title: The use of thiolated polymers as carrier matrix in oral peptide delivery--proof of concept.
abstract: It was the aim of this study to develop an oral delivery system for the peptide drug antide. The stability of the therapeutic peptide towards gastrointestinal peptidases was evaluated. The therapeutic agent and the permeation mediator glutathione were embedded in the thiolated polymer chitosan-4-thio-butylamidine conjugate (chitosan-TBA conjugate) and compressed to tablets. Drug release studies were performed in the dissolution test apparatus according to the Pharmacopoeia Europea using the paddle method and demineralized water as release medium. In order to avoid mucoadhesion of these delivery systems already in the oral cavity and oesophagus tablets were coated with a triglyceride. These tablets were orally given to pigs (weight: 50+/-2 kg; Edelschwein Pietrain). Moreover, antide was administered intravenously, subcutaneously and orally in solution. Results showed stability of antide towards pepsin, trypsin and chymotrypsin. In contrast, antide was rapidly degraded by elastase. Consequently a stomach-targeted delivery system was designed. Drug release studies demonstrated an almost zero-order controlled release of antide over 8 h. In vivo studies demonstrated a relative bioavailability of 34.4% for the subcutaneous administration. Oral administration of antide in solution led to no detectable concentrations of the drug in plasma at all. In contrast, administering antide being incorporated in the thiolated polymer resulted in a significant uptake of the peptide. The absolute and relative bioavailability was determined to be 1.1% and 3.2%, respectively.
authors.affiliation: Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University Innsbruck, Innrain 52, Josef Möller Haus, 6020 Innsbruck, Austria. andreas.bernkop@uibk.ac.at
authors.forename: Andreas
authors.initials: A
authors.lastname: Bernkop-Schnürch
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Pinter
authors.forename: Davide
authors.initials: D
authors.lastname: Guggi
authors.forename: Hermann
authors.initials: H
authors.lastname: Kahlbacher
authors.forename: Gudrun
authors.initials: G
authors.lastname: Schöffmann
authors.forename: Maximilian
authors.initials: M
authors.lastname: Schuh
authors.forename: Ivo
authors.initials: I
authors.lastname: Schmerold
authors.forename: Maria Dorly
authors.initials: MD
authors.lastname: Del Curto
authors.forename: Mauro
authors.initials: M
authors.lastname: D'Antonio
authors.forename: Pierandrea
authors.initials: P
authors.lastname: Esposito
authors.forename: Christian
authors.initials: C
authors.lastname: Huck
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002686:Chitin / Q000031:analogs & derivatives* / Q000737:chemistry; D002918:Chymotrypsin / Q000378:metabolism; D004337:Drug Carriers / Q000493:pharmacokinetics*; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D009842:Oligopeptides / Q000097:blood / Q000493:pharmacokinetics*; D010196:Pancreatic Elastase / Q000378:metabolism; D010434:Pepsin A / Q000378:metabolism; D011108:Polymers / Q000493:pharmacokinetics; D013438:Sulfhydryl Compounds / Q000737:chemistry*; D013552:Swine; D014357:Trypsin / Q000378:metabolism
chemical_list: D004337:Drug Carriers; D009842:Oligopeptides; D011108:Polymers; D013438:Sulfhydryl Compounds; C493042:chitosan-4-thiobutylamidine; D002686:Chitin; C057022:iturelix; D002918:Chymotrypsin; D010196:Pancreatic Elastase; D014357:Trypsin; D010434:Pepsin A