JPH0482835A - Remedy for dyspigmentation - Google Patents

Abstract

PURPOSE:To obtain the subject remedy for dyspigmentaiton capable of effective remedy of intractable dyspigmentation such as senile mole, mole due to exposure to the sun, pigmentation after inflammation and endogenous liver spots without side effects by using liquiritin as an active component. CONSTITUTION:Liquiritin represented by the formula and already known as a melanin production inhibitor, preferably an extract from glycyrrhiza, especially one obtained by extracting glycyrrhiza using a lower alcohol and further extracting the resultant extract using n-butanol is blended as an active component, e.g. in case of percutaneous administration, in an amount of 0.01-20wt.%, preferably 0.1-10wt.% on liquiritin content base to obtain the objective remedy for dyspigmentation applied to a diseased part mainly by percutaneous administration and capable of remarkably effective remedy of the above-mentioned diseases the remedy of which was said to be difficult until now and in which a change for the worse is said to cause serious symptoms such as canceration without a side effect.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to a therapeutic agent for hyperpigmentation, and more specifically, it relates to senile lentigines, solar lentigines, and solar lentigines, which have traditionally been difficult to treat. The present invention relates to a drug for effectively treating pigmentation diseases such as post-inflammatory pigment spots and intrinsic melasma that are not caused by external stimuli such as sunburn, without side effects.

[Conventional technology and its problems]

Continuous oral administration of vitamin C is used to treat pigmentation disorders such as intrinsic melasma, senile lentigines, solar lentigines, and post-inflammatory pigment spots, but the degree of pigmentation In advanced cases, continuous oral administration of vitamin C often does not improve the condition.

Furthermore, hyperpigmentation is caused by an abnormal increase in the amount of melanocytes within the epidermis, and this is caused by an increase in the number of melanocytes and their enhanced function. As a method to suppress the excessive production of melanin and prevent the effects of ultraviolet rays that enhance melanocyte function, substances that scatter light such as powders such as talc, zinc white, and titanium oxide, or ultraviolet absorbers such as para-aminobenzoic acid are used. A method using ointments, etc. containing

It is also known to use external preparations containing substances that inhibit melanin production in the epidermis, and depigmenting agents such as ascorbic acid and glutathione.

However, these external preparations are mainly intended to prevent pigmentation that increases due to sunlight, and even if these external preparations are used alone, they cannot be expected to have any significant effect as a treatment for pigmentation disorders. .

The applicant has been conducting research in search of effective drugs for the treatment of hyperpigmentation, and has been researching drugs containing kojic acid as an active ingredient (
Japanese Patent Application No. 1-161155), combination of placenta extract and kojic acid or kojic acid derivative (Japanese Patent Application Laid-open No. 63-8310), combination of cyclodextrin and kojic acid (Japanese Patent Application Laid-Open No. 63-8311) , combination of placenta extract and ergothioneine (JP-A-63-8335), combination of placenta extract and liver extract (JP-A-1-38774)
It has been revealed that a melanin production-suppressing topical melanin production agent containing liver water extracts of mammals and birds as an active ingredient (Japanese Unexamined Patent Publication No. 618313) is effective as a melanin production-inhibiting topical drug used in topical therapy for hyperpigmentation.

In the process of further testing these inventions and continuing research in search of a drug that is effective as a pigmentation treatment, the present inventor has discovered that melanin production has Liquiritin, which was only known to have an effect as an inhibitor, has a completely different onset mechanism that is caused by external stimuli such as senile lentigines, solar lentigines, post-inflammatory pigment spots, and sunburn. Does not treat pigmentation diseases such as endogenous melasma without having side effects.
Furthermore, we have found that it can be effectively treated, and have completed the present invention.

[A means of saving to solve problems]

That is, the present invention was completed based on the above-mentioned new findings obtained by the present inventors, and provides a therapeutic agent for hyperpigmentation that contains liquiritin as an active ingredient.

Further, according to the present invention, there is provided a pigmentation treatment agent which is an extract obtained by extracting liquiritin from licorice with a lower alcohol and further extracting with n-butanol.

Liquiritin used as a pigmentation treatment agent in the present invention is a compound having the following structural formula.

H This compound is contained in licorice, and in the present invention, a liquiritin-containing extract of licorice extract may be used as an active ingredient of an external preparation.

Licorice, which is the raw material for the extract of the present invention, is a medicinal plant of the Fabaceae family, and its powder has been used as an expectorant, anti-inflammatory, and antispasmodic since ancient times.

In addition, licorice extract is listed in the Japanese Pharmacopoeia as an orally administered agent for cough suppression, expectoration, gastritis, gastrointestinal function adjustment, and treatment of eczema, etc.

As the liquiritin of the present invention, licorice extract (published in the Japanese Pharmacopoeia) obtained by soaking dry powder of licorice in water, filtering it, extracting it with ethanol, and evaporating the filtrate can be used. Preferably, dry powder of licorice is soaked in water, extracted with a lower alcohol such as ethanol, methanol, etc., the extract is further extracted with n-butanol, and the resulting extract is filtered to separate insoluble matter, An extract with a high content of liquiritin obtained by concentration is used.

Senile lentigines associated with skin aging and solar lentigines caused by excessive exposure to sunlight, which are the target diseases of the drug of the present invention, are
It is a disease in which the symptoms worsen as the number of melanocytes existing in the skin increases, and it may eventually turn into cancer. Post-inflammatory pigment spots are dark brown pigment spots that remain after the healing of some skin disease and are intractable It is a disease.

Intrinsic melasma is not extrinsic melasma caused by normal sunburn, but is intrinsic melasma caused by hormonal abnormalities or the use of various drugs to treat internal diseases, and is an intractable pigmentation disorder. .

Since the drug of the present invention is mainly applied to the affected area by transdermal administration, its formulation forms include ointments, solutions, lotions, creams, aerosols, poultices, plasters, and the like. The formulation is made into a transdermal drug using a conventional formulation method using auxiliaries, additives, spreaders, etc. that are commonly used in these formulations.

The content of liquiritin, which is an active ingredient contained in this transdermal preparation, is 0.01 to 20% by weight, preferably 0.01 to 20% by weight.
It is 1 to 10% by weight.

When using this transdermal drug, usually twice a day (in the morning,
Apply liberally to the affected area (before going to bed).

The toxicity of liquiritin, the active ingredient of the present invention, is extremely low, with an LD50 of 2.160 mg in mice when administered subcutaneously.
/kg, and 2,370 mg/kg in rats, making it an extremely safe drug.

〔Example〕

Hereinafter, the present invention will be explained in detail with reference to Examples.

Liquiritin used in the examples was obtained by the following method.

Production method: 50 kg of licorice is ground, ethanol 400β is added thereto, and reflux heat extraction is carried out for 2 hours. Repeat this operation twice to completely concentrate the extract at below 60°C, producing 15 kg of concentrate.
get. This was dissolved in 100β of water. Add saturated hydrated η-butanol 1001 to this, stir well at room temperature for 30 minutes, and leave to stand to separate the butanol layer.

The same amount of n-butanol is further added to the residual liquid, and the same operation is repeated twice. The three n-butanol layers were combined and washed twice with 100β water to remove sugar, tannins, etc.

The water-washed butanol extracts are combined and the butanol is distilled off at a temperature below 60°C. Add 3001 water to the residue and dissolve by heating.
Insoluble matter is filtered off. The filtrate was further concentrated to 50A and 1
Leave to stand overnight and separate the supernatant by decantation. Concentrate this supernatant at below 60°C to obtain 1 kg of dry flavonoid fraction.
get. The yield is 2% from the raw material.

Example 1 Liquid (weight%) Liquiritin 2.0 Glycerin
5.0 Sorbitol
4.0 Polyoxyl stearate 40 1
．． 55 Ethanol 10.0 Sodium hydrogen sulfite 0.05 Um
0.02 Lium 0.5 to 100 These are dissolved, and the liquid preparation and EDTA nina triglutamate purified water are mixed and stirred.

Example 2 Emulsion lotion Liquiritin Propylene glycol Ascorbic acid Purified water Soybean lecithin dl-α-Tocopherol Ethanol Polyethylene glycol 400 Purified water Purified water EDTA disodium (% by weight) 1.0 0.02 Sodium hydrogen tartrate 02A, B, The components of C are mixed and stirred to dissolve them to obtain an emulsion lotion.

Example 3 Oily ointment (wt%) Liquiritin 0.1 Polysorbate 2
0 5.0 Dextran
0.07 ethanol
5.0 White Vaseline ~100
Beef tallow 20.0 secnol 2.0 dl-α-tocopherol 0.1 glycerin monostearate
5. Stir and mix O8. Mix and stir B while heating, and when cooled, mix with 8 to obtain an oil-based ointment.

Example 4 Water-soluble ointment carboxyvinyl polymer 10 Propylene glycol 10.0 Ethanol
8.0 Diisopropanolamine
0.15 triacetin 30
．． 0 xanthungam 2. O Purified water 3.0 Sodium bisulfite 0.03 Purified water
~100 Liquiritin
1. Mix and dissolve the ingredients to make a gel. Then B,
Add C and D sequentially to make a water-soluble ointment.

Example 5 Emulsion ointment (wt%) White petrolatum 25.0 Silicone oil
5.0 stearyl alcohol
22.0 Propylene glycol
12,0 Sucrose fatty acid ester 5.0 Stearic acid Podl-α-tocoliquiritin Purified water While heating each component, make an emulsion-type ointment.

Example 6 Cream Purified Water 1.3-Butylene Glycol Sorbitol di-PCA Sodium (50% liquid) Carboxyvinyl Polymer Polysorbate 60 Monostearic Acid Lyceride Cefnol Petrolatum Myristic Acid Octyl Dodecyl Octyl Dodecanol Rioquin 40 2.5 Ferol 015 ~100 and cooled (wt%) ~100 3.0 7.0 3.0 Squalane 11.0dl-α-
Tocopherol 0.15 purified water
10,0 liquiritin
2. Heat and dissolve A and B, add B to 8, emulsify, and cool to make cream. Separately, C is dissolved and added to the cream.

Example 7 Aerosol (wt%) Liquiritin 2.0 Cetanol
1.2 Propylene glycol
4.0 Stearic acid 8
．． 0 Purified Water ~100 Freon 123/141b (57:43) 7.
0 Mix and dissolve each component and put it in an aerosol container to make an aerosol.

Example 8 Poultice (wt%) Δ Sorbicune monooleate 1.0 Purified water
~100 Sodium polyacrylate 70 Ammonium chloride
o3 concentrated glycerin 200 titanium oxide 4.0 liquidin
50 A and B are dissolved by heating, B is added to A, stirred uniformly, and cooled. After cooling, it is applied to a liniment to make a poultice.

Example 9 Plastering agent (wt%) polystyrene-polyisoprene-polystyrene rubber
36.0 liquid paraffin
250 Ester gum 15.0 Polybutene 13.0 Butylhydroquine toluene 1.0 Polyacrylic acid
30.0 liquitin
Heat and melt 10.0Δ, add B little by little and stir evenly. After gradually adding C to this mixture, it is spread into a coating agent to form a plaster agent.

Next, using the drug of the present invention, endogenous melasma, senile lentigo,
The results of a clinical trial regarding the therapeutic effects of post-inflammatory pigment spots are shown.

Clinical test (1) Cream of test sample Example 6 [2] Target patients Patients visiting university hospital, 60 patients with intrinsic melasma, 28 senile lentigines
23 people had post-inflammatory pigment spots.

(3) Test method Twice a day (in the morning and before bedtime), apply the test sample to the left side of the affected area of the face.
．． A sufficient amount of 5 g was applied, and the right side was not applied and tested as a control.

(4) Judgment After application, the left side (treated side) and right side (non-treated side) were compared over time to visually judge the treatment status.

The criteria for evaluation were as follows.

Excellent effect; most of the pigment spots have faded.

Effective; judged to be quite effective.

Slightly effective: Pigmentation has slightly disappeared.

(5) Results It was as shown in Table 1 below.

Chapter 1 Table The numbers in the table indicate the number of people.

In this study, the treatment period was as early as one month, and the effect was seen after four months at the latest.

〔Effect of the invention〕

According to the present invention, treatment of endogenous melasma, senile lentigines, solar lentigines, post-inflammatory pigment spots, etc., which have been considered difficult to treat and whose worsening is said to cause serious symptoms, can be treated. It is possible to provide a drug that cures hyperpigmentation very effectively and without side effects.

Claims (1)

[Scope of Claims] 1. A therapeutic agent for hyperpigmentation, characterized by containing liquiritin as an active ingredient. 2. The agent for treating hyperpigmentation according to claim 1, wherein the liquiritin is liquiritin extracted from licorice. 3. After extracting licorice with lower alcohol,
Claim 2: The extract is further extracted with n-butanol.
The agent for treating hyperpigmentation as described in Section 1.