Preparation and Anti-Migraine Pharmacodynamic Evaluation of Puerarin-Loaded Chitosan-Modified β-Cyclodextrin Nasal Supramolecular Gel
Puerarin, a principal isoflavone from Pueraria lobata, exhibits anti-migraine activity but suffers from poor oral bioavailability and limited blood-brain barrier penetration. This study reports a puerarin-loaded chitosan-modified β-cyclodextrin supramolecular gel (Pur@CS-β-CD Gel) for intranasal delivery. Formulation optimization employed single-factor experiments and Box-Behnken design-response surface methodology (BBD-RSM). The optimal formulation comprised CS-β-CD and sodium carboxymethylcellulose at a mass ratio of 1:9, total polymer concentration 2.6%, and puerarin 40 mg. The resulting gel displayed a three-dimensional porous architecture, pH 6.5, favorable stability, and a biphasic in vitro release profile: 82.75% cumulative release within 4 h followed by sustained release. No nasal mucosal irritation was observed. In a chronic migraine rat model induced by nitroglycerin, Pur@CS-β-CD Gel significantly ameliorated behavioral deficits, reduced brain levels of calcitonin gene-related peptide (CGRP) and interleukin-1β (IL-1β), and elevated 5-hydroxytryptamine (5-HT). These pharmacodynamic outcomes are consistent with interruption of trigeminovascular CGRP release, modulation of serotonergic neurotransmission, and attenuation of IL-1β-mediated nociceptive sensitization. The study acknowledges limitations: the animal model only partially recapitulates clinical migraine heterogeneity; long-term safety and immunogenicity of repeated dosing remain unassessed; and direct quantification of brain puerarin concentration was not performed, leaving brain-targeting efficiency unproven. Nonetheless, the optimized gel offers a feasible, non-invasive nasal delivery platform with preliminary anti-migraine efficacy, warranting further pharmacokinetic and mechanistic validation.