Differential Intestinal Mucus Barrier Effects of Chitosan-Based Polymers

Abstract The performance of mucoadhesive polymers such as chitosan (CS) in oral delivery formulations depends on their interaction with the mucus barrier, making ex vivo mucus testing a key step in formulation development. This study reports how CS and its quaternized derivatives, trimethyl chitosan (TMC) and hydroxypropyl trimethyl ammonium chitosan chloride (HACC), influence the gel network and permeability of ex vivo porcine intestinal mucus. CS significantly enhanced retention forces of mucus, reducing macromolecular FD4 diffusion by 2-fold at concentrations higher than 1 mg/mL. CS at 25 mg/mL led to tightening of the mucus network and polymer-mucin hyperentanglements, shown by rheological analysis, where complex viscosity was 40-fold higher than apparent viscosity. In contrast, TMC and HACC induced milder structural changes, primarily decreasing pore size by 3 to 5-fold with limited permeability, together with reduced mucoadhesive interactions from quaternization. These findings provide important insights into polymer-mucus entanglements, assisting the rational design of mucoadhesive and permeability-modulating excipients for oral drug delivery systems.