Drug\nDelivery Applications of Hydrophobic Deep Eutectic\nSolvent-in-Water Nanoemulsions: A Comparative Analysis of Ultrasound\nEmulsification and Membrane-Assisted Nanoemulsification

The emergence of\ngreen chemistry and engineering principles to\nenforce sustainability aspects has ensured the prevalence of green\nsolvents and green processes. Our study addresses this quest by exploring\ndrug delivery applications of hydrophobic deep eutectic solvents (DESs)\nwhich are alternative green solvents. Initially, this work showcases\nthe hydrophobic drug solubilization capabilities of a natural hydrophobic\nDES, menthol, and decanoic acid. To consider biomedical applications\nwherein polar media are encountered, this work further demonstrates\nthe potential drug delivery application of these systems by encapsulating\nthe anti-inflammatory local anesthetic lidocaine in hydrophobic DES-in-water\nnanoemulsions. NMR studies confirm the high solubility of the hydrophobic\ndrug in hydrophobic DES comprising menthol and decanoic acid (1:2\nmolar ratio). Ultrasound emulsification and energy-efficient membrane\nemulsification techniques were employed to disperse 4% (v/v) DES into\na 2% (w/w) Tween 20 surfactant aqueous solution. An isoporous microengineered\nmembrane (nominal pore size ∼ 9 μm) was used to produce\nlidocaine-loaded DES-based nanoemulsions. Such membrane-assisted nanoemulsification\nwas possible because the hydrophobic DES exhibits relatively low interfacial\ntension with the continuous phase and acts as a cosurfactant. Moreover,\nincreased concentrations of lidocaine within the DES resulted in a\nfurther decrease in the interfacial tension and a lower melting point.\nAmong the kinetic models analyzed to evaluate the release of lidocaine\nencapsulated in hydrophobic DES-in-water nanoemulsions, the Korsmeyer–Peppas\nkinetic model provided the best fit. The release constant “<i>n</i>” of <0.5 indicates that the drug release mechanism\nis predominantly governed by diffusion. Additionally, cytotoxicity\nagainst various human cell lines demonstrated the nanoemulsion’s\npotential for anti-inflammatory drug delivery applications. Consequently,\nthe nanoemulsion of DES presents a promising solution for the effective\nloading and delivery of poorly soluble drugs. This innovative approach\nenhances drug solubility and bioavailability, providing a versatile\nplatform for controlled drug release. By leveraging the advantages\nof nanoemulsion technology, our study underscores the potential of\nDES-based formulations to promote drug delivery systems across a variety\nof therapeutic applications.