JPH0570349A - Antiplasmin agent - Google Patents

Abstract

PURPOSE:To obtain an antiplasmin agent, capable of achieving remarkable effects of use with a small amount without any toxic side effects and effective in preventing or treating dermatophathies such as burn, eczema or contact-type dermatitis in which an abnormal rise in plasmin activity participates. CONSTITUTION:An antiplasmin agent is composed of glabridin expressed by the formula. The agent has the above-mentioned effects effective in treating dermatitis in which an abnormal rise in plasmin activity participates. Furthermore, since the glabridin is a chemically stable substance, it can freely be blended in many cosmetics, medicines for external use, etc. When the antiplasmin agent is contained in the medicine for the external use or cosmetic, the agent is preferably regulated to provide 0.01-5.0% concentration expressed in terms of the glabridin. The glabridin in a very small amount is naturally contained in Glycyrrhiza glabra Linne var. which is one species of Glycyrrhiza glabra Linne var. glandulifera Regel et Herder and can be extracted from the root part of the Glycyrrhiza glabra Linne var.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an antiplasmin agent effective for treating skin inflammation caused by ultraviolet ray stimulation and the like.

[0002]

2. Description of the Related Art Irritation of the skin caused by UV stimulation,
As other means for treating skin inflammation such as rough skin, sunburn, burns and eczema, anti-inflammatory agents such as azulene, vitamin agents such as vitamin C, fungicides such as sulfadiazine, antihistamine agents such as diphenhydramine, and antibiotics such as bacitracin. , Corticosteroids such as fluocinolone anacetonide, etc. are appropriately used in combination. However, these drugs are not always satisfactory in terms of safety and efficacy in topical application, and when used in combination with other drugs, they may not be effective. In general, inflammation is considered to be the body's defense response to ecologically harmful stimuli, and when local stimuli are applied to living tissues, acute exudative inflammation first occurs, and vasodilation, vascular hyperpermeability, and leukocyte migration are observed. Be done. Subsequently, repair such as infiltration of mononuclear cells, proliferation of connective tissue, and neovascularization occurs. These are considered to be dynamic defense reactions that try to restore the body to a normal state, but often have far more harmful effects on the body than the original noxious stimulus.

Chemical mediators involved in the pathological changes in each stage of inflammation include active amines such as histamine and serotonin, active peptides such as bradykinin,
Proteolytic enzymes such as plasmin and kallikrein, slow-reacting substances, and lipids such as prostaglandins are well known. In particular, for skin inflammation, the relationship with plasmin, which is a proteolytic enzyme involved in the in vivo fibrinolytic system, is well known, and plasmin activity is observed in skin diseases such as sunburn, burns, eczema, contact dermatitis, and lupus erythematosus. It is believed to be elevated, which is one of the causes of increased inflammation. Heretofore, tranexamic acid and the like have been known as agents for suppressing excessive plasmin activity.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide an external preparation effective for treating skin inflammation associated with the above-mentioned abnormal increase in plasmin activity.

[0005]

The present invention, which has succeeded in achieving the above object, provides an antiplasmin agent comprising glabridin.

[0006]

[Function] Glabridin is a compound having the following structural formula [Chemical formula 1], and is naturally a kind of licorice, Glycyrrhi.
It is contained in za glabra Linne var. (Soviet Union, Afghanistan, Turkish liquorice) in a trace amount, and its pharmacological action is known to be antibacterial action and melanin production inhibitory action (Japanese Patent Laid-Open No. 1-311011).

[Chemical 1]

The present invention is based on the fact that this glabridin has an inhibitory effect on plasmin activity which is different from the above-mentioned known pharmacological actions, and has been found to be effective for the treatment of skin inflammation associated with abnormally increased plasmin activity. Is. In order to extract glabridin from licorice containing glabridin, the root of this licorice or its water (or aqueous ammonia) extraction residue (for example, the residue obtained by extracting glycyrrhizin) is treated with ethyl acetate, methylene chloride, ether,
The extract thus obtained may be appropriately purified by subjecting it to an extraction treatment with an organic solvent such as chloroform.

The antiplasmin agent of the present invention comprising glabridin is used alone or together with other agents in an appropriate base material to prepare an external medicine, and various cosmetics such as lotions, creams, emulsions and packs. It can be used by being contained in. When the antiplasmin agent of the present invention is used by being contained in an external medicine or a cosmetic composition, it is desirable that the concentration of glabridin be about 0.01 to 5.0%.

[0009]

【Example】

Example 1 Isolation of Glabridin from Licorice Licorice Glycyrrhizaglabra Linne var. 1 kg of shredded root
Was heated under reflux with 1000 ml of ethyl acetate for 2 hours to extract the ethyl acetate-soluble component. The solvent of the extract was distilled off and further dried under reduced pressure to obtain 28 g of extract. This was dissolved in 1000 ml of 70 (v / v)% ethanol, the insoluble material was filtered off, and the filtrate was used as a synthetic adsorbent / Diaion HP-2.
Grablidine was adsorbed by flowing it through the column No. 0 (200 ml). Then, after washing the column with 70 (v / v)% ethanol, glabridine was eluted with 2500 ml of 80 (v / v)% ethanol, and the eluate was fractionated into 500 ml fractions. Grabridin was found in the third fraction, which was concentrated under reduced pressure and dried under reduced pressure to obtain about 2.5 g of crude glabridin. The crude product was recrystallized and purified with benzene / hexane (4/2) to obtain 1.1 g of purified glabridin crystals.

Example 2 The plasmin activity-inhibiting action of the glabridin obtained in Example 1 was examined. (1) Preparation of sample solution The following solutions were prepared. Grabridine 5 mg / 40 (v / v)% ethanol 10 ml Grabridine 10 mg / 40 (v / v)% ethanol 10 ml (2) Fibrin plate preparation Warren's method (Wallen et al. Hamostasis, 4,110,19)
According to 75), 100 mg of agarose was dissolved in 10 ml of 0.01M phosphate buffer (pH 7.8) heated with 0.15M sodium chloride, and then cooled to 40 ° C. Plasminogen-removed fibrinogen (Daiichi Pure Chemicals) 16.6 mg was dissolved in this. A thrombin solution (100 units / ml;
Mochida Pharmaceutical Co., Ltd.) After dropping 0.1 ml, petri dish (diameter 9 cm)
Then, the mixture was allowed to cool, and a hole having a diameter of 6 mm was opened in the center to prepare plasminogen-removed fibrinogen.

(3) Measurement of inhibition rate of plasmin activity Ambulus et al. (Ambrus et al., Pediatrics, 32, 1
0,1963), 0.1 ml of the sample solution prepared in (1) above
Plasmin solution (0.4 units / ml; Sigma) 0.1 ml
Add 30 μl and inject 20 μl each into the plate hole.
It was Let stand for 20 hours at 37 ℃, measure the dissolution area,
Compare fibrin lysis area of plates without solution
Then, the plate activity inhibition rate was obtained. As a control,
The same applies to tranexamic acid, which is an antiplasmin agent.
The test was conducted. The results of the above test are as follows:
It wasSample solution Plasmin activity suppression rate  Glabridin (5mg / 10ml) 53% Glabridin (10mg / 10ml) 85% Tranexamic acid (10mg / 10ml) 20%

Example 3: Example of blending with ointment for treating burns Polyethylene glycol (400) 49.8% Polyethylene glycol (4000) 49.8% Acrinol fine powder 0.2% Glabridine 0.2% Burn treatment of the above composition Ointment for cosmetics, and apply it once or twice
Applied to about 1/2 of the burned site of 7 patients who had
It was Tink oil as a control drug on the other half
Was applied. The results are shown below.Applied drug Remarkable effect Effectiveness Invalid  Grabridine-added ointment 6 1 0 tincture oil 3 4 0

Example 4: Example of blending with sunburn anti-inflammatory lotion Ethanol 15% Polyoxyethylene sorbitan monolaurate (20EO) 1.0% Paraoxybenzoic acid 0.2% Perfume 0.2% Grabridine 0.3% Glycerin 5% 1,3-butylene glycol 6.0% Purified water The rest The uniform solution above was mixed to prepare a lotion,
This was applied to 20 girls aged 20 to 25 on the back and arms when bathing in the sea. As a result, all had a remarkable anti-inflammatory effect. Further, no skin irritation reaction due to glabridin was observed.

[0014]

EFFECTS OF THE INVENTION As described above, the antiplasmin agent of the present invention comprising glabridin achieves a remarkable use effect even in a small amount, and no harmful side effects are observed. Further, since glabridin is a chemically stable substance, it can be freely blended in many cosmetics, external preparations and the like. Therefore, according to the present invention, a safe and effective new means is provided for the prevention or treatment of skin diseases associated with abnormally increased plasmin activity such as sunburn, burns, eczema, contact dermatitis, and lupus erythematosus. become.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI technical display location C07D 493/04 106 C 7329-4C

Claims (1)

[Claims] 1. An antiplasmin agent comprising glaburidine.