Enhanced transdermal permeation of caffeine through a skin model using electric field-induced lipid vesicles: a novel approach for drug transport

Caffeine is a highly beneficial compound for human health, known for its anticancer, anti-inflammatory, and antioxidant properties, particularly in protecting the skin from UVB radiation damage. Although caffeine shows excellent potential for transdermal delivery, its hydrophilic nature often requires a chemical enhancer for effective transport. Traditional methods like iontophoresis and electroporation utilize external electric fields to create micro-pores in the skin, enhancing the delivery of hydrophilic molecules. While electroporation is well understood, the molecular mechanisms of iontophoresis are unclear. This investigation presents an innovative mechanism for caffeine transport from an aqueous solution without chemical enhancers using lipid vesicles generated by external electric fields. To investigate the caffeine transdermal transport process, we combined our iontophoresis methodology with molecular dynamics simulations using Gromacs and the Martini force field alongside a practical custom experiment. Our approach employed a constant electric field of 22-25 mV nm^-1, successfully generating lipid vesicles that transport caffeine molecules. Notably, alternating electric fields at 306 K (physiological skin temperature) increased caffeine transport by 20%, and at 323 K, we achieved an impressive 300% increase compared to scenarios without electric fields. Our homemade Franz cell setup showed a permeation rate dependent on the electric field correlated with vesicle formation. Additionally, hyperspectral Raman mapping identified unsaturated carbon and C-N groups as key contributors to vesicle and pore instability. This groundbreaking approach offers significant potential for enhancing transdermal drug delivery systems.