Key Takeaways & Executive Findings
- •• • 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.
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Abstract
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.
1. Introduction
Migraine is a prevalent chronic neurovascular disorder that imposes substantial disability and socioeconomic burden. Existing pharmacological therapies face significant limitations: oral triptans and NSAIDs suffer from low oral bioavailability, poor blood-brain barrier permeability, and systemic adverse effects such as cardiovascular complications and medication-overuse headache. Intranasal administration offers a non-invasive route that bypasses hepatic first-pass metabolism and can potentially deliver drugs directly to the central nervous system via olfactory and trigeminal pathways. However, conventional nasal liquid formulations are rapidly cleared by mucociliary clearance, resulting in short residence time and inconsistent therapeutic efficacy.
To overcome these bottlenecks, this study engineered a supramolecular gel based on chitosan-modified β-cyclodextrin (CS-β-CD) for nasal delivery of puerarin, a natural isoflavone with anti-migraine potential. The CS-β-CD carrier combines the inclusion capacity of β-cyclodextrin with the mucoadhesive and permeation-enhancing properties of chitosan, while the gel matrix formed with sodium carboxymethylcellulose prolongs nasal retention. The formulation was optimized using Box-Behnken design-response surface methodology, and its microstructure, pH, stability, and in vitro release were characterized. Efficacy was evaluated in a nitroglycerin-induced chronic migraine rat model by behavioral assessment and quantification of brain CGRP, 5-HT, and IL-1β. This integrated approach aims to provide a translational foundation for a nose-to-brain delivery system that addresses the dual challenges of rapid clearance and poor CNS penetration.
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ZONG Shiyu, WANG Miao, MA Xinyu, LIU Shuo, REN Jia, CHENG Yunlong, WANG Chunliu (2026). Preparation and Anti-Migraine Pharmacodynamic Evaluation of Puerarin-Loaded Chitosan-Modified β-Cyclodextrin Nasal Supramolecular Gel. Chinese Traditional and Herbal Drugs. https://doi.org/10.7501/j.issn.0253-2670.2026.16.20261609
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Frequently Asked Questions
What is the exact optimized formulation and its critical quality attributes?
The optimal formulation consists of 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 exhibits a three-dimensional porous structure, pH 6.5, and good stability. These parameters were determined via Box-Behnken design-response surface methodology, ensuring a robust and reproducible manufacturing process.
What is the in vitro release profile and its clinical implication?
The gel shows a biphasic release: 82.75% cumulative puerarin release within 4 hours, followed by sustained release. This rapid initial phase is intended to achieve therapeutic concentrations quickly for acute migraine relief, while the sustained phase maintains drug levels for prolonged prophylaxis, potentially reducing dosing frequency and improving patient compliance.
What pharmacodynamic evidence supports anti-migraine efficacy?
In a nitroglycerin-induced chronic migraine rat model, the gel significantly improved behavioral parameters and modulated key biomarkers: reduced brain CGRP and IL-1β levels, and increased 5-HT content. These changes align with inhibition of trigeminovascular CGRP release, anti-inflammatory action, and serotonergic modulation, collectively attenuating neurogenic inflammation and nociceptive sensitization.
What are the major translational limitations of this study?
The study acknowledges three critical gaps: (1) the nitroglycerin-induced animal model only partially mimics human migraine heterogeneity; (2) long-term safety and immunogenicity of repeated nasal dosing were not assessed; and (3) brain puerarin concentration was not directly measured, so brain-targeting efficiency remains unproven. Future work requires LC-MS/MS or fluorescence imaging to quantify nose-to-brain transport and pharmacokinetic parameters.
How does this delivery system address the shortcomings of existing nasal formulations?
Conventional nasal liquids are rapidly cleared by mucociliary action, limiting drug residence and absorption. The CS-β-CD supramolecular gel combines mucoadhesive chitosan, inclusion complexation by β-cyclodextrin, and a gel network that prolongs nasal retention. This design enables sustained release and potentially enhances nose-to-brain transport, as suggested by the observed central biomarker changes, though direct brain quantification is still needed.
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