Choi H K, Flynn G L, Amidon G L
College of Pharmacy, University of Michigan, Ann Arbor 48109-1065, USA.
J Pharm Sci. 1995 May;84(5):581-3. doi: 10.1002/jps.2600840512.
The present study deals with attempts to deliver cyclosporin A into the deeper skin and some of the fundamental reasons why this proves so difficult. Because of different physicochemical requirements for the solution and activity of cyclosporin A and the enhancer, n-decylmethyl sulfoxide, it was hard to demonstrate increases in permeation of cyclosporin A by the enhancer in either aqueous or ethanol/water formulation. Cyclosporin A was prohibitively insoluble in aqueous media and the activity of the enhancer is diminished to ineffectiveness when it is applied in alcoholic media. However, n-decylmethyl sulfoxide action on the stratum corneum could be obtained by pretreating the skin. The effect of pretreatment with this compound on the permeation of cyclosporin A through hairless mouse skin and human skin was studied with side-by-side diffusion cells. The skin was pretreated with 10 mM n-decylmethyl sulfoxide for various durations. Cyclosporin A in an ethanol/water formulation was then placed in the donor cell, with the amount of ethanol being controlled to maintain the highest possible thermodynamic activity. Accumulations of cyclosporin A in receiver cell media, aqueous or ethanol/water, were then assessed. Permeation from two different concentrations of cyclosporin A was compared. The permeability of hairless mouse skin to cyclosporin A was increased by the pretreatment, but results with human skin were more equivocal. It appears that it will take very long pretreatments to ready human skin for topical cyclosporin A therapy.
本研究致力于将环孢素A递送至皮肤深层的尝试以及探究为何这一过程如此困难的一些基本原因。由于环孢素A和增强剂正癸基甲基亚砜在溶液和活性方面存在不同的物理化学要求，因此在水性或乙醇/水配方中，很难证明增强剂能增加环孢素A的渗透。环孢素A在水性介质中极难溶解，而当增强剂应用于含酒精的介质中时，其活性会降低至无效。然而，通过对皮肤进行预处理可以实现正癸基甲基亚砜对角质层的作用。使用并列扩散池研究了用该化合物预处理对环孢素A透过无毛小鼠皮肤和人皮肤的渗透的影响。皮肤用10 mM正癸基甲基亚砜预处理不同时长。然后将乙醇/水配方中的环孢素A置于供体池中，并控制乙醇量以维持尽可能高的热力学活性。随后评估环孢素A在接受池介质（水性或乙醇/水）中的累积量。比较了两种不同浓度的环孢素A的渗透率。预处理增加了无毛小鼠皮肤对环孢素A的渗透性，但人皮肤的结果更不明确。看来要使人皮肤准备好接受局部环孢素A治疗需要很长时间的预处理。
