JPS61197516A - Antihypertestosteronemic agent - Google Patents

Abstract

PURPOSE:To provide the titled agent containing glycyrrhizin or glycyrrhezic acid as an active component, having excellent activity to lower testosterone level in blood, useful for the remedy of hypomenorrhea, sterility and hypertrichosis, etc., and having high safety. CONSTITUTION:The objective agent contains glycyrrhizin of formula I or glycyrrhezic acid of formula II as an active component. The compound of formula I or formula II suppresses the production of testosterone in interstitial cell extremely remarkably. The action is higher in glycyrrhizin than in glycyrrhezic acid. The effective dose of glycyrrhizin is 30-50mg daily for intravenous injection and 150-250mg daily for oral administration, and that of glycyrrhezic acid is 15-35mg daily for intravenous injection and 100-200mg daily for oral administration. The agent is useful for the remedy of hypomenorrhea, sterility, hypertrichosis, acne vulgaris, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to an anti-hypertestosteroneemic agent that is highly effective.

Conventional technology Testosterone (male hormone) is a hormone produced in interstitial cells, but in women, if too much testosterone is secreted, it can lead to oligomenorrhoea, infertility, hirsutism, and spasticity. Diseases such as these occur.

Currently, adrenocortical hormones are used as drugs to reduce the amount of testosterone secreted, but it is well known that various side effects occur when adrenocortical hormones are administered.

SUMMARY OF THE INVENTION The present invention provides an anti-hypertestosteroneemic agent that has a distinct action of lowering blood testosterone.

Means to Solve the Problem The inventors of the present invention focused on the fact that blood testosterone decreased by administering the Chinese herbal medicine prescription ``Tsuyaku Sesocho'', and when they investigated its active substance, they found that glycyrrhetinic acid had a significant effect. They discovered that it has a clear effect on lowering blood testosterone and completed the present invention.

Therefore, the drug of the present invention is useful for treating oligomenorrhoea, infertility, hirsutism, ridge vulgaris, and the like.

Glycyrrhizin is a compound represented by the following formula (1), and glycyrrhetinic acid is a compound represented by the following formula (2).

It is already well known that 113v glycyrrhizin undergoes metabolism in the body and changes to glycyrrhetinic acid. (Therapeutics vol. 1.7 no, 5 p., 704-I), 708
1981 Toyama Pharmaceutical University, 1st Department of Internal Medicine, Yano Sanbe et al.) Furthermore, glycyrrhizin and glycyrrhetinic acid are commercially available from Tokyo Kasei Hanbai Co., Ltd., so they can be used.

Effects of the Invention Next, the fact that glycyrrhizin and glycyrrhetinic acid, which are the main components of the antihypertestosteroneemic agent of the present invention, have the effect of lowering blood testosterone concentration will be explained by giving experimental examples.

Experimental example (1) Animal used: Wistar male rat, 6-7 weeks old (2) Culture solution: Medium 199 (manufactured by DIFCO)
To the solution, add sodium bicarbonate to a final concentration of 0.125%, BSA (bovine serum albumin) to a final concentration of 0.1%, and further adjust the pH to 7.3 with sodium hydroxide.
Adjusted to ~7.5. After adjustment, a mixed gas (oxygen:carbon dioxide = 95:5) was bubbled so that pl+ did not fluctuate.

(3) Incubator: All 90 incubators (Jell) include:
3-isobutyl-methylxanthine (concentration = 0, 44 mg), which is necessary for interstitial cells to accumulate c-AMP (adenosine-phosphate) and produce testosterone.
/-) in 50 cells and 350 cells of culture medium, and 30 of the 90 cells were filled with 10 μg of glycyrrhetinic acid.
100 μg was added to each of another 30 vessels, and glycyrrhetinic acid was not added to the remaining 30 vessels, which were used as controls.

(4) Experimental method: After decapitation of 7 to 10 rats, the testes were immediately taken out, the surrounding membrane was removed, and as much blood vessels as possible were removed, and cells were collected. Collagenase (Worthington Type I) to break down the connective tissue of cells and separate them into individual cells.
25B in PBS containing 1% BSA as a final concentration (
20 volumes of phosphate buffered saline) were added and shaken at 37°C for 10 minutes (100 cycles/ml) to separate interstitial cells (Leydigcells). After shaking, filter through nylon gauze and heat the filtrate at 800~I 000 rpm.
centrifuged at 4°C for 10 minutes. After centrifugation, the supernatant was removed, the enzyme activity was stopped, a small amount of culture medium was added to wash the cells, and the mixture was centrifuged again at 800-100 Orpm for 5 minutes at 4°C. After centrifugation, remove the supernatant, add the culture solution, add 500 d each to the culture vessel while stirring well, and immediately add 3
Shaking culture was carried out at 5° C. for 3 hours in the presence of mixed gas (oxygen: carbon dioxide = 95:5).

Under these conditions, it is possible to culture 100 incubators, and the number of stromal cells per 1 incubator is 10''.

After culturing, transfer the culture solution to a test tube and incubate at 1500 rpm.
Centrifuge at 4°C for 10 minutes, collect the supernatant, and perform RIA
Testosterone production was measured using a radioimmunoassay (radioimmunoassay) method.

(5) Results: When cultured in an incubator without glycyrrhetinic acid, the average production of testosterone was 4.4 (±0,12) ng/m.
- On the other hand, when 10 μg of glycyrrhetinic acid was added, the average amount of testosterone produced was 0.4 (±0.4
7) ng/-, and when 100 μg is added, the average is 0. 1 (±0.01) ng/-, and it was observed that testosterone production in interstitial cells was suppressed very significantly.

Further, as mentioned above, it is clear that glycyrrhizin undergoes metabolism to become glycyrrhetinic acid, and it is clear from the experimental results using glycyrrhetinic acid that glycyrrhizin has a remarkable effect of lowering blood testosterone concentration.

Next, the L Dso value of glycyrrhizin was administered to ddY mice at 3 Q Omg/kg by intravenous administration and 3000 mg/kg by oral administration, but no deaths were observed. LD of glycyrrhetinic acid. The value is dd
100 mg/k intravenously to Y-strain mice
g, no deaths were observed even after oral administration of 3000111 g/kg. As described above, the antihypertestosteroneemic agent of the present invention has extremely low toxicity.
Considering the experimental results of the present invention, the effective dose of glycyrrhizin is 150 to 50 mg per day for intravenous injection, 150 to 250 mg per day for oral administration, and the effective dose of glycyrrhetinic acid is 15 m per day for intravenous injection. ~35m
g. For oral administration, it is considered appropriate to apply ff1loO to 200 mg per day.

Glycyrrhizin or glycyrrhetinic acid, which is the active ingredient of the antihypertestosteroneemic drug of the present invention, can be used alone, and an appropriate solvent, excipient, or
Using adjuvants, etc., liquid preparations,
Preparations such as injections, powders, granules, tablets, half tablets, enteric coated formulations and capsules can be made. Glycyrrhizin or glycyrrhetinic acid can also be used as a combination agent with other pharmaceutically active ingredients.

For oral administration, it can be formulated into tablets, gunpowders, capsules, powders, granules, etc. using at least one excipient such as starch, lactose, sucrose, mannitol, carboxymethyl cellulose, etc.

In addition to the excipients listed above, this type of preparation may contain, for example, lubricants such as magnesium stearate, sodium lauryl sulfate, and talc, dextrin, crystalline cellulose, polyvinylpyrrolidone, gum arabic, corn starch, and gelatin. Disintegrants such as binders, potato starch, carboxymethylcellulose, etc. can be used. It can also be administered as a suspension, emulsion, syrup, or elixir, and these dosage forms may contain flavoring agents and coloring agents.

As a parenteral preparation, it can be mixed with an appropriate base to form a cream,
It can be an ointment, poultice, or semi-annual.

As a diluent, distilled water for injection, physiological saline, aqueous dextrose solution, vegetable oil for injection, propylene glycol, polyethylene glycol, etc. can generally be used. Furthermore, if necessary, an isotonizing agent, a solubilizing agent, a stabilizer, a preservative, a soothing agent, etc. may be added as appropriate. Moreover, in the case of this type of dosage form, it is desirable to dissolve it in a sterile injection medium.

EXAMPLES Next, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1 Carboquine methyl cellulose sodium was added to 10 g of glycyrrhizin according to a conventional method for manufacturing injections, and the mixture was heated at 60°C.
The suspension was added to 1 liter of distilled water for injection heated to 100 mL and suspended, and the mixture was made isotonic with sodium chloride and then sealed in an ampoule.

This injection contains 10 mg of glycyrrhizin in l-. This injection is injected intravenously or intramuscularly at a dose of 3 to 5 depending on the symptoms.

Example 2 The log of glycyrrhetinic acid was calculated according to the conventional method for manufacturing injections.
Add carboxymethyl cellulose sodium, 60
The suspension was added to 1 λ of distilled water for injection heated to 0.degree. C., and the mixture was made isotonic with sodium chloride and then sealed in an ampoule.

This injection contains 10 mg of glycyrrhetinic acid in l-. This injection is administered intravenously or intramuscularly at a dose of 1.5 to 3.5 doses depending on the symptoms.

Example 3 30g of glycyrrhetinic acid was made into fine powder, and this was mixed with lactose t4
0 g and 7 g of magnesium stearate;
This mixture was compressed into tablets with a diameter of 2 mm using a single-shot slug tablet press.
Slug tablets with a diameter of 0 mm and a weight of about 2.3 g were prepared, crushed with an oscillator, sized, and sieved to obtain good granules with particles of 20 to 50 g.

This granule contains 20 mg of glycyrrhetinic acid in 1 g, and is administered at a dose of 2 to 3 g three times a day, depending on the symptoms.

Example 4 50 g of glycyrrhizin was added and mixed with 140 g of microcrystalline cellulose and IO g of magnesium stearate, and this mixture was compressed into tablets with a single-shot tablet machine to form tablets with a diameter of 9 fflln.
, tablets weighing 1200 mg were manufactured.

This tablet contains 50 mg of glycyrrhizin per tablet, and is taken in 3 to 5 tablets a day in several divided doses depending on the symptoms.

Example 5 25 g of glycyrrhetinic acid was made into a fine powder, mixed with 175 g of lactose, and 200 mg each was filled into hard capsules to obtain capsules.

This capsule contains 25 glycyrrhetinic acid in one capsule.
Contains B. Take 4 to 8 capsules a day in several divided doses depending on your symptoms.

Example 6 2.5 g of glycyrrhetinic acid was ground into a fine powder, and 197.5 g of purified cacao butter was added thereto, kneaded on a 606C water bath, and shaped into semi-particles of 2 g each.

This half of the year contains 25mg of glycyrrhetinic acid in one piece.
Use according to symptoms.

Claims (1)

[Claims] An antihypertestosteroneemic agent containing glycyrrhizin or glycyrrhetinic acid as an active ingredient.