BACKGROUND: Oral absorption of low-molecular-weight heparin (LMWH) is limited by its molecular size and negative charge. It has been shown previously that orally administered polymeric nano- or microparticles containing encapsulated LMWH have led to gastrointestinal absorption of heparin in rabbits. METHOD: Based on these investigations, pellets containing two LMWHs, enoxaparin (MW 4500 Da) or bemiparin (MW 3600 Da), and EudragitRS30D (ERS), were prepared using extrusion/ spheronization technique. Uncoated or coated (ERS) pellets were evaluated in vitro and in vivo on rabbits. RESULTS: Enoxaparin pellets showed fast in vitro release in phosphate buffer (pH 7.4) and prolonged in vivo drug absorption after a single oral dose of 600 anti-Xa IU/ kg of body weight, leading to relative bioavailabilities ranging from 9.7 +/- 1.9% to 12.8 +/- 2.7% and anti-Xa activity over the curative dose. Bemiparin included in matrix pellets of ERS and coated with ERS exhibited in vitro prolonged release up to 4 hours and in vivo anti-Xa activity below the therapeutic minimum value of 0.1 IU/mL. CONCLUSION: This study presents LMWH in a pellet dosage form, which compared to nano- or microparticles, may offer a more convenient and industrializable way of manufacture leading to an easier scale-up process.
BACKGROUND: Oral absorption of low-molecular-weight heparin (LMWH) is limited by its molecular size and negative charge. It has been shown previously that orally administered polymeric nano- or microparticles containing encapsulated LMWH have led to gastrointestinal absorption of heparin in rabbits. METHOD: Based on these investigations, pellets containing two LMWHs, enoxaparin (MW 4500 Da) or bemiparin (MW 3600 Da), and EudragitRS30D (ERS), were prepared using extrusion/ spheronization technique. Uncoated or coated (ERS) pellets were evaluated in vitro and in vivo on rabbits. RESULTS:Enoxaparin pellets showed fast in vitro release in phosphate buffer (pH 7.4) and prolonged in vivo drug absorption after a single oral dose of 600 anti-Xa IU/ kg of body weight, leading to relative bioavailabilities ranging from 9.7 +/- 1.9% to 12.8 +/- 2.7% and anti-Xa activity over the curative dose. Bemiparin included in matrix pellets of ERS and coated with ERS exhibited in vitro prolonged release up to 4 hours and in vivo anti-Xa activity below the therapeutic minimum value of 0.1 IU/mL. CONCLUSION: This study presents LMWH in a pellet dosage form, which compared to nano- or microparticles, may offer a more convenient and industrializable way of manufacture leading to an easier scale-up process.
Authors: Dana Hales; Maxime Casteran; Anne Sapin-Minet; Ioan Tomuţa; Marcela Achim; Laurian Vlase; Philippe Maincent Journal: Clujul Med Date: 2015-07-01