Pharmacokinetic evaluation of an oral tablet form of low-molecular-weight heparin and deoxycholic acid conjugate as a novel oral anticoagulant

Jin Woo Park; Ok Cheol Jeon; Sang Kyoon Kim; Taslim A. Al-Hilal; Kyung-Min Lim; Hyun Tae Moon; Choong Yong Kim; Youngro Byun

doi:10.1160/TH10-07-0484

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2011; 105(06): 1060-1071
DOI: 10.1160/TH10-07-0484

New Technologies, Diagnostic Tools and Drugs

Schattauer GmbH

Pharmacokinetic evaluation of an oral tablet form of low-molecular-weight heparin and deoxycholic acid conjugate as a novel oral anticoagulant

Jin Woo Park

¹College of Pharmacy, Seoul National University, Seoul, South Korea

²Amorepacific Corporation R&D center, Gyeonggi-do, South Korea

,

Ok Cheol Jeon

³Mediplex Corp., Seoul, South Korea

,

Sang Kyoon Kim

¹College of Pharmacy, Seoul National University, Seoul, South Korea

,

Taslim A. Al-Hilal

¹College of Pharmacy, Seoul National University, Seoul, South Korea

,

Kyung-Min Lim

²Amorepacific Corporation R&D center, Gyeonggi-do, South Korea

,

Hyun Tae Moon

³Mediplex Corp., Seoul, South Korea

,

Choong Yong Kim

⁴Toxicology Research Center, Korea Research Institute of Chemical Technology, Daejeon, South Korea

,

Youngro Byun

⁵WCU Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Pharmacy, Seoul National University, Seoul, South Korea

› Author Affiliations

Abstract

Summary

This study was designed to develop a solid oral dosage form of deoxycholic acid (DOCA)-conjugated low-molecular-weight heparin (LMWH) and to evaluate its oral absorption, distribution, and metabolic stability for the prospect of providing an orally bioavailable LMWH. The LMWH derivative (LHD) was synthesised and then formulated with solubilisers and other pharmaceutical excipients to form a solid tablet. Its absorption and distribution after oral administration were evaluated in mice, rats, and monkeys. The in vitro metabolic stability of LHD was examined by liver microsome assays. More than 80% of LHD was released from the tablet within 60 minutes, guaranteeing rapid tablet disintegration after oral administration. Oral bioavailability of LHD in mice, rats and monkeys were 16.1 ± 3.0, 15.6 ± 6.1, and 15.8 ± 2.5%, respectively. After the oral administration of ¹³¹I-tyramine-LHD, most of the absorbed drug remained in the blood circulation and was eliminated mainly through the kidneys. LHD was hardly metabolised by the liver microsomes and showed a stable metabolic pattern similar to that of LMWH. In a rat thrombosis model, 10 mg/kg of orally administered LHD reduced thrombus formation by 60.8%, which was comparable to the antithrombotic effect of the subcutaneously injected LMWH (100 IU/ kg). Solid tablets of LHD exhibited high oral absorption and statistically significant therapeutic effects in preventing venous thromboembolism. Accordingly, LHD tablets are expected to satisfy the unmet medical need for an oral heparin-based anticoagulant as an alternative to injectable heparin and oral warfarin.

Keywords

Low-molecular-weight heparin - deoxycholic acid - oral delivery - anticoagulants - solid dosage form

Full Text

References

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