A BIODEGRADABLE TRANSDERMAL PENETRATION ENHANCER BASED ON N-(2-HYDROXYETHYL)-2-PYRROLIDONE .1. SYNTHESIS AND CHARACTERIZATION

Penetration enhancers represent a popular method of increasing drug flux through the skin for local or systemic activity. Unfortunately, it is thought that the local irritation commonly seen with penetration enhancers is directly related to the penetration enhancement ability of the enhancer. A potential method of avoiding irritation while maintaining enhancement is to utilize a 'soft' enhancer which is metabolized to inert components in the viable epidermis after achieving the desired effect in the dead cells of the stratum corneum. In the present report, model fatty acid esters of N-(2-hydroxyethyl)-2-pyrrolidone were synthesized in order to test this approach. It was found that a 2 order of magnitude increase in permeability for hydrocortisone through mouse skin could be achieved in vitro with these enhancers. The ester linkage was readily cleaved by hydrolytic enzymes in plasma and skin homogenates, while having relatively good solution stability at neutral and slightly acidic pH. Finally, these agents appear to have much less irritation potential than traditional penetration enhancers. Thus, this novel class of enhancers has a high potential for increasing drug flux without irritation in transdermal drug delivery.