Oral delivery of chemical conjugates of heparin and deoxycholic acid in aqueous formulation.
BACKGROUND
Heparin, one of the most potent anticoagulants widely used for the treatment and prevention of deep vein thrombosis (DVT) and pulmonary embolism (PE), is currently available to patients only by parental administration. In this study, we propose a new oral delivery system of heparin by conjugating it with deoxycholic acid which reformulated by adding dimethyl sulfoxide to increase its bioavailability.


METHODS
The chemical conjugates (LMWH-DOCA) of low molecular weight heparin (4.5 kDa) with deoxycholic acid (DOCA) were synthesized by controlling the conjugation ratio. The absorption of LMWH-DOCA after its oral administration was measured by anti-FXa assay according to the conjugation ratio of DOCA, concentration of DMSO solution and dose of LMWH-DOCA, respectively. Furthermore, the incidences of mucosal damage by LMWH-DOCA in 10% DMSO solution were evaluated using H&E staining and SEM.


RESULTS
Three kinds of LMWH-DOCA were synthesized according to the DOCA conjugation ratios of LD1, LD2 and LD3, whose anticoagulant activities were 89, 86 and 85 IU/mg, respectively, and the activity of LMWH was 97 IU/mg. LMWH-DOCA was completely dissolved in 10% DMSO solution, and its bioavailability in the oral dose was significantly increased (17.6% for LD2 in 10% DMSO solution) without causing any damages in intestinal tissues.


CONCLUSIONS
The chemical conjugate of heparin and DOCA in the soluble state could be efficiently absorbed in the intestine. Therefore, we propose this system as a new strategy of oral heparin delivery for the treatment of patients who are at high risk to DVT and PE.
Kim
Sang Kyoon
SK
Center for Cell and Macromolecular Therapy, Department of Materials Science and Engineering, Gwangju Institute of Science and Technology, Gwangju, Korea.
Vaishali
Bagalkot
B
Lee
Eunhye
E
Lee
Seulki
S
Lee
Yong-kyu
YK
Kumar
Tadiparthi Suresh
TS
Moon
Hyun Tae
HT
Byun
Youngro
Y
D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants; D002756:Cholagogues and Choleretics; D003840:Deoxycholic Acid / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D004337:Drug Carriers / Q000737:chemistry*; D004338:Drug Combinations; D004339:Drug Compounding / Q000379:methods; D004353:Drug Evaluation, Preclinical; D006493:Heparin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D014867:Water / Q000737:chemistry*
D000925:Anticoagulants; D002756:Cholagogues and Choleretics; D004337:Drug Carriers; D004338:Drug Combinations; D003840:Deoxycholic Acid; D014867:Water; D006493:Heparin