JPH1087488A - Preparation for external use for treating dermatosis - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject highly spreadable and easily applicable medicinal agent having effect comparable to or higher than that of those agents with adrenocortical hormones as active ingredient, by imparting a preparation for external use with specific spreadability. SOLUTION: This medicinal agent contains a vitamin E such as dL-α- tocopherol and squalane afforded, for example, by reducing squalene-found in vegetable oil, having such a spreadability as to be 400 4,000dyne/cm<2> in terms of the yield value determined by spreadmeter method and being pref. 350-540×10<-1> mm in consistency determined by consistency test. This agent for external use is useful for treating rough skin, rash, drug exanthema, keloid, etc.

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, contact dermatitis and psoriasis. It is known that its pharmacological effect is high (Monthly Pharmaceutical Affairs; 26, 8, 55, 1984). And JP-A-62-14
No. 9620 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 heretofore determined that an external preparation for treating skin diseases containing vitamin E and squalane is effective for the above-mentioned intractable skin diseases. I found it. However, in the case of intractable skin diseases, since the hard ointment does not spread well, the application may apply irritation to the affected area and may worsen the symptoms.

[0006]

DISCLOSURE OF THE INVENTION The present invention has been made to solve the above-mentioned problems, and an object of the present invention is to provide an effect which is equal to or higher than that of an external preparation containing a corticosteroid as an active ingredient, and has good spreadability. It is an object of the present invention to provide an external preparation for treating skin diseases which is easy to treat.

[0007]

The external preparation for treating skin diseases of the present invention contains vitamin E and squalane.

[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. Acid tocopherol (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 deep-sea fish, especially in shark liver oil or in vegetable oils such as olive oil, rice bran oil, wheat germ oil, sesame oil, cottonseed oil and the like. It is a substance made. It also includes synthetic squalane obtained by synthesizing from isoprene.

[0010] The above-mentioned vitamin E and squalane are both weak, but have a therapeutic effect on skin diseases. However, if their contents are small, the therapeutic effects on the above-mentioned intractable skin diseases are weak.
If the amount is too large, it may be difficult to maintain the dosage form depending on the base. Therefore, the content of the vitamin E in the external preparation is preferably more than 2% by weight and not more than 70% by weight, more preferably 5% by weight.
More than 60% by weight, more preferably 10 to 50% by weight, and squalane is preferably 2 to 70% by weight, more preferably 5 to 60% by weight, further preferably 10 to 50% by weight. %. Therefore, a particularly preferred combination of the contents in the external preparation is 10 to 50% by weight of vitamin E and 10 to 50% by weight of squalane.

When the external preparation of the present invention is too hard, the elongation at the time of application is poor and there is a risk of irritating the affected area. When the external preparation is too soft, it is difficult to maintain the dosage form as the external preparation, so that the spreadability is reduced by the spread meter method. 400 to 40 with yield value
00 dyne / cm ² , preferably 1000 to 3
000 dyne / cm ² . In the present invention, the extensibility refers to the elongation of the external preparation, and the yield value refers to J
The maximum spreading diameter of the external preparation at 25 ° C. was measured in accordance with the spread meter method of the flow characteristic test of IS K 5101, and the following formula (Masahiko Takano, Hospital Pharmacy; 8, 3,175)
−181, 1982). In the formula, Y represents the yield value (dyne / cm ² ), G represents the weight of the parallel plate (g), V represents the amount of the sample (cm ³ ), and D represents the maximum spreading diameter (cm) of the sample at 25 ° C. Y = 19960 · GV / (πD ³ )

When the external preparation of the present invention is similarly too hard, the elongation at the time of application is poor and there is a risk of irritating the affected area. When the external preparation is too soft, it is difficult to maintain the dosage form as the external preparation. The consistency by the method is 350-540
× 10 ^-1 mm, preferably 400 to 500 × 10
^-1 mm. In the present invention, the above consistency indicates the hardness of the external preparation, and the degree of immiscibility according to the consistency test method of JIS K 2220 is measured by the method of Junichi Miyazaki et al.
20, 1, 42-46, 1960) as measured by a penetrometer.

[0013] The dosage form of the external preparation of the present invention may be, for example, a solution such as an ointment, a cream, a paste, a jelly, a gel formed by dissolving or mixing and dispersing the above drug in a base. Cream and the like), and an ointment is particularly preferred.

The above-mentioned base may be any pharmaceutically acceptable base, and those conventionally known as bases for ointments, creams and the like can be used. For example, fats; olive oil, cocoa oil, Fats and oils such as sesame oil, soybean oil, camellia oil, peanut oil, beef oil, pork oil, pork oil; waxes such as lanolin, vaseline, paraffin, beeswax; resins; plastics; glycols such as propylene glycol and polyethylene glycol; Higher alcohols such as cetyl alcohol and stearyl alcohol; glycerin; water; emulsifiers such as nonionic surfactants and ionic surfactants;
Suspending agents such as gelatin, gum arabic, tragacanth, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, carboxyvinyl polymer, pluronics and the like can be mentioned.

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 sodium hydroxide, hydrochloric acid, and dilute hydrochloric acid;

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 of the present invention include, for example, rough skin, rash, heat rash, soreness, swelling, diaper rash, atopic dermatitis, contact dermatitis, seborrheic dermatitis, Vidar moss Itch, eczematous eczema, housewife eczema, sun dermatitis, insect bite, pruritus cutaneous, prurigo, drug eruption,
Poisoning eruption, psoriasis, psoriasis, palmoplantar pustulosis, lichen planus, lichen planus, psoriasis pylori, doubly psoriasis rosacea, erythema,
Erythroderma, lupus erythematosus, lupus erythematosus, systemic lupus erythematosus, pemphigus, pemphigoid, jugular herpes dermatitis, vitiligo vulgaris, sarcoidosis, cutaneous amyloidosis, keloids, hypertrophic scars, wounds, pressure sores And skin ulcers.

[0018]

Next, embodiments of the present invention will be described. (Example 1) Plastibase (manufactured by Taisho Pharmaceutical Co., Ltd.) 72 (parts by weight) Tocopherol acetate (manufactured by Wako Pure Chemical Industries, Ltd.) 3 Squalane (manufactured by Wako Pure Chemical Industries, Ltd.) 25 The above components are kneaded well so that the whole becomes uniform. Thus, an oily ointment was prepared.

Example 2 Plastibase 62 (parts by weight) Tocopherol acetate 13 Squalane 25 The above components were thoroughly kneaded so that the whole was uniform to prepare an oily ointment.

(Example 3) Plastibase 35 (parts by weight) Tocopherol acetate 55 Squalane 10 The above components were thoroughly kneaded so that the whole was uniform to prepare an oily ointment.

(Example 4) Plastibase 72 (parts by weight) Tocopherol acetate 25 Squalane 3 The above components were thoroughly kneaded so that the whole was uniform to prepare an oily ointment.

(Example 5) Plastibase 62 (parts by weight) Tocopherol acetate 25 Squalane 13 The above components were thoroughly kneaded so that the whole was uniform to prepare an oily ointment.

(Example 6) Plastibase 35 (parts by weight) Tocopherol acetate 10 Squalane 55 The above-mentioned components were thoroughly kneaded so that the whole was uniform to prepare an oily ointment.

Example 7 Tocopherol acetate 20 (parts by weight) Squalane 10 Stearic acid (manufactured by Nacalai Tesque) 2 Stearyl alcohol (manufactured by Nacalai Tesque) 7 Isopropyl myristate (manufactured by NOF Corporation) 7 Octyldodecanol (Henkel) 6) Polyoxyethylene cetyl ether (manufactured by Nikko Chemical) 3) Lipophilic glyceryl monostearate (manufactured by NOF Corporation) 2) Propylene glycol (manufactured by Wako Pure Chemical Industries) 5) Purified water 38 Among the above components, tocopherol acetate, After heating and dissolving and mixing squalane, stearic acid, stearyl alcohol and isopropyl myristate, other ingredients were added and emulsified to prepare a cream.

(Example 8) Tocopherol acetate 10 (parts by weight) Squalane 20 Beeswax (manufactured by Astra Japan) 6 Cetanol (manufactured by Kawaken Fine Chemicals) 5 Reduced lanolin (manufactured by CRODA) 8 Isopropyl myristate 7 Fatty acid glycerin (Henkel) 4) Lipophilic glyceryl monostearate 2 Polyoxyethylene sorbitan laurate (manufactured by Nikko Chemical Co.) 2 Propylene glycol 5 Purified water 31 Of the above components, tocopherol acetate, squalane, beeswax, cetanol, reduced lanolin, myristic acid After heating and dissolving and mixing isopropyl, fatty acid glycerin and lipophilic glyceryl monostearate, other ingredients were added and emulsified to prepare a cream.

(Example 9) Tocopherol acetate 20 (parts by weight) Squalane 10 Diethyl sebacate (manufactured by Wako Pure Chemical Industries) 15 Polyoxyethylene sorbitan monostearate (manufactured by Nikko Chemical Co.) 1 4% aqueous solution of carboxyvinyl polymer (Nikko Chemical Co., Ltd. 10 Triethanolamine 2% aqueous solution (Nakarai Tesque Co., Ltd.) 4 Purified water 40 The above components were kneaded well so that the whole was uniform to prepare a gel.

(Example 10) Tocopherol acetate 10 (parts by weight) Squalane 20 Stearyl alcohol 25 Stearic acid 5 Polyethylene glycol (manufactured by Wako Pure Chemical Industries, Ltd.) 40 The above components are kneaded well to form a uniform gel. An agent was prepared.

(Comparative Example 1) White petrolatum (manufactured by Maruishi Pharmaceutical Co., Ltd.) 80 (parts by weight) Tocopherol acetate 10 Squalane 10 The above components were thoroughly kneaded so that the whole was uniform to prepare an oily ointment.

(Comparative Example 2) Plastibase 98 (parts by weight) Tocopherol acetate 1 Squalane 1 The above components were thoroughly kneaded so that the whole was uniform to prepare an oily ointment.

(Comparative Example 3) White Vaseline 99.5 (parts by weight) Prednisolone (manufactured by Wako Pure Chemical Industries, Ltd.) 0.5 The above components were thoroughly kneaded so that the whole was uniform to prepare an oily ointment. .

The following tests were carried out using the external preparation obtained above as a test agent. The test was performed with n = 5, and the obtained results are average values.

Test Example 1 Effect on TPA-induced mouse epidermal cell proliferation model G. FIG. O'Brien's method (Canser Research; 35, 16
62-1670, 1975). 20 μl of an acetone solution of 30 μg / ml of TPA (12-O-tetradecanoylphorbol-13-acetate, manufactured by Sigma) was applied to the left auricle of a 6-week-old ddy mouse, and thoroughly dried. Next, 0.1 g of the test agent obtained in the above Examples and Comparative Examples was applied to the TPA application site. Six hours after the application, the pinna thickness was measured using a dial thickness gauge. As a control, a base (plastibase) alone was applied in the same manner in place of the test agent, and thereafter the same operation was performed to measure the pinna thickness. From the measurement results of the auricle thickness (A) at the control application site and the auricle thickness (B) at the test agent application site, the auricular edema inhibition rate was calculated by the following equation. Table 1 shows the results. Pinna edema suppression rate (%) = {(AB) / A} × 100

Test Example 2 Measurement of Spreadability The maximum spread diameter was measured according to the spread meter method of a flow characteristic test according to JIS K 5101. In an environment of 25 ° C., the sample holes of the scale plate of the spread meter (manufactured by Rigo Co., Ltd.) are filled with the test agents obtained in the above Examples and Comparative Examples without any gaps, and the surface of the scale plate is spread with a spatula. It was made to be the same plane. The bottom of the sample hole was pushed up so that the bottom surface of the sample hole was flush with the scale plate, and the spread diameter when the spread of the test agent stopped was read and defined as the maximum spread diameter. Next, the method of Takano Masahiko et al. (Hospital Pharmacy; 8, 3,
175-181, 1982), the yield value was calculated from the numerical value of the maximum spreading diameter and the following formula. Table 1 shows the results. Yield value (dyne / cm ² ) = 19960 · GV / (πD
³ ) In the formula, G represents the weight of the parallel plate (115 g), V represents the amount of the sample (0.5 cm ³ ), and D represents the maximum diameter of the sample at 25 ° C. (cm).

[Test Example 3] Measurement of consistency The immiscibility consistency was measured according to the consistency test method of JIS K 2220. In an environment of 25 ° C., a test container (with an inner diameter of about 1) of a consistency tester (manufactured by Masuda Rika Kogyo Co., Ltd.)
(00 mm, depth 65 mm) were filled with the test agents obtained in the above Examples and Comparative Examples without gaps, and the surface was flattened with a spatula. After the sample container was immersed in a constant temperature water bath until the temperature reached 25 ° C., the container was taken out and the tip of a cone was brought into contact with the surface of the sample at the center of the sample container. Then divide the holder is penetrated to 5 seconds in the sample by its own weight a cone, reads an indication of the scale plate is lowered until it stops quietly rack for penetration measurement, the value of 10 ^-1 mm units and penetration . Table 1 shows the results.

[Test Example 4] Evaluation of feeling of use by sensory test The test agents obtained in the above Examples and Comparative Examples were applied to five human skins, and the feeling of use was evaluated according to the following criteria. The average was determined. Table 1 shows the results. 0: very hard, spreading is poor enough to feel resistance at the fingertip during application 1: soft, good expansion at application, but slightly resistance to fingertip 2: very soft, fingertip at application Extend without feeling resistance

"VE" in Table 1 indicates tocopherol acetate,
“SQ” represents squalane, and “PR” represents prednisolone.

[0037]

[Table 1]

[0038]

The external preparation for treating skin diseases according to the present invention is as described above, and has an equal or better therapeutic effect than that of an external preparation containing corticosteroid as an active ingredient, and has a good extension. There is little irritation to the affected area during application. Therefore, an external preparation effective for treating various skin diseases can be obtained.

Claims (4)

[Claims] 1. An external preparation containing vitamin E and squalane, which has a spreadability of 400 to 4000 dyne / cm ² as a yield value by a spread meter method. 2. An external preparation containing vitamin E and squalane, which has a consistency of 35 according to a consistency test method.
An external preparation for treating skin diseases, which has a size of ^{0 to} 540 × 10 ⁻¹ mm. 3. The content of vitamin E is more than 2% by weight and 70%.
The external preparation for treating skin diseases according to claim 1 or 2, wherein the content of squalane is 2% by weight or more and 70% by weight or less. 4. The external preparation is an ointment.
An external preparation for treating skin diseases according to the above.