Li S K, Ghanem A H, Peck K D, Higuchi W I
Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City 84112, USA.
J Pharm Sci. 1998 Jan;87(1):40-8. doi: 10.1021/js970189l.
This report describes the results of iontophoresis experiments involving the transport of polar nonelectrolytes across human epidermal membrane (HEM) at a moderate applied voltage of 2.0 V and where the data are interpreted via a convective transport model and hindered transport theory. A principal finding is that although HEM iontophoresis at 2.0 V resulted in a large increase in HEM porosity, the pore radii of the newly induced pores in HEM as calculated from the iontophoresis data using the hindered transport theory were found to be in the range of 6-12 A. This supports the view that electroporation at these modest applied voltages results in pores with sizes the same order of magnitude but somewhat smaller than those estimated for the preexisting pores in HEM prior to electroporation. This outcome is also important from a practical standpoint, as flux enhancement for large molecules (such as oligonucleotides and polypeptides) arising from electroporation under these conditions would be expected to be significantly less than if the resulting pore sizes were much greater. Providing a "prepulse" of 4.0, 8.0, and 15 V prior to the 2.0 V iontophoresis generally gave greater increases in HEM conductance (and, therefore, in porosity) but did not significantly change the deduced effective pore radii (around 5-9 A). The alteration during and the recovery of HEM after iontophoresis was also investigated. The recovery behavior was found to be dependent upon both the duration of the applied voltage and the magnitude of its effects: the recovery for a HEM sample that experienced a large increase in electrical conductance during iontophoresis was generally poorer than that for a sample that was more resistant to the electric field. Incomplete recovery was generally observed in experiments with long iontophoresis duration (50 min) and with the higher voltages (4.0, 8.0 V, and 15 V). In these cases, the barrier properties of HEM were more greatly altered as indicated by larger increases in the electrical conductance and passive permeability of HEM after iontophoresis.
本报告描述了离子电渗实验的结果，该实验涉及在2.0V的中等施加电压下，极性非电解质跨人表皮膜（HEM）的转运，并且数据通过对流传输模型和受阻传输理论进行解释。一个主要发现是，尽管在2.0V下进行HEM离子电渗导致HEM孔隙率大幅增加，但使用受阻传输理论根据离子电渗数据计算得出的HEM中新诱导孔隙的孔径在6-12埃范围内。这支持了这样一种观点，即在这些适度的施加电压下进行电穿孔会产生尺寸在相同数量级但略小于电穿孔前HEM中预先存在孔隙估计尺寸的孔隙。从实际角度来看，这一结果也很重要，因为在这些条件下电穿孔对大分子（如寡核苷酸和多肽）通量的增强预计会明显小于所得孔径大得多的情况。在2.0V离子电渗之前施加4.0、8.0和15V的“预脉冲”通常会使HEM电导率（进而孔隙率）有更大增加，但并未显著改变推导得出的有效孔径（约5-9埃）。还研究了离子电渗过程中HEM的变化以及离子电渗后HEM的恢复情况。发现恢复行为取决于施加电压的持续时间及其影响的大小：在离子电渗过程中电导率大幅增加的HEM样品的恢复通常比更耐电场的样品差。在长时间离子电渗（50分钟）和较高电压（4.0、8.0V和15V）的实验中，通常观察到恢复不完全。在这些情况下，如离子电渗后HEM的电导率和被动渗透率有更大增加所示，HEM的屏障特性发生了更大改变。
