Sato K, Sugibayashi K, Morimoto Y, Omiya H, Enomoto N
Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Josai University, Saitama, Japan.
J Pharm Pharmacol. 1989 Jun;41(6):379-83. doi: 10.1111/j.2042-7158.1989.tb06481.x.
A method for estimating the in-vitro permeability of human skin to drugs, based on in-vitro permeation studies using animal skins, has been developed. The skins from hairless rats, guinea-pigs, dogs and pigs were used, with nicorandil and deionized water as model drug and solvent in a drug-donor compartment. Diffusion coefficients through the skin barrier, D, and partition coefficients from the drug-donor compartment to skin, K, of the drug, in each species, were calculated by curve-fitting the in-vitro permeation data to a diffusion equation describing the drug permeation through a homogeneous membrane, using a non-linear least squares method. Each barrier thickness, L, was measured microscopically from microtomed skin sections. A positive relationship was found between the skin permeability, Kp, and K value among the four species, but species differences in the D and L values were small in spite of the Kp values being different among the four species. A positive correlation was also observed between the calculated and experimental K values among the four species, and hence it was suggested that the main factor for the species difference in the skin permeability of nicorandil would be the difference in partitioning of the drug from vehicle to stratum corneum. As a result, it has become feasible to predict and estimate skin permeability of nicorandil in humans by substituting each parameter, extrapolated from the animal skin permeation data and partition experiments, in the diffusion equation.
基于使用动物皮肤的体外渗透研究，已开发出一种估算人体皮肤对药物体外渗透性的方法。使用无毛大鼠、豚鼠、狗和猪的皮肤，在药物供体隔室中以尼可地尔和去离子水作为模型药物和溶剂。通过使用非线性最小二乘法将体外渗透数据拟合到描述药物透过均质膜渗透的扩散方程，计算出每种动物中药物透过皮肤屏障的扩散系数D以及从药物供体隔室到皮肤的分配系数K。通过对切片皮肤进行显微镜测量得到每种屏障的厚度L。在这四种动物中，发现皮肤渗透率Kp与K值之间存在正相关关系，尽管这四种动物的Kp值不同，但它们的D值和L值差异较小。在这四种动物中还观察到计算得到的K值与实验得到的K值之间存在正相关，因此表明尼可地尔皮肤渗透率物种差异的主要因素是药物从载体到角质层的分配差异。结果，通过将从动物皮肤渗透数据和分配实验推断出的每个参数代入扩散方程，预测和估算人体中尼可地尔的皮肤渗透率已变得可行。
