Chitosan-based thermosensitive hydrogel for nasal delivery of exenatide: Effect of magnesium chloride

The aim of this research was to evaluate the potential of two chitosan (CS)-based hydrogel systems for nasal delivery of exenatide (EXT) in rats. Both of the EXT-loaded CS/glycerophosphate (GP)/CaCl₂ (EXT/CS/GP/CaCl₂) and EXT/CS/GP/MgCl₂ hydrogel systems had similar in vitro release profiles. However, a difference in metal salt surprisingly resulted in multifaceted differences between the two hydrogel systems, such as EXT stability, gelation time, transepithelial transport, biodistribution and pharmacokinetics. The gelation time of the EXT/CS/GP/MgCl₂ hydrogel (more than 110 min) at 37 °C was much longer than that of the EXT/CS/GP/CaCl₂ hydrogel (8.0-20.4 min). Transepithelial transport analysis showed that the CS/GP/MgCl₂ hydrogel enhanced EXT transport across the Calu-3 cell monolayers more than the CS/GP/CaCl₂ hydrogel (P < 0.05). After nasal administration in the rats, the EXT/CS/GP/MgCl₂ hydrogel increased the distribution of EXT in the targeting organs and the relative bioavailability of EXT in the rats more than the EXT/CS/GP/CaCl₂ hydrogel. Moreover, both EXT/CS/GP/salt hydrogel formulation treatments in high-fat-fed rats significantly decreased food intake and body weight relative to the EXT solution within ten days (P < 0.05). The aforementioned results suggest that the EXT/CS/GP/MgCl₂ hydrogel formulation is more suitable to be used as a nasally delivered EXT formulation for the treatment of weight loss.