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.
Bai
Shuhua
S
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 Coulter Drive, Amarillo, Texas 79106, USA.
Thomas
Chandan
C
Ahsan
Fakhrul
F
D000818:Animals; D001399:Azure Stains / Q000378:metabolism; D004396:Coloring Agents / Q000378:metabolism; D050091:Dendrimers / Q000737:chemistry*; D004337:Drug Carriers / Q000737:chemistry*; D016503:Drug Delivery Systems; D004347:Drug Interactions; D017984:Enoxaparin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008168:Lung / Q000378:metabolism*; D008297:Male; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D017550:Spectroscopy, Fourier Transform Infrared; D020246:Venous Thrombosis / Q000517:prevention & control
D001399:Azure Stains; D004396:Coloring Agents; D050091:Dendrimers; D004337:Drug Carriers; D017984:Enoxaparin; D006495:Heparin, Low-Molecular-Weight; C025818:Azure A