Oral Delivery of Anticoagulant Doses of Heparin

Abstract

Background-Parenteral heparin is the anticoagulant of choice in hospitalized patients. Continued anticoagulation is achieved by subcutaneous administration of low-molecular-weight heparin or with an orally active anticoagulant such as warfarin. An oral heparin formulation would avoid the inconvenience of subcutaneous injection and the unfavorable drug interactions and adverse events associated with warfarin. A candidate delivery agent, sodium N-[8(-2-hydroxybenzoyl)amino]caprylate (SNAC), was evaluated with escalating oral heparin doses in a randomized, double-blind, controlled clinical study for safety, tolerability, and effects on indexes of anticoagulation. Methods and Results-Increases in activated partial thromboplastin time (aPTT), anti-factors IIa and Xa, and tissue factor pathway inhibitor (TFPI) concentrations were detected when normal volunteers were dosed with 10.5 g SNAC/20 000 IU heparin by gavage in some subjects. For the entire group, 30 000 IU SNAC and heparin elevated TFPI from 74.9Ϯ7.6 to 254.2Ϯ12.3 mg/mL (PϽ0.001) 1 hour after dosing (PϽ0.001). Similar changes occurred in anti-factor IIa and anti-factor Xa. aPTT rose from 28Ϯ0.5 to 42.2Ϯ6.3 seconds 2 hours after dosing (PϽ0.01). No significant changes in vital signs, physical examination, ECGs, or clinical laboratory values were observed. Neither 30 000 IU heparin alone nor 10.5 g SNAC alone altered the hemostatic parameters. Emesis was associated with 10.5 g SNAC. A taste-masked preparation of SNAC 2.25 g was administered orally with heparin 30 000 to 150 000 IU. Both aPTT and anti-factor Xa increased with escalating doses of heparin. This preparation was well tolerated. Conclusions-Heparin, administered orally in combination with the delivery agent SNAC, produces significant elevations in 4 indexes of anticoagulant effect in healthy human volunteers. These results establish the feasibility of oral delivery of anticoagulant doses of heparin in humans and may have broader implications for the absorption of macromolecules.

Strategies to Overcome Heparins’ Low Oral Bioavailability

“…A randomized, double-blind, controlled study performed in humans to study the safety and the effect of heparin/SNAC in anticoagulation showed that heparin/SNAC increased the coagulation parameters (APTT, anti-FIIa and FXa, and tissue factor pathway inhibitor) and, that neither heparin or SNAC alone changed these parameters [ 77 ]. A major limitation seems to be heparin high first pass metabolism by heparinase in the liver after GI absorption.…”

Heparin and Related Drugs: Beyond Anticoagulant Activity

“…In some circumstances, such as inflammatory diseases of the lung, local administration of heparin by inhalation is an option, but where systemic effects are required, an efficient and predictable drug absorption profile becomes necessary. Absorption of unmodified, unfractionated, and LMW heparins has been reported following oral administration in rats [154–156], and in rats and humans when administered with the absorption-enhancing delivery agent sodium N-[8(2-hydroxybenzoyl)amino]caprylate (SNAC) [157–160]. Similarly, augmentation of heparin absorption via the pulmonary [161–167] and nasal [168–170] routes has been described, when the drug is coadministered with delivery systems including polyethyleneimines, cyclodextrins, alkylmaltosides, alkanoylsucroses, poly-L-arginine, and within PEGylated nanocarriers.…”

Zanamivir Oral Delivery: Enhanced Plasma and Lung Bioavailability in Rats

“…PEs have been successfully applied to the development of oral dosage forms of various biopharmaceuticals including heparin, insulin, calcitonin, parathyroid hormone, and growth hormone, all of which are advancing through clinical trials (Lee et al ., 1994; Baughman et al ., 1998; Nissan et al ., 2000; Leone-Bay et al ., 2001; Buclin et al ., 2002; Goldberg and Gomez-Orellana, 2003; Kidron et al ., 2004). Accordingly, numerous potential PEs have been identified including surfactants, fatty acids and their derivatives, bile acids, cyclodextrins, etc (Whitehead et al ., 2008b).…”