Discovery of Nanocrystalline Drug–Drug Salts of Vortioxetine with Diclofenac or ( S )-Flurbiprofen as Long-Acting Antidepressant Formulations

Depression is a prevalent and serious mental disorder that constitutes a major global public health challenge. However, due to the complex pathogenesis of depression, traditional antidepressants usually suffer from some limitations such as low efficacy and the need for frequent administration. To address these challenges, this study employed a drug–drug salt strategy to develop new long-acting antidepressants with improved therapeutic efficacy. Two new drug–drug salts of vortioxetine (VOT) with diclofenac (DIC) or (S)-flurbiprofen (SFLU) were synthesized, characterized, and prepared as nanocrystalline formulations. Notably, the formation of VOT-DIC nanocrystals reduced the powder dissolution of VOT at pH 6.8 from 67% to 9%, a critical factor in establishing its sustained-release profile. Both nanocrystal forms exhibited excellent stability over 21 days, forming homogeneous nanosuspensions characterized by low particle size variability and a PDI below 0.3. In the chronic LPS-induced depression model, VOT-DIC nanocrystals significantly ameliorated depressive-like behaviors (decreased immobility in the tail suspension test and enhanced locomotion in the open field test) and the efficacy lasted for 7 days. These improvements were mediated by decreased brain concentrations of pro-inflammatory cytokines (TNF-α and IL-1β) and elevated serotonin activity. In the muscle stimulation test, the VOT-DIC nanocrystals elicited only minimal inflammation, which resolved completely within 7 days of intramuscular administration. These results suggest that VOT-DIC nanocrystals are a promising candidate for long-acting antidepressant formulations.