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Développement de formes orales d'héparine et de formes à libération prolongée de warfarine : Une réponse à l'amélioration de la prévention de la thrombose ?

Abstract : Cardiovascular diseases resulting from thromboembolic events represent a real public health problem cause to their frequency and their severity. Used for the prevention or treatment of thrombosis, heparins and vitamin K antagonists are the two cornerstones of anticoagulant medication. The studies presented in this work describe new dosage forms for these molecules. The first two studies report the development of two new pharmaceutical systems allowing oral administration of low molecular weight heparins (enoxaparin and bemiparin). These systems were manufactured with very simple and widely used pharmaceutical processes: granulation and pelletization. The use of commercial aqueous suspensions of ethylcellulose and polymethacrylate has led to the elimination of organic solvents from the preparation of heparin granules and pellets, which insures the safety of the workers as well as the patients. After oral administration to rabbits, granules and pellets of low molecular weight heparins allowed obtaining anti-Xa activity above the therapeutic threshold of 0.2 U anti-Xa/ml. Thanks to its polycationic nature, Eudragit®RS30D seems to play an important role on the release of heparin from microparticles and, also on its oral absorption. The biological activity of heparins was maintained till 4 and 7 months for the granules and pellets, respectively. Our last study enabled the production of warfarin microparticles based on poly-e-caprolactone and, using the single o/w emulsion solvent extraction /evaporation method. The inclusion of polyvinyl pyrrolidone in the polymeric matrix allowed modifying the released kinetic of warfarin. The subcutaneous administration of warfarin microparticles to rabbits allowed obtaining therapeutical anticoagulant activity (INR 2-3) during 30 hours.
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  • HAL Id : tel-01748315, version 1

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Julien Scala-Bertola. Développement de formes orales d'héparine et de formes à libération prolongée de warfarine : Une réponse à l'amélioration de la prévention de la thrombose ?. Médecine humaine et pathologie. Université Henri Poincaré - Nancy 1, 2009. Français. ⟨NNT : 2009NAN10091⟩. ⟨tel-01748315⟩

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