• • Optimal formulation: CS-β-CD to sodium carboxymethylcellulose mass ratio 1:9, total polymer concentration 2.6%, puerarin loading 40 mg. This specific ratio and concentration yielded a three-dimensional porous gel with pH 6.5, a critical quality attribute for nasal tolerability and mucoadhesion.
• • In vitro release: 82.75% cumulative puerarin release within 4 h, followed by sustained release. This biphasic profile addresses the clinical need for rapid onset (migraine abortive phase) combined with extended action (prophylactic phase), potentially reducing dosing frequency.
• • Pharmacodynamic efficacy: In nitroglycerin-induced chronic migraine rats, the gel significantly reduced brain CGRP and IL-1β levels and increased 5-HT content. These biomarker shifts directly correlate with attenuated neurogenic inflammation and restored neurotransmitter balance, supporting a multi-target anti-migraine mechanism.
• • Safety and translational gap: No nasal mucosal irritation was observed, but brain-targeting efficiency remains unquantified. The absence of LC-MS/MS or imaging data for brain puerarin concentration means that while efficacy is promising, the actual brain bioavailability and nose-to-brain transport fraction are unknown, representing a critical hurdle for clinical translation.