JP2013035762A - Dermatitis therapeutic agent and skin pruritus therapeutic agent - Google Patents

Abstract

A novel dermatitis treatment agent and skin itching treatment agent are provided.
A therapeutic agent for dermatitis comprising lycochalcone A as an active ingredient; a therapeutic agent for skin pruritus comprising lycochalcone A as an active ingredient.
[Selection figure] None

Description

  The present invention relates to a novel therapeutic agent for dermatitis and therapeutic agent for skin pruritus.

The incidence of dermatitis has increased remarkably in recent years as a kind of allergic symptom with changes in the living environment and dietary habits. And not only does it cause inflammation in the skin, but it often accompanies worsening of symptoms due to pruritus. In particular, atopic dermatitis is known to exhibit serious symptoms in a wide age group from children to adults, and diagnostic criteria, severity classification, and treatment methods are summarized as guidelines (Non-patent Document 1). reference).
Conventionally, steroid external preparations have been widely used for the treatment of dermatitis. However, while high effects can be obtained, side effects are also strong, and administration is generally performed under the strict guidance of a doctor. In addition, non-steroidal immunosuppressive agents and anti-inflammatory agents may be administered in addition to these, but none of them can be said to be effective enough and should be used when steroids cannot be prescribed. There are many.

The Japanese Dermatological Association “Japanese Society of Dermatology Atopic Dermatitis Guidelines”

As described above, the conventional dermatitis treatment agents have problems such as many restrictions in use and insufficient effects, and the development of new treatment agents is strongly desired. It is a fact.
This invention is made | formed in view of the said situation, and makes it a subject to provide a novel dermatitis therapeutic agent and a skin pruritus therapeutic agent.

  As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that lycochalcone A, which is known as a component derived from licorice, has an anti-dermatitis action, and the present invention. It came to complete.

That is, to solve the above problem,
The present invention provides a therapeutic agent for dermatitis comprising lycochalcone A as an active ingredient.
The present invention also provides an agent for treating skin pruritus comprising lycochalcone A as an active ingredient.

  ADVANTAGE OF THE INVENTION According to this invention, the novel dermatitis therapeutic agent and skin pruritus therapeutic agent can be provided.

It is a graph which shows the evaluation result of the (1) pruritus action of the mouse | mouth in Example 1. FIG. It is a graph which shows the evaluation result of (2) thickening and edema of the mouse ear in Example 1. It is imaging data which illustrates the degree of (3) abrasion, bleeding, tissue defect, and (4) desquamation / drying / scab of the mouse in Example 1. It is the graph which scored the evaluation result of (1)-(4) in Example 1. FIG. 2 is a graph showing measurement results regarding IgE values in mouse serum in Example 1. FIG. 3 is imaging data illustrating a paraffin section of the back skin of a mouse in Example 1. 2 is a graph showing (a) the number of dermal infiltrated mast cells and (b) the number of dermal infiltrating eosinophils in the paraffin section of the back skin of the mouse in Example 1, respectively.

The therapeutic agent for dermatitis and therapeutic agent for skin pruritus (hereinafter abbreviated as dermatitis therapeutic agent etc.) of the present invention comprises lycochalcone A (hereinafter abbreviated as LicoA) as an active ingredient.
The therapeutic agent for dermatitis etc. of the present invention suppresses all symptoms of dermatitis including itching.
LicoA is contained in an oily extract from Licorice, which is a kind of perennial plant of the leguminous licorice genus, and is represented by the following formula (1).

  LicoA is known to have antibacterial properties, and is recently known as a compound having antimalarial activity, but has never been known to have antidermatitis activity.

The preparation form of the therapeutic agent for dermatitis and the like of the present invention is not particularly limited, depending on the purpose, oral preparations such as tablets, powders, granules, capsules, fine granules, liquids (solutions, etc.); , Injections, patches, ointments, creams, solutions, lotions, emulsions, poultices, tapes, etc., aqueous gels, oily gels, aerosols, powders, parenterals, etc. Just do it. Any of these preparations for treating dermatitis and the like can be produced by known methods.
Among these, the therapeutic agent for dermatitis of the present invention includes a patch, an ointment, a cream, a liquid, a lotion, an emulsion, a poultice, a tape, an aqueous gel, an oily gel, an aerosol, and a powder. It is preferable that it is an external preparation such as.

  When the dermatitis therapeutic agent or the like is in the form of a preparation such as an oral preparation, various additives usually used in the production of these preparations may be blended. Examples of the additive include an excipient, a lubricant, a plasticizer, a surfactant, a binder, a disintegrant, a wetting agent, a stabilizer, a corrigent, a colorant, and a fragrance.

  Examples of the excipient include lactose, glucose, D-mannitol, fructose, dextrin, starch, sodium chloride, sodium bicarbonate, calcium carbonate, sodium alginate, ethyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, silicic anhydride, kaolin and the like. It can be illustrated.

  Examples of the lubricant include magnesium stearate, calcium stearate, stearic acid, talc, corn starch, and macrogol.

  Examples of the plasticizer include polyethylene glycol, propylene glycol, glycerol, triacetin, medium chain fatty acid triglyceride, acetyl glycerol fatty acid ester, triethyl citrate and the like.

Examples of the binder include gelatin, gum arabic, cellulose ester, polyvinyl pyrrolidone, starch syrup, licorice extract, tragacanth, and simple syrup.
Examples of the disintegrant include starch, agar, carmellose calcium, carmellose, crystalline cellulose and the like.
Examples of the wetting agent include gum arabic, polyvinyl pyrrolidone, methyl cellulose, carmellose sodium, and hydroxypropyl cellulose.

Examples of the flavoring agent include sucrose, honey, sodium saccharin, mint, eucalyptus oil, and cinnamon oil.
Examples of the colorant include iron oxide, β-carotene, chlorophyll, and a water-soluble edible tar dye.
Examples of the flavor include lemon oil, orange oil, dl- or l-menthol.

  When the dermatitis therapeutic agent or the like is made into a parenteral preparation, examples of the solvent that can be used include distilled water for injection, a sterile non-aqueous solvent, and a suspension. Preferred examples of the non-aqueous solvent or suspending agent include propylene glycol, polyethylene glycol, glycerin, olive oil, corn oil, ethyl oleate and the like.

  When the dermatitis treatment agent is a parenteral preparation such as a patch, the mixture of each ingredient such as active ingredient and base should be applied thinly on cloth, paper, plastic film, etc. good.

  In addition, when the dermatitis therapeutic agent or the like is used as a preparation for external use among parenteral preparations, a known preparation such as a dispersion system or solubilization system containing LicoA may be used. Various additives that can be blended at this time include petrolatum, liquid paraffin, surfactant, gelling agent, purified water, bactericidal agent, antibacterial agent, lower alcohol, polyhydric alcohol, oil and fat, fatty acid, thickener, pH adjuster. , Chelating agents, pigments, inorganic powders, bases for poultices, adhesives for tapes, fragrances and the like, which are commonly used in the production of external preparations can be exemplified.

In the therapeutic agent for dermatitis and the like of the present invention, optional pharmaceutically acceptable components other than the above components may be appropriately blended as necessary within the range not impeding the effects of the present invention.
Examples of the optional component include a buffer, a preservative, and an antioxidant.

  The additives, solvents, optional components and the like mentioned above may be used singly or in combination of two or more. When two or more kinds are used in combination, the combination and ratio may be appropriately selected according to the purpose.

The therapeutic agent for dermatitis and the like of the present invention can be administered either orally or parenterally, but is preferably administered as an external preparation.
It is preferable to appropriately adjust the dosage of the dermatitis therapeutic agent and the like depending on the age, symptoms, etc. of the patient. In the case of oral administration, it is usually preferable that the amount of LicoA per adult is 0.5 to 1000 mg / person. In the case of parenteral administration, it is usually preferable that the amount of LicoA per adult is 10 to 1000 mg / person per day.
The therapeutic agent for dermatitis and the like of the present invention is administered once or divided into a plurality of times a day.

LicoA can be synthesized according to a known method, and can also be extracted from Licorice.
When LicoA is synthesized, it can be removed by a known method after the reaction. That is, after completion of the reaction, after performing post-treatment such as filtration, washing, extraction, pH adjustment, dehydration, and concentration as necessary, the product may be taken out by crystallization, column chromatography, or the like. Moreover, you may refine | purify the taken-out product by repeating crystallization, column chromatography, etc. further.
Furthermore, LicoA can also be obtained by extracting licorice from a two-layer system of water and an organic solvent according to a known method after processing such as crushing. At this time, if necessary, the obtained extracted component may be subjected to post-treatment, extraction and purification similar to those described above.
A commercially available product may be used as LicoA.

In an allergic reaction, IgE having specificity for an antigen is produced. IgE is a kind of immunoglobulin and remains bound to mast cells (mast cells) or the like present in submucosa or connective tissue. When the same antigen comes into contact again, two IgE molecules are bound with the antigen in between, which triggers cell membrane enzymes to be activated, and chemical mediators such as histamine are found in the granules of the cell. It is released rapidly, and chemical mediators such as leukotrienes, prostaglandins, and platelet activating factors are released from the cell membrane, causing various physiological actions.
On the other hand, the therapeutic agent for dermatitis of the present invention has been shown to reduce the IgE value. The therapeutic agent for dermatitis and the like of the present invention has excellent anti-inflammatory and anti-pruritic effects, and is particularly suitable for atopic dermatitis among dermatitis.

  Hereinafter, the present invention will be described in more detail with specific examples. However, the present invention is not limited to the following examples.

<Anti-dermatitis action of LicoA against pruritus model>
[Example 1]
In a 5-week-old female NC / Nga mouse, the hair on the back was removed, and a crude extract of acarid mite worm body (hereinafter abbreviated as DfE) was applied 3 times a week for 6 to 7 weeks. And applied to the skin of the auricle. Two weeks after the start of DfE application and 30 minutes after DfE application, 200 μL of an ethanol solution containing 5 mg of LicoA was applied to the hair removal part and the skin of the auricle, and the application amount was 15 mg / week / mouse. It adjusted so that it might become.

This mouse was evaluated for anti-dermatitis activity according to the following evaluation criteria (Examples).
(1) pruritus behavior, (2) thickening / edema, (3) abrasion / bleeding / tissue loss, (4) degree of desquamation / drying / scab, 0 for asymptomatic, 1 for mild, 2 for moderate Severity was set to 3, and it evaluated by scoring each. In addition, about the pruritus action, the mouse | mouth image | video was image | photographed for 30 minutes, the scratching action by a hind leg during this period was counted, and it scored based on the numerical value. For the thickening of the ear, the thickness of the ear was measured using a dial ticness gauge and scored based on the measured value.
(5) IgE value in serum was measured.
In addition, about (1)-(5), the average value in six mice was computed.
(6) Paraffin sections of the dorsal skin as the application site were prepared, stained with hematoxylin and eosin, and histopathological analysis of the sections was performed.
(7) A test sample was cut out from the paraffin section in a size of 4 mm × 4 mm, and this sample was stained with toluidine blue and congo red to calculate mast cells and eosinophils. In the calculation, each sample was observed at a magnification of 400 times using a microscope, and the average value was calculated from the number of cells in the dermis of 50 visual fields.

As a reference example, evaluation was performed in the same manner as in the above example except that glycyrrhetinic acid (GA) was used instead of LicoA.
In addition, as a comparative example, evaluation was performed in the same manner as in the above example except that LicoA was not used.
And it evaluated by the method similar to the said Example except having replaced with DfE and using the extract (henceforth abbreviated as MeE) only of the tick culture medium as control.

The evaluation result of (1) is shown in FIG. In FIG. 1, “DfE-LicoA” is a LicoA administration group, “DfE-GA” is a GA administration group, “DfE” is a non-administration group of LicoA and GA (a group in which neither LicoA nor GA was administered). Respectively. This is the same in the following drawings.
As shown in FIG. 1, the number of scratching behaviors was significantly increased in the non-administration group from the third week after the start of DfE application, but was suppressed in the LicoA administration group as in the GA administration group.

The evaluation result of (2) is shown in FIG. Here, thickening of the ear is shown.
As shown in FIG. 2, ear thickening was significantly increased in the non-administered group from the third week after the start of DfE application, but in the LicoA-administered group, it was suppressed as in the GA-administered group, and edema was mild. there were.

Regarding (3) and (4), the imaging data of the DfE application region of the mouse at the end of the application period is shown in FIG. FIG. 3 shows two typical examples for each group.
As shown in FIG. 3, in the non-administered group, the bleeding and erosion sites as shown by the arrows in the figure and the scratches and desquamation sites as shown by the circles are applied by the scratching behavior of the mice. Many sites were observed. This was common to all mice. The mice in the non-administered group showed symptoms corresponding to a model of atopic dermatitis. In contrast, in the LicoA-administered group, as in the GA-administered group, the bleeding and erosion sites, scratches and desquamation sites were not observed at all or were slightly suppressed. The symptoms of dermatitis were milder than in the non-administered group.

The total score of (1) to (4) is shown in FIG.
As shown in FIG. 4, in the LicoA administration group, the dermatitis symptom was slightly suppressed as compared to the non-administration group, as in the GA administration group.

Among (5), the IgE measured value in the serum 6 weeks after the start of DfE application is shown in FIG.
As shown in FIG. 5, the IgE value of the LicoA administration group was smaller than that of the non-administration group, which was consistent with the results of (1) to (4). In addition, the IgE value of the LicoA administration group was even smaller than that of the GA administration group.

The prepared paraffin section for (6) is shown in FIG. FIG. 6 shows two typical examples for each group.
As shown in FIG. 6, in all mice in the non-administered group, marked thickening of the epidermis and dermis and infiltration of inflammatory cells were observed. On the other hand, in the LicoA administration group, as in the GA administration group, thickening of the epidermis and dermis and infiltration of inflammatory cells were suppressed in all mice compared to the non-administration group.

Regarding (7), the number of dermal infiltrated mast cells is shown in FIG. 7 (a), and the number of dermis infiltrating eosinophils is shown in FIG. 7 (b).
As shown in FIG. 7, in the LicoA administration group, the number of dermal infiltrated mast cells and dermis infiltrating eosinophils were smaller than in the non-administration group, as in the GA administration group.

  As described above, clear anti-inflammatory and anti-pruritic effects were observed in the LicoA administration group.

  The present invention can be used for the treatment of dermatitis and pruritus in the medical field.

Claims (2)

  A therapeutic agent for dermatitis comprising lycochalcone A as an active ingredient.   A therapeutic agent for skin pruritus comprising lycochalcone A as an active ingredient.