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

作者：Vetter A; Perera G; Leithner K; Klima G; Bernkop Schnuerch A^*

来源：European Journal of Pharmaceutical Sciences, 2010, 41(3-4): 489-497.

DOI：10.1016/j.ejps.2010.08.001

• Thiomers
• Fondaparinux
• In vivo study
• Cytotoxicity
• Permeation

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 mu g/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 135.3 mu g min/ml and 1.3-fold improved with the tablets. C(max) value of mini-tablets was 0.23 mu g/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.

• 出版日期2010-11-20