Development and Optimization of Thermoreversible in-situ Nasal Gel Loaded With Zavegepant for Treatment of Migraine

Objectives: To develop and optimize a thermoreversible in-situ nasal gel of Zavegepant for effective and rapid treatment of acute migraine, enhancing brain targeting and bioavailability while overcoming limitations of oral formulations. Methods: A 3² full factorial design was employed to evaluate the effects of Pluronic F-127 (X₁) and xanthan gum (X₂) on gelation temperature (Y₁) and mucoadhesive strength (Y₂). Nine formulations (VF1–VF9) were developed and evaluated for physicochemical properties, gelation behavior, mucoadhesion, in-vitro drug release, ex vivo permeation, and in vivo anti-migraine efficacy using a nitroglycerin-induced migraine model in rats. Results: Optimized batch VF2 containing 20% Pluronic F-127 and 0.2% xanthan gum showed a gelation temperature of 34.94 °C and mucoadhesive strength of 5812.2 dyne/cm² with minimal prediction error (<5%). VF2 exhibited sustained ex vivo drug release (83.67% at 8 hours) and steady-state flux of 522.94 μg/cm²/h. In vivo studies demonstrated significant improvement in locomotor activity, photophobia, and mechanical allodynia, with biochemical normalization of CGRP (41.16 pg/mg), MDA, NO, GSH, and SOD levels, comparable to sumatriptan. Stability over 3 months confirmed formulation robustness. Conclusion: The optimized thermosensitive nasal gel (VF2) of Zavegepant presents a promising, non-invasive strategy for acute migraine therapy with sustained drug release, enhanced mucosal retention, and effective CNS delivery. Its clinical potential lies in offering fast, localized treatment with fewer systemic side effects and improved patient compliance.