异烟肼超顺磁性微球粉雾剂的研究

发布时间：2018-05-25 20:16

  本文选题：异烟肼 + 粉雾剂　； 参考：《重庆医科大学》2014年硕士论文

【摘要】：目的结核病是治疗疗程长、不良反应多的严重慢性传染性疾病，异烟肼（isonicotinohydrazide，INH）是治疗肺结核一线用药，对结核杆菌杀菌作用强大，但副作用很大，给药方式多为口服和静注。因肺部给药方式可明显增强INH临床疗效，故本文通过将INH制成超顺磁性微球，然后将微球装入胶囊和装置制成粉雾剂，在外磁场引导下，肺靶向给药，以提高药物局部浓度和生物利用度，减少药物本身的不良反应，减少胃肠道反应、降低肝功能损害，并减少给药次数。为结核病的治疗和INH用药新剂型的开发提供基础。 方法本课题首先采用去溶剂化-交联法制备超顺磁性氧化铁纳米粒（Superparamagnetic iron oxide，SPIO），再将INH、SPIO和其他载体制成混合溶液，喷雾干燥得到1μm-5μm超顺磁性微球，对微球性质进行了检测。然后将微球制成粉雾剂，对粉雾剂质量指标进行了检测。本文同时进行了外磁场制备并检测其磁性强度，并进行了动物体内分布的研究和外磁场对微球粉雾剂肺部分布的影响实验。 结果所得SPIO的zeta电位绝对值约20，平均粒径29.39nm，DPI值0.185，饱和磁化强度为8.223emu/g，剩余磁化强度为0.0199emu/g，矫顽HC等于1.7Oe，符合超小型超顺磁氧化铁粒子标准。Halbach磁体磁强度在8-9cm的深度距离上大于等于20mT(200Gs)，符合外磁场在血管内束缚磁性纳米粒的基本要求。确定了喷雾干燥最优工艺，所制微球电镜下为圆形或者椭圆形小颗粒，Dav=1.552μm，D90=2.351μm，拟合系数=0.951。休止角=38°，振实密度=0.298g/cm3，排空率为97.2%，平均体外沉积率为42%。体外实验中于pH=7.4的PBS液中缓释时间为8h。引湿性为12.4%，需保存于内放硅胶干燥剂的密闭玻璃缸内，，微球在此干燥环境中的4℃和25℃温度下，6个月内稳定，各项理化性质均未发生改变。体内微球肺部浓度明显高于其他器官，单侧外加Halbach磁场组的微球数明显超过不加磁场组。 结论本课题首次将陡脉冲磁场、磁靶向微球与DPI工艺相结合，将三者优点融合后制备出具有磁靶向的异烟肼超顺磁性微球粉雾剂，所得微球粉雾剂各项质量评价指标符合中国药典标准，能在外磁场作用下，靶向给药于肺部局部，对提高INH药物疗效，降低INH对其他器官的损害，提高患者依从性，为结核病的治疗和INH用药新剂型的开发提供了实验基础。
[Abstract]:Objective Tuberculosis is a serious chronic infectious disease with long course of treatment and many adverse reactions. Isoniazid isonicotinohydrazidezide (INH) is a first-line drug for the treatment of pulmonary tuberculosis, which has a strong bactericidal effect on Mycobacterium tuberculosis, but has great side effects. Because the pulmonary administration can obviously enhance the clinical efficacy of INH, the superparamagnetic microspheres were prepared by INH, then the microspheres were put into capsules and devices to make powder aerosols. Under the guidance of the external magnetic field, the drug was targeted to the lung. In order to improve the local concentration and bioavailability of drugs, reduce the adverse reactions of the drugs themselves, reduce gastrointestinal reactions, reduce liver function damage, and reduce the times of administration. To provide a basis for the treatment of tuberculosis and the development of new dosage forms of INH. Methods the superparamagnetic ferric oxide nanoparticles superparamagnetic iron oxide-SPIOO were prepared by desolvation-crosslinking method. The superparamagnetic microspheres were prepared by spray drying, and the properties of the superparamagnetic microspheres were determined. Then the microspheres were made into powder aerosol and the quality index of powder aerosol was determined. At the same time, the external magnetic field was prepared and its magnetic intensity was measured. The distribution in vivo and the effect of external magnetic field on the pulmonary distribution of microsphere aerosol were studied. Results the absolute value of zeta potential of SPIO is about 20, the average particle size is 29.39 nm, the saturation magnetization is 8.223emu / g, the residual magnetization is 0.0199emu / g, the coercive HC is 1.7Oe, and the magnetic intensity of the superparamagnetic iron oxide particle standard. Halbach magnet is within the depth of 8-9cm. The separation is more than or equal to 20 Mt / 200GsL, which meets the basic requirement of external magnetic field binding magnetic nanoparticles in blood vessel. The optimum technology of spray drying was determined. The microspheres prepared were circular or elliptical small particles Davan 1.552 渭 m D90D902.351 渭 m under electron microscope, and the fitting coefficient was 0.951 渭 m. The angle of repose is 38 掳, the vibrational density is 0.298g / cm ~ 3, the emptying rate is 97.2and the average deposition rate is 42g / cm ~ 3. In vitro, the sustained release time in PBS solution of pH=7.4 was 8 h. The hygroscopicity is 12.4, which needs to be stored in the closed glass cylinder containing silica gel desiccant. The microspheres are stable in this drying environment at 4 鈩

本文编号：1934533