ORAL DELIVERY OF ANTICOAGULANT DOSES OF HEPARIN - A RANDOMIZED, DOUBLE-BLIND, CONTROLLED-STUDY IN HUMANS

Background-Parenteral heparin is the anticoagulant of choice in hospit alized patients. Continued anticoagulation is achieved by subcutaneous administration of low-molecular-weight heparin or with an orally acti ve anticoagulant such as warfarin. An oral heparin formulation would a void the inconvenience of subcutaneous injection and the unfavorable d rug interactions and adverse events associated with warfarin. A candid ate delivery agent, sodium N-[8(-2-hydroxybenzoyl)amino]caprylate (SNA C), 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 i n activated partial thromboplastin time (aPTT), anti-factors IIa and X a, and tissue factor pathway inhibitor (TFPI) concentrations were dete cted when normal volunteers were dosed with 10.5 g SNAC/20 000 IU hepa rin by gavage in some subjects. For the entire group, 30 000 TCT SNAG and heparin elevated TFPI from 74.9 +/- 7.6 to 254.2 +/- 12.3 mg/mL (P <0.001) 1 hour after dosing (P<0.001), Similar changes occurred in ant i-factor IIa and anti-factor Xa. aPTT rose from 28 +/- 0.5 to 42.2 +/- 6.3 seconds 2 hours after dosing (P<0.01). 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 SNAG alone altered the hemostatic parameters. Emesis was associated with 10.5 g S NAG. A taste-masked preparation of SNAG 2.25 g was administered orally with heparin 30 000 to 150 000 IU. Both aPTT and anti-factor Xa incre ased with escalating doses of heparin, This preparation was well toler ated. 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 establ ish the feasibility of oral delivery of anticoagulant doses of heparin in humans and may have broader implications for the absorption of mac romolecules.