CN112430320A - 一种多疏水核心侧链聚合物、多疏水核心载药材料及fk506制剂 - Google Patents

一种多疏水核心侧链聚合物、多疏水核心载药材料及fk506制剂 Download PDF

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CN112430320A
CN112430320A CN202011336792.1A CN202011336792A CN112430320A CN 112430320 A CN112430320 A CN 112430320A CN 202011336792 A CN202011336792 A CN 202011336792A CN 112430320 A CN112430320 A CN 112430320A
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林森
南开辉
黄宝珊
王冬梅
张娜
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Abstract

本发明涉及一种多疏水核心侧链聚合物、多疏水核心载药材料及FK506制剂。其中多疏水核心侧链聚合物为聚赖氨酸与γ‑苄基‑L‑谷氨酸‑N‑环内酸酐进行开环聚合反应得到形成的以聚赖氨酸链为骨架，含多条疏水聚谷氨酸苄酯侧链的聚合物。本发明提供的多疏水核心侧链聚合物，在水相溶液中，多疏水侧链聚合物的疏水侧链能够自组装形成多个疏水核心，通过疏水相互作用可以实现对FK506高效负载。该多疏水核心载体与聚乙二醇‑聚谷氨酸两性解离共聚物通过电荷驱动自组装能够形成稳定的纳米结构。

Description

一种多疏水核心侧链聚合物、多疏水核心载药材料及FK506 制剂
技术领域
本发明涉及一种多疏水核心侧链聚合物、多疏水核心载药材料及FK506制剂。
背景技术
FK506是一种疏水性大环内酯类抗生素，具有高效免疫抑制特性。FK506局部应用能够显著减少同种异体角膜移植物中CD4+和CD8+T细胞的浸润，抑制干眼、角膜移植排斥等。眼部独特的解剖结构及生理屏障导致FK506滴眼液的眼部生物利用度极低。主要屏障包括：角膜前屏障、结膜屏障和角膜屏障。前两项可以造成局部给药95％的药物损失。角膜前屏障，即阻碍滴眼液中药物与角膜表面充分接触的因素，包括鼻泪管引流、泪膜周转、反射性眨眼和流泪，是眼表药物迅速流失的主要原因。结膜屏障，即结膜，是一种覆盖于眼睑内和眼球前面的血管化粘膜组织，血管化使进入结膜的大部分药物被吸收到体循环中，加上结膜表面积比角膜表面积大一个数量级，进一步降低了眼表泪液中的药物浓度，使药物无法到达眼睛内部发挥药理活性。角膜屏障，即角膜独特微结构对药物渗透的限制。讨论药物输送时，角膜可被视为三层：角膜上皮、基质和内皮。角膜局部用药的主要障碍是角膜上皮和基质。角膜上皮细胞间紧密连接限制了外源性物质(无论其理化性质)通过细胞旁途径吸收，上皮细胞高度亲脂限制亲水性药物的吸收，基质高度亲水限制亲脂性药物的渗透。由于角膜兼具亲脂性和亲水性，所以要求药物既具有足够的亲脂性以穿透上皮又具有足够的水溶性以分散到基质中，才能更多地透过角膜。另外，FK506分子量大(822kDa)、高疏水性、溶液稳定性差、容易异构化形成两个无免疫抑制作用的同分异构体，为开发FK506的眼科制剂也带来挑战。
延长FK506眼表滞留时间和增强FK506角膜渗透能够有效克服角膜前及角膜屏障，提高FK506滴眼液的眼部生物利用度。市场上，90％以上的滴眼液制剂是传统剂型，包括溶液、混悬剂、软膏等，由于眼表滞留和角膜渗透能力差，生物利用度有限，因此需要频繁给药。
胶束和纳米粒等药物输送系统具有提高疏水性药物溶解度，增加药物缓释，延长药物滞留时间，促进细胞摄取，增强药物角膜渗透的能力。这类药物输送系统既可以提高疏水性药物的眼部生物利用度，又可以较久地维持目标部位有效药物浓度，提高患者依从性。两亲嵌段共聚物能够通过自组装形成纳米胶束，其生物相容性好、制备简便、临界胶束浓度低(可在体液中稳定存在)、易于靶向化修饰等而广泛用于包载疏水性药物，改善疏水性药物在溶液中分散性，优化药物的组织分布，增加生物利用度。但是，受限于疏水基团的含量，通常线型两亲嵌段共聚物载药量较低(约2-10％)，造成药物制剂中不具有治疗效果的辅料(两亲嵌段共聚物等)含量过高，影响制剂的治疗效果。
发明内容
本发明的目的是为了克服现有技术存在的缺点和不足，而提供一种多疏水核心侧链聚合物、多疏水核心载药材料及FK506制剂。
本发明所采取的技术方案如下：一种多疏水核心侧链聚合物，其为聚赖氨酸与γ-苄基-L-谷氨酸-N-环内酸酐进行开环聚合反应得到形成的以聚赖氨酸链为骨架，含多条疏水聚谷氨酸苄酯侧链的聚合物。
所述聚赖氨酸为含4-16个赖氨酸残基的聚合物多肽。
所述聚赖氨酸的氨基与γ-苄基-L-谷氨酸-N-环内酸酐的摩尔比为1:5-50。
一种多疏水核心载药材料，其为如上述的多疏水核心侧链聚合物自组装形成的。
一种FK506制剂，包括如上述的多疏水核心载药材料和负载于多疏水核心载药材料中的FK506。
一种多疏水核心载药材料，其为聚乙二醇-聚谷氨酸两性解离共聚物和如上述的多疏水核心侧链聚合物共组装形成的。
所述聚乙二醇-聚谷氨酸两性解离共聚物的制备过程如下：
(1)甲氧基聚乙二醇氨基和γ-苄基-L-谷氨酸-N-环内酸酐进行开环聚合反应得到两亲性甲氧基聚乙二醇-聚谷氨酸苄酯嵌段共聚物；
(2)对两亲性甲氧基聚乙二醇-聚谷氨酸苄酯嵌段共聚物在碱性条件下进行水解得到聚乙二醇-聚谷氨酸两性解离共聚物。
一种FK506制剂，包括如上述的多疏水核心载药材料和负载于多疏水核心载药材料中的FK506。
本发明的有益效果如下：本发明提供的多疏水核心侧链聚合物，在水相溶液中，多疏水侧链聚合物的疏水侧链能够自组装形成多个疏水核心，通过疏水相互作用可以实现对FK506高效负载。该多疏水核心载体与聚乙二醇-聚谷氨酸两性解离共聚物通过电荷驱动自组装能够形成稳定的纳米结构。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案，下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动性的前提下，根据这些附图获得其他的附图仍属于本发明的范畴。
图1为多疏水核心侧链聚合物的分子式和核磁谱图；
图2为多疏水核心侧链聚合物的扫描电镜图；
图3为不同比例的MHCP与PEG-PGA粉末(分别为1:1、1:0.5、1:0.2、1:0)共自组装得到的体系；
图4为多疏水核心载药体系的载药效率。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚，下面将结合附图对本发明作进一步地详细描述。
实施例1：
一种多疏水核心侧链聚合物(MHCP)，其制备过程如下：
利用固相合成法制备了含不同个数赖氨酸残基(4-16)的聚合物多肽。取聚赖氨酸与BLG-NCA共混(氨基与γ-苄基-L-谷氨酸-N-环内酸酐单体的摩尔比为1:5-1:50)溶于无水DMF。磁力搅拌(氮气氛围，38℃油浴)反应一定时间(2h-72h)。反应结束后，纯水中透析，去除小分子未反应物质，冷冻干燥后即得到多疏水侧链聚合物。
以下化学式为一种多疏水核心侧链聚合物的合成反应式，其中疏水侧链的数量与氨基与γ-苄基-L-谷氨酸-N-环内酸酐单体的摩尔比有关：
Figure BDA0002797396110000041
对所制备的多疏水核心侧链聚合物进行核磁鉴定，如图1所示，可以表明本实施例已经成功合成了含有多个疏水侧链的聚合物。
如图2所示，通过扫描电镜图，可以发现所制备的多疏水核心侧链聚合物可以自组装形成具有多个疏水核心的载药纳米粒(或亚微米)，其具有多个疏水核心，通过疏水相互作用可以实现对FK506高效负载。
实施例2：
一、聚乙二醇-聚谷氨酸(PEG-PGA)两性解离共聚物制备：
采用开环聚合法制备了PEG-PGA：将3g mPEG-NH2溶于15mL三氯甲烷，3.6gγ-苄基-L-谷氨酸-N-环内酸酐(BLG-NCA)溶于60mL无水DMF，两者混合后，磁力搅拌反应48h(氮气氛围，38℃油浴)。反应结束后，溶液用旋转蒸发仪蒸发三氯甲烷(57℃，145rpm)。剩余溶液用透析袋(COMW＝3500Da)在纯水中透析48h，冷冻干燥后即得到两亲性甲氧基聚乙二醇-聚谷氨酸苄酯嵌段共聚物(PEG-PBG)的粉末并称重(4.8g，产率约73％)。称取4g PEG-PBG粉末溶于40mL氯仿，然后加入51mL NaOH溶液(0.43mol/L,溶剂是纯水、甲醇、异丙醇的混合液，体积比为V纯水:V甲醇:V异丙醇＝1:2:2)，室温碱性条件下剧烈搅拌2h，再用等摩尔冰醋酸中和NaOH。中和后的溶液用旋转蒸发仪旋蒸20min蒸发掉氯仿(60℃，100rpm)，剩余溶液用透析袋(COMW＝3500Da)在纯水中透析48h，再冷冻干燥得到2.2g PEG-PGA粉末(产率约55％)。
本实施例采用mPEG5000-NH2作为原料。
二、将实施例1制备得到的多疏水核心侧链聚合物(MHCP)与PEG-PGA粉末在溶剂中溶解，然后缓慢滴加入MES缓冲液(10mM，PH＝5)中，边滴边涡旋震荡，混合液超声20min后，获得共自组装多疏水核心纳米体系(PEG-PGA and MHCP Co-self-assemblynanoparticle,PEG-PGA/MHCP NP)。
如图3所示，为不同比例的MHCP与PEG-PGA粉末(分别为1:1、1:0.5、1:0.2、1:0)共自组装得到的体系，加入PEG-PGA，所得到的体系更加稳定。
三、PEG-PGA/MHCP NP负载FK506
配制MHCP的DMF溶液、PEG-PGA的DMF溶液和FK506的DMF溶液，进行混合，然后缓慢滴加MES缓冲液(10mM，PH＝5)中，边滴边涡旋震荡，混合液超声20min后，装入透析袋(COMW＝3500Da)在大量的纯水中透析6h去除有机溶剂和未包载的FK506，即可获得负载FK506的PEG-PGA/MHCP NP(FK-506NP)。
如图4所示，当FK506与PEG-PGA/MHCP NP的质量比为5:95时，载药量基本达到5％，包封率接近100％；当FK506与PEG-PGA/MHCP NP的质量比为10:90时，载药量约为9.6％，包封率约为96％；当FK506与PEG-PGA/MHCP NP的质量比为20:80时，载药量超过16％。由此可见，本实施例所提供的PEG-PGA/MHCP NP对于亲脂性药物FK506的载药量可以超过16％，现有技术中采用传统两亲嵌段共聚物对于FK506的载药量约2-10％。
以上所揭露的仅为本发明较佳实施例而已，当然不能以此来限定本发明之权利范围，因此依本发明权利要求所作的等同变化，仍属本发明所涵盖的范围。

Claims (8)

1.一种多疏水核心侧链聚合物，其特征在于：其为聚赖氨酸与γ-苄基-L-谷氨酸-N-环内酸酐进行开环聚合反应得到形成的以聚赖氨酸链为骨架，含多条疏水聚谷氨酸苄酯侧链的聚合物。
2.根据权利要求1所述的多疏水核心侧链聚合物，其特征在于：所述聚赖氨酸为含4-16个赖氨酸残基的聚合物多肽。
3.根据权利要求1所述的多疏水核心侧链聚合物，其特征在于：所述聚赖氨酸的氨基与γ-苄基-L-谷氨酸-N-环内酸酐的摩尔比为1:5-50。
4.一种多疏水核心载药材料，其特征在于：其为如权利要求1-3任一项所述的多疏水核心侧链聚合物自组装形成的。
5.一种FK506制剂，其特征在于：包括如权利要求4所述的多疏水核心载药材料和负载于多疏水核心载药材料中的FK506。
6.一种多疏水核心载药材料，其特征在于：其为聚乙二醇-聚谷氨酸两性解离共聚物和如权利要求1-3任一项所述的多疏水核心侧链聚合物共组装形成的。
7.根据权利要求1所述的多疏水核心载药材料，其特征在于：所述聚乙二醇-聚谷氨酸两性解离共聚物的制备过程如下：
(1)甲氧基聚乙二醇氨基和γ-苄基-L-谷氨酸-N-环内酸酐进行开环聚合反应得到两亲性甲氧基聚乙二醇-聚谷氨酸苄酯嵌段共聚物；
(2)对两亲性甲氧基聚乙二醇-聚谷氨酸苄酯嵌段共聚物在碱性条件下进行水解得到聚乙二醇-聚谷氨酸两性解离共聚物。
8.一种FK506制剂，其特征在于：包括如权利要求6所述的多疏水核心载药材料和负载于多疏水核心载药材料中的FK506。
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