JPH11209236A - Testosterone-5α-reductase inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a testosterone-5α-reductase inhibitor exhibiting a strong inhibitory activity on testosterone-5α-reductase and exhibiting an excellent therapeutic effect on acne. SOLUTION: It consists of a solvent extract of Cuachalalate (scientific name: Juliania adstringens).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to testosterone-5.
Testosterone-5 having α-reductase inhibitory action
It relates to an α-reductase inhibitor. The present invention also relates to a skin external preparation for preventing and treating acne, which is capable of preventing and treating acne by incorporating the testosterone-5α-reductase inhibitor.

[0002]

2. Description of the Related Art In recent years, inhibitors of testosterone 5α-reductase (or 5α-hydrogenase) activity involved in the conversion of testosterone to 5α-dihydrotestosterone, which is a so-called active androgen, have been extracted from various plants. ing. In view of the mechanism of action of these substances, it has been proposed to use the substances for acne caused by enhanced sebaceous gland activity, particularly acne vulgaris (acne) (see, for example, 60-146
Nos. 829, 63-88121 and 64-312
No. 5).

According to JP-A-60-146829, various crude drug extracts have 5α-reductase inhibitory activity prepared from the prostate and testis of male rats, and are useful for the prevention or treatment of acne vulgaris. It is stated to be effective. And, high inhibitory activity is observed in Acacia catechu, Gobishi and Yokuinin, and moderate inhibitory activity is observed in Fennel and the like.

According to Japanese Patent Application Laid-Open No. 63-88121, a method for measuring 5α-reductase inhibitory activity using human hair roots is used to determine the number of Rumex japonicus Hout of Polygonaceae.
t. ) Shows high inhibitory activity and can be used as a therapeutic agent for acne vulgaris and the like.

[0005]

The above-mentioned prior arts can attain certain objects, but have an activity of inhibiting testosterone 5α-reductase (hereinafter sometimes referred to as 5α-reductase), and At present, there is a need for the development of additional substances that are effective in preventing acne.

[0006]

As a solution to these problems, the present inventors examined the ability of various substances to inhibit testosterone-5α-reductase. As a result, it was found that the solvent extract of quacharate showed excellent testosterone- It has been found that it has 5α-reductase inhibitory activity and is effective in preventing acne, and has completed the present invention.

That is, the present invention relates to quacharate (Cu
A testosterone-5α-reductase inhibitor comprising a solvent extract of achalalate (scientific name: Juliania adstringens). Further, according to the present invention, there is provided a skin external preparation for preventing and treating acne, which comprises the testosterone-5α-reductase inhibitor. Here, examples of the external preparation for skin for prevention and treatment of acne include prevention or treatment of acne vulgaris (acne).

[0008] Cuachalalate (scientific name:
Juliania adstringens) is sometimes used as a folk medicine or herbal medicine along the Mexican Pacific coast to provide wound healing,
It is already known that it is effective for burning, gingival health, digestive system cancer, hair loss, etc. (JP-A-4-181313)
No report on testosterone-5α-reductase inhibitory action has been reported so far, and it has been found for the first time.

Hereinafter, the configuration of the present invention will be described in detail. Quacharate used in the present invention is a plant that grows particularly in the Acapulco region on the Pacific coast of southern Mexico. Quacharate extract used in the present invention,
The leaves, stems, flowers, bark, seeds, fruits, whole plants and the like of the above quacharate may be soaked or heated under reflux with an extraction solvent, and then filtered and concentrated. As the extraction solvent used in the present invention, any solvent can be used as long as it is a solvent usually used for extraction, for example, alcohols such as methanol and ethanol, hydrous alcohols,
Acetone, an organic solvent such as ethyl acetate, alone,
Alternatively, they can be used in combination. In addition, those obtained by subjecting the extract to a treatment such as partitioning or purification such as chromatography using the above-mentioned solvent can also be used. The obtained extract can be used as it is as the testosterone-5α-reductase inhibitor of the present invention, but may be used after the extraction solvent is distilled off and, if necessary, dried.

[0010] The extract thus obtained contains essential oils, sugars, proteins and the like as a whole, although the contents differ depending on the plant used. Although it is not clear which of these components is derived, as described above, the extract of the present invention exhibits strong 5α-reductase inhibitory activity and prevents acne, particularly acne vulgaris (acne). It has a therapeutic effect.

Therefore, specifically, the testosterone-5α-reductase inhibitor comprising the above extract is useful for skin care, cosmetics, cosmetics for the prevention and treatment of acne vulgaris, and comprehensive acne It can be used as an active ingredient of external preparations for skin including pharmaceutical preparations for prevention and treatment. In addition to the above-mentioned skin disorders, it can also be used for the purpose of preventing or treating other disorders or diseases caused by the action of 5α-reductase. This testosterone-5α-reductase inhibitor is not limited to external use for the skin, and depending on the purpose of use, uses diluents, excipients, and the like known per se as needed, for oral and parenteral use. Dosage form.

The amount of the above-mentioned extract of the present invention can vary depending on the form of the preparation or the purpose of use, and is not specified. However, taking a skin external preparation as an example, the amount of the quacharate extract in that case is 0.005 to 20.0% by weight, preferably 0.01 to 10.0% by weight of the total amount of the external preparation as a dry matter. %. If the amount is less than 0.005% by weight, the effects of the present invention are not sufficiently exhibited, and if the amount is more than 20.0% by weight, it is not preferable because formulation is difficult. Further, even if the content is 10.0% by weight or more, the effect is not so much improved.

The external preparation for skin of the present invention includes ointments, creams,
Any of those conventionally used for skin external preparations such as emulsions, lotions, packs, bath preparations and the like may be used, and the dosage form is not particularly limited.

In addition to the above essential components, cosmetics, cosmetics, and the like may be used depending on the purpose of use within a range that does not impair the effects of the present invention.
Various components, oils, humectants, thickeners, preservatives, antioxidants, fragrances, coloring agents, drugs, and other active ingredients commonly used in quasi-drugs, pharmaceuticals, and the like can be blended.
In addition, sequestering agents such as disodium edetate, trisodium edetate, sodium citrate, sodium polyphosphate, sodium metaphosphate, gluconic acid, caffeine, tannin, verapamil, tranexamic acid and its derivatives, licorice extract, glabridine , Hot water extract of fruit of Karin, various crude drugs, drugs such as tocopherol acetate, glycyrrhizic acid and its derivatives or salts thereof, vitamin C, magnesium ascorbate phosphate, glucoside ascorbate, whitening agents such as arbutin, kojic acid,
Sugars such as glucose, fructose, mannose, sucrose, and trehalose can also be appropriately blended.

On the other hand, the testosterone-5α-reductase inhibitor of the present invention is used in the form of a liquid, syrup, or tablet as an oral or parenteral administration agent in addition to the above-mentioned external skin preparation. be able to. Particularly, in order to prepare a liquid preparation, physiological saline, ethanol or the like can be used as a diluent or carrier.

[0016]

Next, the present invention will be described in more detail by way of examples. Note that the present invention is not limited to this. The compounding amount is% by weight. Prior to the examples, test methods and results of the testosterone-5α-reductase inhibitory effect and the acne vulgaris (acne) improving effect of the plant extract of the present invention will be described.

1. Testosterone-5α-reductase inhibitory effect (1) Preparation of sample Dried product (500 g) of bark portion of quacharate was
The mixture was treated with 7.5 liters of methanol for 5 days to obtain 51.2 g of a dried methanol extract of quacharate. The obtained dried qualaralate extract was dissolved in 80% ethanol to obtain an ethanol solution having a 1% extract content.

(2) Test method and results The effect on 5α-reductase inhibitory activity was determined by the method of Takayasu et al. (S. Takayasu, K. Adachi, J. Clin. Endocrinol. Meta).
b., 34, 1098-1101 (1972)). That is, 50 g of the ethanol solution having the extract content of 1% obtained above was added to the reaction system so that the final sample concentration became 0.05%. Testosterone is 5α-D using human hair root
The amount reduced to HT was measured and testosterone-5-α
-The reductase inhibitory activity was measured and evaluated by obtaining the inhibition rate according to the following formula. Table 1 shows the results. As a reference example, testosterone-5α has already been used.
-The same test as described above was carried out for a methanol extract of Mishimasaiko, which is known to have a reductase inhibitory action. Table 1 also shows the results.

[0019]

## EQU1 ## Inhibition rate (%) = [1-A / B] × 100

A: Amount of 5α-DHT produced when an inhibitor is added B: Amount of 5α-DHT produced when no inhibitor is added

[0021]

[Table 1] 検 Test substance inhibition rate (%) ─────────────── ──────── Quacharate extract 89.2 Mishimasaiko extract 7.4 ───────────────────────

2. Improvement effect of acne vulgaris (acne) (1) Preparation of sample Dried product (500 g) of bark part of quacharalate
The mixture was treated with 7.5 liters of methanol for 5 days to obtain 51.2 g of a dried methanol extract of quacharate. Using the obtained dried qualaralate extract, a lotion was prepared according to the following formulation and production method.

[Formulation] (Phase A) Sorbitol 3.0% by weight Glycerin 5.0 Resorcin 0.02 Ion-exchanged water Remainder (Phase B) Quacharate extract 1.0 Polyoxyethylene (60) hydrogenated castor oil 0.5 95% ethanol 20.3 Perfume Appropriate amount [Production method] Each component of phase A was mixed and dissolved, and a mixed solution of phase B was added thereto with stirring to prepare a lotion as a homogeneous solution.

(2) Test Method and Results Forty males and forty females aged 15 to 21 years old were tested twice daily, after washing their face, a small amount of sample lotion was applied.
After a week, the improvement effect of the acne symptom was tested and evaluated according to the following criteria. As a control, a lotion containing no quacharate extract in the B phase was also prepared. Table 2 shows the test results.

Evaluation criteria : Complete cure: All symptoms disappeared. Significant effect: Significant effect. Effective: All lighten. Invalid: No change before and after use.

[0026]

[Table 2] ─────────────────────────────────── Evaluation (person) Test sample gender ────有効 Efficacy rate in all cases Zenji Excellent effect Effective Invalid (%) ───────────────────────────試 料 Sample of the present invention male 3 688 385 female 17 77 575 control male 0 416 20 20 female 0 614 430 ────────────── ─────────────────────

Hereinafter, examples of the formulation of testosterone-5α-reductase inhibitors according to the present invention in various dosage forms will be described as examples.

Example 1 Cream (formulation) Stearic acid 5.0% by weight Stearyl alcohol 4.0 Isopropyl myristate 18.0 Glycerin monostearate 3.0 Propylene glycol 10.0 Quacharate methanol extract 0.01 Caustic potash 0.2 Sodium bisulfite 0.01 Preservatives Appropriate amount Fragrance Appropriate amount Ion-exchange water residue (Preparation method) Add propylene glycol, quacharate methanol extract and caustic potash to ion-exchange water, dissolve
Heat and maintain at 70 ° C. (aqueous phase). The other components are mixed, melted by heating and kept at 70 ° C. (oil phase). The oil phase is gradually added to the water phase, and after the addition is completed, the temperature is maintained for a while to cause a reaction. Then, homogenize uniformly with a homomixer,
Cool to 30 ° C with good stirring.

Example 2 Cream (Formulation) Stearic acid 2.0% by weight Stearyl alcohol 7.0 Hydrogenated lanolin 2.0 Squalane 5.0 2-Octyldodecyl alcohol 6.0 Polyoxyethylene (25 mol) Cetyl alcohol ether 3.0 Glycerin monostearate 2.0 Propylene glycol 5.0 Quacharate ethanol extract 0.05 Sodium bisulfite 0.03 Ethyl paraben 0.3 Perfume Appropriate amount Ion-exchanged water Residue (Production method) Propylene to ion-exchanged water Add glycol,
Heat and maintain at 70 ° C. (aqueous phase). The other components are mixed, melted by heating and kept at 70 ° C. (oil phase). The oil phase is added to the water phase, pre-emulsified, homogenized with a homomixer, and cooled to 30 ° C. with good stirring.

Example 3 Cream (Formulation) Solid paraffin 5.0% by weight Beeswax 10.0 Vaseline 15.0 Liquid paraffin 41.0 Glycerin monostearate 2.0 Polyoxyethylene (20 mol) Sorbitan monolaurate 2 0.0 Soap powder 0.1 Borax 0.2 Quacharate acetone extract 0.05 Quacharate ethanol extract 0.05 Sodium bisulfite 0.03 Ethyl paraben 0.3 Perfume Appropriate amount Ion-exchanged water Residue (production method)
Soap powder and borax are added to ion-exchanged water, heated and dissolved, and kept at 70 ° C. (aqueous phase). The other components are mixed, melted by heating and kept at 70 ° C. (oil phase). The oil phase is gradually added to the aqueous phase while stirring to carry out the reaction. After completion of the reaction, the mixture is uniformly emulsified with a homomixer, and cooled to 30 ° C. while stirring well after emulsification.

Example 4 Emulsion (Formulation) 2.5% by weight of stearic acid Cetyl alcohol 1.5 Vaseline 5.0 Liquid paraffin 10.0 Polyoxyethylene (10 mol) Monooleate 2.0 Polyethylene glycol 1500 0 Triethanolamine 1.0 Carboxyvinyl polymer 0.05 (Product name: Carbopol 941, BFGoodrich Chemical company) Quacharate acetate ethyl ester extract 0.01 Sodium bisulfite 0.01 Ethyl paraben 0.3 Fragrance Appropriate amount Ion exchange water Residue (Preparation method) Dissolve the carboxyvinyl polymer in a small amount of ion-exchanged water (phase A). Polyethylene glycol 1500 and triethanolamine are added to the remaining ion-exchanged water, dissolved by heating, and kept at 70 ° C. (aqueous phase). The other components are mixed, melted by heating and kept at 70 ° C. (oil phase). The oil phase is added to the water phase, pre-emulsification is performed, the phase A is added, and the mixture is uniformly emulsified with a homomixer.

Example 5 Emulsion (Formulation) Microcrystalline wax 1.0% by weight Beeswax 2.0 Lanolin 20.0 Liquid paraffin 10.0 Squalane 5.0 Sorbitan sesquioleate 4.0 Polyoxyethylene (20 mol) ) Sorbitan monooleate 1.0 Propylene glycol 7.0 Quacharate acetone extract 10.0 Sodium bisulfite 0.01 Ethylparaben 0.3 Perfume Appropriate amount Ion-exchanged water Residue (Production method) Propylene glycol in ion-exchanged water In addition,
Heat and maintain at 70 ° C. (aqueous phase). The other components are mixed, heated and melted and kept at 70 ° C. (oil phase). While stirring the oil phase, the aqueous phase is gradually added thereto, and the mixture is uniformly emulsified with a homomixer. After emulsification, cool to 30 ° C with good stirring.

Example 6 Jelly (Formulation) 95% ethyl alcohol 10.0% by weight Dipropylene glycol 15.0 Polyoxyethylene (50 mol) Oleyl alcohol ether 2.0 Carboxyvinyl polymer 1.0 (Product name: Carbopol) 940, BFGoodrich Chemical company) Caustic soda 0.15 L-arginine 0.1 Quacharate 50% ethanol aqueous solution extract 7.0 Sodium 2-hydroxy-4-methoxybenzophenone sulfonate 0.05 Ethylenediaminetetraacetate 3 Sodium 2 water 0 .05 Methylparaben 0.2 Perfume Appropriate amount Ion-exchanged water Residue (Preparation method) Carbopol 940 is uniformly dissolved in ion-exchanged water, while Quacharate 50 is dissolved in 95% ethanol.
% Ethanol aqueous solution extract, polyoxyethylene (50%
Mol) oleyl alcohol ether is dissolved and added to the aqueous phase. Next, after adding other components, the mixture is neutralized with caustic soda and L-arginine to increase the viscosity.

Example 7 Essence (Formulation) (A phase) Ethyl alcohol (95%) 10.0% by weight Polyoxyethylene (20 mol) octyldodecanol 1.0 Pantothenyl ethyl ether 0.1 Quacharate methanol Extract 1.5 Methylparaben 0.15 (Phase B) Potassium hydroxide 0.1 (Phase C) Glycerin 5.0 Dipropylene glycol 10.0 Sodium bisulfite 0.03 Carboxyvinyl polymer 0.2 (Product name: Carbo Pall 940, BFGoodrich Chemical company) Purified water residue (Preparation method) Dissolve A phase and C phase uniformly, and add A to C phase
Add phases and solubilize. Next, after adding the phase B, filling is performed.

Example 8 Pack (Formulation) (A phase) Dipropylene glycol 5.0% by weight Polyoxyethylene (60 mol) hydrogenated castor oil 5.0 (B phase) Quacharate methanol extract 0.01 Olive oil 5 2.0 Tocopherol acetate 0.2 Ethyl paraben 0.2 Fragrance 0.2 (Phase C) Sodium bisulfite 0.03 Polyvinyl alcohol 13.0 (Saponification degree 90, Degree of polymerization 2,000) Ethanol 7.0 Purified water Residue (Production method) A phase, B phase, and C phase are each dissolved uniformly,
Add phase B to phase and solubilize. Next, this is added to the C phase and then filled.

Example 9 Solid foundation (formulation) Talc 43.1% by weight Kaolin 15.0 Sericite 10.0 Zinc white 7.0 Titanium dioxide 3.8 Yellow iron oxide 2.9 Black iron oxide 0.2 Squalane 8 2.0 Isostearic acid 4.0 POE sorbitan monooleate 3.0 Isocetyl octanoate 2.0 Quacharate ethanol extract 1.0 Preservatives Appropriate amount Fragrance Appropriate amount (Production method) Powdery components of talc to black iron oxide are sufficiently blended. After mixing and adding the oily components of squalane to isocetyl octanoate, quacharate ethanol extract, preservatives and fragrances, the mixture is kneaded well and filled into a container and molded.

Example 10 Emulsified Foundation (Cream Type) (Prescription) (Powder) Titanium Dioxide 10.3% by weight Sericite 5.4 Kaolin 3.0 Yellow Iron Oxide 0.8 Bengala 0.3 Black Iron Oxide 0.2 (oil phase) Decamethylcyclopentasiloxane 11.5 Liquid paraffin 4.5 Polyoxyethylene-modified dimethylpolysiloxane 4.0 (aqueous phase) Purified water 50.0 1,3-butylene glycol 4.5 Acalarate ethanol extract 1.5 Sorbitan sesquioleate 3.0 Preservatives Appropriate amount Flavors Appropriate amount (Preparation method) After heating and stirring the aqueous phase, a well-mixed and pulverized powder portion is added, followed by homomixer treatment. Further, the oil phase mixed by heating is added, and the mixture is treated with a homomixer. Then, a fragrance is added with stirring, and the mixture is cooled to room temperature.

[0038]

As described above, the testosterone-5α-reductase inhibitor of the present invention is testosterone-
It has a strong inhibitory activity against 5α-reductase and has an excellent acne therapeutic effect.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 35/78 ADA A61K 35/78 ADAE (72) Inventor Masahiro Ota 1050 Nippa-cho, Kohoku-ku, Yokohama-shi, Kanagawa Shiseido One Research Center

Claims (2)

[Claims] 1. A testosterone-5α-reductase inhibitor comprising a solvent extract of Cuachalalate (scientific name: Juliania adstringens). 2. Testosterone-5α- according to claim 1.
An external preparation for skin for preventing and treating acne, comprising a reductase inhibitor.