Ionized prodrugs of dehydroepiandrosterone for transdermal iontophoretic delivery

Purpose. The aim of this work was to synthesize ionized dehydroepiandroster one (DHEA) prodrugs with higher water solubility, useful for iontophoretic transdermal application. Methods. The synthesized derivatives were characterized and tested for sens itivity to chemical and enzymatic hydrolysis. Solid state and solution stab ility was also determined. Transdermal iontophoretic anodal transport in vi tro was studied using excised rabbit skin. Results. Two DHEA ionized prodrugs were synthesized: PRO1, a primary amine derivative, and PRO2, a quaternary ammonium salt. The two derivatives posse ss higher water solubility and lower octanol/saline partition coefficients than DHEA. Prodrugs were sensitive to enzymatic hydrolysis: in particular t he primary amine was hydrolyzed faster than the quaternary salt by esterase from porcine liver in vitro. Transdermal flux of the two prodrugs was slig htly higher than the parent drug. In the case of passive diffusion, only DH EA was found in the receptor compartment, indicating the complete breakdown of the prodrug in the skin. Current application gave higher drug flux and a significant amount of prodrug was found in the receptor. Conclusions. The use of ionized prodrugs of DHEA can increase the flux atta inable during transdermal anodal iontophoresis by up to 7 times. but they a re useful for passive transport as well.