JP2001187742A - Testosteron-5-alfa-reductase inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new testosteron-5α-reductase inhibitor, which is useful for prophylaxis and/or therapy of depilation, acne (acne vulgaris), benign prostatic hypertrophy, prostatic cancer and the like. SOLUTION: This testosteron-5α-reductase inhibitor additionally includes herbal medicines, Ecrlipta prostrata L, Saussurea laniceps Hand.-Mazz, Morinda officinalis, Gastrodia elata BL, Cryptomeria D.DON, Cynanchum bungei DECNE, Solanum melongenea L., Notopterygiuim incisum TING and N. forbesii BOISS, Bletilla striata REICHB, Polygonum multifloraum THUNB and Eriobotrya japonica LINDL or their extracts.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

This invention relates to testosterone-5α.
The present invention relates to a testosterone-5α-reductase inhibitor useful for the prevention and treatment of alopecia, acne, benign prostatic hyperplasia, prostate cancer and the like.

[0002]

2. Description of the Related Art Testosterone, a type of male hormone, is reduced by testosterone-5α-reductase, a reductase, to dihydrotestosterone.
It is known that the generated dihydrotestosterone causes atrophy of hair roots and causes hair loss when the accumulation progresses. Therefore, if it can suppress or inhibit the production of dihydrotestosterone, prevent hair loss,
It is thought that it can be treated.

[0003] When the production of dihydrotestosterone increases, sebum secretion ability increases and acne (acne vulgaris) develops. Therefore, if the production of dihydrotestosterone can be suppressed or inhibited, acne can be prevented and prevented. It is thought that treatment can be done.

It is also known that when the production of dihydrotestosterone increases, prostatic hyperplasia and prostate cancer develop. If the production of dihydrotestosterone can be suppressed or inhibited, prostatic hypertrophy and prostate cancer can be prevented. And can be treated. Based on these ideas, the present inventors have proposed various testosterone-5.
We are working on the development of α-reductase inhibitors.

[0005]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a novel testosterone-5α-reductase inhibitor. It is still another object of the present invention to provide a pharmaceutical or cosmetic which has a testosterone-5α-reductase inhibitory activity and can be used as an agent for preventing and / or treating hair loss, acne, prostatic hypertrophy, prostate cancer and the like.

[0006]

Means for Solving the Problems In order to solve the above problems, the present inventors have conducted intensive studies and as a result, have found that a specific plant and a crude drug or an extract thereof have an inhibitory effect on testosterone-5α-reductase. We have found and completed the present invention.

[0007] That is, the present invention relates to a dry lotus plant (Esteraceae Ecli).
pta prostrata L. dried whole plant above ground, snow lotus flower (flower of Ranunculaceae Saussurea laniceps HAND.-MAZZ.), Tomoe Tenten (dried root of Morinda officinalis HOW, dried rape) (Orchidaceae Gastrodia elata BL
Above-ground part of UME, Kashiwa (Cryptomeria D.DON leaves of the genus Cedar), Shiraganju crow (Cynanchum bungei DECNE), Eggplant root (Root of Solanum melongena L., Solanaceae)
topterygium incisum TING and N. forbesii BOISS,
Oviforme CHANG rhizomes dried, N. forbesii BOISS. Var. Oviforme CHANG, white cucumber (Orchidaceae Bletilla striata REICH)
B.fil. Corm prepared and dried), Yokoto (Polygonaceae Po
lygonum multiflorum THUNB aerial part), loquat leaf (dried leaves of Rosaceae Eriobotrya japonica LINDL) and testosterone containing extracts of these crude drugs
It is intended to provide a cosmetic or pharmaceutical containing a 5α-reductase inhibitor and an extract of these plants and crude drugs and exhibiting testosterone-5α-reductase inhibitory activity.

[0008] The present invention also relates to a herbal medicine of dry lotus grass, snow lotus flower, Tomoe Tian, Fiji grass, Kashiwa, Shiraganshu, eggplant, Qiang, white cucumber, Yokoto, loquat, and extraction of these crude drugs. It is also used as an external preparation for skin containing substances.

[0009] The crude drugs used in the present invention are dried lotus grass, snow lotus flower, Tomoe heaven, physaceae, Kashiwa, Shirakanshu, Eggplant, Qiang activity, white cucumber, night squirrel, loquat leaf, which constitute this plant. The entire site or a part of leaves, stems, roots, rhizomes, flowers, and the like can be used as they are, or they can be dried and then pulverized to be used in powder form.

In the present invention, extracts of these crude drugs are preferably used. As a method for obtaining an extract, for example, a generally known method for obtaining an extract by extracting leaves, roots, rhizomes, stems, flowers, and the like of these crude drugs using water and / or a hydrophilic organic solvent may be used. it can. Further, a powder can be obtained from the extract by a generally known solvent removal method such as freeze drying, spray drying, and distillation under reduced pressure. Examples of the hydrophilic organic solvent include lower alcohols having 1 to 4 carbon atoms such as methanol, ethanol, propanol and butanol, and 3 to 4 carbon atoms such as acetone and methyl ethyl ketone.
Examples thereof include ethers having 2 to 4 carbon atoms, such as ketone 4, ethyl ether, and methyl ethyl ether. Particularly, ethanol is preferable. These solvents may be used alone or in combination of two or more. Further, water and these hydrophilic organic solvents may be mixed and used. A preferable extraction solvent as a mixed solvent used by mixing with water is a hydrated alcohol, particularly preferably a hydrated ethanol. The use amount of these extraction solvents is not particularly limited. As a specific method of extraction, for example, a cold immersion method, a hot immersion method, a percolation method, and the like used in producing an extract, a tincture, and the like can be applied. The obtained extract can be used as it is or after further concentration, dilution, or purification. In addition, these extracts and powders,
Purification using column chromatography or the like can be used as a single component.

According to the findings of the present inventors, the testosterone-5α-reductase inhibitory activity of the testosterone-5α-reductase inhibitor according to the present invention expresses the above crude drug and its extract as an active ingredient. . The crude drug or its extract can be used as it is as a testosterone-5α-reductase inhibitor, and is further mixed with components used in ordinary cosmetics, quasi-drugs, pharmaceuticals, etc. to prevent hair loss, acne, etc. In such a case, parenteral administration is preferred. In addition, the crude drug or its extract, hair loss or acne prevention, in the whole composition of the therapeutic agent,
It is preferable to add 0.0001 to 20% by weight, particularly 0.01 to 10% by weight in terms of the dry solid content of the plant (in the case of an extract, the dry solid content of the plant used for the extraction).

The thus-obtained agent for preventing or treating hair loss or acne according to the present invention can be used, for example, by oral administration, topical administration, etc., but is formulated into an external preparation for skin and applied to the skin. This is convenient and preferred. Here, examples of the external preparation for skin include external preparations such as ointments and lotions, cosmetics such as creams, lotions, emulsions, foundations, oily cosmetics, packs, and skin cleansers.

These skin external preparations have a total composition of the crude drug or an extract thereof, which is converted into a dry solid content of the crude drug (in the case of an extract, a dry solid content of the plant used for the extraction in the case of an extract).
It is preferable to add 0001 to 20% by weight, particularly 0.01 to 10% by weight, and it can be produced according to a usual method. In that case, in addition to the crude drug or its extract, components used in ordinary skin external preparations, such as oils,
Surfactants, humectants, medicinal ingredients, alcohols, preservatives, thickeners, pigments, fragrances, and the like can be appropriately combined and compounded within a range that does not impair the effects of the present invention.

[0014]

EFFECT OF THE INVENTION The crude drug and its extract according to the present invention show an excellent testosterone-5α-reductase inhibitory action. The testosterone-5α-reductase inhibitor containing this crude drug or extract can be used to inhibit seborrheic alopecia. It can prevent and treat diseases, acne, benign prostatic hyperplasia, and prostate cancer.

[0015]

Next, the present invention will be further described with reference to examples, but the present invention is not limited to these examples. Extraction method The test liquids in Table 1 were extracted at room temperature three times for 1 day with 10 times the amount of ether after pulverizing the crude drug. The extract was filtered, the filtrate was concentrated under reduced pressure, and freeze-dried to obtain a dry ether extract. The test solutions in Table 2 were extracted three times a day at room temperature three times with 10 times the amount of ether after pulverizing the crude drug.
The extract was filtered, the filtrate was concentrated under reduced pressure, and freeze-dried to obtain a dry ether extract. 5 more residue
The mixture was extracted with 0% ethanol three times at room temperature for one day. The extract was filtered, the filtrate was concentrated under reduced pressure, and freeze-dried to obtain a dry 50% ethanol extract.

Example 1 (Testosterone-5α-reductase inhibitory action) The testosterone-5α-reductase inhibitory action of an extract obtained by extracting from a crude drug was examined. 1. Preparation of Enzyme Solution (S-9) Livers of 5-week-old Slc: SD male rats fasted for 24 hours were perfused with ice-cold Krebs-Ringer solution. 5 times the volume of ice-cooled Tris-HCl buffer (10 mM,
pH 7.2), homogenize, and add 900 g
Centrifuged for 0 minutes. The supernatant was centrifuged at 5000 × g for 10 minutes, and the supernatant was used as an enzyme solution (S-9).
It was stored frozen at 80 ° C. 2. Testosterone-5α-reductase inhibitory action Tris-HCl buffer (10 mM, pH 7.2) 1.0 m
1, 0.3 ml of testosterone (500 μg / ml)
0.2 ml of the test solution and 1.0 of the enzyme solution described in Tables 1 and 2.
of the mixture, and β-nicotinamide adenine dinucleotide phosphate 4-sodium salt (hereinafter referred to as NADPH) (0.77 mg / ml) as a reaction accelerator.
5 ml was added and kept at 37 ° C. for 30 minutes. The reaction was stopped by adding 5 ml of dichloromethane, 0.5 ml of an internal standard substance (n-hexyl p-hydroxybenzoate having a concentration of 0.1 mg / ml) was added, and the mixture was shaken for 10 minutes.
Centrifuged at 3000 rpm for 10 minutes. After removing the supernatant, dichloromethane was distilled off from the remaining dichloromethane layer by topping, and 5 ml of methanol was added thereto, followed by high performance liquid chromatography (hereinafter referred to as HPLC).
Sample. The amount of testosterone was measured by HPLC. The measurement conditions were such that the column used was YMC-PACK.
ODS-AM, and the solvent of the moving bed was methanol / water =
65/35 mixed solvent, the flow rate is 1 ml / min,
The light absorbed was UV 254 nanometers and the column temperature was 40 ° C. The measurement was performed using the internal standard method, and the inhibition rate (%) was determined from the following equation. Inhibition ratio (%) = (amount of testosterone when test solution is added−amount of testosterone for 30 minutes of control) / (amount of testosterone for 0 minutes of control−amount of testosterone for 30 minutes of control) × 100 ・ Amount of testosterone for 0 minute of control: After mixing the Tris-HCl buffer, testosterone, test solution and enzyme solution, before adding NADPH, dichloromethane was added to prevent the reaction from occurring. The amount of testosterone in the control: 30 minutes testosterone amount: Instead, the amount of testosterone when a reaction was performed using a 50% ethanol solution

The experimental results are shown in Tables 1 and 2.

[Table 1] Testosterone-5α of ether extract of various crude drugs
-Reductase inhibitory activity * The conversion amount was determined by measuring the absorption of the UV spectrum and expressed as an internal standard of 1. * The numerical values were represented by the average of the absorption values and the standard deviation of P <0.01.

[Table 2] Testosterone of 50% ethanol extracted extract of various crude drugs (residue after ether extraction is extracted with 50% ethanol)
5α-Reductase inhibitory activity * The conversion amount was measured by measuring the absorption of the UV spectrum, and the internal standard was expressed as 1. * The numerical values were represented by the average of the absorption values and the standard deviation of P <0.01. As is clear from Tables 1 and 2, the extract obtained from the above crude drug showed an inhibitory effect on testosterone-5α-reductase.

Example 2 (Emollient cream) An emollient cream having the following composition was produced by a conventional method. The resulting cream is testosterone-5α-
It was excellent in reductase inhibitory action, and a 21-year-old woman was able to improve acne and the like by using it daily for 2 weeks.

[0019]

[Table 3]

Example 3 (Emollient lotion) An emollient lotion having the following composition was produced by a conventional method. The resulting lotion is testosterone-5
It was excellent in α-reductase inhibitory action, and was used by a 21-year-old woman every day for 2 weeks to improve acne and the like.

[0021]

[Table 4]

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (reference) A61P 17/10 A61P 17/10 17/14 17/14 35/00 35/00 F term (reference) 4C083 AA111 AA112 AC012 AC022 AC072 AC092 AC122 AC182 AC242 AC402 AC422 AC542 AD512 CC01 CC04 CC05 DD23 DD31 EE14 EE22 EE50 4C088 AB03 AB12 AB14 AB26 AB32 AB41 AB43 AB48 AB51 AB89 AB99 AC01 AC02 AC03 AC05 AC11 AC13 BA09 BA10 CA05 CA81 ZA89 ZA26Z

Claims (3)

[Claims] Claims 1. A plant selected from the group consisting of dry lotus grass, snow lotus flower, Tomoe heaven, physaceae, Kashiwano, Shirakanshu crow, eggplant, Qiang activity, white cucumber, night squirrel, and loquat leaf. A testosterone-5α-reductase inhibitor, comprising an extract. 2. A plant selected from the group consisting of dry lotus grass, snow lotus flower, Tomoe Tian, Fiji grass, Kashiwano, Shiraganshu crow, eggplant, Qiang activity, white cucumber, Yokoto, and loquat A testosterone-5α-reductase inhibitory cosmetic, comprising an extract. 3. A plant selected from the group consisting of dry lotus grass, snow lotus flower, Tomoe Tian, Fiji grass, Kashiwano, Shirakanubikara, Eggplant, Qiang activity, White cucumber, Yokoto, and Loquat A testosterone-5α-reductase inhibitory medicament comprising an extract.