A newly developed oral heparin derivative for deep vein thrombosis: non-human primate study.
The development of orally active heparin will have tremendous clinical importance since it can be used to effectively prevent deep vein thrombosis (DVT) in a long-term chronic treatment. We developed in this study a new orally active heparin derivative (Db-LHD), which has heparin chemically conjugated with deoxycholic acid and DMSO molecules by secondary interactions. Db-LHD was prepared in the powder form in soft capsules. When we administered Db-LHD capsules to monkeys, its oral physiological availability was increased up to 16.6%. The maximum anti-FXa activity at 5 mg/kg of Db-LHD was more than twice the minimum effective anti-FXa activity (MEC, 0.1 IU/mL) for preventing DVT, and the anti-FXa activity in plasma was maintained for 10 h above the MEC in monkeys. Also, we evaluated anti-thrombogenic effect of Db-LHD in a rat thrombosis model. A subcutaneous administration of enoxaparin (100 IU/kg), which was the highest recommended dose for the prevention of venous thromboembolism, reduced thrombus formation by 38.9+/-14.2%. On the other hand, 5 mg/kg (425 IU/kg) of orally administered Db-LHD reduced thrombus formation by 51.0+/-2.0. We propose a new orally active heparin, Db-LHD, in a solid dosage form to effectively prevent DVT and PE.
Kim
Sang Kyoon
SK
Department of Materials Science and Engineering, Gwangju Institute of Science and Technology, Gwangju 500-712, Republic of Korea.
Lee
Dong Yun
DY
Kim
Choong Yong
CY
Nam
Jong Hee
JH
Moon
Hyun Tae
HT
Byun
Youngro
Y
D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D002214:Capsules; D002626:Chemistry, Pharmaceutical; D003840:Deoxycholic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D004195:Disease Models, Animal; D004339:Drug Compounding; D017984:Enoxaparin / Q000494:pharmacology; D065427:Factor Xa Inhibitors; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000633:toxicity; D007408:Intestinal Absorption; D008026:Ligation; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011208:Powders; D051381:Rats; D017207:Rats, Sprague-Dawley; D012997:Solvents / Q000737:chemistry; D014682:Vena Cava, Inferior / Q000601:surgery; D020246:Venous Thrombosis / Q000517:prevention & control*
D000925:Anticoagulants; D002214:Capsules; D017984:Enoxaparin; D065427:Factor Xa Inhibitors; D006495:Heparin, Low-Molecular-Weight; C521279:LMWH-DOCA conjugate; D011208:Powders; D012997:Solvents; D003840:Deoxycholic Acid; D004121:Dimethyl Sulfoxide