Inhalable long acting formulations of low molecular weight heparins

Low molecular weight heparins (LMWHs) have recently been used as the drug of choice for the treatment of venous thromboembolic disorders. However, current LMWH therapy has some important limitations including the use of needles to administer the drug and short duration of action. This dissertation attempts to address the current limitations of LMWH therapy by formulating the drug in long circulating particulate carriers that can be administered via the noninvasive pulmonary route. Two types of carriers—dendrimers and liposomes have been used to develop inhalable long acting formulation of the drug. Formulations were characterized by determining the particle size and entrapment efficiency and by studying the drug-carrier interactions. Pulmonary absorption, pharmacological efficacy and safety of the formulations were studied in rodent models. LMWH forms an electrostatic complex with cationic dendrimers and liposomes. PEGylated cationic liposomes produced the highest entrapment efficiency (90.3±0.1%) compared to other carriers. The in vivo data suggest that both PEGylated and non-PEGylated carriers produced an increase in pulmonary absorption of the drug. The PEGylated carriers also showed an overall increase in half-life of anti-factor Xa activity compared to non-PEGylated carriers and plain drugs. In fact, PEGylated cationic liposomes of LMWH increased the half-life of anti-factor Xa activity from 4.9 to 10.6 hours, a 2.2-fold increase compared to plain drug. The relative bioavailability for cationic liposomal formulations was 73.4±19.1% compared to subcutaneous LMWH. LMWH entrapped in PEGylated dendrimers and liposomes produced a statistically significant decrease in thrombus weight compared to saline control and plain LMWH administered via the pulmonary route. The data obtained in rodent models of pulmonary embolism showed that PEGylated liposomal formulations of LMWH were more efficacious in dissolution of thrombus entrapped in pulmonary arterial circuit compared to that of plain LMWH. The broncholaveolar lavage and histopathological studies also suggest that PEGylated cationic liposomes did not produce a major damage to the respiratory epithelium. Overall, the data presented in this dissertation suggest that PEGylated cationic liposomal formulation of LMWH are effective in preventing deep vein thrombosis and pulmonary embolism in rodent models though safety and efficacy of the formulations remain to be established in humans.