CN111925516A - 一种两亲性聚美法仑前药胶束及其制备方法 - Google Patents
一种两亲性聚美法仑前药胶束及其制备方法 Download PDFInfo
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Abstract
本发明提供一种两亲性聚美法仑前药胶束及其制备方法，属于药物制剂制备技术领域，该方法包括以下步骤：以美法仑与聚合物封端试剂为原料，以DCC/HOBT或DCC/DMAP为缩合剂，混合后加入无水DMF和分子筛，无水无氧室温反应2天，得到反应液；将反应液进行透析纯化、冷冻干燥，得到两亲性聚美法仑前药胶束；其中，美法仑与聚合物封端试剂的摩尔比为10～50:1；美法仑与DCC、HOBT的摩尔比为1:1:1或美法仑与DCC、DMAP的摩尔比为1:1:0.2。采用一步法构建可精确调控载药率的聚美法仑前药胶束，操作简单，且反应温度较低，成本低，结构可控，适于工业化生产。
Description
技术领域
本发明属于药物制剂制备技术领域，具体涉及一种两亲性聚美法仑前药胶束及其制备方法。
背景技术
在经济高速发展的今天，癌症仍然是严重威胁人类生命健康的重要疾病之一。在癌症治疗过程中，需要合理的用药，避免过高的血药浓度产生中毒，或者过低的血药浓度无治疗效果，由此产生了缓、控释制剂，这也是DDS的初期发展阶段。
当前，药物递送系统(DDS)的研究目的是以适宜的剂型和给药方式，用最小的剂量达到最好的治疗效果。通过提高载药率、改变化疗药物的体内分布、控制药物的释放等方式，提高化疗药物在肿瘤组织的分布并控制性释放，同时，降低其在正常组织的含量，达到高效抑制肿瘤且减轻毒副作用的目的。然而，现阶段设计的DDS传递系统存在一些缺陷，如制备的复杂性、组分的多样性、载体材料的生物相容性、载药率的不可控性等，限制了其工业化生产并进一步临床应用的可能性。
美法仑，又名苯丙氨酸氮芥，为双功能烷化剂抗肿瘤药物，其中间产物可与DNA中的鸟嘌呤共价结合，使DNA双链内交叉联接，从而阻止肿瘤细胞复制。但是，美法仑的毒性较大，特别是全身给药方式极易造成多种毒副作用。因此，急需开发一种容易制备，且可精确调控载药率的药物缓释体系，通过调控局部给药浓度，使药物能够控制性完全降解成原药小分子，从而降低了全身性毒副作用，安全性好。
发明内容
为解决上述问题，本发明的目的在于提供一种两亲性聚美法仑前药胶束及其制备方法，该方法所采用的原料安全，采用一步法构建可精确调控载药率的聚美法仑前药胶束，操作简单，且反应温度较低，成本低，结构可控，适于工业化生产。
为实现上述目的，本发明的技术方案如下。
一种两亲性聚美法仑前药胶束的制备方法，包括以下步骤：
以美法仑与聚合物封端试剂为原料，以DCC/HOBT或DCC/DMAP为缩合剂，混合后加入无水DMF和分子筛，无水无氧室温反应2天，得到反应液；将反应液进行透析纯化、冷冻干燥，得到两亲性聚美法仑前药胶束；
其中，美法仑与聚合物封端试剂的摩尔比为10～50:1；
美法仑与DCC、HOBT的摩尔比为1:1:1或美法仑与DCC、DMAP的摩尔比为1:1:0.2。
进一步，所述聚合物封端试剂是以羟基或者氨基作为封端基团的聚合物封端试剂。
更进一步，所述聚合物封端试剂为氨基聚乙二醇单甲醚或者羟基聚乙二醇单甲醚。
进一步，美法仑与无水DMF的质量比为1:30-50。
进一步，聚合物封端试剂的分子量为500～20000。
进一步，透析纯化的具体操作是：
将反应液转移至透析袋中，依次用DMF、水进行透析，每次透析2～3天。
根据上述制备方法制得的两亲性聚美法仑前药胶束。
本发明的有益效果：
1、本发明采用一步合成法，以抗肿瘤药物美法仑自身为反应单元，通过控制聚合物封端试剂与美法仑的摩尔比，制备可精确控制载药率的聚美法仑前药胶束。采用经食品药品监督管理局批准的材料，可同时满足临床用药的安全性、有效性和经济性等原则，解决了药物递送系统(DDS)制备的复杂性、受限的载药率、载体材料的生物相容性等问题。本发明的一步合成和可控合成是推进工业化生产并进一步临床应用最佳保证。
2、本发明的方法能够构建新型的聚美法仑前药胶束新制剂，其采用一步合成法、成本低，结构可控，易于工业化生产。为构建安全、有效、经济、可控的聚美法仑前药胶束药物新制剂的临床应用奠定前期的研究基础。
附图说明
图1为本发明实施例1的两亲性聚美法仑前药胶束的制备反应方程式。
图2为本发明实施例1的方法制得的两亲性聚美法仑前药胶束在DMSO-d6中的H1-NMR图。
图3为本发明实施例1的方法制得的两亲性聚美法仑前药胶束在DMSO-d6中的C-H相关谱图。
图4为本发明实施例1的方法制得的两亲性聚美法仑前药胶束与美法仑的紫外吸收曲线。
图5为美法仑溶于甲醇溶液中在259nm处测定的紫外吸收曲线的标准曲线。
图6为本发明实施例2的方法制得的两亲性聚美法仑前药胶束在甲醇溶液中的紫外吸收曲线。
具体实施方式
为了使本发明的目的、技术方案及优点更加清楚明白，以下结合附图及实施例，对本发明进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本发明，并不用于限定本发明。
基于本发明中的实施例，本领域普通技术人员在没有作出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
实施例1
一种两亲性聚美法仑前药胶束的制备方法，包括以下步骤：
将1mmol抗肿瘤药美法仑与0.05mmol的氨基聚乙二醇单甲醚(分子量2000)置于圆底烧瓶中，加入与美法仑等摩尔比的DCC和HOBT，即美法仑与DCC、HOBT的摩尔比为1:1:1；之后加入无水DMF和分子筛，美法仑与无水DMF的质量比为1:40；
待无水无氧室温反应两天后，将反应液转移至透析袋中，用DMF透析三天后，期间换DMF三次，纯水中继续透析两天，期间多次换纯水。
透析结束后，冷冻干燥得两亲性聚美法仑前药胶束。
实施例2
一种两亲性聚美法仑前药胶束的制备方法，包括以下步骤：
将1mmol抗肿瘤药美法仑与0.02mmol的氨基聚乙二醇单甲醚(分子量2000)置于圆底烧瓶中，加入与美法仑等摩尔比的DCC和HOBT，即美法仑与DCC、HOBT的摩尔比为1:1:1；之后加入无水DMF和分子筛，美法仑与无水DMF的质量比为1:50；
待无水无氧室温反应两天后，将反应液转移至透析袋中，用DMF透析三天后，期间换DMF三次，纯水中继续透析两天，期间多次换纯水。
透析结束后，冷冻干燥得两亲性聚美法仑前药胶束。
实施例3
一种两亲性聚美法仑前药胶束的制备方法，包括以下步骤：
将1mmol抗肿瘤药美法仑与0.1mmol的氨基聚乙二醇单甲醚(分子量2000)置于圆底烧瓶中，加入与美法仑等摩尔比的DCC和HOBT，即美法仑与DCC、HOBT的摩尔比为1:1:1；之后加入无水DMF和分子筛，美法仑与无水DMF的质量比为1:30；
待无水无氧室温反应两天后，将反应液转移至透析袋中，用DMF透析三天后，期间换DMF三次，纯水中继续透析两天，期间多次换纯水。
透析结束后，冷冻干燥得两亲性聚美法仑前药胶束。
实施例4
一种两亲性聚美法仑前药胶束的制备方法，包括以下步骤：
将1mmol抗肿瘤药美法仑与0.025mmol的羟基聚乙二醇单甲醚(分子量2000)置于圆底烧瓶中，加入DCC和DMAP，其中，美法仑与DCC、DMAP的摩尔比为1:1:0.2；之后加入无水DMF和分子筛，美法仑与无水DMF的质量比为1:43；
待无水无氧室温反应两天后，将反应液转移至透析袋中，用DMF透析三天后，期间换DMF三次，纯水中继续透析两天，期间多次换纯水。
透析结束后，冷冻干燥得两亲性聚美法仑前药胶束。
实施例5
一种两亲性聚美法仑前药胶束的制备方法，包括以下步骤：
将1mmol抗肿瘤药美法仑与0.025mmol的羟基聚乙二醇单甲醚(分子量500)置于圆底烧瓶中，加入DCC和DMAP，其中，美法仑与DCC、DMAP的摩尔比为1:1:0.2；之后加入无水DMF和分子筛，美法仑与无水DMF的质量比为1:43；
待无水无氧室温反应两天后，将反应液转移至透析袋中，用DMF透析三天后，期间换DMF三次，纯水中继续透析两天，期间多次换纯水。
透析结束后，冷冻干燥得两亲性聚美法仑前药胶束。
实施例5
一种两亲性聚美法仑前药胶束的制备方法，包括以下步骤：
将1mmol抗肿瘤药美法仑与0.025mmol的羟基聚乙二醇单甲醚(分子量10000)置于圆底烧瓶中，加入DCC和DMAP，其中，美法仑与DCC、DMAP的摩尔比为1:1:0.2；之后加入无水DMF和分子筛，美法仑与无水DMF的质量比为1:43；
待无水无氧室温反应两天后，将反应液转移至透析袋中，用DMF透析三天后，期间换DMF三次，纯水中继续透析两天，期间多次换纯水。
透析结束后，冷冻干燥得两亲性聚美法仑前药胶束。
实施例6
一种两亲性聚美法仑前药胶束的制备方法，包括以下步骤：
将1mmol抗肿瘤药美法仑与0.025mmol的羟基聚乙二醇单甲醚(分子量20000)置于圆底烧瓶中，加入DCC和DMAP，其中，美法仑与DCC、DMAP的摩尔比为1:1:0.2；之后加入无水DMF和分子筛，美法仑与无水DMF的质量比为1:43；
待无水无氧室温反应两天后，将反应液转移至透析袋中，用DMF透析三天后，期间换DMF三次，纯水中继续透析两天，期间多次换纯水。
透析结束后，冷冻干燥得两亲性聚美法仑前药胶束。
实施例1～6的反应原理相同，均是以抗肿瘤药物美法仑自身为反应单元，在缩合剂DCC/HOBT或DCC/DMAP的作用下，分子间羧酸与氨基发生缩合/聚合反应，在缩合反应过程中，不同物质量的羟基聚乙二醇单甲醚或者氨基聚乙二醇单甲醚作为大分子封端试剂，使聚合反应一端终止。通过不同摩尔比的美法仑和氨基聚乙二醇单甲醚或羟基聚乙二醇单甲醚，采用一步法构建安全、有效、经济、简单、可精确控制载药率的两亲性聚美法仑前药胶束。
一、结构表征
为了有效地说明本发明的方法成功合成了两亲性聚美法仑前药胶束，采用实施例1为例，对其制备的两亲性聚美法仑前药胶束进行结构表征，经H1-核磁共振图鉴定如图2，C-H相关谱如图3。
由图2可以看出，聚美法仑中的-NH-上的氢在图2中的b位置，-C6H4-上的氢如图2中1，5与2，4位置，-CH2-上的氢在图2中8，9，10，12，14位置，-CH-上的氢在图2中的15位置；氨基聚乙二醇单甲醚中的-CH2-上的氢在图2中a位置。由此可见，本发明通过一步法可成功合成两亲性聚美法仑前药胶束。
由图3可以看出，聚美法仑中的-CH2-，-CH-，-NH-特征峰与氨基聚乙二醇单甲醚中-CH2-的特征峰，由此可进一步说明，本发明通过一步法可成功合成两亲性聚美法仑前药胶束。
二、计算载药率
称取0.65mg两亲性聚美法仑前药胶束溶于20mL甲醇中，得到两亲性聚美法仑前药甲醇溶液。取3mL两亲性聚美法仑前药甲醇溶液于259nm处检测其紫外吸光度值为1.48。采用相同方法制备美法仑/甲醇溶液，并检测其紫外吸收曲线。如图4-5所示，
图4为两亲性聚美法仑前药和原药美法仑的紫外吸收图。
图5为美法仑在甲醇溶液中在259nm处测定的紫外吸收曲线的标准曲线。
由图4可以看出，原药美法仑和两亲性聚美法仑前药胶束的紫外图谱中最大吸收峰的位置没有显著变化。由于图4中原药美法仑和两亲性聚美法仑前药胶束在甲醇中的紫外吸收曲线基本没变，因此，以原药美法仑做标准曲线测定聚美法仑前药中的载药率。
采用上述方法分别对实施例1-2获得的两亲性聚美法仑前药胶束的载药率进行测定。其中，以美法仑标准曲线方法测定实施例1的产品的载药率为60％。采用相同方法测定实施例2的产品的载药率为72％。
综上可得，本发明通过采用一步合成法，以抗肿瘤药物美法仑自身为反应单元，通过控制聚合物封端试剂与美法仑的摩尔比，制备可精确控制载药率的聚美法仑前药胶束。该方法操作简单，成本低，结构可控，易于工业化生产。为构建安全、有效、经济、可控的聚美法仑前药胶束药物新制剂的临床应用奠定前期的研究基础。
以上仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内所作的任何修改、等同替换和改进等，均应包含在本发明的保护范围之内。
Claims (7)
1.一种两亲性聚美法仑前药胶束的制备方法，其特征在于，包括以下步骤：
以美法仑与聚合物封端试剂为原料，以DCC/HOBT或DCC/DMAP为缩合剂，混合后加入无水DMF和分子筛，无水无氧室温反应2天，得到反应液；将反应液进行透析纯化、冷冻干燥，得到两亲性聚美法仑前药胶束；
其中，美法仑与聚合物封端试剂的摩尔比为10～50:1；
美法仑与DCC、HOBT的摩尔比为1:1:1或美法仑与DCC、DMAP的摩尔比为1:1:0.2。
2.根据权利要求1所述的两亲性聚美法仑前药胶束的制备方法，其特征在于，所述聚合物封端试剂是以羟基或者氨基作为封端基团的聚合物封端试剂。
3.根据权利要求2所述的两亲性聚美法仑前药胶束的制备方法，其特征在于，所述聚合物封端试剂为氨基聚乙二醇单甲醚或者羟基聚乙二醇单甲醚。
4.根据权利要求1所述的两亲性聚美法仑前药胶束的制备方法，其特征在于，美法仑与无水DMF的质量比为1:30-50。
5.根据权利要求1所述的两亲性聚美法仑前药胶束的制备方法，其特征在于，聚合物封端试剂的分子量为500～20000。
6.根据权利要求1所述的两亲性聚美法仑前药胶束的制备方法，其特征在于，透析纯化的具体操作是：
将反应液转移至透析袋中，依次用DMF、水进行透析，每次透析2～3天。
7.根据权利要求1-6中任意一项所述制备方法制得的两亲性聚美法仑前药胶束。
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