In vitro and in vivo investigation of low molecular weight heparin–alginate beads for oral administration

Abstract

Low molecular weight heparin (LMWH) and standard heparin are widely used anticoagulants. However, they have very poor oral bioavailability and have to be administered by the parenteral route. Alginates are biodegradable, biocompatible and mucoadhesive polymers which can be used for advantage for the oral administration of LMWH. The aim of the study was to develop LMWH–alginate beads for oral delivery. Alginate beads were prepared based on the 2³ factorial design. In vitro characterization studies of the beads were carried out. In vivo studies were performed on rabbits. The LMWH solutions (5000 IU/kg, with and without 5% dimethyl-β-cyclodextrin), as well as the LMWH–alginate beads were administered to rabbits. The IV solution was also administered (100 IU/kg). The anti-Xa activity was measured in plasma. Area under curve (AUC) and C_max values were determined. Histological investigations were also carried out. The formulation consisting of a 1:2 drug/alginate ratio and cured using 0.5 M CaCl₂ for 15 min gave the best result in terms of encapsulation efficiency and the time for 50% of the drug to be released (t_50%). A significantly higher bioavailability was observed for LMWH–alginate beads than for LMWH solutions. It was concluded that, anticoagulant effectiveness was achieved using alginate beads containing LMWH after oral administration to the rabbits.

• Alginate
• beads
• factorial design
• low molecular weight heparin
• oral drug delivery

Acknowledgements

The help of Serafettin Kirazlı for anti-Xa activity measurements and Dr Fatmanur Tugcu Demiröz for mucoadhesion measurements is greatly acknowledged. The authors are grateful to Prof. Dr. İlbeyi Ağabeyoğlu for his kind help. The authors would like to thank FMC Biopolymer for providing free samples.