The limited aqueous solubility and transdermal permeability of rotundine (RTD) constrain its therapeutic utility in pain management. To address these challenges, a co-amorphous formulation incorporating RTD and syringic acid (SA) were designed to improve solubility, dermal permeation, and pharmacological efficacy. The system's solid-state and molecular attributes were rigorously evaluated via PXRD, DSC, FTIR, NMR, and molecular docking simulations. Findings revealed ion-pair complexation between SA and RTD within the amorphous matrix, yielding enhanced solubility, synchronized dissolution, and modulated stratum corneum lipid organization to promote permeation. In vitro assessments demonstrated an 867-fold solubility enhancement for RTD and a 12-fold increase for SA relative to their crystalline counterparts. Ex vivo Franz cell studies confirmed superior transdermal flux and coordinated release profiles for the co-amorphous formulation. Molecular dynamics simulations elucidated reduced free energy barriers for the neutral ion-pair, corroborating the observed permeation synergy. In vivo analgesic evaluations in acetic acid-induced zebrafish nociception and mouse hot-plate models evidenced rapid, sustained pain relief with the co-amorphous system, mitigating RTD's sedative effects while preserving efficacy. This study highlights co-amorphous drug-drug systems as a versatile, excipient-free platform for transdermal delivery of poorly soluble bioactives, offering a promising strategy for improving the efficacy and safety of pain management treatments. • A dual-drug co-amorphous system was developed to optimize transdermal delivery. • Co-amorphization markedly improves solubility and permeability of poorly soluble rotundine. • Ion-pair formation between syringic acid and rotundine facilitate skin penetration and retention. • Superior analgesic efficacy was demonstrated for topical application without notable sedation.
Chen et al. (Sun,) studied this question.