Journal
JOURNAL OF CONTROLLED RELEASE
Volume 335, Issue -, Pages 422-436Publisher
ELSEVIER
DOI: 10.1016/j.jconrel.2021.05.048
Keywords
Chitosan-centered nanosystems; Intranasal delivery; Histamine inhibition; Allergic rhinitis; Long-term therapy
Funding
- National Natural Science Foundation of China [31500807]
- Taishan Scholar Program, China
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Nanosystems incorporating ketotifen and cetirizine show longer histamine release inhibition and histamine H1 receptor antagonism, providing better therapeutic efficacy for respiratory allergy intervention.
Allergic rhinitis (AR), histamine-mediated upper airway inflammatory disorder, is characterized by sneezing, itching, airway hyperreactivity, etc. Though it is clinically well-managed by non-invasive inhaled antihistamines, for example, ketotifen (KT, histamine release inhibitor) and cetirizine (CTZ, histamine receptor antagonist), inherent defects of short mucosal in situ retention, frequent administration resulting in irritation to mucosa, and lack of target-specific sequential release of dual drug systems which have been proven to be more effective are inevitable, urging for alternative therapeutic strategies. Recent advances in nanotechnology may be pivotal to generating muco-adhesive nanosystems, which is desirable to prolong local retention, reduce dosing frequency and relieve mucosal irritation. In this regard, KT incorporated and CTZ decorated hydroxybutyl chitosan nanoparticles (K subset of CH NPs) were fabricated as nasal adaptive sequential release dual drug system for long-term AR therapy. Nasal adaptive morphology transformation and two-step payload release up to 72 h were achieved in vitro, with - 3-fold higher bio-adhesivity over free drugs appeared. K subset of CH NPs accomplished longer histamine release inhibition (- 24 h) and histamine H1 receptor antagonism (- 6 h), compared with free KT&CTZ of - 12 h and - 2 h, respectively. The nanosystems provided comparable anti-allergic effect to free antihistamines via successive intranasal dropping in AR rat, while encouragingly, significantly (P < 0.05) better therapeutic efficacy at reduced treatment frequency (every 4 days) and dose (half-dose). Therefore, the outcomes establish K subset of CH NPs as effective low-dose and long-interval administered nanosystems to ameliorate histamine-mediated AR inflammation, which could in principal find extensive utilizations in respiratory allergy intervention.
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