Thermosensitive transniosomal <i>in situ</i> gel of hesperetin for intranasal administration: novel approach for Parkinson’s therapy

The present study aims to formulate and evaluate a thermosensitive transniosomal <i>in situ</i> gel of hesperetin (HST-TN) for intranasal delivery to improve its therapeutic efficacy in Parkinson's disease management. HST-TN was prepared <i>via</i> thin film hydration and optimised using Box-Behnken design. The optimised formulation (Opt-HST-TN) was incorporated into a Poloxamer 407-based <i>in situ</i> gel for sustained drug release. Opt-HST-TN exhibited vesicles size (100.50 ± 4.60 nm), PDI (0.247 ± 0.01), zeta potential (-32.50 ± 5.4 mV), and entrapment efficiency (91.71 ± 2.28%). The <i>in vitro</i> drug release study demonstrated 77.58 ± 0.15% drug release from Opt-HST-TN in 24 h. <i>Ex vivo</i> permeation finding showed 82.24% penetration and a flux of 5.16 µg/cm²/h, approximately 2-fold higher than HST suspension. Confocal laser scanning microscopy confirmed that Opt-HST-TN containing Rhodamine B showed superior mucosal penetration (30 µm) than Rhodamine B hydroethanolic solution (20 µm). Further, nasal toxicity studies have confirmed the Opt-HST-TTN's non-irritant nature. The prepared formulation significantly improved motor coordination, grip strength, and locomotor activity in haloperidol-induced Parkinson's disease Wistar rats after intranasal administration. These findings suggest that HST-loaded thermosensitive transniosomal <i>in situ</i> gel is an encouraging intranasal drug delivery system for PD, offering enhanced bioavailability, nasal permeability, and therapeutic efficacy.