title: Thiolated chitosan microparticles: a vehicle for nasal peptide drug delivery.
abstract: 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 micromol 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.
authors.affiliation: Institute of Pharmaceutical Technology and Biopharmaceutics, Center of Pharmacy, University of Vienna, A-1090 Vienna, Austria.
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Krauland
authors.forename: Davide
authors.initials: D
authors.lastname: Guggi
authors.forename: Andreas
authors.initials: A
authors.lastname: Bernkop-Schnürch
mesh_terms: D000281:Administration, Intranasal; D000818:Animals; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D002686:Chitin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D004337:Drug Carriers / Q000737:chemistry / Q000493:pharmacokinetics*; D016503:Drug Delivery Systems; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D005978:Glutathione / Q000008:administration & dosage; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D007328:Insulin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008863:Microspheres; D010316:Particle Size; D051381:Rats; D017208:Rats, Wistar; D013499:Surface Properties
chemical_list: D004337:Drug Carriers; D005456:Fluorescent Dyes; D007004:Hypoglycemic Agents; D007328:Insulin; C493042:chitosan-4-thiobutylamidine; D002686:Chitin; D005978:Glutathione; D016650:Fluorescein-5-isothiocyanate