Chitosan-coated vesicles in thermosensitive gel as a compelling platform for cannabidiol treatment of ocular disorders.
Abstract
Topical ocular delivery of cannabidiol (CBD), a well-known phytocannabinoid with anti-inflammatory and neuroprotective properties, remains challenging because of its poor aqueous solubility, limited bioavailability, and rapid precorneal clearance. Nanocarrier-based and thermoresponsive mucoadhesive systems have emerged as promising approaches to overcome these limitations. We developed an advanced ocular delivery platform, consisting of CBD-loaded nanovesicles coated with chitosan (CS) embedded in a thermosensitive poloxamer-based in situ gel (Tg-CS-VS). Due to its positive charge and mucoadhesive properties, CS interacts with the negatively charged mucins of the tear film, prolonging residence time, promoting close contact with the corneal epithelium and transiently modulating tight junctions. These combined mechanisms markedly enhance the epithelial uptake and bioavailability of poorly soluble drugs such as CBD. A multivariate DoE approach optimized critical formulation parameters, including CS and poloxamer 407 concentrations and process variables. Tg-CS-VS exhibited nanovesicles with a mean diameter of of 176.5 ± 6.3 nm, polydispersity index of 0.215 ± 0.022 and ζ-potential of +24.0 ± 2.4 mV and suitable handling and rheological properties. CBD recovery was 98.3 ± 0.5% and gelation time was 15 s at corneal surface temperature. Mucin binding assays evidenced strong CS-mediated electrostatic interactions, supporting mucoadhesion. Good tolerability of the formulation was evidenced in corneal keratocytes cell line. In vivo studies in normotensive and transiently hypertensive rabbits showed excellent ocular tolerability and significant intraocular pressure (IOP) reduction, with maximal effect observed at 60 min post-administration. Overall, the formulation represents a highly promising, biocompatible system for anterior segment delivery of CBD, achieving efficient encapsulation, prolonged ocular residence and notable IOP-lowering activity. Further studies will explore its long-term therapeutic potential in chronic disease models.