CN117815179A - 一种和厚朴酚脂质体粉雾剂及其制备方法和应用 - Google Patents
一种和厚朴酚脂质体粉雾剂及其制备方法和应用 Download PDFInfo
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Abstract
本发明属于脂质体制剂的制备技术领域,具体涉及一种和厚朴酚脂质体粉雾剂及其制备方法和应用。本发明提供了一种和厚朴酚脂质体粉雾剂,含有重量百分比和厚朴酚脂质体10~35%,载体40~75%,氨基酸0~20%,并且,所述和厚朴酚脂质体由磷脂、胆固醇、聚乙二醇或聚乙二醇化磷脂、和厚朴酚按照重量比4~8:0.8~1:0.3~0.6:1~2组成,所述粉雾剂具有较高的肺部沉积率和良好的递送均一性,给药稳定,疗效确切持久。
Description
技术领域
本发明属于脂质体制剂的制备技术领域,具体涉及一种和厚朴酚脂质体粉雾剂及其制备方法和应用。
背景技术
厚朴为多年生木兰科植物厚朴凹叶厚朴的干燥树皮,是一种临床上常用的中药材,其主要有效成分包括厚朴酚、和厚朴酚、异厚朴酚、四氢厚朴酚、厚朴碱等,其中以厚朴酚、和厚朴酚的含量最高。
研究表明,和厚朴酚具有广泛的药理作用,包括抗菌作用、抗炎作用、抗焦虑作用、抗吗啡戒断反应、抑制儿茶酚胺的分泌、钙调素措抗作用、抗病毒作用、抗肿瘤作用以及抗衰老作用等。目前,对和厚朴酚抗肺癌机制研究已经较为深入,研究发现,和厚朴酚能够(1)抑制I型去乙酰化酶的表达和酶活性,上调死亡受体-5(DR5)的表达,激活肿瘤坏死因子相关的凋亡诱导配体(TRAIL)信号通路;(2)激活与半胱天冬酶无关的凋亡通路;(3)阻滞癌细胞中的微管聚合,破坏微管结构;(4)阻滞蛋白激酶B(AKT)/哺乳动物雷帕霉素靶蛋白(mTOR)信号通路,诱导癌细胞自噬;(5)阻滞磷脂酰肌醇-3激酶(PI3K)/AKT信号通路而抑制癌细胞转移(文献1)。由于和厚朴酚抗瘤机制多样,作用靶点多,具备开发成抗肺癌新药的潜力。
和厚朴酚是疏水性烯丙基联苯酚类结构,水溶性差、生物利用度低,不利于吸收,采用纳米药物技术将其包裹在类脂质双分子层囊泡中,制备成脂质体,能够提高和厚朴酚的溶解性和稳定性,并在增强药效的同时减少药物的毒副作用。
与口服或注射途径给药相比,吸入性给药可以优化药物PK过程,实现快速吸收起效。脂质体吸入给药能在肺中持续释放,延长治疗时间,减少给药频率,并且药物在肺中缓慢释放可降低对肺组织的刺激性和全身不良反应(文献2)。
目前,未见和厚朴酚脂质体吸入给药制剂的相关研究,开发一种稳定给药、药效确切持久的和厚朴酚脂质体吸入剂,能够满足日益增长的临床需求。
现有技术文献:
文献1:张明发,沈雅琴.和厚朴酚及厚朴酚抗肺癌药理作用及机制的研究进展.药物评价研究,2022,45(6),1213-1220。
文献2:高洁、张琪、吴闻哲.脂质体肺部吸入给药研究进展.中国医药工业杂志,2022,53(7).935-942。
发明内容
本发明的目的是为了解决上述技术问题,提供一种稳定给药、药效确切持久的和厚朴酚脂质体粉雾剂及其制备方法。所述脂质体粉雾剂具有较高的肺部沉积率和良好的递送均一性,给药稳定,疗效确切持久。
为了实现上述目的,本发明采用的技术方案如下:本发明提供一种和厚朴酚脂质体粉雾剂,所述脂质体粉雾剂含有如下重量百分比的组分:
和厚朴酚脂质体10~35%
载体40~75%
氨基酸0~20%
并且,所述和厚朴酚脂质体由磷脂、胆固醇、聚乙二醇或聚乙二醇化磷脂、和厚朴酚按照重量比4~8:0.8~1:0.3~0.6:1~2组成。
进一步,所述载体选自乳糖、甘露醇、海藻糖、葡萄糖中的任意一种或其组合,优选为海藻糖和乳糖重量比2:1组成。
进一步,所述氨基酸选自赖氨酸、甘氨酸、精氨酸、亮氨酸、异亮氨酸中的任意一种或其组合。
进一步,所述氨基酸含量为5~15%。
进一步,所述载体和氨基酸的重量比为4~9:1。
本发明所述磷脂,可以为大豆磷脂、氢化大豆卵磷脂、蛋黄卵磷脂、氢化蛋黄卵磷脂、磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰甘油、磷脂酰丝氨酸、神经鞘磷脂、二肉豆蔻磷脂酰胆碱、二油酰磷脂酰胆碱、二月桂酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱或磷脂酸肌醇中的任意一种或其组合,但不局限于此。较佳地,为大豆磷脂、蛋黄卵磷脂或磷脂酰胆碱。
本发明所述聚乙二醇,可以为聚乙二醇1000、聚乙二醇2000、聚乙二醇4000、聚乙二醇8000中的任意一种或其组合,但不局限于此。较佳地,为聚乙二醇2000。
本发明所述聚乙二醇化磷脂,可以为磷脂酰胆碱-聚乙二醇2000(PC-PEG2000)、磷脂酰乙醇胺-聚乙二醇2000(PE-PEG2000)、二硬脂酰磷脂酰乙醇胺-聚乙二醇2000(DSPE-PEG2000)、二硬脂酰磷脂酰胆碱-聚乙二醇2000(DSPC-PEG2000)、二棕榈酰磷脂酰胆碱-聚乙二醇2000(DPPC-PEG2000)、二棕榈酰基磷脂酰乙醇胺-聚乙二醇(DPPE-PEG2000)中的任意一种或其组合,但不局限于此。
进一步,所述脂质体粉雾剂含有添加剂,所述添加剂选自助流剂、润滑剂、抗静电剂、抗黏剂中的任意一种或其组合。具体可以为苯甲酸钠、滑石粉、硬质酸镁、硬脂酸、微粉硅胶、硬酯富马酸钠、泊洛沙姆中的任意一种或其组合,但不限于此。
本发明还提供了一种所述和厚朴酚脂质体粉雾剂具体的制备方法,包括如下步骤:
S1:取磷脂、胆固醇、聚乙二醇或聚乙二醇化磷脂、和厚朴酚,混合均匀,加入有机溶剂充分溶解,蒸发除去有机溶剂,得到一层均匀的磷脂薄膜,抽真空处理除去残余的有机溶剂,向磷脂薄膜中加入磷脂薄膜重量30-60倍的水,搅拌1~1.5h,所得产物进行均质,得到脂质体溶液;
S2、取S1制备的脂质体溶液,搅拌条件下加入载体、氨基酸和添加剂,搅拌20~40min,用0.22μm滤器过滤,滤液冷冻干燥,过180目筛,得到和厚朴酚脂质体粉雾剂。
进一步,S1中所述有机溶剂为无水乙醇、氯仿、二氯甲烷、甲醇中的任意一种或其组合,优选为氯仿与无水乙醇体积比1:1~10的混合溶液或者氯仿与甲醇体积比1:1~10的混合溶液。
本发明还提供了所述和厚朴酚脂质体粉雾剂在制备用于治疗肺癌制剂中的应用。
本发明的有益效果如下:
本发明提供的和厚朴酚脂质体粉雾剂,采用脂质体技术制备获得粒径均一、包封率高、长效释放的和厚朴酚脂质体,再结合载体和/或氨基酸,通过控制粉雾剂制备过程中各组分的配比,制备粉体粒径小、流动性强、肺部沉积率高的粉雾剂。该粉雾剂有良好的肺部吸收效果,并且递送量均一,药物作用持久,对原发性肺癌的治疗具有显著效果。
附图说明
图1是采用蛋白免疫印迹法评价Bcl-2在肺内的表达图。
图2是采用实时荧光PCR检测Caspase-3在肺内的表达水平图。
实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合实施例对本发明进行具体描述,有必要指出的是,以下实施例仅用于对本发明进行解释和说明,并不用于限定本发明。本领域技术人员根据上述发明内容所做出的一些非本质的改进和调整,仍属于本发明的保护范围。
本发明具体实施方式使用的和厚朴酚纯度≥99%。
实施例1制备不同和厚朴酚粉雾剂
1、制备和厚朴酚脂质体粉雾剂(LDPI)
处方:和厚朴酚1.5g,大豆卵磷脂6.5g,胆固醇1.3g,聚乙二醇2000 0.6g。
制备方法:取大豆卵磷脂、胆固醇、聚乙二醇2000、和厚朴酚,混合均匀,加入无水乙醇充分溶解,于50℃蒸发除去有机溶剂,得到一层均匀的磷脂薄膜,抽真空处理除去残余的有机溶剂,向磷脂薄膜中加入400g水,于40℃搅拌1h,所得产物进行均质,得到脂质体溶液,用Nano-ZS90激光粒度分析仪测定脂质体平均粒径和PDI值,离心-超滤法测定和厚朴酚包封率,结果其平均粒径为132.8nm,PDI值0.297,包封率91.6%。
脂质体溶液加入20g乳糖搅拌40min,用0.22μm滤膜过滤,滤液冷冻干燥,过180目筛,即得脂质体粉雾剂。
2、制备和厚朴酚微球粉雾剂(PLGA-MS)
将1g和厚朴酚和8g聚乳酸-羟基乙酸(PLGA),加入40mL二氯甲烷和20mL丙酮涡旋溶解成有机相,将有机相倒入300mL5%PVA溶液中,5000rpm剪切2min,形成初乳,将初乳倒入4L2%PVA溶液中,室温400rpm搅拌4h,有机溶剂充分挥发,PLGA固化形成微球,水洗3次,得到微球混悬液。测定混悬液中,和厚朴酚微球包封率为86.3%。
在微球混悬液中,以混悬液体积计,加入5%甘露醇,冷冻干燥,得到和厚朴酚微球粉雾剂。
3、制备和厚朴酚喷雾干燥粉雾剂(NSD)
称取和厚朴酚1.5g,溶于少量无水乙醇中,搅拌溶解得到和厚朴酚乙醇溶液;称取6g海藻糖,加入1L水中,搅拌溶解后,加入和厚朴酚乙醇溶液,搅拌均匀,0.22μm滤膜过滤,喷雾干燥,收集干粉,即得。
实施例2不同和厚朴酚粉雾剂性能研究
1、空气动力学粒径测定
用量筒法测定实施例1制备粉雾剂的振实密度(n=5),用激光粒度仪测定粒子的几何粒径(De)。按照如下公式计算空气动力学粒径。
其中,Da和De分别为空气动力学粒径和几何学粒径(D50);ρp为有效颗粒密度,为振实密度的1.26倍;ρo为参照密度,等于1g/cm3;χ为动态形态因子(球形时χ=1)。结果见表1。
表1不同粉雾剂空气动力学粒径测定结果
粉雾剂 | Da(μm) |
LDPI | 2.91±0.008 |
PLGA-MS | 2.14±0.006 |
NSD | 3.29±0.012 |
由表1可知,不同方法制备的粉雾剂,其空气动力学粒径均在1~5μm,适合肺部吸入。
2、粉雾剂肺部沉积率测定
取实施例1制备的粉雾剂,分别填装入3#胶囊内,精密称重,取20粒胶囊,分次放入吸入器(TWISTER)内,连接吸入药物粒度分布测定仪(NGI),调节空气流速达到60±5L/min,测定细微粒子(FPF)比例,以去离子水冲洗NGI中装置、喉部、1级至8级室,收集冲洗液转入25mL容量瓶中,用无水乙醇定容。测定溶液中和厚朴酚的含量,并计算粉雾剂的FPF值:
结果测得粉雾剂的FPF结果见表2。
表2不同粉雾剂FPF检测结果
处方 | FPF(%) |
LDPI | 10.67 |
PLGA-MS | 4.22 |
NSD | 1.68 |
由表2可知,和厚朴酚脂质体粉雾剂(LDPI)具有更好的FPF值,表明LDPI达到肺部的有效药物量最多。
实施例3不同粉雾剂对大鼠原发性肺癌的治疗效果评价
模型建立和给药
30只健康大鼠随机分成6组,每组5只,1组为模型组,1组为正常组,1组为阳性对照组,3组为和厚朴酚药物组(分别为LDPI组、PLGA-MS组和NSD组),其中,模型组、阳性对照组和和厚朴酚药物组造模,造模方法为:取适量的3-甲基胆蒽(MCA)和N,N-二甲基亚硝胺(DEN)加入碘化油注射液中,70℃加热20h(每3h振荡摇匀),其中MCA为均匀混悬状态,DEN完全溶解,得到含100mg/mL MCA和10% DEN碘化油混悬液作为原发性肺癌诱变剂。取0.1mL肺癌诱变剂通过气管插管喷入大鼠肺中,正常饲养条件下饲养45天得到原发性肺癌大鼠。
3组药物组分别给药实施例1制备的LDPI、PLGA-MS和NSD,阳性对照组给药吉西他滨粉末,同一时间进行大鼠气管插管给药,每3天给药1次,给药量均以含药量2mg计,连续给药5次,模型组和正常组气管喷入生理盐水0.2mL,肺部给药方法:用喉镜撑开大鼠喉部,暴露气管,用细的软管进行气管插管,尾端用三通阀连接至预充生理盐水的1.0mL注射器,打开三通阀,将生理盐水喷入肺部。药物组和阳性对照组给药则先将粉末放入三通阀内,注射器先压缩空气,打开三通阀后,压缩空气将粉末喷入肺部。
2、肺组织中标志物含量测定
末次给药完成后3天麻醉处死大鼠,取左肺中叶,称重,加入9倍质量生理盐水(4℃),匀浆,用ELISA试剂盒测定匀浆中TNF-α和VEGF;用BCA蛋白浓度测定试剂盒测定匀浆中总蛋白的量。结果见表3。
取右肺中叶和下叶组织,置于10%甲醛溶液中,-80℃保存。
采用蛋白免疫印迹法评价Bcl-2在肺内的表达,采用实时荧光PCR检测Caspase-3在肺内的表达水平,结果见图1和图2。
表3各组大鼠肺组织中标志物含量测定结果
TNF-α是典型的炎症免疫标志物,总蛋白量增多标志炎症反应,而VEGF可诱导血管生成,促进肿瘤组织生长,由上表可知,模型组肺组织中炎症因子TNF-α和总蛋白明显增多,VEGF高度表达,与模型组相比,阳性对照组和药物组均能降低肺癌模型大鼠的TNF-α、VEGF以及总蛋白含量,LDPI组降低效果明显优于PLGA-MS组和NSD组。
Bcl-2是抑凋亡蛋白,Caspase-3是重要的细胞凋亡标志物,Bcl-2的高表达,预示着细胞的增值旺盛,Caspase-3的表达增高,预示着细胞不可逆的发生凋亡。检测结果表明,模型组与正常组相比,Bcl-2表达较多,由图1和图2可知,3个药物组与模型组相比,均能不同程度的降低Bcl-2表达,提高Caspase-3表达,其中,LDPI组效果最为显著。
实施例4和厚朴酚脂质体粉雾剂组方研究
按照表4处方制备和实施例1所述方法制备和厚朴酚脂质体粉雾剂。
表4处方1-3和厚朴酚脂质体粉雾剂
制备方法:取大豆卵磷脂、胆固醇、聚乙二醇2000、和厚朴酚,混合均匀,加入无水乙醇充分溶解,于50℃蒸发除去有机溶剂,得到一层均匀的磷脂薄膜,抽真空处理除去残余的有机溶剂,向磷脂薄膜中加入400g水,于40℃搅拌1h,所得产物进行均质,得到脂质体溶液,处方1直接将脂质体溶液用0.22μm滤膜过滤,滤液冷冻干燥,过180目筛,即得粉雾剂;处方2在脂质体溶液中加入乳糖搅拌40min,用0.22μm滤膜过滤,滤液冷冻干燥,过180目筛,即得粉雾剂;处方3在脂质体溶液中加入乳糖和甘氨酸搅拌40min,用0.22μm滤膜过滤,滤液冷冻干燥,过180目筛,即得粉雾剂。
1、脂质体粉雾剂性能测定
对处方1-3制备的粉雾剂,按照实施例1所述方法测定平均粒径、PDI值、和厚朴酚包封率,结果见表5。
表5不同处方脂质体粉雾剂平均粒径、PDI值和包封率测定结果
处方 | 平均粒径(nm) | PDI | 包封率 |
处方1 | 115.4 | 0.253 | 90.2% |
处方2 | 132.8 | 0.297 | 91.6% |
处方3 | 127.3 | 0.249 | 93.7% |
由表5可知,处方1-3制备的粉雾剂,其脂质体的平均粒径在115~133nm,PDI值均小于0.3,包封率均高于90%,表明处方1-3粒径均一,包封效果较佳。将复溶后的溶液分别在4℃放置10天,测定其平均粒径、PDI值以及包封率,结果处方1-3各值无明显变化,脂质体具有良好的稳定性。
2、脂质体粉雾剂释放度测定
采用动态透析法测定脂质体粉雾剂的体外释放度,具体方法为:取处方1-3制备的粉雾剂0.6mg,用3ml人工肺液完全分散后置于截留相对分子质量为8000-14000的透析袋,以50ml人工肺液为释放介质,控制温度为37℃,转速100r/min,分别与0.5、1、2、4、6、8、12、24h取样1ml,同时补充等温等量释放介质,测定样品中和厚朴酚的含量,并计算累积释放度,结果,处方1-3制备的脂质体粉雾剂在第1h时累积释放8.6-15.7%,第4h累积释放31.5-36.9%,第12h累积释放65.4-74.7%,第24h累积释放均达到85%以上,表明处方1-3粉雾剂均具有良好的缓释效果。
3、粉雾剂肺部沉积率测定
按照实施例2所述方法测定处方1-3粉雾剂的FPF,结果见下表6。
表6不同处方脂质体粉雾剂FPF检测结果
由表6可知,添加了载体和氨基酸的处方3具有最高的FPF值,表明处方3达到肺部的有效药物量最多,处方2次之。
实施例5载体和氨基酸配比对肺部沉积率的影响
按照表7处方,以及实施例4处方3所述方法制备和厚朴酚脂质体粉雾剂。
表7处方4-7和厚朴酚脂质体粉雾剂
按照实施例2测定处方4-7粉雾剂肺部沉积率,并与处方3进行对比,结果见表8。
表8不同处方和厚朴酚脂质体粉雾剂FPF检测结果
由表8可知,氨基酸与载体的用量对FPF结果有影响,当载体和氨基酸的重量比为4~9:1时,FPF可达到14%以上。
实施例6不同载体对肺部沉积率和递送均一性的影响
按照表9处方,以及实施例4处方3所述方法制备处方8-15和厚朴酚脂质体粉雾剂。
表9处方8-15和厚朴酚脂质体粉雾剂
按照实施例2测定处方8-15粉雾剂FPF,再按照下述方法测定处方6、8-15的递送剂量均一性,结果见表10。
递送剂量均一性实验
按照《中国药典》2020版四部通则0111吸入制剂,吸入粉雾剂项下递送剂量均一性检测装置和方法测定,分别取处方6、8-15粉雾剂,每个处方各取3份样品,精密称重,连接测定装置与适配器,调节真空泵流速至90L/min,抽吸时间2.8s,卸下装置和适配器,用去离子水淋洗适配器,装置管与管中滤纸,合并洗液与滤纸至50ml容量瓶中,无水乙醇稀释至刻度,摇匀,离心,取上清液作为供试品溶液。测定每个处方第一份样品的第1、2、3吸,第二份样品的第28、29、30、31吸,第三份样品的第58、59、60吸的供试品溶液中和厚朴酚的递送量,结果每份样品10次抽吸递送量的平均值,并计算RSD%,结果见表10。
表10不同处方和厚朴酚脂质体粉雾剂递送剂量均一性检测结果
处方 | 10次递送剂量RSD% |
处方6 | 2.7 |
处方8 | 3.7 |
处方9 | 3.2 |
处方10 | 5.4 |
处方11 | 4.7 |
处方12 | 2.8 |
处方13 | 2.4 |
处方14 | 2.9 |
处方15 | 3.2 |
由表10可知,处方6、9、12、13和15递送剂量均一性优于其他处方,尤其是处方13,递送剂量均一性最优。
实施例7
处方:
制备方法:取蛋黄卵磷脂、胆固醇、DSPE-PEG2000、和厚朴酚,混合均匀,加入无水乙醇充分溶解,于50℃蒸发除去有机溶剂,得到一层均匀的磷脂薄膜,抽真空处理除去残余的有机溶剂,向磷脂薄膜中加入180g水,于25℃搅拌1h,所得产物进行均质,得到脂质体溶液,搅拌条件下加入葡萄糖和精氨酸搅拌40min,用0.22μm滤膜过滤,滤液冷冻干燥,过180目筛,即得粉雾剂。
实施例8
制备方法:取磷脂酰乙醇胺、胆固醇、DPPE-PEG2000、和厚朴酚,混合均匀,加入无水乙醇充分溶解,于50℃蒸发除去有机溶剂,得到一层均匀的磷脂薄膜,抽真空处理除去残余的有机溶剂,向磷脂薄膜中加入650g水,于25℃搅拌1h,所得产物进行均质,得到脂质体溶液,搅拌条件下加入甘露醇和赖氨酸搅拌40min,用0.22μm滤膜过滤,滤液冷冻干燥,过180目筛,加入硬脂酸镁,即得粉雾剂。
实施例9
制备方法:取二月桂酰磷脂酰胆碱、胆固醇、DPPC-PEG2000、和厚朴酚,混合均匀,加入无水乙醇充分溶解,于50℃蒸发除去有机溶剂,得到一层均匀的磷脂薄膜,抽真空处理除去残余的有机溶剂,向磷脂薄膜中加入6.5L水,于25℃搅拌1h,所得产物进行均质,得到脂质体溶液,搅拌条件下加入乳糖、海藻糖和赖氨酸搅拌40min,喷雾干燥,即得粉雾剂。
实施例10
制备方法:取磷脂酰丝氨酸、胆固醇、PEG8000,加入无水乙醇200ml溶解,45℃搅拌条件下将和厚朴酚的乙醇溶液缓慢加入,于50℃蒸发除去有机溶剂,加入200ml pH6.5PBS缓冲液,冰浴探头超声分散10min,得到脂质体溶液,搅拌条件下加入甘露醇、海藻糖和异亮氨酸搅拌40min,喷雾干燥,即得粉雾剂。
实施例11
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制备方法:取磷脂酸肌醇、胆固醇、PC-PEG2000、和厚朴酚,混合均匀,加入氯仿:无水乙醇(1:1v/v)充分溶解,于50℃蒸发除去有机溶剂,得到一层均匀的磷脂薄膜,抽真空处理除去残余的有机溶剂,向磷脂薄膜中加入600g水,于25℃搅拌1h,所得产物进行均质,得到脂质体溶液,搅拌条件下加入乳糖、甘露醇、亮氨酸搅拌40min,用0.22μm滤膜过滤,滤液冷冻干燥,过180目筛,即得粉雾剂。
本发明实施例7-11为较优的实施方案,经测定,其脂质体粉雾剂性能良好,复溶后脂质体的平均粒径在112~143nm,PDI值均小于0.3,包封率为91.4%~95.8%,粉雾剂的FPF值为11.06%~15.17%,并对原发性肺癌大鼠模型具有良好的抗癌疗效。本发明所述各组实施例仅为示例性的,并不代表以任何方式限制本发明的范畴。
Claims (10)
1.一种和厚朴酚脂质体粉雾剂,其特征在于,所述脂质体粉雾剂含有如下重量百分比的组分:
和厚朴酚脂质体 10~35%
载体 40~75%
氨基酸 0~20%
并且,所述和厚朴酚脂质体由磷脂、胆固醇、聚乙二醇或聚乙二醇化磷脂、和厚朴酚按照重量比4~8:0.8~1:0.3~0.6:1~2组成。
2.根据权利要求1所述的和厚朴酚脂质体粉雾剂,其特征在于,所述载体选自乳糖、甘露醇、海藻糖、葡萄糖中的任意一种或其组合。
3.根据权利要求1所述的和厚朴酚脂质体粉雾剂,其特征在于,所述载体为海藻糖和乳糖重量比2:1组成。
4.根据权利要求1所述的和厚朴酚脂质体粉雾剂,其特征在于,所述氨基酸选自赖氨酸、甘氨酸、精氨酸、亮氨酸、异亮氨酸中的任意一种或其组合。
5.根据权利要求1所述的和厚朴酚脂质体粉雾剂,其特征在于,所述氨基酸含量为5~15%。
6.根据权利要求1所述的和厚朴酚脂质体粉雾剂,其特征在于,所述载体和氨基酸的重量比为4~9:1。
7.根据权利要求1所述的和厚朴酚脂质体粉雾剂,其特征在于,所述脂质体粉雾剂含有添加剂,所述添加剂选自助流剂、润滑剂、抗静电剂、抗黏剂中的任意一种或其组合。
8.根据权利要求1-7任一项所述的和厚朴酚脂质体粉雾剂的制备方法,其特征在于,包括如下步骤:
S1:取磷脂、胆固醇、聚乙二醇或聚乙二醇化磷脂、和厚朴酚,混合均匀,加入有机溶剂充分溶解,蒸发除去有机溶剂,得到一层均匀的磷脂薄膜,抽真空处理除去残余的有机溶剂,向磷脂薄膜中加入磷脂薄膜重量30~60倍的水,搅拌1~1.5 h,所得产物进行均质,得到脂质体溶液;
S2:取S1制备的脂质体溶液,搅拌条件下加入载体、氨基酸和添加剂,搅拌20~40min,用0.22μm滤器过滤,滤液冷冻干燥,过180目筛,得到和厚朴酚脂质体粉雾剂。
9.根据权利要求8所述的和厚朴酚脂质体粉雾剂的制备方法,其特征在于,S1中所述有机溶剂为无水乙醇、氯仿、二氯甲烷、甲醇中的任意一种或其组合。
10.权利要求1-7任一项所述的和厚朴酚脂质体粉雾剂在制备用于治疗肺癌制剂中的应用。
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