CN109248145A - 一种共载小分子药物与大分子药物的组合体系 - Google Patents

一种共载小分子药物与大分子药物的组合体系 Download PDF

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CN109248145A
CN109248145A CN201811170432.1A CN201811170432A CN109248145A CN 109248145 A CN109248145 A CN 109248145A CN 201811170432 A CN201811170432 A CN 201811170432A CN 109248145 A CN109248145 A CN 109248145A
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何伟
尹莉芳
肖青青
张凯
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China Pharmaceutical University
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Abstract

本发明属于药物制剂，药物递送等领域，特别涉及小分子与大分子共递送体系的设计和应用。本发明设计的组合体系，可以同时递送一种小分子药物，例如紫杉醇，东凌草甲素等，和一种大分子药物，例如蛋白质，抗体等，可以在保证载体高安全性低毒性，同时通过两种作用机制进入体内发挥作用，诸多实例证明该体系在体外具有较高的细胞毒性，优良的体内抗肿瘤增殖效果。

Description

一种共载小分子药物与大分子药物的组合体系
技术领域
本发明设计药物制剂，药物递送领域，特别涉及一种注射用小分子前药与大分子药物共同递送的设计和应用。
背景技术
近年来，随着缓控释制剂技术，固体分散技术，纳米技术等制剂技术的发展，的确解决了一部分难溶性药物的成药性的问题，但是，仍然有极大的一部分难溶性药物由于溶解性差，生物利用度低而极大的限制了其在临床上的应用，因此，将小分子的难溶性药物与透明质酸，双亲性蛋白质等高分子合成制成难溶性药物的前药，不仅可以提高难溶性药物的溶解度，还能通过修饰主动靶头，使其主动靶向到肿瘤部位或者相应的受体部位发挥药效，经过形成前药也更加易于与脂质体等纳米制剂进行自组装，从而实现药物的共同递送。
脂质体具备同细胞膜相似的磷脂双分子层结构，具备纳米制剂的典型特点，将活性药物载入脂质体内，可以利用脂质体的被动靶向作用使活性药物蓄积到肿瘤部位，此外，大分子蛋白药物的递送由于易被水解至今仍然没有被完美的解决，常用的大分子药物的递送方法多为直接静脉或者皮下注射，本发明采用脂质体制备技术，利用薄膜分散法或者逆相蒸发法将大分子药物如anti-CTLA-4，CXCL10等载入脂质体的内核，再与小分子蛋白前药自组装形成特殊的纳米组合体系，可以同时递送小分子前药和大分子药物，制成具备主动与被动双重靶向作用，从而蓄积到病灶部位通过两种不同的作用机理发挥药效。
发明内容
本发明一方面将小分子药物与PLGA等高分子或者蛋白制备形成水溶性前药，亦可在高分子材料或者蛋白的表面修饰主动靶头，另一方面将大分子蛋白或者抗体包裹进入脂质体内核，通过涡旋或者搅拌的方法，使两个组分自组装形成具备主动与被动双重靶向的纳米体系。
本发明具体技术方案
为了实现小分子前药与大分子药物的共同递送，本发明的具体实施技术方案如下：
1)通过薄膜分散法或者逆相蒸发法，制备包裹大分子药物的脂质体，待用；
2)将小分子前药溶于PBS等水相溶剂中，在涡旋或者搅拌的条件下将小分子前药加入到脂质体溶液中，使溶解完全且混合均匀；
3)将步骤2)制得的小分子前药与大分子脂质体的组合体系静置，得到自组装的纳米体系，粒径小于1000nm。
附图说明
附图1为实施例1所制的复合体系的透射电镜图片；
附图2为实施例1所制的复合体系的血清稳定性粒径变化图片；
附图3为实施例2所制的小分子前药与脂质体组装的复合体系的荧光共振能量转移图片；
附图4为实施例3所制的小分子前药与脂质体组装的复合体系的荧光共振能量转移图片；
附图5，附图6为实施例5所制的小分子前药与脂质体组装的复合体系的细胞毒性随药物浓度变化图片.
具体实施方式
实施例1
处方：
小分子前药 10mg
温度响应型脂质体 30mg
大分子药物anti-CTLA-4 1.0mg
制备方法：
利用薄膜分散-探头超声法制备包载1mg大分子药物的温度响应型脂质体，待用。10mg 小分子前药加入到包载1mg anti-CTLA-4的脂质体溶液中，涡旋半分钟，将小分子前药与包载 anti-CTLA-4的温度响应型脂质体混合溶液静置，得到自组装的共载小分子前药与anti-CTLA-4 的纳米复合体系。
利用动态光散射测定实施例1制得的复合体系的粒径约为100±1.25m，分散系数为0.158 ±0.02，zeta电位为-6.23±1.48，透射电镜如附图1所示。血清中的稳定性数据如附图2所示。
实施例2
处方：
制备方法：
利用薄膜分散-探头超声法制备包载1mg大分子药物和0.5mg的罗丹明B的温度响应型脂质体，待用，将10mg FITC标记的小分子前药按照与脂质体的不同比例加入到脂质体溶液中，涡旋半分钟，将小分子前药与包载anti-CTLA-4的温度响应型脂质体混合溶液静置，得到自组装的共载小分子前药与anti-CTLA-4的纳米复合体系。
利用荧光分光光度计考察不同比例的FITC标记的小分子前药和脂质体组装之后的荧光共振转移情况和组合情况。实验结果如附图3所示。
实施例3
处方：
制备方法：
利用薄膜分散-探头超声法制备包载1mg大分子药物和0.5mg的罗丹明B的温度响应型脂质体，待用，将10mg FITC标记的小分子前药按照与脂质体的不同比例加入到脂质体溶液中，涡旋半分钟，将小分子前药与包载CXCL10的温度响应型脂质体混合溶液静置，得到自组装的共载小分子前药与CXCL10的纳米复合体系。
利用荧光分光光度计考察不同比例的FITC标记的小分子前药和脂质体组装之后的荧光共振转移情况和组合情况。实验结果如附图4所示。
实施例4
处方：
小分子前药 10mg
温度响应型脂质体 30mg
大分子药物BSA 1.0mg
制备方法：
利用逆相蒸发-探头超声法制备包载1mg大分子药物的温度响应型脂质体，待用。10mg 小分子前药加入到包载1mg BSA的脂质体溶液中，涡旋半分钟，将小分子前药与包载BSA的温度响应型脂质体混合溶液静置，得到自组装的共载小分子前药与BSA的纳米复合体系。
利用动态光散射测定实施例4制得的复合体系的粒径约为110±2.4nm，分散系数为0.248± 0.05，zeta电位为-7.65±0.65。
实施例5
处方：
小分子前药 10mg
温度响应型脂质体 30mg
大分子药物anti-CTLA-4 1.0mg
制备方法：
利用薄膜分散-探头超声法制备包载1mg大分子药物的温度响应型脂质体，待用。10mg 小分子前药加入到包载1mg anti-CTLA-4的脂质体溶液中，涡旋半分钟，将小分子前药与包载anti-CTLA-4的温度响应型脂质体混合溶液静置，得到自组装的共载小分子前药与anti-CTLA-4 的脂质体体系。进行MTT细胞毒性试验，分组为游离的anti-CTLA-4，包载anti-CTLA-4的脂质体，共载小分子前药与大分子药物的脂质体等，42℃水浴释放后的载anti-CTLA-4脂质体，包载将分组各组药物与B16F10细胞进行共孵育进行体外细胞毒性评价。
具体操作方法如下：将B16F10细胞以8000个/孔接种于96孔板中，孵育24小时后，将不同浓度的分组药物加入到96孔板中，孵育24小时后，取20μL四甲基偶氮唑蓝(5mg/mL)加入各孔内，继续孵育4小时，弃去孔内液体，加入二甲亚砜200μL，振摇，使结晶充分溶解，在490nm波长下用酶标仪测定各样品的吸光度值，同时测定空白组吸光度值，并计算细胞存活率。
结果表明，同一浓度下，脂质体的细胞毒性显著高于游离药物，且脂质载体在实验浓度下存活率均高于80％，表明此体系载体安全性高，且可以保留所递送抗肿瘤药物的细胞毒性。实验结果如附图5，附图6所示。

Claims (10)

1.一种成分为小分子药物和大分子药物的组合体系，应用广泛，小分子药物先与高分子材料或者蛋白分子形成前药，再与包载大分子药物的脂质载体组装得到复合体系。
2.权利要求书1所述的小分子药物主要包括但不限于紫杉醇，多西紫杉醇，姜黄素，冬凌草甲素，黄芩素，吲哚美辛，胆固醇，丹参酮等难溶性药物，其能与高分子材料或者蛋白分子合成形成水溶性的前药。
3.权利要求书1所述的前药中的高分子材料包括PLA，PLGA，PLA-PLGA，PEI，透明质酸等，蛋白质分子包括白蛋白，细胞色素，转铁蛋白，乳球蛋白等包含羟基，氨基等活性基团可用于前药合成的高分子材料或者蛋白。
4.权利要求书1所述的包载大分子的脂质载体包括但不限于温度敏感型脂质体，温度响应型阳离子化脂质体，长循环脂质体，纳米乳，脂质纳米粒等，以脂质体为最优。
5.权利要求书1所述的脂质体包载的大分子药物包括anti-TGF-β，anti-CTLA4，CXCL10，anti-PD-1，anti-PD-L1，anti-CD47，IL-2等抗体或者蛋白质大分子药物。
6.权利要求书1所述的组合体系，其特征在于小分子药物与大分子药物作用于两种不同的作用靶点，从而用于抗肿瘤治疗或者其他心血管疾病的治疗。
7.权利要求书1所述的脂质体的制备方法包括薄膜分散法，逆相蒸发法等常用的脂质体制备方法。
8.权利要求书1所述的组合体系的组合方法为，小分子药物前药用PBS等适宜溶剂溶解，在涡旋或搅拌的条件下加入至脂质体溶液中，自组装形成小分子前药和脂质体的自组装纳米体系。
9.权利要求书1所述的组合体系，脂质体外层可连接透明质酸，叶酸，细胞穿透肽，导向肽等主动靶向的靶头，制备所得的脂质体粒径小于1000nm，因此，整个体系具备主动与被动靶向双重靶向作用。
10.权利要求书1～权利要求书9所述的纳米组合体系在药物制剂，药物递送等领域的应用。
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