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TRANSDERMAL IONTOPHORESIS AND POLYPEPTIDE DELIVERY

透皮离子电渗疗法和多肽输送

基本信息

批准号：
2608906
负责人：
William I Higuchi
金额：
$ 19.46万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
1989
资助国家：
美国
起止时间：
1989-12-01 至 1999-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2608906
关键词：
electrical potential electroporation human tissue iontophoresis therapy laboratory rat membrane permeability molecular size proteins skin absorption solvents transdermal drug delivery

项目摘要

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).

该提案旨在实施一种新的、系统的方法（制定），在过去的项目期间），以研究离子电渗运输人体皮肤的特性。长期目标是获得一个基本的，全面了解与信息，成为一个重要的基本数据库的一部分，以实质性地帮助药物输送科学家在合理设计的实用离子电渗系统，透皮药物递送，特别是用于多肽药物递送。的方法结合了严格的理论框架（修改后的能斯特，普朗克理论）与明智设计的实验，以因素出对人体皮肤离子电渗疗法的各种贡献。物理的影响化学因素，如分子大小/构型和电荷渗透物、电解质溶液的离子强度和pH，以及离子电渗疗法的模式（连续D.C.与脉冲D.C.）于将系统地研究渗透物的离子电渗通量。一般的问题将得到解决：是多肽运输（两者）被动和离子电渗）符合雅阁修正的能斯特-普朗克理论？场致孔诱导（电穿孔）现象与人表皮膜（HEM）的关系将受到特别关注，并将寻求以下问题的答案。HEM如何渗透率和孔径随施加的振幅和持续时间而变化电压？直接场效应的相对贡献和对流（电渗）溶剂流动与电穿孔的变化？下交流脉冲或正弦交流电的电压方案产量电穿孔效应？化学促渗剂的作用通过几种不同的机制运作，调查，并量化不同机制的重要性。这些增强子的情况将包括（a）直接相互作用的药剂用HEM增加有效孔径和/或孔隙率，（B）影响弯曲速率、程度和/或弯曲程度的增强剂，电穿孔的阈值电压，和（c）影响电穿孔的试剂。电渗的方向和大小。最后，选择研究将进行评估的重要结果的临床相关性，以上在体内动物模型中的体外HEM研究（在本发明期间开发的），项目前期）。