Enhancing effect of pyrrolidone derivatives on transdermal drug delivery. I.

In order to develop potential dermal absorption enhancers, we prepared 9 pyrrolidone derivatives and compared their physicochemical characteristics, transdermal absorbabilities and promoting actions on transdermal delivery of phenolsulfonphthalein (Phenol red) as a model of unabsorbable drug. The preparing pyrrolidones included 1-methyl, 1-hexyl and 1-lauryl-2-pyrrolidone, and their 4-carboxy or 4-methoxycarbonyl substituted derivatives. They showed various lipophilicities according to the nature of an introduced functional group. In an in vitro experiment, phenol red applied with any pyrrolidone showed a penetration through an excised rat skin although the dye applied alone could not transfer. Especially 1-hexyl- and 1-lauryl- substituted derivatives showed superior promoting effect to 1-methyl-substituted derivatives. A lag time for Phenol red appearance to the receptor phase was prolonged with the elongation of a 1-substituted alkyl chain of enhancer. On the other hand, 1-methyl- and 1-hexyl-substituted derivatives penetrated through a rat skin but 1-lauryl-substituted derivatives showed little transfer. Introduction of a 4-carboxy or 4-methoxycarbonyl group to 1-alkyl-2-pyrrolidone reduced the enhancer permeability, decreased the promoting effect and prolonged the lag time. The hydrolysis of 4-methoxycarbonyl derivatives to 4-carboxy derivatives in the skin was observed. The skin accumulation of Phenol red at 10 h increased with an enhancement of dye transfer. However, there is no relationship between enhancer accumulation in the skin and its penetration. The promoting action of 1-methyl, 1-hexyl and 1-lauryl-2-pyrrolidone was supported by an in vivo absorption experiment.