Synthesis and characterization of pH tolerant and mucoadhesive (thiol-polyethylene glycol) chitosan graft polymer for drug delivery.

The objective of this study was to generate a water-soluble thiolated chitosan to enable the permeation-enhancing effect of chitosan at pH of at least 5.5 without losing the advantages of improved mucoadhesive properties. Therefore, the thiol-bearing polyoxyethylene ligand {O-(3-carboxylpropyl)-O'-[2-[3-mercaptopropionylamino)ethyl]-polyethyleneglycol} was conjugated via amide bond formation to the amino group of chitosan. Resulting novel chitosan derivative (Chito-PEG-SH) exhibited 250 μmol free thiol groups per gram polymer. By the attachment of the thiol-bearing PEG ligand, an improvement of permeation-enhancing effect on rat intestine (2.7-fold improvement) as well as on a Caco-2 monolayer model (1.9-fold improvement) could be found. Cytotoxicity studies on Caco-2 cells revealed no change in biocompatibility. Mucoadhesion was improved 3.1-fold by the formation of disulfide bonds with mucus glycoproteins. The mucoadhesive effect of Chito-PEG-SH turned out to be similar to thiolated chitosan and more pronounced than mucoadhesive properties of unmodified chitosan. The graft polymer is soluble in water and aqueous solutions over a broad pH range. In aqueous media, the novel polymer does not precipitate at pH of 8.6 or less. According to these results, Chito-PEG-SH might show potential as auxiliary agent in oral drug delivery where its solubility even up to pH 8 is likely beneficial.