Synthesis and in vitro transdermal penetration enhancing activity of lactam N-acetic acid esters

A homologous series of N-acetic acid esters of 2-pyrrolidinone and 2-piperidinone has been prepared and evaluated for its ability to enhance the skin content and flux of hydrocortisone 21-acetate in hairless mouse skin in vitro. Enhancement ratios (ER) were determined for flux (J) 24-hour diffusion cell receptor cell concentrations (Q(24)), and 24-h full-thickness mouse skin steroid content (SC) and compared to control values (no enhancer present). In addition, in an attempt to abrogate toxicity, these dermal penetration enhancers were designed to have the potential for biodegradation by dermal esterases. 2-Oxopyrrolidine-alpha-acetic acid dodecyl ester (5) showed the highest enhancement ratios for J(ER 67.33) and Q(24) (ER 180.66). 2-Oxopipelidine-alpha-acetic acid decyl ester (10) showed a high Q(24) (ER 162.07) but a lower J (ER 12.67). 2-Oxopyrrolidine-alpha-acetic acid decyl ester (3) showed the highest enhancement ratio for SC (ER 8.7). The ER Q(24) for 3, 5 and 10, as well as other lactam N-acetic acid esters in this work, were significantly higher than the ER found using Atone as enhancer.(dagger)