ESTRADIOL PERMEATION ACROSS HUMAN SKIN, SILASTIC AND SNAKE SKIN MEMBRANES - THE EFFECTS OF ETHANOL-WATER COSOLVENT SYSTEMS

Considerable interest in using the transdermal route for drug administration has strengthened the need for investigations of vehicle effects. The influence of ethanol on the in vitro transport behaviour of saturated oestradiol (OE) solutions through excised human skin and model membranes (silastic, human skin-silastic sandwich and snake skin) was investigated over 0-90% w/w ethanol/water vehicle compositions. Human skin showed a maximum flux of OE (1.45 +/- 0.39 mu g cm(-2) h(-1)) at ethanol vehicle contents between 40 and 60% w/w. Silastic membranes were used to help elucidate the mechanisms of ethanol as an enhancer. Partition coefficients and uptake of OE by stratum corneum and silastic membranes from the co-solvent systems were determined and the results suggested that the enhanced permeation of OE from vehicles with ethanol concentrations up to 60% w/w was partially related to increased drug solubility in the stratum corneum. The other part was related to ethanol effects on stratum corneum components. The decrease of OE flux from vehicles with higher ethanol concentrations was due to ethanol dehydration effects on the stratum corneum. This was confirmed by measuring the uptake of ethanol and water from different concentrations of ethanol; increasing ethanol concentration in the donor produced a significant decrease in the stratum corneum water content. Also, when the skin hydration was controlled using the skin-silastic sandwich model, the OE flux did not significantly decrease at high ethanol concentration. Ethanol actions were further investigated by measuring the permeation rate of OE through a model animal membrane, shed snake skin. Different results were obtained than for human skin and silastic membrane. The maximum flux of OE through dorsal snake skin appeared at higher ethanol vehicle concentration (80% w/w) when compared with human skin. Ventral snake skin showed increasing OE flux up to 40% w/w ethanol which remained essentially constant up to 90% ethanol. The results obtained with snake skin were attributed to the lower water content of this membrane.