Inoue K, Ogawa K, Suzuki Y, Okada J, Kusai A, Ikeda M, Nishimura K
Product Development Laboratories, Sankyo Company, Limited, Tokyo, Japan.
Drug Dev Ind Pharm. 2000 Jan;26(1):45-53. doi: 10.1081/ddc-100100326.
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.
为了评估酮替芬透过角质层（SC）的途径和屏障成分，在不同的供体pH值下研究了脱脂对渗透和分配的影响。假设离子化的酮替芬（KTH+）和非离子化的酮替芬（KT）在渗透和分配中均独立起作用，估算了这两种物质的固有渗透系数和SC/水分配系数。脱脂使KTH+的渗透率增大了100倍。这表明脂质相起到了对KTH+的屏障作用。KT的固有渗透率比KTH+大100倍。脱脂并未导致KT渗透率的显著变化。这表明在脱脂的SC中，KT透过脂质相的渗透率与透过水相的渗透率相当；也就是说，脂质相对KT而言是一条高渗透性途径。另一方面，KT透过脱脂SC的渗透系数是透过厚度与SC相当的纯水层的1/34。由于这表明KT透过蛋白质相的渗透率远低于透过水相的渗透率，因此可以认为蛋白质相对KT的渗透起到了屏障作用。从这些结果可以得出结论，KT的主要渗透途径是通过脂质相。脱脂使KT的SC/水分配系数减半，但该值仍大于100。这些结果表明，蛋白质相不仅起到屏障作用，还作为KT的储存库。此处获得的知识将有助于酮替芬透皮治疗系统的制剂设计和促进剂的选择。
