Thiolated chitosan: Development and in vivo evaluation of an oral delivery system for leuprolide

The aim of the present study was to develop an oral delivery system for the peptide drug leuprolide. Gel formulations based on unmodified chitosan/reduced glutathione (GSH) and chitosan–thioglycolic acid (chitosan–TGA)/GSH were prepared, and their effect on the absorption of leuprolide was evaluated in vitro and in vivo in male Sprague Dawley rats. Transport studies were performed with freshly excised rat intestinal mucosa mounted in Ussing-type chambers. Due to the addition of gel formulations comprising 0.5% (m/v) unmodified chitosan/0.5% (m/v) GSH and 0.5% (m/v) chitosan–TGA/0.5% (m/v) GSH, the transport of leuprolide across excised mucosa was improved up to 2.06-fold and 3.79-fold, respectively, in comparison with leuprolide applied in buffer (Papp = 2.87 ± 0.77 × 10−6 cm/s).In vivo, the addition of oral gel formulation comprising 8 mg of unmodified chitosan, 1 mg of GSH and 1 mg of leuprolide increased the area under the plasma concentration–time curve (AUC0–8) of leuprolide 1.39-fold in comparison with leuprolide having been administered just in saline. Moreover, the administration of oral gel formulation comprising 8 mg of chitosan–TGA, 1 mg of GSH and 1 mg of leuprolide resulted in a further enhanced leuprolide plasma concentration, and the area under the plasma concentration–time curve (AUC0–8) of leuprolide was increased 3.72-fold in comparison with the control. With the oral gel formulation comprising 8 mg of chitosan–TGA, a relative bioavailability (versus s.c. injection) of 4.5% was achieved in contrast to the control displaying a relative bioavailability of 1.2%. Thus, according to the achieved results, it is suggested that chitosan–TGA in combination with GSH is a valuable tool for improving the oral bioavailability of the peptide drug leuprolide.

Graphical abstractEnhanced absorption of leuprolide in the presence of chitosan-thioglycolic acid (chitosan-TGA)/reduced glutathione (GSH) (▴).Figure optionsDownload full-size imageDownload as PowerPoint slide