Effect of chiral enhancers on the permeability of optically active and racemic metoprolol across hairless mouse skin

Abstract

The stratum corneum, the rate-limiting barrier in transdermal drug delivery, is chiral in nature and enantiomers behave differently with respect to their transport across the skin, resulting in enantioselective permeation. The permeation characteristics of individual enantiomers of metoprolol free base (MB) were investigated using hairless mouse skin. The influence of chiral permeation enhancers, l-menthol and (+/-)-linalool, on the permeation of MB was also investigated. In the absence of enhancers, the permeation profiles of R- and S-MB from donor solutions containing either RS-MB or pure enantiomers are comparable (p < 0. 05). In presence of enhancers, l-menthol and (+/-)-linalool, the flux values were increased 2.4- to 3.0-fold, respectively, and the permeation profiles of R- and S-MB from donor solutions containing RS-MB are comparable (p < 0.05). However, when donor vehicle contains pure enantiomers, the permeation enhancing effect of l-menthol on S-MB was significantly higher (by 25%) than on R-MB (p < 0.05). Further, in presence of l-menthol, the flux of S-MB from donor solution containing pure S-MB was 35% higher than the flux of RS-MB from racemate. No such effect was seen with (+/-)-linalool. In all the investigations, no enantiomeric inversion was observed during the permeation process. The lag times were shorter in the case of l-menthol compared with (+/-)-linalool.