Intranasal thermosensitive hydrogel of agomelatine solid dispersion for better management of depression

Agomelatine (AGM) is a unique melatonergic antidepressant drug. However, it possesses low aqueous solubility, first-pass metabolism, and reduced bioavailability. The aim of the current study was to formulate AGM in an intranasal gel to achieve higher drug efficacy and enhanced treatment compliance. Initially, solid dispersions of AGM with either Soluplus®, Kolliphor® P188, or 2-Hydroxypropyl-β-cyclodextrin (2-HPβ-CD) were prepared at different drug: carrier ratios (1:1,1:2, and 1:4 w/w), and their in vitro dissolution properties were studied. The formulation with optimal dissolution properties was further characterized by solid-state characterization studies and then incorporated into a thermosensitive hydrogel system utilizing Pluronic F 127 (PF 127) and Hydroxypropyl methyl cellulose (HPMC-K4M) as thermosensitive and mucoadhesive polymers, respectively. Sol-gel transition temperature (Tsol-gel), viscosity, gel strength, in vitro release study, and ex vivo mucoadhesive force were evaluated. Moreover, the selected formulation (G1) was evaluated for ex vivo permeation and nasal ciliotoxicity. In vivo, the antidepressant effect of G1 was evaluated in a rat model of chronic unpredictable mild stress followed by behavioral assessment and determination of brain-derived neurotrophic factor (BDNF), monoamine neurotransmitters, and proinflammatory cytokines levels in rats' brain. The dissolution study revealed that AGM/2-HPβ-CD complex at 1:4 w/w was superior in enhancing AGM dissolution properties and the solid-state characterization studies showed the amorphous nature of AGM. The optimal gel formulation (G1) containing 20.0% PF 127 and 0.2% HPMC-K4M exhibited optimal Tsol-gel, viscosity, and gel strength with enhanced permeation of AGM through sheep nasal mucosa. Histopathological examination of nasal mucosa treated with G1 displayed no inflammation or necrosis. In vivo, rats treated intranasally with G1 displayed increased levels of BDNF and monoamine neurotransmitters, and reduced proinflammatory cytokines levels in rats' brain. Eventually, intranasally administrated thermosensitive hydrogel enhanced AGM bioavailability by targeting the brain and avoiding hepatic first-pass metabolism, thus enhancing its antidepressant effect.