Department of Pharmacokinetics and Pharmacodynamics and Global Center of Excellence Program, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka 422-8526, Japan.
J Pharm Sci. 2012 Jun;101(6):2074-81. doi: 10.1002/jps.23102. Epub 2012 Mar 2.
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.
本研究的主要目的是开发博来霉素（BLM）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。采用射流粉碎机系统制备 BLM-RP，重点对其形态、稳定性、粒径分布和吸入性能进行理化性质表征。在加速条件下，BLM-RP 的稳定性优于 BLM 溶液。级联撞击器分析表明，其发射剂量和细颗粒分数分别约为 99%和 46%，具有较高的吸入性能。BLM-RP（3mgBLM/kg）经气管内给药可使大鼠肺部胶原产生和炎症细胞募集分别增加约 1.5 倍和 29 倍。胶原过度表达与 BLM-RP 处理大鼠肺组织苦味酸天狼星红染色结果一致。吸入性曲尼司特（TL；100μg/rat），一种抗纤维化药物，可减轻炎症/纤维化反应，使募集的炎症细胞和胶原含量分别减少 32%和 59%，验证了该肺纤维化动物模型的有效性。从这些发现可以看出，稳定性得到改善的 BLM-RP 可能成为药物发现中用于抗纤维化候选药物的肺纤维化模型的有益研究工具。
