CN114762731A - 一种延长基因药物在温和条件下储存时间的方法 - Google Patents
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Abstract
本发明属于药物制剂技术领域，具体涉及一种延长基因药物在温和条件下储存时间的方法，包括如下步骤：取设定量的PEG固体于40‑60℃下加热熔化，得到透明的液体；趁热加入基因药物原液后搅拌均匀，静置冷却凝固；基因药物原液通过如下方法获得：以聚乙烯亚胺(PEI)为载体，与DNA反应形成复合纳米粒，加入设定量的葡萄糖和/或蔗糖溶液，混匀，得基因药物原液。本发明方法可以有效延长基因药物在温和条件下的储存时间，降低基因药物对低温的要求，减少储存能耗和方便运输。
Description
技术领域
本发明属于药物制剂技术领域，具体涉及一种延长基因药物在温和条件下储存时间的方法。
背景技术
核酸类药物在当今社会有着举足轻重的地位。核酸类疫苗的制备、储存和运输受到各方重视。然而核酸是大分子药物，其性质不稳定，容易受到多种环境因素的影响。性质的不稳定导致其储存和运输条件比较苛刻，使其应用范围大大缩小，使用效率也随之降低。因此，迫切需要一种新的药物制剂形式，用来存储和运输核酸类药物，使其能够在尽可能温和的条件下(本发明所指的温和条件是指温度4-25℃的环境下) 长时间保持其活性，并且能够很好的释放出来，达到很好作用效果。
发明内容
为了克服现有技术中存在的不足，本发明提供了一种延长基因药物在温和条件下储存时间的方法，该方法可以使基因药物在较为温和的条件下，较为长期的储存及运输，提高基因药物的可用性，克服当下基因药物储存及运输难题。
为了实现本发明目的，所采用的技术方案为：
一种延长基因药物在温和条件下储存时间的方法，包括如下步骤：
取设定量的PEG于40-60℃下加热融化，得到透明的液体，趁热加入基因药物原液混匀，冷却凝固；
基因药物原液通过如下方法获得：以聚乙烯亚胺(PEI)为载体，与DNA 反应形成复合纳米粒，加入设定量的葡萄糖和/或蔗糖溶液，混匀，得基因药物原液，葡萄糖和/或蔗糖溶液与DNA的质量比为0-10：1。
进一步的，PEI分子量为800-25000。
葡萄糖和/或蔗糖溶液，用于使基因药物在PEG液体中能够更好的分散，葡萄糖和/或蔗糖溶液与DNA的质量比优选1:1。
PEG用量会影响基因药物的储存时间，但过多应用一方面造成材料浪费，加入量过少则对基因药物储存时间的提升作用不明显，因此作为优选，基因药物原液与熔化后的PEG体积比为1:2-1:20(优选1:5)。
进一步的，冷却凝固条件为：于4-25℃环境下。
进一步的，PEG的分子量为1000-20000。
与现有技术相比，本发明方法可以有效延长基因药物在温和条件下的储存时间，降低基因药物储存对低温的要求，减少储存能耗和方便运输。
附图说明
图1本发明实施例2所测PEI25k-DNA粒径。
图2本发明实施例3所测PEG2000-PEI25k样品所测转染效果图。
图3本发明实施例4所测转染效果图。
图4本发明实施例4所测转染定量图。
具体实施方式
聚乙二醇是聚环氧乙烷与水的加聚物，简称PEG。分子量在700以下的聚乙二醇，在20℃时为无色无臭不挥发粘稠液体，略有吸水性；分子量在700～ 900之间的为半固体；分子量1000及以上者为浅白色蜡状固体或絮片状石蜡或流动性粉末。随着分子量的提高，其水溶性、蒸汽压、吸水性和有机溶剂的溶解度等相应下降，而凝固点、相对密度、闪点和粘度则相应提高，对热稳定，与许多化学品不起作用，不水解，平均分子量的不同，性质也有差异。
PEG作为重要的水溶性药用辅料，它涉及许多类型的中药制剂的制备，例如注射剂、栓剂、软膏剂，滴丸剂等。其作为载体，可以作为制剂的骨架材料，起到缓控释作用；其作为修饰材料，既可以修饰脂质体以、小分子药物以及纳米颗粒，还可以修饰蛋白质、多肽以及乳剂等。目前，PEG修饰药物的新技术已进入了实际应用阶段，其新型药物传递系统正逐步用于中药的开发与研制中， PEG成为了使用极为广泛的中药药用辅料以及国内外学者研究开发的热点材料。
本专利选取两种两种非病毒载体作为基因药物模型材料，分别为聚乙烯亚胺(PEI)和Lipo293脂质体。
PEI是目前广泛应用的非病毒类载体之一。PEI具有较好的质子缓冲能力，可以通过“质子海绵”效应从内体中逃逸。聚乙烯亚胺的分子量变化很大，从400 Da到800kDa范围内均有分布。在于DNA的复合过程中，PEI的分子量越大，正电荷密度越高，则越容易与DNA形成复合纳米粒，这有利于提高转染效率。研究表明，表面所带正电荷密度是影响PEI的细胞毒性和转染效率的重要因素，同时分子量大小也会产生很大影响，适合作为基因载体的分子量在5～25kDa。
Lipo293转染试剂是一种用于293系列细胞的商品化转染试剂。它是一种新型阳离子脂质体。转染效率在70％以上，而且有着很低的细胞毒性。Lipo293可以在转染过程无需更换培养基，降低成本及简化操作步骤，因为血清的存在不会影响转染效率，这样可以减少避免很多阳离子脂质体因为需要在转染时去除血清而对细胞造成的损伤。
基于以上分析，下面结合附图和具体实施例对本发明作更进一步的说明。
实施例1：PEG复溶
称取相应质量的PEG于离心管中，于60℃条件下水浴融化。液体澄清透明后，取出，于4℃条件下静置凝固，待完全凝固后加入对应体积的PBS复溶。
实施例2：PEI与DNA结合
将150μg/mL PEI滴加至不断涡旋的150μg/mL DNA中混匀，无白色絮状沉淀产生，静置反应得到PEI/DNA。
实施例3：PEG2000-PEI25k-DNA-Glu样品体外转染实验
称取PEG2000样品于60℃水浴条件下加热熔化；取质量比为1:1的PEI25k与 DNA，分别加入DMEM培养基稀释，将PEI25k稀释液不断涡旋滴加到DNA稀释液中，混匀，静置反应20min；加入与DNA质量比为1的葡萄糖溶液(葡萄糖溶液中葡萄糖浓度为1mg/ml)，混匀，静置10min；对照组(无PEG无葡萄糖)加DMEM培养基补足相应体积。将PEI25k-DNA-Glu样品加入到熔化完全的 PEG2000中，搅拌混匀，室温下凝固完全，得PEG2000-PEI25k-DNA-Glu样品。
培养293T细胞，传代2-3次；293T细胞按照15万/mL细胞密度加入到24 孔板中，培养16-18h，待细胞密度达到70％以上时取PEG2000-PEI25k-DNA-Glu 样品加入DMEM培养基使样品复溶，复溶温度25-37℃(参考人体温度为最高值)待到固体全部溶解，再取出24孔板，吸掉上层培养基，加入溶解后的样品，放回培养箱。培养4-6h后弃上清液，加入1mL DMEM完全培养基，培养24h 后，观察转染情况并用荧光倒置显微镜拍照观察。
实施例4：长期实验
PEG2000-PEI25k-DNA-Glu样品制备：称取PEG2000样品60℃水浴条件下加热融化；取质量比为1:1的PEI25k与DNA，分别加入DMEM培养基稀释，将DNA 稀释液不断涡旋滴加到PEI25k稀释液中，混匀，静置反应20min；加入与DNA 质量比为1的葡萄糖溶液，混匀，静置10min；对照组(无PEG无葡萄糖)加 DMEM培养基补足相应体积。将PEI25k-DNA-Glu样品加入到融化完全的PEG2000中，搅拌混匀，室温下凝固完全，放于4℃和25℃密封保存。
培养293T细胞，传代2-3次；293T细胞按照15万/mL细胞密度加入到24 孔板中，培养16-18h，待细胞密度达到70％以上时，进行加样。
取出不同时间点(0天、3天和14天)制备的PEG2000-PEI25k-DNA-Glu样品，加入DMEM培养基使PEG2000复溶，待到固体全部溶解，取出24孔板，吸掉上层培养基，加入溶解后的样品，放回培养箱。培养4-6h后弃上清液，加入1mL DMEM完全培养基，培养24h后，观察转染情况并拍照。
以上所述仅是本发明的优选实施方式，应当指出：对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。
Claims (5)
1.一种延长基因药物在温和条件下储存时间的方法，其特征在于：包括如下步骤：取设定量的PEG固体于40-60℃下加热熔化，得到透明的液体；趁热加入基因药物原液后搅拌均匀，静置冷却凝固；
基因药物原液通过如下方法获得：以聚乙烯亚胺(PEI)为载体，与DNA反应形成复合纳米粒，加入设定量的葡萄糖和/或蔗糖溶液，混匀，得基因药物原液，葡萄糖和/或蔗糖溶液与DNA的质量比为0-10:1。
2.根据权利要求1所述的延长基因药物在温和条件下储存时间的方法，其特征在于：所述PEG的分子量为1000-20000。
3.根据权利要求1所述的延长基因药物在温和条件下储存时间的方法，其特征在于：PEI分子量为800-25000。
4.根据权利要求1所述的延长基因药物在温和条件下储存时间的方法，其特征在于：葡萄糖和/或蔗糖溶液与DNA的质量比为1:1。
5.根据权利要求1所述的延长基因药物在温和条件下储存时间的方法，其特征在于：冷却凝固条件为：于4-25℃环境下。
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