Granules in the improvement of oral heparin bioavailability

Low molecular weight heparins (LMWHs), mainly used for the prevention of deep vein thrombosis, are so far only administered by parenteral route. Presumably, due to their large size and negative charge, LMWHs are not absorbed efficiently across the mucus of the gastrointestinal tract. Since parenteral administration requires medical assistance and is not the most convenient route of application, the development of an oral dosage form of heparin would improve patients’ comfort and replace vitamin K antagonists. Thus, we developed granules of two LMWHs, enoxaparin and bemiparin, based on primary granules of microcrystalline cellulose and loaded with ethylcellulose (Aquacoat®ECD) or a polycationic polymer (Eudragit®RS30D (ERS)) or their mixtures. The highest maximal plasma anti-Xa activities and the highest bioavailabilities for enoxaparin granules (0.45 ± 0.12 IU/mL; 19.00 ± 0.30%, respectively) and for bemiparin granules (0.54 ± 0.08 IU/mL; 29.02 ± 4.12%, respectively) were found after oral administration of granules loaded with ERS alone at a dose of 600 IU anti-Xa/kg to rabbits. These results confirm the oral absorption of LMWH from granules loaded with polycationic polymer and open up this technology for peptides and proteins that are very sensitive to organic solvents and have poor drug absorption from the gastrointestinal tract.