TRANSDERMAL CONTROLLED ADMINISTRATION OF ESTRADIOL DERIVATIVES AND STRUCTURE-KINETIC RELATIONSHIPS.

摘要

A skin permeation system was developed to overcome the deficiencies noted in the currently available in vitro diffusion cells.; The role of drug reservoir concentration in the kinetics of skin permeation was evaluated by incorporating PEG 400 into saline solution to act as a solubilizer. The equilibrium solubility of estradiol was observed to increase exponentially as increasing the volume fraction of PEG 400. The permeation rate of estradiol across the hairless mouse skin was measured at various PEG 400 concentrations. The permeability coefficients were determined and found to decrease as increasing the PEG 400 concentration. A linear relationship was established between the permeability coefficients and the (skin/vehicle) partition coefficients. The diffusivity at steady-state was calculated.; The kinetics of uptake of estradiol and its subsequent metabolism to estrone were examined. The results demonstrated the rate-limiting role of stratum corneum in the uptake, metabolism and binding of estradiol.; The kinetics of the simultaneous skin permeation and bioconversion of five estradiol esters was studied. The equilibrium solubilities of estradiol esters in the lipophilic silicone fluid and in hydrophilic PEG 400/saline solution were determined and found to be dependent upon the alkyl chain length of the esters. The partition coefficient of the compounds was observed to decrease as increasing the chain length.; During the course of skin permeation, the estradiol esters were metabolized by esterase to form estradiol. The rate of appearance of estradiol from the estradiol esters was observed to be a function of ester concentration. The metabolism of estradiol esters was observed to follow first-order kinetics and the rate constants determined were found to be dependent upon the location and a chain length of the ester.; A theoretical and experimental methodology was developed to provide a rigorous investigation on the skin permeation and metabolism of prodrugs. The data generated in these investigations show the interrelationship of solubility, lipophilicity, skin permeability coefficient and bioconversion rate of topically applied prodrugs (estradiol esters).