CN114617849A - 具有核壳结构的玉米醇溶蛋白复合纳米粒子及其制备方法 - Google Patents
具有核壳结构的玉米醇溶蛋白复合纳米粒子及其制备方法 Download PDFInfo
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Abstract
本发明公开了具有核壳结构的玉米醇溶蛋白复合纳米粒子的制备新方法,即雾化/反溶剂溶析法。本方法具体步骤如下:(1)将玉米醇溶蛋白和两亲性复合成分A按一定比例溶解到乙醇‑水体系中,配置得到溶液相;(2)将一定质量的水溶性复合成分B溶于水中,配得反溶剂相;(3)调整好雾化喷嘴尺寸,打开空气压缩机,设置雾化压力;(4)打开溶液进样泵,将步骤(1)得到的溶液相以一定流速经雾化喷嘴喷入步骤(2)得到的反溶剂相中,形成复合纳米粒子混悬液;(5)将步骤(4)所得复合纳米粒子混悬液冷冻干燥,得到玉米醇溶蛋白复合纳米粒子粉末。相对于常规相分离法,本发明雾化/反溶剂溶析法可实现不同极性材料的复合,快速形成内疏外亲的具有核壳结构的复合纳米粒子,操作简单;所得复合纳米粒子粒径小、分布窄,分散性和稳定性好,适用于亲水性和疏水性活性成分的封装和递送,用于医药、食品等领域。
Description
技术领域
本发明涉及具有核壳结构的玉米醇溶蛋白复合纳米粒子及其制备方法。
背景技术
随着国际医药产业格局的变化,创新药物研发风险加剧。与开发一个新分子实体相比,开发药物新剂型的创新路径具有周期短、投资少、风险小和回报高等特点。我国2020版《药品注册管理办法》中明确将改剂型和改给药途径等“具有明显临床优势”的药品作为改良型新药申报。其中,基于各种纳米载体的药物递送系统(Drug Delivery System, DDS)是现代药剂学中新制剂和新剂型研究的主要方向。为满足精准化医疗的需求,DDS已由最初的前体药、缓释剂,逐步发展为速控型、靶向型和可视化输送等精准化剂型。
载材作为DDS的重要组成部分,其选择和针对性修饰改性对于DDS的发展极为重要,也是目前面临的关键问题。目前用于DDS的载材包括聚乳酸、聚乙二醇和多嵌段共聚物等合成高分子体系,及多糖、脂类和蛋白等生物大分子载材,这些材料各具特色。相比于合成高分子材料,天然大分子材料具有可再生性、良好的生物相容性和降解产物毒副作用小等优势。其中,蛋白类载材可实现利用蛋白质冠冕的生物特性来改变DDS被单核吞噬细胞系统识别和清除,增强DDS的隐蔽效应和生物靶向性。Abraxane®的上市充分证实了蛋白类载材的优势和市场潜力。
作为从玉米中提取的天然生物大分子化合物之一,玉米醇溶蛋白(Zein)被证实是一种较为理想的DDS载材:(1)作为可食用性植物蛋白,其安全可再生,提取工艺简单,价格便宜;(2)其大分子结构和易自组装特性,对疏水性小分子药物和蛋白、多肽等大分子药物具有很高的载药效率;(3)其较强的输水性,可提高药物的稳定性和实现药物的控缓释;(4)其可利用自身蛋白质冠冕的生物特性来改变DDS被单核吞噬细胞系统识别和清除;(5)其表面具备大量可供修饰的基团(羟基、氨基和羧基等),易针对性地进行改性修饰。然而,单一Zein-DDS在中性或生理pH溶液中易聚集,再分散性和稳定性差;在载药量、靶向递送和药物释放方面存在不足,难实现对亲水性药物的封装;同时,Zein的蛋白质性质可能会导致体内免疫原性反应。
除载材外,DDS的精准构建是获取所需粒子结构和确保产品最终性能的保障。目前,Zein-DDS的制备大多采用传统相分离法,即将溶液相与反溶剂相直接混合,所得DDS通常聚集严重、产品粒径较大且分布宽。不同于传统相分离法,超临界反溶剂技术和喷雾干燥技术在DDS制备过程中,借助独特的喷嘴设计先将溶液雾化为液滴,再由液滴成核获取微纳米粒子,所得DDS分散性好,且粒径分布均匀。然而,超临界反溶剂技术和喷雾干燥技术事先需将所有材料溶于同一溶剂体系中,不适用于溶解性质不同的多元复合体系。同时,由于DDS制备过程中,药物和载体共沉淀析出,难以一步获取具有多层或核壳结构的纳米复合粒子。
发明内容
本发明的目的在于针对现有技术中Zein-DDS粒径分布不均匀,易聚集和再分散性差等弊端,提供一种,大小均匀、再分散性好、具有核壳结构的Zein复合纳米粒子及其制备方法。本发明的Zein复合纳米粒子中,Zein形成疏水性内核,复合成分形成亲水性壳层,适用于亲水性和疏水性活性成分的封装和递送,用于医药、食品等领域。
本发明结合相分离法、超临界反溶剂技术和喷雾干燥技术的相关理念,提出了一种Zein复合纳米粒子的制备新方法,即雾化/反溶剂溶析法。
本发明目的通过如下技术方案实现:
一种具有核壳结构的Zein复合纳米粒子的制备方法,包括如下步骤:
(1)溶液相的配置:将Zein和复合成分A按一定质量比溶解到乙醇-水体系中,配置得到总浓度为2.5~15 mg/mL的均一溶液相。
(2)反溶剂相的配置:将一定质量的复合成分B溶于水中,配得浓度为0.1~0.5 mg/mL的均一反溶剂相。
(3)复合纳米粒子混悬液的制备:调整雾化喷嘴尺寸(0.1~1.0 μm),打开空气压缩机,设置雾化压力(50~300 kPa);打开溶液进样泵,将10~50 mL步骤(1)得到的溶液相以流速0.5~2.5 mL/min经雾化喷嘴喷入50~250 mL步骤(2)得到的反溶剂相中,得到均一、稳定的复合纳米粒子混悬液。
(4)冻干:将步骤(3)得到的复合纳米粒子混悬液冷冻干燥,得到Zein复合纳米粒子粉末。
为进一步实现本发明目的,优选地,步骤(1)所述复合成分A为卵磷脂、羟丙基甲基纤维素和聚乙二醇-聚乳酸共聚物等可溶于乙醇-水体系的两亲性聚合物。
优选地,步骤(1)所述Zein和复合成分A的质量比为1:1~10:1,所述乙醇-水体系中乙醇体积百分比含量为60~90%。
优选地,步骤(2)所述复合成分B为羧甲基壳聚糖、酪蛋白酸钠、海藻酸钠和聚乙烯吡咯烷酮等水溶性聚合物。
优选地,步骤(3)所述混悬液中纳米粒子分布均匀,无明显沉淀,乙醇体积百分比含量低于25%。
优选地,所述冷冻干燥时间为12~48 h,冷冻干燥中冷阱温度低于-30 ℃。
一种Zein复合纳米粒子,由上述制备方法制得:由Zein、复合成分A和B通过亲疏水作用、静电吸附和氢键等非共价作用力复合,形成具有明显核壳结构的复合纳米粒子,粒径为100~500 nm;冻干后粉末在水中具有很好的再分散性和稳定性。
与现有技术相比,本发明具有如下优点:
(1)所述雾化/反溶剂溶析法,溶液相先被雾化为微小液滴再与反溶剂相接触,纳米粒子由雾化后均匀的液滴形成,可通过溶液浓度、喷嘴尺寸、雾化压力、溶液流速和复合载材配比等操作参数,有效调控最终产物的粒度大小,所制备颗粒粒径分布窄、分散性好。
(2)所述溶液相中,两亲性复合材料A可改善Zein液滴的润湿性,减少喷入反溶剂相中的阻力,避免在反溶剂相表面聚集。
(3)所述反溶剂相中,水溶性复合成分B可避免所得复合纳米粒子混悬液的团聚,提高冻干后粉末的再分散性和稳定性。
(4)所述Zein复合纳米粒子具有核壳结构,其中Zein分子形成疏水性内核,复合成分形成亲水性壳层,适用于亲水性和疏水性活性成分的封装和递送,用于医药、食品等领域。
(5)本发明可快速获取具有核壳结构的复合纳米粒子,操作简单,制备条件温和,产品收率高,残留溶剂少。
附图说明
图1为具有核壳结构的Zein复合纳米粒子的制备流程示意图;
图2为实施例1所得Zein复合纳米粒子的透射电镜图;
图3为实施例1所得Zein复合纳米粒子的粒径分布图;
图4为实施例1所得Zein复合纳米粒子冻干粉再分散后随时间的变化图。
具体实施方式
为更好理解本发明,结合附图和实施例对本发明作进一步描述,但需要说明的是,本发明所要求的保护范围并不局限于下面实施例所表述的范围。
一种具有核壳结构的Zein复合纳米粒子的制备方法,其流程如图1所示,主要制备过程为先将Zein和复合成分A按一定质量比溶解到乙醇-水体系中,配置得到溶液相;同时,将一定质量的复合成分B溶于水中,配得反溶剂相;然后,调整雾化喷嘴尺寸,打开空气压缩机,设置雾化压力;打开溶液进样泵,将溶液相以一定流速经雾化喷嘴喷入反溶剂相中,形成复合纳米粒子混悬液;随后,将得到的复合纳米粒子混悬液冷冻干燥,得到Zein复合纳米粒子粉末。
实施例1
一种具有核壳结构的Zein复合纳米粒子的制备方法。包括以下步骤:
(1)溶液相的配置:将质量比为10:3的Zein和大豆卵磷脂溶解到70%乙醇体积百分比含量的乙醇-水体系,配置得到总浓度为6.5 mg/mL的均一溶液相。
(2)反溶剂相的配置:将10 mg的水溶性羧甲基壳聚糖溶于100 mL水中,配得浓度为0.1 mg/mL的均一反溶剂相。
(3)复合纳米粒子混悬液的制备:调整雾化喷嘴尺寸为0.7 μm,打开空气压缩机,设置雾化压力为100 kPa;打开溶液进样泵,将20 mL步骤(1)得到的溶液相以1.5 mL/min流速经雾化喷嘴喷入100 mL步骤(2)得到的反溶剂相中,得到均一、稳定的复合纳米粒子混悬液。
(4)冻干:将步骤(3)得到的复合纳米粒子混悬液冷冻干燥24 h,得到Zein复合纳米粒子粉末。
所得Zein复合纳米粒子的透射电镜图如图2所示,具有明显的核壳结构。所得Zein复合纳米粒子的粒径分布图如图3所示,粒径大小为206.9±48.73 nm,粒径分布窄。所得Zein复合纳米粒子冻干粉可被再分散到水中形成混悬液,如图4所示,混悬液静置12小时内粒子稳定、无明显沉淀。
实施例2
一种具有核壳结构的Zein复合纳米粒子的制备方法。包括以下步骤:
(1)溶液相的配置:将质量比为5:1的Zein和羟丙基甲基纤维素溶解到80%乙醇体积百分比含量的乙醇-水体系,配置得到总浓度为6 mg/mL的均一溶液相。
(2)反溶剂相的配置:将15 mg的酪蛋白酸钠溶于100 mL水中,配得浓度为0.15mg/mL的均一反溶剂相。
(3)复合纳米粒子混悬液的制备:调整雾化喷嘴尺寸为0.5 μm,打开空气压缩机,设置雾化压力为150 kPa;打开溶液进样泵,将20 mL步骤(1)得到的溶液相以1 mL/min流速经雾化喷嘴喷入100 mL步骤(2)得到的反溶剂相中,得到均一、稳定的复合纳米粒子混悬液。
(4)冻干:将步骤(3)得到的复合纳米粒子混悬液冷冻干燥24 h,得到Zein复合纳米粒子粉末。
所得Zein复合纳米粒子粉末粒径为346.5±52.23 nm,粒径分布窄,具有好的再分散性和稳定性,经透射电镜表征证实具有核壳结构。
实施例3
一种具有核壳结构的Zein复合纳米粒子的制备方法。包括以下步骤:
(1)溶液相的配置:将质量比为2:1的Zein和蛋黄卵磷脂溶解到60%乙醇体积百分比含量的乙醇-水体系,配置得到总浓度为6 mg/mL的均一溶液相。
(2)反溶剂相的配置:将20 mg的海藻酸钠溶于100 mL水中,配得浓度为0.2 mg/mL的均一反溶剂相。
(3)复合纳米粒子混悬液的制备:调整雾化喷嘴尺寸为0.2 μm,打开空气压缩机,设置雾化压力为200 kPa;打开溶液进样泵,将10 mL步骤(1)得到的溶液相以1 mL/min流速经雾化喷嘴喷入50 mL步骤(2)得到的反溶剂相中,得到均一、稳定的复合纳米粒子混悬液。
(4)冻干:将步骤(3)得到的复合纳米粒子混悬液冷冻干燥24 h,得到Zein复合纳米粒子粉末。
所得Zein复合纳米粒子粉末粒径为180.7±32.53 nm,粒径分布窄,具有好的再分散性和稳定性,经透射电镜表征证实具有核壳结构。
实施例4
一种具有核壳结构的Zein复合纳米粒子的制备方法。包括以下步骤:
(1)溶液相的配置:将质量比为5:1的Zein和聚乳酸-聚乙二醇-聚乳酸共聚物溶解到85%乙醇体积百分比含量的乙醇-水体系,配置得到总浓度为6 mg/mL的均一溶液相。
(2)反溶剂相的配置:将50 mg的水溶性羧甲基壳聚糖溶于100 mL水中,配得浓度为0.5 mg/mL的均一反溶剂相。
(3)复合纳米粒子混悬液的制备:调整雾化喷嘴尺寸为0.5 μm,打开空气压缩机,设置雾化压力为100 kPa;打开溶液进样泵,将20 mL步骤(1)得到的溶液相以0.75 mL/min流速经雾化喷嘴喷入100 mL步骤(2)得到的反溶剂相中,得到均一、稳定的复合纳米粒子混悬液。
(4)冻干:将步骤(3)得到的复合纳米粒子混悬液冷冻干燥24 h,得到Zein复合纳米粒子粉末。
所得Zein复合纳米粒子粉末粒径为351.8±42.84 nm,粒径分布窄,具有好的再分散性和稳定性,经透射电镜表征证实具有核壳结构。
Claims (5)
1.具有核壳结构的玉米醇溶蛋白复合纳米粒子的制备方法,其特征在于包括如下步骤:
(1)溶液相的配置:将玉米醇溶蛋白和复合成分A按一定质量比溶解到乙醇-水体系中,配置得到总浓度为2.5~15 mg/mL的均一溶液相;所述玉米醇溶蛋白和复合成分A的质量比为1:1~10:1,所述乙醇-水体系中乙醇体积百分比含量为60~90%;
(2)反溶剂相的配置:将一定质量的复合成分B溶于水中,配得浓度为0.1~0.5 mg/mL的均一反溶剂相;
(3)复合纳米粒子混悬液的制备:调整雾化喷嘴尺寸(0.1~1.0 μm),打开空气压缩机,设置雾化压力(50~300 kPa);打开溶液进样泵,将10~50 mL步骤(1)得到的溶液相以流速0.5~2.5 mL/min经雾化喷嘴喷入50~250 mL步骤(2)得到的反溶剂相中,得到均一、稳定的复合纳米粒子混悬液;
(4)冻干:将步骤(3)得到的复合纳米粒子混悬液冷冻干燥,得到玉米醇溶蛋白复合纳米粒子粉末;所述冷冻干燥时间为12~48 h,冷冻干燥中冷阱温度低于-30 ℃。
2.根据权利要求1所述的具有核壳结构的玉米醇溶蛋白复合纳米粒子的制备方法,其特征在于:步骤(1)所述复合成分A为卵磷脂、羟丙基甲基纤维素和聚乙二醇-聚乳酸共聚物等可溶于乙醇-水体系的两亲性聚合物。
3.根据权利要求1所述的具有核壳结构的玉米醇溶蛋白复合纳米粒子的制备方法,其特征在于:步骤(2)所述复合成分B为羧甲基壳聚糖、酪蛋白酸钠、海藻酸钠和聚乙烯吡咯烷酮等水溶性聚合物。
4.根据权利要求1所述的具有核壳结构的玉米醇溶蛋白复合纳米粒子的制备方法,其特征在于:步骤(3)所述混悬液中纳米粒子分布均匀,无明显沉淀,乙醇体积百分比含量低于25%。
5. 一种玉米醇溶蛋白复合纳米粒子,其特征在于其由权利要求1-4任一项所述制备方法制得:由玉米醇溶蛋白、复合成分A和B通过亲疏水作用、静电吸附和氢键等非共价作用力复合,形成具有明显核壳结构的复合纳米粒子,粒径为100~500 nm;冻干后粉末在水中具有很好的再分散性和稳定性。
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