In vitro and in vivo evaluation of oral heparin-loaded polymeric nanoparticles in rabbits

Background-Owing to its short half-life and lack of oral absorption, heparin has to be administered by the parenteral route. An oral heparin formulation, however, would avoid the disadvantages of parenteral injections and would L consequently be highly desirable for patients. Polymeric nanoparticles (NPs) prepared with biodegradable poly-epsilon-caprolactone (PCL) and poly(lactic-co-glycolic acid) (PLGA) and nonbiodegradable positively charged polymers (Eudragit RS and RL), used alone or in combination, were evaluated in vitro and in vivo after a single oral administration of heparin-loaded NPs in rabbits. Methods and Results-After oral administration of heparin-loaded NPs in rabbits (600 IU/kg), increases in both anti-factor Xa activity and activated partial thromboplastin time (aPTT) were detected with each formulation. Moreover, the anti-Xa activity was detected for a longer period than when a heparin solution was administered intravenously. A peak concentration of 0.16+/-0.01 IU/mL and an average aPTT of 24 seconds (2-fold increase) were obtained 7 hours after oral dosing of Eudragit RL/PCL NPs containing heparin, exhibiting an absolute bioavailability of 23%. Conclusions-The significant increases in anti-factor Xa activity and aPTT confirmed the oral absorption in rabbits of heparin released from polymeric NPs.