In Vitro and In Vivo Evaluation of Oral Heparin–Loaded Polymeric Nanoparticles in Rabbits

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Abstract
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 consequently be highly desirable for patients. Polymeric nanoparticles (NPs) prepared with biodegradable poly-ε-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.