This study tests the hypothesis that pegylated cationic
liposomes are a viable carrier for inhalable formulations of
low molecular weight heparin, an anionic
drug. Cationic liposomal formulations of
low molecular weight heparin were prepared by the hydration method using 1,2-dioleoyl-3-trimethylammonium-propane (
chloride salt),
cholesterol and 1,2-distearoyl-sn-glycero-3-
phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000]. The formulations were characterized for particle size, entrapment efficiency, pulmonary absorption and pharmacological efficacy. For absorption studies, the formulations were administered to anesthetized male Sprague-Dawley rats via the pulmonary route and
drug absorption was monitored by measuring plasma anti-
factor Xa activity. The pharmacological efficacy of the formulations was studied in rodent models of
pulmonary embolism and
deep vein thrombosis. The mean particle size of the
liposomes was 104.8+/-20.7 nm and the
drug entrapment efficiency was 90.3+/-0.1%. The half-life of the cationic liposomal formulation was 10.6+/-0.2h, a 2.2-fold increase compared to
low molecular weight heparin formulated in saline, and the relative bioavailability was approximately 73.4+/-19.1% when compared to subcutaneously administered
drug. A once-every-other-day inhaled dose of the formulation showed similar efficacy in reducing
thrombus weight as a once-daily dose of subcutaneously administered
drug. Likewise, cationic liposomal formulations administered via the pulmonary route 6h prior to embolization in the lungs showed a thrombolytic effect comparable to that of
low molecular weight heparin administered subcutaneously 2h before embolization. Histological examination of lung tissue and measurement of injury markers in bronchoalveolar lavage fluid suggest that the formulations did not produce extensive damage. The results demonstrate that pegylated cationic
liposomes could be a viable carrier for an inhalable formulation of
low molecular weight heparin.