CN110755632A - 脑靶向钩藤碱纳米制剂、制备方法及在静脉注射药物中的应用 - Google Patents

脑靶向钩藤碱纳米制剂、制备方法及在静脉注射药物中的应用 Download PDF

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CN110755632A
CN110755632A CN201911188188.6A CN201911188188A CN110755632A CN 110755632 A CN110755632 A CN 110755632A CN 201911188188 A CN201911188188 A CN 201911188188A CN 110755632 A CN110755632 A CN 110755632A
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rhynchophylline
targeting
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brain
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付春梅
徐瑞聆
王珺滢
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Sichuan University
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Abstract

本发明公开了一种脑靶向钩藤碱纳米制剂、制备方法及在静脉注射药物中的应用，制剂由以下质量百分含量的原料制成：钩藤碱0.1％～0.3％、嵌段聚合物0.3％～0.9％、靶向作用物质(w/v)0.5％～5％、非离子表面活性剂(w/v)0.5％～5％、其余为水；其中，嵌段聚合物为具有亲水性片段和疏水性片段的两亲性嵌段聚合物。本发明钩藤碱纳米制剂粒径小、粒度分布窄、结构稳定、体内滞留时间长、具有较好的脑靶向性、可降解。制备方法条件温和，简单易行，有效解决了钩藤碱转化成异钩藤碱的问题。本发明的脑靶向钩藤碱纳米制剂可以在制备静脉注射药物中应用。

Description

脑靶向钩藤碱纳米制剂、制备方法及在静脉注射药物中的 应用
技术领域
本发明属于技术领域，涉及靶向药物制剂、制备方法及应用，尤其涉及一种脑靶向钩藤碱纳米制剂、制备方法及在静脉注射药物中的应用。
背景技术
阿尔茨海默病(AD)是一种由中枢神经系统病变引起的神经系统退行性疾病。目前世界上约有2400万人患有该病，预计到2050年，患者数量将接近1亿。AD已成为全球老年人的第4位主要死亡原因。目前美国食品和药物管理局(FDA)批准上市的治疗AD的药物仅有五种，但这些临床药物为单靶点作用，只能缓解疾病症状，不能阻止其进展，而且一些药物还存在肝毒性等一系列副作用。
钩藤碱(Rhynchophylline)是茜草科植物钩藤的带钩枝条所提取的生物碱，
结构为：
钩藤碱具有降血压、抗心律失常、抗炎、神经保护等作用。据研究显示，其治疗AD主要药理作用为抑制炎症反应、抗谷氨酸兴奋毒性、减轻Aβ神经毒性、抑制tau蛋白过度磷酸化等，其中主要作用是减轻Aβ神经毒性。而且钩藤碱具有多靶点效应的优点、毒性作用低、副作用也小。
然而，钩藤碱的临床应用受限于溶解度低、代谢快、脑内含量低、生物利用度低等缺点，不利于其进行临床推广。
现有技术中，虽然有多种制备纳米粒的方法，如常用的包封率高的溶剂蒸发法，但因钩藤碱在高温、超声等剧烈条件下易异构化成异构体-异钩藤碱，该方法不宜采用。
发明内容
本发明要解决的技术问题在于，针对现有技术的缺陷，提供一种粒径小、粒度分布窄、结构稳定、体内滞留时间长、可降解的脑靶向钩藤碱纳米制剂。
本发明进一步要解决是：制备条件温和，有效解决了钩藤碱转化成异钩藤碱的问题，且方法简单易行，纳米粒子分散性好的制备方法。
本发明还解决了钩藤碱纳米制剂在制备静脉注射药物中的应用。
本发明解决其技术问题所采用的技术方案是：
一种脑靶向钩藤碱纳米制剂，由以下质量百分含量的原料制成：钩藤碱0.1％～0.3％、嵌段聚合物0.3％～0.9％、靶向作用物质(w/v)0.5％～5％、非离子表面活性剂(w/v)0.5％～5％、其余为水；其中，嵌段聚合物为具有亲水性片段和疏水性片段的两亲性嵌段聚合物。
进一步地，所述的脑靶向钩藤碱纳米制剂中，优选由以下质量百分含量的原料制成：钩藤碱0.2％～0.3％、嵌段聚合物0.5％～0.8％、靶向作用物质(w/v)1％～3％、非离子表面活性剂(w/v)1％～3％、其余为水。
进一步地，所述的脑靶向钩藤碱纳米制剂中，优选所述嵌段聚合物为PLGA(聚乳酸-羟基乙酸共聚物)、PCL(聚己内酯)或它们的衍生物。
进一步地，所述的脑靶向钩藤碱纳米制剂中，优选衍生物选择脂肪族聚酯类衍生物mPEG-PLGA和mPEG-PCL，所述PLGA衍生物是mPEG-PLGA，其中PLGA分子量为3-16kD；LA/GA＝(50：50)-(75:25)；PEG分子量为400-4000；所述PCL衍生物是mPEG-PCL，其中，PCL分子量为1000-20000；PEG分子量为1000-5000。
进一步地，所述的脑靶向钩藤碱纳米制剂中，优选所述靶向作用物质为转铁蛋白、乳铁蛋白、载脂蛋白、葡萄糖、吐温80、冰片、血管肽素、唾液酸或甘露糖。
进一步地，所述的脑靶向钩藤碱纳米制剂中，优选所述的非离子表面活性剂为聚乙烯醇、维生素E聚乙二醇琥珀酸酯或者泊洛沙姆188。
一种脑靶向钩藤碱纳米制剂的制备方法，包括如下步骤：
(1)称取以下质量百分含量的原料：钩藤碱0.1％～0.3％、嵌段聚合物0.3％～0.9％、靶向作用物质0.5％～5％、非离子表面活性剂0.5％～5％、其余为水；
(2)常温下，取嵌段共聚物和钩藤碱溶于有机溶剂中，按原料比例涡旋混匀得到混合溶液；将非离子表面活性剂溶于水缓慢滴加到混合溶液中，搅拌形成纳米混悬液；
(3)纳米混悬液离心10-20min后，缓冲溶液洗脱，即得载药嵌段共聚物纳米粒；
(4)搅拌下，将靶向作用物质加入所得的载药嵌段共聚物纳米粒中，缓慢搅拌20-40min，即得脑靶向钩藤碱纳米制剂。
进一步地，所述的脑靶向钩藤碱纳米制剂的制备方法中，优选所述有机溶剂为二氯甲烷、氯仿、N,N-二甲基甲酰胺或二甲基亚砜。
进一步地，所述的脑靶向钩藤碱纳米制剂的制备方法中，优选所述PLGA衍生物是mPEG-PLGA，其中PLGA分子量为3-16kD；LA/GA＝(50：50)-(75:25)；PEG分子量为400-4000；所述PCL衍生物是mPEG-PCL，其中，PCL分子量为1000-20000；PEG分子量为1000-5000。
一种脑靶向钩藤碱纳米制剂在制备静脉注射药物中的应用。
本发明的技术方案具有以下技术效果：
本发明的脑靶向钩藤碱纳米制剂表面光滑圆整、无粘连、粒度分布窄，具体粒径在100～200nm。其结构稳定，体内滞留时间长，具有较好的脑靶向性，可降解。本发明通过嵌段聚合物的载药作用，将钩藤碱与嵌段聚合物通过分子间相互作用后形成钩藤碱纳米粒，再通过靶向作用物质进行表面修饰，修饰后的钩藤碱纳米粒能被血液中的载脂蛋白(Apolipoprotein，Apo)E或B吸收，接着由低密度脂蛋白(LDL)受体介导的内吞和胞转作用，透过血-脑屏障(blood-brain barrier，BBB)，转运入脑，并在脑细胞外液达到有效的浓度，实现持续和更均匀地输送药物到病变部位，用于有效治疗阿尔兹海默症和潜在的其他脑部疾病。另外，本发明可以通过调整嵌段聚合物种类或配比,以调节钩藤碱的释放速度,使其具有缓释特性。并且钩藤碱与嵌段聚合物附着或交联，提高了钩藤碱的溶解度，使钩藤碱在体内的血药浓度提高，并通过靶向作用物质将钩藤碱靶向脑部，使更多的钩藤碱富集于脑部神经元处，达到更好的治疗作用。
其中，嵌段聚合物是由具有亲水性片段和疏水性片段的两亲性嵌段聚合物在水溶液中自发形成的一种自组装结构，其包封率较高，可到达60％左右，使得装载药物的能力增强，载药量较高。
本发明选择的嵌段聚合物具有良好的生物相容性、无毒、结构稳定、体内滞留时间长、可降解等特点，可以应用于载小分子中药提取物或难溶性药物。
本发明的制备方法条件温和，能有效包裹钩藤碱，防止其异构化，制备产品稳定性强。
本发明的脑靶向钩藤碱纳米制剂粒度分布均匀，安全性高，适合静脉注射，能有效到达脑部疾病部位。
附图说明
下面将结合附图及实施例对本发明作进一步说明，附图中：
图1本发明实施例1的钩藤碱-mPEG-PLGA-吐温80纳米粒的扫描电镜图；
图2本发明实施例1的钩藤碱纳米粒的粒径分布图。
图3本发明实施例1及其对比的体外溶血实验图；
图4本发明实施例1及其对比对小鼠脑微血管内皮细胞的毒性影响；
图5a-5e本发明实施例1及其对比在小鼠脑微血管内皮细胞的摄取实验的结果；
图6本发明实施例1及其对比在体外BBB(小鼠脑微血管内皮细胞模拟)渗透实验的结果；
图7本发明实施例1的小鼠体内钩藤碱纳米粒体内分布对比图；
图8本发明实施例1及其对比在体内药动学实验的结果。
具体实施方式
为了对本发明的技术特征、目的和效果有更加清楚的理解，现对照附图详细说明本发明的具体实施方式。
一种脑靶向钩藤碱纳米制剂，由以下质量百分含量的原料制成：钩藤碱0.1％～0.3％、嵌段聚合物0.3％～0.9％、靶向作用物质(w/v)0.5％～5％、非离子表面活性剂(w/v)0.5％～5％、其余为水；其中，嵌段聚合物为具有亲水性片段和疏水性片段的两亲性嵌段聚合物。
进一步地，所述的脑靶向钩藤碱纳米制剂中，优选由以下质量百分含量的原料制成：钩藤碱0.2％～0.3％、嵌段聚合物0.5％～0.8％、靶向作用物质(w/v)1％～3％、非离子表面活性剂(w/v)1％～3％、其余为水。
进一步地，所述的脑靶向钩藤碱纳米制剂中，优选所述嵌段聚合物为PLGA、PCL或它们的衍生物。衍生物选择脂肪族聚酯类衍生物。
进一步地，所述的脑靶向钩藤碱纳米制剂中，优选所述PLGA衍生物是mPEG-PLGA，其中PLGA分子量为3-16kD；LA/GA＝((50：50)-(75:25)；PEG分子量为400-4000；其中最优选PLGA分子量选择3kD、9kD、11kD、15kD或16kD；LA/GA＝75:25或50：50；PEG分子量为400、800、1000、2000或4000；
所述PCL衍生物是mPEG-PCL，其中，PCL分子量为1000-20000；PEG分子量为1000-5000。其中最优选PCL分子量为1000、2000、5000、10000或20000；PEG分子量为1000、2000或5000。
进一步地，所述的脑靶向钩藤碱纳米制剂中，优选所述靶向作用物质为转铁蛋白、乳铁蛋白、载脂蛋白、葡萄糖、吐温80、冰片、血管肽素、唾液酸或甘露糖。
进一步地，所述的脑靶向钩藤碱纳米制剂中，优选所述的非离子表面活性剂为聚乙烯醇、维生素E聚乙二醇琥珀酸酯或泊洛沙姆188。
一种脑靶向钩藤碱纳米制剂的制备方法，包括如下步骤：
(1)称取以下质量百分含量的原料：钩藤碱0.1％～0.3％、嵌段聚合物0.3％～0.9％、靶向作用物质0.5％～5％、非离子表面活性剂0.5％～5％、其余为水；
(2)常温下，取嵌段共聚物和钩藤碱溶于有机溶剂中，按原料比例涡旋混匀得到混合溶液；取适量非离子表面活性剂溶于水配置成水溶液，将混合溶液缓慢滴加到非离子表面活性剂水溶液中，搅拌形成纳米混悬液；
(3)纳米混悬液离心10-20min后，缓冲溶液洗脱，即得载药嵌段共聚物纳米粒；
(4)搅拌下，将靶向作用物质加入所得的载药嵌段共聚物纳米粒中，缓慢搅拌20-40min，即得脑靶向钩藤碱纳米制剂。
进一步地，所述的脑靶向钩藤碱纳米制剂的制备方法中，优选所述有机溶剂为二氯甲烷、氯仿、N,N-二甲基甲酰胺或二甲基亚砜。
进一步地，所述的脑靶向钩藤碱纳米制剂的制备方法中，优选所述PLGA衍生物是mPEG-PLGA，其中PLGA分子量为3-16kD；LA/GA＝(50：50)-(75:25)；PEG分子量为400-4000；所述PCL衍生物是mPEG-PCL，其中，PCL分子量为1000-20000；PEG分子量为1000-5000。
一种脑靶向钩藤碱纳米制剂在制备静脉注射药物中的应用。
本发明可以通过以下实验验证产品性能：
一、钩藤碱纳米粒的粒径测定
采用激光散射粒径分析仪或透射电子显微镜测定或观察钩藤碱纳米粒的粒径。取钩藤碱纳米粒溶液用纯化水稀释100倍，于25℃用激光散射粒径分析仪测定(ZetsizerNano ZS90)，重复测定三次记录粒径均值。将钩藤碱纳米粒溶液稀释5倍以后，滴在铜网上，2％磷钨酸钠染色后，HITACHIH-600透射电子显微镜观察粒子形态。
二、钩藤碱纳米粒的包封率测定
采用离心法测定钩藤碱纳米粒的包封率。取钩藤碱纳米粒溶液，4℃条件下超速冷冻离心1h(离心机转速45000rpm)，得纳米粒沉淀。取纳米粒沉淀，加一定量DMSO消解至澄明，离心，取上清液2ul注入HPLC,用甲醇-水(60:40，v/v)作为流动泪，流速为1ml/min，柱温为30℃，检查波长为254nm，采用外标法计算钩藤碱的浓度。并按下式计算包封率；
包封率(％)＝纳米粒沉淀中的钩藤碱量/钩藤碱的投料量*100％。
三、钩藤碱纳米粒的体外溶血实验
采用2％红细胞悬液体外溶血试管观察法，家兔心脏采血，分离红细胞后用0.9％氯化钠注射液配成2％浓度的红细胞悬液，按体外溶血试验方法依次加入钩藤碱纳米粒，未修饰吐温80的纳米粒，钩藤碱标准溶液和红细胞悬液、0.9％氯化钠注射液或5％葡萄糖注射液、纯水，于37±0.5℃孵箱中温育，分别于温育开始后进行肉眼观察，4h后离心，取上清液于545nm处测定吸光度，计算溶血率(％)。
四、钩藤碱纳米粒对小鼠微血管内皮细胞的毒性影响
通过体外细胞毒实验考察钩藤碱纳米粒对小鼠脑微血管内皮细胞(bEnd.3)有无影响。进行体外细胞实验：于-150℃冰箱取出脑微血管内皮细胞，37℃水浴迅速解冻，转入离心管中，加DMEM培养液10ml，1500rpm离心洗涤两次。然后转入培养瓶中，加入含青链霉素和10％胎牛血清的DMEM培养液，在37℃，5％CO2的孵箱中培养，细胞密度达70～80％时，用0.25％胰蛋白酶-0.02％EDTA消化液消化，收集对数生长期的细胞，制成适宜浓度的细胞悬液，取100ul接种于96孔培养板中，培养24h，细胞贴壁后，分成多个试验组加入药物①空白对照组；②钩藤碱原药；③空白载体(组装与未组装吐温80)④未组装吐温80钩藤碱的纳米粒；⑤组装吐温80负载钩藤碱体系。每个试验点设置6个复孔。37℃、5％CO2培育一定时间后，每孔加入MTT(5mg/ml)20ul继续培养4h，吸弃培养液，加入二甲基亚砜(DMSO)150ul，置振荡器振荡10min后，于酶标仪测定570nm波长处的吸光值(A)。重复试验三次。按下式计算细胞抑制率。
细胞生长抑制百分率(％)＝(1-(实验组A-无细胞培养液组A)/(空白细胞组A-无细胞培养液组A))×100％
五、钩藤碱纳米粒对小鼠微血管内皮细胞的摄取结果影响。
按照钩藤碱纳米粒的制备方法，采用具有荧光的红细胞膜荧光探针(DiD)代替钩藤碱，制备得到T80-NPS-DiD粒及各对照制剂。将bEnd.3细胞培养于24孔板内，摄取实验开始前，使用双无培养基将T80-NPS-DiD粒及各对照制剂的浓度稀释至25ng/mL。然后将24孔板中培养基移弃，使用HBSS平衡缓冲液清洗细胞1次，然后分别加入1mL双无培养基稀释的T80-NPS-DiD粒及各对照制剂，每组3个复孔；继续于培养箱中孵育1.5h，3h，5h，7h，9h；于相应时间点，移去培养基，PBS清洗3次，然后于流式细胞仪中检测摄取情况。
六、钩藤碱纳米粒对小鼠微血管内皮细胞模拟体外BBB渗透实验影响。
将bEnd.3细胞接种于24孔Transwell板的聚碳酸酯膜上；然后在Transwell板的基底侧(Basolateral side)加入1mL DMEM完全培养液，放入37℃，含5％CO2细胞培养箱内培养，每两天换一次培养液，培养两周后每日换液；继续培养至21天，采用细胞电阻仪测定跨上皮细胞电阻，确定其细胞单层的致密性和完整性，选用电阻值大于200Ω·cm2的孔进行实验。移弃上述符合要求的孔内培养基，用预热(37℃)的HBSS缓冲液(pH 7.35)清洗细胞2次，再在顶侧小室中加入500μl含血清的HBSS缓冲液，基底侧加入1500μl HBSS。然后将Transwell细胞板置于37℃孵箱中，转运30min、60min、120min、180min和270min，在设置的各时间点，分别取各组基底侧溶液200μl，收集于1.5mL EP管中，再补加200μl新鲜HBSS缓冲液于基底侧孔板中。取收集的基底侧溶液，加入甲醇消解，过膜于进样瓶中，测钩藤碱含量。
七、钩藤碱纳米粒对体内脑分布结果影响。
按照具体本发明制备方法制备载有荧光DiD的纳米粒，各取200μl尾静脉注射入小鼠体内，于两小时后，处死小鼠，快速解剖分离得到心、肝、脾、肺、肾、脑后，于小动物活体成像仪器拍照观察荧光分布情况。
八、钩藤碱纳米粒对体内药动学实验影响。
SD系大鼠18只,雌雄各半,体重200～250g，,随机分为3组,给药前禁食12h以上,自由饮水,3组分别尾静脉注射钩藤碱原药，未负载吐温80钩藤碱的纳米粒和负载吐温80负载钩藤碱体系。给药剂量为0.8mg·kg-1,给药后分别于5,15,30,60,120,240,480min断尾取血约0.5mL,5 000r·min-1离心10min分离血浆,备用。用乙腈沉淀蛋白后高速离心，过膜于进样瓶中，测钩藤碱的血药浓度。
以下通过具体实施例进行详细说明：
实施例1
取mPEG-PLGA(其中PLGA分子量为15kD，PEG分子量为2000LA/GA＝75:25)100mg，钩藤碱60mg溶于1ml N,N-二甲基甲酰胺中，涡旋混匀。在磁力搅拌器的作用下，缓慢滴入1％(w/v)PVA水溶液中，所得纳米粒混悬液高速离心后用磷酸缓冲溶液洗脱2次后，加入1％(w/v)吐温80缓慢搅拌30分钟后得脑靶向钩藤碱纳米制剂(钩藤碱-mPEG-PLGA-吐温80纳米粒)。
以实施例1为例，将上述验证产品性能结果详细说明如下：
如图1-2所示，实施例1钩藤碱纳米制剂中，包封率为60％，纳米粒粒径分布均匀，平均粒径为145nm。通过如图3所示的体外溶血实验，实施例1钩藤碱-mPEG-PLGA-吐温80纳米粒、未负载吐温80的纳米粒和钩藤碱标准溶液均没有溶血现象。如图4所示的小鼠微血管内皮细胞的毒性实验结果中，实施例1钩藤碱-mPEG-PLGA-吐温80纳米粒/空白载体、未负载吐温80的纳米粒/空白载体和钩藤碱原药对bEnd.3细胞均没有毒性作用。如图5a-5e所示的小鼠微血管内皮细胞的摄取实验(1.5h、3h、5h、7h、9h的曲线图)，从图中看：空白载体(实线)对bEnd.3细胞的摄取无时间依赖性。实施例1的钩藤碱-mPEG-PLGA-吐温80纳米粒(长虚线)和未负载吐温80的纳米粒(短虚线)对bEnd.3细胞的摄取呈时间依赖性，且实施例1的钩藤碱-mPEG-PLGA-吐温80纳米粒摄取效果最好。如图6所示的体外BBB(小鼠微血管内皮细胞模拟)渗透实验，相比游离钩藤碱溶液、未负载吐温80钩藤碱纳米粒，实施例1的钩藤碱-mPEG-PLGA-吐温80纳米粒穿透BBB的能力最强。如图7所示的小鼠体内钩藤碱纳米粒体内分布对比图显示：实施例1的钩藤碱-mPEG-PLGA-吐温80纳米粒在脑内荧光最显著，表示纳米粒能穿越BBB进入脑内。
实施例2
取mPEG-PLGA(其中PLGA分子量为3kD，PEG分子量为3000，LA/GA,50:50)60mg，钩藤碱20mg溶于1ml N,N-二甲基甲酰胺中，涡旋混匀。在磁力搅拌器的作用下，缓慢滴入1％(w/v)PVA水溶液中，所得纳米粒混悬液高速离心后用磷酸缓冲溶液洗脱2次后，加入1％(w/v)吐温80缓慢搅拌30分钟后得钩藤碱-mPEG-PLGA-吐温80纳米粒。平均粒径为170nm,包封率为49％。实验检测体外溶血实验未发生溶血现象，对bEnd.3细胞均没有毒性作用，纳米粒对bEnd.3细胞的摄取呈时间依赖性。体外BBB渗透实验和小鼠体内分布实验中，本实施例的钩藤碱纳米制剂具有较强的BBB穿透能力。
实施例3
取PLGA50mg，钩藤碱20mg溶于1ml氯仿中，涡旋混匀。在磁力搅拌器的作用下，缓慢滴入2％(w/v)维生素E聚乙二醇琥珀酸酯水溶液中，所得纳米粒混悬液高速离心后用磷酸缓冲溶液洗脱2次后，加入2％(w/v)吐温80缓慢搅拌30分钟后得钩藤碱-PLGA-吐温80纳米粒。平均粒径为167nm,包封率为51％。实验检测体外溶血实验未发生溶血现象，对bEnd.3细胞均没有毒性作用，纳米粒对bEnd.3细胞的摄取呈时间依赖性。体外BBB渗透实验和小鼠体内分布实验中，本实施例的钩藤碱纳米制剂具有较强的BBB穿透能力。
实施例4
取PLGA90mg，钩藤碱40mg溶于1ml氯仿中，涡旋混匀。在磁力搅拌器的作用下，缓慢滴入1％(w/v)维生素E聚乙二醇琥珀酸酯水溶液中，所得纳米粒混悬液高速离心后用磷酸缓冲溶液洗脱2次后，加入2％(w/v)吐温80缓慢搅拌30分钟后得钩藤碱-PLGA-吐温80纳米粒。平均粒径为190nm,包封率为39％。实验检测体外溶血实验未发生溶血现象，对bEnd.3细胞均没有毒性作用，纳米粒对bEnd.3细胞的摄取呈时间依赖性。体外BBB渗透实验和小鼠体内分布实验中，本实施例的钩藤碱纳米制剂具有较强的BBB穿透能力。
实施例5
取mPEG-PCL(其中PEG分子量为1000，PCL分子量为1000)60mg，钩藤碱20mg溶于1ml二氯甲烷中，涡旋混匀。在磁力搅拌器的作用下，缓慢滴入1％(w/v)泊洛沙姆188水溶液中，所得纳米粒混悬液高速离心后用磷酸缓冲溶液洗脱2次后，加入0.5％(w/v)吐温80缓慢搅拌30分钟后得钩藤碱-mPEG-PCL-吐温80纳米粒。平均粒径为150nm,包封率为55％。实验检测体外溶血实验未发生溶血现象，对bEnd.3细胞均没有毒性作用，纳米粒对bEnd.3细胞的摄取呈时间依赖性。体外BBB渗透实验和小鼠体内分布实验中，本实施例的钩藤碱纳米制剂具有较强的BBB穿透能力。
实施例6
取mPEG-PCL(其中PEG分子量为20000，PCL分子量为5000)80mg，钩藤碱40mg溶于1ml二氯甲烷中，涡旋混匀。在磁力搅拌器的作用下，缓慢滴入0.5％(w/v)脱水山梨醇单硬脂酸酯水溶液中，所得纳米粒混悬液高速离心后用磷酸缓冲溶液洗脱2次后，加入0.5％(w/v)吐温80缓慢搅拌30分钟后得钩藤碱-mPEG-PCL-吐温80纳米粒。平均粒径为146nm,包封率为45％。实验检测体外溶血实验未发生溶血现象，对bEnd.3细胞均没有毒性作用，纳米粒对bEnd.3细胞的摄取呈时间依赖性。体外BBB渗透实验和小鼠体内分布实验中，本实施例的钩藤碱纳米制剂具有较强的BBB穿透能力。
实施例7
取mPEG-PLGA((其中PLGA分子量为16kD，PEG分子量为4000，LA/GA50:50)LA/GA＝50：50)50mg，钩藤碱20mg溶于1ml N,N-二甲基甲酰胺中，涡旋混匀。在磁力搅拌器的作用下，缓慢滴入2％(w/v)聚氧乙烯蓖麻油甘油醚水溶液中，所得纳米粒混悬液高速离心后用磷酸缓冲溶液洗脱2次后，加入2％(w/v)吐温80缓慢搅拌30分钟后得钩藤碱-mPEG-PLGA-吐温80纳米粒。平均粒径为167nm,包封率为51％。实验检测体外溶血实验未发生溶血现象，对bEnd.3细胞均没有毒性作用，纳米粒对bEnd.3细胞的摄取呈时间依赖性。体外BBB渗透实验和小鼠体内分布实验中，本实施例的钩藤碱纳米制剂具有较强的BBB穿透能力。
实施例8
取mPEG-PLGA((其中PLGA分子量为10kD，PEG分子量为400，LA/GA60:30)LA/GA＝50：50)60mg，钩藤碱40mg溶于1ml N,N-二甲基甲酰胺中，涡旋混匀。在磁力搅拌器的作用下，缓慢滴入1％(w/v)聚氧乙烯蓖麻油甘油醚水溶液中，所得纳米粒混悬液高速离心后用磷酸缓冲溶液洗脱2次后，加入1％(w/v)转铁蛋白缓慢搅拌30分钟后得钩藤碱-mPEG-PLGA-转铁蛋白纳米粒。平均粒径为190nm,包封率为39％。实验检测体外溶血实验未发生溶血现象，对bEnd.3细胞均没有毒性作用，纳米粒对bEnd.3细胞的摄取呈时间依赖性。体外BBB渗透实验和小鼠体内分布实验中，本实施例的钩藤碱纳米制剂具有较强的BBB穿透能力。
上述实施例1-8中，靶向作用物质可以被乳铁蛋白、载脂蛋白、冰片、血管肽素、唾液酸或甘露糖替换，其作用相同，靶向效果与上述实施例相近。
实施例9
上述实施例1-8制备的钩藤碱纳米制剂，其粒度都在170nm以下，可以用于制备静脉注射药物。在静脉注射后5min，游离钩藤碱的血浆浓度-时间曲线(如图8所示)显示最大血药浓度为164.4ng/ml，然后迅速降低。与游离钩藤碱组相比，未负载吐温80钩藤碱纳米制剂组(536.3ng/mL)和负载吐温80钩藤碱纳米制剂组(673ng/mL)的最大血药浓度(Cmax)显著高于游离钩藤碱组。此外，负载吐温80钩藤碱纳米制剂组的血药浓度-时间曲线下面积(AUC)为412.63ng/mL*h，是游离钩藤碱组的3倍(136.06ng/mL*h)。此外,负载吐温80钩藤碱纳米制剂组(1938.76ml/h/kg)的清除率(CL)比游离钩藤碱(5912.78ml/h/kg)低，表明钩藤碱制成纳米制剂降低了药物从体内的清除速率，而暴露剂量增加，显著提高钩藤碱的生物利用度和药理作用。

Claims (10)

1.一种脑靶向钩藤碱纳米制剂，其特征在于，由以下质量百分含量的原料制成：钩藤碱0.1％～0.3％、嵌段聚合物0.3％～0.9％、靶向作用物质(w/v)0.5％～5％、非离子表面活性剂(w/v)0.5％～5％、其余为水；其中，嵌段聚合物为具有亲水性片段和疏水性片段的两亲性嵌段聚合物。
2.根据权利要求1所述的脑靶向钩藤碱纳米制剂，其特征在于，由以下质量百分含量的原料制成：钩藤碱0.2％～0.3％、嵌段聚合物0.5％～0.8％、靶向作用物质(w/v)1％～3％、非离子表面活性剂(w/v)0.5％～2％、其余为水。
3.根据权利要求1或2所述的脑靶向钩藤碱纳米制剂其特征在于，所述嵌段聚合物为PLGA、PCL或它们的衍生物。
4.根据权利要求3所述的脑靶向钩藤碱纳米制剂其特征在于，所述PLGA衍生物是mPEG-PLGA；其中PLGA分子量为3-16kD；LA/GA＝(50：50)-(75:25)；PEG分子量为400-4000；
所述PCL衍生物是mPEG-PCL，其中PCL分子量为1000-20000；PEG分子量为1000-5000。
5.根据权利要求1所述的脑靶向钩藤碱纳米制剂其特征在于，所述靶向作用物质为转铁蛋白、乳铁蛋白、载脂蛋白、葡萄糖、吐温80、冰片、血管肽素、唾液酸或甘露糖。
6.根据权利要求1所述的脑靶向钩藤碱纳米制剂其特征在于，所述的非离子表面活性剂为聚乙烯醇、维生素E聚乙二醇琥珀酸酯、聚氧乙烯蓖麻油甘油醚、脱水山梨醇单硬脂酸酯或泊洛沙姆188。
7.一种脑靶向钩藤碱纳米制剂的制备方法，其特征在于，包括如下步骤：
(1)称取以下质量百分含量的原料：钩藤碱0.1％～0.3％、嵌段聚合物0.3％～0.9％、靶向作用物质(w/v)0.5％～5％、非离子表面活性剂(w/v)0.5％～5％、其余为水；
(2)常温下，取嵌段共聚物和钩藤碱溶于有机溶剂中，按原料比例涡旋混匀得到混合溶液；将非离子表面活性剂溶于水缓慢滴加到混合溶液中，搅拌形成纳米混悬液；
(3)纳米混悬液离心10-20min后，缓冲溶液洗脱，即得载药嵌段共聚物纳米粒；
(4)搅拌下，将靶向作用物质加入所得的载药嵌段共聚物纳米粒中，缓慢搅拌20-40min，即得脑靶向钩藤碱纳米制剂。
8.根据权利要求1所述的脑靶向钩藤碱纳米制剂的制备方法，其特征在于，所述有机溶剂为二氯甲烷、氯仿、N,N-二甲基甲酰胺或二甲基亚砜。
9.根据权利要求1所述的脑靶向钩藤碱纳米制剂的制备方法，其特征在于，所述PLGA衍生物是mPEG-PLGA，其中，PLGA分子量为3-16kD；LA/GA＝(50：50)-(75:25)；PEG分子量为400-4000；
所述PCL衍生物是mPEG-PCL，其中，PCL分子量为1000-20000；PEG分子量为1000-5000。
10.一种脑靶向钩藤碱纳米制剂在制备静脉注射药物中的应用。
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