Anticoagulant efficacy of solid oral formulations containing a new heparin derivative.

The need for an efficacious and safe oral anticoagulant that does not require monitoring has been largely unmet. Many efforts have centered on preparing orally available heparin to improve patient compliance. In this study, novel orally active heparin derivatives (LHD), i.e. low molecular weight heparin (LMWH) conjugated with deoxycholic acid (DOCA), were evaluated in vitro and in vivo for their enhancement effect of oral heparin absorption. After oral administration of 10 mg/kg of water-soluble LHD, Ws-LHD1.5 showed optimum oral efficacy and its bioavailability was about 24% in rats. The oral absorption of LHD1.5 was also enhanced by several solubilizers, among which Poloxamer 407 provided the best results. When 5 mg/kg of LHD1.5 with Poloxamer 407 was orally administered to monkeys, the maximum anti-FXa activity in plasma was 0.26 +/- 0.04 IU/mL and its bioavailability was 17.4%. In a rat thrombosis model, 5 mg/kg of orally administered LHD1.5 formulated with Poloxamer reduced thrombus formation by 63.9 +/- 16.6%, which was higher than the efficacy of clinically used enoxaparin (49.4 +/- 17.8% at 100 IU/kg, sc). Considering the oral absorption efficacy and therapeutic effect, the conjugation ratio was optimized as about 1.5 molecules of DOCA per mole of heparin. Therefore, LHD1.5 with Poloxamer 407 can be further formulated as a solid oral anticoagulant drug.