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

Abstract

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.

Fucosylated Chondroitin Sulfate 9–18 Oligomers Exhibit Molecular Size-Independent Antithrombotic Activity while Circulating in the Blood

“…With the general improvement of human living standards and the aging of the population, thrombotic disease has become a serious human health concern over the past few decades. Heparin and low-molecular weight heparins (LMWHs) are in widespread use as anticoagulants for the treatment of thrombotic diseases, especially during surgical situations. − However, heparin and LMWHs always have the risk of serious bleeding during therapy and cannot be orally administered. − Thus, researchers have continued to search for other effective and safer anticoagulant drugs.…”

Subchronic Oral Toxicity of Salcaprozate Sodium (SNAC) in Sprague-Dawley and Wistar Rats

“…This is consistent with the rapid absorption and elimination reported for SNAC. 6 No hematological effects were reported in SD rats. Decreased globulin concentrations at 2000 mg/kg/d SNAC were observed at interim and terminal sampling points, and there were slight increases in liver and kidney weights.…”

“…The potential therapeutic applications of SNAC as a delivery agent for oral forms of heparin and insulin have been explored in a number of clinical investigations. [1][2][3][4][5][6] However, limited information about the nonclinical safety of SNAC itself was found in the published scientific literature. A review article describing the development of an oral heparin formulation describes the results of SNAC toxicological studies in experimental animals but only in very general terms.…”

Peri- and Postnatal Developmental Toxicity of Salcaprozate Sodium (SNAC) in Sprague-Dawley Rats

“…alcaprozate sodium (SNAC) (sodium 8-((2hydroxybenzoyl)amino) octanoate, CAS RN 203787-91-1) is classified as an oral absorption promoter. Although several clinical investigations have explored the potential therapeutic applications of SNAC as a delivery agent for oral forms of heparin and insulin, [1][2][3][4][5][6] limited information about the nonclinical safety of SNAC itself was found in the published scientific literature. In a published review article on the development of an oral heparin formulation, 7 the results of SNAC toxicological studies are given, but the item provides no details regarding their conduct.…”