含固体脂质纳米粒的肺部给药制剂研究

发布时间：2019-03-04 15:29

【摘要】：近年来国内外开展了大量基于纳米载体的肺部给药研究,和其他纳米载体相比,固体脂质纳米粒(SLN)因具有良好的生理相容性和体内可降解性。因此从安全性方面考虑,SLN更适合作为肺部传递药物的载体。将SLN用于肺部给药不仅可以起到肺部缓释作用,而且能发挥肺部给药特有的优势,但有关SLN肺部给药的适用性研究相对较少,因此本研究以香豆素-6、鱼腥草挥发油等为模型药物,旨在对SLN作为肺部给药载体在雾化吸入液、干粉吸入剂、吸入气雾剂的应用进行研究。 首先,本论文分别采用荧光酶标法和气相色谱法对香豆素-6和鲜鱼腥草挥发油的体内外含量测定方法进行了考察,结果方法在检测范围内的线性、准确度、精密度以及提取回收率等均满足含量测定要求,且鱼腥草挥发油中α-蒎烯和乙酸龙脑酯含量均小于1%,而甲基正壬酮含量约为10%,因此可将甲基正壬酮作为鱼腥草挥发油含量测定的指标性成分。 其次,本论文对SLN制备方法和工艺,以及不同脂质和不同粒径的香豆素-6和鱼腥草挥发油SLN的体外缓释性进行了考察。结果显示,制备SLN以高速分散法剪切速率为24000r/min,剪切时间为10min为最佳。不同脂质的香豆素-6SLN以山嵛酸甘油酯的体外缓释性最好,不同粒径SLN均有明显的体外缓释性,然而粒径对SLN的体外缓释性影响不明显。 然后,本论文对上述方法制备的SLN水混悬液开展了其作为雾化吸入液的吸入特性评价,考察了雾化液滴大小,雾化前后粒径、电位和体外缓释性的变化,以及不同脂质和不同粒径的SLN的肺部缓释性。结果发现SLN水混悬液雾化后液滴粒径为3.4-3.8μm,雾化前后SLN粒径、电位以及体外缓释性均无明显变化,山嵛酸甘油酯比硬脂酸缓释性更好。此外药代动力学结果表明,常规制剂肺部给药的肺部药物分布的AUC仅为静脉给药6倍,而SLN水混悬液可提高26-44倍；不同粒径的SLN均有较好的肺部缓释性,但粒径对肺部缓释性影响亦不明显。 SLN水混悬液需要脱水才能进一步以干粉吸入剂和吸入气雾剂的形式用于肺部给药。因此以再分散粒径、电位和产率为考察指标,对SLN喷干保护剂的类别和配比以及喷雾干燥参数入口温度、雾化流量、抽气速率、进液速率进行了考察。结果显示,在加入40%亮氨酸,入口温度为100℃,雾化流量为742L/h,抽气速率为21m3/h,进液速率2.8mL/min的条件下,可得粒径和电位变化不大,产率为40%左右的SLN喷干粉末,并且喷干粉体外缓释性无明显变化,粉末在扫描电镜下成片状颗粒。 本论文进一步对SLN喷干粉作为干粉吸入剂的可吸入性进行了评价,并对亮氨酸提高药物微粒可吸入性的机理进行了研究。结果当亮氨酸加入量为40%,喷雾干燥脂质浓度为2mg/mL时,可得排空率为94%,MMAD为3.7μm,可吸入比例高达48.6%的SLN干粉；亮氨酸提高药物的可吸入性的机理不是提高了微粒的Tg,而是在药物微粒表面形成一层保护薄膜使药物吸湿性降低而提高了其可吸入性。 最后,本论文考察了SLN对气雾剂可吸入性的影响。结果显示,湿法球磨法可制备平均粒径为2.4μm分布均匀的硫酸沙丁胺醇微粒,将其制备成气雾剂后,加入20%SLN喷干粉可将其可吸入比例从8.7%提高到18.5%,而球磨和气雾剂制备操作均未改变药物的晶体状态。 综上所述,SLN水混悬液可以雾化吸入液的形式用于肺部给药,实现鱼腥草的肺部缓释；通过添加亮氨酸为保护剂将其喷雾干燥后,可以干粉吸入剂的形式用于肺部给药；而将其干粉加入气雾剂中可增加其他药物的可吸入性,可为进一步制备复方吸入气雾剂的研发奠定基础。
[Abstract]:In recent years, a large number of nano-carrier-based pulmonary administration has been carried out at home and abroad, and solid lipid nanoparticles (SLN) have good physiological and in-vivo degradability as compared with other nano-carriers. As a result, the SLN is more suitable as a carrier for the delivery of a drug to the lungs in terms of safety. The application of the SLN to the lung can not only play a role in the sustained-release of the lung, but also can play a unique advantage in the lung administration, but the applicability of the SLN pulmonary administration is relatively small, so the study takes the coumarin-6, the cordate houttuynia volatile oil and the like as a model drug, The aim of this study was to study the application of SLN as a pulmonary drug carrier in the application of aerosol inhalation, dry powder inhalant and inhalation aerosol. First, the method of determination of the external content of coumarin-6 and the volatile oil of fresh Herba Houttuyniae by using a fluorescent enzyme method and a gas chromatography, and the linearity and accuracy of the method in the detection range were obtained. The content of methyl n-nonone is less than 1%, and the content of methyl n-nonone is about 10%. Therefore, the content of n-nonanone as volatile oil of Herba Houttuyniae can be determined as the content of volatile oil of Herba Houttuyniae. In addition, that method and process for the preparation of SLN and the in vitro release of the volatile oil SLN of different lipid and different particle size were carried out in vitro. The results show that the shear rate of SLN is 24000r/ min and the shear time is 10 min. The results showed that the in vitro release of various lipid-based coumarin-6SLN was the best in the in vitro release of the caprylic acid glyceride, and the SLN with different grain diameters had obvious in-vitro release, but the effect of particle size on the in vitro release of SLN was the best. It is not obvious. Then, the SLN water suspension prepared by the above method is used as the suction characteristic evaluation of the atomization suction liquid, and the change of the size of the atomized liquid drop, the particle size, the electric potential and the in vitro release property before and after the atomization, as well as the SLN with different lipid and different particle size are investigated. The results showed that the particle size of the liquid drop was 3.4-3.8. m after the atomization of the SLN water-mixed suspension, the size and potential of the SLN before and after the atomization, and the in-vitro slow-release were not changed. In addition, the results of the pharmacokinetics show that the AUC of the pulmonary drug distribution in the conventional preparation is only 6 times that of the intravenous administration, while the SLN water suspension can be improved by 26-44 times, and the SLN with different particle sizes has good pulmonary slow release, but the particle size is good for the sustained-release lung of the lung. The response is not obvious. The SLN water suspension needs to be dehydrated in order to further take the form of a dry powder inhalant and a suction aerosol The type and the ratio of the SLN spray dry protective agent and the inlet temperature of the spray drying parameters, the atomization flow rate, the air extraction rate, the liquid inlet, The results showed that with the addition of 40% leucine, the inlet temperature was 100 鈩，

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