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-p iperidinone has been prepared and evaluated for its ability to enhance the skin content and flux of hydrocortisone 21-acetate in hairless mo use 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 contr ol values (no enhancer present). In addition, in an attempt to abrogat e toxicity, these dermal penetration enhancers were designed to have t he potential for biodegradation by dermal esterases. 2-Oxopyrrolidine- alpha-acetic acid dodecyl ester (5) showed the highest enhancement rat ios for J(ER 67.33) and Q(24) (ER 180.66). 2-Oxopipelidine-alpha-aceti c 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 a nd 10, as well as other lactam N-acetic acid esters in this work, were significantly higher than the ER found using Atone as enhancer.(dagge r)