Molecularly designed deep eutectic solvents based on choline for site-specific delivery of luteolin in the oral...

Deep eutectic solvents (DESs) present a promising and sustainable approach for enhancing the solubility and permeability of poorly water-soluble drugs. In this study, DESs were explored as a novel formulation strategy to improve the intraoral delivery of luteolin (LUT), a bioactive flavonoid with significant pharmaceutical potential. Choline chloride (ChCl) served as a hydrogen bond acceptor (HBA), while various hydrogen bond donors (HBD), including fructose, glycerol, oxalic acid, sucrose, maltose, sorbitol, and xylitol, were tested at different HBA to HBD molar ratios. Among these formulations, DESs prepared with glycerol (Gly) at ChCl:Gly molar ratios of 1:2 (DESA) and 1:3 (DESB) demonstrated the highest efficacy, increasing LUT solubility by 87-fold and 95-fold, respectively. The analysis of the DES formulations via attenuated total reflectance-Fourier transform infrared (ATR-FTIR) spectroscopy revealed the formation of hydrogen bonding (HB) and π-π interactions between LUT and the DES matrix, facilitating the enhanced solubilization. Additionally, rheological studies showed that the prepared formulations exhibited pseudoplastic behavior, ensuring the ease of handling and retention in the buccal cavity, while in vitro drug release studies demonstrated a notable improvement in LUT dissolution, as compared to the neat drug. Molecular modelling via density functional theory (DFT) calculations and molecular dynamics (MD) simulations unraveled the electronic redistribution and HB interactions governing the LUT-loaded DES formation, while in vitro cell viability and anti-inflammatory studies revealed lack of cytotoxic effect in a human gingival fibroplast cell model and enhanced anti-inflammatory effect. Finally, ex vivo permeation studies using porcine buccal tissues demonstrated that DESs enhanced LUT partitioning and accumulation within the mucosal tissue by 14-fold compared to the neat drug. These findings underscore the potential of choline-based DESs as an effective delivery system for enhancing the buccal administration of LUT, offering a promising strategy to improve its solubility, permeability, and, therefore, therapeutic efficacy.