Drug Delivery Applications of Hydrophobic Deep Eutectic Solvent-in-Water Nanoemulsions: A Comparative Analysis of Ultrasound Emulsification and Membrane-Assisted Nanoemulsification

The emergence of green chemistry and engineering principles to enforce sustainability aspects has ensured the prevalence of green solvents and green processes. Our study addresses this quest by exploring drug delivery applications of hydrophobic deep eutectic solvents (DESs) which are alternative green solvents. Initially, this work showcases the hydrophobic drug solubilization capabilities of a natural hydrophobic DES, menthol, and decanoic acid. To consider biomedical applications wherein polar media are encountered, this work further demonstrates the potential drug delivery application of these systems by encapsulating the anti-inflammatory local anesthetic lidocaine in hydrophobic DES-in-water nanoemulsions. NMR studies confirm the high solubility of the hydrophobic drug in hydrophobic DES comprising menthol and decanoic acid (1:2 molar ratio). Ultrasound emulsification and energy-efficient membrane emulsification techniques were employed to disperse 4% (v/v) DES into a 2% (w/w) Tween 20 surfactant aqueous solution. An isoporous microengineered membrane (nominal pore size ∼ 9 μm) was used to produce lidocaine-loaded DES-based nanoemulsions. Such membrane-assisted nanoemulsification was possible because the hydrophobic DES exhibits relatively low interfacial tension with the continuous phase and acts as a cosurfactant. Moreover, increased concentrations of lidocaine within the DES resulted in a further decrease in the interfacial tension and a lower melting point. Among the kinetic models analyzed to evaluate the release of lidocaine encapsulated in hydrophobic DES-in-water nanoemulsions, the Korsmeyer-Peppas kinetic model provided the best fit. The release constant "n" of <0.5 indicates that the drug release mechanism is predominantly governed by diffusion. Additionally, cytotoxicity against various human cell lines demonstrated the nanoemulsion's potential for anti-inflammatory drug delivery applications. Consequently, the nanoemulsion of DES presents a promising solution for the effective loading and delivery of poorly soluble drugs. This innovative approach enhances drug solubility and bioavailability, providing a versatile platform for controlled drug release. By leveraging the advantages of nanoemulsion technology, our study underscores the potential of DES-based formulations to promote drug delivery systems across a variety of therapeutic applications.