Synthesis, characterization and evaluation of thiolated quaternary ammonium-chitosan conjugates for enhanced intestinal drug permeation

Abstract

In a previous report quaternary ammonium-chitosan conjugates (N +-Chs) endowed with intestinal drug permeability-enhancing properties were described. They are characterized by short pendant chains of n adjacent diethyl-dimethylene-ammonium groups substituted onto the primary amino group of the chitosan (Ch) repeating units. In the present work two N +-Chs, one having DS (degree of substitution) = 59.2 ± 4.5%, n = 1.7 ± 0.1 (N +(60)-Ch), the other one having DS = 40.6 ± 1.3%, n = 3.0 ± 0.2 (N +(40)-Ch) were used to synthesize novel multifunctional non-cytotoxic Ch derivatives, each carrying thiol along with quaternary ammonium groups (N +-Ch–SH), with increased potential to enhance transepithelial drug transport. They have been obtained by transforming the residual free amino groups of N +(60)-Ch and N +(40)-Ch into 3-mercaptopropionamide moieties. The former yielded 4.5 ± 0.7% thiol-bearing groups, the latter, 5.2 ± 1.1% of such groups, on a Ch repeating unit basis. The multifunctional derivatives have improved the ability of the parent N +-Chs to enhance the permeability of the water-soluble macromolecular fluorescein isothiocyanate dextran, MW 4400 Da (FD4) and that of the lipophilic dexamethasone (DMS) across the excised rat intestinal mucosa and Caco-2 cell monolayer, respectively. The data from the present work altogether point to a synergism of quaternary ammonium and thiol groups to improve the intestinal drug absorption enhancing properties of the multifunctional Ch derivatives.