Bai Shuhua, Thomas Chandan, Ahsan Fakhrul
Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 1300 Coulter Drive, Amarillo, Texas 79106, USA.
J Pharm Sci. 2007 Aug;96(8):2090-106. doi: 10.1002/jps.20849.
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.
带正电荷的树枝状大分子与低分子量肝素（LMWH）依诺肝素形成复合物，且所得药物 - 树枝状大分子复合物在肺部给药后能有效预防深静脉血栓形成。采用傅里叶变换红外（FTIR）光谱法和天青A测定法评估树枝状大分子与依诺肝素之间的相互作用。通过将依诺肝素 - 树枝状大分子制剂经肺部给予麻醉大鼠，并通过测量血浆抗Xa因子活性监测药物吸收，研究聚酰胺 - 胺（PAMAM）树枝状大分子增强依诺肝素肺部吸收的效果。在啮齿动物模型中评估优化后的制剂预防深静脉血栓形成的功效。通过研究制剂对蛙腭模型中黏液纤毛转运速率（MTR）的影响以及测量大鼠支气管肺泡灌洗液中的损伤标志物来测试制剂的安全性。FTIR数据和天青A测定法揭示了阳离子树枝状大分子的氨基与依诺肝素的羧基和硫酸根之间的离子相互作用。带正电荷的树枝状大分子使依诺肝素的相对生物利用度提高了40%，而带负电荷的树枝状大分子则无此作用。含有1% G2或0.5% G3 PAMAM树枝状大分子加依诺肝素的制剂在大鼠模型中预防深静脉血栓形成的效果与皮下注射依诺肝素相同。这些制剂对MTR没有不利影响，也不会对肺部造成广泛损伤。带正电荷的树枝状大分子是依诺肝素肺部给药的合适载体。它们可能通过降低药物分子的负表面电荷密度来增强低分子量肝素的肺部吸收。
