CN113698589B - 一种维生素e琥珀酸酯磷脂化合物及其应用 - Google Patents
一种维生素e琥珀酸酯磷脂化合物及其应用 Download PDFInfo
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- CN113698589B CN113698589B CN202111017565.7A CN202111017565A CN113698589B CN 113698589 B CN113698589 B CN 113698589B CN 202111017565 A CN202111017565 A CN 202111017565A CN 113698589 B CN113698589 B CN 113698589B
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- polyethylene glycol
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- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 18
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Classifications
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- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
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Abstract
本发明属于药物制剂技术领域,具体公开了一种维生素E琥珀酸酯磷脂化合物及其应用,在该化合物中,磷脂酸分子的两条长脂肪酸链中的至少一条被维生素E琥珀酸酯取代,磷酸基团上的一个氢原子可被聚乙二醇醚取代,另一个氢原子可被胆碱、乙醇胺或肌醇取代,该化合物具有两亲性,能起到生物表面活性剂的作用,在药物制剂中可作为增溶剂、吸收促进剂、乳化剂以及水难溶性和脂溶性药物传递系统载体。本发明维生素E琥珀酸酯磷脂化合物制得的纳米载药系统包封率高、稳定性好,且安全可靠,适合推广应用。
Description
技术领域
本发明属于药物制剂技术领域,更具体地,涉及一种维生素E琥珀酸酯磷脂化合物及其应用。
背景技术
表面活性剂被放置到溶液中后,会迅速降低溶液的界面张力,但是随着量的增加,表面活性剂分子在水溶液表面的浓度呈上升趋势,饱和后,如果继续加入表面活性剂,此时溶液的界面张力不再发生变化。表面活性剂分子这时就会迅速转入溶液内部,从而形成亲水基向外疏水基向内的表面活性剂分子缔合体,称之为胶束(micelles)。胶束是一种热力学稳定体系,在药学中被广泛用于难溶性药物的增溶,经增溶后的药物可达到临床治疗所需浓度,从而提高生物利用度。
磷脂是生物膜的组成成分,生物体内存在其相关分解酶,很容易代谢,因而磷脂具有生物降解性和生物兼容性,磷脂分子中的两条长脂肪酸链使之具有疏水性。然而,磷脂分子量较小,形成的囊泡和胶束稳定性不够,作为长循环和缓释材料的应用方面受到很大的限制。目前的解决办法是在其中加入含有长循环的组分:聚乙二醇(PEG)、多聚糖、环糊精等成为长循环磷脂,以提高磷脂胶束或胶囊的稳定性。已有文章报道了不同链长的PEG形成的聚乙二醇-二硬脂酰基磷脂酰乙醇胺(PEG-DSPE)胶束的特性。
维生素E琥珀酸聚乙二醇酯(TPGS)是维生素E的水溶性衍生物,由亲水的极性聚乙二醇头和亲酯的非极性维生素E琥珀酸酯尾组成,临界胶束浓度为0.026%,HLB值(Hydrophile-Lipophile Balance Number,亲水亲油平衡值)为13。TPGS最早由Eastman公司于1950年开发上市,并且被美国药典收载为药用辅料。但TPGS自身药物包封率和胶束稳定性不佳,限制了其在难溶性药物传递系统载体中的应用。
发明内容
针对现有技术的缺陷,本发明的目的在于提供一种维生素E琥珀酸酯磷脂化合物及其应用,该化合物是一种两亲性生物表面活性剂,制成粒径为10nm-1000nm的纳米颗粒,可作为增溶剂、吸收促进剂、乳化剂以及水难溶性和脂溶性药物传递系统载体,旨在解决现有的表面活性剂自身药物包封率和胶束稳定性不佳的问题。
为实现上述目的,本发明提供了一种维生素E琥珀酸酯磷脂化合物,该化合物的结构式如下所示:
其中,R1是维生素E琥珀酸酯;
R2是维生素E琥珀酸酯或羟基;
R3是聚乙二醇醚或氢原子;
X是胆碱、乙醇胺、肌醇或氢原子。
优选地,所述聚乙二醇醚为mPEG200、mPEG400、mPEG600、mPEG800、mPEG1000、mPEG1500、mPEG2000或mPEG4000。
按照本发明的另一方面,提供了一种维生素E琥珀酸酯磷脂化合物的制备方法,其包括如下步骤:将维生素E琥珀酸酯与溶血磷脂溶解于有机溶剂中,并加入二环己基碳二亚胺和4-二甲氨基吡啶进行避光反应,反应结束后除去有机溶剂,纯化制得维生素E琥珀酸酯-溶血磷脂酰偶联物。
优选地,所述制备方法还包括如下步骤:
S1、将所述维生素E琥珀酸酯-溶血磷脂酰偶联物溶于有机溶剂中,加入氢化钠进行反应,反应结束后除去有机溶剂和过量的氢化钠,纯化制得维生素E琥珀酸酯-溶血磷脂酸钠;
S2、取聚乙二醇醚溶于有机溶液中得到混合物A,在三乙胺中加入对甲苯磺酰氯得到混合物B,将混合物A和混合物B混合反应,反应结束后萃取,并除去有机溶液,纯化制得聚乙二醇醚对甲苯磺酸酯;
S3、将步骤S1制得的维生素E琥珀酸酯-溶血磷脂酸钠和步骤S2制得的聚乙二醇醚对甲苯磺酸酯混合反应,纯化制得聚乙二醇醚-维生素E琥珀酸酯磷脂化合物。
优选地,所述溶血磷脂为溶血磷脂酰胆碱、溶血磷脂酰乙醇胺、溶血磷脂酰肌醇或溶血磷脂酸。
按照本发明的另一方面,提供了上述维生素E琥珀酸酯磷脂化合物在制备抗肿瘤药物中的应用。
按照本发明的另一方面,提供了一种纳米载药系统,其以上述维生素E琥珀酸酯磷脂化合物作为药物载体。
优选地,该纳米载药系统为脂质体、纳米粒或纳米胶束。
优选地,该纳米载药系统是通过直接溶解法、熔融法、溶剂蒸发法或透析法,将所述维生素E琥珀酸酯磷脂化合物与水难溶性药物自组装形成的载药纳米胶束。
优选地,所述纳米载药系统的粒径为10nm-1000nm。
总体而言,通过本发明所构思的以上技术方案与现有技术相比,具有以下有益效果:
(1)本发明化合物对磷脂酸三处进行修饰,一是PEG修饰,改善化合物亲水性,增强长循环功能;二是进行维生素E琥珀酸酯修饰,改善化合物亲脂性,有利于包载疏水性物质,三是在磷脂的磷酸基团修饰成卵磷脂或脑磷脂等,进一步提高其水溶性,该化合物临界胶束浓度低,作为载体包载难溶性药物包封率高,稳定性好。
(2)本发明利用溶血磷脂的强表面活性,通过天然可降解生物材料维生素E琥珀酸酯与溶血磷脂的缩合反应制备两亲性表面活性剂,制备工艺简单,均采用生物安全性材料,反应条件温和,适合大规模生产应用;同时以该表面活性剂作为递药载体提高体内安全性,降低其溶血性。
(3)本发明采用维生素E琥珀酸酯磷脂化合物作为递药载体适于包载多种水难溶性药物,并可制备成多种剂型,其包封率高,稳定性好,可有效提高药物的疗效。
附图说明
图1是本发明实施例1提供的维生素E琥珀酸双酯-溶血磷脂酰偶联物合成路线示意图;
图2是本发明实施例4制备的多西他赛-VES-lyso-mPEG纳米胶束溶液的电镜图。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白,以下结合附图及实施例,对本发明进行进一步详细说明。应当理解,此处所描述的具体实施例仅仅用以解释本发明,并不用于限定本发明。
本发明提供的一种维生素E琥珀酸酯磷脂化合物,其结构式如下所示:
其中,R1是维生素E琥珀酸酯;
R2是维生素E琥珀酸酯或羟基;
R3是聚乙二醇醚或氢原子;
X是胆碱、乙醇胺、肌醇或氢原子。
表面活性剂的包封率、稳定性与其化学结构密切相关,表面活性剂作为两亲性物质,含有亲水基团和疏水基团。本发明化合物对磷脂酸三处进行修饰:R1、R2用维生素E琥珀酸酯进行修饰,改善化合物的亲脂性,有利于包载疏水性物质;R3用聚乙二醇醚进行修饰,改善化合物的亲水性,提高其长循环效应;X用含羟基的物质进行修饰,可以进一步提高其水溶性。本发明对磷脂酸的亲水头部和疏水尾部分别做了修饰,增强了表面活性剂的两亲性,有助于提高其作为载体包载难溶药物的包封率和稳定性,且临界胶束浓度低。
一些实施例中,上述结构式中的R3优选为聚乙二醇醚,聚乙二醇醚可以为mPEG200、mPEG400、mPEG600、mPEG800、mPEG1000、mPEG1500、mPEG2000或mPEG4000,优选为mPEG2000或mPEG4000。本发明引入聚乙二醇醚作为维生素E琥珀酸酯磷脂化合物的亲水基团,以改善其亲水性;聚乙二醇醚链越长,与水结合能力越强,其亲水性也越好。
本发明还提供了一种维生素E琥珀酸酯磷脂化合物的制备方法,其包括如下步骤:将维生素E琥珀酸酯与溶血磷脂溶解于有机溶剂中,并加入二环己基碳二亚胺和4-二甲氨基吡啶进行避光反应,反应结束后除去有机溶剂,纯化制得维生素E琥珀酸酯-溶血磷脂酰偶联物。
溶血型磷脂是一类具有较强表面活性的磷脂,但是其在血液中会使红细胞及其他细胞膜破裂,引起溶血或细胞坏死。本发明通过将溶血磷脂与维生素E琥珀酸酯发生缩合反应,制得维生素E琥珀酸酯-溶血磷脂酰偶联物,提高了溶血磷脂本身疏水端的疏水性,同时降低其溶血性,提高体内安全性。
一些实施例中,溶血磷脂与维生素E琥珀酸酯缩合会产生维生素E琥珀酸单酯-溶血磷脂酰偶联物和维生素E琥珀酸双酯-溶血磷脂酰偶联物的混合物,通过制备色谱技术可分离纯化得到维生素E琥珀酸单酯-溶血磷脂酰偶联物或维生素E琥珀酸双酯-溶血磷脂酰偶联物。
一些实施例中,维生素E琥珀酸酯与溶血磷脂的摩尔比不小于2:1,由于缩合反应过程中存在空间位阻效应,维生素E琥珀酸酯过量,使得提高产物中维生素E琥珀酸双酯-溶血磷脂酰偶联物的产率。
一些实施例中,该维生素E琥珀酸酯磷脂化合物中磷脂键上连接有聚乙二醇醚,其制备方法包括如下步骤:
S1、将维生素E琥珀酸酯-溶血磷脂酰偶联物溶于有机溶剂中,加入氢化钠进行反应,反应结束后除去有机溶剂和过量的氢化钠,纯化制得维生素E琥珀酸酯-溶血磷脂酸钠;
S2、取聚乙二醇醚溶于有机溶液中得到混合物A,在三乙胺中加入对甲苯磺酰氯得到混合物B,将混合物A和混合物B混合反应,反应结束后萃取,并除去有机溶液,纯化制得聚乙二醇醚对甲苯磺酸酯;
S3、将步骤S1制得的维生素E琥珀酸酯-溶血磷脂酸钠和步骤S2制得的聚乙二醇醚对甲苯磺酸酯混合反应,纯化制得聚乙二醇醚-维生素E琥珀酸酯磷脂化合物。
一些实施例中,所述溶血磷脂为溶血磷脂酰胆碱、溶血磷脂酰乙醇胺、溶血磷脂酰肌醇或溶血磷脂酸。
本发明还提供了维生素E琥珀酸酯磷脂化合物在制备抗肿瘤药物中的应用,以该两亲性的维生素E琥珀酸酯磷脂化合物为载药系统载体包载难溶性药物,对药物起到优异的增溶作用,且包封率高,稳定性好,有利于提高抗肿瘤药物的疗效。
本发明提供的一种纳米载药系统,是以上述维生素E琥珀酸酯磷脂化合物作为药物载体,可包载多种水难溶性药物,例如多西他赛、阿霉素、伏立康唑、紫杉醇、喜树碱等,但不局限于所列药物。
本发明纳米载药系统可制成多种剂型,例如脂质体、纳米粒或纳米胶束等,自组装效果好,稳定性好。具体地,通过溶剂蒸发法、直发乳化溶剂扩散法、盐析乳化-扩散法、纳米沉积法、凝聚法或乳液聚合法,将维生素E琥珀酸酯磷脂化合物与水难溶性药物自组装形成载药纳米粒。通过薄膜分散法、逆相蒸发法、冷冻干燥法、超声波分散法、喷雾干燥法、膜挤压法或高压均质法,将维生素E琥珀酸酯磷脂化合物与水难溶性药物自组装形成载药脂质体。通过直接溶解法、熔融法、溶剂蒸发法或透析法,将维生素E琥珀酸酯磷脂化合物与水难溶性药物自组装形成载药纳米胶束。
一些实施例中,本发明两亲性药物载体可可制成不同剂型的纳米载药系统,其粒径可以为10nm-1000nm,具体地,制得的载药纳米胶束或纳米粒粒径为10nm-100nm,载药脂质体粒径为100nm-1000nm。
以下结合具体实施例,对上述技术方案详细说明。
本发明提供的维生素E琥珀酸酯磷脂化合物制备过程中所用原料药及辅料均可由市场购得。
实施例1维生素E琥珀酸酯-溶血磷脂酰偶联物的制备
本实施例中使用的溶血磷脂(lyso)为溶血磷脂酰胆碱,利用无水二氯甲烷作为溶剂制备了维生素E琥珀酸酯-溶血磷脂酰偶联物(VES-lyso),具体制备方法如下:
取维生素E琥珀酸酯(VES)0.02mol与溶血磷脂酰胆碱0.01mol溶于500mL二氯甲烷,加入二环己基碳二亚胺0.02mol和4-二甲氨基吡啶0.02mol,室温下避光反应3d,反应结束后过滤,滤液用0.1mol/L盐酸溶液洗涤两次,无水硫酸钠干燥,旋转蒸发除去溶剂,硅胶柱(三氯甲烷:甲醇:水=65:25:4)纯化,除溶剂干燥,然后通过制备色谱技术得到维生素E琥珀酸双酯-溶血磷脂酰偶联物(VES-lyso)。VES-lyso的合成反应式如图1所示。
实施例2聚乙二醇单甲醚-维生素E琥珀酸双酯磷脂化合物的制备
本实施例制备了聚乙二醇单甲醚-维生素E琥珀酸双酯磷脂化合物(mPEG-VES-lyso),具体制备方法如下:
取实施例1制备的VES-lyso 0.01mol溶于500mL二氯甲烷,冰浴,缓慢加入氢化钠0.03mol,升至室温反应20min,反应结束旋转蒸发除去溶剂,常温下加入无水乙醇,充分混合使过量氢化钠除尽,过滤除去乙醇,以无水乙醇洗涤沉淀多次后放入真空干燥箱室温下干燥24h,即得维生素E琥珀酸双酯-溶血磷脂酸钠。
取聚乙二醇单甲醚2000(mPEG2000)6.0g搅拌溶解于20mL二氯甲烷后,在15mL三乙胺中加入3.5mmol对甲苯磺酰氯,将该三乙胺与二氯甲烷溶液混合,反应12h,反应结束后向反应液中滴加浓度为1mol/L盐酸溶液,萃取出有机层,再使用二氯甲烷萃取水相,合并有机相,向有机相中加入过量的无水碳酸纳,充分搅拌后过滤,旋转蒸发除去二氯甲烷,再加入无水乙醇析出沉淀,过滤后得到沉淀,置于真空干燥箱干燥24h,聚乙二醇单甲醚对甲苯磺酸酯2000需在真空干燥下储存。
取0.01mol维生素E琥珀酸双酯-溶血磷脂酸钠和0.01mol聚乙二醇单甲醚对甲苯磺酸酯2000溶于30mL的甲苯,室温搅拌溶解,升温至90℃,反应4h,反应结束后待溶液温度降至室温,离心,沉淀以二氯甲烷离心,再取出沉淀,真空干燥可得目标两亲性磷脂化合物VES-lyso-mPEG。
实施例3VES-lyso-mPEG临界胶束浓度的测定
本实施例采用威廉米吊片法测定了25℃下各浓度VES-lyso-mPEG水溶液的表面张力,方法如下:准确称取10mg VES-lyso-mPEG置于100mL容量瓶中,以去离子水溶解并定容,即得到1×10-4g/mL的VES-lyso-mPEG标准水溶液;静置稳定后,用移液管移取溶液50mL转移至100mL容量瓶,定容即得到5×10-5g/mL的VES-lyso-mPEG水溶液,以此类推不断按照不同比例进行稀释,分别配制1×10-5g/mL、5×10-6g/mL、1×10-6g/mL、5×10-7g/mL、1×10-7g/mL的VES-lyso-mPEG水溶液;准确称取VES-lyso-mPEG置于100mL容量瓶中,以去离子水溶解并定容,即得到1×10-2g/mL、1×10-3g/mL的VES-lyso-mPEG标准水溶液。
通过表面张力测试实验得到,在25℃条件下VES-lyso-mPEG的临界胶束浓度为2.37×10-5g/mL。
实施例4多西他赛-VES-lyso-mPEG纳米胶束的制备
本实施例采用薄膜分散法制备了多西他赛-VES-lyso-mPEG纳米胶束,具体制备方法如下:
称取多西他赛20mg,VES-lyso-mPEG 80mg,用2mL二氯甲烷充分溶解,旋转蒸发除去二氯甲烷形成薄膜,加入4mL去离子水溶解薄膜形成多西他赛-VES-lyso-mPEG纳米胶束水溶液。
实验测得多西他赛-VES-lyso-mPEG胶束溶液平均粒径为28nm,粒度大小均匀,载多西他赛包封率为98.1%。其胶束电镜图如图2所示,其粉体圆整度适中,大小较均一。胶束溶液在40℃稳定性试验箱放置1个月依然澄清、无混浊,测得载多西他赛包封率为96.9%。
实施例5阿霉素-VES-lyso-mPEG纳米胶束的制备
本实施例采用透析法制备了阿霉素-VES-lyso-mPEG纳米胶束,具体制备方法如下:
称取阿霉素20mg,VES-lyso-mPEG80mg,用2mL无水乙醇充分溶解,混合溶液倒入透析袋中,用1L去离子水透析24h,透析后过滤,形成阿霉素-VES-lyso-mPEG纳米胶束水溶液。
实验测得本实施例载药纳米胶束平粒径为34nm,粒度大小均匀,分布较窄,胶束成形良好,载阿霉素包封率为96.8%。胶束溶液在40℃稳定性试验箱放置1个月依然澄清、无混浊,测得载阿霉素包封率为96.2%。
实施例6伏立康唑-VES-lyso-mPEG纳米胶束的制备
本实施例采用直接溶解法制备了伏立康唑-VES-lyso-mPEG纳米胶束,具体制备方法如下:
称取伏立康唑20mg,VES-lyso-mPEG 60mg,用4mL去离子水充分溶解,室温搅拌4h,过滤,形成伏立康唑-VES-lyso-mPEG纳米胶束水溶液。
实验测得本实施例载药胶束溶液平均粒径为27nm,粒度大小均匀,载伏立康唑包封率为95.8%。胶束溶液在40℃稳定性试验箱放置1个月依然澄清、无混浊,测得载伏立康唑包封率为94.2%。
本领域的技术人员容易理解,以上所述仅为本发明的较佳实施例而已,并不用以限制本发明,凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等,均应包含在本发明的保护范围之内。
Claims (8)
1.一种纳米载药系统,其特征在于:以维生素E琥珀酸酯磷脂化合物作为药物载体,该化合物的结构式如下所示:
其中,R1是维生素E琥珀酸酯;
R2是维生素E琥珀酸酯或羟基;
R3是聚乙二醇醚或氢原子;
X是胆碱、乙醇胺、肌醇或氢原子。
2.根据权利要求1所述的纳米载药系统,其特征在于::所述聚乙二醇醚为mPEG200、mPEG400、mPEG600、mPEG800、mPEG1000、mPEG1500、mPEG2000或mPEG4000。
3.根据权利要求1所述的纳米载药系统,其特征在于:所述维生素E琥珀酸酯磷脂化合物的制备方法包括如下步骤:将维生素E琥珀酸酯与溶血磷脂溶解于有机溶剂中,并加入二环己基碳二亚胺和4-二甲氨基吡啶进行避光反应,反应结束后除去有机溶剂,纯化制得维生素E琥珀酸酯-溶血磷脂酰偶联物。
4.根据权利要求3所述的纳米载药系统,其特征在于:所述维生素E琥珀酸酯磷脂化合物的制备方法还包括如下步骤:
S1、将所述维生素E琥珀酸酯-溶血磷脂酰偶联物溶于有机溶剂中,加入氢化钠进行反应,反应结束后除去有机溶剂和过量的氢化钠,纯化制得维生素E琥珀酸酯-溶血磷脂酸钠;
S2、取聚乙二醇醚溶于有机溶液中得到混合物A,在三乙胺中加入对甲苯磺酰氯得到混合物B,将混合物A和混合物B混合反应,反应结束后萃取,并除去有机溶液,纯化制得聚乙二醇醚对甲苯磺酸酯;
S3、将步骤S1制得的维生素E琥珀酸酯-溶血磷脂酸钠和步骤S2制得的聚乙二醇醚对甲苯磺酸酯混合反应,纯化制得聚乙二醇醚-维生素E琥珀酸酯磷脂化合物。
5.根据权利要求3所述的纳米载药系统,其特征在于:所述溶血磷脂为溶血磷脂酰胆碱、溶血磷脂酰乙醇胺、溶血磷脂酰肌醇或溶血磷脂酸。
6.根据权利要求1所述的纳米载药系统,其特征在于:该纳米载药系统为脂质体、纳米粒或纳米胶束。
7.根据权利要求1所述的纳米载药系统,其特征在于:该纳米载药系统是通过直接溶解法、熔融法、溶剂蒸发法或透析法,将所述维生素E琥珀酸酯磷脂化合物与水难溶性药物自组装形成的载药纳米胶束。
8.根据权利要求1所述的纳米载药系统,其特征在于:所述纳米载药系统的粒径为10nm-1000nm。
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维生素E琥珀酸酯磷脂前药的设计、合成及其抗肿瘤活性研究;侯永鹏;中国优秀硕士学位论文全文数据库工程科技Ⅰ辑;B016-392 * |
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