JP3126161B2 - External preparation for treating inflammatory skin diseases - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an external preparation for the treatment of various inflammatory skin diseases containing geranyl acetate as an active ingredient, and more particularly to the treatment of the above-mentioned diseases which has remarkable efficacy and has no fear of side effects. External preparations.

[0002]

2. Description of the Related Art Conventionally, as an external preparation for skin used for the treatment of various inflammatory skin diseases as described above, an external preparation composed of synthetic adrenocortical hormone has been widely used, and its pharmacological effect is known to be high. Have been.

[0003]

However, topical skin preparations based on synthetic corticosteroids, when applied to the skin, increase the susceptibility to infection, make the skin thinner, weaken the blood vessel wall, and increase the pilosebaceous system. In addition to causing side effects such as abnormal activation,
Transdermally absorbed drugs can have systemic side effects, and their use requires extreme caution. There is also a topical skin preparation consisting of a nonsteroidal anti-inflammatory agent and an antihistamine, but its therapeutic effect is much lower than that of a topical corticosteroid.

The present invention has been made to solve the above-mentioned problems of the conventional external preparation for treating inflammatory dermatosis, and an object of the present invention is to provide a skin comprising adrenal cortical hormone. It is an object of the present invention to provide an external preparation for treating inflammatory skin diseases, which has a pharmacological effect equal to or higher than that of an external preparation and shows little or no side effects.

[0005]

Means for Solving the Problems The inventors of the present invention have conducted intensive studies to achieve the above object, and as a result, it has been found that a naturally occurring specific substance is used in a model of inflammatory skin disease caused by type III and type IV allergy. The inventors have found that the present invention has a remarkable effect, and have completed the present invention.

That is, the external preparation for treating inflammatory skin diseases according to the present invention is characterized by containing geranyl acetate as an active ingredient in a carrier and / or excipient.

Geranyl acetate is a substance that is widely present in nature and is listed in the permission standards for cosmetic varieties, and its safety has been confirmed (J. Amer. College Toxicol. 1).
(2), 37, 1982). Geranyl acetate is widely used in cosmetics and soaps, but it has never been known that it has a therapeutic effect on inflammatory skin diseases.

[0008] The amount of the external preparation for treating inflammatory skin diseases according to the present invention depends on the type and severity of the inflammatory skin diseases, the size of the affected area, etc., but is preferably 0 per day as the amount of geranyl acetate. 0.01-1 g / 3.14 cm
It is in the range of ² . Of course, this external preparation may be applied separately 3 to 4 times / day. Since geranyl acetate is a highly safe substance as described above, there is no problem even if the applied amount is such a large amount.

The dosage form of geranyl acetate as an external preparation for skin is not particularly limited, and various forms such as cream, paste, gel, ointment, emulsion, lotion or solution and patch such as tape can be used. Dosage forms can be appropriately adopted. When the external preparation of the present invention is formed into a cream, paste, gel, ointment, milky lotion, lotion or solution, any conventionally known carriers or excipients can be widely used, for example, white petrolatum, beeswax, etc. , Liquid paraffin, glycerin, cellulose derivatives, polyethylene glycol, ointment base (Plastibase), silicone, bentonite, alcohol,
Water, starch, olive oil and the like are used alone or in combination of two or more. To form the external preparation of the present invention into a form such as a tape or other patch, the adhesive layer contains geranyl acetate at a required ratio. As the adhesive in the same layer, an acrylic adhesive, a rubber adhesive, a silicone adhesive, or the like is used.

The amount of geranyl acetate to be contained in the external preparation according to the present invention is preferably 10 to 50% by weight.
Range. The reason is that when the content is less than 10% by weight, the therapeutic effect of inflammatory skin disease is not sufficiently exhibited, and when the content is more than 50% by weight, the fluidity becomes high, and especially in the case of a cream or an ointment, the dosage form cannot be held. It is. A particularly preferred range for the content of geranyl acetate is 15 to 35% by weight.

As the method for producing and using the external preparation for skin of the present invention, the method for producing and using ordinary external preparation for skin can be applied as it is.

[0012] The pharmacological action of the external preparation for treating inflammatory skin diseases according to the present invention is, as described in the test examples described below, a model of a type 4 allergic experimental animal, which is a 4-hour xenogeneic passive cutaneous anaphylaxis (hcterologous PCA) in rats.
As an experimental animal model of response and type IV allergy, it was shown that a topical skin preparation containing a required amount of geranyl acetate exerted an effect on rat delayed skin hypersensitivity (DTH) reaction.

[0013] The inflammatory skin diseases to be treated by the external preparation of the present invention include atopic dermatitis, contact dermatitis, seborrheic dermatitis, lichen widard, monetary eczema, housewife eczema, sun dermatitis, Insect bites, pruritus cutis, prurigo, drug eruption, poisoning eruption,
Psoriasis, psoriasis psoriasis, palmoplantar pustulosis, lichen planus, lichen planus, pyophyton piliosis, doubly rose pityriasis, erythema, erythroderma,
Various skin diseases such as lupus erythematosus, lupus erythematosus, systemic lupus erythematosus, pemphigus, pemphigoid, jugular herpes dermatitis, alopecia areata, vitiligo vulgaris, sarcoidosis, cutaneous amyloidosis, keloids, and hypertrophic scars It is.

[0014]

According to the present invention, there is provided an external preparation for treating an inflammatory skin disease which has a pharmacological effect equal to or higher than that of a conventional external preparation comprising corticosteroids and has little or no side effect. Can be provided.

[0015]

EXAMPLES Next, the effects described above will be demonstrated with reference to examples of the present invention.

Example 1 (Ointment) Geranyl acetate (manufactured by Wako Pure Chemical Industries, Ltd.) 20 g Ointment base ("Plastibase" manufactured by Nippon Squibb Co., Ltd.) 80 g Total amount 100 g Geranyl acetate and ointment base were well kneaded at the above ratio, and geranyl was added. An ointment containing 20% by weight of acetate was obtained.

Example 2 (Solution) Geranyl acetate (manufactured by Wako Pure Chemical Industries, Ltd.) 20 g Olive oil 80 g Total amount 100 g Geranyl acetate was dissolved in olive oil in the above ratio.
A solution containing 20% by weight of geranyl acetate was obtained.

Example 3 (Tape preparation) 302.0 g (65 mol%) of 2-ethylhexyl acrylate, 98.0 g (35 mol%) of vinylpyrrolidone and 40.0 mg of 1,6-hexamethylene glycol dimethacrylate (0.02 mol%) was charged into a separable flask, and 400 g of ethyl acetate was further added to adjust the monomer concentration to 50% by weight. This solution was heated to a temperature of 60 ° C. under a nitrogen atmosphere, and then a polymerization initiator solution obtained by dissolving 2 g of lauroyl peroxide in a mixed solvent of 100 g of cyclohexane and 240 g of ethyl acetate was added little by little. And a solid concentration of 3
A 5% by weight acrylic adhesive in ethyl acetate was obtained.

To this ethyl acetate solution, geranyl acetate (manufactured by Wako Pure Chemical Industries, Ltd.) was added so that the content of geranyl acetate in the solid after drying was 10% by weight, and the whole liquid was uniformly dispersed with a dissolver. The mixture was mixed to prepare a coating solution.

Next, the above-mentioned coating solution was applied on release paper formed by subjecting a 38 μm-thick polyethylene terephthalate (PET) film to silicon treatment.
After drying for minutes, an adhesive base layer having a thickness of 80 μm was formed.
Then, a copolymer of PET and ethylene-vinyl acetate (P
A support having a thickness of 34 μm obtained by laminating ET-EVA) was adhered to the adhesive base layer. Thus, a tape preparation containing 10% by weight of geranyl acetate was prepared.

Comparative Example 1 An ointment containing 0.1% by weight of dexamethasone was obtained in the same manner as in Example 1, except that dexamethasone, a synthetic corticosteroid, was used instead of geranyl acetate.

Comparative Example 2 An ointment containing 0.5% by weight of prednisolone was obtained in the same manner as in Example 1 except that prednisolone, a synthetic corticosteroid, was used instead of geranyl acetate.

Test Example 1 (Effect on Type III Allergy Model) i) Preparation of Rabbit Anti-Ovalbumin Serum The method of Eda et al. (Nihon Pharmacological Journal, vol. 66, p. 237, 1970)
Year), rabbit anti-ovalbumin serum was prepared by the following method. That is, an antigen solution was prepared which was an equal volume mixed emulsion of a 2 mg / ml solution of ovalbumin (manufactured by Sigma) dissolved in physiological saline and complete Freund's adjuvant (manufactured by Difco). 0.5 ml of this antigen solution
Were injected into the left and right renal muscles of white New Zealand male rabbits weighing about 3 kg four times a week. Seven days after the final injection, blood was collected from the carotid artery, and only serum was separated and obtained, and used as rabbit anti-ovalbumin serum. The antiserum had a guinea pig 4-hour xenogeneic PCA titer of 1: 8000.

Ii) Action on rat 4 hours heterologous PCA reaction The above rabbit anti-ovalbumin serum was diluted 8-fold with physiological saline to prepare an injection solution, and 0.05 ml of the solution was injected into a male Wistar rat weighing about 200 g. Was injected intradermally.

Next, geranyl acetate 2 of Example 1
The test agent in which 0.1 g of 0% by weight ointment was placed on a circular polyethylene sheet piece having a radius of 1 cm was applied to an antiserum injection site of rat skin.

Next, 4 hours after the antiserum injection, 0.5 mg containing 2 mg / ml ovalbumin as the corresponding antigen was added.
Heterologous PCA reactions were elicited by intravenous injection of 2.5 ml / kg of a% Evans blue saline solution.

[0027] The leaked dye at the site where the intradermal reaction was induced was determined by the method of Harada et al. (J. Pharm. Pharmacol. 23, 2
18, page 1971). That is, the animal was sacrificed 30 minutes after the antigen injection, the skin of the antigen-antibody reaction area was cut into small pieces, and this was immersed in a mixture of 3 volumes of 0.3% Na ₂ SO ₄ aqueous solution and 7 volumes of acetone for 48 hours or more. The mixture was left to extract the leaked dye. The pigment extracted in this way is
Colorimetric determination was performed at 0 nm.

As a control for the above test, a placebo in which only an ointment base was placed on a piece of polyethylene sheet was used in place of the above test agent, and the other points were the same as in the above operation to determine the amount of dye extraction. did.

From the results of these quantifications, the ratio of the amount of dye extracted at the site to which the test agent was applied to the amount of dye extracted at the control site to which placebo was applied was determined, and this was defined as the dye leakage inhibition rate.

As a comparative test, Comparative Example 1 was used instead of the ointment containing 20% by weight of geranyl acetate of Example 1.
Ointment containing 0.1% by weight of dexamethasone and Comparative Example 2
Using the ointment containing 0.5% by weight of prednisolone, the other operations were performed in the same manner as described above, and the respective dye leakage inhibition rates were determined.

The results of the effect on the type III allergy model thus measured are shown in Table 1.

[0032]

[Table 1]

As is clear from the table, the ointment containing 20% by weight of geranyl acetate was used in a 4-hour xenogeneic PCA reaction in rats as a model of type III allergic skin reaction.
It shows almost the same rate of inhibition of pigment leakage as the ointment containing 0.1% by weight of dexamethasone and the ointment containing 0.5% by weight of prednisolone, and has a remarkable antiallergic activity.

Test Example 2 (Action on Type IV Allergy Model) BCG (Bacillus Calmette-Gue) suspended in physiological saline
rin) 0.2 ml of a bacterial solution (manufactured by Nippon BCG) was heated in an autoclave at a temperature of 121 ° C. for 5 minutes, and then injected intraperitoneally into 9-week-old Wistar rats.

Next, 7 days after the BCG injection, 0.1 ml of a purified tuberculin solution (manufactured by Nippon BSG) dissolved in physiological saline was injected into the back skin of the shaved hair.

Then, geranyl acetate 2 of Example 1
The test agent in which 0.1 g of 0% by weight ointment was placed on a circular polyethylene sheet having a radius of 1 cm was applied to a tuberculin injection site of rat skin.

Next, 24 hours after the injection of tuberculin, the diameter of the formed erythema was measured.

Thereafter, the animals were sacrificed, and the tuberculin reaction site was punched out with a punch having a diameter of 16 mm, and the weight of this portion was measured. A physiological saline solution was used as a reference in the above test, and the other points were the same as in the above operation.
The difference between the weight of the punched portion at the physiological saline solution injection site and the weight of the punched portion at the tuberculin reaction site was defined as the expanded weight.

As a control for the above test, a placebo having only an ointment base placed on a piece of polyethylene sheet was used in place of the above-mentioned test agent. Measurements and expansion weight measurements were made.

From the measurement results of the erythema diameter, the ratio of the erythema diameter at the site where the test agent was applied to the erythema diameter at the control site to which the placebo was applied was determined, and this was used as the erythema inhibition rate. The ratio of the swelling weight of the test agent-applied site to the swelling weight of the control site was determined as the suppression rate of swelling.

As a comparative test, the ointment containing 20% by weight of geranyl acetate of Example 1 was replaced with Comparative Example 1
Ointment containing 0.1% by weight of dexamethasone and Comparative Example 2
Using an ointment containing 0.5% by weight of prednisolone, the rest of the procedure was carried out in the same manner as described above, and the erythema suppression rate and the swelling suppression rate were determined.

Table 2 shows the inhibition rate of erythema and Table 3 shows the inhibition rate of the swelling weight, which were measured as the effects on the type IV realg model.

[0043]

[Table 2]

[0044]

[Table 3]

As is clear from these tables, in the rat delayed type skin hypersensitivity reaction which is a model of type IV allergic skin reaction, the ointment containing 20% by weight of geranyl acetate was replaced by the ointment containing 0.1% by weight of dexamethasone and the ointment containing prednisolone 0.1% by weight. It shows almost the same erythema suppression rate and swelling suppression rate as the 5% by weight ointment, indicating that it has antiallergic activity.

Claims (1)

(57) [Claims] 1. An external preparation for treating inflammatory skin diseases, comprising geranyl acetate as an active ingredient in a carrier and / or excipient.