CN105273209A - 一种改性壳聚糖与聚(2-丙烯酰胺-2-甲基丙磺酸)复合微球的制备 - Google Patents
一种改性壳聚糖与聚(2-丙烯酰胺-2-甲基丙磺酸)复合微球的制备 Download PDFInfo
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Abstract
本发明公开了一种改性壳聚糖(CS)与聚(2-丙烯酰胺-2-甲基丙磺酸)(PAMPS)互穿网络复合微球的制备方法。首先制备壳聚糖与聚(2-丙烯酰胺-2-甲基丙磺酸)混合物溶液，再以戊二醛作交联剂，通过反向悬浮的方法制备粒径集中分布在300-500μm的互穿网络型CS/PAMPS复合微球，用丁二酸酐与复合微球反应，使CS中的游离氨基转变成羧基，以提高微球负载荷正电药物的能力。结果显示：改性CS/PAMPS复合微球可以快速并大量负载阿霉素，较其它微球有明显改善的载药潜力。
Description
技术领域
本发明涉及一种生物可降解的壳聚糖(CS)与聚(2-丙烯酰胺-2-甲基丙磺酸)(PAMPS)的复合微球制备，属于生物材料与缓释技术领域。
背景技术
肿瘤的介入疗法是将栓塞微球利用手术方式将其置入特定部位，通过阻断肿瘤供血和营养物质的供应，达到治疗癌症的目的。这种治疗方式的优点：对周身毒副作用较小；对肿瘤治疗彻底；避免癌细胞的再转移等。可是也有其固有缺陷，如：治疗周期长；会有疼痛、发热、呕吐等不良反应。为了增强对肿瘤细胞的杀伤力度，缩短治疗周期，很多学者开始尝试在栓塞微球上负载化疗药物，制备成载药栓塞微球。目前，栓塞微球负载药物的方式比较单一，最常用的载药方式是将化疗药物直接包覆在微球内部，通过扩散方式释放药物。这种载药方式的优点是载药量大且可以控制。由于化疗药物参与微球合成的多步反应，流失严重且部分药物分解失活，这也限制了该微球的推广。
为了改善现有载药微球的制备工艺，本实验选择新的载药方式：利用溶胀吸收和正负离子间的静电吸附作用，使药物快速负载。壳聚糖是一种生物相容性好，无毒，无害，可以生物降解的大分子，其与醛类反应所得微球溶胀性好，可生物降解，是比较理想的药物载体。2-丙烯酰胺-2-甲基丙磺酸(AMPS)是一种携带有磺酸基团和双键的有机物，其中双键可以在引发剂作用下打开发生聚合反应，形成聚(2-丙烯酰胺-2-甲基丙磺酸)。磺酸基在水中电离出氢离子显示负电性，可以和阿霉素分子发生静电吸附。本文利用反向悬浮交联法制备出PAMPS与壳聚糖的互穿网络型微球，为了减小载药过程中壳聚糖中游离氨基对阿霉素分子的屏蔽干扰，本发明中用丁二酸酐与壳聚糖中游离氨基反应，使其转变成羧基，最终得到改性互穿网络CS/PAMPS复合微球，以提高微球负载荷正电药物的能力。利用壳聚糖微球的良好溶胀性和磺酸基对阿霉素分子的静电吸附，达到快速大量载药的目的。
发明内容
本发明提供一种表面经功能化后可以通过静电吸附和溶胀吸收二重方式负载阿霉素的改性CS/PAMPS复合微球制备方法。首先制备了CS/PAMPS混合溶液，然后利用此混合液制备CS/PAMPS复合微球，并用丁二酸酐与微球中的游离氨基(-NH2)反应，制备出改性互穿网络CS/PAMPS复合微球，利用微球中的游离磺酸基团和羧基与氨基静电作用和微球良好的溶胀性来负载阿霉素。
本发明的有益效果：
①改性CS/PAMPS复合微球可以利用静电吸附和溶胀吸收两种方式负载药物，微球中富含羧基和磺酸基团，对于荷正电药物例如阿霉素载药量大、载药速度快、无泄漏。
②以壳聚糖为主要成分，微球可生物降解。
③通过改性CS/PAMPS复合微球，减小了壳聚糖中氨基对于阿霉素的屏蔽，提高了载药潜能。
附图说明
图1(a)交联剂戊二醛加入量为4.0g时的微球照片；(b)是交联剂加入量为6.0g时的CS微球照片；(c)是交联剂加入量为3.0g时的CS微球照片；(d)是交联剂加入量为6.0g时的CS微球照片。
图2不同微球的红外谱图；(a：CS微球；b：CS/PAMPS复合微球；c：丁二酸酐改性CS/PAMPS微球)。
图3不同微球在生理盐水中的直径变化曲线；(a：CS微球；b：CS/PAMPS复合微球；c：丁二酸酐改性CS/PAMPS微球)。
图4复合载药微球在不同pH的PBS缓冲溶液中的药物(阿霉素)释放曲线；(a：pH＝4.0；b：pH＝5.0；c：pH＝6.0；d：pH＝7.0；e：pH＝7.4)。
具体实施方式：
实施例1：CS/PAMPS混合溶液的制备：机械搅拌下，向48g蒸馏水中加入1g冰醋酸和2.0g壳聚糖(CS)，待完全溶解后加入2-丙烯酰胺-2-甲基丙磺酸(AMPS)，氮气保护下加入一定量的N，N-亚甲基双丙烯酰胺(MBA)和过硫酸钾(K2S2O8)，60℃下反应3小时，所得溶液呈乳白状。
实施例2：CS/PAMPS复合微球的制备：在烧杯中加入50mL石蜡油，机械搅拌下加入司班80和10mL上述混合液，30分钟后加入4.0g戊二醛溶液(25％)和1mL盐酸(36％)，25℃反应1.5小时，经抽滤、洗涤、干燥后得到CS/PAMPS复合微球。
实施例3：改性互穿网络CS/PAMPS复合微球的制备：取3.0g丁二酸酐溶于50mLDMF中，磁力搅拌下加入1.0gCS/PAMPS复合微球，于40℃下反应1.5h，经过滤、洗涤、干燥后得到改性复合微球。
实施例4：改性互穿网络CS/PAMPS复合载药微球的制备：配制浓度为0.25mg/mL的盐酸阿霉素溶液40mL，称取150mg改性CS/PAMPS复合微球放入其中，低速搅拌下进行药物负载反应。
实施例5：精确称取150mg改性CS/PAMPS复合微球5次，分别置于pH值为4.0、5.0、6.0、7.0和8.0的盐酸阿霉素溶液中，避光环境中磁力搅拌48小时。在不同时间点，用紫外分光计得出溶液中阿霉素的浓度。
实施例6：用光学显微镜对微球进行拍照，图1中a是交联剂加入量为4.0g时的CS微球照片；b是交联剂加入量为6.0g时的CS微球照片；c是交联剂加入量为3.0g时的CS微球照片；d是交联剂加入量为7.0g时的CS微球照片。结果显示：a、b和d中微球外观圆整，分散性良好。b与a相较，微球颜色明显加深，这是交联剂加入量增加导致的结果。由图可知交联剂的最佳加入量为4.0g。
实施例7：图2显示不同微球的红外谱图，a：CS微球；b：CS/PAMPS复合微球；c：丁二酸酐改性CS/PAMPS微球。
实施例8：图3中是不同微球在生理盐水中的直径变化曲线。a：CS微球；b：CS/PAMPS复合微球；c：丁二酸酐改性CS/PAMPS微球。结果显示：CS微球及其改性微球的溶胀性良好，溶胀平衡时微球直径可以增大到干燥状态时的2倍；用丁二酸酐修饰后的微球溶胀性较CS微球好；微球的溶胀性由其自身的特性及交联剂戊二醛的加入量所决定。丁二酸酐修饰后，亲水性基团(-COOH)的引入，导致微球的吸水性能提高，溶胀性变大。在CS/PAMPS复合微球中，亲水性基团(磺酸基团)的引入也会提高复合微球的溶胀性能。
实施例9：图4是改性互穿网络CS/PAMPS复合载药微球在不同pH下的缓冲溶液(PBS)中的药物释放曲线(a：pH＝4.0；b：pH＝5.0；c：pH＝6.0；d：pH＝7.0；e：pH＝7.4)。结果显示：在不同pH的PBS溶液中，改性CS/PAMPS复合载药微球对阿霉素的释放量随着pH值的增大而增多。结果分析：多数阿霉素分子通过静电吸附作用负载于复合微球内部。pH值显著影响释放速度。微球中负性电荷官能团较多，在低pH值下，负性电荷官能团质子化，不易电离，微球紧缩，导致药物分子难以释放；而在高pH时，官能团电离出质子，微球溶胀，孔道变大，药物释放加快。
Claims (3)
1.一种改性壳聚糖(CS)与聚(2-丙烯酰胺-2-甲基丙磺酸)(PAMPS)复合微球。其特征是改性壳聚糖与聚(2-丙烯酰胺-2-甲基丙磺酸)形成了互穿网络结构。该微球以微米级的改性壳聚糖微球为主体，通过互穿网络方式引入带有磺酸基团的PAMPS。其中磺酸基团的含量占复合微球重量的1％-40％。
2.一种微米级CS/PAMPS复合微球的制备新方法，其特征是首先将壳聚糖、2-丙烯酰胺-2-甲基丙磺酸和N，N-亚甲基双丙烯酰胺(MBA)，按照一定重量比例制备成混合溶液，在氮气保护和引发剂作用下，加热到60℃下反应3小时，使AMPS聚合，得到PAMPS预聚物与壳聚糖的混合溶液，再将戊二醛溶液(25％)添加到上述溶液中混合均匀。量取50mL石蜡油置于250mL烧杯中，机械搅拌下滴加1.50g司班80，数分钟后再滴加CS/PAMPS和戊二醛的混合溶液，乳化半小时后滴加数滴(0.5mL到2.0mL之间)浓盐酸，常温下反应3小时，经乙醇破乳、洗涤后得到直径在100微米到650微米之间的微球。该微球的合成配方按下列条件：
(1)CS与PAMPS的重量比范围为：3∶2到3∶0.5。
(2)AMPS的聚合用引发剂过硫酸钾，或过硫酸铵，用量占AMPS单体重量的1～5％。
(3)在AMPS聚合的同时，添加N，N-亚甲基双丙烯酰胺，将AMPS进行轻度交联，MBA用量占AMPS的0.5％-1％。
(4)聚合物重量(壳聚糖与2-丙烯酰胺-2-甲基丙磺酸重量之和)占溶液总重量的百分比为为：2％-5％。
(5)石蜡油与混合溶液体积比(即油水比)范围为：3∶1-10∶1。
3.权利要求2所述CS/PAMPS复合微球的改性反应，其特征是以权力要求2所述微球为主体，按照一定比例与丁二酸酐混合后加入到50mL的N，N-二甲基甲酰胺(DMF)溶液中，反应5小时后过滤微球，用95％乙醇和去离子水依次洗涤，最后真空恒温干燥后得到丁二酸酐改性的复合微球。
(1)复合微球与丁二酸酐的重量比在1∶1到1∶10之间。
(2)改性反应在20～25℃温度范围内进行。
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| CN114478927A (zh) * | 2022-01-26 | 2022-05-13 | 科睿驰（深圳）医疗科技发展有限公司 | 一种栓塞微球及梯度交联制备方法 |
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