Respirable dry powder formulation of bleomycin for developing a pulmonary fibrosis animal model.
Respirable dry powder formulation of bleomycin for developing a pulmonary fibrosis animal model.
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用于开发肺纤维化动物模型的博莱霉素可吸入干粉制剂。
DOI：
10.1002/jps.23102
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发表时间：
2012
期刊：
影响因子：
--
通讯作者：
Onoue S
中科院分区：
文献类型：
--
作者：
Aoki Y;Kojo Y;Yamada S;Onoue S
本研究的主要目的是开发博来霉素（BLM）的可吸入粉末（RP）制剂，作为开发肺纤维化动物模型的研究工具。采用气流粉碎法制备了BLM-RP，并对其理化性质进行了表征，包括形态、稳定性、粒径分布和吸入性能。在加速条件下，BLM-RP在稳定性方面优于BLM溶液上级。级联撞击器分析表明，高吸入性能的排放剂量和细颗粒分数分别约为99%和46%。在大鼠中的BLM-RP（3 mg BLM/kg）的肠内给药导致肺中胶原蛋白产生和炎性细胞的募集分别显著增加约1.5倍和29倍。胶原过度表达与BLM-RP处理的大鼠肺组织的天狼猩红染色结果一致。吸入曲尼司特（TL; 100 μg/大鼠），一种抗纤维化剂，可以改善炎症/纤维化反应，募集的炎症细胞和胶原蛋白含量分别减少32%和59%，验证了肺纤维化动物模型。根据这些发现，具有改善的稳定性的BLM-RP可以是用于开发抗纤维化候选药物的药物发现中的肺纤维化模型的有益的研究工具。
The main purpose of the present study was to develop a respirable powder (RP) formulation of bleomycin (BLM) as a research tool for developing a pulmonary fibrosis animal model. The BLM-RP was prepared with a jet-milling system, the physicochemical properties of which were characterized focusing on morphology, stability, particle size distribution, and inhalation performance. Under an accelerated condition, the BLM-RP was superior to BLM solution in terms of its stability. Cascade impactor analyses demonstrated high inhalation performance with emitted dose and fine particle fraction of approximately 99% and 46%, respectively. Intratracheal administration of the BLM-RP (3 mg BLM/kg) in rats led to significant increases in collagen production and recruitment of inflammatory cells in lung by approximately 1.5- and 29-fold, respectively. The collagen overexpression was consistent with the results from picrosirius red staining of lung tissues in the rats treated with BLM-RP. Inhaled tranilast (TL; 100 μg/rat), an antifibrotic agent, could ameliorate inflammatory/fibrotic responses with reductions of recruited inflammatory cells and collagen content by 32% and 59%, respectively, validating the pulmonary fibrosis animal model. From these findings, the BLM-RP with improved stability could be a beneficial research tool for developing a pulmonary fibrosis model in drug discovery for antifibrotic drug candidates.