JPH08109128A - Preparation for treating allergic dermatopathy for external use - Google Patents

Abstract

PURPOSE: To obtain a preparation for external use having excellent therapeutic effects on allergic dermatitis, especially atopic dermatitis. CONSTITUTION: This preparation for treating allergic dermatitis for external use contains at least one or more selected from docosahexaenoic acid and eicosapentaenoic acid and ester derivatives thereof as active ingredients.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an external preparation for treating allergic skin diseases.

[0002]

2. Description of the Related Art In recent years, allergic skin diseases have rapidly increased due to changes in living environment, complication, and changes in eating habits. This allergic skin disease includes atopic dermatitis, psoriasis, contact dermatitis, etc., all of which are recurrent and accompanied by severe pruritus. Mast cells, eosinophils, and Langerhans cells of the skin are involved in the development of these skin diseases, and histamine, eosinophil chemotactic factor (ECF) from these cells by the skin cells receiving specific antigen presentation. -A), leukotrienes which are arachidonic acid metabolites, or chemical mediators such as thromboxane are released. It is believed that allergic skin diseases develop due to the action of these chemical mediators.

For such allergic skin diseases,
Conventionally, various treatment methods such as improvement of living environment, avoidance of allergen by dietary therapy, administration of anti-allergic agents and steroid agents have been performed. In recent years, therapeutic methods using immunosuppressive agents such as cyclosporine have been tried. However, since steroids, which play a central role in the above-mentioned treatments, have strong side effects, there is a problem that application to infants and long-term administration must be avoided. Moreover, recently, there have been many reports of intractable cases in which sufficient improvement is not observed even with such steroid drugs. In addition, cyclosporine, which is used as an immunosuppressant, can cause serious renal damage, requiring careful administration. As described above, in spite of the rapid increase in the number of patients, a definitive treatment method for allergic skin diseases has not yet been established. Therefore, there is a strong demand for a therapeutic drug that does not cause side effects such as steroids and cyclosporine and is safe and that can provide a sufficient therapeutic effect.

By the way, docosahexaenoic acid and eicosapentaenoic acid are long-chain essential fatty acids mainly contained in fish fat, and they have been found to have various actions such as prevention of hypertension and prevention of skin aging. It is used as a food material for promoting health. In addition, these fatty acids have higher affinity for cyclooxygenase and lipoxygenase, which are enzymes for metabolizing arachidonic acid, than arachidonic acid itself, so they are metabolized in place of arachidonic acid, resulting in inflammation and allergic reaction. It has been suggested that the production of chemical mediators may be suppressed (Prostaglandins vol.20, p401-410, 1981). Therefore, it is reported that these fatty acids are expected to have therapeutic effects on allergic diseases, and in fact, oral administration of eicosapentaenoic acid has been shown to improve atopic dermatitis (Therapeutics vol.28, p709, 1994). ).

[0005]

Means for Solving the Problems The present inventor has conducted extensive studies in the hope that such docosahexaenoic acid and eicosapentaenoic acid will be excellent therapeutic agents for allergic skin diseases. The present invention has been completed by confirming that a remarkable therapeutic effect can be obtained by directly administering this external preparation to the disease site.

That is, the present invention provides an external preparation for the treatment of allergic skin diseases, which contains, as an active ingredient, at least one selected from docosahexaenoic acid, eicosapentaenoic acid, and ester derivatives thereof. . The external preparation of the present invention is characterized by high safety and excellent therapeutic effect. Surprisingly, a remarkable therapeutic effect is observed even for intractable diseases which are not improved by steroid therapy.

The docosahexaenoic acid and eicosapentaenoic acid used in the present invention can be easily obtained by hydrolyzing natural glycerin esters obtained from fish fat and the like to remove the glycerin moiety. As the docosahexaenoic acid and eicosapentaenoic acid of the present invention, for example, salts with sodium or potassium can be selected.

Examples of the ester derivative of docosahexaenoic acid or eicosapentaenoic acid used in the present invention include glycerin esters and lower alkyl esters. Of these, glycerin esters can be easily extracted from natural resources as natural glycerin esters as described above. On the other hand, lower alkyl esters can be easily produced by dehydration condensation of docosahexaenoic acid or eicosapentaenoic acid with an aliphatic lower alcohol. Examples of such lower alkyl esters include methyl ester, ethyl ester, propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, t-butyl ester and the like, preferably methyl ester, ethyl ester, propyl ester. And particularly preferably ethyl ester.

The contents of docosahexaenoic acid and eicosapentaenoic acid, and their ester derivatives in the external preparation of the present invention are not particularly limited, but when these are used alone, the content is based on the total weight of the preparation. On the other hand, it may be in the range of 0.01 to 40% by weight,
More preferably within the range of 20% by weight, 0.1-1
It is particularly preferable if it is 0% by weight. When two or more components selected from these are contained at the same time,
The total content of these compounds may be in the range of 0.01 to 40% by weight based on the total weight of the preparation,
More preferably within the range of 20% by weight, 0.1-1
It is particularly preferable if it is 0% by weight.

The external preparation provided by the present invention is not particularly limited as long as the active ingredient can be directly administered to the topical surface of the skin, and examples thereof include oily ointment, emulsion ointment (cream), water-soluble ointment. Ointment, gel, lotion, etc.
Although preparations such as tapes and patches can be used,
Of these, emulsion ointments and lotions are preferred. These preparations can be prepared by a method known per se in the field of pharmaceutics.

The external preparation of the present invention comprises, if necessary, an external preparation base, an absorption promoter, which is commonly used in the field of external preparations.
Moisturizer, thickener, emulsifier, colorant, fragrance, antioxidant,
Stabilizers, bactericides, preservatives and the like can be contained.
Here, examples of the external preparation base include white petrolatum, cetanol, stearyl alcohol, stearic acid, white beeswax, liquid paraffin, lauromacrogol, squalane, squalene, lanolin, isobutyl myristate, and medium-chain fatty acid triglyceride. Among them, white petrolatum, squalane, cetanol, stearyl alcohol and the like are preferable. Examples of the absorption promoter include urea, crotamiton, diethyl sebacate, diisopropyl adipate and the like. Examples of the moisturizing agent include polyhydric alcohols such as glycerin, sorbitol, propylene glycol, 1,3-butanediol, sodium pyrrolidonecarboxylate, and sodium hyaluronate. Among them, glycerin, propylene glycol, sodium hyaluronate and the like are preferable. As the thickener, gum arabic, guar gum, locust bean gum, carrageenan, carboxymethyl cellulose, sodium carboxymethyl cellulose, polyacrylic acid salts, polyacrylic acid esters, natural latex, vinyl acetate resin emulsion, polyvinyl alcohol, hydroxypropyl cellulose, Examples thereof include hydroxypropylmethyl cellulose, and among them, polyacrylic acid salts, carboxymethyl cellulose / sodium, etc. are preferable. As the emulsifier, glycerin fatty acid ester, sucrose fatty acid ester (sugar ester), sorbitan fatty acid ester, propylene glycol fatty acid ester, lecithin,
Examples thereof include polyoxyethylene fatty acid ester, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, and the like. Among them, polyoxyethylene castor oil, polyoxy Ethylene fatty acid ester, glycerin fatty acid ester and the like are preferable. Examples of the fragrance include eucalyptus oil, lavender oil, menthol, peppermint oil, rose oil, orange oil, cherry flavor, fruit flavor, vanillin, vanilla flavor and the like. As the antioxidant, L-ascorbic acid, ascorbic acid stearic acid ester, ascorbyl palmitate, sodium ascorbate, erythorbic acid, sodium erythorbate, isopropyl citrate, dl-α-tocopherol, d-δ-tocopherol, dibutylhydroxytoluene. (BHT), butylhydroxyanisole (BH
A) and the like can be mentioned, but among them, ascorbyl palmitate, ascorbic acid stearate, L-ascorbic acid, dl-α-tocopherol, d-δ-tocopherol and the like, or a combination thereof is preferable. As a stabilizer, polysorbate, polyethylene glycol, ethanol, acetone, light anhydrous silicic acid, EDTA
Etc. Examples of preservatives include paraoxybenzoic acid esters, benzalkonium chloride, sorbic acid, phenol, chlorobutanol, chlorocresol and benzyl alcohol.

In addition, the external preparation of the present invention may contain at the same time medicinal ingredients such as steroids, antiallergic agents and immunosuppressants, which have been conventionally used for treating allergic skin diseases. it can.

The administration of the external preparation of the present invention can be varied over a wide range depending on the symptoms, the area of the onset site, the age, the body weight, the mode of administration of the drug, etc.
A dose in the range of 1-5 g is standard and usually 1
Apply directly to the affected area once or several times a day.

[0014]

[Examples] The external preparations of the present invention will be described in more detail below with reference to test examples and pharmaceutical formulation examples in which they were actually administered to patients. However, such description does not limit the present invention at all. Needless to say.

Test Example 1 (1) A 7-month-old boy. From around 2 months after birth, wet eczema appeared on the face, trunk, and extremities, and gradually worsened. An allergy test at 3 months of age showed IgE 53.8 IU / ml, egg 3+, and milk 3.1+, but wheat, rice, soybean, house dust, and mites were <1 negative. About 3 months after birth, started to take atopic milk, intal, and apply mild steroid ointment. However, since the symptoms are not improved by the above treatment, the treatment with the external preparation of the present invention was started 7 months later. As the external preparation of the present invention, the external preparation described in Formulation Example 1 below was used, and about 1 g was applied directly to the affected area twice a day. As a result, a prominent improvement was observed in which most eczema disappeared one week after the start of treatment with this drug. In addition,
During the observation period, no side effects or abnormalities in the affected area were observed.

(2) A 7-month-old boy. Eczema appeared mainly on the face from about 1 month after birth, and steroid ointment was sometimes applied, but the symptoms gradually worsened. Allergy test at 3 months old showed IgE5.2IU / ml, egg white, milk,
Negative of <1 for wheat, rice, soybean, house dust and mite. Started taking antiallergic agents from about 3 months after birth. Mothers were prohibited from eating eggs because they were breast milk. Five months after birth, the baby food without eggs was started. But,
Since the symptoms still do not improve with the above treatment,
The treatment with the external preparation of the present invention was started about 7 months after birth. As the external preparation of the present invention, the external preparation described in Formulation Example 1 below was used, and about 1 g was applied directly to the affected area twice a day. As a result, erythema, crust, scales, erosion, thickening, etc. were observed on the face, elbow joint, and lower leg at the start of treatment, but one week later, erythema
The scales and erosion disappeared, and only a slight thickening remained after 3 weeks. No side effects or abnormalities in the affected area were observed during the observation period.

(3) A 4-month-old boy. From around 4 months, erythema and papule scars began to be recognized on the face, so treatment with the external preparation of the present invention was started. As the external preparation of the present invention, the one described in Formulation Example 1 below is used, and about 1 g
Once, it was applied directly to the affected area. As a result, the above symptoms disappeared and healed one week after the start of treatment. When administration was continued for 3 weeks thereafter, no side effects or abnormalities in the affected area were observed and the patient was completely cured.

Test Example 2 The symptoms of the affected area of patients with atopic dermatitis were scored according to the following criteria, and the clinical effects of the external preparation of the present invention were quantitatively examined. The symptom scores are as follows: erythema, papules, scales, crusts, pruritus, infiltration, thickening, scratches, and erosion of 9 items, the degree of each symptom is high (3), moderate (2),
It was evaluated in four grades of mild (1) and no symptom (0), and the total of the numerical values was used as the symptom score at the time of observation. As the external preparation of the present invention, the external preparation described in Formulation Example 6 below was used, and the symptoms were observed at 1-week intervals. The results are shown in Table 1 below.

[0019]

[Table 1]

Of the cases shown in Table 1, in cases 2 to 8, antiallergic agents and / or steroid agents generally used for atopic dermatitis were administered as pretreatment agents, but improvement was observed. It is a patient with refractory atopy who was not treated. Cases 1, 3 and 7 were treated with the external preparation of the present invention alone, and other cases were treated with an antiallergic agent in combination. As a result, the external preparation of the present invention showed a remarkable therapeutic effect on atopic skin diseases regardless of whether or not it was used in combination.

Formulation examples of the external preparation of the present invention are shown below. Formulation Example 1 (Cream) N Neopowder DHA20 (manufactured by NOF CORPORATION) 3.0 g Contents: docosahexaenoic acid triglyceride about 4.4% eicosapentaenoic acid triglyceride about 1.2% white petrolatum 2.5 g stearyl alcohol 2.0 g Propylene glycol 1.2 g Polyoxyethylene hydrogenated castor oil 60 0.4 g Glycerin monostearate 0.1 g Methyl paraoxybenzoate 0.01 g Propyl paraoxybenzoate 0.01 g Purified water Residual total amount 13.0 g

Formulation Example 2 (Cream) docosahexaenoic acid 1.5 g eicosapentaenoic acid 1.5 g white petrolatum 4.0 g cetanol 1.0 g salami beeswax 0.5 g sorbitan sesquioleate 0.5 g lauromacroma Goal 0.05 g Ethyl paraoxybenzoate 0.01 g Butyl paraoxybenzoate 0.01 g Purified water Residual total amount 13.0 g

Formulation Example 3 (cream) docosahexaenoic acid 3.0 g white petrolatum 4.0 g cetanol 1.0 g salami beeswax 0.5 g sorbitan sesquioleate 0.5 g lauromacrogol 0.05 g paraoxybenzoic acid Ethyl 0.01 g Butyl paraoxybenzoate 0.01 g Purified water Residual total amount 13.0 g

Formulation Example 4 (Cream) Eicosapentaenoic acid 3.0 g White petrolatum 2.5 g Stearyl alcohol 2.0 g Propylene glycol 1.2 g Polyoxyethylene hydrogenated castor oil 60 0.4 g Glycerin monostearate 0.1 g Methyl paraoxybenzoate 0.01 g Propyl paraoxybenzoate 0.01 g Purified water Residual total amount 13.0 g

Formulation Example 5 (greasy ointment) Eicosapentaenoic acid 3.0 g Zinc oxide 2.0 g Liquid paraffin 1.0 g White ointment Residual amount 13.0 g

Formulation Example 6 (Cream) Eicosapentaenoic acid 4.5 g White petrolatum 25.0 g Stearyl alcohol 15.5 g Propylene glycol 12.0 g Polyoxyethylene hydrogenated castor oil 60 4.0 g Glycerin monostearate 1.0 g Methylparaben 0.1 g Propylparaben 0.1 g d-δ-tocopherol 0.05 g Ascorbyl palmitate 0.02 g Perfume 0.1 g 1/30 M lactic acid buffer 10.0 g Purified water residual amount Total amount 100.0 g

Formulation Example 7 (Cream) Docosahexaenoic acid 4.5 g White petrolatum 25.0 g Stearyl alcohol 15.5 g Propylene glycol 12.0 g Polyoxyethylene hydrogenated castor oil 60 4.0 g Glycerin monostearate 1 0.0 g methylparaben 0.1 g propylparaben 0.1 g d-δ-tocopherol 0.05 g ascorbyl palmitate 0.02 g fragrance 0.1 g 1/30 M lactic acid buffer 10.0 g purified water residual amount total Quantity 100.0 g

Formulation Example 8 (Cream) Ethyl eicosapentaenoate 4.5 g White petrolatum 25.0 g Stearyl alcohol 15.5 g Propylene glycol 12.0 g Polyoxyethylene hydrogenated castor oil 60 4.0 g Monostearic acid Glycerin 1.0 g Methylparaben 0.1 g Propylparaben 0.1 g d-δ-tocopherol 0.05 g Ascorbyl palmitate 0.02 g Perfume 0.1 g 1/30 M lactic acid buffer 10.0 g Refined water residue Quantity Total quantity 100.0 g

Formulation Example 9 (Cream) Ethyl docosahexaenoate 4.5 g White petrolatum 25.0 g Stearyl alcohol 15.5 g Propylene glycol 12.0 g Polyoxyethylene hydrogenated castor oil 60 4.0 g Glycerin monostearate 1.0 g Methylparaben 0.1 g Propylparaben 0.1 g d-δ-tocopherol 0.05 g Ascorbyl palmitate 0.02 g Perfume 0.1 g 1/30 M lactic acid buffer 10.0 g Purified water residual amount Total amount 100.0 g

Formulation Example 10 (Cream) Ethyl eicosapentaenoate 2.0 g White petrolatum 10.0 g Squalane 10.0 g Cetyl alcohol 4.5 g Stearyl alcohol 3.0 g Polyoxyethylene hydrogenated castor oil 60 3. 0 g Glycerin monostearate (self-emulsifying type) 1.5 g Methylparaben 0.1 g 1,3-butylene glycol 5.0 g Dibutylhydroxytoluene (BHT) 0.02 g Fragrance 0.01 g Purified water All remaining amount Quantity 100.0 g

Formulation Example 11 (gel ointment) eicosapentaenoic acid 10.0 g squalene 2.0 g polyoxyethylene (20EO) cetyl ether 3.0 g glyceryl monostearate 1.0 g petrolatum 5.0 g methylparaben 0 .1 g d-.delta.-tocopherol 0.1 g propylene glycol 3.0 g carboxyvinyl polymer 1.0 g triethanolamine 1.0 g ascorbic acid 0.2 sodium g edetate 0.05g perfume 0.05g seminal Residual water production Total amount 100.0 g

Formulation Example 12 (Gel Ointment) Ethyl docosahexaenoate 3.0 g Isopropyl myristate 3.0 g Stearyl alcohol 2.0 g Polyoxyethylene hydrogenated castor oil 60 2.0 g Methylparaben 0.05 g Propylparaben 0. 1 g butylhydroxytoluene 0.02 g ascorbyl palmitate 0.05 g 1,3-butylene glycol 5.0 g 70% sorbitol liquid 5.0 g sodium edetate 0.05 g carboxyvinyl polymer 1.0 g triethanolamine 1. 0 g Fragrance 0.01 g Purified water Residual amount Total 100.0 g

Formulation Example 13 (Lotion) Eicosapentaenoic acid 1.0 g Squalene 5.0 g Monostearate polyethylene glycol (40EO) 3.0 g Glycerin monostearate 2.0 g Stearic acid 1.0 g Methylparaben 0 1 g d-δ-tocopherol 0.05 g propylene glycol 5.0 g ascorbic acid 0.1 g eucalyptus oil 0.05 g purified water residual amount total amount 100.0 ml

Formulation Example 14 (Lotion) Ethyl eicosapentaenoate 2.0 g Squalane 8.0 g Polyoxyethylene (20EO) cetyl ether 3.0 g Glycerin monostearate (self-emulsifying type) 1.0 g Cetyl alcohol 3.0 g methylparaben 0.1 g butylhydroxytoluene 0.02g ascorbyl stearate 0.02g carboxyvinyl polymer 0.1 g triethanolamine 0.1 g propylene glycol 5.0 g perfume 0.01g refining Water remaining total 100.0 ml

Formulation Example 15 (lotion) docosahexaenoic acid 2.5 g liquid paraffin 7.5 g behenyl alcohol 2.0 g beef tallow hardened oil 3.0 g purified soybean lecithin 1.0 g methylparaben 0.1 g cholesterol 0.3 g d-δ-tocopherol 0.05 g glycerin 8.0 g sodium hyaluronate 0.05 g fragrance 0.01 g purified water residual amount total amount 100.0 ml

Formulation Example 16 (Lotion) Ethyl docosahexaenoate 5.0 g Liquid paraffin 2.0 g Octyldodecyl myristate 3.0 g Polyoxyethylene hydrogenated castor oil 60 3.0 g Glycerin monostearate 2.0 g Propylparaben 0.75 g Methylparaben 0.25 g Butylhydroxyanisole 0.02 g Propylene glycol 5.0 g Sodium pyrrolidonecarboxylate 1.0 g Fragrance 0.01 g Purified water Residual total amount 100.0 ml

Formulation Example 17 (Patch) Ethyl eicosapentaenoate 1.0 g Diethyl sebacate 1.0 g Sorbitan sesquioleate 1.5 g Polyoxyethylene (20) sorbitan monooleate 0.5 g Polyacrylic acid Sodium 5.0 g Sodium carboxymethyl cellulose 3.0 g Dry aluminum hydroxide gel 0.1 g Sodium edetate 0.05 g Titanium dioxide 1.0 g Glycerin 10.0 g Gelatin 2.0 g Lavender oil 0.1 g Dibutyl Hydroxytoluene (BHT) 0.02 g Purified water Residual amount Total 100.0 g After kneading the above components uniformly, 1000 g / m 2
Spread at a ratio of ² and cut into a predetermined size to obtain a patch.

Formulation Example 18 (patch) docosahexaenoic acid 0.5 g squalane 1.0 g castor oil 0.5 g sorbitan sesquioleate 1.0 g polyoxyethylene (20) sorbitan monooleate 0.5 g poly Sodium acrylate 4.0 g Carboxyvinyl polymer 2.0 g Polyvinyl alcohol 1.0 g Aluminum glycinate 0.05 g Sodium edetate 0.03 g Glycerin 8.0 g 70% sorbitol liquid 4.0 g Eucalyptus oil 0.1 g d-δ-tocopherol 0.02 g ascorbyl palmitate 0.5 g purified water residual amount total 100.0 g After kneading the above components uniformly, 1000 g / m on the nonwoven fabric
It is spread at a ratio of ² and cut into a predetermined size to obtain the patch of the present invention.

Formulation Example 19 (Tape) Ethyl eicosapentaenoate 10.0 g Styrene-isoprene-styrene copolymer 49.88 g Rosin ester 30.0 g Liquid paraffin 10.0 g Butylhydroxyanisole 0.02 g Eucalyptus oil 0 0.1 g Total amount 100.0 g A solution obtained by mixing the above components is applied to polyester release paper so that the thickness after drying becomes 20 μm, and this is dried at 100 ° C. for 5 minutes. The obtained adhesive layer is attached to a polyester support having a thickness of 12 μm to obtain the tape preparation of the present invention.

Formulation Example 20 (tape) docosahexaenoic acid 10.0 g alicyclic saturated hydrocarbon resin 49.97 g styrene-isoprene-styrene block copolymer 20.0 g polybutene 12.0 g polyethylene glycol 400 5.0 g squalane 3.0 g butylhydroxytoluene 0.02 g fragrance 0.01 g total amount 100.0 g The solution obtained by mixing the above components was applied onto a polyester release paper so that the thickness after drying would be 20 μm. Apply and dry at 100 ° C. for 5 minutes. The obtained adhesive layer is attached to a polyester support having a thickness of 12 μm to obtain the tape preparation of the present invention.

[0041]

As shown in the above Examples, the external preparation of the present invention has an extremely excellent therapeutic effect on allergic skin diseases, and was applied to patients who are ineffective in treatment with antiallergic agents and steroids. Even in some cases, significant improvement is observed. Furthermore, there are almost no side effects as seen with steroids. Therefore, the external preparation of the present invention is expected to be an excellent therapeutic drug for allergic skin diseases such as atopic dermatitis, psoriasis, contact dermatitis, etc., especially for refractory atopic skin diseases. .

Claims (7)

[Claims] 1. An external preparation for the treatment of allergic skin diseases, which comprises, as an active ingredient, at least one selected from docosahexaenoic acid, eicosapentaenoic acid, and ester derivatives thereof. 2. An ester derivative of docosahexaenoic acid and eicosapentaenoic acid is combined with glycerin in a mono- or di-form.
Alternatively, the external preparation for treating allergic skin diseases according to claim 1, which is a triester. 3. The external preparation for treating allergic skin diseases according to claim 1, wherein the ester derivative of docosahexaenoic acid and eicosapentaenoic acid is a lower alkyl ester. 4. The external preparation for treating allergic skin diseases according to claim 3, wherein the lower alkyl ester is ethyl ester. 5. The external preparation for treating atopic skin diseases according to any one of claims 1 to 4. 6. The external preparation for treating psoriasis according to any one of claims 1 to 4. 7. An external preparation for treating contact dermatitis according to claim 1.