CN114470308A - 一种大孔聚丙烯酸钠栓塞微球的制备工艺 - Google Patents
一种大孔聚丙烯酸钠栓塞微球的制备工艺 Download PDFInfo
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- CN114470308A CN114470308A CN202210192296.6A CN202210192296A CN114470308A CN 114470308 A CN114470308 A CN 114470308A CN 202210192296 A CN202210192296 A CN 202210192296A CN 114470308 A CN114470308 A CN 114470308A
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- macroporous
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- sodium polyacrylate
- microspheres
- acrylate
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Classifications
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Abstract
本发明公开了一种大孔聚丙烯酸钠栓塞微球的制备工艺,涉及医疗器械技术领域,以分散剂和水为连续相,以单体丙烯酸酯类化合物、交联剂多烯烃化合物、致孔剂、引发剂为分散相,悬浮聚合大孔型聚丙烯酸酯微球,再通过水解工艺得到大孔聚丙烯酸钠栓塞微球。所制得的大孔聚丙烯酸钠栓塞微球有较高的弹性、载药量大。本发明首次采用悬浮聚合工艺,得到的大孔型微球有较好的粒内微孔通道,便于分子粒内扩散,有更好的离子交换动力学性能,更适合中分子化疗药物快速进入孔通道和功能基团的交换大幅提高了载药能力;大孔型微球聚合更加均匀,相比之下有更高的强度和更好的弹性。
Description
技术领域
本发明涉及医疗器械技术领域,具体说是一种大孔聚丙烯酸钠栓塞微球的制备工艺。
背景技术
介入治疗学是近些年发展起来的一门新型学科,目前已经和传统的内科、外科并列为临床三大支柱性学科。栓塞治疗是介入治疗的重要组成部分,栓塞疗法通过阻断为肿瘤供血的血管、畸形的血管或出血的血管,已经在动静脉畸形、血管增大型肿瘤、子宫纤维瘤、子宫肌瘤、血供丰富型肿瘤等方面取得了较好的疗效,具有广泛的应用前景。
经导管介入栓塞术(简称TACA)的关键是选择合适的栓塞剂。目前临床应用最广泛的是微球型栓塞剂。第一代的栓塞微球主要是明胶微球、淀粉微球、聚乳酸微球、壳聚糖微球、海藻酸钠微球、聚乙烯醇微球等。这些微球有的形状不规整、尺寸不均一,从而导致介入手术中出现漂移、堵塞血管、误栓等副作用,对正常组织造成损伤。有些微球虽然表面光滑、形状规整、尺寸也比较均匀,但微球弹性和伸缩性很差,通导性不好,很难形变顺利通过微细导管又能很快恢复到原状,从而造成血管的不完全栓塞。还有的微球不能键合化疗药物或者是载药量低,或者是载上药不能够在血管内缓释。
目前公开的发明专利和市售栓塞微球产品主要是凝胶型产品,凝胶型栓塞微球存在微孔较小的问题,导致载药时,对中分子的化疗药物,更多是在微球颗粒表面进行载药,载药量较低。且凝胶型微球聚合时在链增长瞬间放热,会导致温度急剧上升而暴聚现象,所以存在交联不均的现象。
发明内容
为解决上述问题,本发明的目的是提供一种大孔聚丙烯酸钠栓塞微球的制备工艺。
本发明为实现上述目的,通过以下技术方案实现:
一种大孔聚丙烯酸钠栓塞微球的制备工艺,包括以下步骤:
将分散剂加入到水,搅拌均匀,在40~90℃下保温0.5~5小时,得到连续相,备用,其中分散剂和水的质量比为0.1~10:100;所述分散剂为明胶、聚乙烯醇、羟甲基纤维素、羧乙基纤维素、甲基羟乙基纤维素、木质素、聚二甲基二烯丙基氯化铵和油酸钠中的一种或两种;
所述丙烯酸酯类化合物为甲基丙烯酸甲酯、丙烯酸甲酯、甲基丙烯酸乙酯、丙烯酸乙酯、甲基丙烯酸丁酯、丙烯酸丁酯、丙烯酸缩水甘油酯、甲基丙烯酸缩水甘油酯、乙二醇二甲基丙烯酸酯、乙二醇二丙烯酸酯、丙二醇二甲基丙烯酸酯、季戊四醇四甲基丙烯酸酯、季戊四醇三甲基丙烯酸酯、季戊四醇二甲基丙烯酸酯、葡萄糖五甲基丙烯酸酯、葡萄糖四甲基丙烯酸酯、葡萄糖三甲基丙烯酸酯和葡萄糖二甲基丙烯酸酯中的一种或两种;
所述多烯烃类化合物为二乙烯苯、丁二烯、丙烯酸烯丙酯、二甲基丙烯酸乙二醇酯、衣康酸烯丙酯、N,N,-亚甲基双丙烯酰胺、三聚异氰酸烯丙酯、二乙二醇二乙烯基醚中的一种或多种组合;
所述致孔剂为苯、甲苯、邻二甲苯、对二甲苯、环己烷、正庚烷、正辛烷、甲基环己烷、乙酸丁酯、丁酸乙酯、二异丙基甲酮、二氯乙烷、二氯丙烷、甲基异丙基甲酮、甲基异丙基甲酮、四氯化碳、异丁醇、环己醇、二丙酮醇、二甲醚、氯苯、二异丁基酮、甲乙酮、乙二醇、异辛醇、200号汽油、液体石蜡和硝基苯中的一种或两种;
所述引发剂为过氧化苯甲酰或偶氮二异丁腈;
所述碱液为碳酸钠水溶液或氢氧化钠水溶液;
所述碱液的质量浓度为10~25%。
优选的,所述分散剂为明胶、聚乙烯醇、羟甲基纤维素、羧乙基纤维素或甲基羟乙基纤维素中的一种或两种。
优选的,所述丙烯酸酯类化合物为甲基丙烯酸甲酯、甲基丙烯酸乙酯、丙烯酸乙酯、甲基丙烯酸丁酯、丙烯酸丁酯、丙烯酸缩水甘油酯和甲基丙烯酸缩水甘油酯中的一种或两种。
优选的,所述多烯烃类化合物为丙烯酸烯丙酯、二甲基丙烯酸乙二醇酯、衣康酸烯丙酯、二乙二醇二乙烯基醚或三聚异氰酸烯丙酯。
优选的,所述致孔剂为苯、甲苯、乙酸丁酯、二氯乙烷、甲基异丙基甲酮或二异丁基酮。
优选的,所述碱液为氢氧化钠水溶液。
优选的,分散剂和水的质量比为0.6~8:100。
另一种优选的,分散剂和水的质量比为1~5:100。
本发明相比现有技术具有以下优点:
本发明的大孔聚丙烯酸钠栓塞微球的制备工艺,首次采用悬浮聚合工艺,得到的大孔型微球有较好的粒内微孔通道,便于分子粒内扩散,有更好的离子交换动力学性能,更适合中分子化疗药物快速进入孔通道和功能基团的交换,大幅提高了载药能力;大孔型微球聚合更加均匀,相比之下有更高的强度和更好的弹性。
本发明的大孔型微球制备时,所选致孔剂为良溶剂,或者是混合溶剂的溶解度参数与聚丙烯酸酯的溶解度参数接近,该条件的选择使本发明得到的微球粒内大孔并非超微孔,而是要获得更多的中微孔。由于栓塞微球在使用时,除了载药缓释外,还要承担阻塞血液中营养物质到达肿瘤细胞的目的,若是超大型孔,会导致糖类、蛋白质等营养物质穿过微球孔道;本发明采用良溶剂或者溶解度参数与聚合物相近的混合溶剂制孔,不仅孔更均匀,而且更多的是微孔,也对大分子营养物质提高了阻塞效果。
本专利所制得的栓塞微球压缩形变率达到50%以上,对阿霉素载药量大于50mg/g微球。本发明大孔聚丙烯酸钠栓塞微球的孔径为2-100nm。
具体实施方式
本发明的目的是提供一种大孔聚丙烯酸钠栓塞微球的制备工艺,以下结合具体实施例来对本发明作进一步的描述。
实施例1
一种大孔聚丙烯酸钠栓塞微球的制备工艺,包括以下步骤:
将50kg步骤所得连续相加入到反应釜中,将8kg丙二醇二甲基丙烯酸酯、1.6kgN,N-亚甲基双丙烯酰胺、0.4kg三聚异氰酸烯丙酯、4kg苯和0.15kg过氧化苯甲酰混合均匀,加入到反应釜中,在105r/min的转速下,升温至65℃,搅拌反应8小时,得到聚合物;
所述碱液为氢氧化钠水溶液;所述碱液的质量浓度为10%。
实施例2
一种大孔聚丙烯酸钠栓塞微球的制备工艺,包括以下步骤:
将50kg步骤所得连续相加入到反应釜中,将8.5kg葡萄糖三甲基丙烯酸酯、0.7kg二乙二醇二乙烯基醚、0.8kg二甲基丙烯酸乙二醇酯、7kg甲苯和0.15kg偶氮二异丁腈混合均匀,加入到反应釜中,在140r/min的转速下,升温至70℃,搅拌反应8小时,得到聚合物;
所述碱液为碳酸钠水溶液;所述碱液的质量浓度为25%。
实施例3
一种大孔聚丙烯酸钠栓塞微球的制备工艺,包括以下步骤:
将50kg步骤所得连续相加入到反应釜中,将丙烯酸丁酯3kg、丙烯酸缩水甘油酯6.3kg、丙烯酸烯丙酯0.7kg、甲苯4kg、过氧化苯甲酰0.1kg混合均匀,加入到反应釜中,在110r/min的转速下,升温至65℃,搅拌聚合10小时,得到聚合物;
所述碱液为碳酸钠水溶液;所述碱液的质量浓度为20%。
实施例4
一种大孔聚丙烯酸钠栓塞微球的制备工艺,包括以下步骤:
将50kg步骤所得连续相加入到反应釜中,将甲基丙烯酸甲酯5.5kg、甲基丙烯酸缩水甘油酯3.5kg、二甲基丙烯酸乙二醇酯1kg、甲苯4.5kg、过氧化苯甲酰0.1kg混合均匀,加入到反应釜中,在115r/min的转速下,升温至65℃,搅拌反应12小时,得到聚合物;
所述碱液为氢氧化钠水溶液;所述碱液的质量浓度为20%。
实施例5
一种大孔聚丙烯酸钠栓塞微球的制备工艺,包括以下步骤:
将50kg步骤所得连续相加入到反应釜中,将丙烯酸丁酯6kg、甲基丙烯酸甲酯2.8kg、丙烯酸烯丙酯1.2kg、二氯乙烷5kg、过氧化苯甲酰0.15kg混合均匀,加入到反应釜中,在110r/min的转速下,升温至65℃,搅拌反应10小时,得到聚合物;
所述碱液为氢氧化钠水溶液;所述碱液的质量浓度为15%。
实施例6
一种大孔聚丙烯酸钠栓塞微球的制备工艺,包括以下步骤:
将50kg步骤所得连续相加入到反应釜中,将甲基丙烯酸缩水甘油酯4kg、甲基丙烯酸甲酯5kg、三聚异氰酸烯丙酯1kg、乙酸丁酯5kg、偶氮二异丁腈0.15kg混合均匀,加入到反应釜中,在130r/min的转速下,升温至70℃,搅拌反应8小时,得到聚合物;
所述碱液为碳酸钠水溶液;所述碱液的质量浓度为25%。
实施例7
一种大孔聚丙烯酸钠栓塞微球的制备工艺,包括以下步骤:
将50kg步骤所得连续相加入到反应釜中,将甲基丙烯酸丁酯4kg、甲基丙烯酸甲酯5kg、衣康酸烯丙酯1kg、甲基异丁基甲酮5kg、偶氮二异丁腈0.1kg混合均匀,加入到反应釜中,在120r/min的转速下,升温至65℃,搅拌反应10小时,得到聚合物;
所述碱液为氢氧化钠水溶液;所述碱液的质量浓度为20%。
实施例8
一种大孔聚丙烯酸钠栓塞微球的制备工艺,包括以下步骤:
将50kg步骤所得连续相加入到反应釜中,将丙烯酸乙酯7.5kg、甲基丙烯酸甲酯1.5kg、衣康酸烯丙酯1.0kg、二异丁基酮7kg、偶氮二异丁腈0.15kg混合均匀,加入到反应釜中,在140r/min的转速下,升温至70℃,搅拌反应9小时,得到聚合物;
所述碱液为氢氧化钠水溶液;所述碱液的质量浓度为10%。
对实施例1-8所得的大孔聚丙烯酸钠栓塞微球进行性能测试,性能参数如表1所示。
表1实施例1-8所得的大孔聚丙烯酸钠栓塞微球进行性能测试结果
平均粒径μm | 压缩形变率% | 阿霉素载药量(mg/g微球) | |
实施例1 | 655 | 56 | 53.3 |
实施例2 | 468 | 58 | 57.2 |
实施例3 | 442 | 56 | 56.0 |
实施例4 | 372 | 54 | 54.2 |
实施例5 | 783 | 58 | 53.9 |
实施例6 | 392 | 52 | 56.3 |
实施例7 | 443 | 54 | 53.1 |
实施例8 | 251 | 57 | 51.3 |
通常临床使用的栓塞微球粒径范围在50-1200μm之间,本发明制得的大孔型聚丙烯酸钠栓塞微球粒径合适;压缩形变率达到50%以上,弹性好;对阿霉素载药量50mg/g微球以上,载药量大。
Claims (7)
1.一种大孔聚丙烯酸钠栓塞微球的制备工艺,其特征在于:包括以下步骤:
将分散剂加入到水中,搅拌均匀,在40~90℃下保温0.5~5小时,得到连续相,备用,其中分散剂和水的质量比为0.1~10:100;所述分散剂为明胶、聚乙烯醇、羟甲基纤维素、羧乙基纤维素、甲基羟乙基纤维素、木质素、聚二甲基二烯丙基氯化铵和油酸钠中的一种或两种;
所述丙烯酸酯类化合物为甲基丙烯酸甲酯、丙烯酸甲酯、甲基丙烯酸乙酯、丙烯酸乙酯、甲基丙烯酸丁酯、丙烯酸丁酯、丙烯酸缩水甘油酯、甲基丙烯酸缩水甘油酯、乙二醇二甲基丙烯酸酯、乙二醇二丙烯酸酯、丙二醇二甲基丙烯酸酯、季戊四醇四甲基丙烯酸酯、季戊四醇三甲基丙烯酸酯、季戊四醇二甲基丙烯酸酯、葡萄糖五甲基丙烯酸酯、葡萄糖四甲基丙烯酸酯、葡萄糖三甲基丙烯酸酯和葡萄糖二甲基丙烯酸酯中的一种或两种;
所述多烯烃类化合物为二乙烯苯、丁二烯、丙烯酸烯丙酯、二甲基丙烯酸乙二醇酯、衣康酸烯丙酯、N,N-亚甲基双丙烯酰胺、三聚异氰酸烯丙酯、二乙二醇二乙烯基醚中的一种或多种组合;
所述致孔剂为苯、甲苯、邻二甲苯、对二甲苯、环己烷、正庚烷、正辛烷、甲基环己烷、乙酸丁酯、丁酸乙酯、二异丙基甲酮、二氯乙烷、二氯丙烷、甲基异丙基甲酮、甲基异丙基甲酮、四氯化碳、异丁醇、环己醇、二丙酮醇、二甲醚、氯苯、二异丁基酮、甲乙酮、乙二醇、异辛醇、200号汽油、液体石蜡和硝基苯中的一种或两种;
所述引发剂为过氧化苯甲酰或偶氮二异丁腈;
所述碱液为碳酸钠水溶液或氢氧化钠水溶液;
所述碱液的质量浓度为10~25%。
2.根据权利要求1所述的一种大孔聚丙烯酸钠栓塞微球的制备工艺,其特征在于:所述分散剂为明胶、聚乙烯醇、羟甲基纤维素、羧乙基纤维素或甲基羟乙基纤维素中的一种或两种。
3.根据权利要求1所述的一种大孔聚丙烯酸钠栓塞微球的制备工艺,其特征在于:所述丙烯酸酯类化合物为甲基丙烯酸甲酯、甲基丙烯酸乙酯、丙烯酸乙酯、甲基丙烯酸丁酯、丙烯酸丁酯、丙烯酸缩水甘油酯和甲基丙烯酸缩水甘油酯中的一种或两种。
4.根据权利要求1所述的一种大孔聚丙烯酸钠栓塞微球的制备工艺,其特征在于:所述多烯烃类化合物为丙烯酸烯丙酯、二甲基丙烯酸乙二醇酯、衣康酸烯丙酯、二乙二醇二乙烯基醚或三聚异氰酸烯丙酯。
5.根据权利要求1所述的一种大孔聚丙烯酸钠栓塞微球的制备工艺,其特征在于:所述致孔剂为苯、甲苯、乙酸丁酯、二氯乙烷、甲基异丙基甲酮或二异丁基酮。
6.根据权利要求1所述的一种大孔聚丙烯酸钠栓塞微球的制备工艺,其特征在于:所述碱液为氢氧化钠水溶液。
7.根据权利要求1所述的一种大孔聚丙烯酸钠栓塞微球的制备工艺,其特征在于:分散剂和水的质量比为1~5:100。
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