Novel therapeutic deep eutectic solvents based on mirtazapine and medium-chain fatty acids for enhancing the transdermal delivery of mirtazapine.

The severe hepatotoxicity caused by oral administration of the antidepressant mirtazapine (MTZ) remains a pressing issue that needs to be addressed. Therapeutic deep eutectic solvents (THEDES) for transdermal delivery, which exhibit high biocompatibility, biodegradability, thermodynamic stability, and low toxicity, have received considerable attention as a means of protecting drugs from the hepatic first-pass effect. In this study, three new highly thermodynamically stable THEDES based on MTZ and medium-chain fatty acids (MCFA) (C10-C12) were developed for transdermal delivery of MTZ to evaluate their potential as topical agents for antidepressant treatment. The combination of Fourier transform infrared (FTIR) spectroscopy, 1H nuclear magnetic resonance (1H NMR), and molecular dynamics simulations demonstrated that hydrogen bonding promoted the formation of THEDES. The in vitro penetration test revealed that the MTZ-DA THEDES, formed by the combination of MTZ and decanoic acid (DA), exhibited the optimal cumulative penetration amount (97.7 ± 14.4 µg/cm2) and permeation flux (4.97 ± 0.79 µg/cm2/h). The ATR-FTIR results confirmed that the permeation enhancing effect was achieved by promoting changes in the νCH2 region of the lipid structure of the stratum corneum. The in vivo transdermal delivery subsequently revealed that the relative bioavailability of MTZ increased 6.4-fold and exhibited 24-h sustained release characteristics. Ultimately, the results of the cytotoxicity assay and skin irritation test indicated that the formulation was safe for use on the skin. Overall, safe and highly permeable MTZ-DA THEDES could be a potential topical formulation for the management of depression.