Trimethylated chitosan as polymeric absorption enhancerfor improved peroral delivery of peptide drugs

The absorption enhancing effects of chitosan and its derivatives have been intensively studied in recent years. It has been shown that thesecompounds are potent absorption enhancers. Chitosan is only soluble in acidic environments and is therefore incapable of enhancingabsorption in the small intestine, the main absorption area in the gastrointestinal tract. Special emphasis has been placed on the absorptionenhancing properties of N-trimethyl chitosan chloride (TMC), a partially quaternised derivative of chitosan, due to its solubility in neutraland basic environments. TMC is prepared by the reductive methylation of chitosan. The degree of quaternisation can be altered by increasingthe number of reaction steps or by increasing the reaction time. Although the molecular weight of the polymer increases with addition of themethyl groups, a net decrease in the molecular weight is observed due to a decrease in the chain length of the polymer. TMC, like chitosan,possesses mucoadhesive properties. In vitro studies performed on Caco-2 cell monolayers showed a pronounced reduction in thetransepithelial electrical resistance (TEER). TMC is also able to increase the permeation of hydrophilic compounds such as [14C]-mannitoland [14C] polyethylene glycol 4000 ([14C] PEG 4000, MW4000) across the cell monolayers. It was also shown that the degree ofquaternisation of the polymer plays an important role on its absorption enhancing properties, especially in neutral environments wherechitosan is ineffective as an absorption enhancer. The reduction in TEER is an indication of the opening of the tight junctions located betweenepithelial cells. Opening of the tight junctions will result in enhancement of absorption via the paracellular route. Confocal laser scanningmicroscopy confirmed transport of large hydrophilic compounds via the paracellular route as well as the mechanism of action of the polymerin which redistribution of the cytoskeletal F-actin is provoked, which leads to the opening of the tight junctions. Various in vivo studies indifferent animal models confirmed the ability of TMC to increase the absorption of the peptide drugs buserelin and octreotide afterintraduodenal or -jejunal administration. However, TMC has always been administered as a solution in these studies. The impracticality ofadministering a solution, as well as the fact that most peptides are unstable in the presence of water, have led to the need for a solid oraldosage form with which TMC can be administered together with peptide drugs. Recent studies have focused on the development and in vivoevaluation of solid oral dosage forms.