James L. Winkle College of Pharmacy, Academic Health Center, University of Cincinnati, Cincinnati, Ohio, USA.
J Pharm Sci. 2010 Dec;99(12):4928-39. doi: 10.1002/jps.22216.
Accurate values of partition and diffusion coefficients within the lower skin layers are among the information required to estimate skin concentrations of permeants following topical application. For highly lipophilic compounds these parameters also play a significant role in determining systemic absorption rates. In this study methodology is described for making more accurate in vitro measurements of partition and diffusion coefficients in dermis. Isolated human dermis obtained from surgical reduction was mounted in side-by-side diffusion cells in the presence and absence of a dialysis membrane (5000 MW cut-off) placed between the dermis and the donor solution. Permeation of N,N-diethyltoluamide (DEET) and diclofenac across the composite membrane system, as well as steady-state skin concentrations, were measured by radiochemical techniques. For the highly protein bound compound, diclofenac, dermis permeability, and partition coefficient determined in the presence of the dialysis membrane were significantly higher than those determined in its absence. No significant differences were observed for the moderately protein bound DEET. The results show that, in the absence of a stratum corneum barrier, attention must be given to the diffusion of soluble proteins in order to obtain accurate estimates of transport and partitioning parameters for highly protein bound solutes in dermis.
准确的分配系数和扩散系数是预测经皮给药后皮肤中渗透物浓度所必需的信息之一。对于高度亲脂性化合物，这些参数在确定全身吸收速率方面也起着重要作用。本研究描述了一种更准确地测量真皮中分配系数和扩散系数的体外方法。从手术切除中获得的离体人真皮在有和没有透析膜（5000MW 截止值）的情况下安装在并排扩散细胞中，透析膜置于真皮和供体溶液之间。通过放射性化学技术测量 N，N-二乙基甲苯酰胺（DEET）和双氯芬酸在复合膜系统中的渗透以及稳态皮肤浓度。对于高度蛋白结合化合物双氯芬酸，在存在透析膜的情况下测定的真皮渗透性和分配系数明显高于不存在透析膜的情况下。对于中度蛋白结合的 DEET，未观察到显著差异。结果表明，在不存在角质层屏障的情况下，必须注意可扩散蛋白质的扩散，以便准确估计真皮中高度蛋白结合溶质的传输和分配参数。
