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首页> 外文期刊>Journal of pharmaceutical sciences. >Development of polyethylene glycol-conjugated alendronate, a novel nitrogen-containing bisphosphonate derivative: evaluation of absorption, safety, and effects after intrapulmonary administration in rats.
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Development of polyethylene glycol-conjugated alendronate, a novel nitrogen-containing bisphosphonate derivative: evaluation of absorption, safety, and effects after intrapulmonary administration in rats.

机译：聚乙二醇共轭阿仑膦酸盐的开发，一种新型的含氮双膦酸酯衍生物：大鼠肺内给药后的吸收，安全性和效果评估。

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Bisphosphonates are widely used for the treatment of bone diseases, including hypercalcemia and osteoporosis. However, the bioavailability (BA) of orally administered bisphosphonates is low, at approximately 0.9%-1.8%. In addition, the oral administration of bisphosphonates is associated with mucosal damage, including gastritis, gastric ulcer, and erosive esophagitis. Here, to develop a new delivery system for bisphosphonates that improve their BA and safety, we developed polyethylene glycol (PEG)-conjugated alendronate, a novel nitrogen-containing bisphosphonate derivative. We evaluated the absorption and safety of PEG-alendronate in rats following intrapulmonary administration. The BA of PEG-alendronate after intrapulmonary administration was approximately 44 +/- 10% in rats, which was similar to that of alendronate (54 +/- 3.9%). Alendronate significantly increased total protein concentration and lactate dehydrogenase activity in bronchoalveolar lavage fluid, suggesting that pulmonary epithelium was locally damaged by intrapulmonary administration of alendronate. In marked contrast, PEG-alendronate did not significantly increase the markers following intrapulmonary administration. In an osteoporosis model in rats, intrapulmonary administration of PEG-alendronate effectively inhibited decreases in the width of the growth plate to a level similar to that achieved by intrapulmonary administration of alendronate. These results indicate that pulmonary delivery of PEG-alendronate is a promising approach for the treatment of bone diseases.
机译：双膦酸盐广泛用于治疗骨病，包括高钙血症和骨质疏松症。但是，口服双膦酸盐的生物利用度（BA）较低，约为0.9％-1.8％。另外，口服双膦酸盐与粘膜损害有关，包括胃炎，胃溃疡和糜烂性食管炎。在这里，为了开发一种新的双膦酸盐递送系统，以改善其BA和安全性，我们开发了聚乙二醇（PEG）共轭的阿仑膦酸盐，一种新型的含氮双膦酸盐衍生物。我们评估了肺内给药后PEG-阿仑膦酸酯在大鼠中的吸收和安全性。肺内给药后，PEG-阿仑膦酸盐的BA在大鼠中约为44 +/- 10％，与阿仑膦酸盐的BA类似（54 +/- 3.9％）。阿仑膦酸盐显着增加了支气管肺泡灌洗液中的总蛋白浓度和乳酸脱氢酶活性，表明肺上皮被肺内给药阿仑膦酸盐局部损伤。形成鲜明对比的是，肺内给药后，PEG-阿仑膦酸酯没有显着增加标志物。在大鼠的骨质疏松症模型中，肺内给予PEG-阿仑膦酸酯可有效抑制生长板宽度的减少，使其水平类似于肺内给予阿仑膦酸盐所达到的水平。这些结果表明，肺部递送PEG-阿仑膦酸酯是治疗骨疾病的有前途的方法。

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