From Solution and Solid Dosage Forms in Rat, Dog, and Monkey Models

www.pharmtech.com arenteral low molecular weight heparin (LMWH) has replaced warfarin as the standard of care for the prevention of deep vein thrombosis (DVT) and pulmonary embolism in high-risk, hospitalized patients undergoing joint replacement or abdominal surgery (1). LMWH is favored over antivitamin K oral anticoagulants such as warfarin because it produces a rapid onset of anticoagulant activity and has a short physiological half-life (2). Compared with warfarin, LMWH has a significantly lower incidence of drug–drug interaction. Anticoagulation with LMWH typically is evidenced by its effect on plasma LMWH concentrations measured by the anti-Factor Xa assay. The target therapeutic range for DVT prophylaxis is 0.1–0.2 IU/mL (2). With the use of fixed doses, continuous monitoring generally is unnecessary, and untoward hemorrhage rarely occurs. The major disadvantage of LMWH therapy is that it must be parenterally administered because it is ineffective when dosed orally (3,4). Thus, LMWH usually is replaced by oral warfarin for outpatient therapy. Unfortunately, this switch from parenteral LMWH to oral warfarin often requires prolonged hospitalization for the patient because the delayed onset of action, the prolonged half-life, and the variable response to warfarin necessitate a gradual increase in dose as the LMWH dose is slowly decreased. An oral LMWH formulation would allow for continuous LMWH treatment of outpatients, thereby eliminating the need to change to warfarin. Several recent attempts to develop effective oral LMWH formulations have been reported. For example, LMWH complexes with tertiary diamines have shown limited oral bioavailability Oral Low Molecular Weight Heparin Absorption From Solution and Solid Dosage Forms in Rat, Dog, and Monkey Models