MECHANISM AND ENHANCEMENT OF TRANSDERMAL ABSORPTION

本修订版中提出的研究的长期目标 竞争续签申请是为了获得详细的了解 皮肤屏障功能使适宜的药物经皮给药 可以得到增强和优化。因为对安全和安全的持续需求 调节生育的有效药物，基本的应用 所描述的机制研究最终将解决透皮吸收问题 提供避孕类固醇。该项目的具体目标 [1]在活体人体内，使用反射红外(IR)进行测定 光谱，皮肤(特别是角质层)的依赖性 (Sc)对药物结构和性能的渗透。[2]为了评估， (再次)在体内使用反射红外光谱，观察其穿透效果 促进剂对SC屏障功能和药物通透性的影响。13]解读 红外数据，连同其他生物物理测量，以确定 促进剂对SC的作用机制(S)。[4]发展和发展 优化人角质形成细胞“气/液”培养体系，模拟 表皮屏障具有物理、化学和形态上的功能。 [5]确定(I)生物物理性质，以及(Ii) 培养的SC的渗透性与人类的相当 皮肤。[6]研究药物在体内的并行转运和代谢 角质形成细胞培养系统。主要的实验策略 涉及：(A)使用衰减全反射红外光谱技术 在体内探讨SC屏障功能的生物物理基础 药物透过SC的途径及作用机制(S) 促进渗透的作用；和(B)发展一种 与表皮相似的角质形成细胞培养系统 活体组织的形态、SC脂组成、生化、 新陈代谢和屏障功能。因此，研究已经设计好了， 检查、确定和关联物理、化学和 定义皮肤(特别是SC)屏障的生物参数 功能。归根结底，提出的研究意在回答 以下问题：(1)S的作用机制(途径)是什么 经皮渗透？(2)药物的皮肤屏障是怎样的？ 渗透构造？什么是关键的化学和生物物理？ 功能障碍的构成和要求？(3)可能吗？ 用渗透增强剂可逆地颠覆SC屏障？做什么 这些代理起作用了吗？(4)派生的基本信息可以应用于 解决避孕药使用中的重要问题 透皮途径？

The long-term objective of the research proposed in this revised Competing Renewal application is to attain a detailed understanding of skin barrier function so that the transdermal delivery of suitable drugs may be enhanced and optimized. Because of a continued need for safe and efficacious agents to regulate fertility, applications of the basic mechanistic studies described will ultimately address the transdermal delivery of contraceptive steroids. The specific aims of the project are: [1] To determine, in vivo in man, using reflectance infrared (IR) spectroscopy, the dependence of skin (and, particularly, stratum corneum (SC)) permeation on drug structure and properties. [2] To evaluate, (again) in vivo using reflectance IR, the effects of 'penetration enhancers' on SC barrier function and drug permeability. 13] To interpret the IR data, together with other biophysical measurements, to determine the mechanism(s) of enhancer action on the SC. [4] To develop and optimize a human keratinocyte, 'air/liquid', culture system, which mimics epidermal barrier function physically, chemically, and morphologically. [5] To establish that (i) the biophysical properties, and (ii) the permeability, of the SC of the culture are comparable to those of human skin. [6) To study the concurrent transport and metabolism of drugs in the keratinocyte culture system. The principal experimental strategies involve: (a) the use of attenuated total reflectance IR spectroscopy to probe, in vivo, the biophysical basis of SC barrier function, the pathways of drug permeation across the SC, and the mechanism(s) of penetration enhancer action; and (b) the development of an 'epidermal-equivalent' keratinocyte culture system, which resembles the in vivo tissue in morphology, SC lipid composition, biochemistry, metabolism, and barrier function. Studies have been designed, therefore, to examine, determine, and correlate the physical, chemical and biological parameters which define skin (and, specifically, SC) barrier function. Ultimately, the research proposed is intended to answer the following questions: (1) What are the mechanism(s) (pathways) of transdermal penetration? (2) How is the cutaneous barrier to drug permeation constructed? What are the key chemical and biophysical constituents and requirements of a functional barrier? (3) Is it possible to reversibly subvert the SC barrier with penetration enhancers? How do these agents work? (4) Can the basic information derived be applied to solving the important problem of contraceptive steroid delivery by the transdermal route?