In-situ forming Poloxamer-based Hydrogel Containing Thiolated Chitosan Nanoparticles as Intranasal Galantamine Delivery system

Abstract

Introduction: Considering the blood-brain barrier, drug delivery approaches for Alzheimer's disease is limited. To overcome this problem, delivering the drug via nasal route seems to be an appropriate approach as an alternative way to the systemic administration due to direct targeting of the brain. Objectives: In this study, a new drug delivery system as a mucoadhesive in-situ forming hydrogel for Galantamine was prepared. Methods: Mucoadhesive Nanoparticles (NPs) were prepared by thiolation of Chitosan with Mercaptopropionic acid. The Galantamine-loaded Thiolated Chitosan NPs (TCS-NPs) were synthesized via two methods. In-vitro release studies from the synthesized hydrogel were carried out using the dialysis bag. FT-IR spectroscopy, DLS, TEM, SEM, rheometer were used to analyze the structure of prepared formulations. In-vitro cell cytotoxicity of prepared hydrogel on Caco-2 cells was evaluated using the MTT method. The cell viability of hydrogels was determined by DAPI- staining and live/dead kit. Cellular uptake of FITC-labeled NPs was evaluated by Fluorescence Microscopy analysis on A172 cells. Ex-vivo studies on sheep nasal mucosa and brain were also evaluated. Results: The obtained results demonstrated that the thiolation value of CS was 198.6 µmol/g. Galantamine-loaded NPs prepared via ionic gelation showed no entrapment efficiency, while when they were prepared via desolvation method, the achieved entrapment efficiency was 40%. The cumulative drug release at the pH of 6.4 was 96 percent in 48 hours. Our results confirmed that drug-loaded-TCS NPs@PLX are non-toxic for encapsulation of Galantamine and the developed hydrogel displayed excellent biocompatibility in cell models in vitro. The TCS-NPs could gain access to the intracellular environment of epithelial cells. Also the ex-vivo results on sheep mucosa and brain showed no serious damage to the tissues in histopathological studies. Conclusion: Poloxamer-based hydrogels containing TCS NPs could be particularly efficient for delivery of therapeutic agents to the brain via the nasal route.