JP2001163718A - Sebum secretion inhibitor and preparation for external use for skin - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a sebum secretion inhibitor which shows remarkable effect more than conventional articles using plant extracts and is stable. SOLUTION: This sebum secretion inhibitor is obtained by including lycochalcone A which is first confirmed to have androgen receptor binding inhibitory effect and testosterone-5-α-reductase inhibitory effect.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a sebum secretion inhibitor which is an external preparation for suppressing excessive sebum secretion from the epidermis, and a skin external preparation containing the same.

[0002] The present invention also relates to androgen receptor binding inhibitors and testosterone 5α-reductase inhibitors.

[0003]

2. Description of the Related Art A very small amount of fat is constantly secreted from the surface of the skin. When secretion of this fat, called sebum, becomes excessively active, seborrhea, acne, comedone, papules, pustules and other diseases are caused. Cause.

[0004] Hypersecretion of sebum often occurs when male hormones, collectively called androgens, act excessively. In that case, the secretion of sebum can be optimized by suppressing the action of androgen.

[0005] Testosterone, a typical androgen, does not act in the molecular form secreted from its producing organ, but enters the cells of the target organ and enters 5α-dihydrotestosterone (5α-reductase) by testosterone 5α-reductase. It has been confirmed that after being reduced to DHT), it binds to a receptor and exerts an action as an androgen. Therefore, as a means for preventing damage due to excessive activity of testosterone, 5%
There are a method of inhibiting the action of testosterone 5α-reductase, which reduces to α-DHT, and a method of inhibiting the binding of 5α-DHT generated from testosterone to a receptor so that no androgen action is not exhibited.

For these methods, the effectiveness of some crude drug extracts has been confirmed. For example, JP
Testosterone 5α-reductase inhibitors described in JP-146829A include Asenyaku, Fennel, Licorice, Kengoshi, Gobishi, Peony, Shazenshi, Senso, Rhubarb, Clover, Betel nut, Rosin, Cuckoo Thistle, Gennoshoko, Kagosou, Psycho, Extracts such as intin, age, yokuinin, soybean, nigaki, oyster, catalpa, jasper, and valerian are used as active ingredients.

[0007] Substances that are effective for inhibiting the binding of 5α-DHT to the androgen receptor include, but are not limited to, assembly, purple radish, gibbon, liquorice, rhubarb, chixin ginseng, kumazasa, chimpanzee, areca, clove, psycho, yoquinin. Extracts such as senkyu, peonies, pomegranate, squid, toki, onji, chinensis, kagosou, nigaki, fennel, gennoshoko, catalpa, soybean, keikai, kanokoso, kengoshi, senso, agetsu, rosin and the like are known (Japanese Unexamined Patent Publication No. 64-64). 3
No. 126).

[0008]

SUMMARY OF THE INVENTION An object of the present invention is to find a substance having both a testosterone 5α-reductase inhibitory action and an androgen receptor binding inhibitory action, and a conventional sebum secretion using a plant extract whose quality is not stable. An object of the present invention is to provide a sebum secretion inhibitor that is more effective and more stable than an inhibitor.

Another object of the present invention is to provide a novel skin external preparation excellent in the action of suppressing sebum secretion.

Yet another object of the present invention is to provide a testosterone 5α-reductase inhibitor and an androgen receptor binding inhibitor which are more effective and more stable than those comprising conventional plant extracts. is there.

[0011]

The above objects have been attained by the following inventions.

A sebum secretion inhibitor comprising lycochalcone A as an active ingredient.

[0013] An external preparation for skin obtained by adding lycochalcone A to provide a sebum secretion inhibitory action.

An androgen receptor binding inhibitor comprising lycochalcone A as an active ingredient.

[0015] A testosterone-5α-reductase inhibitor comprising lycochalcone A as an active ingredient.

Each of the above-mentioned inventions utilizes an androgen receptor binding inhibitory effect and a testosterone-5α-reductase inhibitory effect, which were first confirmed for lycochalcone A.

Lycochalcone A is a kind of oil-soluble licorice flavonoid having the structure shown in Chemical formula 1.

[0018]

Embedded image

Lycochalcone A has a conventional antibacterial effect (JP-A-62-181202), a platelet aggregation inhibiting effect (JP-A-4-297418), and an antitumor effect (JP-A-6-218418).
-122623) and the like, but no androgen receptor binding inhibitory action or testosterone-5α-reductase inhibitory action was known.

[0020]

BEST MODE FOR CARRYING OUT THE INVENTION Lycochalcone A comprises ethanol,
It is a yellow crystal that is soluble in ethyl acetate, methylene chloride, chloroform, etc. and insoluble in water. Although synthesis is possible, licorice (Glycyrrhiza inflat)
a, Glycyrrhiza echinata), which may be extracted and purified using the above organic solvent.

Lycochalcone A is used as a sebum secretion inhibitor, an androgen receptor binding inhibitor or testosterone-5α.
-When formulated as a reductase inhibitor, it is formulated into an arbitrary dosage form using an appropriate solvent, excipient, and other optional auxiliaries as necessary.

When lycochalcone A is added to produce an external preparation for skin, lycochalcone A is used as a powder or in the form of a solution, and is added and mixed at an optional stage in the process for producing an external preparation for skin.

Examples of the external preparation for skin suitable for imparting the sebum secretion inhibiting effect by adding lycochalcone A include hair cosmetics such as hair tonic, shampoo and rinse; and cosmetics such as lotion, cream, emulsion and pack Materials: There are other ointments and bath preparations.

The external preparation for skin according to the present invention is Ricochalcon A
In addition to the main agent, any physiologically active substances and auxiliaries,
For example, the base is a general skin external preparation containing an astringent, a bactericidal / antibacterial agent, a whitening agent, an ultraviolet absorber, a humectant, a cell activator, an anti-inflammatory / antiallergic agent, an antioxidant / active oxygen scavenger, etc. It does not matter if it does. In that case,
Synergism with other active ingredients used in combination may lead to better effects than normally expected.

[0025] Ricochalcon A is used in the external preparation for skin according to the present invention.
The following are specific examples of those which can be expected to have good results by being contained together.

Astringents: citric acid, tartaric acid, lactic acid or salts of these organic acids; aluminum chloride, aluminum / potassium aluminum sulfate, allantochlorohydroxyaluminum, allantoindihydroxyaluminum, zinc paraphenolsulfonate, zinc sulfate, waremokou extract, age extract Hamamelis extract, genoshoex extract, chacatechins, mugwort extract, lycopodium extract, hypericum extract, rhubarb extract, cornflower extract, horsetail extract, kizuta extract, cucumber extract, malonier extract, salvia extract, melissa extract.

Bactericidal and antibacterial agents: benzoic acid, sodium benzoate, p-hydroxybenzoate, distearylmethylammonium chloride, benzethonium chloride, alkyldiaminoethylglycine chloride, acrylhexidine hydrochloride, orthophenylphenol, photosensitive dye No. 101, photosensitive dye 201 No., salicylate sodium salicylate, sorbic acid, halocarban, resorcinol, parachloroenol,
Phenoxyethanol, bisabolol, hinokitiol, menthol, chitosan, chitosan hydrolyzate, waremokou extract, kudin extract, enmeiso extract, loquat extract, awaulushi extract, hop extract, yucca extract, aloe extract, cahig extract, gajutsu extract and the like.

Whitening agents: ascorbic acid and its derivatives, sulfur, placenta extract, kojic acid and its derivatives,
Glucosamine and its derivatives, azelain and its derivatives, arbutin and its derivatives, hydroxycinnamic acid and its derivatives, glutathione, arnica extract, ougon extract, senkyu extract, soybean extract, psycho extract, boufu extract, Hamabofu extract, mannentake mycelium culture Or an extract thereof, Gymnema extract, linden extract, peach leaf extract, rhubarb extract, red bean extract, hamamelis extract, horse chestnut extract, hypericum perforatum extract, hydrangea extract, etc.

UV absorber: β-isopropylfuranone derivative, urocanic acid, ethyl urocanate, oxybenzone, oxybenzonesulfonic acid, tetrahydroxybenzophenone, dihydroxydimethoxybenzophenone, dihydroxybenzophenone, sinoxate, methyl diisopropylcinnamate, octyl methoxycinnamate , Para-aminobenzoic acid and its esters, butylmethoxydibenzoylmethane, titanium oxide, β-carotene, γ-oryzanol, rice bran extract, aloe extract,
Birch extract, birch extract, chamomile extract, kogomegusa extract, hawthorn extract, henna extract, kyogurumi extract, horse chestnut extract,
Ginkgo biloba extract, chamomile extract, etc.

Moisturizers: serine, glycine, threonine,
Alanine, collagen, hydrolyzed collagen, hydronectin, fibronectin, keratin, elastin, royal jelly, chondroitin heparin, glycerophospholipid, glyceroglycolipid, sphingolipid, sphingolin glycolipid, linoleic acid or its esters, eicosapentaenoic acid or its Esters, pectin, algae colloid, fermented product of bifidobacteria, fermented product of lactic acid bacteria, yeast extract, litchi mycelium culture or extract thereof, wheat germ oil, avocado oil, rice haiga oil, jojoba oil, soybean phospholipid, γ- Oryzanol, below-flower oil extract, yellow oak nexus, jiou extract, syrup extract, diatom extract, kidachi aloe extract, burdock extract, horse chestnut extract, mannen wax extract, arnia extract, wheat bran, Menukaekisu like.

Cell activator: riboflavin or its derivative, pyridoxine or its derivative, nicotinic acid or its derivative, pantothenic acid or its derivative, α-tocopherol or its derivative, arnica extract, carrot extract, panax ginseng extract, eleuthero extract,
Loofah extract, safflower extract, Ashitaba extract, loquat leaf extract, Hikikoshi extract, Sakinoshita extract, Huangmui extract, Salvia extract, Garlic extract, Mannenrou extract and the like.

Anti-inflammatory and anti-allergic agents: azulene, allantoin, aminocaproic acid, indomethacin, lysozyme chloride, epsilon aminocaproic acid, oxybenzone, glycyrrhizic acid or its derivatives, glycyrrhetinic acid or its derivatives, photosensitive dyes 301 and 401
No., diphenhydramine hydrochloride, tranexamic acid or a derivative thereof, adenosine phosphate, estradiol, ethrone, ethinylestradiol, cortisone, hydrocortisone, prednisolone, progesterone, corticosterone, arnica extract, intinko extract, sanshin extract, juyaku extract, horse chestnut Extract, licorice extract, touki extract, mugwort extract,
Waremokou extract, Gentian extract, Psycho extract, Senkyu extract, Bohu extract, Yarrow extract, Perilla extract, etc.

Antioxidant / active oxygen scavengers: dibutylhydroxytoluene, butylhydroxyanisole, propyl gallate, baicalin, baicalein, superoxide dismutase, catalase, rosemary extract, melissa extract, ougon extract, age extract, loquat leaf extract, Hop extract, Hamamelis extract,
Peony extract, sage extract, kina extract, chamomile extract, eucalyptus extract, perilla extract, ginkgo leaf extract, thyme extract, cardamom extract, caraway extract, nutmeg extract, mace extract, laurel extract, clove extract, turmeric extract, willow extract, etc.

The androgen receptor binding inhibitor and testosterone 5α-reductase inhibitor according to the present invention can be used for inhibiting sebum secretion and other diseases based on excessive androgen activity such as male pattern baldness, hirsutism, acne. It can be widely used for prostatic hypertrophy and the like.

[0035]

The present invention will be described below with reference to examples. In each of Examples 4 to 6, “parts” means parts by weight.

Example 1 The androgen receptor binding inhibitory effect of lycochalcone A was tested by the following test method. Test method: androgen-dependent mouse breast cancer cell SC-3
Cells were cultured for 1.0% in MEM-2 medium containing 2% FBS.
Seed in a 96-well microplate at a cell density of × 10 ⁴ cells / well / 100 μl, 37 ° C., 5% CO 2
Cultured under ₂ -95% air. After 24 hours, HMB supplemented with lycochalcone A and 10 ⁻⁹ mol of DHT
The medium is replaced with a medium (Ham F12 + MEM medium containing 0.5% BSA) and cultured for 48 hours. Thereafter, the medium is replaced with a MEM-2 medium containing 0.97 mM MTT, and after culturing for 2 hours, the medium is replaced with isopropanol to extract blue formazan produced in the cells. With respect to isopropanol containing the eluted blue formazan, the absorbance at 570 nm where the absorption maximum point of blue formazan is measured. In addition, in order to correct the influence of the adherent cells, the absorbance at 650 nm was also measured at the same time, and the difference between the two absorbances was used as a value proportional to the amount of blue formazan produced. Is). In parallel with the above, in order to see the effect of lycochalcone A alone on SC-3 cells, adding lycochalcone A alone without adding DHT to the HMB medium,
Perform the same culture and measurement. Furthermore, as a control, when the cells were cultured in an HMB medium to which lycochalcone A and DHT were not added,
The same measurement is performed when the cells are cultured in the HMB medium containing only HT. From the measurement results, the binding inhibition rate showing an anti-androgen action is calculated by the following equation.

Binding inhibition rate (%) = [｛(AB)-(C
-D)｝ / (AB)] × 100 where A: Absorbance without DHT and without lycochalcone A B: Absorbance without DHT and without lycochalcone A C: DHT and lycochalcone A D: Absorbance when DHT is not added and lycochalcone A is added

The above-mentioned inhibition rate is measured by changing the concentration of the lycochalcone A solution stepwise, and the concentration of the lycochalcone A solution which inhibits the binding of androgen by 50% is determined by interpolation.

Ricochalcon A confirmed by the above test
Androgen receptor binding 50% inhibitory concentration of 3.5p
pm.

Example 2 Testosterone 5 of Ricochalcon A was prepared according to the following test method.
The α-reductase inhibitory effect was tested. Test method: 4.2 mg of testosterone (Tokyo Kasei) was dissolved in 1 ml of propylene glycol, and 20 μl of the solution was dissolved in N.
ADPH (manufactured by Oriental Yeast) at a concentration of 1 mg / m
1 mM 5 mM Tris-HCl buffer (pH
7.2) Add 825 μl and mix. Furthermore, 80 μl of an ethanol solution of lycochalcone A and 75 μl of S-9 (rat liver homogenate; manufactured by Oriental Yeast) are mixed and incubated at 37 ° C. for 30 minutes. Thereafter, 1 ml of methylene chloride is added to stop the reaction, the methylene chloride layer is separated, and dihydroxytestosterone, androstanediol and the like as reaction products are quantified by gas chromatography. Separately, as a control, the same treatment and analysis were performed in the case where the same amount of the solvent was added instead of the lycochalcone A solution. Lycochalcone A relative to the amount of reaction product when no lycochalcone A was added
The ratio of the amount of reaction product at the time of addition was determined, and testosterone 5
α-Reductase inhibition rate. In the above method, the testosterone 5α-reductase inhibition rate at each concentration was determined by variously changing the lycochalcone A concentration in the reaction solution,
From the results, the concentration of lycochalcone A that inhibits the enzyme activity by 50% is determined by interpolation.

Ricochalcon A confirmed by the above test
The testosterone 5α-reductase 50% inhibitory concentration was 55.0 ppm. In the above test, the protein denaturation rate when the concentration of lycochalcone A was 50 ppm was 0.5%, and it was confirmed that the inhibition of testosterone 5α-reductase by lycochalcone A was not due to denaturation of the enzyme. Was.

Example 3 Absorbent cotton impregnated with a 0.01% ethanol solution of lycochalcone A was fixed on the left side of the forehead of 10 healthy subjects with a bandage, and absorbent cotton impregnated only with ethanol was fixed on the right side. Fix it. After a lapse of 8 hours, each absorbent cotton is removed, and the sebum absorbed in the absorbent cotton by extracting with ethanol is collected.
The squalene therein is quantified by gas chromatography. From the difference between the amounts of squalene quantified for the left and right absorbent cotton, the rate of inhibition of sebum secretion by lycochalcone A is calculated.

The results of the above test were as follows. Recovered sebum amount (mg / 4cm ² ) Lycochalcone A applied part 0.121 ± 0.070 Control part 0.171 ± 0.065 Sebum secretion inhibition rate (%) 29.2

Example 4 (Production example of hair tonic) 0.01 parts of resorcin was added to purified water at 60 ° C. and dissolved. Separately, lycochalcone A0.
2 parts, pyridoxine hydrochloride 0.1 part, D-pantothenyl alcohol 0.1 part, 1-menthol 0.1 part, 1,3-
4.0 parts of butylene glycol and an appropriate amount of perfume were dissolved, and the obtained ethanol solution was added to the above aqueous resorcinol solution, mixed, and cooled using a heat exchanger.

Example 5 (Example of lotion production) In 15 parts of ethanol, 0.2 parts of Ricochalcon A, and polyoxyethylene sorbitan monolaurate (20EO).
5 parts, polyoxyethylene lauryl ether (20E
O) 0.5 part and an appropriate amount of perfume were dissolved. Separately, 4.0 parts of 1,3-butylene glycol, 4.0 parts of oleyl alcohol and an appropriate amount of preservative were dissolved in 75 parts of purified water, and the above ethanol solution was added thereto and mixed.

Example 5 (Preparation example of cream) 0.2 parts of Ricochalcon A, 10.0 parts of beeswax,
5.0 parts of cetanol, 8.0 parts of hydrophilic lanolin, 32.0 parts of squalane, and glyceryl monostearate
Five parts were heated to 70 ° C. and mixed to prepare an oil phase. Separately, 0.3 parts of aloe extract in 30.0 parts of purified water, polyoxyethylene sorbitan monolaurate (20EO)
2.0 parts, 5.0 parts of polyethylene glycol, 5.0 parts of ethanol, an appropriate amount of preservative, and an appropriate amount of flavor are dissolved,
The aqueous phase was prepared. The oil phase and the aqueous phase were mixed and emulsified using a homogenizer.

[0047]

EFFECTS OF THE INVENTION The sebum secretion inhibitor, androgen receptor binding inhibitor and testosterone 5α-reductase inhibitor of the present invention containing lycochalcone A as an active ingredient are more effective than those of the conventional composition-unstable plant extract. The effect is certain. In addition, since the active ingredient lycochalcone A is a substance contained in licorice which has been used in crude drugs since ancient times and there is no problem in terms of safety, hair cosmetics, skin cosmetics and the like containing this are It is suitable for ameliorating unpleasant symptoms caused by excessive androgen.

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Claims (4)

[Claims] 1. A sebum secretion inhibitor comprising lycochalcone A as an active ingredient. 2. An external preparation for skin obtained by adding lycochalcone A to provide an effect of inhibiting sebum secretion. 3. An androgen receptor binding inhibitor comprising lychochalcon A as an active ingredient. 4. A testosterone-5α-reductase inhibitor comprising lycochalcone A as an active ingredient.