Development and in vivo bioavailability study of an oral fondaparinux delivery system.
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.
Vetter
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A
Department of Pharmaceutical Technology, Institute of Pharmacy, Leopold-Franzens-University Innsbruck, 6020 Innsbruck, Austria. Anja.Vetter@uibk.ac.at
Perera
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G
Leithner
K
K
Klima
G
G
Bernkop-Schnürch
A
A
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
D000925:Anticoagulants; D005782:Gels; D011134:Polysaccharides; D014622:Vaginal Creams, Foams, and Jellies; D000077425:Fondaparinux