电致孔是采用短时、高压电脉冲在皮肤上产生暂时的水性释药通道的经皮促渗技术，具有可实现生物大分子的经皮给药和程序化、反馈给药的优势。本论文针对临床应用对电致孔经皮给药技术提出的两个基本要求：提高药物渗透量和减小药物滞留量，通过动物皮肤体外试验和数值模拟，分析和提出了在有限的脉冲能量范围内，强化药物经电致孔透皮释药过程的途径和方法。从电致孔形成过程的热力学特征出发，研究指出减小电致孔的边壁张力、改变角质层的化学结构，可维持和扩展脉冲时形成的水性通道。表面活性剂同时具有以上作用。体外试验表明，通过在供给液中添加表面活性剂和使用表面活性剂对皮肤预处理，可明显延长电致孔的存在时间，并增加孔道的面积。表面活性剂的渗透性、对表面张力的减小的程度以及和脂质双分子作用的强弱是影响表面活性剂的上述效果的主要因素。对药物经电致孔的传质过程的研究表明，除维持和扩展作为传质通道的电致孔外，表面活性剂还可改善亲脂药物在角质细胞间隙的脂环境与角质细胞内的水环境间的分配性质，使亲脂药物沿着阻力较小的电致孔－细胞内水性基质途径传输，从而使药物、尤其是亲脂性药物的传质速率大幅度提高，在皮肤中的滞留量显著减小。在实验研究的基础上，本文将皮肤电致孔抽象为多层脂质膜电致孔，建立了“多层脂质膜”电致孔模型。其要点为电致孔首先在多层膜表面产生而后向膜内部传递，膜上电压随电致孔发展而重新分布。以该模型为基础进行的数值模拟，较好电致孔是采用短时、高压电脉冲在皮肤上产生暂时的水性释药通道的经皮促渗技术，具有可实现生物大分子的经皮给药和程序化、反馈给药的优势。本论文针对临床应用对电致孔经皮给药技术提出的两个基本要求：提高药物渗透量和减小药物滞留量，通过动物皮肤体外试验和数值模拟，分析和提出了在有限的脉冲能量范围内，强化药物经电致孔透皮释药过程的途径和方法。从电致孔形成过程的热力学特征出发，研究指出减小电致孔的边壁张力、改变角质层的化学结构，可维持和扩展脉冲时形成的水性通道。表面活性剂同时具有以上作用。体外试验表明，通过在供给液中添加表面活性剂和使用表面活性剂对皮肤预处理，可明显延长电致孔的存在时间，并增加孔道的面积。表面活性剂的渗透性、对表面张力的减小的程度以及和脂质双分子作用的强弱是影响表面活性剂的上述效果的主要因素。对药物经电致孔的传质过程的研究表明，除维持和扩展作为传质通道的电致孔外，表面活性剂还可改善亲脂药物在角质细胞间隙的脂环境与角质细胞内的水环境间的分配性质，使亲脂药物沿着阻力较小的电致孔－细胞内水性基质途径传输，从而使药物、尤其是亲脂性药物的传质速率大幅度提高，在皮肤中的滞留量显著减小。在实验研究的基础上，本文将皮肤电致孔抽象为多层脂质膜电致孔，建立了“多层脂质膜”电致孔模型。其要点为电致孔首先在多层膜表面产生而后向膜内部传递，膜上电压随电致孔发展而重新分布。以该模型为基础进行的数值模拟，较好的反映了皮肤电致孔过程的动力学特征，揭示了孔道边壁张力对皮肤电致孔大小和数目的影响方式和程度。以上述研究为基础，本文开展了大分子药物胰岛素经电致孔透皮传输过程的强化研究。采用表面活性剂CTAB阻止胰岛素的聚集、强化电致孔过程；采用硫代硫酸钠对皮肤进行预处理减少其在角蛋白基质中的滞留；采用透析膜隔离电极避免胰岛素在脉冲下失活；上述方法在同等的电脉冲条件下可使胰岛素的渗透量提高4倍以上，在皮肤中的滞留量减小至少50％。的反映了皮肤电致孔过程的动力学特征，揭示了孔道边壁张力对皮肤电致孔大小和数目的影响方式和程度。以上述研究为基础，本文开展了大分子药物胰岛素经电致孔透皮传输过程的强化研究。采用表面活性剂CTAB阻止胰岛素的聚集、强化电致孔过程；采用硫代硫酸钠对皮肤进行预处理减少其在角蛋白基质中的滞留；采用透析膜隔离电极避免胰岛素在脉冲下失活；上述方法在同等的电脉冲条件下可使胰岛素的渗透量提高4倍以上，在皮肤中的滞留量减小至少50％。

Skin electroporation, which involves the creation of transient aqueous pathways across stratum corneum by application of shot high-voltage electric pulses, has been shown to possess significant potential for the transdermal delivery of macromolecules and sequencing controlled drug administration. Improving the transdermal permeation rate and diminishing the drug entrapment in the skin are of practical importance to meet the primary needs in clinic. The main objective of this thesis was to enhance the transdermal drug delivery via electroporation without raising pulsing energy.The in vitro studies and the thermodynamic analysis of the process of skin electroporation indicated that the life-time and the size of electropore could be well improved by reducing the edge energy of the pore and modifying the lipid structure. Surfactants which are known to have both the two functions, were shown to prolong the life-time of electropore and increase the pore area in the in vitro studies. The effects of surfactants are dependant on its permeability in the skin, degree of reduction of the interfacial tension and the interaction of the lipid bilayer.In addition to significantly promoting the electroporation, surfactants exhibited to alter the partition of lipophilic drug between the aqueous matrix within corneocytes and lipid surround the corneocytes so that the transport route of lipophilic drug was partly switched to the electropore-aqueous matrix pathway, which has less mass transfer resistance. As a result, with the addition of the surfactants into the donor solution and/or the pretreatment of the skin by the surfactants, the transdermal delivery rate of drug, especially the lipophilic drug, was remarkably increased.The effects of surfactants on the electroporation and mass transfer across skin via electropore were further studied by numerical simulation. An electroporated multilamellar lipid model was proposed to describe the skin electroporation. The main points of this model are that the electropore is first created in the surface lamellar and then extended into interior lamellar, and meanwhile the electric potential across the multilamellar is developed and then redistributed. The numerical simulation of skin electroporation based on this model successfully revealed the dynamic characteristic of skin electroporation and the effects of pore edge energy on the amount and size of the electropore in the skin. To access the potential of electroporation for the delivery of macromolecule, the above discussed enhancing approaches were applied to improve the transdermal delivery of insulin, a widely used macromolecule drug. Surfactant CTAB was employed to inhibit the association of insulin and to enhance the percutaneous transport via electroporation in the in vitro experiments. Sodium thiosulfate was used to reduce the entrapment of insulin in the cross-linked keratin matrix within corneocyte before insulin was administrated. The electrodes were isolated from insulin by dialyser to avoid the denatured of insulin during electric pulsing. The results demonstrated that the transdermal accumulated amount of insulin was increased by more than four folds and the percentage of entrapped insulin was decreased by at least 50%.