A newly developed oral heparin derivative for deep vein thrombosis: Non-human primate study
- 作者：Sang Kyoon Kim ; Dong Yun Lee ; Choong Yong Kim ; Jong Hee Nam ; Hyun Tae Moon ; Youngro Byun
- 关键词：Heparin ; Deep vein thrombosis ; Oral delivery ; Bioavailability ; Conjugate
- 刊名：Journal of Controlled Release
- 出版年：2007
- 期刊代码：25_01683659
- 类别：pha
- 出版时间：6 November 2007
- 卷：123
- 期：2
- 页码：155-163
- 文件大小：684 K
摘要
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.