Imanidis Georgios, Luetolf Peter
Institute of Pharmaceutical Technology, University of Basel, Switzerland.
J Pharm Sci. 2006 Jul;95(7):1434-47. doi: 10.1002/jps.20551.
An extended model for iontophoretic enhancement of transdermal drug permeation under constant voltage is described based on the previously modified Nernst-Planck equation, which included the effect of convective solvent flow. This model resulted in an analytical expression for the enhancement factor as a function of applied voltage, convective flow velocity due to electroosmosis, ratio of lipid to aqueous pathway passive permeability, and weighted average net ionic valence of the permeant in the aqueous epidermis domain. The shift of pH in the epidermis compared to bulk caused by the electrical double layer at the lipid-aqueous domain interface was evaluated using the Poisson-Boltzmann equation. This was solved numerically for representative surface charge densities and yielded pH differences between bulk and epidermal aqueous domain between 0.05 and 0.4 pH units. The developed model was used to analyze the experimental enhancement of an amphoteric weak electrolyte measured in vitro using human cadaver epidermis and a voltage of 250 mV at different pH values. Parameter values characterizing the involved factors were determined that yielded the experimental enhancement factors and passive permeability coefficients at all pH values. The model provided a very good agreement between experimental and calculated enhancement and passive permeability. The deduced parameters showed (i) that the pH shift in the aqueous permeation pathway had a notable effect on the ionic valence and the partitioning of the drug in this domain for a high surface charge density and depending on the pK(a) and pI of the drug in relation to the bulk pH; (ii) the magnitude and the direction of convective transport due to electroosmosis typically reflected the density and sign, respectively, of surface charge of the tissue and its effect on enhancement was substantial for bulk pH values differing from the pI of epidermal tissue; (iii) the aqueous pathway predominantly determined passive permeability of the studied compound despite its measurable lipophilicity and therefore the lipid pathway did not notably affect enhancement. Hence, the proposed model can provide a good quantitative insight into the interplay between different phenomena and permeant properties influencing iontophoresis and can potentially be used as a predictive tool of the process.
基于先前修正的能斯特 - 普朗克方程（该方程包含对流溶剂流的影响），描述了一种恒压下离子导入增强透皮药物渗透的扩展模型。该模型得出了增强因子的解析表达式，该表达式是施加电压、电渗引起的对流流速、脂质与水性途径被动渗透率之比以及水性表皮区域中渗透物的加权平均净离子价的函数。利用泊松 - 玻尔兹曼方程评估了脂质 - 水性区域界面处的双电层导致的表皮与本体相比pH值的变化。针对代表性表面电荷密度对其进行了数值求解，得出本体与表皮水性区域之间的pH差值在0.05至0.4个pH单位之间。所开发的模型用于分析使用人体尸体表皮在体外测量的两性弱电解质在不同pH值下250 mV电压时的实验增强情况。确定了表征相关因素的参数值，这些参数值得出了所有pH值下的实验增强因子和被动渗透系数。该模型在实验增强和计算增强以及被动渗透率之间提供了非常好的一致性。推导得出的参数表明：（i）对于高表面电荷密度，水性渗透途径中的pH变化对该区域中药物的离子价和分配有显著影响，且取决于药物相对于本体pH的pK(a)和pI；（ii）电渗引起的对流传输的大小和方向通常分别反映了组织表面电荷的密度和符号，并且对于与表皮组织pI不同的本体pH值，其对增强的影响很大；（iii）尽管所研究的化合物具有可测量的亲脂性，但水性途径主要决定了其被动渗透率，因此脂质途径对增强没有显著影响。因此，所提出的模型可以很好地定量洞察影响离子导入的不同现象和渗透物性质之间的相互作用，并有可能用作该过程的预测工具。
