Liphophilic complexation of heparin based on bile acid for oral delivery

Oral delivery of heparin will offer great advantages over injectable heparin therapy in the treatment of patients with deep vein thrombosis. Since heparin absorption in the intestine is restricted due to its physicochemical properties, we designed a bile acid derivative, cationic deoxycholylethylamine (DCEA), to be complexed with anionic low molecular weight heparin (LMWH). Complexation between LMWH and DCEA was saturated above 1:10 molar ratio and improved lipophilicity of LMWH. The LMWH/DCEA complex was completely solubilized in 80% propylene glycol solution. The oral absorption of LMWH in rats was proportional to the molar ratio of DCEA and the administered dose of complex. The C-max values to the complex molar ratios of 1:0, 1:3, 1:5 and 1:10 were about 0.07, 0.27, 0.83, and 0.47 IU/ml, respectively, and the C-max values to the doses of 10, 25, 50 mg/kg were 0.16, 0.44, and 0.83 IU/ml, respectively. The LMWH/DCEA complex was found to be absorbable through all regions of the small intestine of rats without causing tissue damage. This study demonstrates the feasibility of oral heparin delivery using the cationic DCEA for chronic administration in clinical trials as an effective therapy. (c) 2007 Elsevier B.V. All rights reserved.