Cationic liposomes as carriers for aerosolized formulations of an anionic drug: Safety and efficacy study

This study tests the hypothesis that pegylated cationic liposomes area 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 +/- 0.2 h, a 2.2-fold increase compared to low molecular weight heparin formulated in saline, and the relative bioavailability was similar to 73.4 +/- 19.1% when compared to subcutaneously administered drug. A once-every-other-clay 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 6 h prior to embolization in the lungs showed a thrombolytic effect comparable to that of low molecular weight heparin administered subcutaneously 2 h 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. (C) 2009 Elsevier B.V. All rights reserved.