Dendrimers as a carrier for pulmonary delivery of enoxaparin, a low-molecular weight heparin

This study was designed to test the hypothesis that positively charged dendrimers form a complex with enoxaparin, a low-molecular weight heparin (LMWH), and that the resulting drug-dendrimer complex is effective in preventing deep vein thrombosis after pulmonary administration. Fourier Transform Infrared (FTIR) spectroscopy and the azure A assay were used to evaluate interactions between dendrimers and enoxaparin. The efficacy of polyamidoamine (PAMAM) dendrimers in enhancing pulmonary absorption of enoxaparin was studied by administering enoxaparin-dendrimer formulations into the lungs of anesthetized rats and monitoring drug absorption by measuring plasma anti-factor Xa activity. The optimized formulations were evaluated for their efficacy in preventing deep vein thrombosis in a rodent model. The safety of the formulations was tested by studying their effects on mucociliary transport rate (MTR) in a frog palate model and by measuring injury markers in rat bronchoalveolar fluid. The FTIR data and azure A assay revealed ionic interactions between the amino groups of cationic dendrimers and the carboxylic and sulfate groups of enoxaparin. Positively charged dendrimers increased the relative bioavailability of enoxaparin by 40%, while a negatively charged dendrimer had no effect. Formulations containing 1% G2 or 0.5% G3 PAMAM dendrimer plus enoxaparin were as efficacious in preventing deep vein thrombosis in a rat model as subcutaneously administered enoxaparin. The formulations did not adversely affect the MTR or produce extensive damage to the lungs. Positively charged dendrimers are a suitable carrier for pulmonary delivery of enoxaparin. They enhance pulmonary absorption of LMWH probably by reducing negative surface charge density of the drug molecule. (c) 2007 Wiley-Liss, Inc.