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From the EUPENN Clinical Trials Group, Center for Experimental
Therapeutics, University of Pennsylvania School of Medicine, Philadelphia, Pa
(S.C.K., F.C.-L., G.A.F.); Clinical Development, Emisphere Technologies, Inc,
Hawthorne, NY (R.A.B., R.K.A.); and Harris Laboratories, Lincoln, Neb (J.K.).
Correspondence to Garret A. FitzGerald, MD, Center for Experimental Therapeutics, University of Pennsylvania School of Medicine, Room 905, Stellar-Chance Laboratories, 422 Curie Blvd, Philadelphia, PA 19104-6100. E-mail garret{at}spirit.gcrc.upenn.edu
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 74.9±7.6 to 254.2±12.3 mg/mL
(P<0.001) 1 hour after dosing
(P<0.001). Similar changes occurred in anti-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 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.
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports
Oral Delivery of Anticoagulant Doses of Heparin
A Randomized, Double-Blind, Controlled Study in Humans
Key Words: heparin • anticoagulants • oral administration
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