Dual-controlled transdermal delivery of levonorgestrel and estradiol: enhanced permeation and modulated delivery

Abstract

The feasibility of developing a membrane-controlled reservoir-type dual-controlled transdermal delivery system for the simultaneous transdermal delivery of levonorgestrel (LNG) and estradiol (E2) was studied. The skin permeation profiles were observed to follow a zero-order kinetics throughout the course of 72-h permeation studies in the hydrodynamically well-calibrated Valia-Chien permeation cells. The skin permeation rate of LNG from its aqueous saturated solution was extremely low (0.03 μg cm −2 h −1 ), but was enhanced exponentially by the addition of ethanol. The rate of skin permeation was observed to be first enhanced as increasing the volume fraction of ethanol in the donor solution, which reached the maximal rate of 7.69 μg cm −2h −1 at 70% (v/v) of ethanol, and then declined with the further increase in the volume fraction. The peak permeation rate achieved by 70% (v/v) of ethanol was further increased with the addition of skin permeation enhancers, such as azone and oleic acid. The permeation of LNG through the (ethylene/vinyl acetate) copolymer (EVA) membrane-covered hairless rat skin also showed the same zero-order permeation kinetics, with rate increased as increasing the weight fraction of vinyl acetate in the copolymer, but decreased as increasing the thickness of the membrane. Moreover, the permeation rate of LNG across the membrane-covered rat skin increased linearly with the increase of oleic acid concentration. The skin permeation rate of E2 across both hairless rat and human cadaver skin covered with EVA membrane was found to be controlled by variation in the loading dose of E2 in the reservoir formulation without affecting the permeation rate of LNG. The ratio of the permeation rate of LNG over E2 could be modulated by varying the loading doses of E2 and LNG. Thus, it was possible to achieve the dual-controlled delivery of LNG and E2 at a specific ratio of delivery rate, for contraception or treatment of postmenopausal syndromes, by controlling the composition of reservoir formulation, the weight fraction of vinyl acetate in the EVA membrane and its thickness, as well as the loading doses of LNG and E2.