喜炎平注射液雾化吸入给药可行性探索研究

Exploratory study on inhalation drug adminstrion of Xiyanping Injection

目的通过雾化微细粒子空气动力学特性测定和小鼠经口鼻雾化吸入毒性研究,评估喜炎平注射液雾化吸入可行性,为其临床应用提供参考。方法采用新一代级联撞击器和雾化器系统(采用2种雾化器,压缩空气雾化器和超声雾化器,测算药物雾化吸入空气动力学直径(MMAD)、几何标准偏差(GSD)、微细粒子分数(FPF),并采用呼吸模拟器测定喜炎平注射液雾化吸入的递送总量和递送速率。采用inExpose吸入染毒暴露系统,小鼠经口鼻吸入喜炎平注射液低、中、高剂量(25、50、125 mg/kg,是临床等效剂量的3、6、15倍)连续4周,停药恢复2周,吸入正常空气为对照组。观察小鼠一般状态,每组动物在给药期结束和恢复期结束各处死10只,雌雄各半。小鼠处死前取血,检测血液学指标、血清生化指标;动物均乙醚吸入麻醉后进行尸体剖检,原位观察组织外观,重点观察其口腔黏膜、鼻中隔黏膜、气管及肺部;剖取主要脏器——脑、肝、脾、肾、心、肺,进行脏器系数检测;取左肺进行HE染色,观察组织病理学变化。结果喜炎平注射液可以雾化吸入肺部(支气管、细支气管)并有一定比例在肺部沉降存留,儿童、成人模式下递送总量、递送速率依次增加。吸入刺激性结果显示,试验期间未观察到动物死亡和咳呛等刺激性异常表现;与对照组比较,喜炎平注射液各剂量组动物血液学指标、血清生化、脏器系数、主要组织检查、肺部组织病理学均无显著改变。结论在体外雾化吸入模拟条件下,喜炎平注射液可吸入肺部(支气管、细支气管),并有一定比例在肺部沉降存留;连续吸入4周对小鼠呼吸道黏膜和肺部无显著刺激性和病理学改变,初步认为其雾化吸入给药是安全可行的。

Objective To explore the feasibility inhaled atomized Xiyanping Injection through determination of aerodynamic characteristics of atomized fine particles and safety of atomized inhalation in mice provide reference for clinical application.Mehtods The new generation of cascade impactor and atomizer system(There were two kinds of atomizers,the compressed air atomizer:Germany Bray medical atomizer Turbo BOY N and the ultrasonic atomizer:Yuyue medical atomizer 503 M)was used with COPLEY Scientific Limited CITDAS software to calculate mass median aerodynamic diameter(MMAD),geometric standard deviation(GSD)and fine particle fraction(FPF).The total delivery amount and delivery rate of Xiyanping Injection were measured by respiratory simulator.Inexpose inhalation exposure system was used,mice were exposed to low,medium and high doses of Xiyanping injection(25,50 and 125 mg/kg,which were 3,6 and 15 times of the clinical equivalent dose)through oral and nasal inhalation for 4 consecutive weeks,withdrawal for two weeks of drug,mice in the control group inhaled normal air.To observe the general state of mice,10 mice in each group were killed at the end of the administration period and the end of the recovery period,half male and half female.Blood samples were taken before the mice were killed to detect the changes of hematological indexes and serum biochemistry;autopsy was performed after the animals were anesthetized with ether inhalation,and the appearance of the tissues was observed in situ,focusing on the oral mucosa,nasal septum mucosa,trachea and lung;the main organs brain,liver,spleen,kidney,heart and lung were dissected to detect the organ coefficient;the left lung was stained with HE to observe the histopathology change.Results Xiyanping Injection can be atomized into the lungs(bronchi and bronchioles)and a certain proportion of it remains in the lungs.The total delivery amount and delivery rate of Xiyanping Injection increase in turn in children and adults.The results of inhalation irritation showed that no death and cough were observed during the experiment.Compared with control group,there were no significant changes in hematological indexes,serum biochemistry,organ coefficient,main histological examination and lung histopathology in all dose groups of Xiyanping Injection.Conclusion Under the condition of in vitro the existing nebulized inhalation,Xiyanping Injection can be inhaled into the lungs(bronchi,bronchioles)and a high proportion of drugs remain in the lungs,and there was no obvious irritation to the respiratory mucosa,indicating that the application of nebulized inhalation is relatively safe and feasible.