A Nasal Gel Formulation of Ubrogepant Nanoparticles for Enhanced and Rapid Brain Delivery in the Treatment of Migraine

Background Ubrogepant is a first-generation gepant-class drug approved for the oral treatment of migraine. Purpose This work aimed at developing an intranasal gel consisting of ubrogepant nanoparticles (NPs), with the aim of improving its therapeutic efficacy through rapid and longer action in the brain. Materials and Methods The ubrogepant NPs were prepared using poly(lactic- co -glycolic) acid (PLGA), polyvinyl alcohol (PVA), and polysorbate 80. These NPs were then formulated into a thermo-reversible gel by using an optimized polymer, stabilizer, and process. The gel formulation was then tested by in vitro and ex vivo assays for drug release and permeation, and the pharmacodynamics and pharmacokinetics were evaluated in Sprague–Dawley rats. Results The PLGA NPs were optimally formulated in a mucoadhesive gel, which caused significant improvement in permeability and drug retention in the nasal mucosa. The in vivo studies indicated higher concentrations of ubrogepant in the brain, with a rapid absorption compared to the intranasal NP or oral ubrogepant delivery. The rapid absorption and sustained levels in the brain were translated into significantly improved efficacy of the gel formulation in the nitroglycerin (NTG)-induced migraine model in rats. Conclusion The optimized gel formulation of the ubrogepant NPs validated the potential of intranasal use of ubrogepant for the treatment of migraine.