CN111760022A - 一种人免疫球蛋白脂质体药物组合物及其制备方法 - Google Patents
一种人免疫球蛋白脂质体药物组合物及其制备方法 Download PDFInfo
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- CN111760022A CN111760022A CN202010790793.7A CN202010790793A CN111760022A CN 111760022 A CN111760022 A CN 111760022A CN 202010790793 A CN202010790793 A CN 202010790793A CN 111760022 A CN111760022 A CN 111760022A
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- human immunoglobulin
- liposome
- pharmaceutical composition
- lecithin
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Abstract
本发明公开了一种人免疫球蛋白脂质体药物组合物及其制备方法，包括人免疫球蛋白、卵磷脂、胆固醇，其中人免疫球蛋白的质量百分含量是0.1‑1％；卵磷脂的质量百分含量为1‑10％；胆固醇的质量百分含量是0.05‑1.0％。本发明的人免疫球蛋白脂质体药物组合物包封率高、载药量高、稳定性好、药效较市售注射液显著提高。此方法能降低人免疫球蛋白因分离不纯导致的过敏性反应，也可减少人免疫球蛋白在血液中的分解，快速透过组织到达病症系统。
Description
技术领域
本发明涉及脂质体制备技术领域，特别是涉及一种人免疫球蛋白脂质体药物组合物及其制备方法。
背景技术
人免疫球蛋白(Immunoglobulin,Ig)是人体对外来抗原(如细菌、病毒及其它毒素或异物)进行免疫应答的主要物质，又称抗体。IgG是再次免疫应答的主要抗体，具有中和毒素作用、中和病毒作用、调理作用、介导抗体依赖的细胞介导的细胞毒性作用(an tibody-dependent cell-mediated cytoxicity,ADCC)、激活补体经典途径、并可透过胎盘传输给胎儿，因此IgG有多能免疫球蛋白之称。
临床使用IgG制剂始于20世纪40年代，经低温乙醇工艺提取的IgG制品用于增强受体的免疫力以预防病毒性传染病，如传染性肝炎、麻疹等。现如今人免疫球蛋白已经被用于多种临床疾病，包括：原发性体液免疫缺陷如X联锁低免疫球蛋白血症；继发性免疫球蛋白缺陷病，如新生儿败血症等；特发性血小板减少性紫癜和川崎综合征；预防慢性B淋巴细胞白血病患者或HIV感染儿童的治疗；防止新近接受同种异体骨髓移植的患者发生移植物抗宿主病、间质性肺炎和感染等。
脂质体(liposome)是一种由成膜脂类分子自组装形成的具有类似生物膜双分子层的超分子结构(微囊)，具有外层亲水和内层疏水的双层结构。其大小通常在几十纳米到几十微米。脂质体作为药物传输载体已得到广泛应用。与非载药脂质体药物制剂相比,载药脂质体可以提高药物的治疗效果并且降低药物在体内传输过程中的毒副作用。它把药物分子嵌入、吸附或包裹在脂质体内，通过强化的渗透和保持效应(Enhanced Permeation andRetention,EPR效应)将药物输送到病灶组织,使病灶区药物浓度增高,在提高治疗效果的同时明显降低毒副作用。
目前，人免疫球蛋白的临床使用主要有两种方式，一种是静脉注射，另一种是肌肉注射。将人免疫球蛋白做成脂质体，可以用卵磷脂和胆固醇将免疫球蛋白分子包裹起来，避免免疫球蛋白与组织和器官的接触避免不良反应的发生。
发明内容
本发明就是针对上述存在的缺陷而提供一种人免疫球蛋白脂质体药物组合物及其制备方法。本发明的人免疫球蛋白脂质体药物组合物包封率高、载药量高、稳定性好、药效较市售注射液显著提高。此方法能降低人免疫球蛋白因分离不纯导致的过敏性反应，也可减少人免疫球蛋白在血液中的分解，快速透过组织到达病症系统。
本发明的一种人免疫球蛋白脂质体药物组合物及其制备方法技术方案为，一种人免疫球蛋白脂质体药物组合物，包括人免疫球蛋白、卵磷脂、胆固醇，其中人免疫球蛋白的质量百分含量是0.1-1％；卵磷脂的质量百分含量为1-10％；胆固醇的质量百分含量是0.05-1.0％。
该人免疫球蛋白脂质体药物组合物为一种注射用溶液或一种冻干粉针剂。
所述的人免疫球蛋白是将血浆用低温乙醇蛋白分离法分段沉淀提取免疫球蛋白组分，经超滤或冷冻干燥脱醇、浓缩和灭活病毒处理等工序制得，其免疫球蛋白纯度应不低于90％，其中包括免疫总球蛋白以及分离提纯的IgG、IgA、IgM等。
所述的血浆是取健康献血员的新鲜血浆或保存期不超过2年的冰冻血浆(每批最少应由1000名以上健康献血员的血浆混合)。
所述的卵磷脂选自高纯蛋黄卵磷脂(EPCS)、氢化大豆卵磷脂(HSPC)、二棕搁酰磷脂酰胆碱(DPPC)、磷脂酰胆碱、蛋黄卵磷脂、大豆卵磷脂、磷脂酰丝氨酸、二肉豆范酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱、磷脂酰乙醇胺、鞘磷脂中的至少一种。
所述的人免疫球蛋白脂质体，还包含渗透压调节剂和pH调节剂。
所述的渗透压调节剂为葡萄糖、甘露醇、蔗糖、乳糖、海藻糖、半乳糖中的至少一种。
所述的pH调节剂选自乳酸、乳酸钠、柠檬酸、柠檬酸钠、磷酸二氢钠、磷酸氢二钠中的至少一种。
一种所述的人免疫球蛋白脂质体的制备方法，其特征在于，包括以下步骤：
(1)将人免疫球蛋白、卵磷脂、胆固醇，加适量注射用有机溶媒，在0-40℃下溶解，得有机相；
(2)水相为注射用水；将有机相在搅拌条件下注入水相中，混匀，得脂质体粗品；
(3)将脂质体粗品进行均质乳化，再将其置于挤出器中依次通过不同孔径的挤出膜挤出，得脂质体溶液；
(4)取冻干保护剂，放入脂质体溶液中，搅拌溶解后加注射用水定容；用pH调节剂调节pH值；
(5)通过0.22μm膜除菌至孵育罐内于25±1℃进行21天孵育灭活病毒。
步骤(1)中的注射用有机溶媒是丙二醇、无水乙醇、叔丁醇中的一种，用量为人免疫球蛋白、卵磷脂、胆固醇混合物质量的1-10％。
步骤(3)中所述的挤出膜孔径为2.0μm、1.0μm、0.8μm、0.6μm、o.4μm中的至少一种，依次通过大孔径到小孔径的挤出。
步骤(5)中灭活病毒后的人免疫球蛋白脂质体无菌分装后灌装或冻干制备成人免疫球蛋白脂质体冻干粉针。
本发明的有益效果为：本发明的人免疫球蛋白脂质体药物组合物包封率高、载药量高、稳定性好、药效较市售注射液显著提高。此方法能降低人免疫球蛋白因分离不纯导致的过敏性反应，也可减少人免疫球蛋白在血液中的分解，快速透过组织到达病症系统。
具体实施方式：
为了更好地理解本发明，下面用具体实例来详细说明本发明的技术方案，但是本发明并不局限于此。
实施例1
量取人免疫球蛋白纯化液适量(按免疫球蛋白计约100mg)、高纯卵磷脂(EPCS)2g，胆固醇0.5g，加丙二醇2g，在37℃下加热溶解，得有机相；
称取注射用水90g，加热至37℃，得水相；
将有机相在搅拌条件下注入水相中，混匀，得脂质体粗品；
将脂质体粗品置于高压均质机中进行均质乳化，再将其置于0.8μm挤出器中挤出；
称取适量冻干保护剂，放入上述脂质体溶液中，搅拌溶解后加注射用水定容至全量；
用pH调节剂调节脂质体的pH值至7.0；
将上述脂质体通过0.22μm膜除菌至孵育罐内于25±1℃进行21天孵育灭活病毒，然后无菌分装，灌装，冻干制备成人免疫球蛋白脂质体冻干粉针。
Claims (10)
1.一种人免疫球蛋白脂质体药物组合物，其特征在于，包括人免疫球蛋白、卵磷脂、胆固醇，其中人免疫球蛋白的质量百分含量是0.1-1％；卵磷脂的质量百分含量为1-10％；胆固醇的质量百分含量是0.05-1.0％。
2.根据权利要求1所述的人免疫球蛋白脂质体药物组合物，其特征在于，所述的人免疫球蛋白是将血浆用低温乙醇蛋白分离法分段沉淀提取免疫球蛋白组分，经超滤或冷冻干燥脱醇、浓缩和灭活病毒处理等工序制得，其免疫球蛋白纯度应不低于90％。
3.根据权利要求1所述的人免疫球蛋白脂质体药物组合物，其特征在于，所述的卵磷脂选自高纯蛋黄卵磷脂、氢化大豆卵磷脂、二棕搁酰磷脂酰胆碱、磷脂酰胆碱、蛋黄卵磷脂、大豆卵磷脂、磷脂酰丝氨酸、二肉豆范酰磷脂酰胆碱、二硬脂酰磷脂酰胆碱、磷脂酰乙醇胺、鞘磷脂中的至少一种。
4.根据权利要求1所述的人免疫球蛋白脂质体药物组合物，其特征在于，还包含渗透压调节剂和pH调节剂。
5.根据权利要求4所述的人免疫球蛋白脂质体药物组合物，其特征在于，所述的渗透压调节剂为葡萄糖、甘露醇、蔗糖、乳糖、海藻糖、半乳糖中的至少一种。
6.根据权利要求4所述的人免疫球蛋白脂质体药物组合物，其特征在于，所述的pH调节剂选自乳酸、乳酸钠、柠檬酸、柠檬酸钠、磷酸二氢钠、磷酸氢二钠中的至少一种。
7.一种如权利要求1所述的人免疫球蛋白脂质体药物组合物的制备方法，其特征在于，包括以下步骤：
(1)将人免疫球蛋白、卵磷脂、胆固醇，加注射用有机溶媒，在0-40℃下溶解，得有机相；
(2)水相为注射用水；将有机相在搅拌条件下注入水相中，混匀，得脂质体粗品；
(3)将脂质体粗品进行均质乳化，再将其置于挤出器中依次通过不同孔径的挤出膜挤出，得脂质体溶液；
(4)取冻干保护剂，放入脂质体溶液中，搅拌溶解后加注射用水定容；用pH调节剂调节pH值；
(5)通过0.22μm膜除菌至孵育罐内于25±1℃进行21天孵育灭活病毒。
8.根据权利要求7所述的人免疫球蛋白脂质体药物组合物的制备方法，其特征在于，步骤(1)中的注射用有机溶媒是丙二醇、无水乙醇、叔丁醇中的一种，用量为人免疫球蛋白、卵磷脂、胆固醇混合物质量的1-10％。
9.根据权利要求7所述的人免疫球蛋白脂质体药物组合物的制备方法，其特征在于，步骤(3)中所述的挤出膜孔径为2.0μm、1.0μm、0.8μm、0.6μm、o.4μm中的至少一种，依次通过大孔径到小孔径的挤出。
10.根据权利要求7所述的人免疫球蛋白脂质体药物组合物的制备方法，其特征在于，步骤(5)中灭活病毒后的产品无菌分装后灌装或冻干制备成人免疫球蛋白脂质体冻干粉针。
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