Ionic liquids (ILs) show promises as chemical penetration enhancers (CPEs) for transdermal delivery of macromolecular drugs. However, their high viscosity and strong drug-IL affinity may limit drug diffusion and release from the drug-loaded IL (one-step strategy). Herein, a two-step strategy was used by applying choline-based ILs as pretreatment agents followed by insulin solution to improve penetration. Insulin remained stable in the ILs and are released slowly from the IL matrices. In vitro and in vivo studies showed that two-step treatment enhanced insulin penetration compared to one-step treatment, with choline citrate ([Ch][Ci]) and choline geranate ([Ch][Ge]) performing the best. In a diabetic rat model, two-step treatment with [Ch][Ge] reduced blood glucose levels to below 80% within 8 h, while one-step treatment only maintained for 12 h. Trans-epidermal water loss and molecular dynamics simulations suggested that variations in release rates and skin condition accounted for the differences between the two strategies. Physical characterization confirmed that ILs enhanced transdermal delivery of insulin by permeabilizing stratum corneum and opening tight junctions. Preliminary safety assessment indicated mild irritation by [Ch][Ge], whereas [Ch][Ci] showed good biocompatibility. It is concluded that ILs hold potential in enhancing transdermal delivery of insulin.
Keywords: Choline; Drug delivery; Insulin; Ionic liquids; Pretreatment; Transdermal.
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