CN114748637B - 苯硼酸修饰型纳晶药物稳定系统及其制备方法和应用 - Google Patents
苯硼酸修饰型纳晶药物稳定系统及其制备方法和应用 Download PDFInfo
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- CN114748637B CN114748637B CN202210394655.6A CN202210394655A CN114748637B CN 114748637 B CN114748637 B CN 114748637B CN 202210394655 A CN202210394655 A CN 202210394655A CN 114748637 B CN114748637 B CN 114748637B
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Abstract
本发明公开了一种苯硼酸修饰型纳晶药物稳定系统及其制备方法和应用,该纳晶药物稳定系统由稳定剂包覆苯硼酸修饰型纳晶药物形成;其中,苯硼酸结构分子与药物通过化学键键合修饰药物,稳定剂通过硼酸酯键、主客体相互作用或配位作用与上述修饰型纳晶药物结合。该纳晶药物稳定系统制备方法简便,稳定剂结构不受限制,制得的纳晶系统稳定性好、生物安全性高、功能可调,适于作为经口服、吸入、注射、眼用、透皮、黏膜等多种给药途径的慢性病、炎症感染、肿瘤、自身免疫等疾病的药物及诊断剂。
Description
技术领域
本发明涉及一种基于苯硼酸修饰型纳晶药物的稳定系统及其制备方法和应用,尤其涉及一种制备便捷性、稳定性、生物安全性、功能可调性均显著提升的纳晶药物稳定系统及其制备方法和应用。
背景技术
药物递送系统是一种在空间、时间及剂量上全面调控药物在生物体内分布的制剂技术,可实现药物增效减毒的作用。目前,常见的药物递送载体有脂质体、胶束、乳剂、微球等多种类型,基于这些载体的递送系统具有载药量低、载体生物相容性差、载体不易降解代谢或代谢不明确存在潜在风险、载体构建过程复杂且质量批次差异大、制剂工艺复杂难放大等缺点,使其不易于临床应用。
纳晶药物主要由纯药物纳米颗粒和稳定纳米晶所需的稳定剂组成。纳晶药物具有载药效率高、不依赖载体设计与合成、辅料用量低、制备过程简单易于产业化等优点。然而,尽管目前已有多种纳晶药物制剂上市,该剂型仍存在一些制备难点:稳定剂一般须具有两亲性,借助物理作用稳定纳晶药物,因此,稳定剂在体内易于从纳晶药物表面脱落,稳定剂的选择须基于反复试验,甚至无法匹配最佳稳定剂用于制备稳定的纳晶制剂,无法灵活调控稳定剂结构以获得靶向等不同功能特性以满足不同的制剂应用需求。此外,常规纳晶制剂不具有病灶响应释放特性,可能会导致药效不佳。
发明内容
发明目的:针对现有药物递送系统存在的制备工艺受限、安全性风险、仅能满足一定功能等不足,本发明旨在提供一种制备便捷性、稳定性、生物安全性、功能可调性均显著提升的纳晶药物稳定系统及其制备方法和应用。
技术方案:作为本发明涉及的第一方面,本发明的纳晶药物稳定系统由稳定剂包覆苯硼酸修饰型纳晶药物形成;所述苯硼酸修饰型纳晶药物为苯硼酸结构分子与药物通过化学键键合修饰;所述稳定剂通过硼酸酯键、主客体相互作用或配位作用与苯硼酸修饰型纳晶药物结合。
苯硼酸(Phenylboronic acid,PBA)分子由苯环和硼酸两个基本结构组成。硼酸为路易斯酸,硼原子缺电子,三取代的硼原子具有三角平面几何结构,空p轨道垂直于分子平面,提供了电子交换的可能性。苯硼酸可以与顺式邻二醇(1,2-二醇、1,3-二醇)形成环状硼酸酯键,可以与各种杂原子(包括氧、硫、磷和氮)形成配位作用;此外PBA可以与主体分子的疏水空腔形成主客体包合作用。苯硼酸酯键、配位作用可具有pH响应性、活性氧响应性,包合作用可被生物成分(如三磷酸腺苷等)竞争等。
常见富含顺式邻二醇、疏水空腔或氮、硫、氧杂原子的分子包括多糖、环糊精、多酚、蛋白质、含氧或氮原子高分子。多糖是由多个单糖分子缩合、失水而成,是一类分子结构复杂且庞大的糖类物质,具有丰富的邻二醇(1,2-二醇、1,3-二醇)结构。多糖长期重复给药无明显蓄积作用,具有良好的生物相容性,此类稳定剂较多,具有生物活性如肿瘤靶向、血栓靶向、抗炎、抗菌、抗氧化、免疫调节、抗肿瘤、抗辐射、抗病毒、降血糖、降血脂、保护肝脏、神经保护等作用。环糊精是一系列环状低聚糖的总称,通常含有6~12个葡萄糖单元,各葡萄糖单元均以1,4-糖苷键结合成环。由于连接葡萄糖单元的糖苷键不能自由旋转,环糊精呈锥形圆环。由于环糊精的外缘亲水而内腔疏水,提供疏水结合部位,作为主体可包合各种适当的客体。多酚是一类含有丰富邻二酚羟基结构的生物相容性物质。蛋白质是由氨基酸以脱水缩合的方式组成的多肽链经过盘曲折叠形成的具有一定空间结构的物质;蛋白质中一定含有氧、氮元素,也可能含有硫、磷等元素。
本发明的苯硼酸修饰型纳晶药物稳定系统中,稳定剂以邻二醇(1,2-二醇、1,3-二醇)结构与PBA结构分子形成苯硼酸酯键,或以疏水空腔与PBA形成包合作用,或以各种杂原子(包括氧、硫、磷和氮)与PBA形成配位作用等,以发挥稳定化功能,同时赋予药物纳晶病灶响应性。苯硼酸修饰型药物经简单工艺操可稳定结合上述多种稳定剂及其衍生物,不仅降低高度稳定化纳晶药物的制备工艺难度,更显著扩展了纳晶药物稳定剂的选择范围和目标制剂的应用潜能。
优选,所述苯硼酸修饰型纳晶药物稳定系统粒径为10nm~600nm,载药量为5%~95%;所述多糖与修饰型药物纳晶的质量比为1:20~20:1。
优选,所述药物包括阿霉素、表阿霉素、萘普生、喜树碱、紫杉醇、姜黄素、阿奇霉素、槲皮素中的一种或多种。
优选,所述苯硼酸结构分子包括氟、甲氧基、硝基或三氟甲基取代的或者无取代的羧基苯硼酸、氨基苯硼酸、羟基苯硼酸、乙烯基苯硼酸、巯基苯硼酸、甲酰基苯硼酸、氨甲基苯硼酸、溴甲基苯硼酸、羟甲基苯硼酸、丙烯酰氨基苯硼酸、丙烯酸酯苯硼酸中的一种或多种。
优选,所述稳定剂包括透明质酸、硫酸软骨素、肝素、壳聚糖、葡聚糖、普鲁兰多糖、直链淀粉、菊糖、果聚糖、水溶性纤维素、岩藻多糖、红藻多糖、三叶青多糖、枸杞多糖、黄芪多糖、茯苓多糖、香菇多糖、甲壳素、槲皮素、山柰酚、杨梅素、花色苷、木犀草、儿茶酚、没食子儿茶酚、没食子儿茶酚没食子酸酯、表没食子儿茶素没食子酸酯、二没食子酰基-D-葡萄糖、三没食子酰基葡萄糖、四没食子酰基葡萄糖、五没食子酰基葡萄糖、没食子酸、双没食子酸、单宁酸、鞣花单宁、鞣花酸、水解单宁、聚多巴胺、精蛋白、胶原蛋白、酪蛋白、载脂蛋白、明胶、白蛋白、乳清蛋白、大豆蛋白、小麦蛋白、单细胞蛋白、叶蛋白、鱼蛋白、醇溶蛋白、聚乙烯醇、聚乙烯吡咯烷酮、聚乙二醇、泊洛沙姆、聚(乙烯亚胺)、聚氧乙烯、乙交酯丙交酯共聚物、聚乳酸-羟基乙酸共聚物、聚甲基丙烯酸羟乙酯、环糊精、聚环糊精、环糊精接枝聚合物中的一种或多种;还可以选自上述稳定剂的衍生物,例如酯类、醚类、糖基化类等衍生物。
作为本发明涉及的第二方面,本发明的苯硼酸修饰型纳晶药物稳定系统的制备方法包括以下步骤:
(1)制备修饰型纳晶药物;
(2)制备纳晶药物稳定系统
方法一:分步制备纳晶药物稳定系统
配制稳定剂溶液,将步骤(1)制备的修饰型纳晶药物与稳定剂溶液混合,调节pH至7.0~8.0,混合,除去溶剂,即得纳晶药物稳定系统;
方法二:一步法制备纳晶药物稳定系统
分别配制修饰型纳晶药物、稳定剂溶液,两种溶液混合后与修饰型纳晶药物的不良溶剂混合,调节pH至7.0~8.0,混合,除去溶剂,即得纳晶药物稳定系统;
或将修饰型纳晶药物溶液与以修饰型纳晶药物不良溶剂溶解的稳定剂溶液混合,调节pH至7.0~8.0,混合,除去溶剂,即得纳晶药物稳定系统。
其中,步骤(1)制备修饰型纳晶药物的具体操作如下:
以常规反溶剂沉淀法、溶剂蒸发法、超临界流体技术、微流控技术、冻融法或超声法制备苯硼酸修饰型纳晶药物。
步骤(2)制备纳晶药物稳定系统的具体操作如下:
方法一:分步制备纳晶药物稳定系统
配制稳定剂溶液,将步骤(1)制备的修饰型纳晶药物与稳定剂溶液简单混合,调节pH至7.0~8.0,混合一段时间后,并经超声、均质、匀浆或介质研磨操作,采用透析、超滤或蒸发除去溶剂,制得高效稳定化纳晶药物稳定系统。
方法二:一步法制备纳晶药物稳定系统
分别配制修饰型纳晶药物、稳定剂溶液,两种溶液混合后与修饰型纳晶药物的不良溶剂经微流控技术快速混合,或简单混合并经超声、均质、匀浆或介质研磨操作,调节pH至7.0~8.0,采用透析、超滤或蒸发除去溶剂,即得纳晶药物稳定系统;
或分别配制修饰型纳晶药物、稳定剂溶液,将修饰型纳晶药物溶液与稳定剂溶液经微流控技术快速混合,或简单混合并经超声、均质、匀浆或介质研磨操作,调节pH至7.0~8.0,采用透析、超滤或蒸发除去溶剂,即得纳晶药物稳定系统。其中,稳定剂溶液是由修饰型纳晶药物的不良溶剂溶解稳定剂所得。
更具体地,所述混合时间为1~24h;所述超声频率为100~600W,超声时间是1~30min;所述均质是通过高压均质机或微射流均质机实施的,均质压力为300~1200Pa,均质次数为1~20次;所述匀浆是通过匀浆机实现的,转速为1000~10000rpm,匀浆时间为30~300s;所述介质研磨机器转速为400~800rpm,研磨时间为1~10h;所述微流控技术是一种在以微米为单位尺寸的通道内处理少量流体(10-9~10-18l)的技术,将流体分别注入不同通道,控制其相对体积流速比例并实现快速混合。所述的药学上可接受的溶剂为二甲亚砜、N,N-二甲基甲酰胺、甲酰胺、乙醇、丙酮、甲醇、四氢呋喃、二氯甲烷、三氯甲烷、乙酸乙酯、异丙醇中的一种或多种。
作为本发明涉及的第三方面,本发明的药物组合物包含上述纳晶药物稳定系统以及药学上可接受的载体。
上述药物组合物为液体注射剂、口服溶液剂、滴眼剂、气雾剂、喷雾剂、粉雾剂或冻干制剂。其中,可添加的冻干保护剂包括精氨酸、天冬氨酸等氨基酸、白蛋白、明胶、聚维酮、氯化钠、谷氨酸钠、枸橼酸盐、醋酸盐、磷酸盐中的一种或多种。
作为本发明涉及的第四方面,上述纳晶药物稳定系统可制备为经口服、吸入、注射、眼用、透皮或黏膜给药的疾病预防剂、治疗剂或诊断剂,尤其是适于慢性病、炎症感染、肿瘤、自身免疫疾病等相关疾病的预防、治疗或诊断。
有益效果:与现有技术相比,本发明具有如下显著优点:
(1)稳定剂不使用两亲性结构,并且稳定剂结构不受限制,可直接以多种作用方式稳定包覆苯硼酸修饰型药物,药物系统具有病灶特异性释药功能,发挥增效减毒的作用;
(2)制备工艺简便,扩展了纳晶药物稳定剂的选择范围,并且可灵活调控药物系统功能特性。
附图说明
图1A为实施例1中阿霉素纳米晶(NC)、苯硼酸化阿霉素纳米晶(PFNC)、阿霉素纳米晶@葡聚糖-脱氧胆酸(NDA)、阿霉素纳米晶@葡聚糖-苯硼酸脱氧胆酸(NDPA)、苯硼酸化阿霉素纳米晶@葡聚糖(PFND)的粒径分布及稀释稳定性图;
图1B为实施例1中阿霉素纳米晶(NC)、苯硼酸化阿霉素纳米晶(PFNC)、阿霉素纳米晶@葡聚糖-脱氧胆酸(NDA)、阿霉素纳米晶@葡聚糖-苯硼酸脱氧胆酸(NDPA)、苯硼酸化阿霉素纳米晶@葡聚糖(PFND)的电位图;
图2为实施例1中苯硼酸化阿霉素纳米晶@葡聚糖(PFND)的透射电镜图;
图3A为实施例1中苯硼酸化阿霉素纳米晶(PFNC)、苯硼酸化阿霉素纳米晶@葡聚糖(PFND)的含10%血清的PBS稀释稳定性图;
图3B为实施例1中苯硼酸化阿霉素纳米晶(PFNC)、苯硼酸化阿霉素纳米晶@葡聚糖(PFND)的培养基稀释稳定性图;
图4A为实施例2中苯硼酸化阿霉素纳米晶(PFNC)、苯硼酸化阿霉素纳米晶@聚乙烯吡咯烷酮(PFNP)的粒径分布及稀释稳定性图;
图4B为实施例2中苯硼酸化阿霉素纳米晶(PFNC)、苯硼酸化阿霉素纳米晶@聚乙烯吡咯烷酮(PFNP)的电位图;
图5A为实施例3中苯硼酸化阿霉素纳米晶(PFNC)、苯硼酸化阿霉素纳米晶@壳聚糖-β-环糊精(PFND)的粒径分布及稀释稳定性图;
图5B为实施例3中苯硼酸化阿霉素纳米晶(PFNC)、苯硼酸化阿霉素纳米晶@壳聚糖-β-环糊精(PFND)的电位图;
图6A为实施例4中苯硼酸化萘普生纳米晶(PFNC)、苯硼酸化萘普生纳米晶@葡聚糖(PFND)的粒径分布及稀释稳定性图;
图6B为实施例4中苯硼酸化萘普生纳米晶(PFNC)、苯硼酸化萘普生纳米晶@葡聚糖(PFND)的电位图;
图7A为实施例5中苯硼酸化萘普生纳米晶(PFNC)、苯硼酸化萘普生纳米晶@双没食子酸(PFNA)的粒径分布及稀释稳定性图;
图7B为实施例5中苯硼酸化萘普生纳米晶(PFNC)、苯硼酸化萘普生纳米晶@双没食子酸(PFNA)的电位图;
图8A为实施例6中苯硼酸化紫杉醇纳米晶(PNC)、苯硼酸化紫杉醇纳米晶@透明质酸(PNH)的粒径分布及稀释稳定性图;
图8B为实施例6中苯硼酸化紫杉醇纳米晶(PNC)、苯硼酸化紫杉醇纳米晶@透明质酸(PNH)的电位图;
图9A为实施例7中苯硼酸化紫杉醇纳米晶(PNC)、苯硼酸化紫杉醇纳米晶@白蛋白(PNB)的粒径分布及稀释稳定性图;
图9B为实施例7中苯硼酸化紫杉醇纳米晶(PNC)、苯硼酸化紫杉醇纳米晶@白蛋白(PNB)的电位图;
图10A为实施例8中苯硼酸化喜树碱纳米晶(PNNC)、苯硼酸化喜树碱纳米晶@壳聚糖(PNNS)的粒径分布及稀释稳定性图;
图10B为实施例8中苯硼酸化喜树碱纳米晶(PNNC)、苯硼酸化喜树碱纳米晶@壳聚糖(PNNS)的电位图;
图11A为实施例9中苯硼酸化喜树碱纳米晶(PNNC)、苯硼酸化喜树碱纳米晶@聚乙烯醇(PNNA)的粒径分布及稀释稳定性图;
图11B为实施例9中苯硼酸化喜树碱纳米晶(PNNC)、苯硼酸化喜树碱纳米晶@聚乙烯醇(PNNA)的电位图;
图12为实施例1中苯硼酸化阿霉素纳米晶@葡聚糖(PFND)在pH 7.4、pH5.5及pH5.5含10mM H2O2条件下,阿霉素纳米晶@葡聚糖-脱氧胆酸(NDA)及阿霉素纳米晶@葡聚糖-苯硼酸脱氧胆酸(NDPA)在pH 5.5含10mM H2O2条件下的释放行为;
图13为实施例1中阿霉素纳米晶(NC)、苯硼酸化阿霉素纳米晶(PFNC)、阿霉素纳米晶@葡聚糖-脱氧胆酸(NDA)、阿霉素纳米晶@葡聚糖-苯硼酸脱氧胆酸(NDPA)、苯硼酸化阿霉素纳米晶@葡聚糖(PFND)的在体肿瘤组织分布图;
图14为实施例1中苯硼酸化阿霉素纳米晶(PFNC)、苯硼酸化阿霉素纳米晶@葡聚糖(PFND)的体内药效的瘤重。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
实施例1:反溶剂沉淀制备苯硼酸化阿霉素纳米晶或阿霉素纳米晶;均质制备阿霉素纳米晶@葡聚糖-脱氧胆酸、阿霉素纳米晶@葡聚糖-苯硼酸脱氧胆酸或苯硼酸化阿霉素纳米晶@葡聚糖。
(1)制备苯硼酸化阿霉素纳米晶或阿霉素纳米晶
阿霉素经4-羧基-3-氟苯硼酸修饰后得到苯硼酸化阿霉素,结构如上图所示。称量5mg苯硼酸化阿霉素或阿霉素,加入100μl DMSO溶解,将100μl苯硼酸化阿霉素或阿霉素溶液缓慢滴入5ml水中,磁力搅拌器1000rpm剧烈搅拌15min,5000rpm离心5min,取上清,得到澄清溶液。
(2)制备阿霉素纳米晶@葡聚糖-脱氧胆酸、阿霉素纳米晶@葡聚糖-苯硼酸脱氧胆酸或苯硼酸化阿霉素纳米晶@葡聚糖
经酯化反应得到葡聚糖-脱氧胆酸,于脱氧胆酸上修饰苯硼酸、并经硼酸酯键耦联葡聚糖得到葡聚糖-苯硼酸脱氧胆酸,配置2ml葡聚糖-脱氧胆酸、葡聚糖-苯硼酸脱氧胆酸或葡聚糖水溶液(1mg/ml),加入上述制备得到的5ml阿霉素纳米晶或苯硼酸化阿霉素纳米晶溶液,调节pH至7.5,500rpm搅拌混合2h后,500bar高压均质循环5次,1000bar循环5次,超滤后制备得到阿霉素纳米晶@葡聚糖-脱氧胆酸、阿霉素纳米晶@葡聚糖-苯硼酸脱氧胆酸或苯硼酸化阿霉素纳米晶@葡聚糖。
实施例2:微流控技术制备苯硼酸化阿霉素纳米晶及苯硼酸化阿霉素纳米晶@聚乙烯吡咯烷酮。
苯硼酸化阿霉素如实施例1所示,称量10mg苯硼酸化阿霉素,加入2ml乙醇溶解,与等体积水注入微流控设备中,调节苯硼酸阿霉素溶液流速为100μl/min、水流速为100μl/min,得到澄清溶液,旋蒸除去有机溶剂,得到苯硼酸化阿霉素纳米晶;
称量10mg苯硼酸化阿霉素,加入1ml乙醇溶解,称量10mg聚乙烯吡咯烷酮,加入1ml乙醇溶解,混合上述溶液,与等体积水注入微流控设备中,调节苯硼酸化阿霉素-聚乙烯吡咯烷酮溶液流速为100μl/min、水流速为100μl/min,得到澄清溶液,旋蒸除去有机溶剂,调节溶液pH至7.4,600rpm下搅拌混合1h,得到苯硼酸化阿霉素纳米晶@聚乙烯吡咯烷酮。
实施例3:超声制备苯硼酸化阿霉素纳米晶及苯硼酸化阿霉素纳米晶@壳聚糖-β-环糊精
经化学修饰得到β-环糊精接枝的壳聚糖,苯硼酸化阿霉素如实施例1所示,称量5mg苯硼酸化阿霉素,加入100μl DMSO溶解,配置1mg/ml壳聚糖-β-环糊精水溶液,将100μl苯硼酸化阿霉素溶液缓慢滴入5ml水或壳聚糖-β-环糊精水溶液中,磁力搅拌器800rpm剧烈搅拌10min,300W探头超声5min,透析除去有机溶剂得到苯硼酸化阿霉素纳米晶或苯硼酸化阿霉素纳米晶@壳聚糖-β-环糊精。
实施例4:溶剂蒸发法制备苯硼酸化萘普生纳米晶;超声制备苯硼酸化萘普生纳米晶@葡聚糖。
(1)制备苯硼酸化萘普生纳米晶
萘普生经3-氨基-4-氟苯硼酸修饰后得到苯硼酸化萘普生,结构如上图所示。称量5mg苯硼酸化萘普生,加入1ml氯仿溶解,将苯硼酸化萘普生溶液滴入5ml水中,1000rpm涡旋15min,200W探头超声20min,旋转蒸发除去有机溶剂后得到澄清溶液。
(2)制备苯硼酸化萘普生纳米晶@葡聚糖
配置2ml葡聚糖水溶液(0.25mg/ml),加入上述制备得到的5ml苯硼酸化萘普生纳米晶溶液,调节pH至7.3,600rpm搅拌混合4h后,300W超声20min,制备得到苯硼酸化萘普生纳米晶@葡聚糖。
实施例5:混合超声制备苯硼酸化萘普生纳米晶及苯硼酸化萘普生纳米晶@双没食子酸。
苯硼酸化萘普生如实施例4所示,称量5mg苯硼酸化萘普生,加入200μlDMSO溶解后,将200μl苯硼酸化萘普生溶液滴入5ml水中,800rpm搅拌2h,200W超声15min,透析除去DMSO,得到苯硼酸化萘普生纳米晶;
称量5mg苯硼酸化萘普生,加入100μl DMSO溶解,称量5mg双没食子酸,加入100μlDMSO溶解,混合上述溶液,将200μl苯硼酸化萘普生-双没食子酸溶液滴入5ml水中,调节溶液pH至7.4,800rpm搅拌2h,200W超声15min,透析除去DMSO,得到苯硼酸化萘普生纳米晶。
实施例6:超声法制备苯硼酸化紫杉醇纳米晶;匀浆法制备苯硼酸化紫杉醇纳米晶@透明质酸
(1)制备苯硼酸化紫杉醇纳米晶
紫杉醇经4-羟甲基苯硼酸修饰后得到苯硼酸化紫杉醇,结构如上图所示。称量5mg苯硼酸化紫杉醇,加入100μl甲醇溶解,将100μl苯硼酸化紫杉醇溶液滴入5ml水中,800rpm搅拌5min,300W探头超声15min,得到澄清溶液。
(2)制备苯硼酸化紫杉醇纳米晶@透明质酸
配置3ml透明质酸水溶液(0.2mg/ml),加入上述制备得到的5ml苯硼酸化紫杉醇纳米晶溶液,调节pH至7.8,800rpm搅拌混合12h后,1000rpm匀浆3min,制备得到苯硼酸化紫杉醇纳米晶@透明质酸。
实施例7:微流控技术制备苯硼酸化紫杉醇纳米晶及苯硼酸化紫杉醇纳米晶@白蛋白。
苯硼酸化紫杉醇如实施例6所示,称量5mg苯硼酸化紫杉醇,加入1ml甲醇溶解,与两倍体积水注入微流控设备中,调节苯硼酸紫杉醇溶液流速为60μl/min、水流速为120μl/min,得到澄清溶液,旋蒸除去有机溶剂,得到苯硼酸化紫杉醇纳米晶;
称量5mg苯硼酸化紫杉醇,加入1ml甲醇溶解,称量5mg白蛋白,加入2ml纯水溶解,两种溶液注入微流控设备中,调节苯硼酸化紫杉醇溶液流速为60μl/min、白蛋白溶液流速为120μl/min,得到澄清溶液,旋蒸除去有机溶剂,调节溶液pH至7.4,600rpm下搅拌混合2h,得到苯硼酸化紫杉醇纳米晶@白蛋白。
实施例8:微流控技术制备苯硼酸化喜树碱纳米晶;介质研磨制备苯硼酸化喜树碱纳米晶@壳聚糖
(1)制备苯硼酸化喜树碱纳米晶
喜树碱经4-羧基-2-硝基苯硼酸修饰后得到苯硼酸化喜树碱,结构如上图所示。称量10mg苯硼酸化喜树碱,加入5ml乙醇溶解,将苯硼酸化喜树碱溶液与等体积水注入微流控设备中,调节苯硼酸化喜树碱溶液流速为80μl/min、水流速为80μl/min,旋转蒸发除去有机溶剂后,得到澄清溶液。
(2)制备苯硼酸化喜树碱纳米晶@壳聚糖
配置2ml壳聚糖水溶液(1mg/ml),加入上述制备得到的5ml苯硼酸化喜树碱纳米晶溶液,调节pH至7.5,600rpm搅拌混合6h后,600rpm介质研磨2h,制备得到苯硼酸化喜树碱纳米晶@壳聚糖。
实施例9:混合匀浆制备苯硼酸化喜树碱纳米晶及苯硼酸化喜树碱纳米晶@聚乙烯醇。
苯硼酸化喜树碱如实施例8所示,称量5mg苯硼酸化喜树碱,加入100μlDMF溶解后,将100μl苯硼酸化喜树碱溶液滴入5ml水中,600rpm搅拌2h,5000rpm匀浆分散2min,透析除去DMF,得到苯硼酸化喜树碱纳米晶;
称量5mg苯硼酸化喜树碱,加入100μl DMF溶解,称量7.5mg聚乙烯醇,加入5ml纯水溶解,将100μl苯硼酸化喜树碱溶液滴入5ml聚乙烯醇溶液中,调节溶液pH至7.4,600rpm搅拌2h,5000rpm匀浆分散2min,透析除去DMF,得到苯硼酸化喜树碱纳米晶@聚乙烯醇。
实施例10
将实施例6制备的苯硼酸化紫杉醇纳米晶@透明质酸加入2.5%蔗糖进行冻干保存。
实施例11:葡聚糖稳定化苯硼酸化阿霉素纳晶的制剂学表征
取实施例1制备的阿霉素纳米晶(NC)、苯硼酸化阿霉素纳米晶(PFNC)、阿霉素纳米晶@葡聚糖-脱氧胆酸(NDA)、阿霉素纳米晶@葡聚糖-苯硼酸脱氧胆酸(NDPA)、苯硼酸化阿霉素纳米晶@葡聚糖(PFND),采用马尔文粒径仪分别测定样品的粒径及电位。结果如图1A、1B所示,不同制剂粒径和电位的变化表明目标制剂的成功制备;采用透射电子显微镜观察PFND的形状,结果如图2所示,目标稳定化纳晶制剂形态均一性较好。
取实施例1制备的NC、PFNC、NDA、NDPA、PFND,分别使用pH 7.4PBS稀释30倍,采用马尔文粒径仪测定稀释后样品的粒径以考察其稀释稳定性。结果如图1A所示,纳晶颗粒在包覆两亲性载体、多糖后稀释稳定性较裸露的纳晶药物有所改善,纳晶药物经化学作用包覆稳定剂相较于经两亲作用包覆稳定剂,稀释稳定效果更优。
取PFNC和PFND制剂,使用培养基、含10%血清的PBS稀释10倍,37℃、100rpm摇床放置,采用马尔文粒径仪分别测定样品的粒径。结果如图3A和3B所示,苯硼酸化药物纳晶被多糖包覆稳定后,较裸露的纳晶更耐受模拟的生理环境,进一步证明苯硼酸结构分子的化学修饰、多糖的包覆于本发明设计中的必要性。
实施例12:聚乙烯吡咯烷酮稳定化苯硼酸化阿霉素纳米晶的制剂学表征
取实施例2制备的苯硼酸化阿霉素纳米晶(PFNC)、苯硼酸化阿霉素纳米晶@聚乙烯吡咯烷酮(PFNP)制剂,采用马尔文粒径仪分别直接测定样品的粒径及电位、及测定以pH7.4PBS稀释30倍后的粒径,以对比考察制剂的稀释稳定性。结果如图4所示,两个制剂粒径和电位的变化表明聚乙烯吡咯烷酮的成功包覆,稀释稳定性的差别证明苯硼酸化纳米晶在修饰外层高分子稳定剂后较裸露纳晶的稳定性显著提高。
实施例13:壳聚糖-β-环糊精稳定化苯硼酸化阿霉素纳米晶的制剂学表征
取实施例3制备的苯硼酸化阿霉素纳米晶(PFNC)、苯硼酸化阿霉素纳米晶@壳聚糖-β-环糊精(PFND)制剂,采用马尔文粒径仪分别直接测定样品的粒径及电位、及测定以pH7.4PBS稀释30倍后的粒径,以对比考察制剂的稀释稳定性。结果如图5所示,两个制剂粒径和电位的变化表明壳聚糖-β-环糊精的成功包覆,稀释稳定性的差别证明苯硼酸化纳米晶在修饰外层环糊精接枝聚合物稳定剂后较裸露纳晶的稳定性显著提高。
实施例14:葡聚糖稳定化苯硼酸化萘普生纳晶的制剂学表征
取实施例4制备的苯硼酸化萘普生纳米晶(PFNC)、苯硼酸化萘普生纳米晶@葡聚糖(PFND)制剂,采用马尔文粒径仪分别直接测定样品的粒径及电位、及测定以pH 7.4PBS稀释30倍后的粒径,以对比考察制剂的稀释稳定性。结果如图6所示,两个制剂粒径和电位的变化表明葡聚糖的成功包覆,稀释稳定性的差别证明苯硼酸化纳米晶在修饰外层多糖稳定剂后较裸露纳晶的稳定性显著提高。
实施例15:双没食子酸稳定化苯硼酸化萘普生纳晶的制剂学表征
取实施例5制备的苯硼酸化萘普生纳米晶(PFNC)、苯硼酸化萘普生纳米晶@双没食子酸(PFNA)制剂,采用马尔文粒径仪分别直接测定样品的粒径及电位、及测定以pH 7.4PBS稀释30倍后的粒径,以对比考察制剂的稀释稳定性。结果如图7所示,两个制剂粒径和电位的变化表明双没食子酸的成功包覆,稀释稳定性的差别证明苯硼酸化纳米晶在修饰外层多酚稳定剂后较裸露纳晶的稳定性显著提高。
实施例16:透明质酸稳定化苯硼酸化紫杉醇纳晶的制剂学表征
取实施例6制备的苯硼酸化紫杉醇纳米晶(PNC)、苯硼酸化紫杉醇纳米晶@透明质酸(PNH)制剂,采用马尔文粒径仪分别直接测定样品的粒径及电位、及测定以pH 7.4PBS稀释30倍后的粒径,以对比考察制剂的稀释稳定性。结果如图8所示,两个制剂粒径和电位的变化表明外层多糖稳定剂的成功包覆,稀释稳定性的差别证明苯硼酸化纳米晶在修饰外层多糖稳定剂后较裸露纳晶的稳定性显著提高。
实施例17:白蛋白稳定化苯硼酸化紫杉醇纳晶的制剂学表征
取实施例7制备的苯硼酸化紫杉醇纳米晶(PNC)、苯硼酸化紫杉醇纳米晶@白蛋白(PNB)制剂,采用马尔文粒径仪分别直接测定样品的粒径及电位、及测定以pH 7.4PBS稀释30倍后的粒径,以对比考察制剂的稀释稳定性。结果如图9所示,两个制剂粒径和电位的变化表明外层白蛋白的成功包覆,稀释稳定性的差别证明苯硼酸化纳米晶在修饰外层蛋白稳定剂后较裸露纳晶的稳定性显著提高。
实施例18:壳聚糖稳定化苯硼酸化喜树碱纳晶的制剂学表征
取实施例8制备的苯硼酸化喜树碱纳米晶(PNNC)、苯硼酸化喜树碱纳米晶@壳聚糖(PNNS),采用马尔文粒径仪分别直接测定样品的粒径及电位、及测定以pH 7.4PBS稀释30倍后的粒径,以对比考察制剂的稀释稳定性。结果如图10所示,两个制剂粒径和电位的变化表明外层多糖稳定剂的成功包覆,稀释稳定性的差别证明苯硼酸化纳米晶在修饰外层多糖稳定剂后较裸露纳晶的稳定性显著提高。
实施例19:聚乙烯醇稳定化苯硼酸化喜树碱纳晶的制剂学表征
取实施例9制备的苯硼酸化喜树碱纳米晶(PNNC)、苯硼酸化喜树碱纳米晶@聚乙烯醇(PNNA),采用马尔文粒径仪分别直接测定样品的粒径及电位、及测定以pH 7.4PBS稀释30倍后的粒径,以对比考察制剂的稀释稳定性。结果如图11所示,两个制剂粒径和电位的变化表明外层聚乙烯醇的成功包覆,稀释稳定性的差别证明苯硼酸化纳米晶在修饰外层高分子稳定剂后较裸露纳晶的稳定性显著提高。
实施例11~19的结果也证明药物在修饰苯硼酸后可在药物纳晶表面稳定包覆多糖、环糊精接枝聚合物、多酚、蛋白、高分子稳定剂进而得到高效稳定化的纳晶药物制剂。
实施例20:葡聚糖稳定化苯硼酸化阿霉素纳晶的体外释放表征
取实施例1制备得到的NDA、NDPA、PFND制剂,采用透析法考察阿霉素的释放行为。将2ml制备的制剂溶液转移到透析袋(MWCO:3000Da)中,在37℃下放入48ml的释放介质(含0.1%Tween-80的PBS),100rpm摇晃。在预先设定的时间,取出1ml的释放液,并加入等量的新鲜释放介质。采用酶标仪测定硼酸化阿霉素的浓度。释放介质分别为pH 7.4、pH 5.5和pH5.5加10mM H2O2。结果如图12所示,经硼酸酯键包覆多糖稳定剂的苯硼酸化药物纳晶在正常生理环境下(pH 7.4)泄露较少、比较稳定,同时相较于经两亲作用包覆、无响应性稳定剂的纳晶具有pH和活性氧响应释药特性。
实施例21:葡聚糖稳定化苯硼酸化阿霉素纳晶的体内分布表征
Balb/c小鼠(18-20g)随机分为5组(n=5),原位接种4T1细胞,肿瘤大小约为200mm3时,静脉注射实施例1中NC、PFNC、NDA、NDPA、PFND(给药剂量以5mg/kg阿霉素折算)。12h后,用放射免疫沉淀分析缓冲液(RIPA,每10mg肿瘤组织100μl)溶解肿瘤,冰浴探头超声处理15min。将裂解液在4℃下14000g离心10min,收集上清液进行荧光测定。结果如图13所示,与图1中的稀释稳定性数据趋势一致,表明苯硼酸化纳晶药物制剂在外层经化学作用包覆多糖稳定剂后相较于纳晶药物经两亲性包覆稳定剂具有较好的生理稳定性,有益于其向实体瘤蓄积。
实施例22:葡聚糖稳定化苯硼酸化阿霉素纳晶在4T1细胞模型的体内药效
Balb/c小鼠(18-20g)随机分为3组(n=5),原位接种4T1细胞,当肿瘤大小达到100mm3左右时,静脉注射生理盐水、实施例1中PFNC、PFND(给药剂量以5mg/kg阿霉素折算),每3天静脉注射一次,注射4次。在实验结束时,根据机构指南对小鼠实施安乐死,并对肿瘤进行解剖和称重。结果如图14所示,葡聚糖稳定化苯硼酸阿霉素纳晶制剂抑制肿瘤生长效果较好,表明本发明设计的苯硼酸化、多糖包覆纳米晶具有较好的稳定性、响应释放特性,体内应用效果较好。
Claims (8)
1.一种苯硼酸修饰型纳晶药物稳定系统,其特征在于,由稳定剂包覆苯硼酸修饰型纳晶药物形成;所述苯硼酸修饰型纳晶药物为苯硼酸结构分子与药物通过化学键键合修饰;所述稳定剂通过硼酸酯键、主客体相互作用或配位作用与苯硼酸修饰型纳晶药物结合;
所述药物为阿霉素、萘普生、喜树碱、紫杉醇中的一种或多种;
所述苯硼酸结构分子包括氟、硝基取代的或者无取代的羧基苯硼酸、氨基苯硼酸、羟甲基苯硼酸中的一种或多种;
所述稳定剂包括透明质酸、壳聚糖、甲壳素、葡聚糖、香菇多糖、岩藻多糖、黄芪多糖、双没食子酸、没食子儿茶酚没食子酸酯、表没食子儿茶素没食子酸酯、二没食子酰基-D-葡萄糖、三没食子酰基葡萄糖、四没食子酰基葡萄糖、五没食子酰基葡萄糖、单宁酸、鞣花单宁、鞣花酸、白蛋白、载脂蛋白、乳清蛋白、聚乙烯醇、聚乙烯吡咯烷酮、聚乙二醇、泊洛沙姆、聚(乙烯亚胺)、环糊精、聚环糊精、环糊精接枝聚合物中的一种或多种;
所述的苯硼酸修饰型纳晶药物稳定系统的制备方法包括以下步骤:
(1)制备修饰型纳晶药物;
(2)制备纳晶药物稳定系统
方法一:分步制备纳晶药物稳定系统
配制稳定剂溶液,将步骤(1)制备的修饰型纳晶药物与稳定剂溶液混合,调节pH至7.0~8.0,混合,除去溶剂,即得纳晶药物稳定系统;
方法二:一步法制备纳晶药物稳定系统
分别配制修饰型纳晶药物、稳定剂溶液,两种溶液混合后与修饰型纳晶药物的不良溶剂混合,调节pH至7.0~8.0,混合,除去溶剂,即得纳晶药物稳定系统;
或将修饰型纳晶药物溶液与以修饰型纳晶药物不良溶剂溶解的稳定剂溶液混合,调节pH至7.0~8.0,混合,除去溶剂,即得纳晶药物稳定系统。
2.根据权利要求1所述的苯硼酸修饰型纳晶药物稳定系统,其特征在于,粒径为10nm~600nm。
3.根据权利要求1所述的苯硼酸修饰型纳晶药物稳定系统,其特征在于,载药量为5%~95%。
4.根据权利要求1所述的苯硼酸修饰型纳晶药物稳定系统,其特征在于,所述稳定剂与苯硼酸修饰型药物纳晶的质量比为1:20~20:1。
5.一种权利要求1~4任一所述的苯硼酸修饰型纳晶药物稳定系统的制备方法,其特征在于,包括以下步骤:
(1)制备修饰型纳晶药物;
(2)制备纳晶药物稳定系统
方法一:分步制备纳晶药物稳定系统
配制稳定剂溶液,将步骤(1)制备的修饰型纳晶药物与稳定剂溶液混合,调节pH至7.0~8.0,混合,除去溶剂,即得纳晶药物稳定系统;
方法二:一步法制备纳晶药物稳定系统
分别配制修饰型纳晶药物、稳定剂溶液,两种溶液混合后与修饰型纳晶药物的不良溶剂混合,调节pH至7.0~8.0,混合,除去溶剂,即得纳晶药物稳定系统;
或将修饰型纳晶药物溶液与以修饰型纳晶药物不良溶剂溶解的稳定剂溶液混合,调节pH至7.0~8.0,混合,除去溶剂,即得纳晶药物稳定系统。
6.一种药物组合物,其特征在于,包含权利要求1~4任一所述的苯硼酸修饰型纳晶药物稳定系统以及药学上可接受的载体。
7.一种权利要求1~4任一所述的苯硼酸修饰型纳晶药物稳定系统或权利要求6所述的药物组合物在制备经口服、吸入、注射、眼用、透皮或黏膜给药的疾病预防剂、治疗剂或诊断剂中的应用。
8.根据权利要求7所述的应用,其特征在于,所述疾病为炎症感染、肿瘤。
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