Thiolated chitosan microparticles: A vehicle for nasal peptide drug delivery

The goal of this study was to develop a microparticulate delivery system based on a thiolated chitosan conjugate for the nasal application of peptides. Insulin was used as model peptide. For thiolation of chitosan 2-iminothiolane was covalently linked to chitosan. The resulting chitosan–TBA (chitosan-4-thiobutylamidine) conjugate featured 304.89 ± 63.45 μmol thiol groups per gram polymer. 6.5% of these thiol groups were oxidised. A mixture of the chitosan–TBA conjugate, insulin and the permeation mediator reduced glutathione were formulated to microparticles. Control microparticles comprised unmodified chitosan and insulin. As second control served mannitol–insulin microparticles. All microparticulate systems were prepared via the emulsification solvent evaporation technique. In 100 mM phosphate buffer pH 6.8 chitosan–TBA–insulin microparticles swelled 4.39 ± 0.52-fold in size, whereas chitosan based microparticles did not swell at all. Chitosan–TBA microparticles showed a controlled release of fluorescein isothiocyanate (FITC)-labelled insulin over 6 h. Nasal administered chitosan–TBA–insulin microparticles led to an absolute bioavailability of 7.24 ± 0.76% (means ± S.D.; n = 3) in conscious rats. In contrast, chitosan–insulin microparticles and mannitol–insulin microparticles exhibited an absolute bioavailability of 2.04 ± 1.33% and 1.04 ± 0.27%, respectively (means ± S.D.; n = 4). Because of these results microparticles comprising chitosan–TBA and reduced glutathione seem to represent a useful formulation for the nasal administration of peptides.