In-vivo skin pharmacokinetics of liarozole - percutaneous-absorption studies with different formulations of cyclodextrin derivatives in rats

The aim of the study was to evaluate whether 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD) can be used as transdermal absorption enhancer for liarozole. Therefore, we used an in vivo model where transdermal drug absorption in rats can be studied under physiological conditions by cannulating the peripheral skin vein draining the area of the skin which is used for drug application, and collecting the blood (Vollmer et al., 1992a). We compared liarozole, applied as a 1% aqueous solution, in different formulations. We varied the pH, the concentration of HPbetaCD and tested another cyclodextrin derivative (2,6-dimethyl-beta-cyclodextrin, DIMEB). In addition, we compared the absorption with a formulation of 40% propylene glycol/10% oleic acid (PG/OA) and after stripping the stratum corneum. HPbetaCD was a moderate enhancer at a concentration of 20% (4.9% HPbetaCD was ineffective) and increased the flux of liarozole at pH 4 from 0.138-0.151 (control) to 0.421-0.487 nmol per h (i.e., 3-fold) after a lag time of 84-104 min (95% limits of confidence), whereas the same formulation at pH 7 did not reach steady state during 4.5 h. The absorption of liarozole in 20% aqueous solution of DIMEB was slightly decreased (by a factor of 0.6), in PG/OA it increased by a factor 1.7 and the flux after stripping the stratum corneum reached 91.4-101.4 nmol/h with a lag time of 10-16 min. Therefore, a 20% aqueous solution of HPbetaCD appears to be a suitable transdermal absorption enhancer for liarozole.