title: Development and in vivo bioavailability study of an oral fondaparinux delivery system.
abstract: Fondaparinux is an agent of choice for the prevention and initial treatment of venous thromboembolism (VTE) as well as myocardial infarction. Nevertheless, as a negatively charged molecule fondaparinux can pass the intestinal epithelial barrier after oral administration only partially. It was therefore the aim of this study to design a highly efficient small-intestinal-targeted oral delivery system for fondaparinux based on thiolated polycarbophil (PCP-Cys) and glutathione (GSH) combined with sodium decanoate. The formulations were tested in vitro with regard to their release, cytotoxicity profiles and their permeation-enhancing properties across small-intestinal mucosa. For the in vivo study, rats were treated with a single oral dose of fondaparinux gels or mini-tablets (5mg/kg) and the subcutaneous and intravenous groups with a dose of 200μg/kg fondaparinux. The anti-factor Xa activity in the plasma was measured. In the presence of PCP-Cys/GSH/sodium decanoate the uptake of fondaparinux from the intestinal mucosa was 4.1-fold improved. The area under concentration-time curve in rat plasma from 0 to 24h with PCP-Cys/GSH/sodium decanoate gel was 135.3μgmin/ml and 1.3-fold improved with the tablets. C(max) value of mini-tablets was 0.23μg/ml and the absolute bioavailability of 4.4% was 6.2-fold improved, while the control solution was not absorbed orally. PCP-Cys/GSH/sodium decanoate demonstrated potential for increasing the oral bioavailability of the indirect factor Xa inhibitor as an alternative to currently used subcutaneous delivery.
authors: Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University Innsbruck, 6020 Innsbruck, Austria. Anja.Vetter@uibk.ac.at
authors: A
authors: A
authors: Vetter
authors: G
authors: G
authors: Perera
authors: K
authors: K
authors: Leithner
authors: G
authors: G
authors: Klima
authors: A
authors: A
authors: Bernkop-Schnürch
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D001682:Biological Availability; D018938:Caco-2 Cells; D002470:Cell Survival; D000077425:Fondaparinux; D005782:Gels; D006801:Humans; D007421:Intestine, Small; D008297:Male; D011134:Polysaccharides / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014622:Vaginal Creams, Foams, and Jellies
chemical_list: D000925:Anticoagulants; D005782:Gels; D011134:Polysaccharides; D014622:Vaginal Creams, Foams, and Jellies; D000077425:Fondaparinux