Prevention effect of orally active heparin derivative on deep vein thrombosis

Summary

The use of heparin as the most potent anticoagulant for the prevention of deep vein thrombosis and pulmonary embolism is nevertheless limited, because it is available to patients only by parenteral administration. Toward overcoming this limitation in the use of heparin, we have previously developed an orally active heparin-deoxycholic acid conjugate (LMWH-DOCA) in 10% DMSO formulation. The present study evaluates the anti-thrombogenic effect of this orally active LMWH-DOCA using a venous thrombosis animal model with Sprague-Dawley rats. When 5 mg/kg of LMWH-DOCA was orally administered in rats, the maximum anti-FXa activity in plasma was 0. 35 ± 0. 02, and anti-FXa activity in plasma was maintained above 0. 1 IU/ml [the minimum effective anti-FXa activity for the prevention of deep venous thrombosis (DVT) and pulmonary embolism (PE)] for five hours. LMWH-DOCA (5 mg/kg, 430 IU/kg) that was orally administered reduced the thrombus formation by 56. 3 ± 19. 8%;on the other hand, subcutaneously administered enoxaparin (100 IU/kg) reduced the thrombus formation by 36. 4 ± 14. 5%. Also, LMWH-DOCA was effectively neutralized by protamine that was used as an antidote. Therefore, orally active LMWH-DOCA could be proposed as a new drug that is effective for the longterm prevention of DVT and PE.

Keywords

Low-molecular-weight heparin - deoxycholic acid - chemical conjugate - oral delivery - deep vein thrombosis

• References

• 1 Warkentin TE, Levine MN, Hirsch J. et al. Heparininduced thrombocytopenia in patients treated with lowmolecular-weight heparin or unfractionated heparin. N EnglJ Med 1995; 332: 1330-5.
• 2 Hirsch J, Raschke R, Warkentin TE. et al. Heparin: mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy and safety. Chest. 1995 108. (Suppl 4)
• 3 Yuyan J, Nathalie U, Monique MA. et al. In vitro and in vivo evaluation of oral heparin-loaded polymeric nanoparticles in rabbits. Circulation 2002; 105: 230-5.
• 4 Constantia EK, Davide G, Nina L. et al. Development and in vivo evaluation of an oral delivery system for low molecular weight heparin based on thiolated polycarbophil. Pharm Res 2003; 20: 931-6.
• 5 Money SR, York JW. Development of oral heparin therapy for prophylaxis and treatment of deep venous thrombosis. Cardiovasc Surg 2001; 09: 211-8.
• 6 Grau E, Tenias JM, Real E. Home treatment of deep venous thrombosis with low molecular weight heparin: long-term incidence of recurrent venous thromboembolism. Am J Hematol 2001; 67: 10-4.
• 7 Breddin HK, Hach-Wunderle V, Nakov R. Effect of a low molecular weight heparin on thrombus regression and recurrent thromboembolism in patients with deepvein thrombosis. N Engl J Med 2001; 344: 626-31.
• 8 Dunn JM, Hollister AS. Oral bioavailability of heparin using a novel delivery system. Curr Ther Res 1995; 56: 738-45.
• 9 Couvreur P, Duchéne D, Kalles I. Formulation of porly-available drugs for oral administration. Symposium. Paris: Editions de Sante; 1996
• 10 Gattefossé SA. Microemulsions. Formulation Guide (patented technology), 1998..
• 11 Dal Pozzo A, Acquasaliente M, Geron MR. New heparin complexes active by intestinal absorption. I. Multiple ion pairs with basic organic compounds. Thromb Res 1989; 56: 119-24.
• 12 Malkov D, Huai-zhen W, Dinh S. et al. Pathway of oral absorption of heparin with sodium N-[8-(2 hydroxybenzoyl)amino]caprylate. Pharm Res 2002; 19: 1180-4.
• 13 Mark DG, Jeffrey DM, Andrea LB. Orally administered heparin for preventing deep venous thrombosis. Am J Surg 1998; 176: 176-8.
• 14 Lee YK, Moon HT, Byun YR. Preparation of slightly hydrophobic heparin derivatives which can be used for solvent casting in polymeric formulation. Thromb Res 1998; 92: 149-56.
• 15 Lee YK, Kim SH, Byun YR. Oral delivery of new heparin derivatives in rats. Pharm Res 2000; 17: 1259-64.
• 16 Lee YK, Nam JH, Shin HC. et al. Conjugation of low-molecular-weight heparin and deoxycholic acid for the development of a new oral anticoagulant agent. Circulation 2001; 104: 3116-20.
• 17 Kim SK, Vaishali B, Lee E. et al. Oral delivery of chemical conjugates of heparin and deoxycholic acid in aqueous formulation. Thromb Res 2006; 117: 419-27.
• 18 Sundaram M, Qi Y, Langer R. et al. Rational design of low-molecular weight heparins with improved in vivo activity. PNAS 2003; 100: 651-6.
• 19 Byun Y, Kim SK. Drug formulation containing a solubilizer for enhancing solubility, absorption, and permeability. US patent 11/188,217, filed on 21 July 2005
• 20 Büller HR, Davidson BL, Decousus H. et al. Fondaparinux or enoxaparin for the initial treatment of symptomatic deep venous thrombosis. Ann Intern Med 2004; 140: 867-73.
• 21 Grau E, Real E, Pastor E. et al. Home treatment of deep vein thrombosis: a two-years experience of a single institution. Haematologica 1998; 83: 438-41.