Topical oil-in-water emulsion compositions containing ketoconazo

Details Topical oil-in-water emulsion compositions containing ketoconazo Topical oil-in-water emulsion compositions containing ketoconazo

1995-06-14

1997-08-05

Jarvis, William R. A.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Cyclopentanohydrophenanthrene ring system doai

514174, 514252, 514887, A61K 3156, A61K 3158, A61K 31495, A61K 3150

Patent

active

056542933

DESCRIPTION:

BRIEF SUMMARY
CROSS-REFERENCE TO RELATED APPLICATIONS

This application is based upon PCT Application Serial No. PCT/EP 94/00092, filed Jan. 12, 1994, which claims priority from European Application Serial No. 93.200.145.6, filed on Jan. 21, 1993.
Mykosen 23(8), 426-439 (1980) reports on the activity of ketoconazole in the presence of triamcinolone acetonide.
WO 92/18133 discloses a liquid aqueous solution containing an antifungal and asteroid for use as a mouthwash.
Glucocorticoid based compositions are being used since a long time to treat inflammations of the skin. On the other hand, ketoconazole compositions have proved to be effective in the treatment of mycotic infections. Skin diseases, however, are often characterized by the combination of both inflammatory conditions and mycotic infections, since the inflammatory processes of the skin create predisposing conditions for the growth and proliferation of pathogenic micro-organisms. A single-drug therapy with an anti-inflammatory or an antifungal agent alone therefore is often insufficient to treat various skin diseases.
Up till now, the preparation of a formulation comprising both ketoconazole and a glucocorticoid was hindered by the destabilization of the steroid in the presence of ketoconazole. The stability problems involved in combining a 17-ester steroid with an imidazole antifungal agent are known from e.g. U.S. Pat. No. 5,002,938.
The present invention provides physicochemically stable compositions for the treatment of skin disorders of various pathologies, which comprise in one formulation both ketoconazole and an acetonide glucocorticosteroid.
The present invention is concerned with topical compositions, comprising ketoconazole, an acetonide glucocorticosteroid and a dermatologically acceptable carrier, characterized by a pH above 2.5 and below 6; the preparation of said compositions; and the use of said compositions for the treatment of inflammations and/or mycotic infections of the skin. The subject compositions are characterized by their dual pharmacological activity, being their anti-microbial and anti-inflammatory action. Unexpectedly, it was found that the anti-inflammatory activity of acetonide glucocorticosteroids, in particular that of desonide, was potentiated in the presence of ketoconazole. Therefore, the present invention is further concerned with the use of ketoconazole as a potentiator of the anti-inflammatory activity of acetonide glucocorticosteroids, in particular that of desonide. As a consequence, a less potent steroid can be used when compared to conventional compositions having a comparable anti-inflammmatory activity, which is likely to reduce the incidence and severity of adverse reactions associated with the topical use of steroids.
Further, the excellent physicochemical stability of the subject compositions is unexpected in view of the prior-art. The term "stable compositions" as used hereinbefore and hereinafter relates to a composition wherein the decrease in the desonide content is below 12%, preferably below 10% and most preferably below 6% after storage for 6 months at 30.degree. C. or below.
Ketoconazole is the generic name of 1-acetyl-4-[4-[2-(2,4-dichlorophenyl)-2imidazol-1-ylmethyl-1,3-dioxolan-4- ylmethoxy]phenyl]piperazine. The term "ketoconazole" as used herein comprises ketoconazole in the free base form, the pharmaceutically acceptable addition salts, the stereochemically isomeric forms thereof and the tautomeric forms thereof. The preferred ketoconazole compound is the (.+-.)-(cis) form of the free base form.
The acid addition forms may be obtained by reaction of the base form with an appropriate acid. Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, ethanedioic, propanedioic, butanedioic, (Z)-butenedioic, (E)-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-

REFERENCES:
patent: 4883792 (1989-11-01), Timmons et al.
F. Hogl et al., "The Influence of Steroids on the Antifungal and Antibacterial Activities of Imidazole Derivatives", MYKOSEN, vol. 23, No. 8, Aug. 1980, pp. 426-439. (Translation of the article is also included.)

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