Enhancing effects of six chemical enhancers on the permeation of ketotifen through excised hairless mouse skin from aqueous donor solutions buffered at pH 5 and 10

The enhancing effects of d-limonene, 1-dodecyl azacycloheptan-2-one (Azone), capric acid, oleic acid, lauroyl sarcosine (LS), and N,N-di-methyldodecylamine N-oxide (LDAO) were evaluated at pH 5 and 10 on the permeation of ketotifen through hairless mouse skin from its aqueous solution. d-Limonene and Azone showed remarkable enhancing effects at pH 10, while these effects were marginal at pH 5. These results were explained in relation to enhancer pooling in the stratum corneum, which is thought to be useful only for the permeation of unprotonated ketoti-fen. Capric acid showed remarkable effects at pH 5, but its effect was negligible at pH 10, suggesting the creation of aqueous channels having high permselectivity to protonated ketotifen. The effect of oleic acid, LS, and LDAO were negligible at either pH. The effect of a 1:1 mixture of d-limonene and capric acid was less than that of either enhancer alone at either pH. This result could also be explained by the enhancer pooling, which may be less permeable matrices for unprotonated ketotifen than d-limonene alone. These findings may provide useful information for the optimization of transdermal ketotifen formulations containing permeation enhancers.