Dendrimers as a carrier for pulmonary delivery of enoxaparin, a low-molecular weight heparin
Dendrimers as a carrier for pulmonary delivery of enoxaparin, a low-molecular weight heparin
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DOI：
10.1002/jps.20849
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发表时间：
2007-08-01
影响因子：
3.8
通讯作者：
Ahsan, Fakhrul
中科院分区：
文献类型：
--
作者：
Bai, Shuhua;Thomas, Chandan;Ahsan, Fakhrul
本研究旨在验证带正电荷的树状大分子与依诺肝素（一种低分子量肝素）形成复合物的假设，以及由此产生的药物-树状大分子复合物在肺部给药后有效预防深静脉血栓形成。采用傅里叶变换红外光谱（FTIR）和蔚蓝A法评价树状大分子与依诺肝素的相互作用。通过将依诺肝素树状大分子注入麻醉大鼠肺部，并通过测定血浆抗Xa因子活性来监测药物吸收，研究了聚氨基胺（PAMAM）树状大分子增强依诺肝素肺吸收的作用。在啮齿类动物模型中评估了优化后的配方对预防深静脉血栓形成的功效。通过研究其对蛙腭粘膜纤毛运输速率（MTR）的影响和测量大鼠支气管肺泡液损伤标志物，验证了制剂的安全性。FTIR数据和blue A分析显示阳离子树状大分子的氨基与依诺肝素的羧基和硫酸盐基之间存在离子相互作用。带正电荷的树状大分子使依诺肝素的相对生物利用度提高了40%，而带负电荷的树状大分子则没有影响。含有1% G2或0.5% G3 PAMAM树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给药依诺肝素相同。这些制剂不会对MTR产生不利影响，也不会对肺部造成广泛损害。带正电的树状大分子是肺输送依诺肝素的合适载体。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肝素的肺吸收。(c) 2007 Wiley-Liss, Inc。
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.