DEVELOPMENT AND OPTIMIZATION OF A METHOTREXATE TOPICAL FORMULATION

A topical methotrexate (MTX) formulation that would achieve optimal drug buildup in the epidermis and diminish potential systemic toxicity could be of great utility in the treatment of a variety of hyperproliferative skin disorders. In an attempt to develop an optimized MTX topical formulation containing pharmaceutically acceptable excipients, a 2(3) factorial design was used to investigate the effects of a fatty alcohol, propylene glycol, and ethanol on the in vitro skin permeation and uptake of MTX. In vitro skin permeation studies were performed using excised human epidermis mounted in flow-through diffusion cells. The results of steady-state flux and skin uptake of MTX from these formulations ranged from 0.035 to 0.315 mu g/cm(2)/hr and 1.146 to 7.929 mu g/cm(2), respectively. Response surface analysis was used to determine the optimum formulation in terms of skin permeation and uptake of MTX. An optimized cream formulation was developed and compared to a gel formulation containing 3% Atone in hairless mice to evaluate the uptake of MTX in the treated and untreated skin sites as well as the distribution of MTX in the blood and liver following topical application. The results of the in vivo study demonstrated the localization of MTX at the treated site for both formulations without significant uptake of MTX in the distant untreated epidermis and dermis. The levels of MTX in the blood and liver following topical application of the optimized cream were significantly less than those of the gel formulation with 3% Azone.