Ionic liquid form of donepezil: Preparation, characterization and formulation development

The aim of this study was to transform donepezil into ionic liquids (ILs) to promote its skin permeability for developing a new delivery mode of donepezil. Donepezil ILs were formed by pairing with docusate, ibuprofen and four unsaturated fatty acids. The synthesized ionic liquids were fully characterized by thermal analysis, fourier transform infrared spectroscopy, and nuclear magnetic resonance spectrometer analysis. Physicochemical properties, such as solubility and partition coefficients, were measured at 25 °C. The potential toxicity of ILs was evaluated against human neuroblastoma SH-SY5Y cells. In vitro Electrophorus electricus acetylcholinesterase inhibitory activity and docking study were also conducted to evaluate the potential effect on inhibition of acetylcholinesterase activity after the formation of ILs. Blood-Brain Barrier (BBB) Parallel Artificial Membrane Permeability Assay and Skin Parallel Artificial Membrane Permeability Assay were carried out to evaluate the BBB permeability and skin permeability, respectively. Furthermore, drug-in-adhesive transdermal patches were prepared to explore the feasibility of developing donepezil ILs for transdermal delivery. Ionic liquids with α-linolenic and docosahexaenoic acid were more permeable through artificial skin membrane than the free base of donepezil, indicated by 1.9- and 1.55-fold increase in the permeability coefficients, respectively. In addition, donepezil ILs loaded adhesive patches had advantage in skin permeation compared to the corresponding free base patch. The formation of ionic liquid provided a new versatile platform to facilitate transdermal delivery.