MECHANISM AND ENHANCEMENT OF TRANSDERMAL ABSORPTION

本修订本建议的研究长远目标 竞争续约申请是为了获得详细的了解， 皮肤屏障功能使得合适药物的透皮递送 可以被增强和优化。 由于持续需要安全和 调节生育力的有效药物， 所描述的机制研究将最终解决透皮 提供避孕类固醇。 项目的具体目标 是：[1]为了确定，在人体内，使用反射红外（IR） 光谱学、皮肤（特别是角质层）的依赖性 (SC))渗透对药物结构和性质的影响。[2]为了评估， （再次）在体内使用反射IR， 增强剂对SC屏障功能和药物渗透性的影响。13]解释 红外数据，以及其他生物物理测量，以确定 增强子对SC作用的机制。[4]开发和 优化人角质形成细胞"空气/液体“培养系统， 表皮屏障功能的物理，化学和形态学。 [5]确定（i）生物物理特性，和（ii） 渗透性，SC的文化是可比的那些人 皮肤[6)研究药物在大鼠体内的同时转运和代谢， 角质形成细胞培养系统。 主要实验策略 涉及：（a）使用衰减全反射红外光谱， 探针，在体内，SC屏障功能的生物物理基础， 药物通过SC渗透的途径，以及 渗透促进剂作用;和（B）开发一种 “表皮等效”角质形成细胞培养系统，其类似于 在形态学、SC脂质组成、生物化学 代谢和屏障功能。 因此，设计了一些研究， 检查，确定，并将物理，化学和 定义皮肤（特别是SC）屏障的生物学参数 功能 最终，这项研究旨在回答 （1）什么是机制（S）（途径） 透皮渗透？(2)皮肤对药物的屏障如何 渗透构造？什么是关键的化学和生物物理 功能性屏障的组成和要求？(3)有没有可能 可逆地破坏SC屏障的渗透促进剂？怎么 这些代理人工作吗？(4)所得出的基本信息能否应用于 解决了避孕类固醇递送的重要问题， 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?