Objective To develop a puerarin-loaded supramolecular gel based on chitosan-modified β-cyclodextrin (Pur@CS-β-CD Gel), optimize its formulation, and evaluate its potential for nasal delivery and anti-migraine efficacy. Methods The Pur@CS-β-CD Gel formulation was optimized using single-factor experiments and Box-Behnken design-response surface methodology (BBD-RSM). The optimized Pur@CS-β-CD Gel was characterized for its microstructure, pH value, stability, and in vitro release profile. A chronic migraine rat model was established. The therapeutic efficacy was assessed through behavioral indicators and by measuring the levels of calcitonin gene-related peptide (CGRP), 5-hydroxytryptamine (5-HT), and interleukin-1β (IL-1β) in brain tissue. Results The optimal formulation consisted of CS-β-CD and sodium carboxymethylcellulose at a mass ratio of 1:9, a total polymer concentration of 2.6%, and 40 mg of puerarin. The resulting Pur@CS-β-CD Gel exhibited a three-dimensional porous structure, a pH of 6.5, good stability, and a biphasic in vitro release profile characterized by an initial rapid release (82.75% within 4 h) followed by sustained release, with no obvious nasal-mucosal irritation. Pharmacodynamic studies demonstrated that Pur@CS-β-CD Gel significantly improved migraine-related behavioral performance in rats, reduced CGRP and IL-1β levels, and increased 5-HT content in the brain. Conclusion The Pur@CS-β-CD Gel demonstrates a feasible preparation process, favorable properties for nasal administration, and effective anti-migraine activity, providing an experimental basis for the development of novel nasal delivery systems and migraine therapies.

puerarin  /  supramolecular gel  /  process optimization  /  nasal administration  /  chronic migraine  /  pharmacodynamic evaluation