The present investigation determined the molecular structure and the pharmacokinetic and pharmacodynamic profiles of oral unfractionated heparin containing oral absorption enhancer sodium N- [8-(2-hydroxybenzoyl) amino]caprylate, salcaprozate sodium (SNAC) and assessed the safety and tolerability of the orally dosed heparin solid dosage form versus other routes. Sixteen healthy men were included in this single-dose, 3-way crossover, randomized, open-label study. Disaccharide compositional analysis was performed using capillary high-performance liquid chromatography with electrospray ionization mass spectrometry detection. The pharmacodynamics of heparin were obtained from analysis of plasma anti-factor Xa, anti-factor IIa, activated partial thromboplastin time, and total tissue factor pathway inhibitor data. The molecular weight properties and the disaccharide composition of orally administered unfractionated heparin/SNAC and parenterally administered unfractionated heparin are identical and consistent with the starting pharmaceutical standard heparin. Furthermore, the anti-factor Xa/ anti-factor IIa ratio achieved is of approximately 1:1. This is the first true pharmacokinetic study to measure the chemical compositions of heparin administered by different routes.
KeywordsOral heparin; anticoagulants; pharmacokinetics; pharmacodynamics; solid dosage form; heparin composition Heparin, a natural sulfated and highly acidic glycosaminoglycan, is a potent inhibitor of coagulation, primarily through formation of a complex with antithrombin (AT), resulting in
NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript indirect inhibition of factor Xa, factor IIa, and other AT-dependent coagulation factors in addition to other AT-independent pathways. 1-3 Parenteral administration of heparin has been shown to prevent venous thrombosis and pulmonary embolism, as well as reduce the incidence of myocardial infarction and death in patients with unstable angina and stroke. 1,4-8 Various low molecular weight heparins (LMWHs) have also established clinical efficacy in the prevention and treatment of thromboembolic disorders. [3][4][5] Clinical benefit has been associated with heparin-induced prolongation of activated partial thromboplastin time (aPTT) 1.5-to 2.5-fold besides effects on anti-factor Xa and anti-factor IIa, as well as an increase in plasma levels of tissue factor pathway inhibitor (TFPI). 1,2,[4][5][6][7][8] Heparin is not orally absorbed, presumably because of its size and polyanionic charge, and hence is administered parenterally, either by continuous or intermittent infusion or by subcutaneous (SC) injection. 9 However, a formulation that would result in absorption of heparin after oral administration would provide an attractive alternative to parenteral heparin. In that regard, several attempts to develop effective nonparenteral heparin formulations have been reported, but they have met with limited success. [10][11][12][13][14][15][16] In contrast, synthesized delivery agents based on...