磷脂修饰纳米晶的肺部给药制剂研究

发布时间：2018-05-06 20:46

  本文选题：肺部缓释 + 药代动力学　； 参考：《北京协和医学院》2017年硕士论文

【摘要】：肺部给药是治疗呼吸道疾病的最佳给药方式,然而临床上使用的吸入制剂给药频次多,病人依从性差,因此需要开发肺部缓释制剂。然而,由于没有合适的载体和评价技术,目前并没有成熟的制剂技术能够实现肺部缓释。针对聚合物高分子材料肺部不相容,可使用辅料较少的现状,我们选择了布地奈德、环索奈德和丙酸氟替卡松作为模式药物,选择微米晶和纳米晶的制剂形式,进行体内外一致性评价的探索。选择不同粒径的鱼腥草挥发油固体脂质纳米粒和纳米晶混悬液一起,进行可吸入性的比较。本文首先建立了三种可吸入性糖皮质激素的体内外含量测定方法。以湿法球磨和高压均质的方法制备了环索奈德和丙酸氟替卡松纳米晶和微米晶混悬液,并对丙酸氟替卡松纳米晶进行了磷脂修饰。以Spraytec和NGI评价了五种化合物的可吸入性,以改进的Transwell溶出装置测其体外溶出。微米晶和纳米晶混悬液大鼠肺部给药后,测其肺泡灌洗液、肺组织、肠组织和血中的药物含量。其中肺泡灌洗液中含量代表药物未溶出的药物含量,肠组织中的药物含量代表清除到肠道的药物含量,血中代表吸收进入系统循环的药物含量。实验结果表明,以肺泡灌洗液中药物含量代表药物在肺内的溶出和体外溶出具有一定的关联性。环索奈德微米晶可以实现在肺部的长时间驻留。纳米晶制剂可以减少肺部纤毛清除,提高肺部生物利用度。磷脂修饰的纳米晶可以减少肺部纤毛清除,提高药物在肺部的有效生物利用度,其有效生物利用度是纳米晶的1.7倍,是微米晶的4.2倍。
[Abstract]:Pulmonary administration is the best way to treat respiratory diseases. However, the inhaled drugs are used more frequently and the patients' compliance is poor, so it is necessary to develop the lung sustained-release preparation. However, due to the lack of suitable carrier and evaluation technology, there is no mature preparation technology to achieve sustained release of lung. In view of the pulmonary incompatibility of polymeric polymer materials and the low availability of excipients, we chose budesonide, cyclonide and fluticasone propionate as model drugs, and microcrystalline and nanocrystalline formulations. To explore the consistency evaluation in vivo and in vitro. The absorbability of Houttuynia cordata volatile oil solid lipid nanoparticles and nanocrystalline suspensions were compared. Three methods for the determination of inhalable glucocorticoids in vivo and in vitro were established. The suspension of fluticasone propionate and fluticasone propionate nanocrystals were prepared by wet ball milling and high pressure homogenization. The phospholipids of fluticasone propionate nanocrystals were modified by phospholipid. The absorbability of five compounds was evaluated by Spraytec and NGI, and the dissolution in vitro was measured by an improved Transwell dissolution device. The drug contents in alveolar lavage fluid, lung tissue, intestinal tissue and blood were measured after administration of microcrystalline and nanocrystalline suspension in lung of rats. The content in alveolar lavage fluid represents the drug content that the drug is not dissolved, the drug content in the intestinal tissue represents the drug content that clears the intestine, and the blood represents the drug content absorbed into the circulation of the system. The results showed that the drug content in alveolar lavage fluid was related to the dissolution of drugs in the lung and in vitro. Cysolide microcrystals can be used to stay in the lungs for a long time. Nanocrystalline preparation can reduce pulmonary cilia clearance and improve lung bioavailability. Phospholipid modified nanocrystalline can reduce the clearance of pulmonary cilia and improve the effective bioavailability of drugs in the lung. The effective bioavailability of phospholipid modified nanocrystals is 1.7 times as much as that of nanocrystals and 4.2 times of that of micron crystals.
【学位授予单位】：北京协和医学院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R943
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本文编号：1853810