Modelling of non-invasive drug delivery through skin electroporation
Résumé
The skin presents an accessible and convenient route for non-invasive drug delivery. Transdermal delivery platforms, such as nicotine patches, can effectively administer drugs through the epidermis in a controlled manner. Advantages include increased bioavailability, sustained steady-state blood concentration levels, self-administration and reduced frequency of dosing, which in turn improve patient compliance and quality of life. However passive diffusion of drugs through the skin is only achieved for low MW (<400-500 Da), relatively lipophilic molecules (logP around 2 to 3). Electroporation can temporarily increase the permeability of the skin allowing bigger or more hydrophilic molecules to overcome the skin barrier. We have developed a drug delivery platform, consisting of a nanocomposite, electrically-conductive hydrogel, acting as a drug reservoir and an electrode for the application of electrical pulses. Double-wall Carbon Nanotubes (DWCNTs, 2.5 mg/ml) are incorporated into an agarose hydrogel matrix, to increase the electrical conductivity and rigidity of the system.The electrical conductivity and impedance of the nanocomposite hydrogels under varying water content and DWCNT concentration is measured. DC conductivity is measured using an Ampere meter with an integrated electrical source (Keithley 2410 SMU), while AC impedance is measured with a broadband dielectric analyser (Novocontrol Alpha-A). Electroporation experiments are made on freshly isolated, hairless mouse skin.A numerical model of mouse skin is developed, considering the conductivity and width of the skin layers. Finite Element Method (FEM) simulations of the model in steady state, under electrical field application are computed. The conductivity measurements reveal an electrical percolation threshold between 1.25 and 2.5 mg/ml CNT, concentration after which the conductivity increases by two orders of magnitude.The FEM simulations show that the system’s electrical and geometrical properties play an important role in the distribution of the electric field through the skin, under electroporation conditions. These simulations will allow us to optimize the parameters before applying them to ex vivo experiments for validation.