Deep eutectic solvents based on matrine and menthol: A novel and safe transdermal penetration enhancer

Transdermal drug delivery has attracted extensive attention due to its ability to bypass the first-pass metabolism, maintain plasma drug concentrations, and improve patient compliance. However, the transdermal delivery of hydrophilic drugs is still quite challenging. This study aims to develop a novel deep eutectic solvent (DES) composed of matrine (MT) from sophora flavescens Aiton and menthol (Men) from Mentha canadensis to enhance the transdermal delivery of hydrophilic drugs. Geniposide (GS) was selected as the model drug. Combining multiple experimental techniques and theoretical calculations, it was demonstrated that the formation of MT-Men DES was primarily driven by hydrogen bonding, with van der Waals forces playing a supplementary role. In vitro penetration tests showed that the MT-Men (1:1) DES significantly enhanced the cumulative permeation percentage of GS, achieving a 5.77-fold increase compared to the GS aqueous solution. In vivo pharmacokinetic results indicated that MT-Men (1:1) DES significantly increased the transdermal bioavailability of GS by 2.32-fold and sustained permeation over 24 h. In a rheumatoid arthritis (RA) model, GS@MT-Men (1:1) DES effectively exerted anti-inflammatory effect. Skin irritation and cytotoxicity tests indicated that both MT-Men (1:1) DES and GS@MT-Men (1:1) DES exhibited excellent biocompatibility and safety for the skin. In conclusion, this study innovatively develops a novel and safe transdermal penetration enhancer that might help address the challenges of transdermal delivery of hydrophilic drugs.