Development and in vivo bioavailability study of an oral fondaparinux delivery system

• Published in: European journal of pharmaceutical sciences 2010-11, Vol.41 (3), p.489-497
• Main Authors: Vetter, A., Perera, G., Leithner, K., Klima, G., Bernkop-Schnürch, A.
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Anticoagulants - administration & dosage; Anticoagulants - blood; Anticoagulants - pharmacokinetics; Biological and medical sciences; Biological Availability; Caco-2 Cells; Cell Survival; Cytotoxicity; Fondaparinux; Gels; General pharmacology; Humans; In vivo study; Intestine, Small; Male; Medical sciences; Permeation; Pharmaceutical technology. Pharmaceutical industry; Pharmacology. Drug treatments; Polysaccharides - administration & dosage; Polysaccharides - blood; Polysaccharides - pharmacokinetics; Rats; Rats, Sprague-Dawley; Thiomers; Vaginal Creams, Foams, and Jellies
• ISSN: 0928-0987; 1879-0720
• DOI: 10.1016/j.ejps.2010.08.001

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 (5 mg/kg) and the subcutaneous and intravenous groups with a dose of 200 μg/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 24 h with PCP-Cys/GSH/sodium decanoate gel was 135.3 μg min/ml and 1.3-fold improved with the tablets. C max value of mini-tablets was 0.23 μg/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.