CN115177589A - 一种紫杉醇脑靶向脂质体和其制备方法及应用 - Google Patents
一种紫杉醇脑靶向脂质体和其制备方法及应用 Download PDFInfo
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- CN115177589A CN115177589A CN202110373409.8A CN202110373409A CN115177589A CN 115177589 A CN115177589 A CN 115177589A CN 202110373409 A CN202110373409 A CN 202110373409A CN 115177589 A CN115177589 A CN 115177589A
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- cholesterol
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Abstract
本发明涉及药物制剂领域,涉及一种紫杉醇脑靶向脂质体及其制备方法和应用。具体公开了一种紫杉醇脑靶向脂质体,其特征在于,包括紫杉醇胆固醇复合物和脂质体材料,脂质体材料包括磷脂、胆固醇、磷脂‑聚乙二醇、磷脂‑聚乙二醇‑狂犬病毒衍生肽聚合物、葡萄糖,在所述紫杉醇胆固醇复合物中紫杉醇与胆固醇的重量比例为1:0.1~1:1,优选1:0.2~1:0.5。所述紫杉醇脑靶向脂质体通过表面修饰RVG15肽显著提高药物的血脑屏障透过率,具有较好的脑靶向性,从而实现紫杉醇入脑治疗脑胶质瘤的目的。本发明同时提供了一种紫杉醇脑靶向脂质体制备方法,方法简单可行,生产成本较低,制得的脂质体跨血脑屏障效率较高,毒性较小,具有较好的临床应用前景。
Description
技术领域
本发明涉及涉及一种紫杉醇脑靶向脂质体及其制备方法,本发明还涉及该紫杉醇脑靶向脂质体的用途,属医药制剂技术领域。
背景技术
脑胶质瘤是最常见的脑部肿瘤之一,其对躯体和认知可引起复杂的损害。但由于血脑屏障(blood brain barrier,BBB)的存在,治疗难度较大。血脑屏障是由脑毛细血管内皮细胞、星形胶质细胞的终足、周细胞及血管基膜共同构成的严密结构。与其他组织相比,BBB几乎没有细胞间隙,从而有效地限制溶质或药物的细胞外扩散。除此之外,BBB上还存在高效的外排系统,如P-糖蛋白等。这种严密的结构限制了外部生物体和有毒化学物质通过BBB从而保护大脑,但是这种严密的天然屏障也使得98%的小分子药物和几乎所有的大分子药物难以入脑,因此BBB是药物有效运送到脑部病灶的主要障碍。紫杉醇(paclitaxel,Taxol)具有重要的抗肿瘤活性,是目前临床上应用最广泛的化疗药物之一。但由于紫杉醇不能透过血脑屏障,限制了其在脑肿瘤上的应用。因此,开发一种能够显著改善紫杉醇(及其它化疗药物)对BBB的渗透性和在脑肿瘤组织聚集的药物释放系统具有很高的临床应用价值。
针对脑靶向治疗的瓶颈问题,目前有很多新的穿血管肽被开发出来,它们能特异性穿过脑血管进入脑组织,因此通过这些肽可以将效果非常好但不能穿过BBB的治疗药物递送进入大脑,扩大了脑部疾病的治疗领域。狂犬病毒糖蛋白衍生的29肽(RVG29)可与神经细胞表达的n型乙酰胆碱受体(nAchR)特异性结合,从而特异性的穿过BBB,进入大脑。但由于RVG29肽链过长,不利于制备粒径较小的纳米粒,课题组前期对狂犬病毒糖蛋白衍生肽进行了重新筛选,得到一条与RVG29活性相当且长度相对较短的15肽片段RVG15,其脑靶向效率与RVG29肽相当,肽链长度减小一半,更有利于形成小粒径纳米粒,且极大的节约了生产工序和成本,便于实现脑靶向递送的临床应用。本课题组前期构建了RVG15肽修饰的脑靶向载体递送核酸入脑,用于脑胶质瘤的治疗,体内外研究均得到较好效果,相关研究成果已申请专利(黄伟.一种狂犬病毒糖蛋白衍生肽修饰的脑靶向核酸递送载体及其应用:中国,201710277357.8[P].2017-4-25.)。本课题组前期还构建了具有血脑屏障穿透功能的磷脂-聚乙二醇-狂犬病毒衍生肽(DSPE-PEG-RVG-15),其作为药物递送载体,递送DOX入脑,用于脑胶质瘤的治疗,所得的纳米粒粒径较小,跨血脑屏障效率较高,高效低毒,具有较好的发展前景,相关研究成果已申请专利(黄伟.一种磷脂-聚乙二醇-狂犬病毒衍生肽聚合物,其制备方法及应用:中国,201810833188.6[P].2018-7-25.)。
脂质体(liposome)是由磷脂双分子定向排列而成的封闭囊状结构,主要以磷脂与胆固醇为骨架,将药物包封于类脂双分子层中或内核所形成的超微型球状体。由于其生物相容性和生物可降解性,脂质体具有透过BBB和延长体内循环时间的能力。由于其亲水性和疏水性组分,脂质体可以包封水溶性和亲脂性药物,从而增加药物在体内的生物利用度。由于这些独特优良的性质,脂质体已被广泛用作纳米载体穿过BBB用于治疗各种脑部疾病。脂质体穿过BBB的机制可能是通过亲脂内皮细胞的被动扩散,内吞作用或与脑毛细血管内皮细胞融合等。
本发明构建了狂犬病毒糖蛋白衍生肽RVG15修饰的脑靶向脂质体,可包载递送紫杉醇入脑,达到治疗脑胶质瘤的目的。除此之外,还对那些体外有效但体内难以透过BBB的药物入脑治疗脑部疾病提供了一种新策略。
发明内容
本发明解决的技术问题是提供一种紫杉醇脑靶向脂质体,其制备方法,以及在制备治疗脑胶质瘤的药物中的用途。
为解决本发明的技术问题,本发明提供了如下技术方案:
本发明技术方案的第一方面是提供了一种紫杉醇脑靶向脂质体,其包含紫杉醇胆固醇复合物、磷脂、胆固醇、磷脂-聚乙二醇、磷脂-聚乙二醇-狂犬病毒衍生肽聚合物、葡萄糖,在所述紫杉醇胆固醇复合物中紫杉醇与胆固醇的重量比例为1:0.1~1:1,优选1:0.2~1:0.5。
在本发明中,所述紫杉醇胆固醇复合物,按重量百分数计算,占脂质体材料的0.1%-50%,优选1%-10%。
在本发明中,所述的脂质体中的磷脂包括所有类型的磷脂,包括但不限于大豆磷脂、卵磷脂、磷脂酰乙醇胺、磷酯酰丝氨酸、磷脂酰肌醇、磷脂酰甘油、二磷脂酰甘油;优选卵磷脂,更优选大豆卵磷脂。
在本发明中,所述的脂质体中的胆固醇,按重量百分数计算,占脂质体材料的0.1%-50%,优选2.5%-25%。
在本发明中,所述的脂质体中的磷脂-聚乙二醇,按重量百分数计算,占脂质体材料的1%-80%,优选10%-30%。
在本发明中,所述的脂质体中的磷脂-聚乙二醇-狂犬病毒衍生肽聚合物中的狂犬病毒衍生肽RVG15的序列为Tyr Thr Ile Trp Cys Asp Ile Phe Thr Asp Ser Arg GlnLys Arg,按重量百分数计算,所述的脂质体中的磷脂-聚乙二醇-狂犬病毒衍生肽聚合物占脂质体材料的1%-80%,优选10%-30%。
在本发明中,所述的脂质体中的葡萄糖为5%葡萄糖注射液。
本发明技术方案的第二方面是提供了第一方面所述的紫杉醇脂质体的制备方法,其特征在于,包括如下步骤:将紫杉醇与胆固醇,按所述比例混合,加入适量有机溶剂溶解,在合适的温度条件下搅拌,在合适的温度条件下旋蒸除去有机溶剂,真空干燥得到紫杉醇胆固醇复合物;按处方比例称取紫杉醇胆固醇复合物,大豆卵磷脂,胆固醇,磷脂-聚乙二醇,磷脂-聚乙二醇-狂犬病毒衍生肽聚合物,溶于氯仿至完全溶解成澄清的溶液,经0.22μm滤膜除菌过滤后加入旋转瓶中置恒温水浴(40℃±2℃)进行减压成干燥脂质膜;将上述形成脂质膜的旋转瓶放入真空干燥箱中,在40℃条件下真空干燥1-2小时;在上述形成脂质膜的旋转瓶内加入5%葡萄糖溶液,在40℃水浴条件下进行水化至混悬液无肉眼可见不溶物,然后将水化液体经冰水浴探头超声,用挤压过膜或超声等方法进行整粒,得到符合粒径要求的紫杉醇脑靶向脂质体混悬液。
本发明技术方案的第三方面是提供了本发明第一方面所述的紫杉醇脑靶向脂质体在制备治疗脑胶质瘤的药物中的用途。
本发明提供的紫杉醇脑靶向脂质体特别地具有如下的优点:
1)本发明制备的紫杉醇脑靶向脂质体具有包封率高,稳定性好的优点。
2)本发明制备的紫杉醇脑靶向脂质体具有血脑屏障渗透性好、生物相容性好和体内长循环的优点,从而能有效提高紫杉醇对脑胶质瘤的治疗效果。
3)本发明制备的紫杉醇脑靶向脂质体具有安全性好,耐受剂量大的优点。与市售普通注射液相比,本发明提供的脂质体不含乙醇和Cremphor EL,降低了紫杉醇制剂的血管刺激性和毒副作用,提高安全性,增大耐受剂量。
附图说明
图1:紫杉醇脑靶向脂质体的动态光散射(DLS)粒径分布图
图2:紫杉醇脑靶向脂质体的动态光散射(DLS)电位图
图3:紫杉醇脑靶向脂质体的透射电镜图
图4:紫杉醇脑靶向脂质体体外释放曲线
图5:脑靶向脂质体溶血实验结果图
图6:脑靶向脂质体对大鼠神经胶质瘤C6细胞毒性实验结果图
图7:脑靶向脂质体对人脑微血管内皮HBMEC细胞毒性实验图
图8:紫杉醇注射液对大鼠神经胶质瘤C6细胞的增殖抑制结果图
图9:紫杉醇脑靶向脂质体对大鼠神经胶质瘤C6细胞的增殖抑制结果图
图10:香豆素6标记的脂质体在大鼠神经胶质瘤C6细胞的摄取情况
图11:香豆素6标记的脂质体在大鼠神经胶质瘤C6细胞的摄取情况
图12:荷C6-luc脑胶质瘤小鼠注射载DiR的脂质体后各时间点的活体成像图
图13:荷C6-luc脑胶质瘤小鼠注射载DiR的脂质体后各时间点的的荧光强度定量图
具体实施方式
以下实施例旨在说明本发明而不是对本发明的进一步限定。下面参照实施例进一步详细阐述本发明,但本发明并不限于这些实施例以及使用的制备方法。而且,本领域技术人员根据本发明的描述可以对本发明进行等同替换、组合、改良或修饰,但这些都将包括在本发明的范围内。
实施例1:紫杉醇胆固醇复合物的制备
表1为紫杉醇胆固醇复合物的组成:
按上述处方量称取紫杉醇和胆固醇,置于具塞三角瓶中,加入丙酮1000ml将其溶解,在50℃温度条件下搅拌2小时,转移至旋转蒸发仪中,旋转蒸发去除丙酮,在50℃温度条件下真空干燥15小时,得到紫杉醇胆固醇复合物。
实施例2:紫杉醇脑靶向脂质体的制备
表2为紫杉醇脑靶向脂质体的处方组成:
制备方法:在100ml茄形瓶中,将10.4mg紫杉醇胆固醇复合物、293mg大豆卵磷脂、14.7mg胆固醇、19.12mg磷脂-聚乙二醇与33.18mg磷脂-聚乙二醇-狂犬病毒衍生肽聚合物溶于6ml氯仿至完全溶解成澄清的溶液,经0.22μm滤膜除菌过滤后加入旋转瓶中置恒温水浴(40℃±2℃)进行减压成干燥脂质膜;将上述形成脂质膜的旋转瓶放入真空干燥箱中,在40℃条件下真空干燥1-2小时;在上述形成脂质膜的旋转瓶内加入5%葡萄糖溶液,在40℃水浴条件下进行水化至混悬液无肉眼可见不溶物,然后将水化液体经冰水浴探头超声进行整粒,得到符合粒径要求的紫杉醇脑靶向脂质体。
紫杉醇脑靶向脂质体的物理性质:粒径:以动态光散射法测定,为129.3nm,PDI为0.288;电位:以动态光散射法测定,为-16.1mV;包封率:经高效液相色谱法测定,为98.76%;载药量:经高效液相色谱法测定,为1.52%。
实施例3:紫杉醇脑靶向脂质体体外释放度的测定
将紫杉醇脑靶向脂质体溶液0.5ml(含紫杉醇0.6mg)转移至透析袋中,两端扎紧后置于30ml的含有0.5%吐温80的pH 7.4等渗PBS缓冲液中,以中国药典2015版四部溶出度测定法之第三法(小杯法)的装置和方法,37℃恒温振荡,回旋速度为100rpm。在2、4、6、8、10、12、24、30、36、48、60、72、96h定时取出0.5ml释放介质,同时补充同温同体积新鲜释放介质。取出的释放介质离心(12000rpm,10min)后,应用高效液相色谱法测定紫杉醇的累积含量,同法测定市售紫杉醇注射液体外释放度。
表3为释放度数据:
结果如图4所示,结果显示,在pH7.4释放介质中,紫杉醇注射液组药物释放在24h已达到37.86%,而纳米粒在24h药物释放为20.01%,脂质体的药物释放明显慢于市售紫杉醇注射液,呈缓释效果。
实施例4:脑靶向脂质体的溶血实验
用眼眶取血的方法取新鲜ICR小鼠血液,用竹签迅速搅拌除去纤维蛋白后,加0.9%生理盐水于转速为1200rpm离心机离心洗涤15min,反复数次直至上清液不显红色为止,所得红细胞用0.9%生理盐水配制成2%(v/v)的红细胞混悬液,临用时摇匀,实验时新鲜配制。
取空白脑靶向脂质体制剂,以0.9%生理盐水分别稀释成浓度为0.1、0.25、0.5、0.75、1mg/ml的溶液,各取200μl,另取同体积新鲜蒸馏水作为阳性对照管,取同体积0.9%生理盐水作为阴性对照管。向上述各管中分别加入2%红细胞混悬液200μl,轻轻摇匀后置37℃的水浴中保温1h,后取出Ep管,将取出的Ep管1200rpm离心15min,吸取上清液在575nm处测定各管溶液的吸光度(A)。根据下式计算各浓度溶血度:
溶血度(%)=[(A样品-A阴性)/(A阳性-A阴性)]×100
表4为各个浓度空白脑靶向脂质体的溶血情况
浓度(mg/ml) | 0.1 | 0.25 | 0.5 | 0.75 | 1 |
溶血度(%) | 1.65±0.25 | 1.97±0.14 | 2.43±0.16 | 2.81±0.10 | 3.24±0.11 |
图5与表4表明,空白脑靶向脂质体在浓度为0.1,0.25,0.5,0.75和1mg/ml时均不存在溶血现象,溶血度均小于5%,表明该空白胶束具有良好的安全性和相容性。
实施例5:材料的细胞毒性研究
将空白脑靶向脂质体制剂用培养液稀释成预定浓度的溶液。每个浓度设6个复孔,并设对照组和调零组。将大鼠神经胶质瘤C6细胞、人脑微血管内皮HBMEC细胞以3×103个/孔的密度接种于96孔板中,继续培养24h后,介质以含有0.0001、0.001、0.01、0.05、0.1、1、10μg/ml的空白胶束浓度的新鲜培养液替换,分别继续培养24h或48h。每孔加入CCK-8试剂20μl。继续孵育1-4h,于450nm处测定吸收值,并以650nm为参考波长。计算细胞活力,公式如下:
细胞活力(%)=[(OD实验-OD调零)/(OD对照-OD调零)]×100
表5为空白脑靶向脂质体对大鼠神经胶质瘤C6细胞的增殖抑制情况
表6为空白脑靶向脂质体对人脑微血管内皮HBMEC细胞的增殖抑制情况
图6-7与表5-6表明,空白脑靶向脂质体在所测定的浓度范围内,C6、HMBEC细胞的活力均在85%以上,表明材料本身对细胞毒性较小。说明本专利提供的脑靶向脂质体在安全性方面存在优势。
实施例6:细胞增殖抑制的研究
将紫杉醇注射液和紫杉醇脑靶向脂质体用培养液稀释成预定浓度的溶液。每个浓度设6个复孔,并设对照组和调零组。将大鼠神经胶质瘤C6细胞以3×103个/孔的密度接种于96孔板中,继续培养24h后,介质以含有0.01、0.05、0.1、1、10、50μg/ml的空白胶束浓度的新鲜培养液替换,分别继续培养24h或48h。每孔加入CCK-8试剂20μl。继续孵育1-4h,于450nm处测定吸收值,并以650nm为参考波长。计算细胞活力和细胞增殖抑制率,公式如下:
细胞增殖抑制率(%)=[1-(OD实验-OD调零)/(OD对照-OD调零)]×100
表7为紫杉醇注射液对大鼠神经胶质瘤C6细胞的增殖抑制情况
表8为紫杉醇脑靶向脂质体对大鼠神经胶质瘤C6细胞的增殖抑制情况
图8-9与表7-8表明,在药物浓度为0.01-50μg/mL的范围中,紫杉醇脑靶向脂质体对细胞的增殖抑制强于市售紫杉醇注射液。
实施例7:香豆素6标记的脑靶向脂质体的制备
按上述实施例1中脂质体的制备方法,制备香豆素6标记的脂质体。称取处方量的大豆卵磷脂、胆固醇、磷脂-聚乙二醇和磷脂-聚乙二醇-狂犬病毒衍生肽聚合物(未修饰的脂质体不加聚合物)溶于氯仿至完全溶解成澄清的溶液,再向其中加入一定量的香豆素6氯仿溶液,使最终香豆素6的浓度约为10μg/ml或50μg/ml,经0.22μm滤膜除菌过滤后加入旋转瓶中置恒温水浴(40℃±2℃)进行减压成干燥脂质膜;将上述形成脂质膜的旋转瓶放入真空干燥箱中,在40℃条件下真空干燥1-2小时;在上述形成脂质膜的旋转瓶内加入5%葡萄糖溶液,在40℃水浴条件下进行水化至混悬液无肉眼可见不溶物,然后将水化液体经冰水浴探头超声进行整粒,即得香豆素6标记的脂质体Cou-6-Lip、Cou-6-RVG15-Lip。
实施例8:流式细胞仪考察脂质体细胞摄取效率
利用流式细胞仪定量考察RVG15修饰的脑靶向脂质体进入细胞的能力。将人脑微血管内皮HBMEC以1.5×105个细胞/孔接种于12孔板中,于37℃、5%CO2培养箱中培养24小时,待细胞贴壁后,弃去培养基,将游离Cou-6、Cou-6-Lip和Cou-6-RVG15-Lip用无血清培养基稀释后分别加入到孔板内,使最终Cou-6的浓度为1μg/ml,再置于37℃、5%CO2培养箱中继续孵育4小时,每组设置3个复孔。培养结束后,用冷PBS缓冲液洗两次,胰酶消化后500g离心5min收集细胞,PBS重悬后用流式细胞仪检测细胞摄取情况。
摄取结果如图10所示。由摄取结果可见,RVG15修饰的脂质体配体能一定程度上增加人脑微血管内皮HBMEC对脂质体的摄取,与无修饰的脂质体相比,增加了2.06倍。
实施例9:激光共聚焦显微镜观察脂质体入胞情况
利用激光共聚焦显微镜定性观察人脑微血管内皮HBMEC对RVG15修饰的脑靶向脂质体的摄取情况。将HBMEC以1.5×105个细胞/孔接种于底部预先放置细胞爬片的12孔板中,在37℃、5%CO2培养箱中培养24小时,待细胞贴壁后,将游离Cou-6、Cou-6-Lip和Cou-6-RVG15-Lip用无血清培养基稀释后分别加入到孔板内,使最终Cou-6的浓度为5μg/ml,再置于37℃、5%CO2培养箱中培养4小时。培养结束后,弃去培养液并用PBS清洗两次,4%多聚甲醛避光固定20分钟,PBS清洗后用DAPI工作液染核15min,最终用PBS清洗后取出12孔板底部细胞爬片置于载玻片上,抗荧光淬灭剂处理后用激光共聚焦显微镜观察,结果如图11所示。
结果表明,RVG15修饰的脂质体能一定程度上增加人脑微血管内皮HBMEC对脂质体的摄取。
实施例10:DiR标记的脑靶向脂质体的制备
按上述实施例1中脂质体的制备方法,制备DiR标记的脂质体。称取处方量的大豆卵磷脂、胆固醇、磷脂-聚乙二醇和磷脂-聚乙二醇-狂犬病毒衍生肽聚合物(未修饰的脂质体不加聚合物)溶于氯仿至完全溶解成澄清的溶液,再向其中加入一定量的DiR乙醇溶液,使最终DiR的浓度约为1μg/ml,经0.22μm滤膜除菌过滤后加入旋转瓶中置恒温水浴(40℃±2℃)进行减压成干燥脂质膜;将上述形成脂质膜的旋转瓶放入真空干燥箱中,在40℃条件下真空干燥1-2小时;在上述形成脂质膜的旋转瓶内加入5%葡萄糖溶液,在40℃水浴条件下进行水化至混悬液无肉眼可见不溶物,然后将水化液体经冰水浴探头超声进行整粒,即得DiR标记的脂质体DiR-Lip、DiR-RVG15-Lip。
实施例11:脑靶向脂质体在体内透过血脑屏障的效率
取4周龄的ICR小鼠,荷C6-luc脑胶质瘤小鼠模型建立7天后,将小鼠随机分为3组,每组3只,按DiR 10μg/kg的剂量分别尾静脉200μl的实施例10制备的DiR-Lip、DiR-RVG15-Lip以及生理盐水。给药后1、4、8和24h,将小鼠用异氟烷麻醉,用小动物活体成像仪观察体内荧光现象。结果见图12(每组分别选取一只代表性小鼠拍照)、图13。
表9为ICR小鼠脑部荧光强度值。
由表9及图12-13可知,与无靶头的脂质体相比,以RVG15肽修饰的脂质体在1、4、8、24h内脑内荧光强度均显著高于无靶头的脂质体,两组载DiR胶束在脑内荧光强度具有显著性差异,给药后1h、4h、8h和24h,RVG15肽修饰的脂质体在脑内的药物浓度分别是未修饰的脂质体的2.70、3.59、4.28、3.00倍。表明RVG15肽连接到脂质体上后可显著提高纳脂质体穿透血脑屏障的能力,确证了RVG15肽修饰的脂质体具有脑靶向性。
Claims (9)
1.一种紫杉醇脑靶向脂质体,其特征在于,包括紫杉醇胆固醇复合物和脂质体材料,脂质体材料包括磷脂、胆固醇、磷脂-聚乙二醇、磷脂-聚乙二醇-狂犬病毒衍生肽聚合物、葡萄糖,在所述紫杉醇胆固醇复合物中紫杉醇与胆固醇的重量比例为1:0.1~1:1,优选1:0.2~1:0.5。
2.根据权利要求1所述的紫杉醇脑靶向脂质体,其特征在于:按重量百分数计算,所述紫杉醇胆固醇复合物占脂质体材料的0.1%-50%,优选1%-10%。
3.根据权利要求1所述的紫杉醇脑靶向脂质体,其特征在于:所述的脂质体中的磷脂包括所有类型的磷脂,包括大豆磷脂、卵磷脂、磷脂酰乙醇胺、磷酯酰丝氨酸、磷脂酰肌醇、磷脂酰甘油、二磷脂酰甘油。
4.根据权利要求1所述的紫杉醇脑靶向脂质体,其特征在于:按重量百分数计算,所述的脂质体中的胆固醇占脂质体材料的0.1%-50%,优选2.5%-25%。
5.根据权利要求1所述的紫杉醇脑靶向脂质体,其特征在于:按重量百分数计算,所述的脂质体中的磷脂-聚乙二醇占脂质体材料的1%-80%,优选10%-30%。
6.根据权利要求1所述的紫杉醇脑靶向脂质体,其特征在于:所述的脂质体中的磷脂-聚乙二醇-狂犬病毒衍生肽聚合物中的狂犬病毒衍生肽RVG15的序列为Tyr Thr Ile TrpCys Asp Ile Phe Thr Asp Ser Arg Gln Lys Arg,按重量百分数计算,所述的脂质体中的磷脂-聚乙二醇-狂犬病毒衍生肽聚合物占脂质体材料的1%-80%,优选10%-30%。
7.根据权利要求1所述的紫杉醇脑靶向脂质体,其特征在于:所述的脂质体中的葡萄糖为5%葡萄糖注射液。
8.权利要求1-6任一所述的紫杉醇脂质体的制备方法,其特征在于,包括如下步骤:将紫杉醇与胆固醇,按所述比例混合,加入适量有机溶剂溶解,在合适的温度条件下搅拌,在合适的温度条件下旋蒸除去有机溶剂,真空干燥得到紫杉醇胆固醇复合物;按处方比例称取紫杉醇胆固醇复合物,大豆卵磷脂,胆固醇,磷脂-聚乙二醇,磷脂-聚乙二醇-狂犬病毒衍生肽聚合物,溶于氯仿至完全溶解成澄清的溶液,经0.22μm滤膜除菌过滤后加入旋转瓶中置恒温水浴40℃±2℃进行减压成干燥脂质膜;将上述形成脂质膜的旋转瓶放入真空干燥箱中,在40℃条件下真空干燥1-2小时;在上述形成脂质膜的旋转瓶内加入5%葡萄糖溶液,在40℃水浴条件下进行水化至混悬液无肉眼可见不溶物,然后将水化液体经冰水浴探头超声,用挤压过膜或超声等方法进行整粒,得到符合粒径要求的紫杉醇脑靶向脂质体混悬液。
9.权利要求1-7任一所述的紫杉醇脑靶向脂质体在制备治疗脑胶质瘤的药物中的用途。
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