Oxymatrine-fatty acid deep eutectic solvents as novel penetration enhancers for transdermal drug delivery: Formation mechanism and enhancing effect.

Transdermal delivery of drugs is commonly limited by low skin permeability. The aim of the study was to synthesize deep eutectic solvents (DESs) based on oxymatrine (OMT) and fatty acids with various alkyl chain lengths (LCFAs) as novel vehicles, to solubilize the water-insoluble drug and enhance percutaneous penetration. Quercetin (QUE) was selected as a model drug. Combining differential scanning calorimetry (DSC), Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), and molecular simulations demonstrated that the formation of DESs was mediated by charge-assisted hydrogen bonding. Physicochemical properties including stability, viscosity, and solubilization capacity were also studied. Subsequently, the effect of three stable DESs on drug release and skin permeability was evaluated. The results showed that QUE was solubilized well and presented a different sustained release behavior in DESs. Meanwhile, DESs enhanced the skin permeation of OMT and QUE, which was influenced by alkyl chain lengths of LCFAs, whereas DES consisting of lauric acid (LA) exhibited the highest enhancing effect. FTIR, DSC, and molecular docking further demonstrated consistency between micro molecular mechanism and macro penetration behavior. Additionally, HaCaT cells treated with DESs showed high cell viability, suggesting their good skin safety. Taken together, OMT-LCFA DESs would be a promising penetration enhancer for transdermal drug delivery, which also provides guidance for the design of new DESs.