Oral delivery of new heparin derivatives in rats.

PURPOSE

In this study, conjugates of heparin and deoxycholic acid were synthesized in order to enhance the heparin absorption in the GI tract. Oral delivery of heparin is a preferred therapy in the treatment of patients who are at high risk of deep vein thrombosis and pulmonary embolism.

METHODS

Several different kinds of heparin derivatives were synthesized, and their absorption in the GI tract was determined by activated partial thromboplastin time (aPTT) and factor Xa (FXa) assay. Any histological changes caused by heparin derivatives were examined by hematoxylin and eosin (H&E) stain and transmission electron microscopy (TEM).

RESULTS

After administering heparin-DOCA orally, the clotting time in aPTT assay was increased with the increase of the coupled DOCA amount. The maximum clotting time of heparin-DOCA was 136+/-33 sec at 200 mg/kg of oral dose. This value was 7 times higher than the baseline. The absorption of heparin-cholesterol, heparin-palmitic acid, and heparin-lauric acid conjugates in the GI tract was lower than that of heparin-DOCA. Histological examination of the GI tract indicated that heparin derivatives did not cause any damage to the microvilli and the cell layer.

CONCLUSIONS

DOCA coupled with heparin greatly enhanced absorption of heparin in the GI tract, and this enhancing effect was induced without changing the tissue structure of the GI wall.