title: Oral insulin delivery: the potential of thiolated chitosan-insulin tablets on non-diabetic rats.
abstract: It was the aim of this study to develop a delivery system providing an improved efficacy of orally administered insulin utilizing a thiolated polymer. 2-Iminothiolane was covalently linked to chitosan. The resulting chitosan-TBA (chitosan-4-thiobutylamidine) conjugate exhibited 453.5+/-64.1 micromol thiol groups per gram polymer. 3.1% of these thiol groups were oxidised. Additionally, the enzyme inhibitors BBI (Bowman-Birk-Inhibitor) and elastatinal were covalently linked to chitosan representing 3.5+/-0.1% and 0.5+/-0.03% of the total weight of the resulting polymer conjugate, respectively. Chitosan-TBA conjugate (5 mg), insulin (2.75 mg), the permeation mediator reduced glutathione (0.75 mg) and the two inhibitor conjugates (in each case 0.75 mg) were compressed to so-called chitosan-TBA-insulin tablets. Control tablets consisted of unmodified chitosan (7.25 mg) and insulin (2.75 mg). Chitosan-TBA-insulin tablets showed a controlled release of insulin over 8 h. In vitro mucoadhesion studies showed that the mucoadhesive/cohesive properties of chitosan were at least 60-fold improved by the immobilisation of thiol groups on the polymer. After oral administration of chitosan-TBA-insulin tablets to non-diabetic conscious rats, the blood glucose level decreased significantly for 24 h corresponding to a pharmacological efficacy of 1.69+/-0.42% (means+/-S.D.; n=6) versus s.c. injection. In contrast, neither control tablets nor insulin given in solution showed a comparable effect. According to these results the combination of chitosan-TBA, chitosan-enzyme-inhibitor conjugates and reduced glutathione seems to represent a promising strategy for the oral application of insulin.
authors.affiliation: Institute of Pharmaceutical Technology and Biopharmaceutics, Center of Pharmacy, University of Vienna, Althanstr. 14, A-1090 Vienna, Austria/Europe.
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: D000269:Adhesives / Q000008:administration & dosage / Q000494:pharmacology; D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose; D002686:Chitin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D048271:Chitosan / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D003692:Delayed-Action Preparations / Q000138:chemical synthesis / Q000493:pharmacokinetics; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism; D005978:Glutathione / Q000737:chemistry / Q000378:metabolism; D007096:Imidoesters / Q000737:chemistry / Q000493:pharmacokinetics; D007328:Insulin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D007332:Insulin Infusion Systems; D007413:Intestinal Mucosa / Q000166:cytology / Q000187:drug effects; D009093:Mucus / Q000378:metabolism; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D013552:Swine; D013607:Tablets / Q000737:chemistry* / Q000493:pharmacokinetics; D013678:Technology, Pharmaceutical / Q000379:methods / Q000639:trends; D014358:Trypsin Inhibitor, Bowman-Birk Soybean / Q000737:chemistry / Q000378:metabolism
chemical_list: D000269:Adhesives; D001786:Blood Glucose; D003692:Delayed-Action Preparations; D004791:Enzyme Inhibitors; D007096:Imidoesters; D007328:Insulin; D009842:Oligopeptides; D013438:Sulfhydryl Compounds; D013607:Tablets; D014358:Trypsin Inhibitor, Bowman-Birk Soybean; C493042:chitosan-4-thiobutylamidine; D002686:Chitin; C005905:methyl 4-mercaptobutyrimidate; D048271:Chitosan; D005978:Glutathione; C010718:elastatinal