JPH11255651A - Androgen-receptor coupling inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject inhibitor giving a sure effect in use, inhibiting the coupling of androgen with its receptor, capable of treating syndromes caused by the surplus of the androgen and useful for hair cosmetics, skin cosmetics, etc., by compounding berberine as an active ingredient. SOLUTION: This androgen-receptor coupling inhibitor contains berberine or its salt as an active ingredient. Berberine hydrochloride and berberine tannate are nitrogen-containing heterocyclic compounds gathered in Japanese pharmacopeia, and the berberine is plentifully contained in Coptis japonica, Phellodendri cortex, etc., having been utilized as galenicals, and can easily and highly purely be obtained by extracting the galenicals and subsequently purifying the extract. The objective inhibitor may be compounded with an astringent, an antibacterial agent, an antibiotic, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an androgen receptor binding inhibitor which inhibits binding of androgen to its receptor (receptor), and a hair cosmetic, a skin cosmetic and a treatment for prostatic hypertrophy containing the same. It relates to the agent.

[0002]

2. Description of the Related Art Many steroid hormones bind to receptors in the form of molecules secreted from producing organs and express their actions. In the case of male hormones collectively called androgens, for example, testosterone is produced in cells of target organs. And then is reduced to 5α-dihydrotestosterone (5α-DHT) by testosterone 5α-reductase and then binds to a receptor to exert its action as an androgen.

[0003] Androgens are important hormones, but when they act excessively, male pattern baldness, hirsutism, seborrhea, acne, benign prostatic hyperplasia, prostate tumors, precocious boyhood, etc.
Induces various undesirable symptoms. Therefore, it is conceivable to improve these undesired symptoms by suppressing the action of excess androgen. As a means for this, the action of testosterone 5α-reductase, which reduces testosterone to active 5α-DHT, is inhibited. Thus, there can be a method of suppressing the generation of active 5α-DHT, and a method of inhibiting the binding of 5α-DHT generated from testosterone to a receptor so that no action is exhibited.

In practice, the latter method is considered to be effective. For this purpose, substances effective in inhibiting the binding of 5α-DHT to the androgen receptor include assembly,
Purple crab, giant gourd, licorice, rhubarb, chix carrot, kumazasa, chimpanzee, areca, clove, psycho, yokunin, senkyu, peony,
Asenyaku, Touki, Onji, Shazenshi, Kagosou,
Extracts such as nigaki, fennel, genoshoko, catalpa, soybean, scallop, valerian, kengoshi, senso, agetsu, rosin and the like are known (Japanese Patent Application Laid-Open No. 64-3).
No. 126). However, in many cases, the composition of these plant extracts is not constant, and their efficacy and safety are uncertain. Therefore, they have not been easy to use as an androgen receptor binding inhibitor.

[0005]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide an androgen receptor binding inhibitor whose use effect is certain,
It is to provide a novel means for the treatment of said unfavorable condition caused by excess androgen.

[0006]

DISCLOSURE OF THE INVENTION The present invention provides an androgen receptor binding inhibitor comprising berberine or a salt thereof as an active ingredient, and a hair cosmetic, a skin cosmetic and a cosmetic containing the same. It is intended to provide a remedy for prostatic hypertrophy.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION Berberine is a nitrogen-containing heterocyclic compound whose hydrochloride and tannate are listed in the Japanese Pharmacopoeia. It is abundantly contained in spinach and oak used as crude drugs, extracted from these crude drugs,
A highly purified product can be easily obtained by purification (13th revised edition of the Japanese Pharmacopoeia, C-405).

Berberine and its salts are listed in the Japanese Pharmacopoeia because of its bactericidal action against intestinal harmful bacteria,
This is because it has an effect of suppressing intestinal putrefaction and fermentation, a bile secretion effect, and the like, which is effective in treating diarrhea and the like. Inhibition of androgen-receptor binding is independent of the known effects of the berberine and was found for the first time by the present inventors.

An example of a test confirming the inhibitory effect of berberine on androgen-receptor binding is shown below.

Test Method: Androgen-dependent mouse breast cancer cells SC-3 cells were cultured in MEM containing 2% FBS (MEM-
2) Seed a 96-well microplate at a cell density of 1.0 × 10 ⁴ cells / well / 100 μl using a medium, 37 ° C., 5%
Culture under CO ₂ -95% air. Twenty-four hours later, the sample and HMB medium supplemented with 10 ^-9 mol DHT (0.
The medium is changed to Ham F12 + MEM medium containing 5% BSA, and the cells are cultured for 48 hours. Thereafter, the medium was treated with 0.97 mM MT.
The medium is exchanged with a MEM-2 medium containing T, and after culturing for 2 hours, the medium is exchanged with isopropanol to extract blue formazan generated 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 is also measured at the same time, and the difference between the two absorbances is taken as a value proportional to the amount of blue formazan produced (the absorbance in the following formula for calculating the binding inhibition ratio is the corrected absorbance). ). In parallel with the above, in order to examine the effect of the sample alone on SC-3 cells, the same culture and measurement are performed by adding only the sample without adding DHT to the HMB medium. Further, as a control, the same measurement is performed when the cells are cultured in an HMB medium to which a sample and DHT are not added, and when the cells are cultured in an HMB medium to which only DHT is added without adding a sample. From the measurement results, the binding inhibition rate showing an anti-androgen action is calculated by the following equation.

The binding inhibition rate (%) = [{(AB)-(C
−D)} / (AB)] × 100 where A: absorbance when DHT is added and no sample is added B: absorbance when DHT is not added and no sample is added C: DHT is added and sample is added Absorbance D: Absorbance without DHT and sample

The above-mentioned inhibition rate is measured by changing the concentration of the sample solution in a stepwise manner, and the concentration (ppm) of the sample solution that inhibits the binding of androgen by 50% is determined by an interpolation method.

When the above measurement was carried out using berberine chloride of the Japanese Pharmacopoeia as a sample, the 50% inhibitory concentration was 1.
It was 85 ppm. Also, in a similar measurement performed on a spinach extract having a berberine content of 32% and an oak extract having a berberine content of 25%, the 50% inhibitory concentrations were 4.51 ppm and 77.3 ppm, respectively.

The androgen receptor binding inhibitor of the present invention can be used alone as a dermatological agent, an oral agent or a suppository, or can be widely used as a component of any external dermatological agent, cosmetic, pharmaceutical product and the like. In particular, it is suitable as an external preparation for skin such as hair cosmetics and skin cosmetics, and a main agent of a therapeutic agent for prostatic hypertrophy.

The preparation of the androgen receptor binding inhibitor of the present invention can be carried out in the same manner as in the case of a conventional pharmaceutical berberine preparation. However, any physiologically active substance or auxiliary agent such as astringent depending on the use can be prepared. Agent, disinfectant / antibacterial agent, whitening agent,
By blending an ultraviolet absorber, a humectant, a cell activator, an anti-inflammatory / anti-allergic agent, an anti-oxidant / active oxygen scavenger, etc., the use can be facilitated and the use effect can be improved.

The following are specific examples of those which can be expected to produce good results when formulated into the androgen receptor binding inhibitor according to the present invention and an external preparation for skin containing the same.

Astringents: citric acid, tartaric acid, lactic acid or salts of these organic acids; aluminum chloride, aluminum potassium potassium 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-hydroxybenzoic acid ester, distearylmethylammonium chloride, benzethonium chloride, alkyldiaminoethylglycine chloride, krylhexidine 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, cahid extract, gajutsu extract and the like.

Whitening agent: 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 extracts thereof, gymnema extract, linden extract, peach leaf extract, rhubarb extract, botanical extract, hamamelis extract, horse chestnut extract, hypericum perforatum extract, hydrangea extract, oil-soluble licorice extract (licorice hydrophobic flavone,
Gravlidine, glabrene, lycochalcone A) and the like.

Ultraviolet 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, ginkgo biloba extract, horse chestnut extract,
Ginkgo biloba extract, chamomile extract, oil-soluble licorice extract and the like.

Humectants: 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, colloidal alge, fermented bifidobacteria, fermented lactic acid bacteria, yeast extract, litchi mycelium culture or extract thereof, wheat germ oil, avocado oil, rice higa 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.

[0025]

Example 1 Absorbent cotton impregnated with a 0.01% ethanol solution of berberine chloride was fixed on the left side of the forehead of 10 healthy subjects with a bandage, and a control solution (containing berberine on the right side). Immobilized absorbent cotton). After a lapse of 8 hours, each cotton wool is removed, and extracted with ethanol to collect the sebum absorbed by the cotton wool, and the squalene therein is quantified by gas chromatography. The sebum secretion inhibition rate of berberine chloride is calculated from the difference between the amounts of squalene determined for the left and right absorbent cotton.

Table 1 shows the results of the above test and the results of a test using a spinach extract having a berberine content of 32% instead of berberine chloride.

[0027]

[Table 1] Sample sebum secretion inhibition rate (%) Berberine chloride 45.8 Ouren extract 17.0

Example 2 2 having symptoms of male pattern baldness and seborrheic dermatitis of the head
Ten males aged 6 to 47 years were divided into five use groups and five non-use groups, and the use group received berberine chloride at 0.02.
A 50% aqueous solution of ethanol containing 50% by weight was used twice a day for one month, in the morning and evening, in place of the usual hair tonic. For the non-use group, a 50% aqueous ethanol solution was used under the same conditions in place of the hair tonic which is usually used. Everyone was allowed to wash their hair under the same conditions on the test start date and test end date, and the number of hair removals at that time was counted. In order to make the conditions uniform, the hair was washed under the same conditions 24 hours before the hair washing for measuring the number of hair removal. Table 2 shows the test results.

[0029]

Table 2 Hair loss test start date ( test ) Test end date (test) Reduction rate (%, mean ± SE) Use group subject A 105 72 subject B 92 52 subject C 84 41 subject D 78 38 subject E 94 41 46 .76 ± 4.358 Non-use group subject F 101 85 subject G 96 88 subject H 89 70 subject I 102 90 subject J 77 72 12.70 ± 2.666

Example 3 Raw material A: Berberine chloride (Japanese Pharmacopoeia) 0.02 parts by weight Resorcinol 0.01 Dipotassium glycyrrhizinate 0.1 Carrot extract 0.5 Raw material B: Pyridoxine hydrochloride 0.1 D-pantothenyl alcohol 0 .1 l-menthol 0.05 1,3-butylene glycol 4.0 perfume qs ethanol 25.0

The raw material A was dissolved in 70.0 parts by weight of purified water at 60 ° C., and a mixed solution of the raw material B was added thereto, followed by stirring and cooling to produce a hair tonic.

Example 4 Raw material A: Arnica extract 0.5 parts by weight 1,3-butylene glycol 4.0 Dipotassium glycyrrhizinate 0.2 Oleyl alcohol 4.0 Preservatives Appropriate amount Raw material B: Berberine tannate (Japanese Pharmacopoeia) 0.02 Polyoxyethylene sorbitan monolaurate (20EO) 1.5 Polyoxyethylene lauryl ether (20EO) 0.5 Perfume Appropriate amount Ethanol 15.0

After dissolving Arnica extract in 1,3-butylene glycol, the remaining raw material is directly charged into 70 parts by weight of purified water to prepare an aqueous solution of raw material A. Raw material B there
Was added and stirred to produce a lotion.

Example 5 Raw Material A: Stearyl glycyrrhetinate 0.1 parts by weight beeswax 10.0 cetanol 5.0 hydrophilic lanolin 8.0 squalane 37.5 glyceryl monostearate 2.0 γ-oryzanol 0.05 Raw material B: Berberine 0.02 Polyoxyethylene sorbitan monolaurate (20EO) 2.0 Polyethylene glycol 5.0 Preservatives Appropriate amount Perfume Appropriate amount

The above-mentioned raw material B is added to 40.0 parts by weight of purified water and heated to 70 ° C. to be dissolved. The mixture of the raw material A heated to 70 ° C. was added thereto, and the mixture was emulsified using a homogenizer to produce a cream.

[0036]

The androgen receptor binding inhibitor of the present invention comprising berberine as an active ingredient is more effective than those comprising a plant extract whose composition is unstable, and berberine has been used as a drug. Since its general properties have been sufficiently confirmed by being a compound, it is suitable for improving unpleasant symptoms caused by excess androgen when formulated in hair cosmetics, skin cosmetics, remedies for prostatic hypertrophy, and the like. Things.

Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 7/48 A61K 7/48 // A61K 35/78 35/78 C C07D 491/147 C07D 491/147

Claims (4)

[Claims] An androgen receptor binding inhibitor comprising berberine or a salt thereof as an active ingredient. 2. A hair cosmetic comprising the androgen receptor binding inhibitor according to claim 1. 3. A skin cosmetic comprising the androgen receptor binding inhibitor according to claim 1. 4. An agent for treating prostatic hypertrophy, comprising the androgen receptor binding inhibitor according to claim 1.