Synthesis and evaluation of N-acetylprolinate esters - novel skin penetration enhancers

A series of N-acetylproline esters (alkyl side chain length, 5-18) were syn thesized and tested for potential skin penetration enhancement activity usi ng modified Franz diffusion cells and hairless mouse skin as the penetratio n barrier. Benazepril and hydrocortisone were used as model drugs and were applied as saturated solutions in propylene glycol. The enhancers were adde d at a concentration of 5% (w/v). Drug flux, permeability coefficient and e nhancement ratios for permeability coefficient were determined. Atone was u sed as the positive control. While all the compounds tested increased the s kin penetration of hydrocortisone, the 5- and 8- carbon esters had no signi ficant effect on the skin penetration of benazepril. The highest fluxes wer e obtained with 11, 12, and 18-carbon esters and they were comparable to At one. There was no significant difference between the fluxes obtained with 2 and 5% (w/v) concentrations of the 12-carbon eater on hydrocortisone perme ation. The 16-carbon ester, where ethanol was used as a cosolvent, signific antly increased the fluxes of both the drugs compared to the control. Diffe rential scanning calorimetric studies suggested that the enhancers may be a cting on the lipids of the stratum corneum and their effect was similar to that of Atone. The membrane/vehicle partition coefficient studies indicated an increase in benazepril partition coefficient with enhancer treatment co mpared to the control. Maximum flux increase was obtained with the 11 and 1 2 carbon (alkyl chain length) eaters for both benazepril and hydrocortisone . The 18- carbon eater which has a cis-double bond in the alkyl side chain, also increased the flux significantly. (C) 1999 Elsevier Science B.V. All rights reserved.