M sucrose, 1 mM EDTA, and 3 mM calcium chloride] was added. Containing 50mM Tris-HCl buffer (pH=7.4)]
was added, homogenized, and the filtrate obtained by filtering through gauze was used as a standard.

(2) Preparation of crude drug extract 5α-reductase inhibitor Add 10 times the amount of water, methanol or a mixture thereof to 1 to 10 g of crude drug, and shake and extract for about 1 hour, or
After extraction under heating and reflux for an hour, the mixture was centrifuged at 2500 rpm for 15 minutes. The supernatant liquid was filtered through filter paper, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude drug extract, which was diluted with water or methanol as necessary to prepare an inhibitor.

(3) Measurement of 5α-reductase inhibitory activity Add 0.8 ml of incubation buffer [25 mM phosphate buffer (pH=6.5) containing 0.25 M sucrose and 1.25 M NADPH] [1. 2-3H]
Testosterone 10 μl (1 μci) and cold testosterone (2.52 nmol total testosterone)
0.25 ml of the enzyme solution obtained in step (1) was added, 10 μl of the enzyme inhibitor obtained in step (2) was added, and shaking culture was performed at 32° C. for 1 hour. Next, 2 ml of chloroform/methanol (2/1) mixture was added to stop the reaction, followed by centrifugation (
3000 rpm x 5 minutes) to separate the extract. This extract was subjected to TLC (thin layer chromatography), and fractions corresponding to testosterone, dihydrotestosterone, and androstanediol were cut out and placed in a vial, 10 ml of scintillator (Permaflow V) was added, and radioactivity was detected using a liquid scintillation counter. was measured. The results are expressed as inhibition rate %, where the enzyme activity value is 100 (inhibition rate 0%), which is the conversion rate of testosterone to metabolites when no inhibitor consisting of crude drug extract is added. The results are shown in "Table 1".

0010

[Table 1] Inhibitory activity of 5α-reductase inhibitors composed of various crude drug extracts

Herbal medicine name
Extraction solvent concentration* Inhibition rate (%
) Asenyaku methanol 0.1
100
water 0.1
79 Fennel Methanol
0.1 59 Ondi methanol 0.1
64 Licorice
Methanol 0.1 56
Kengoshi Methanol 0
．． 1 92 Gobaishi
Methanol 0.001 10
0 Peony Methanol
0.001 50 Shazenshi
Methanol 0.1
59 Senso water
0.1 50
Rhubarb Methanol 0.1
70 clove
Methanol 0.1
70 water
0.1 75
Areca nut methanol 0
．． 1 89 Rosin
Methanol 0.1
62 Cuckoo Thistle Methanol
0.1 52 Gennoshoko Methanol 0.1
51 Kagosou Methanol 0.1 49 Saiko Methanol 0.1
46 Soyou
Methanol 0.1 4
7 inch methanol
0.1 43 Agetsu
Methanol 0.1
81 Yokuinin Methanol 0.1 100
Methanol 0.
01 12 Nigaki
Methanol 0.1
46 Keigai water
0.1 56
Cattlepea methanol 0.1
84
Methanol 0.01
54 Jozan Methanol 0.1 100
Methanol 0.0
1 30 Valerian
Methanol 0.1 70
*Concentration of crude drug extract in enzyme reaction solution (dry weight%)

[0011] As is clear from "Table 1", the enzyme inhibitor according to the present invention has a herbal medicine extract in the reaction system of 0.001
~1.0 (wt%) if present, 50% or more of 5α
-It was found to exhibit a reductase inhibitory effect. The present invention will be explained in more detail by giving examples and test examples below.

Example 1 Extraction method (methanol concentrated extract of licorice) 10 g of dried licorice and 100 ml of methanol were mixed into 200 m
After heating under reflux for 1 hour (or extracting by immersion with 100 ml of cold methanol for 3 hours), the extract is concentrated under reduced pressure. Yield 0.7g

Example 2 Extraction method (licorice powder extract) 1 g of dried licorice and 100 ml of water are placed in a 200 ml eggplant-shaped flask, and the procedure is repeated in the same manner as in Example 1, and the resulting extract is freeze-dried. Yield 0.12g

Formulation example 1 (tablet) Ingredients
Mixture
Quantity Herbal medicine extract
50mg
Maltitol (powder mulch: manufactured by Towa Kasei Kogyo Co., Ltd.)
600mg LHPC (LH-20)
(Manufactured by Shin-Etsu Chemical Co., Ltd.)
346mg fragrance

1mg magnesium stearate
3mg

100
0mg After mixing in the above ratio, tablets were manufactured by compressing each tablet to a weight of about 333mg. Each dose is 3 tablets.

Formulation Example 2 (Capsule) Ingredients
Mixing amount
Herbal medicine extract
40mg lactose

356mg Magnesium stearate 4mg


400mg (2 capsules) Mix at the above ratio and fill with a capsule filling machine. Each dose is 2 capsules.

Formulation example 3 (oral liquid) Ingredients
Mixing amount
Herbal medicine extract
300mg white sugar

3000mg citric acid

150mg fragrance
0.
03ml
Whole amount
30ml Dissolve the above ingredients in water to make a total volume of 30ml, and use this as a single dose.

Test Example 1 The hair growth effect of the 5α-reductase inhibitor according to the present invention was investigated on five men exhibiting androgenetic alopecia. Licorice methanol extract was contained in 70% ethanol at a ratio of 1.0 (W/V)% to serve as an inhibitor, and about 10 ml of it was applied to the hair removal area of the head twice a day for 3 months. The reduction in hair loss at the site, the generation of new hair, and the state of growth were regularly observed, and the hair growth effect of the inhibitor was comprehensively evaluated using the following criteria. Very effective... ＋++ Quite effective... ++ Effective... ＋ Effectiveness is doubtful... ± No effect... - The results are shown in "Table 2" below.

[0018]

[Table 2] 5α consisting of methanol extract of licorice
-Hair growth effect of reductase inhibitors on androgenetic alopecia patients

experimenter age
Result

alopecia seborrhea
Side effects A 27
＋＋ ＋
None B 30
± −
None C 36
＋ ＋
None D 42
＋ ＋
None E 3
0 ++ ＋
None As is clear from Table 2, the enzyme inhibitor according to the present invention was found to have an excellent hair growth promoting effect.

Test Example 2 The therapeutic effect of the enzyme inhibitor according to the present invention on acne vulgaris was investigated in five patients with acne vulgaris. Approximately 1 g of an O/W type cream prepared according to Example 7 from an oil phase component containing 1.0% methanol extract of licorice and water was applied to the affected area once a day for 4 weeks. Periodic observations were made, and the therapeutic effects of the extract were comprehensively evaluated using the aforementioned criteria.

[Table 3] 5 containing methanol extract of licorice
Therapeutic effects of α-relactase inhibitors on acne vulgaris patients

Experimenter gender
Age Yui
Fruit
acne
seborrhea side effects
therapeutic effect

A Female 16
++ ＋ None
B Female 19
+ ++ None C Male 21
＋＋ ＋
None D Male
17 + ±
None E Female 18 ±
± None As is clear from Table 3, the enzyme inhibitor of the present invention was found to be useful for acne vulgaris.

Claims (1)

[Claims] Claim 1: Acalyx, fennel, onji, licorice, kengoshi, gobaishi, peony, chazenshi, senso, rhubarb, clove, areca nut, rosin,
Cuckoo thistle, Gennoshoko, Kagosou, Saiko,
A testosterone 5α-reductase inhibitor containing a solvent-extracted extract of a herbal medicine selected from the group consisting of inchin, elegans, yokuinin, soybean, bittern, staghorn, Japanese sage, valerian, and valerian.