Transdermal insulin delivery using choline-based ionic liquids (CAGE)

Transdermal delivery of pharmaceuticals using ionic liquids and deep eutectic solvents (DES) has attracted significant interest due to the inherent tunability of the molecules and their capacity to transport large molecules across the skin. Several key properties of DESs including viscosity, miscibility and possible transport enhancement can be controlled through the choice of ions and their ratio in DES. Herein we investigate the effect of cation/anion ratio using Choline and Geranic acid (CAGE) based DES. We synthesized variants of CAGE by controlling the ratio of Choline to Geranic acid over a range of 1:4 to 2:1. Physicochemical properties including viscosity, conductivity and diffusivity were measured. Effect of CAGE on skin permeability was assessed using insulin in ex vivo porcine skin. Each variant was found to have distinct properties, including interionic interactions, viscosity, and conductivity. In addition, the effect of CAGE on stratum corneum lipids, as assessed by FTIR, was dependent on its composition. Transport enhancement was also composition-dependent, as the variants containing excess geranic acid (1:2 and 1:4, but not geranic acid alone) exhibited higher insulin delivery into the dermis compared to other compositions, demonstrating the importance of investigating the effect of ion ratios on drug delivery.