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Etude in vitro et in vivo de deux héparines de bas poids moléculaire microencapsulées de rapports anti-Xa/anti-IIa différents : la nadroparine et la tinzaparine

Abstract : Microparticles of low molecular weight heparin (LMWH) were prepared according to the double emulsion and extraction method using a non biodegradable polycationic polymer (Eudragit® RS) alone or blended according to different ratios with a biodegradable polymer (poly(lactic-co-glycolic) acid). Two LMWH presenting different anti-Xa/anti-IIa ratios were tested: nadroparin (3.6) and tinzaparin (1.8). LMWH microparticles facilitate i) the encapsulation of heparin active long chains (ACL) compared to active short chains (BCL) (anti-Xa/anti-IIa ratio decreased) ii) the in vitro release of short chains (anti-Xa/anti-IIa ratio increased) whereas long chains are held inside the microparticles. Nevertheless, when compared to ACL chains, the relative amount of BCL chains released is dependent (case of nadroparine) or not (case of tinzaparin) on the polymeric composition. This difference can be mainly due to the properties of Eudragit® RS to hold ACL chains of nadroparin. After an oral administration in rabbits of nadroparin microparticles, some formulations exhibited absorption of ACL and BCL chains: in this case, plasmatic anti-Xa/anti-IIa ratios in the same range than those observed following the subcutaneous injection were obtained. Such a result shows the potential of microparticles to be a good substitute of the commercial injectable dosage form, if the oral absorption is confirmed in human. During gastro-intestinal studies by confocal microscopy, the absorption site was not identified. Nevertheless, contrary to in vivo results, permeation studies on a cell cultured epithelium (Caco-2) demonstrated that BCL heparin chains were absorbed whereas ACL chains were not. However, the mechanism responsible of the cell permeation is still to be identified.
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https://hal.univ-lorraine.fr/tel-01748316
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  • HAL Id : tel-01748316, version 1

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Lucie Javot. Etude in vitro et in vivo de deux héparines de bas poids moléculaire microencapsulées de rapports anti-Xa/anti-IIa différents : la nadroparine et la tinzaparine. Médecine humaine et pathologie. Université Henri Poincaré - Nancy 1, 2009. Français. ⟨NNT : 2009NAN10093⟩. ⟨tel-01748316⟩

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