Skin electroporation for transdermal drug delivery: the influence of the order of different square wave electric pulses

Electroporation can be used as an active enhancement method for intra- and transdermal drug delivery. Differences in response of skin to electric pulses depend on their amplitude, duration and number and have been a point of interest in the past. While protocols consisting of the same repetitive, mostly exponentially decaying pulses have been used before, this study is focused on comparing different combinations of square wave short high voltage (HV) and longer low voltage (LV) electroporation pulses. Our in vitro experimental results show that longer LV pulses significantly increase subsequent passive transport of calcein through dermatomed pig skin, while short HV pulses alone result in negligible calcein passive transdermal transport. Surprisingly, when the long LV pulses are preceded by short duration HV pulses, the total calcein transported is reduced significantly. This result is explained using a theoretical physics based model of individual local transport region (LTR) evolution during the applied LV pulse. The theoretical model shows that HV pulses alter the structure of the stratum corneum in such a way that when the LV pulses are applied, insufficient thermal energy is generated to initiate LTR expansion. Together, the experimental results and theoretical predictions show that the total pulse energy alone cannot account for total solute transport: that the order of the types of pulses administered must also be considered. Our findings open a direction for further improvement of the method using new protocols.