Evaluation of derivatives of 3-(2-oxo-1-pyrrolidine) hexahydro-1H-azepine-2-one as dermal penetration enhancers:: side chain length variation and molecular modeling

The present study examined the enhancement effect of two series of compounds derived from 3-(2-oxo-1-pyrrolidine)hex ahydro-1H-azepine-2-one. One series possessed alkyl side chains (series I) and the other alkyl ester side chains (series II). An in vitro diffusion study was performed to investigate the effect of variation in alkyl/alkyl ester side chain length of two series of compounds on the permeation of hydrocortisone (HC) across hairless mouse skin. The permeability coefficient (P), 24 h receptor concentration (Q,,) and skin content (SC), as well as the enhancement ratios (ER) for each parameter were recorded, A parabolic relationship was observed between the ER,, and the alkyl side chain length of the enhancers. The relationship between the length of ester side chains and ER, appeared to be relatively linear with R-2 of 0.9676. The relationship between the calculated lipophilicity (CL) and enhancement activity of the enhancers showed that for CL 5-9, series I showed higher P values compared with Azone((R)), but this was not observed with series II. For CL values 4.57-7.75, a significant correlation existed between P of HC and CL of series II compounds (R-2 = 0.9967). 1-Tetradecyl-3-( 2-oxo-1-pyrrolidine)-epsilon -caprolactam showed the highest P and Q(24), with 40.5- and 18.6-fold increases over the control. In conclusion. the alkyl side chain series of compounds showed more enhancing activity than the alkyl ester side chain series. (C) 2001 Published by Elsevier Science B.V.