JPH013126A - Androgen receptor binding inhibitor - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Application Field) The present invention relates to an androgen receptor binding inhibitor, and particularly to an androgen receptor binding inhibitor containing an extract of a herbal medicine as an active ingredient.

The androgen receptor binding inhibitor according to the present invention is useful for treating androgen-dependent diseases such as hirsutism, spasticity, androgenic baldness,
It can be used for the prevention and treatment of benign prostatic hyperplasia, prostate tumors, precocious male puberty, etc.

(Prior Art) The above-mentioned androgen-dependent diseases are caused by excessive male hormone activity of testosterone. The effect of reducing male hormone activity, that is, the anti-androgenic effect, can be achieved, for example, by inhibiting the activity of the enzyme that reduces testosterone to 5α-didrotestosterone (5α-DHT), or by inhibiting the binding of 5α-old IT to the androgen receptor. brought about by inhibiting the

The extracts of various herbal medicines have the former anti-Anti-I/rogens effect,
That is, it has already been reported that it has the effect of inhibiting the activity of the enzyme that reduces testosterone to 5α-former IT (see Japanese Patent Laid-Open Publication No. 146829/1982). In addition, the present inventors also discovered that the extract of Oriental chinensis shows an inhibitory effect on the activity of reductase, and also reported that the inhibitory substance is oleanolic acid, an oleanane-type triterpene compound (Japanese Patent Laid-Open Publication No. 126218/1983). reference).

(Problems to be Solved by the Invention and Objectives of the Invention) Of the two types of anti-androgen effects mentioned above, the latter anti-androgen effect, that is, the effect of inhibiting the binding between 5α-DHT and androgen receptors, is more effective. Although it is thought to be effective, there have been no comparable reports to date on whether this binding-inhibiting effect exists in crude drug extracts.

Therefore, the purpose of the present invention is to search for herbal medicines that exhibit androgen receptor binding inhibitory action, and to provide an androgen receptor binding inhibitor that is an effective anti-androgen agent by using the extract as an active ingredient. .

(Means and effects for solving the problem and achieving the objective) The present inventors extracted extracts from various herbal medicines and conducted intensive research on their pharmacological effects. The present invention has been completed based on the discovery that the compound has an effect of inhibiting body binding.

That is, according to the present invention, the Japanese assembly, the purple assembly,
Scutellariae, licorice, rhubarb, ginseng, kumazasa, chimpi, betel nut, clove, saiko, yokuinin, nebula, peony, asenyaku, toki, Japanese sardine, Japanese radish, kagosou, bittern, fenugreek, genus ginseng, Japanese poppy, soybean, staghorn, valerian, The above-mentioned problems are solved by an androgen receptor binding inhibitor, which is characterized by containing as an active ingredient an extract of at least one crude drug selected from Kengoshi, Senso, Eizu, and Rosin. The above objectives are achieved.

Extraction can be carried out by immersing dried, shredded or ground whole herbal herbs in an extraction solvent, followed by filtration or centrifugation. Pentane, hexane,
Aliphatic hydrocarbons such as heptane and cyclohexane, halogenated hydrocarbons such as methylene chloride, chloroform, and carbon tetrachloride, alcohols such as methanol and ethanol, acetic acid,
Acid solutions such as formic acid, alkaline solutions such as sodium hydroxide and potassium hydroxide, ethers such as diethyl ether and petroleum ether, esters such as ethyl acetate, ketones such as acetone, or water can be used alone or in combination. can. For extraction, a Soxhlet extractor, etc. can be used, and the extraction conditions, that is, extraction solvent profile, extraction temperature, immersion time, and number of extractions, should be determined by preliminary experiments, taking into account the type of crude drug used as the raw material, the type of extraction solvent, etc. The appropriate one will be set.

Generally, when a 70% (V/V) ethanol aqueous solution is selected as the extraction solvent and the extraction is performed at room temperature, about 5-
It is preferable to perform extraction by immersing in a solvent of about 10 times the volume (V/W) for about one day to one week, and repeat this extraction operation about two times. The obtained extract can be used as an active ingredient of the androgen receptor binding inhibitor according to the present invention after being diluted or concentrated, or freeze-dried, and then made into a powder or paste form. Formulation can be carried out by conventional methods, and is usually made into oral preparations, suppositories, or external preparations, and internal preparations include tablets, capsules, powders, fine granules, granules, oral liquid preparations, etc. It can also be made into external skin preparations such as acupuncture preparations, lotions, and external creams (ointments). Prior to formulation, the extract is concentrated and adsorbed onto a pharmaceutical carrier to form a formulation composition, and excipients can be added to this composition to form a formulation. This helps improve the dispersibility of the extract.

Conventional carriers for pharmaceutical preparations include dextrin,
Starch, lactose, light silicic anhydride, magnesium metasilicate aluminate, etc. can be used.

(Examples, etc.) Next, the present invention will be described in further detail with reference to extraction examples of crude drug extracts, medicinal efficacy test examples of extracted extracts, and formulation examples as manufacturing examples.

11 Wholesale'' (extraction of herbal medicine extract) 960g of crushed dried whole plant of Jasmine japonica, 10g of crushed whole of dried Jasperum japonica, 15g of crushed dried Ogre
g, 15 g of shredded dried licorice, 15 g of shredded dried rhubarb, 7.52 g of shredded dried ginseng,
15g of shredded dried Kumazasa, shredded with dried Chin! T!
J15g and 15g of dried betel nut shreds were immersed in a 10 times volume (V/W) Noah 0% (V/V) ethanol aqueous solution, left at room temperature for 1-6 days and nights, and then filtered to obtain the primary extract. were obtained respectively.

Five times the volume (V/W) of the above solvent was added to each extraction residue and treated in the same manner as above to obtain secondary extracts. - The following extracts were obtained by combining the secondary extract and the secondary extract and drying under reduced pressure.

Jasmine japonica extract 275g Jasmine japonica extract 2.77g Scutellariae extract 547g Licorice extract
2.90g rhubarb extract
5.51g Ginseng extract 3
．． 29g Kumazasa extract 2.11
g Chinpi extract 6.24g Areca nut extract 1.23g Snore test example (androgen receptor binding inhibition production) This test was performed using the method of Takayasu et al. (r J, St.
eroidBiochem, J Vol. 19 No. 1141-
1146, 1983).

a) Preparation of androgen receptor solution Male Syrian hamsters were castrated and fla
The sebaceous glands of the NK gland were removed and treated with 50mM) Lis-HCl buffer (pl(7,4), 1.5mM EDT^,
1mM DTT, ]OmM Na2MoO4 and 10%
(W/V) After homosynating the above sebaceous glands with a 5-100 times volume solution containing glycerol, 3000 r
pm, centrifuge for 10 minutes at 0-4°C and collect 1 supernatant.
, 7 This supernatant was further centrifuged at 30,000.4I rpm and 0-4°C for 1 hour to collect the supernatant.

The supernatant obtained this second time is used as the androgen receptor solution.

b) Measurement of androgen receptor binding inhibitory activity InM [
3H]-RI881 (methyl 1 helienolone, 86.
A mixed solution (total 1150 μm) of 0C4/mmol), I μM triamcinolone ace I nide, the receptor solution according to item a) above, and various concentrations of specimen samples (each extract obtained according to Reference Example 1) was prepared. After incubation for 16 hours at 0°C, activated charcoal in an amount of 0.5% and 0.05%
500 μm of solution containing % amount of Dextran T-70
was added and left at 0°C for 10 minutes, then heated at 3000r
Centrifuge for 10 minutes at 100 pm to obtain a supernatant. This supernatant 30
After collecting 0 μm and mixing with liquid scintillation cocktail, [3H
]-The specific binding amount of RI881 is measured, and the obtained data is introduced into the following formula to determine the inhibitory activity as the inhibition rate.

Inhibition rate (%) ・[(c −s)/cl x 100C
: Receptor protein and [3H]- when no specimen sample is added
Amount of specific binding to R1881 S: Amount of specific binding between the receptor protein and [''H]-R1881 when the specimen sample was added C) Results The results were as shown in the table below.

Preparation agent (liniment agent) Prescription: Oriental chinensis extract (Reference example 1) 300ml) To Heragan I 50g glycerin 30ml ethanol
100ml purified water
-Remainder 1- Total amount 10100O Collect ethanol in a mortar, add tragacanth and stir thoroughly, add Jasperia japonica extract and glycerin and stir, then add 500ml of purified water and stir thoroughly. A liniment agent was produced by making the paste into a paste, and adding purified water to the paste while stirring to make the total amount 10,100O.

Manufactured U (lotion) Prescription: Oriental japonica extract (Reference example 1) 45ml 1 hydroxypropylcellulose 1g macrogol 40
0 10ml purified water
- 11-2-Jushu'' total volume 1 Oml Thoroughly mix the Aspergillus japonica extract and Macrogol 400, add and mix hydroxypropyl cellulose and purified water to this mixture, and process with a vacuum homogenizer to form a lotion. was manufactured.

11 Salmon Yu (manufacture of pharmaceutical composition) Concentrate the Oriental chinensis extract obtained in the process of Reference Example 1 to a volume of 1725, add 10 times the volume (W/W) of dextrin to this concentrate, and mix to homogenize. A composition was prepared.

1 Anal Takumi' (external cream or ointment) formulation: Pharmaceutical composition (Reference example 2> 30g diethyl sebacate 8g whale *
5g Polyoxyethylene oil ether sodium phosphate 6g Sodium benzoate 0.5g Vaseline
--- 21ils - total amount 100g The various ingredients were blended according to the above formulation and a cream or ointment for external use was produced by a conventional method.

Suppositories (suppositories) Prescription: Composition for formulation (Reference example 2) 60mg oily base (cacao butter>1640ml) 1
The pharmaceutical composition was added to a melt of 700 mg of cacao butter (higher fatty acid glyceride), stirred and dispersed, and then molded by a conventional method to produce a suppository.

Product description 1 (powder) Prescription: Pharmaceutical composition (Reference example 2> 30mg lactose
800mg cornstarch 1000mg per 170ml package Various ingredients were blended according to the above recipe and a powder was produced by a conventional method.

"Ichimata So" (granules) Prescription: Pharmaceutical composition (Reference example 2) 30 mg lactose
754mg cornstarch 200mg hydroxypropylcellulose 1000mg per 16ml package Mix the formulation composition, lactose, and cornstarch,
An aqueous solution of hydroxypropyl cellulose was added to this mixture and kneaded, and granules were produced by a conventional method using a cylindrical extrusion granulator.

Formulation Example 7 (tablets, coated tablets, and sugar-coated tablets) formulation; Formulation composition (Reference example 2) 30B crystalline cellulose 40 mg lactose
52, 5mg cornstarch
30 mg Magnesium stearate 160 mg per 7.5 ml tablet Various ingredients were blended according to the above recipe and tablets were manufactured by a conventional method. A water-soluble coating of the following formulation was applied to these tablets in a conventional manner to produce coated tablets, and further sub-coating and coloring of the following formulation were applied in a conventional manner to produce sugar-coated tablets.

Water-soluble coating formulation/Hydroxypropyl cellulose 40g Macrogol 6000 ]Og titanium oxide
3g talc
5g purified water 9
42g sub-coating formula: white sugar 40g gelatin 0.5g gum arabic
1.4g precipitated calcium carbonate 22g talc
156g purified water
20g Color Link formula: white sugar 10g titanium oxide 73g lake pigment
56g purified water
5g Established (Hard Capsule) Prescription: Pharmaceutical Composition (Reference Example 2> 30mg Lactose
]004mg cornstarch 40mg hydroxypropylcellulose 16■-1 Mix the composition for capsule formulation, lactose, and cornstarch,
An aqueous solution of hydroxypropylcellulose was added to this mixture and kneaded, and the mixture was made into granules by a conventional method using a cylindrical extrusion granulator. The granules were filled into hard gelatin capsules to produce hard capsules.

(Effects of the Invention) The androgen receptor binding inhibitor according to the present invention can be used for the prevention and treatment of androgen-dependent diseases, such as hirsutism, dysentery, male pattern baldness, benign prostatic hyperplasia, prostate tumors, and precocious male puberty. I'll come.

The active ingredient of the androkene receptor-binding group inhibitor according to the present invention can be obtained from various herbal medicines including Aspergillus japonica, and therefore, the present invention is advantageous in terms of availability of raw materials and cost.

One. 1:1

Claims (1)

[Claims] (1) Japanese japonica, purple japonica, scutellariae, licorice, rhubarb, ginseng, kumazasa, chimpi,
At least one kind selected from areca nut, clove, saiko, yokuinin, senkyu, peony, asenyaku, trumpet, onji, shazenshi, kagosou, bittern, fennel, gennoshoko, kasapage, soyou, kaigai, valerian, kengoshi, senso, eijitsu, and rosin. An androgen receptor binding inhibitor characterized by containing an extract of a crude drug as an active ingredient.