JPH08310923A - Testosterone 5alpha-reductase inhibitor - Google Patents

Abstract

PURPOSE: To obtain a novel testosterone 5α-reductase inhibitor which is effective for treating and preventing a variety of diseases in which androgenic hormone participates. CONSTITUTION: Orange peels, sage leaves and flowers, peppermint leaves, eucalyptus leaves, mugwort leaves, lavender flowers, rose flowers, rosemary leaves and the like are subjected to steam distillation and the essential oils collected as products are used as active ingredients for this inhibitor.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a testosterone 5α-reductase inhibitor which is effective in treating and preventing various diseases involving androgen.

[0002]

2. Description of the Related Art Male pattern baldness, alopecia, hirsutism, acne and seborrhea caused by hypersecretion of sebum, and purulent sweating gland inflammation caused by dysfunction of apocrine gland are male hormones. It is thought that testosterone is the cause of onset or an exacerbation factor. That is, the male hormone testosterone secreted from the organs attached to the male reproductive organs is transported to the target organ by the bloodstream and selectively taken up, and then converted into highly active dihydroxytestosterone by intracellular testosterone 5α-reductase. , It is thought that the mechanism of action is that it binds to intracellular receptors, acts on the nucleus, suppresses cell division in hair mother cells, prevents hair growth, and promotes proliferation in sebaceous gland cells. .

Therefore, for the treatment of various diseases related to testosterone, a substance that inhibits the action of testosterone 5α-reductase or a substance having an antiandrogen action has been used or proposed.

However, conventional testosterone 5α-
The substances proposed as reductase inhibitors have not been widely and generally used because of their insufficient effects and safety problems. Further, conventional anti-androgen agents such as oxendron, diproterone acetate, chloryadinone acetate, etc. are all steroid agents, and often have side effects when administered to a living body for a long time, which is a problem in terms of safety.

[0005]

SUMMARY OF THE INVENTION An object of the present invention is to provide means for enabling the treatment and prevention of the above-mentioned diseases caused by dihydroxytestosterone without depending on the steroid drug which has a problem of safety. .

[0006]

The present invention provides a highly safe novel testosterone 5α-reductase inhibitor, namely, orange (Citrus aurantium L.) pericarp, sage (Salvia officinalis L.) leaves and flowers, peppermint (Mentha). piperita L. leaves, Eucalyptus (Euca)
lyptus globulus L. leaf, mugwort (Artemisia prin)
ceps P.P. And Artemisia mongolia F.) leaves, lavender (Lavandula vera DC) flowers, rose (Rosa)
centifolia L. flower and rosemary (Rosmari)
(Nus off-icinalis L.) leaves, which contain as an active ingredient an essential oil obtained by steam distillation from a plant selected from the group consisting of leaves.

All of the above-mentioned essential oils are commercially available and can be used as they are in the present invention, but they can also be produced from a raw material plant by a conventional method of steam distillation. That is, the steam is continuously supplied to the sedimentary layer of the raw material plant to bring the plant into a heated state, and the steam after passing the heated plant sedimentary layer is cooled by a cooler to collect a condensate, which Collect the oil layer that separates when left to stand. Since a part of the essential oil is also dispersed or dissolved in the aqueous layer, it may be recovered by organic solvent extraction and used.

The essential oil obtained from the above specific plant by steam distillation shows an excellent testosterone 5α-reductase inhibitory action. This enzyme inhibitory action was confirmed by the following tests.

Test method: Dissolve 4.2 mg of testosterone (Tokyo Kasei Co., Ltd.) in 1 ml of propylene glycol,
NADPH (ORIENTAL YEAST) was added to 20 μl to a concentration of 1 m.
5 mM Tris-HCl buffer (pH 7.2) 8 dissolved in g / ml
Add 25 μl. To this, 80 μl of sample solution (solution of essential oil in ethanol) and 75 μl of S-9 (rat liver homogenate; ORIENTAL YEAST) were added, and the mixture was mixed at 37 ° C. for 3 days.
Incubate for 0 minutes. Then methylene chloride 1
The reaction was stopped by adding ml, and the methylene chloride layer was separated,
The reaction products such as dihydroxytestosterone and androstanediol are quantified by gas chromatography. From the ratio of the amount of reaction product when the essential oil was added to the amount of reaction product when the sample essential oil was not added, testosterone 5α
-Determine the reductase inhibition rate.

In the above method, the concentration of essential oil in the reaction solution was variously changed to obtain the testosterone 5α-reductase inhibitory rate, and the enzyme activity was determined to be 50% by interpolation from the results.
Determine the essential oil concentration to inhibit.

A protein denaturation test was also conducted in order to confirm that the enzyme inhibitory action was not due to denaturation of the protein of the enzyme. The test was carried out by adding 1 ml of the sample solution to 9 ml of phosphate buffer (pH 6.8) containing 0.02% of fetal serum albumin (Fr.V: SIGMA), stirring for 10 minutes, filtering with a membrane filter, and liquid chromatography. It was carried out by a method of quantifying albumin by chromatography (Note: the concentration of essential oil in the reaction solution was 50 ppm). Table 1 shows the test results.

[0022]

TABLE 1 specimen 50% inhibitory concentration (ppm) protein modification ratio (%) Orange essential oil 15 17.0 sage essential oil> 2000 0.1 Peppermint essential oil 22 0.9 Eucalyptus essential oil 50 0.6 Artemisia essential oil 22 2.1 Lavender essential oil 18 4.3 Rose essential oil 17 0.8 Rosemary essential oil 2000 0.1

As is clear from Table 1, orange essential oil,
Peppermint essential oil, eucalyptus essential oil, mugwort essential oil, lavender essential oil and rose essential oil showed very high testosterone 5α-reductase inhibitory activity. Sage essential oil and rosemary essential oil were active at relatively high concentrations.
The protein denaturing effect was hardly observed except for some orange essential oil. The protein denaturing action of orange essential oil,
Given the strong activity of this essential oil, it is speculated that it is only related to a small portion of the enzyme inhibition rate measured.

The testosterone 5α-reductase inhibitor according to the present invention is used in various diseases, such as androgenetic alopecia, in which the action of androgen is the cause or aggravation factor.
It can be used as an external preparation for the prevention and treatment of hirsutism, seborrhea and acne associated with hypersecretion of sebum, suppurative sweat gland inflammation, axillary odor, and the like.

The testosterone 5α-reductase inhibitor of the present invention may be in any form suitable for external use, such as an ointment, lotion, emulsion, tonic, spray, suspension or solution. In formulating, in addition to the essential oil as an active ingredient, lower alcohols such as ethanol, higher alcohols such as cetanol, polyhydric alcohols such as propylene glycol, water-soluble cellulose derivatives such as hydroxypropyl cellulose, various oil and fat components. ,
An auxiliary agent such as a petrolatum, a wax, a silicone, a surfactant, a diluent such as a zinc oxide, a suspending agent, an aromatic agent, a moisturizing agent, and a preservative can be appropriately added. The appropriate content of essential oil in these preparations is about 0.01 to 1% by weight.

The essential oil, which is the active ingredient, induces some undesired inflammation on the skin in the range of the above preferable compounding amount.

The testosterone 5α-reductase inhibitor of the present invention is used alone in the above-mentioned applications, and is also compounded with any other external preparation for skin or cosmetics and applied to the skin in accordance with their use. You may do it.

[0028]

【Example】

Example 1 A testosterone 5α-reductase inhibitor of the present invention comprising an essential oil in a 0.05% by weight ethanol solution was prepared, and its sebum secretion inhibitory effect was tested by the following method. Test method: Absorbent cotton (4 cm ² ) moistened with the inhibitor of the present invention was applied to the left side of the forehead of a healthy person, and absorbent cotton moistened with the control solution (ethanol) was applied to the right side of the forehead of the same subject. Fix each with a bandage. After the lapse of 8 hours, the absorbent cotton is removed, and the sebum secreted at the part to which the absorbent cotton is applied and absorbed by the absorbent cotton is extracted with ethanol. For the obtained extract, squalene, which is the main component of secreted sebum, was quantified by gas chromatography, and sebum secretion was suppressed from the ratio of the squalene secretion amount of the inhibitor of the present invention to the squalene secretion amount of the control liquid use site. Find the rate.
Table 2 shows the results of the tests conducted on 20 test subjects.

[0029]

[Table 2] Squalene secretion amount (average value; mg / 4cm ² ) Reagent Site of the present invention Control site of control solution Sebum secretion suppression rate (%) Orange essential oil 0.112 0.168 33.3 Sage essential oil 0.170 0.186 8.6 peppermint essential oil 0.150 0.200 25.0 eucalyptus essential oil 0.150 0.174 13.8 mugwort essential oil 0.134 0.186 28.0 lavender essential oil 0.114 0.162 29.6 Rose essential oil 0.134 0.184 27.2 Rosemary essential oil 0.154 0.162 4.9

Example 2 Lavender essential oil was added to 50% ethanol at a concentration of 0.05%.
The testosterone 5α-reductase inhibitor of the present invention was prepared by dissolving.

Nine males aged 25 to 35 with androgenetic alopecia and seborrheic dermatitis symptoms were substituted with the above-mentioned inhibitor for the usual hair tonic for two months, morning and evening. It was sprayed on the head once each time.

On the start and end dates of the trial test, the test subjects were made to wash their hair under the same conditions, and the number of hair loss at that time was measured. The results are shown in Table 3, and it was confirmed that the testosterone 5α-reductase inhibitor of the present invention has an effect of reducing the amount of hair loss.

[0033]

[Table 3] Number of Hair Loss (Number) Subject Test Start At Test End A 115 81 B 78 50 C 103 45 D 110 75 E 95 39 F 78 38 G 92 52 H 49 32 I 74 41

Example 3 A testosterone 5α-reductase inhibitor of the present invention was prepared by dissolving sage essential oil and rosemary essential oil in 50% ethanol to a concentration of 0.05%.

The effect of the above inhibitor was confirmed in the same manner as in Example 2 on 8 males aged 25 to 35 having androgenetic alopecia and seborrheic dermatitis symptoms. . The results are shown in Table 4, and it was confirmed that the testosterone 5α-reductase inhibitor of the present invention has an effect of reducing the amount of hair loss.

[0036]

[Table 4] Number of hair loss (lines) Subject test Start of test End of test A 88 72 B 106 72 C 77 45 D 131 75 E E 102 39 F 101 38 G 83 52 H 94 32

Use Example 1 (Example of blending in tonic) Peppermint essential oil 0.05 g Pyridoxine hydrochloride 0.1 g Resorcin 0.01 g D-pantothenyl alcohol 0.1 g Dipotassium glycyrrhizinate 0.1 g Carrot extract extract 0.5 g Menthol 0.1 05g 1,3-butylene glycol 5.0g ethanol 15.0g distilled water 79.09g

Use Example 2 (example mixed in lotion) Wormwood essential oil 0.05 g Dipotassium glycyrrhizinate 0.2 g 1,3-butylene glycol 4.0 g Oleyl alcohol 4.0 g POE sorbitan monolaurate (20EO) 1.5 g POE lauryl ether (20EO) 0.5 g Ethanol 15.0 g Methyl parahydroxybenzoate 0.05 g Ethyl parahydroxybenzoate 0.05 g (Add distilled water to make the total amount 100.0 g)

Use Example 3 (Example of Compounding in Cream) Peppermint Essential Oil 0.01 g Orange Essential Oil 0.01 g Stearyl Glycyrrhetinate 0.1 g Beeswax 10.0 g Cetanol 5.0 g Hydrophilic Lanolin 8.0 g Squalane 37.5 g Glyceryl Monostearate 2.0g POE / sorbitan monolaurate (20EO) 2.5g Polyethylene glycol 5.0g Methyl parahydroxybenzoate 0.05g Ethyl parahydroxybenzoate 0.05g (total amount is 100.0g by adding distilled water) And)

[0040]

The constituents of the testosterone 5α-reductase inhibitor of the present invention are essential oils collected from plants that have been used as herbs and crude drugs for a long time, and their safety has been confirmed. Therefore, according to the present invention, it is not necessary to depend on a steroid drug having a safety problem, and treatment and prevention of various diseases caused by dihydroxytestosterone can be performed more easily than before.

Claims (1)

[Claims] 1. An orange (Citrus aurantium L.) pericarp, sage (Salvia officinalis L.) leaves and flowers,
Leaves of peppermint (Mentha piperita L.), leaves of eucalyptus (Eucalyptus globulus L.), mugwort (Artemisi)
a princeps P. And Artemisia mongolia F.) leaves,
Lavender (Lavandula vera DC) flower, rose (R
osa centifolia L. ) Flowers and rosemary (Ros
marinusofficinalis L.) A testosterone 5α-reductase inhibitor, which contains, as an active ingredient, an essential oil obtained by steam distillation from a plant selected from the group consisting of leaves.