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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
1   College of Pharmacy, Seoul National University, Seoul, South Korea
2   Amorepacific Corporation R&D center, Gyeonggi-do, South Korea
,
Ok Cheol Jeon
3   Mediplex Corp., Seoul, South Korea
,
Sang Kyoon Kim
1   College of Pharmacy, Seoul National University, Seoul, South Korea
,
Taslim A. Al-Hilal
1   College of Pharmacy, Seoul National University, Seoul, South Korea
,
Kyung-Min Lim
2   Amorepacific Corporation R&D center, Gyeonggi-do, South Korea
,
Hyun Tae Moon
3   Mediplex Corp., Seoul, South Korea
,
Choong Yong Kim
4   Toxicology Research Center, Korea Research Institute of Chemical Technology, Daejeon, South Korea
,
Youngro Byun
5   WCU Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology and College of Pharmacy, Seoul National University, Seoul, South Korea
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Publikationsverlauf

Received: 06. Juli 2010

Accepted after major revision: 10. Februar 2011

Publikationsdatum:
28. November 2017 (online)

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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
 

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