【摘要】：近年來國(guó)內(nèi)外開展了大量基于納米載體的肺部給藥研究,和其他納米載體相比,固體脂質(zhì)納米粒(SLN)因具有良好的生理相容性和體內(nèi)可降解性。因此從安全性方面考慮,SLN更適合作為肺部傳遞藥物的載體。將SLN用于肺部給藥不僅可以起到肺部緩釋作用,而且能發(fā)揮肺部給藥特有的優(yōu)勢(shì),但有關(guān)SLN肺部給藥的適用性研究相對(duì)較少,因此本研究以香豆素-6、魚腥草揮發(fā)油等為模型藥物,旨在對(duì)SLN作為肺部給藥載體在霧化吸入液、干粉吸入劑、吸入氣霧劑的應(yīng)用進(jìn)行研究。 首先,本論文分別采用熒光酶標(biāo)法和氣相色譜法對(duì)香豆素-6和鮮魚腥草揮發(fā)油的體內(nèi)外含量測(cè)定方法進(jìn)行了考察,結(jié)果方法在檢測(cè)范圍內(nèi)的線性、準(zhǔn)確度、精密度以及提取回收率等均滿足含量測(cè)定要求,且魚腥草揮發(fā)油中α-蒎烯和乙酸龍腦酯含量均小于1%,而甲基正壬酮含量約為10%,因此可將甲基正壬酮作為魚腥草揮發(fā)油含量測(cè)定的指標(biāo)性成分。 其次,本論文對(duì)SLN制備方法和工藝,以及不同脂質(zhì)和不同粒徑的香豆素-6和魚腥草揮發(fā)油SLN的體外緩釋性進(jìn)行了考察。結(jié)果顯示,制備SLN以高速分散法剪切速率為24000r/min,剪切時(shí)間為10min為最佳。不同脂質(zhì)的香豆素-6SLN以山崳酸甘油酯的體外緩釋性最好,不同粒徑SLN均有明顯的體外緩釋性,然而粒徑對(duì)SLN的體外緩釋性影響不明顯。 然后,本論文對(duì)上述方法制備的SLN水混懸液開展了其作為霧化吸入液的吸入特性評(píng)價(jià),考察了霧化液滴大小,霧化前后粒徑、電位和體外緩釋性的變化,以及不同脂質(zhì)和不同粒徑的SLN的肺部緩釋性。結(jié)果發(fā)現(xiàn)SLN水混懸液霧化后液滴粒徑為3.4-3.8μm,霧化前后SLN粒徑、電位以及體外緩釋性均無明顯變化,山崳酸甘油酯比硬脂酸緩釋性更好。此外藥代動(dòng)力學(xué)結(jié)果表明,常規(guī)制劑肺部給藥的肺部藥物分布的AUC僅為靜脈給藥6倍,而SLN水混懸液可提高26-44倍；不同粒徑的SLN均有較好的肺部緩釋性,但粒徑對(duì)肺部緩釋性影響亦不明顯。 SLN水混懸液需要脫水才能進(jìn)一步以干粉吸入劑和吸入氣霧劑的形式用于肺部給藥。因此以再分散粒徑、電位和產(chǎn)率為考察指標(biāo),對(duì)SLN噴干保護(hù)劑的類別和配比以及噴霧干燥參數(shù)入口溫度、霧化流量、抽氣速率、進(jìn)液速率進(jìn)行了考察。結(jié)果顯示,在加入40%亮氨酸,入口溫度為100℃,霧化流量為742L/h,抽氣速率為21m3/h,進(jìn)液速率2.8mL/min的條件下,可得粒徑和電位變化不大,產(chǎn)率為40%左右的SLN噴干粉末,并且噴干粉體外緩釋性無明顯變化,粉末在掃描電鏡下成片狀顆粒。 本論文進(jìn)一步對(duì)SLN噴干粉作為干粉吸入劑的可吸入性進(jìn)行了評(píng)價(jià),并對(duì)亮氨酸提高藥物微�？晌胄缘臋C(jī)理進(jìn)行了研究。結(jié)果當(dāng)亮氨酸加入量為40%,噴霧干燥脂質(zhì)濃度為2mg/mL時(shí),可得排空率為94%,MMAD為3.7μm,可吸入比例高達(dá)48.6%的SLN干粉；亮氨酸提高藥物的可吸入性的機(jī)理不是提高了微粒的Tg,而是在藥物微粒表面形成一層保護(hù)薄膜使藥物吸濕性降低而提高了其可吸入性。 最后,本論文考察了SLN對(duì)氣霧劑可吸入性的影響。結(jié)果顯示,濕法球磨法可制備平均粒徑為2.4μm分布均勻的硫酸沙丁胺醇微粒,將其制備成氣霧劑后,加入20%SLN噴干粉可將其可吸入比例從8.7%提高到18.5%,而球磨和氣霧劑制備操作均未改變藥物的晶體狀態(tài)。 綜上所述,SLN水混懸液可以霧化吸入液的形式用于肺部給藥,實(shí)現(xiàn)魚腥草的肺部緩釋；通過添加亮氨酸為保護(hù)劑將其噴霧干燥后,可以干粉吸入劑的形式用于肺部給藥；而將其干粉加入氣霧劑中可增加其他藥物的可吸入性,可為進(jìn)一步制備復(fù)方吸入氣霧劑的研發(fā)奠定基礎(chǔ)。
[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，

本文編號(hào)：2434395