JPH10109935A - External use preparation for treating skin disease - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an external use preparation for skin diseases having immediate effect because of high initial releasing property of vitamin E from a base and having effect equivalent to or more than that of external use preparation containing adrenal cortical hormone as an active ingredient and hardly having adverse effect. SOLUTION: This external user preparation comprises an ointment containing vitamin E (e.g. vitamin E acetic acid ester) and squalane and the content of vitamin E is >2wt.% and <=70wt.% and the content of squalane is 2-70wt.% and the external preparation has high vitamin E initial release property from the base (preferably >=10% release ratio of vitamin E from an ointment base after 3hr from starting release examination). Hydrocarbon gel, macrogol, etc., is used as the base.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

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

[0002]

2. Description of the Related Art Conventionally, external preparations containing corticosteroids have been widely used for the treatment of skin diseases, especially for intractable skin diseases such as atopic dermatitis and contact dermatitis. It is known to be highly effective (Monthly Pharmaceutical Affairs; 26, 8, 55, 1984). And Japanese Patent Application Laid-Open No. Sho 62-1496.
No. 20 discloses an external preparation containing corticosteroid as a main active ingredient.

[0003] However, topical corticosteroids are
For the application site, increased susceptibility, thinning of the skin,
The drug may cause side effects such as weakening of the blood vessel wall and abnormal activation of the pilosebaceous system.In addition, there is the possibility that transdermally absorbed drugs may cause systemic side effects. Attention is needed. For this reason, in the Japanese Pharmacopoeia, the upper limit of the concentration of dexamethasone and prednisolone, which are typical corticosteroids, is regulated to about 0.1 to 0.5% by weight in the external preparation.

On the other hand, external preparations for treating skin diseases having few side effects include external preparations composed of non-steroidal anti-inflammatory drugs and antihistamines. However, for the above-mentioned intractable skin diseases, corticosteroids are used. Its effects are very weak compared to those containing (new drugs and treatments; 25,298,41,1984).

[0005] In order to solve these problems, the present inventors have proposed that an external preparation for the treatment of skin diseases containing vitamin E and squalane has been effective for the above-mentioned intractable skin diseases. Have found it expensive. However, depending on the base of the ointment, the initial release of the active ingredient is poor,
Even if vitamin E and squalane were contained, the effect was sometimes low.

[0006]

DISCLOSURE OF THE INVENTION The present invention has been made to solve the above problems, and an object of the present invention is to provide an immediate effect due to a high initial release of vitamin E from a base, and to provide an effective use of corticosteroids. An object of the present invention is to provide an external preparation for treating skin diseases which has an effect equal to or higher than that of an external preparation as a component and has few side effects.

[0007]

The external preparation for treating skin diseases according to the present invention comprises an ointment containing vitamin E and squalane, the content of vitamin E being more than 2% by weight and not more than 70% by weight, and squalane. Is 2 to 70% by weight, and the initial release of vitamin E from the base is high.

[0008] The above-mentioned vitamin E refers to tocopherol (vitamin E) and its derivatives. Examples of those listed in the Japanese Pharmacopoeia include dl-α-tocopherol, tocopherol acetate (vitamin E acetate), and succinic acid. Tocopherol calcium acid (vitamin E
Succinate) and the like. Examples not listed in the Japanese Pharmacopoeia include, for example, α-tocopherol, β-tocopherol, γ-tocopherol, δ-tocopherol, tocopherol nicotinate (vitamin E nicotinate), tocopherol phosphate (vitamin E phosphate) and the like. Is mentioned.

The above-mentioned squalane is used to reduce squalene which is an unsaturated hydrocarbon present in liver oil or vegetable oil of deep-sea fishes, particularly sharks, for example, olive oil, rice bran oil, wheat germ oil, sesame oil and cottonseed oil. Is a saturated hydrocarbon. Further, a synthetic squalane obtained by using geranylacetone and an acetylene compound as raw materials is also included.

[0010] Vitamin E and squalane are both weak but have a therapeutic effect on skin diseases. However, if the content in the external preparation is small, the therapeutic effect on intractable skin diseases as described above is weak, and if too large, the external preparation is not effective. Is difficult to maintain. Therefore, the content in each external preparation is limited to more than 2% by weight and 70% by weight or less of vitamin E, preferably 5 to 60% by weight, and most preferably 1 to 60% by weight.
0 to 50% by weight, and squalane is 2 to 70% by weight.
And preferably 5 to 60% by weight, most preferably 10 to 50% by weight. Further, the total content of vitamin E and squalane in the external preparation is preferably 5 to 70% by weight, more preferably 10 to 60% by weight.

[0011] The dosage form of the external preparation of the present invention is limited to an ointment prepared by dissolving or mixing and dispersing the above-mentioned drug in a base to form a paste, jelly, cream, gel or the like. In addition, usually, the cream-shaped one is called a cream, and the gel-shaped one is called a gel.These creams and gels are also included in the ointment in the present invention. Shall be

The above-mentioned base may be any pharmaceutically acceptable base, and those conventionally known as bases for ointments can be used. As the base, for example, hydrocarbon gel (for example, trade name: Plastibase, manufactured by Taisho Pharmaceutical Co., Ltd.); fat; lanolin such as reduced lanolin; petrolatum such as white petrolatum; paraffin; waxes such as beeswax; resin; Glycols such as propylene glycol and polyethylene glycol (for example, macrogol); higher alcohols such as cetyl alcohol and stearyl alcohol; higher fatty acids such as stearic acid; glycerins such as fatty acid glycerin and lipophilic glyceryl monostearate; water; Nonionic surfactants such as oxyethylene sorbitan laurate, emulsifiers such as ionic surfactants; gelatin, gum arabic, tragacanth gum, methylcellulose, hydroxypropylcellulose, hydroxymethylcellulose, Vinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymers include suspending agents such as pluronics.

When the above-mentioned base is used alone,
Even if the release of vitamin E is low, the release can be enhanced by devising the shape such as cream or gel by using two or more of the above bases in combination.

[0014] If necessary, a dissolving agent such as isopropyl myristate, medium-chain fatty acid triglyceride, oleic acid, ethanol, D-sorbitol, etc .; BHT, EDT
A, stabilizers such as gallic acid esters; preservatives and bactericides such as benzoic acids, sorbic acids, and paraoxybenzoic acid esters; pH regulators such as NaOH, HCl, and phosphoric acid may be added.

The external preparation for treating skin diseases of the present invention needs to have a high initial release of vitamin E from the base. The above-mentioned releasability is determined according to the Japanese Pharmacopoeia Dissolution Test Method 2 and specifically, the sample (ointment) is contained in a test solution.
Vitamin E released into the test solution from the ointment base
The amount is determined over time, and is determined as a release rate with respect to the amount of vitamin E in the original sample.

In the external preparation for treating skin diseases of the present invention, it is particularly preferable that the release rate of vitamin E from the ointment base is 10% or more by 3 hours after the start of the release test.

The amount of the external preparation for treating skin diseases of the present invention varies depending on the type of the disease, the degree of the symptoms, the size of the affected part, etc., but the amount of the external preparation is preferably 0.01 to 10 g per day. Yes, and apply it to the affected area once or at appropriate times.

The diseases to be treated by the external preparation for treating skin diseases according to the present invention include, for example, rough skin, rash, heat rash, soreness, rash, diaper rash, atopic dermatitis, contact dermatitis, seborrheic skin Inflammation, lichen widdard, eczematous eczema, housewife eczema, sun dermatitis, insect bites, skin pruritus, prurigo, drug eruption, toxic rash, psoriasis, psoriasis, palmoplantar pustulosis,
Lichen planus, lichen planus, psoriasis piliformis, pike rosacea pityris, erythema, erythroderma, lupus erythematosus, lupus erythematosus, pemphigus, pemphigoid, juling Herpes dermatitis, vitiligo vulgaris, sarcoidosis, cutaneous amyloidosis, keloids, hypertrophic scars, wounds, pressure sores, skin ulcers and the like.

[0019]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described with reference to embodiments. (Example 1) (Oil-based ointment) Plastibase (Taisho Pharmaceutical) 72 parts by weight Tocopherol acetate (Wako Pure Chemical Industries) 3 parts by weight Squalane (Wako Pure Chemical Industries) 25 parts by weight Kneading well with the above composition An ointment was prepared.

(Example 2) (Oil-based ointment) Plastibase (manufactured by Taisho Pharmaceutical Co., Ltd.) 62 parts by weight Tocopherol acetate (manufactured by Wako Pure Chemical Industries) 13 parts by weight Squalane (manufactured by Wako Pure Chemical Industries) 25 parts by weight The mixture was kneaded to prepare an ointment.

(Example 3) (Oil-based ointment) Plastibase (manufactured by Taisho Pharmaceutical) 35 parts by weight Tocopherol acetate (manufactured by Wako Pure Chemical Industries) 55 parts by weight Squalane (manufactured by Wako Pure Chemical Industries) 10 parts by weight Good in the above composition The mixture was kneaded to prepare an ointment.

(Example 4) (Hydrophilic ointment) Macrogol ointment (manufactured by Maruishi Pharmaceutical Co., Ltd.) 72 parts by weight Tocopherol acetate (manufactured by Wako Pure Chemical Industries) 25 parts by weight Squalane (manufactured by Wako Pure Chemical Industries) 3 parts by weight And kneaded well to prepare an ointment.

(Example 5) (Hydrophilic ointment) Macrogol ointment (manufactured by Maruishi Pharmaceutical Co., Ltd.) 62 parts by weight Tocopherol acetate (manufactured by Wako Pure Chemical Industries) 25 parts by weight Squalane (manufactured by Wako Pure Chemical Industries) 13 parts by weight And kneaded well to prepare an ointment.

(Example 6) (Hydrophilic ointment) Macrogol ointment (manufactured by Maruishi Pharmaceutical Co., Ltd.) 35 parts by weight Tocopherol acetate (manufactured by Wako Pure Chemical Industries) 10 parts by weight Squalane (manufactured by Wako Pure Chemical Industries) 55 parts by weight And kneaded well to prepare an ointment.

(Example 7) (Cream) Tocopherol acetate (manufactured by Wako Pure Chemical Industries) 10 parts by weight Squalane (manufactured by Wako Pure Chemical Industries) 20 parts by weight Beeswax (manufactured by Astra Japan) 6 parts by weight Setanol (Kawaken Fine Chemical) 5 parts by weight Reduced lanolin (manufactured by CRODA) 8 parts by weight Isopropyl myristate (manufactured by NOF Corporation) 7 parts by weight Fatty acid glycerin (manufactured by Henkel) 4 parts by weight Lipophilic glycerin monostearate (manufactured by NOF Corporation) 2 parts by weight Polyoxyethylene sorbitan laurate ester 2 parts by weight (Nikko Chemical Co., Ltd.) Propylene glycol (Wako Pure Chemical Industries, Ltd.) 5 parts by weight Purified water 31 parts by weight Tocopherol acetate, squalane,
Beeswax, cetanol, reduced lanolin, isopropyl myristate, fatty acid glycerin and lipophilic glyceryl monostearate were heated and melt-mixed, and then other components were added and emulsified to prepare a cream.

Example 8 (Gel) Tocopherol acetate (manufactured by Wako Pure Chemical) 20 parts by weight Squalane (manufactured by Wako Pure Chemical) 10 parts by weight Stearyl alcohol (manufactured by Nakarai Tesque) 25 parts by weight Stearic acid (Nacalai) 5 parts by weight of polyethylene glycol (manufactured by Wako Pure Chemical Industries, Ltd.) 40 parts by weight The above composition was kneaded well to prepare a gel agent.

(Comparative Example 1) Beeswax (manufactured by Astra Japan) 70 parts by weight Tocopherol acetate (manufactured by Wako Pure Chemical Industries) 10 parts by weight Squalane (manufactured by Wako Pure Chemical Industries) 20 parts by weight An ointment was prepared.

(Comparative Example 2) Plastibase (manufactured by Taisho Pharmaceutical) 98 parts by weight Tocopherol acetate (manufactured by Wako Pure Chemical Industries) 1 part by weight Squalane (manufactured by Wako Pure Chemical Industries) 1 part by weight An ointment was prepared.

(Comparative Example 3) White Vaseline (manufactured by Maruishi Pharmaceutical Co., Ltd.) 99.5 parts by weight Prednisolone (manufactured by Wako Pure Chemical Industries) 0.5 part by weight The above composition was kneaded well to prepare an ointment.

The external preparations obtained in the above Examples and Comparative Examples were subjected to the following tests 1 to 4. Each test was performed with n = 5, and the obtained results are average values.

[Test Example 1] Measurement of release properties The ointment obtained in the above Examples or Comparative Examples was 42 mm in diameter.
The sample was weighed on an ointment disk having a depth of 1 mm, used as a sample, and tested with a 60 (V / V)% aqueous 2-propanol solution (900 ml) at 32 ° C. and 100 revolutions per minute according to the Japanese Pharmacopoeia dissolution test second method. Was. Release test start 1, 3, 6, and 2
The test liquid was collected after 4 hours. The amount of tocopherol acetate in the collected test solution was quantified by liquid chromatography. From these results and the following formula, the release rate (%) A with respect to the amount of tocopherol acetate in the sample was determined, and the release rate at each sampling time is shown in Table 1.

A = (B / C) × 100 where B is the amount of tocopherol acetate in the test solution (m
g) C: amount of tocopherol acetate in the sample (mg)

Test Example 2 Effect on Rat Delayed Contact Skin Hypersensitivity Reaction (Type IV Allergic Reaction) The abdominal skin of 5-week-old Wistar rats was shaved, and then 20% 2,4-dinitrochlorobenzene ( DNCB,
20 μl of an acetone solution (manufactured by Wako Pure Chemical Industries, Ltd.) was applied and left for 2 weeks to sensitize. After creating the feeling, the back skin was shaved.
A contact dermatitis was induced by applying 20 μl of a 5% DNCB acetone solution. Next, 0.1 g of the ointment obtained in the above example or comparative example was placed on a circular polyethylene sheet piece having a radius of 1 cm and applied to the site of DNCB reaction induction in rat skin.

Immediately thereafter, 0.5% Evans'blue physiological saline solution was intravenously injected at a rate of 2.5 ml / kg (a sample not administered with Evans blue was also prepared).

With respect to the rats to which the above-mentioned Evans blue was administered, the animals were sacrificed one hour later, and the dye leaked to the skin at the reaction site was analyzed by the method of Harada et al. (Journal of Pharmaceuti
cs Pharmacology; 23,218,1971), the skin at the reaction site was cut into small pieces, and immersed and left in a mixed solution of 0.3% sodium sulfate aqueous solution: acetone = 3: 7 (volume ratio) for 48 hours or more to extract leaked pigment. did. Then, the extracted pigment was added to 6
Colorimetric determination was performed at 20 nm. As a control, instead of the above-mentioned ointment, only the ointment base (the ointment base corresponding to each of Examples and Comparative Examples) was applied in the same manner, and then the same operation was performed to perform colorimetric quantification of the extracted pigment. . From the quantitative results of the pigment extraction amount (D) at the control application site and the pigment extraction amount (E) at the ointment application site, the pigment leakage inhibition rate of edema occurring 1 hour after induction was calculated by the following formula. The results are shown in Table 1. Dye leakage inhibition rate (%) = {(DE) / D} × 100

For the rats to which Evans Blue was not administered, the erythema intensity at the reaction site was measured 24 hours after the induction of the reaction by using a colorimeter (CR-200, manufactured by Minolta).
Was measured. As a control, instead of the above-mentioned ointment, only an ointment base (an ointment base corresponding to each of Examples and Comparative Examples) was similarly applied, and then the same operation was performed to measure the erythema intensity. From the measurement results of the erythema intensity (F) at the control application site and the erythema intensity (G) at the ointment application site, the erythema suppression rate of erythema that developed 24 hours after induction was calculated by the following formula. The results are shown in Table 1. Erythema inhibition rate (%) = {(FG) / F} × 100

[Test Example 3] Influence on body weight due to change in body weight [0037] The body weight of all rats subjected to the measurement of erythema intensity in Test Example 2 before and after the test was measured, and the effect of side effects on the whole body was determined from the change. Was. The results are shown in Table 1.

[Test Example 4] Evaluation of feeling of use by sensory test The external preparation obtained in the above example was applied to five human skins, and the feeling of use was evaluated according to the following criteria, and the average value was determined. Was. The results are shown in Table 1. Evaluation criteria 0: Stickiness, flow, etc. are remarkable, and usability is poor 1: Stickiness, flow, etc. are recognized. 2: No stickiness, no flow, etc., very good usability

[0039]

[Table 1]

Table 1 also shows the contents (% by weight) of tocopherol acetate, squalane and prednisolone in each external preparation.

[0041]

The external preparation for the treatment of skin diseases according to the present invention is as described above, and has an immediate effect due to the high initial release of vitamin E from the base, and also contains adrenocortical hormone as a main component. Has fewer side effects than external preparations. Therefore, an external preparation useful for treating various skin diseases can be obtained.

Claims (2)

[Claims] 1. An ointment containing vitamin E and squalane, wherein the content of vitamin E exceeds 2% by weight.
An external preparation for the treatment of skin diseases, characterized in that the content of squalane is 0% by weight or less and the squalane content is 2 to 70% by weight, and the initial release of vitamin E from the base is high. 2. The release rate of vitamin E from an ointment base is as follows:
2. A value of 10% or more by 3 hours after the start of the release test.
An external preparation for treating skin diseases according to the above.