TESTOSTERONE SKIN PERMEATION ENHANCEMENT BY MENTHOL THROUGH FORMATIONOF EUTECTIC WITH DRUG AND INTERACTION WITH SKIN LIPIDS

The aim of this investigation was to elucidate the mechanism of skin p ermeation enhancement of the lipophilic drug, testosterone, by menthol . Menthol was found to form eutectic mixtures with testosterone, chole steryl oleate, and ceramides, DSC measurements showed that menthol dra stically lowers the T-m of testosterone, from 153.7 to 39.9 degrees C. The decrease in T-m resulted in an increase in the solubility of test osterone in an aqueous ethanol vehicle by 2.8-fold, which caused a cor responding 2.8-fold increase in the flux of testosterone. A further in crease in skin flux, to eight times the base line, could be attributed to the effect of menthol on the skin barrier properties. This assumpt ion is supported by DSC results showing that menthol decreases the T,o f cholesteryl oleate and ceramides and modifies the thermogram profile of isolated stratum corneum. The results of this investigation indica te that menthol affects skin permeation by a dual mechanism: by formin g a eutectic with the penetrating compound, thereby increasing its sol ubility, and by altering the barrier properties of the stratum corneum . Moreover, this study indicates that both types of interactions must be taken into-consideration when using chemical enhancers and that dec reasing the melting temperature of the permeant through formation ai a eutectic could be one approach for increasing solubility and permeati on rates.