The skin permeation mechanism of ketotifen: evaluation of permeation pathways and barrier components in the stratum corneum.

To evaluate the pathways and barrier components in the stratum corneum (SC) for the permeation of ketotifen, the effect of delipidization on the permeation and partition was examined under several donor pHs. Assuming that ionized ketotifen (KTH+) and un-ionized ketotifen (KT) contribute independently in both permeation and partition, the intrinsic permeability coefficients and SC/water partition coefficients of both species were estimated. Delipidization enlarged the permeability of KTH+ 100 times. This suggested that the lipid phase functions as the barrier against KTH+. KT has an intrinsic permeability 100 times larger than that of KTH+. Delipidization did not result in a significant change in permeability of KT. This suggested that the permeability of KT through the lipid phase is comparable to that through the aqueous phase in delipidized SC; that is, the lipid phase functions as a highly permeable pathway for KT. On the other hand, the permeability coefficient of KT through delipidized SC was 1/34 of that through the pure aqueous layer, which had a thickness equivalent to SC. Since this suggests that the permeability of KT through the proteinaceous phase is much lower than that through the aqueous phase, the proteinaceous phase can be assumed to function as a barrier against the permeation of KT. From these results, it is concluded that the predominant permeation pathway for KT is through the lipid phase. The SC/water partition coefficient of KT was cut in half by delipidization, but the value was still more than 100. These results show that the proteinaceous phase functions not only as the barrier, but also as the depot for KT. The knowledge obtained here will be useful for formulation design and for the selection of enhancers in a transdermal therapeutic system of ketotifen.