TOPICAL COMPOSITION

Abstract: Pharmaceutical compositions which comprise a com­ pound of the formula (I): wherein X is a chlorine or bromine atom or a methoxyl, methylthio or alkyl group of 1-4 carbon atoms; Y is a -CHR₁-CH₂- or -CR₁=CH- group where R₁ is a hydrogen atom or a methyl group and A is a CHOH or CO group, and a topically effective pharmaceutically acceptable carrier, pos­ sess local topical anti-inflammatory activity, and possess systemic anti-inflammatory activity when administered topically.

Description: This invention relates to the treatment of inflammation by topical administration, and a pharmaceutical composition therefor. UK Patent No.1474377 discloses pharmaceutical compositions which comprise a compound of the formula (I): wherein X is a chlorine or bromine atom or a methoxy, methylthio or alkyl group of 1-4 carbon atoms; Y is a -CHR₁-CH₂- or -CR₁=CH- group where R₁ is a hydrogen atom or a methyl group and A is a CHOH or CO group, and a pharmaceutically acceptable carrier, and its use in the treatment of inflammation. The patent only teaches oral administration of the compound of formula (I). EP-A-0 021 587 discloses compounds of formula A: wherein R is a hydrogen atom or a methyl group and the dotted line represents an optional double bond when R is a methyl group. Such compounds are disclosed as being topically effective anti-inflammatory agents. We have now found that the compounds of the formula (I) unexpectedly possess local topical anti-inflammatory activity, and possess systemic anti-inflammatory activity when administered topically. Accordingly, the present invention provides the use of a compound of formula (I) for the manufacture of a medicament for the treatment or prophylaxis of inflammation by topical administration to mammals, including humans. The compounds of formula (I) will be administered as a pharmaceutical composition for topical administration, for example as a cream, ointment, lotion or gel. The compounds of formula (I) may be used in the topical treatment of atopic and contact dermatitis, psoriasis, eczema and other inflammatory dermatoses and in inflammatory conditions of eyes, ears, nose and throat. They may also be used in the treatment by topical administration of osteo- and rheumatoid arthritis and sprains, strains, tendinitis and bursitis. It will be appreciated that the topically effective amount of the compound of the formula (I) used will depend on a number of factors such as the nature and severity of the disorder being treated, and the specific compound being used. However, by way of illustration it is believed that effective therapy can be achieved using roughly similar amounts of the compounds of formula (I) as would be used of hydrocortisone. A typical formulation suitable for treating an adult human will suitably contain 0.1 to 10%, more suitably 0.5 to 5% of the compound of formula (I). A topical pharmaceutical composition for the method of treatment of the present invention may be administered from 1 to 6 times daily, and more usually from 2 to 4 times daily. The present invention also provides a topically effective anti-inflammatory pharmaceutical composition which comprises a compound of formula (I) together with a topical pharmaceutically acceptable carrier. Cream, ointment, lotion or gels, that may be used for compounds of the formula (I) are conventional formulations well known in the art, for example, as described in standard text books of pharmaceutics and cosmetics, such as Harry's Cosmeticology published by Leonard Hill Books, and the British Pharmacopoeia. A standard emulsifying oil-in-water or water-in-oil vehicle or an anhydrous polyethylene glycol base are examples of such suitable formulations. Examples of oils suitable for inclusion in a standard emulsifying ointment base include mineral oils, vegetable oils, synthetic fatty acid esters, fatty alcohols, lanolin and its derivatives. The compositions of this invention will normally include a suitable emulsifier. The composition can range from liquid through semi-liquid to gel types according to the type of emulsion and quantity of any thickening agent which may be present. Examples of emusifiers include polyhydric alcohol esters such as sorbitan monostearate, fatty acid esters such as glyceryl monostearate, and polyester derivatives of fatty acids or fatty alcohols. The compositions may also contain anti-oxidants and other conventional ingredients such as preservatives, perfumes and alcohol. Advantageously, a penetrating agent such as 'Azone' may also be included. The compositions of this invention may further contain other therapeutic agents such as anti-infective agents and/or anti-viral agents. Suitable anti-infective agents include the topically applicable antibacterial, anti-yeast and anti-fungal agents already in use in topical anti-inflammatory preparations. As anti-viral agents, there may be particularly mentioned anti-herpes agents. In the compounds of formula (I) X is preferably methoxy, Y is preferably CHR₁-CH₂ where R₁ is a hydrogen atom, and A is preferably a CO group, so that a preferred compound of formula (I) for use in the treatment and compositions of the present invention is that of formula (II): Further compounds of formula (I) are also disclosed in UK Patent No. 1474377. The compounds of formulae (I) and (II) may be prepared as described in UK Patent No 1474377. The compound of formula (II) may also be prepared as described in European Patents No. 0003074 or 0003643. The following pharmacological data illustrate the efficacy of the compounds of formula (I) in the topical treatment or prophylaxis of inflammation. Pharmacological Data The compound of formula (II) was tested for topical anti-inflammatory activity in an animal model based on that described by Fregnan G.B. and Torsello, A.L. (1975), Current Therapeutical Research 17 , No.4, 375-381. In outline the method is as follows:- Animals: Rats, Charles River Wistar Strain, female, 9/group. Weight range 200-240g. Irritant: Irritant solution applied consists of 1% croton oil in tetrahydrofuran. Procedure: 0.05 ml of irritant solution is placed on each ear, the compound under test being included in the irritant solution on one ear. 6 hours later the ears are removed by cutting along the hairline and weighed. -ve controls - no irritant solution. +ve controls - irritant solution on both ears. The results are as shown in the Table, where the compound of formula (II) is denoted (II). Toxicity No toxic effects were observed in the above test.

Claims: The use of a compound of the formula (I): wherein X is a chlorine or bromine atom or a methoxyl, methylthio or alkyl group of 1-4 carbon atoms; Y is a -CHR₁-CH₂- or -CR₁=CH- group where R₁ is a hydrogen atom or a methyl group and A is a CHOH or CO group, for the manufacture of a medicament for the treatment or prophylaxis of inflammatory conditions by topical administration to mammals. The use according to claim 1 in which the compound of formula (I) is 4-(6'-methoxy-2'-naphthyl) -butan-2-one. An anti-inflammatory pharmaceutical composition for topical administration which comprises a compound of the formula (I) wherein X is a chlorine or bromine atom or a methoxyl, methylthio or alkyl group of 1-4 carbon atoms; Y is a -CHR₁-CH₂- or -CR₁=CH- group where R₁ is a hydrogen atom or a methyl group and A is a CHOH or CO group, and a pharmaceutically acceptable topically effective carrier. A composition according to claim 3 in which the compound of formula (I) is 4-(6'-methoxy-2'-naphthyl) -butan-2-one.

Inventors: MANGAN, FRANK RICHARD, THOMSON, MICHAEL JOHN
Applicants: BEECHAM GROUP PLC
Application year: 1985
Main classification: A61K31
IPC codes: A61K31, C07C45, C07C313, A61P29, C07C49, C07C323, C07C67, C07C27, C07C41, C07C33, C07C43