CN110200939A - 四氧化三铁-大豆多糖-奥扎格雷钠复合纳米材料的制备方法 - Google Patents
四氧化三铁-大豆多糖-奥扎格雷钠复合纳米材料的制备方法 Download PDFInfo
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Abstract
本发明涉及四氧化三铁‑大豆多糖‑奥扎格雷钠复合纳米材料的制备,通过高压均质使得大豆蛋白和大豆多糖形成复合物;将二价铁盐和三价铁盐溶解于去离子水中,在快速搅拌下滴加入上述乳液中,维持体系一定的pH,超声振荡,使其充分分散,加热至一定的温度,收集其中的固相,经洗涤、冷冻、干燥后即得蛋白多糖‑磁性纳米微粒复合物;将奥扎格雷钠配制成一定浓度的溶液,与蛋白多糖‑磁性纳米粒子复合物按照的一定比例混合,调节该混合体系pH,超声分散,持续搅拌,在沉淀形成的同时,由于吸附作用而使体系中的多糖‑磁性粒子复合物、奥扎格雷钠发生共沉淀,形成大小为5nm‑30nm的复合纳米粒子。本发明具有安全无毒、磁响应性强和生物可接受性好的优点。
Description
技术领域
本发明涉及一种磁性纳米微粒的制备方法,具体为四氧化三铁-大豆多糖-奥扎格雷钠复合纳米材料的制备方法。
背景技术
奥扎格雷钠的化学名为:反式-3-4-(1H-咪唑基-1-甲基)苯基-2-丙烯酸钠。注射用奥扎格雷钠为无色透明液体,作为血栓烷(TX)合酶的抑制剂,它能阻碍前列腺素H2(PGH2)生成血栓烷A2(TXA2),并促使血小板所衍生的PGH2转向内皮细胞,因而被用于治疗急性血栓性脑梗塞以及脑梗塞所伴随的运动障碍,同时因其还能改善蛛网膜下腔出血手术后的脑血管痉挛收缩和并发脑缺血症状,受到临床治疗的广泛应用。奥扎格雷钠作为一种常用药物,其不良反应较少,但目前在使用中存在一个较大的弊端,即无论是在改善急性期脑血栓症还是改善手术后的并发症中,均需要将奥扎格雷钠溶于电解质液或者是葡萄糖溶液中,进行最高达24h的持续滴注,并且这种持续滴注还会维持1-2周,长时间的滴注不仅给患者生理上带来很大的痛苦与不便,还会作为心理压力成为患者手术期间过度应激的一个重要来源,因而寻求高效、快速的奥扎格雷钠给药新途径成为目前急需解决的问题。
磁性微球的出现是纳米技术领域的新拓展,磁性微球由载体微球和配基结合而成,在外加磁场作用下能产生磁性,并作出定向移动,磁场去除后磁性消失,能与多数生物高分子如多聚糖、蛋白质具有良好的生物相容性,在生物工程特别是生物医药领域有广泛的应用前景。磁性微球表面功能化的基团能与生物高分子活性基团相连接,可在其表面稳定的固定有生物活性的物质,从而使得其成为了药物载体,借助外加磁场的导向作用,进行药物的靶向运输,减少副作用,提高药物效率,靶向药物对磁性载体粒子的要求比较严格,如要求其具有生物相容性好、可生物降解、无毒性、尺寸小、磁性强等特点。随着纳米技术的发展,由大分子有机物如蛋白质(乳蛋白、玉米醇溶蛋白)、多糖(淀粉、纤维素)等与磁性物质制备的磁性纳米颗粒因具有可降解性、环境友好性和生物兼容性而逐渐成为食品和医药领域研究的热点。磁性纳米微粒乳液具有抗沉降及抗乳析等动力学稳定性,能显著提高脂溶性物质的水溶性,同时由于其中的磁性微粒具备超顺磁性,磁性强,载药量高,且制备简单,是促进药品利用度的一种有效手段。因而,将奥扎格雷钠负载在磁性纳米材料上,制备一种磁性纳米药物转移载体,通过磁导向作用提高奥扎格雷钠的器官靶向活性,减少其不良反应,提高给药速度,具有十分重要的理论和临床意义。本研究提出了一种磁纳米微粒为载体的奥扎格雷钠注射液研制方法,能改变药物在体内的分布、释药速度,还能提高药物利用度,减轻患者生理应激。
发明内容
随着社会的不断进步,人们越来越注重身体健康,基于对健康的考虑以及一些道德、宗教文化禁忌的因素,植物性蛋白逐渐成为食品、医药工业上更为合适的蛋白原料。但是蛋白质的一些特性限制了其进一步的应用。蛋白质/多糖体系的出现不仅改善了蛋白的一些缺陷,还表现出了更优异的性能。蛋白质/多糖纳米颗粒具有生物兼容性、可降解性和环境友好性,可以作为生物活性物质和营养物质输送的载体。
本研究首次将大豆蛋白/大豆多糖体系运用到奥扎格雷钠缓释微粒的制备中,操作简单,在制作过程中舍弃了对包裹药物有较大影响的有机溶剂,代之以对体系无任何影响的天然植物油,同时采用改良法制备纳米微粒,制备条件温和,纳米微粒在制备过程中不被破坏,同时还添加了Fe3O4磁性物质,使制备的奥扎格雷钠磁性纳米微粒不仅成为良好的药物转移载体,而且还能更有效地到达靶器官。在临床应用中减少了用药量、降低毒副作用,完全可以实现医生监督下的自主用药。
本发明是按照以下步骤进行的:
1.以大豆蛋白、大豆多糖作为制备材料,通过对蛋白和多糖相互作用的调控,并通过高压均质破坏大豆蛋白中原有的聚集体,使得大豆蛋白和大豆多糖形成复合物,得到大豆蛋白/大豆多糖的复合溶液体系。2.大豆蛋白和大豆多糖复合物溶液溶解于去离子水中,调节体系中大豆蛋白与大豆多糖的比例,使体系中蛋白与多糖的质量比为1:5,体系pH 3.5稳定。搅拌2h后,加入植物油,高速搅拌1min,然后利用高压微射流纳米均质机均质3min,80℃加热1小时即得到包含有纳米粒子的乳液。所有乳液贮藏条件为4℃下贮藏。
3.将二价铁盐和三价铁盐溶解于去离子水中,在快速搅拌下滴加入上述乳液中,维持体系一定的pH,超声振荡,使其充分分散,加热至一定的温度,采用常规方法收集其中的固相,经洗涤、冷冻、干燥后即得蛋白多糖-磁性纳米微粒复合物;其中,二价铁盐和三价铁盐是氯化亚铁和三氯化铁,二价铁盐与三价铁盐摩尔数之比是0.1:1~10∶1;搅拌速度是800rpm~3000rpm;加热温度是60℃~100℃,加热时间是5分钟~60分钟。pH为8、9、10时,产物颜色为黑褐色、黑色、黑色。
4.将奥扎格雷钠配制成一定浓度的溶液,与大豆蛋白/多糖-磁性纳米粒子复合物按照的一定比例混合。将该混合物调节pH,超声分散10min,37℃恒温反应48h,再次调节pH,由于吸附作用而使体系中的多糖-磁性粒子复合物、奥扎格雷钠发生共沉淀,形成以下几种磁性纳米乳液:以蛋白多糖聚合物为载体,奥扎格雷钠和含铁的磁性粒子均匀混合于蛋白多糖聚合物之中的微粒;以蛋白多糖聚合物为壳体,奥扎格雷钠和含铁的磁性粒子被包裹在蛋白多糖聚合物构成的壳体内;以蛋白多糖聚合物为壳体,奥扎格雷钠和含铁的磁性粒子被包裹在蛋白多糖聚合物构成的壳体内,同时壳体上会含有少量的奥扎格雷钠和含铁磁性粒子。上述的方法中,由于无需使用交联剂进行交联聚合,并充分利用二价铁盐和三价铁盐在碱性条件下的化学反应中的吸附作用及共沉淀作用,使主含四氧化三铁的含铁磁性粒子方便、快捷、牢固地被包裹在多糖聚合物内,并避免了奥扎格雷钠的活性成分发生不必要的反应,显著提高奥扎格雷钠活性。按照本发明方法制备的磁性纳米微粒,平均尺寸大小是5nm-30nm,颗粒形貌呈球形,具有超顺磁性。
本发明中,蛋白多糖聚合物可以被生物体降解,安全无毒;由于微粒尺寸极小,因此可以有效防止巨噬细胞捕获,同时,完全能够实现静脉给药;更重要的是,利用含铁磁性粒子的性质,在外加磁场作用下,可以实现奥扎格雷钠的靶向性给药,达到减少用药量、减少给药时间、降低毒副作用的目的。
由于采用了上述技术方案,本发明具有如下的优点:
1.采用可生物降解的大豆蛋白/大豆多糖多糖聚合物,安全无毒;
2.磁性纳米颗粒中主含四氧化三铁Fe3O4,具有较好的磁响应性,在外加磁场的导向下可改变奥扎格雷钠的靶向性给药,达到减少用药量、减少给药时间、降低毒副作用的目的;
3.改善了生物可接受性,可实现静脉给药;
4.制备方法简便,使用仪器较少,对实验室要求较低,适用于大规模生产。
具体实施方式
下面结合具体实施例,进一步详细阐明本发明。实施例中未注明具体条件的实验方法,通常按照常规条件以及手册中所述的条件,或按照制造厂商所建议的条件;所用的通用设备、材料、试剂等,如无特殊说明,均可从商业途径得到。
一四氧化三铁磁性纳米颗粒的制备
准确称取二价铁盐和三价铁盐,溶解于去离子水中并快速搅拌,高压蒸汽灭菌4小时,收集黑色磁性溶液,反应产物1000r/min离心3min,取上清液,再6000r/min离心4min,收集黑色沉淀,双蒸水洗洗洗3次,得四氧化三铁磁性颗粒,-20℃保存。
二四氧化三铁-蛋白多糖纳米复合物的制备
大豆蛋白酸化后溶解于去离子水中,大豆多糖用去离子水溶解,边搅拌边加入大豆蛋白溶液,得到大豆蛋白/大豆多糖的复合物溶液。将上述四氧化三铁磁性纳米颗粒加入蛋白多糖复合物溶液中,快速搅拌,维持体系一定的pH,超声振荡,使其充分分散,加热至一定的温度,经洗涤、冷冻、干燥后即得蛋白多糖-磁性纳米微粒复合物。
三四氧化三铁-大豆多糖-奥扎格雷钠复合纳米材料
准确称取奥扎格雷钠,将其配制成一定的溶液,与大豆蛋白/多糖-磁性纳米粒子复合物按照一定比例混合,将该混合物调节pH,超声分散10min,37℃恒温反应48h,再次调节pH,在沉淀形成的同时,由于吸附作用而使体系中的多糖-磁性粒子复合物、奥扎格雷钠发生共沉淀,将载药磁颗粒用强磁铁进行吸附,重新分散溶于去离子水中,测定磁性颗粒中载药量,载药率为0.988%。
以上内容是结合具体的优选实施方式对本发明所作的进一步详细说明,不能认定本发明的具体实施只局限于这些说明。对于本发明所属技术领域的普通技术人员来说,在不脱离本发明构思的前提下,还可以做出若干简单推演或替换,都应当视为属于本发明的保护范围。
Claims (8)
1.一种四氧化三铁-大豆多糖-奥扎格雷钠复合纳米材料的制备方法,其特征在于该方法按以下步骤进行:
(1)制备四氧化三铁-大豆多糖纳米微粒复合物
大豆蛋白酸化后溶解于去离子水中,大豆多糖用去离子水溶解,边搅拌边加入大豆蛋白溶液,得到大豆蛋白/大豆多糖的复合物溶液,将二价铁盐和三价铁盐溶解于去离子水中在剧烈搅拌下,加入上述复合物溶液中,在快速搅拌下滴加入上述乳液中,维持体系一定的pH,超声振荡,使其充分分散,加热至一定的温度,经洗涤、冷冻、干燥后即得蛋白多糖-磁性纳米微粒复合物;
(2)制备四氧化三铁-大豆多糖-奥扎格雷钠复合纳米材料
将奥扎格雷钠配制成一定浓度的溶液,与大豆蛋白/多糖-磁性纳米粒子复合物按照的一定比例混合,将该混合物调节pH,超声分散10min,37℃恒温反应48h,再次调节pH,由于吸附作用而使体系中的多糖-磁性粒子复合物、奥扎格雷钠发生共沉淀,形成四氧化三铁-大豆多糖-奥扎格雷钠复合纳米材料乳液。
2.根据权利要求1所述的四氧化三铁-大豆多糖微粒复合物的制备方法,其特征在于:步骤一中磁性纳米颗粒包含四氧化三铁和大豆蛋白多糖。
3.根据权利要求1所述的四氧化三铁-大豆多糖-奥扎格雷钠复合纳米材料的制备方法,其特征在于:步骤一中磁性纳米颗粒包含四氧化三铁、大豆蛋白多糖、奥扎格雷钠。
4.根据权利要求2所述的四氧化三铁-大豆多糖复合微粒的制备方法,其特征在于:步骤一具体方法为大豆蛋白和大豆多糖复合物溶液中加入0.03%的叠氮化钠,二价铁盐用去离子水溶解,在剧烈搅拌下,加入上述复合物溶液中,同时加热,调节pH,收集黑色磁性溶液,经离心、去离子水洗涤、干燥等步骤后,即得到四氧化三铁-大豆多糖复合微粒,冷冻保存备用。
5.根据权利要求2所述的四氧化三铁-大豆多糖复合微粒的制备方法,其特征在于:所述四氧化三铁采用化学共沉淀法合成,在室温或高温的条件下,在Fe2+和Fe3+盐共存的溶液中,加入碱液可以制备粒径3-15nm的可在水中分散的Fe3O4磁性颗粒,其反应方程式如下:
Fe2++2Fe3++8OH--→Fe3O4+4H2O
6.根据权利要求3所述的四氧化三铁-大豆多糖-奥扎格雷钠复合纳米材料的制备方法,其特征在于:
(1)大豆蛋白/大豆多糖乳液浓度为1%、植物油与大豆蛋白/大豆多糖乳液配比为2:8;
(2)搅拌速率800r/min、药物浓度2mg/mL、制备温度25℃、搅拌时间30min;
(3)纳米微粒平均载药量为31.5%,平均药物包封率为91.0%;
(4)经冷冻干燥后,得到四氧化三铁-大豆多糖-奥扎格雷钠纳米微粒。
7.根据权利要求1-4任一项所述的四氧化三铁-大豆多糖-奥扎格雷钠复合纳米材料的制备方法,其特征在于:大豆蛋白和大豆多糖复合物溶液中,大豆蛋白与大豆多糖的质量比为1:5。
8.根据权利要求1-4任一项所述的四氧化三铁-大豆多糖-奥扎格雷钠复合纳米材料的制备方法,其特征在于:四氧化三铁的合成中,搅拌速度是800rpm~3000rpm;加热温度是40℃~100℃,加热时间是5分钟~60分钟。
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