Pharmacokinetics and Pharmacodynamics of Oral Heparin Solid Dosage Form in Healthy Human Subjects.

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. 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 non-parenteral heparin formulations have been reported, but they have met with limited success. The present investigation determined the molecular structure, pharmacokinetic (PK), and pharmacodynamic (PD) profiles of oral unfractionated heparin (UFH) containing oral absorption enhancer Sodium N-[8-(2-hydroxybenzoyl) amino] caprylate, salcaprozate sodium (SNAC) and assessed the safety and tolerability of orally dosed heparin solid dosage form versus other routes. Sixteen healthy men were included in this single-dose, three-way crossover, randomized, open-label study. The different arms of the study were as follow: Treatment A- Subjects randomized to Treatment A received two capsules of UFH/SNAC soft gelatin capsules for a total dose of 75,000 U heparin sodium with 150 mL of water; Treatment B: Subjects randomized to Treatment B received 1 mL of heparin sodium USP parenteral 10,000 U/mL via SC injection; Treatment C: Subjects randomized to receive 75,000 U heparin sodium milled powder for oral solution with 150 mL of water; and Treatment D: Subjects randomized to receive 0.5 mL of heparin sodium USP parenteral 5,000 U/mL via IV bolus. Each subject was randomly assigned to receive three of the four treatments so that a total of 12 subjects received each treatment. To characterize the PK of SNAC after oral heparin/SNAC administration and the PD of heparin following the administration of heparin IV, SC, PO alone and PO as heparin/SNAC, 21 blood samples were drawn from all of the subjects receiving treatment A, B, C, and D at the following time points: within 30 minutes pre-dose, at 2, 5, 10, 15, 20, 25, 30, 35, 40, 45 minutes, and at 1,1.5, 2, 2.5, 3, 3.5, 4, 5, 6, and 8 hours post-dose. Blood was drawn into sodium citrate tubes for assessment of anti-factor Xa, anti-factor IIa, aPTT, and SNAC. Disaccharide compositional analysis was performed using capillary high-performance liquid chromatography with electrospray ionization mass spectrometry detection. The PD of heparin was obtained from analysis of plasma anti-factor Xa, anti-factor IIa, aPTT, and total tissue factor pathway inhibitor (TFPI) data. The molecular weight properties and the disaccharide composition of orally administered UFH/SNAC and parenterally administered UFH are identical and consistent with the starting standard UFH administered and achieved anti-factor Xa: anti-factor IIa of 1:1. This is the first true pharmacokinetic study to measure the chemical compositions of heparin administered by different routes.