TRANSDERMAL IONTOPHORESIS AND POLYPEPTIDE DELIVERY

透皮离子电渗疗法和多肽输送

• 批准号: 2022341
• 负责人: William I Higuchi
• 金额: $ 18.86万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-12-01 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2022341
• 关键词: electrical potential; electroporation; human tissue; iontophoresis therapy; laboratory rat; membrane permeability; molecular size; proteins; skin absorption; solvents; transdermal drug delivery

This proposal seeks to implement a novel, systematic approach (developed during the past project period) to study the iontophoretic transport properties of human skin. The long term objective is to gain a basic and comprehensive understanding with the information to become a significant part of the fundamental data base to materially assist drug delivery scientists in the rational design of practical iontophoretic systems for trans- dermal drug delivery, especially for polypeptide drug delivery. The approach combines a rigorous theoretical framework (the modified Nernst- Planck theory) with judiciously designed experiments to factor out the various contributions to human skin iontophoresis. The effects of physical chemical factors such as the molecular size/configuration and charge of the permeant, the ionic strength and pH of the electrolyte solution, and the mode of iontophoresis (continuous D.C. versus pulsed D.C.) upon the iontophoretic flux of the permeant will be systematically investigated. The general question will be addressed: is polypeptide transport (both passive and iontophoretic) in accord with the modified Nernst-Planck theory? The phenomenon of field induced pore induction (electroporation) with the human epidermal membrane (HEM) will receive particular attention, and answers to the following questions will be sought. How do HEM permeability and pore size vary with amplitude and duration of the applied voltage? How do the relative contributions of the direct field effect and convective (electroosmotic) solvent flow vary with electroporation? Under what voltage regimens may alternating pulses or sinusoidal A.C. yield electroporation effects? The actions of chemical permeation enhancers operating via several different mechanisms will be systematically investigated, and the importance of the different mechanisms quantified. These enhancer situations will include (a) agents interacting directly with HEM to increase the effective pore size and/or the porosity/ tortuosity ratio, (b) enhancers influencing the rate, extent, and/or the threshold voltage of electroporation, and (c) agents influencing the direction and magnitude of electroosmosis. Finally, select studies will be conducted to assess the clinical relevance of important outcomes from the above in vitro HEM studies in an in vivo animal model (developed during the past project period).

这项提议寻求实施一种新颖的、系统的方法(已开发 在过去的项目期内)研究电离层迁移 人类皮肤的特性。长期目标是获得一个基本的和 全面了解和掌握这些信息将成为具有重要意义的 基本数据库的一部分，用于实质性地协助药物输送 科学家在合理设计实用的离子导入系统 经皮给药，尤其是多肽药物的给药。这个 该方法结合了严格的理论框架(改进的能斯特- 普朗克理论)，通过精心设计的实验来分析 对人体皮肤离子导入的各种贡献。体育运动的影响 化学因素，如分子大小/构型和电荷 电解液的离子强度和pH值，以及 离子导入方式(连续直流电与脉冲直流电)在此之前 我们将系统地研究该装置的离子导入通量。 一般的问题将被解决：多肽运输(两者 无源和离子导入)符合改进的Nernst-Planck 理论上？场致气孔诱导(电穿孔)现象 与人的表皮膜(下摆)将受到特别关注， 并将寻求以下问题的答案。下摆怎么样？ 渗透率和孔大小随施加的幅度和持续时间而变化 电压呢？直接场效应和直接场效应的相对贡献 对流型(电渗型)溶剂流量随电穿孔而变化？在……下面 什么电压方案可以产生交流脉冲或正弦交流 电穿孔效应？化学渗透促进剂的作用 通过几种不同的机制进行操作将是系统性的 并对不同机制的重要性进行了量化。 这些增强情况将包括：(A)代理直接相互作用 用折边来增加有效孔径和/或孔隙率 曲折比，(B)影响速度、程度和/或 电穿孔的阈值电压，以及(C)影响电穿孔的因素 电渗的方向和大小。最后，精选研究将是 进行的目的是评估从 在活体动物模型中进行的上述体外HEM研究(在 过去的项目期)。