Summary

The development of heparin oral form has been a subject of international research for a long time. Promising results have been obtained in vivo in terms of anti-Xa activity with different strategies and notably microparticles but studies concerning the anti-IIa activity and the anti-Xa/anti-IIa ratio have never been presented. Anti-Xa activities, anti-IIa activities and anti-Xa/anti-IIa ratios provided by nadroparin Eudragit® RS and poly (D,L-lactic-co-glycolic acid) (PLGA) microparticles were determined in vitro and in vivo and an evaluation of their pharmacokinetic parameters compared to subcutaneous injection was performed. Nadroparin was encapsulated into microparticles prepared by the double emulsion method using Eudragit® RS alone or in mixture with PLGA of two kinds, i.e. with (PLGA S) or without (PLGA H) esterification of the acid ending. Microparticles characterisation was performed (size, anti-Xa and anti-IIa activities entrapped and released) before their oral administration in rabbits. In vitro anti-Xa/anti-IIa ratios released from nadroparin microparticles were higher than the ratio of the commercial solution. After oral administration, whatever the formulation, sustained anti-Xa and anti-IIa activities were obtained compared to the subcutaneous injection with a peak concentration at 4 hours (up to 0.59 anti-Xa U/ml and 0.11 anti-IIa U/ml for PLGA S 50% / ERS 50% formulation). Anti-Xa and anti-IIa relative bioavailabilities were high, up to 40% (ERS 100% formulation). Anti-Xa/anti-IIa ratios were within range already obtained for subcutaneous injection, i.e. between 5 and 15. Nadroparin microparticles of nadroparin are promising oral dosage form performing sustained and well controlled anti-Xa, anti-IIa activities and anti-Xa/anti-IIa ratio.