JPH08259465A - External preparation for treating skin desease - Google Patents

Abstract

PURPOSE: To obtain an external preparation containing a nonsteroidal anti- inflammatory agent and sodium cromoglycate as active ingredients, hardly having adverse effects, having pharmacodynamic effects at least comparable to adrenocortical hormones and useful for treating skin deseases. CONSTITUTION: This external preparation contains preferably 1 to 60wt.% of a non-steroidal anti-inflammatory agent such as indomethacin, piroxicam, ketoprofen, flurbiprofen or felbinac, preferably 1 to 60wt.% of sodium cromoglycate, preferably 1 to 60wt.% of propylene glycol and if necessary, percutaneous absorption absorbefacient.

Description

Detailed Description of the Invention

[0001]

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

[0002]

2. Description of the Related Art Conventionally, an external preparation composed of a synthetic corticosteroid has been widely used for the treatment of intractable skin diseases such as contact dermatitis and atopic dermatitis, and it is known that its pharmacological effect is high. (Monthly Pharmaceutical Affairs; 26,8,55,1984
). In addition, an external preparation comprising a nonsteroidal anti-inflammatory drug or an antihistamine is also used, but the effect on the intractable skin diseases as described above is not sufficient as compared with the external preparation of corticosteroids (new drug and treatment; 35,298,1984). ).

However, synthetic external agents for corticosteroids may cause side effects at the site of application, such as increased infectivity, thinning of the skin, weakening of the blood vessel wall, and abnormal activation of the pilosebaceous system. In addition, the transdermally absorbed drug may cause systemic side effects, and conversely, if the dose is reduced, the effect is reduced, so that the administration period is extended and the side effects may be exacerbated.

On the other hand, sodium cromoglycate is highly safe and is widely used against allergic diseases and chronic dermatitis as disclosed in, for example, Japanese Patent Publication No. 5-501714 and Japanese Unexamined Patent Publication No. 3-118321. It is used. Indomethacin, piroxicam, ketoprofen, flurbiprofen, felbinac, etc. are nonsteroidal anti-inflammatory agents, and as external preparations, osteoarthritis, periarthritis of the shoulders, tendonitis, peritenitis, epicondylitis of the humerus. ,
It is used for symptoms such as muscle pain and swelling and pain after trauma.

However, it has not been disclosed so far that a nonsteroidal anti-inflammatory drug such as indomethacin, piroxicam, ketoprofen, flurbiprofen, and felbinac is used in combination with sodium cromoglycate to treat skin diseases as an external preparation. It was

[0006]

DISCLOSURE OF THE INVENTION The present invention is intended to solve the above-mentioned problems, and an object thereof is to treat skin diseases having few side effects and having the same or greater efficacy as an external corticosteroid preparation. It is to provide an external preparation.

[0007]

The external preparation for the treatment of skin diseases of the present invention comprises a non-steroidal anti-inflammatory drug, sodium cromoglycate (cromolyn, disodium cromoglycate; hereinafter referred to as "DSCG"), and propylene glycol. Contains.

Examples of the non-steroidal anti-inflammatory agent include indomethacin, piroxicam, ketoprofen, flurbiprofen, felbinac, tenoxicam, oxaprozin, thiaprofenic acid, fentiazaz, bucolom, tolmetin sodium, acemethacin, emorfazone, tiaramide hydrochloride, Mepyrizole,
Examples include tinoridine hydrochloride, loxoprofen sodium, pranoprofen, fenoprofen calcium, naproxen, ibuprofen, aluminoprofen, diflunisal, floctafenin, flufenamic acid, aluminum flufenamic acid, mefenamic acid, tolfenamic acid, among which indomethacin, It is preferable to contain one or more selected from the group consisting of piroxicam, ketoprofen, flurbiprofen, or felbinac.

The above-mentioned indomethacin and ketoprofen are listed in the Japanese Pharmacopoeia as anti-inflammatory drugs, piroxicam, flurbiprofen and felbinac are also widely used as anti-inflammatory drugs, and DSCG is widely used as an anti-allergic drug and anti-asthma drug. There is.

The content of the non-steroidal anti-inflammatory drug and DSCG in the external preparation varies depending on the kind of the non-steroidal anti-inflammatory drug, but when the content is large, it does not dissolve in the base, and especially in the case of ointments and creams Since it becomes impossible to retain the mold and the effect becomes insufficient when the mold becomes less, the amount is preferably 1 to 60% by weight, more preferably 5 to 40% by weight, and further preferably 10 to 30% by weight.

The above-mentioned propylene glycol is a non-steroidal anti-inflammatory drug and a DSCG dissolving agent, and the content in the external preparation varies depending on the amounts of the non-steroidal anti-inflammatory drug and DSCG. Since the non-steroidal anti-inflammatory drug and DSCG become insoluble when the mold cannot be retained and the amount becomes small, 1 to 60% by weight is preferable.

In the present invention, a transdermal absorption enhancer is contained in the external preparation, if necessary. When the content of the above absorption enhancer in the external preparation is large, the therapeutic effect of DSCG and the nonsteroidal anti-inflammatory agent is not particularly enhanced, but may cause skin irritation or the like on the contrary, and when it is small, the transdermal absorption effect of the drug is increased. Since it is no longer sufficient, it is preferably 0.3 to 30% by weight, more preferably 0.5 to 10% by weight.

Examples of the above-mentioned percutaneous absorption enhancer include fatty acid ester, compounds having an amide bond, and 2 to 2 carbon atoms.
The divalent carboxylic acid of 10 and its salt, polyoxyethylene alkyl ether phosphate ester and its salt, lactic acid, lactic acid ester, citric acid, etc. are mentioned.

The fatty acid ester has 10 to 18 carbon atoms.
Is a reaction product of the fatty acid of 1) with an alcohol having 1 to 20 carbon atoms. Examples of the fatty acid having 10 to 18 carbon atoms include saturated fatty acids such as capric acid, undecylic acid, lauric acid, tridecylic acid, myristic acid, palmitic acid and stearic acid; unsaturated compounds such as oleic acid, linoleic acid and linolenic acid. Fatty acid etc. are mentioned.

Examples of the alcohol having 1 to 20 carbon atoms include methanol, ethanol, propanol,
Isopropanol, butanol, isobutanol, amyl alcohol, isoamyl alcohol, hexanol,
Examples thereof include aliphatic saturated alcohols such as heptanol, octanol, capryl alcohol, nonyl alcohol, decyl alcohol, lauryl alcohol, myristyl alcohol, palmityl alcohol and stearyl alcohol, and aliphatic unsaturated alcohols such as allyl alcohol. Examples of the fatty acid ester include isopropyl myristate, isopropyl palmitate, isopropyl laurate, isopropyl stearate and the like.

The compound having an amide bond is
Examples thereof include N-acyl sarcosine, fatty acid mono- or diethanolamide and alkylene oxide adducts thereof. As the above N-acyl sarcosine,
For example, N-lauroyl sarcosine and the like can be mentioned. Examples of the fatty acid mono- or diethanolamide and alkylene oxide adducts thereof include lauroyl monoethanolamide, palmitic acid monoethanolamide, myristic acid diethanolamide, and lauric acid.
Examples thereof include myristic acid diethanolamide, coconut oil fatty acid monoethanolamide, polyoxyethylene-added lauroyl monoethanolamide, polyoxyethylene-added coconut oil fatty acid monoethanolamide, and the like.

Examples of the divalent carboxylic acid having 2 to 10 carbon atoms and salts thereof include oxalic acid, malonic acid, fumaric acid, maleic acid, tartaric acid, malic acid, succinic acid, glutaric acid, adipic acid and fumaric acid. , Isophthalic acid, terephthalic acid and the like, and salts thereof such as sodium salt, potassium salt, magnesium salt and aluminum salt.

The above polyoxyethylene alkyl ether phosphoric acid ester and its salt are phosphoric acid ester and its salt of a derivative obtained by addition-polymerizing ethylene oxide to alcohol. Examples of the alkyl group include a methyl group and an ethyl group. Group, propyl group, isopropyl group, butyl group, t-butyl group, pentyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl group, dodecyl group, lauryl group, stearyl group, palmityl group, myristyl group, cetyl group And the like. Examples of the salt include sodium salt, potassium salt, magnesium salt, aluminum salt and the like. Examples of the lactic acid ester include esters of lactic acid and alcohols having 1 to 20 carbon atoms, such as myristyl lactate and cetyl lactate. As the transdermal absorption promoter, fatty acid ester and N-acyl sarcosine are particularly preferable among the above.

The dosage form of the external preparation of the present invention is not particularly limited, and examples thereof include creams, pastes, gels, ointments, emulsions, lotions, liniments, mousses, sprays or solutions, and patches. Can be mentioned. When molding in the form of a cream, paste, gel, ointment, emulsion, lotion, liniment or solution, a conventionally known base can be used as necessary, for example, petrolatum, beeswax, hydrocarbon gel. Ointment base such as ointment (for example, trade name Plastibase, manufactured by Taisho Pharmaceutical Co., Ltd.), liquid paraffin, polyethylene glycol,
Examples thereof include cellulose, alcohol, water, starch, olive oil and the like.

The external preparation of the present invention is produced by a usual method such as well kneading each component and, if necessary, a base,
Further, it is used by a usual use method such as being applied directly to an affected area or impregnated with a cloth or the like.

The applied amount of the external preparation for treating skin diseases of the present invention varies depending on the kind of the non-steroidal anti-inflammatory agent to be blended, the kind of disease and the degree of symptoms, the size of the affected area, and the like. 1 as the amount of the anti-inflammatory drug
The daily dose is preferably 0.02 to 1 g, and this is applied in a suitable number of times.

The skin diseases to be treated by the external preparation of the present invention include skin diseases including conventional adaptation diseases of synthetic adrenocortical hormone external preparations, for example, atopic dermatitis, contact dermatitis, and greasy skin. Leaky dermatitis, Vidal lichen, coin-shaped eczema, housewife eczema, sun dermatitis, insect bite, pruritus cutaneus, prurigo, drug eruption, toxic eruption, psoriasis, psoriasis vulgaris, palmaris pustulosis,
Lichen planus, lichen planus, erythema schizophrenia, erythema erythema gingiva, erythema, erythroderma, lupus erythematosus, systemic lupus erythematosus, pemphigus, pemphigus vulgaris, Jouling Herpes dermatitis, alopecia areata, vitiligo vulgaris, sarcoidosis, cutaneous amyloidosis, keloids, hypertrophic scars and the like can be mentioned.

The pharmacological action of the external preparation for the treatment of intractable skin diseases of the present invention is as shown in the examples described below, in which non-allergic skin inflammatory reaction in rats and rat 4-hour allogeneic passive skin as an experimental animal model for type I allergy Anaphylaxis (homo
rolagous PCA) reaction and rat delayed-type cutaneous hypersensitivity reaction (DTH) as an experimental animal model of type IV allergy, and a skin external preparation containing a dose of DSCG and a non-steroidal anti-inflammatory drug was only adrenal cortex hormone. The same or higher effect was obtained as compared with the external preparation.

[0024]

EXAMPLES The present invention will be described with reference to examples. (Examples and Comparative Examples) DSCGs having the compositions shown in Tables 1 to 5,
To each ingredient such as non-steroidal anti-inflammatory drug, propylene glycol, absorption enhancer, etc., add plastibase (manufactured by Taisho Pharmaceutical Co., Ltd.) as a base, and olive oil as a liniment agent so that the total amount becomes 100. The mixture was thoroughly kneaded to obtain external preparations for treating skin diseases of Examples and Comparative Examples.

The following materials were used other than the base material. -Sodium cromoglycate (DSCG, Sigma) -Indomethacin (Sigma) -N-lauroyl sarcosine (Nacalai Tesque) -Piroxicam (Sigma) -Ketoprofen (Sigma) -Flurbiprofen (Sigma)・ Felbinac (manufactured by Sigma)

In the table, "DS" is "sodium cromoglycate", "IM" is "indomethacin" and "P".
"C" is "piroxicam", "KP" is "ketoprofen", "FP" is "flurbiprofen", "FN" is "felbinac", "PG" is "propylene glycol", and "IP" is "myristic acid". Isopropyl "," L
"S" represents "N-lauroyl sarcosine", "DM" represents "dexamethasone", and "PD" represents "prednisolone".

[0027]

[Table 1]

[0028]

[Table 2]

[0029]

[Table 3]

[0030]

[Table 4]

[0031]

[Table 5]

Test Example 1 Effect of DNCB-induced primary skin irritation reaction on non-allergic cutaneous inflammatory reaction 7-week-old Wistar rat abdominal skin was shaved, and then 2% 2,4-dinitrochlorobenzene ( 20 μl of acetone solution (DNCB, manufactured by Wako Pure Chemical Industries, Ltd.) was applied and well dried to induce non-allergic dermatitis. Then, 0.1 mg of the ointment obtained in the above-mentioned Examples and Comparative Examples or 0.1 ml of the liniment preparation were respectively applied to rat skin D
At the NCB reaction-inducing site, the ointment was placed on a circular polyethylene sheet piece with a radius of 1 cm and applied so as to contact the skin,
The liniment agent was applied directly onto the skin by covering it with a piece of circular polyethylene sheet having a radius of 1 cm.

Twenty-four hours after the induction of the reaction, the erythema intensity at the reaction site was measured by a color difference meter (CR-200, manufactured by Minolta). As a control, an ointment base or olive oil alone was applied in the same manner instead of the above-mentioned test agent, and then the same operation was performed to measure the erythema intensity. The erythema inhibition rate was calculated by the following formula from the above measurement results of the erythema intensity (A) at the control application site and the erythema intensity (B) at the test agent application site. The results are shown in Tables 1-5. Erythema suppression rate (%) = {(AB) / A} × 100

Test Example 2 Effect of PCA Reaction on Type I Allergic Reaction (1) Preparation of Rat Anti-DNP-As Serum Tada and Okumura Method (Journal of
Immunology; 106,1002,1971), rat anti-DNP
-As serum was prepared. The extract of Ascaris suum was extracted according to the method of Strejan and Campbell (Journal of Immunology; 98,893,1967), which was then extracted from the method of Eisen et al. (Journal of Ame).
rican Chemical Society; 75,4583,1953) and combined with 2,4-dinitrophenylsulfate (DNP) to give D
NP-bound Ascarisuum (DNP-As) was obtained.

1 mg of the above DNP-As was dissolved in 1 ml of physiological saline in which 1 × 10 ¹⁰ pertussis killed bacteria were suspended, and the solution was subcutaneously injected into the foot pads of female rats weighing about 200 g. Five days later, 0.5 mg of DNP-As was dissolved in 0.5 ml of physiological saline and injected into the left and right muscles. Eight days after the first injection, blood was collected from the abdominal aorta and the serum was separated to obtain rat anti-DNP-As serum.

(2) PCA reaction The above-mentioned rat anti-DNP-As serum was diluted with physiological saline and 0.05 ml of the diluted serum was injected into the dorsal skin of male rats weighing 120 to 200 g. After 45 hours, 0.1 mg of the ointment obtained in the above Examples and Comparative Examples and 0.1 ml of the liniment preparation were respectively treated with anti-DNP- of rat skin in the same manner as in Test Example 1 above. As serum was applied at the injection site. 3 hours later, 0.5% Evans' blue physiological saline solution containing DNP-As antigen was intravenously injected at a rate of 2.5 mg / kg, and P
CA reaction was evoked.

After 30 minutes, the animals were sacrificed and the dye leaked to the skin of the reaction part was analyzed by the method of Harada et al. (Journal of Pharm).
aceutics Pharmacology; 23,218,1971), the reaction skin was finely cut, and the leaked pigment was extracted by immersing the reaction skin in a mixed solution of 0.3% sodium sulfate: acetone = 3: 7 (volume ratio) for 48 hours or more. . The extracted dye was then colorimetrically determined at 620 nm. As a control, an ointment base or olive oil alone was applied in the same manner instead of the above-mentioned test agent, and then the same operation was performed to perform colorimetric quantification of the extracted pigment. The dye leakage suppression rate was calculated by the following formula based on the quantitative results of the above-mentioned amount of dye extraction (C) at the control application site and the amount of dye extraction at the test agent application site (D). The results are shown in Tables 1-5. Dye leakage suppression rate (%) = {(C−D) / C} × 100

[Test Example 3] Action and effect on type IV allergic reaction by DTH reaction 5 weeks old Wistar rats were shaved on the ventral skin, and then 20% 2,4-dinitrochlorobenzene (DNCB,
20 μl of acetone solution (manufactured by Wako Pure Chemical Industries, Ltd.) was applied and left for 2 weeks for sensitization. After creating the feeling, the back skin was shaved and 0.
20 μl of 5% DNCB acetone solution was applied to induce contact dermatitis. Next, 0.1 mg of the ointment obtained in the above Examples and Comparative Examples and 0.1 ml of the liniment preparation were applied to the rat skin DNCB reaction-inducing site in the same manner as in Test Example 1 above. .

Twenty-four hours after the reaction was induced, the erythema intensity at the reaction site was measured by a color difference meter (CR-200, manufactured by Minolta). As a control, an ointment base or olive oil alone was applied in the same manner instead of the above-mentioned test agent, and then the same operation was performed to measure the erythema intensity. From the measurement results of the erythema intensity (E) at the control application site and the erythema intensity (F) at the test agent application site, the erythema inhibition rate was calculated by the following formula. The results are shown in Tables 1-5. Erythema suppression rate (%) = {(E−F) / E} × 100

[Test Example 4] Effects on whole body due to change in body weight The body weight of the rat used in Test Example 3 above was measured,
The effects of side effects on the whole body were examined. The results are shown in Tables 1-5.

The external preparations for treating skin diseases of the present invention were found to have the same or higher effects as those of the external preparations containing adrenocortical hormones (Comparative Examples 1 and 2) in Test Examples 1, 2 and 3. In Test Example 4, the external preparation containing adrenocortical hormone had a side effect of weight loss, whereas the external preparation of the present invention did not have a side effect of weight loss. Also, with the external preparations containing the non-steroidal anti-inflammatory agent or DSCG alone (Comparative Examples 4, 5, 7, 8, 10, 13 and 14), almost no effect was observed in Test Examples 1, 2 and 3. .

[0042]

The external preparation for the treatment of skin diseases of the present invention is as described above, and it is useful for the treatment of skin diseases because it has a sufficient therapeutic effect equivalent to or more than that of the external preparation of corticosteroids, but has few side effects. The external preparation is obtained.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 47/10 A61K 47/10 G // (A61K 31/19 31:35) (A61K 31/405 31:35) (A61K 31/54 31:35)

Claims (3)

[Claims] 1. An external preparation for the treatment of skin diseases, which comprises a non-steroidal anti-inflammatory drug, sodium cromoglycate, and propylene glycol. 2. The treatment for skin diseases according to claim 1, wherein the non-steroidal anti-inflammatory agent is one or more selected from the group consisting of indomethacin, piroxicam, ketoprofen, flurbiprofen, and felbinac. Topical agent. 3. The content of the nonsteroidal anti-inflammatory drug is 1 to 6.
0% by weight, sodium cromoglycate content 1-6
0 wt% and propylene glycol content 1-6
The external preparation for treating skin diseases according to claim 1 or 2, which is 0% by weight.