药学学报, 2021, 56(10): 2642-2649
引用本文:
李瑞滕, 刘岩, 章辉, 袁伯川, 杜丽娜, 金义光. 治疗细菌性肺炎的肉桂油β-环糊精包合物粉雾剂研究[J]. 药学学报, 2021, 56(10): 2642-2649.
LI Rui-teng, LIU Yan, ZHANG Hui, YUAN Bo-chuan, DU Li-na, JIN Yi-guang. Cinnamon oil-β-cyclodextrin inclusion complex dry powder inhalers for the treatment of bacterial pneumonia[J]. Acta Pharmaceutica Sinica, 2021, 56(10): 2642-2649.

治疗细菌性肺炎的肉桂油β-环糊精包合物粉雾剂研究
李瑞滕1,2, 刘岩2, 章辉2, 袁伯川2, 杜丽娜1,2*, 金义光2*
1. 山东中医药大学药学院, 山东 济南 250355;
2. 军事科学院军事医学研究院辐射医学研究所, 北京 100850
摘要:
细菌性肺炎是临床常见疾病,但抗生素滥用易致耐药菌产生和流行。从天然产物中寻找新型抗菌有效成分可用于治疗细菌性肺炎。肺吸入制剂将药物直接递送于肺部感染组织,利于细菌性肺炎治疗。肉桂油(cinnamon oil,CO)是从肉桂中提取的抗菌抗炎挥发油成分,由于其油脂性质和挥发性,制备成肺吸入制剂较困难。本文制备了肉桂油β-环糊精包合物(CO-β-cyclodextrin inclusion complex,CO-β-CD),并经冻干得到粉雾剂,其空气动力学粒径为1.34 μm,微细粒子比例(fine particle fraction,FPF)达30.90%,适合肺吸入给药。CO-β-CD对金葡菌(Staphylococcus aureus,SA)的最小杀菌浓度为2 mg·mL-1。所有动物实验经军事科学院军事医学研究院伦理委员会批准且实验均按照相关指导原则和规定进行。小鼠经气管给予较高剂量(100 mg·kg-1) CO-β-CD时未见明显毒性。小鼠腹腔注射地塞米松后气管喷入SA建立细菌性肺炎模型,CO-β-CD和青霉素分别经气管给药。两者均能减轻小鼠肺部损伤,显著增加生存率。与青霉素相比,CO-β-CD可显著减轻肺组织中炎性细胞浸润,且血液中白细胞、中性粒细胞的数量及肺组织中肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、白细胞介素-6(interleukin-6,IL-6)水平与正常组无显著差异,表明CO-β-CD获得满意的体内抗菌的同时,还具有明显抗炎作用。CO-β-CD粉雾剂是一种有潜力的细菌性肺炎治疗肺吸入制剂。
关键词:    肉桂油      包合物      β-环糊精      细菌性肺炎      肺吸入     
Cinnamon oil-β-cyclodextrin inclusion complex dry powder inhalers for the treatment of bacterial pneumonia
LI Rui-teng1,2, LIU Yan2, ZHANG Hui2, YUAN Bo-chuan2, DU Li-na1,2*, JIN Yi-guang2*
1. College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China;
2. Institute of Radiation Medicine, Academy of Military Medicine Sciences, Academy of Military Sciences, Beijing 100850, China
Abstract:
Bacterial pneumonia is a common clinical disease and the abuse of antibacterial leads to the production and prevalence of resistant bacteria. Novel antibacterial active ingredients can be found from natural products for the treatment of bacterial pneumonia. Pulmonary delivery systems can directly deliver drugs to infected lung tissues, favoring the treatment of bacterial pneumonia. Cinnamon oil (CO) is a volatile oil extracted from cinnamon, which has antibacterial and anti-inflammation functions. However, the preparation of its pulmonary delivery systems is difficult because of its oil and volatile properties. Here, CO-β-cyclodextrin inclusion complex (CO-β-CD) was prepared. Its dry powder inhalers (DPIs) were obtained by lyophilization. The DPIs had the aerodynamic diameter of 1.34 μm and the fine particle fraction (FPF) of 30.90%, which was suitable for pulmonary delivery. The minimal bactericidal concentration of CO-β-CD was 2 mg·mL-1 against Staphylococcus aureus (SA). The animal experiments were approved by the Ethics Committee of Academy of Military Medical Sciences and the experiments were conducted in accordance with relevant guidelines and regulations. A high intratracheal (i.t.) dose (100 mg·kg-1) of CO-β-CD did not show significant toxicity to the mice. Bacterial pneumonia mice models were established after intraperitoneal injection of dexamethasone and then i.t. administration of SA. CO-β-CD and penicillin were separately i.t. administered to the mice. Both of them alleviated the lung injury of mice and remarkably increased the survival rates. Compared to penicillin, CO-β-CD significantly reduced the infiltration of inflammatory cells and the numbers of leukocytes and neutrophils in the blood, and the levels of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the lung tissues were similar to those of the healthy mice, indicating that CO-β-CD had the capability of anti-inflammation besides antibacterial effect in vivo. CO-β-CD dry powder inhalers are a potential pulmonary delivery system for the treatment of bacterial pneumonia.
Key words:    cinnamon oil    inclusion complex    β-cyclodextrin    bacterial pneumonia    pulmonary inhalation   
收稿日期: 2021-03-08
DOI: 10.16438/j.0513-4870.2021-0331
基金项目: 国家科技重大专项-重大新药创制专项(2018ZX09J18104-001).
通讯作者: 杜丽娜,Tel:86-10-66930216,E-mail:dulina@188.com;金义光,Tel:86-10-66931220,E-mail:jinyg@sina.com
Email: dulina@188.com;jinyg@sina.com
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