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国产纳米脂质体突破量产瓶颈

2019-07-25 05:48:30     来源:中新网     责任编辑:刘欣

  国产纳米脂质体突破量产瓶颈 网红药物“快递员”降“薪”了

  通讯员 唐 塘 本报记者 张 晔

  人一生病,往往就要挂水吃药。但是,药物进入人体后,想要到达指定位置,滞留更长时间,更好地被吸收,还要避免被“友军误伤”,并非一帆风顺。

  近20年来,越来越多的新型纳米药物制剂涌入市场,拥有载体中“小笼包”之称的纳米脂质体应运而生。这种由脂质双分子层形成的粒径在纳米级别的囊泡,可将毒副作用大、稳定性差、降解快的药物包裹其中。通过与细胞膜融合,将携带的药物浓集于病灶部位,以实现靶向给药,同时可以提高疗效、降低毒性、增强稳定性。  

  近日,东南大学顾宁教授带领团队,打破国外的技术壁垒,攻克了纳米脂质材料的关键技术,建成了国内首条、国际上规模最大的脂质纳米粒生产线,并获得江苏省科技进步一等奖。

  那么,这种纳米级别的“小不点”,是如何担当起“打包”“运送”一条龙服务重任的?纳米脂质体除了在药物载体中大显身手,还有哪些不为人知的用途?

  被誉为“返老还童”的秘密武器

  脂质体的形成,要感谢一种叫磷脂的物质所拥有的自组装性质。磷脂是一种两亲性物质,一端亲水一端亲油,由于自身分子构型的特殊性,磷脂在水里会自发组装成双分子膜的结构,把一部分包在里面,通常被称为“囊泡”。

  最早的脂质体是在水中天然形成的。在科学家发现了它的特殊本领后,就尝试用人工方法合成磷脂化合物,以达到大批量制造的目的。脂质体的直径通常是几十纳米到零点几毫米,“纳米脂质体”就是粒径为纳米级别的脂质体。

  脂质纳米材料的膜结构跟细胞膜非常接近,为药物递送和吸收提供了方便。因此,脂质体可以将有效成分包裹后导入细胞,让有效成分轻易进入细胞。

  在许多常见药物中,都有脂质体的功劳。比如抗肿瘤药物、靶向网状内皮系统药物、蛋白质及核酸类药物、抗菌药物、抗炎激素药物等。而且,以脂质体为载体的药物“皮实不娇贵”,怎么给药都可以,静脉注射、皮下和肌肉注射、口服给药、肺部给药、皮肤给药都不在话下。

  “脂质体的大小与给药途径和药物释放速率有关,但纳米级别的脂质体作为药物载体优势明显。”顾宁教授告诉记者,如柔红霉素脂质体,其粒径为60—120纳米,由于其粒径小,进入血液循环后不易被网状内皮系统的吞噬细胞所识别,从而能在血液循环中滞留较长的时间。同时,该药物制剂没有明显的心脏毒性。

  近年来,越来越多的纳米脂质体药物涌入国际市场,成为国际上发展最快的一种高端药物制剂。纳米脂质体不仅在制药界大显身手,还在化妆品中担当专业“快递员”。它可以很好地保持化妆品的活性,使生长因子等成分更快更完全地进入皮肤角质层从而增强细胞修复力。因此,脂质体包裹被誉为“返老还童”的秘密武器。

  亲油亲水“两亲性”增加量产难度

  近年来,在国际药学界,灵巧多能的纳米脂质体几乎已成“网红”。

  目前,全球共有29个纳米脂质体药物获批上市。此外,还有87个纳米脂质体药物处于临床研究阶段,132个纳米脂质体药物处于临床前研究阶段。其中,获得美国食品与药物管理局(FDA)批准上市的纳米脂质体药物有13个。

  与此形成鲜明对比的是,我国仅有3个纳米脂质体药物获得生产批文,分别为注射用紫杉醇脂质体、盐酸多柔比星脂质体、注射用两性霉素B脂质体。

  而在10年前,我国的相关药物和化妆品更是一片空白,中国老百姓根本接触不到此类药物和化妆品,因为当时脂质纳米材料的关键技术都掌握在外国人手中。

  纳米脂质体药物在国际上的市场占有量逐年增加,而我国在该领域的产业化发展一直较慢,“究其原因,一是纳米脂质体药物所需要的脂质纳米材料完全靠进口,其价格远远超过原料药本身;二是国产脂质体药物制剂的质量、纯度和稳定性有待提升;三是脂质纳米材料的组装技术及脂质纳米药物的制剂工艺水平要求高、难度大。”顾宁教授告诉记者。

  20世纪70年代,脂质体刚开始作为药物载体时,由于结构极不稳定和药物包封率低而一度被人们忽视。随着对脂质体的深入研究,现在已初步解决了存在的问题。20世纪90年代初期,经济、高效的抗真菌和抗癌药物脂质体产品先后投入市场,极大推动了脂质体的研究与发展。

  脂质纳米材料具有独特的亲水、亲油“两亲性”,使得在同一药物里同时添加亲油亲水药物和活性成分成为了可能。

  但是,科研人员也发现,脂质纳米材料“两亲性”是一把“双刃剑”,它在为载药提供了便利的同时,也增加了量产的难度。因此,脂质纳米材料制备工艺复杂,导致很难去除杂质,中间体及产品难于纯化,因而很难实现量产。

  “风吹两边倒”用好也是宝

  制备纳米脂质体的原材料并不复杂,但是掌握不了门道,就做不出合格的纳米脂质体。

  做得好的脂质体,有着磷脂双分子外壳,跟细胞膜的结构很相似,个头又很小,直径基本都在150纳米以下,有助于活性物的渗透。

  实现脂质纳米材料国产化,合成工艺路线尤为重要。为此,顾宁教授团队提出了创新的脂质纳米材料合成纯化新工艺。他们通过自制的分离填料和自主的分离纯化技术,实现了高纯度脂质纳米药用载体材料的产业化。

  脂质纳米材料一端亲水一端亲油,看似“风吹两边倒”的墙头草特性,如何用好也大有讲究。科研人员经过反复实验终于找到了“锦囊妙计”。“我们创造性地将油溶性药物放在亲油的外层,水溶性药物放在亲水的内层,最大程度地发挥了药物的作用,真正做到扬长避短。”顾宁教授说道。

  据顾宁教授介绍,他们研发的脂质纳米材料合成纯化新工艺,采用“一锅煮”反应制备关键中间体,产率成倍提升。同时,采用脂质体配位技术,突破了甘草酸药物磷脂复合物组装的关键瓶颈,将甘草酸二铵和脂质材料磷脂酰胆碱络合,形成脂质复合物,大幅改善了甘草酸的亲脂性,使其更易穿越消化道的多重膜结构进入血液循环,有效解决了甘草酸口服生物利用度低的难题。

  项目成功后,国内脂质纳米材料的价格大幅下降,显著降低了脂质体药物的整体成本。此外,脂质纳米粒技术已在国内一线化妆品公司得到广泛应用,在制备具有美白、抗衰老、去皱等功能的化妆品中大显身手。

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