Study of the Effective Dose of a Topical Antifungal Agent, Omoconazole Nitrate, on the Basis of Percutaneous Pharmacokinetics in Guinea-pigs and Mice

Abstract

The clinically useful optimum dose of omoconazole nitrate, a topical antifungal agent, has been examined by analysing the percutaneous pharmacokinetics of the drug to assess its pharmacological activity in an in-vivo study. Creams containing omoconazole nitrate were prepared on a pilot basis. The therapeutic effect of the omoconazole nitrate creams was examined in an in-vivo pharmacological dermatophytosis infection model in guinea-pigs. Creams containing 0.25% or higher concentrations of omoconazole nitrate resulted in significant inhibition compared with no treatment and with vehicle-treated controls. In the mycological examination no growth of dermatophytes was observed for creams containing 1% or higher concentrations. In an in-vitro hairless mouse skin-permeability test a non-linear least squares program based on a fast inverse Laplace transform algorithm was used to calculate the partition and diffusion parameters of omoconazole nitrate in the stratum corneum and viable epidermis. The time-course of drug concentrations in the skin of the guinea-pig, estimated on the basis of these parameters, led to predictions that percutaneous drug concentrations on the guinea-pig would require 10 or more days to reach equilibrium in the skin; that drug concentrations in the corneum-viable epidermis border, where dermatophytes are considered to grow, would exceed the minimum effective concentration when 0.1% higher concentration creams were used; and that for binding to keratin drug concentrations would reach the practical minimum effective concentration when creams containing 0.5% or more omoconazole nitrate were used. These results show that partition and diffusion parameters obtained from in-vitro skin permeation studies can be used to predict in-vivo percutaneous pharmacokinetics and to estimate therapeutically effective concentrations.

Animal Model of Dermatophytosis

“…The methods of abrading back skin include the use of sandpaper [22, 23, 25, 31, 33, 45, 47, 48, 54, 58], a roughened pestle [40, 41], a steel brush [50], pumice stone [17], shaving [51, 57, 59], and tape stripping [21, 26–30, 32, 35, 36, 46, 51, 52]. The abrasion techniques using sandpaper, a roughened pestle, and a pumice stone are simple and easy; however, such techniques may lead to skin wounds such as an ulcer, which subsequently can be confused with lesions produced during dermatophyte infections [51].…”

“…The tinea corporis animal model was used to estimate the efficacy of antifungal agents like bifonazole [21, 22, 25, 26, 35, 46, 52], clotrimazole [22, 23, 25, 35, 37, 40, 46, 52], miconazole [37, 44], tolnaftate [12, 22, 25, 37, 40], griseofulvin [28, 29, 37, 40, 65], ketoconazole [12, 18, 20, 29, 37, 40], omoconazole [32, 36], terbinafine [26, 29, 40, 41, 47, 48, 50, 58, 65], econazole [40], butenafine [22, 23, 33], naftifine [22], itraconazole [20, 27, 41, 50, 51, 59, 65], amorolfine [21, 65], sertaconazole [44], saperconazole [24], latoconazole [25], fluconazole [27, 28, 31, 41, 65], SCH 39304 [31, 54], lanoconazole [30, 33, 48], mupirocin [18], laudamonium [17], KP-103 [33], neticonazole [33], R126638 [59], voriconazole [57], ciclopirox [58], pramiconazole [50], luliconazole [48], and Astragalus verus Olivier [45]. …”