title: Thiolated chitosans: development and in vitro evaluation of an oral tobramycin sulphate delivery system.
abstract: The aim of the present study was to develop and evaluate an oral delivery system for tobramycin sulphate intended to improve the oral bioavailability. Chitosan was thiolated by the immobilisation of N-acetylcysteine (NAC) to the amino groups of the polymer. The permeation enhancing effect of the resulting chitosan-NAC conjugate in combination with the permeation mediator glutathione (GSH) was evaluated both in Ussing-type chambers across freshly excised rat intestinal mucosa and Caco-2 cells using the poorly orally absorbed aminoglycoside tobramycin sulphate as model drug. Additionally, the release profile from tablets containing tobramycin sulphate, chitosan-NAC and glutathione was determined. The obtained thiomer chitosan-NAC displayed 962.2+/-53.2 micromol thiol groups per gram polymer of which 35.5+/-5.0% were oxidised. In comparison to buffer only, tobramycin sulphate uptake in presence of 0.5% (w/v) unmodified chitosan, 0.5% (w/v) chitosan-NAC, 0.5% (w/v) glutathione and the combination of 0.5% (w/v) glutathione and 0.5% (w/v) chitosan-NAC was improved 1.2-fold, 1.3-fold, 1.5-fold and 2.0-fold, respectively, across rat small intestine and 2.6-fold, 2.7-fold, 1.6-fold and 3.3-fold, respectively, across Caco-2 cell monolayer. Almost 90% of the tobramycin sulphate was released from tablets within 4h. The developed drug delivery system containing chitosan-NAC and glutathione is a promising tool for oral tobramycin sulphate administration showing improved gastrointestinal uptake and a sustained release.
authors.affiliation: Institute of Pharmacy, Leopold-Franzens-University Innsbruck, Innrain 52, Josef-Möller-Haus, 6020 Innsbruck, Austria.
authors.forename: Juliane
authors.initials: J
authors.lastname: Hombach
authors.forename: Herbert
authors.initials: H
authors.lastname: Hoyer
authors.forename: Andreas
authors.initials: A
authors.lastname: Bernkop-Schnürch
mesh_terms: D000111:Acetylcysteine / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D000284:Administration, Oral; D000818:Animals; D001692:Biological Transport; D018938:Caco-2 Cells; D048271:Chitosan / Q000138:chemical synthesis / Q000737:chemistry*; D002851:Chromatography, High Pressure Liquid; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics; D004847:Epithelial Cells / Q000378:metabolism; D005978:Glutathione / Q000737:chemistry; D006801:Humans; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism*; D007421:Intestine, Small / Q000378:metabolism; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D013607:Tablets; D013678:Technology, Pharmaceutical / Q000379:methods; D014031:Tobramycin / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics*; D014700:Verapamil / Q000008:administration & dosage / Q000493:pharmacokinetics
chemical_list: D003692:Delayed-Action Preparations; D013438:Sulfhydryl Compounds; D013607:Tablets; D048271:Chitosan; D014700:Verapamil; D005978:Glutathione; D014031:Tobramycin; D000111:Acetylcysteine