Estudo comparativo da liberação e permeação cutânea do clotrimazol em formulações semissólidas disponíveis no mercado farmacêutico brasileiro

Abstract

Clotrimazole (CTZ) is an antifungal drug used to treat superficial mycoses, and there are many topical drug products with clotrimazole approved in Brazil. The generic drugs can be registered in Brazil with formulations qualitative and quantitative different from the reference list drug, and the chemical composition of formulations is determinant for drug release from the drug product, for percutaneous absorption and to exert pharmacological effect, so the evaluation of in vitro drug release and skin permeation of CTZ on generic drug products in comparison with the reference list drug Canesten® show relevance to evaluate the generic drug products equivalence. The aim of this study was to compare the generics A, B, C and D and the reference list drug through in vitro drug release and skin permeation to evaluate the formulations interference on drug release and skin permeation as well as the evaluation of in vitro drug release as a regulatory tool. It was necessary the development and validation of the analytical quantification method of CTZ. The method showed linearity (0,8 µg/mL a 20 µg/mL), selectivity for peak purity evaluation, no interfering dermal and epidermal and also proven to be precise and accurate. The in vitro drug release and skin permeation were performed in vertical diffusion cell “Franz” type of 1,86 cm2 diffusional area. The in vitro drug release studies were performed according the USP 37, used cellulose ester membranes, receptor fluid sodium lauryl sulfate 1,5% and the assay was conducted at 32°C. The flux results from in vitro drug release of generics A, B, C and D in comparison with Canesten® during 6 hours of the studies are not within 75%-133,33%, corresponding the 90% confidence interval, therefore in accordance to the method, the generics and reference cannot be considered similar. The in vitro skin permeation studies were carried out using 750 µm dermatomized pigs ears skin, lasted 24 hours and the results showed that the CTZ epidermal penetration in generic D was statistically different from the other drug products studied; there was even dermal permeation, which was not showed for the other drug products. The pH and droplet size distribution were also evaluated in all formulations, however it was not possible to verify the influence of these parameters on in vitro drug release and skin permeation, whereas the generic D had the highest droplet size and in vitro skin permeation 2 times higher than the other tested drug products. The results of the studies demonstrated the influence of formulations on in vitro drug release and skin permeation of CTZ and the possibility of using the in vitro drug release method as a regulatory tool for approval and post approval changes of topical generic drug products.