Evaluation of Chitosan–Pimelate Buccal Film Loaded with Duloxetine-Modified Sage Lipid Carriers Nanoformulation for Effective Antidepressant Activity in a Rat Model

Introduction: Chitosan-pimelate (CS-Pim) mucoadhesive buccal films were developed to improve the therapeutic efficacy of duloxetine (DLX) using sage oil-based lipid carriers (DLX-SLCs). This buccal nanoplatform addresses DLX’s limited oral bioavailability and extensive first-pass metabolism by providing a non-invasive route with enhanced mucosal permeability and sustained release. Methods: DLX-SLCs were optimized and characterized for particle size, zeta potential, and entrapment efficiency. The carriers incorporated into CS-Pim buccal films, which were evaluated for physicochemical properties, morphology, hydrophilicity, and mucoadhesive strength. In vivo antidepressant efficacy was assessed in a lipopolysaccharide (LPS)-induced rat depression model using behavioral tests, biochemical markers, and histopathological analysis. Results: Optimized DLX-SLCs yielded an average size of 130.9± 2.4 nm, zeta potential of − 28.4 ± 2.3 mV, and entrapment efficiency of 79.9 ± 3.8%. The selected film exhibited desirable physicochemical attributes, including uniform thickness, pH (7.08 ± 0.03), drug content (99.1 ± 0.4%), tensile strength (10.07 ± 0.34 N/cm 2 ), elongation at break (109.9 ± 7.3%), swelling index (124%), mucoadhesive strength (48.9 ± 2.38 g), and smooth surface via SEM. FTIR and DSC confirmed successful polymer modification, drug encapsulation, and amorphous dispersion of DLX within the matrix. Contact angle analysis confirmed improved hydrophilicity. DLX-SLCs buccal films exhibited superior curative efficacy compared to pure-DLX and the marketed-DLX in lipopolysaccharide (LPS)-induced rat depression model. Behavioral assessments demonstrated a 60% reduction in immobility time, an increase in open-arm entries, and sucrose preference by a 3.29-fold and 2-fold, respectively, compared to the LPS group. Biochemical analyses revealed reduced TNF-α, IL-1β, and cortisol levels by 67.6%, 64.4%, and 53%, respectively. Alongside increased serotonin and GABA levels by 1.64-fold and 3.5-fold, respectively. Histopathological findings confirmed significant neuroprotective effects. Conclusion: DLX-SLCs incorporated into CS-Pim buccal films provide enhanced antidepressant efficacy and neuroprotective benefits, representing a bioadhesive and patient-compliant alternative to conventional DLX formulations for depression treatment. Keywords: antidepressant, buccal, chitosan, duloxetine, mucoadhesion, pimelic acid