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

The stratum corneum, the rate-limiting barrier;in transdermal drug delivery , is chiral in nature and enantiomers behave differently with respect to th eir transport across the skin, resulting in enantioselective permeation. Th e permeation characteristics of individual enantiomers of metoprolol free b ase (MB) were investigated using hairless mouse skin. The influence of chir al permeation enhancers, l-menthol and (+/-)-linalool, on the permeation of MB was also investigated. In the absence of enhancers, the permeation prof iles of R- and S-MB from donor solutions containing either RS-MB or pure en antiomers are comparable (p < 0.05). In presence of enhancers, l-menthol an d (+/-)-linalool, the flux values were increased 2.4- to 3.0-fold, respecti vely, and the permeation profiles of R- and S-MB from donor solutions conta ining 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 presenc e of l-menthol, the nux of S-MB from donor solution containing pure S-MB wa s 35% higher than the flux of RS-MB from racemate. No such effect was seen with (+/-)-linalool. In all the investigations, no enantiomeric inversion-w as observed during the permeation process. The lag times were shorter in th e case of l-menthol compared with (+/-)-linalool. (C) 1999 Wiley-Liss, Inc.