CN105560243B - 一种注射用哌拉西林钠舒巴坦钠组合物的制备方法 - Google Patents
一种注射用哌拉西林钠舒巴坦钠组合物的制备方法 Download PDFInfo
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Abstract
本发明涉及一种注射用哌拉西林钠舒巴坦钠组合物的制备方法。该组合物含有哌拉西林钠、舒巴坦钠、聚氰基丙烯酸烷基酯、聚乙烯吡咯烷酮、海藻糖、甘氨酸等，具有复溶性好、稳定性佳等特点。制备方法简单，采用冷冻干燥即可获得。
Description
技术领域
本发明涉及一种注射用哌拉西林钠舒巴坦钠组合物的制备方法。
背景技术
哌拉西林钠是一种青霉素类抗生素，其通过干扰细菌细胞壁的合成而起到杀菌作用，被广泛用于革兰阴性菌引起的各种感染性疾病的预防和治疗。由于含有β-内酰胺环，易被细菌产生的β-内酰胺酶水解而产生耐药性。舒巴坦钠是β-内酰胺酶抑制剂，对于金黄色葡萄球菌和多数革兰阴性菌所产生的β-内酰胺酶有不可逆的竞争性抑制，因此舒巴坦钠常与青霉素类或头孢菌素类药物联用，有很好的抗菌协同作用。
哌拉西林钠舒巴坦钠复方制剂临床用量大，疗效确切，市场前景好，和大多数头孢菌素类抗生素一样，都是由哌拉西林钠和舒巴坦钠无菌原料分装或冻干制得。其存在一个共同的缺陷就是制剂稳定差，不能满足有效期的质量要求。
发明内容
本发明提供一种哌拉西林钠舒巴坦钠无菌粉针剂及其制备方法，该注射剂具有复溶性好、稳定性佳等特点，克服了现有技术中存在的不足。
本发明的技术方案为：
一种注射用哌拉西林钠舒巴坦钠组合物，其特征在于所述组合物中各组分的重量份数为：
哌拉西林钠 4重量份；
舒巴坦钠 1重量份；
聚氰基丙烯酸烷基酯 2-6重量份；
聚乙烯吡咯烷酮 0.5-1重量份；
海藻糖 5-10重量份；
甘氨酸 5-10重量份；
吐温 1-2重量份。
在本发明的技术方案中，所述聚氰基丙烯酸烷基酯，优选地，为聚氰基丙烯酸甲酯，聚氰基丙烯酸乙酯，聚氰基丙烯酸丙酯，聚氰基丙烯酸正丁酯，聚氰基丙烯酸异丁酯中的一种；
作为优选的技术方案，吐温优选吐温80或吐温20；
作为优选的技术方案，所述PVP选自PVPk10，PVPk17或PVPk30中的一种。
作为优选的技术方案，所述组合物中还可以加入抗氧化剂、pH值调节剂或EDTA钙中的一种或几种。
如上述任意技术方案，所述组合物为粉针剂。
在本发明的药物组合物中聚氰基丙烯酸烷基酯是纳米微球载体材料，海藻糖可以增加复溶速度；甘氨酸作为赋形剂和冻干支持剂使用，并且聚乙烯吡咯烷酮 （PVP）同时具有作为影响微球释放的修饰材料和调节微球表面活性的作用；吐温作为表面活性剂使用。
本发明还提供一种注射用头孢美唑钠和克拉维酸钾的药物组合物的制备方法，包括如下步骤：
(1)按配方比例称取各组分：
(2)将哌拉西林钠和舒巴坦钠依次加入注射用水中，搅拌溶解后加入聚氰基丙烯酸烷基酯、吐温和聚乙烯吡咯烷酮，继续搅拌3h，加入海藻糖和甘氨酸至完全溶解，调节pH至5-7，0.22μm滤膜无菌过滤；
(3)分装，冷冻干燥。
所述冷冻干燥的方法包括如下步骤：
A、产品的预冻：将待干燥的料液稀释到质量浓度为20~35%，1~2h内迅速降温至-30℃～-40℃，料液变为块状结构；
B、退火：将上述块状物料在4-5h内升温至-10~0℃，然后在0.5-1h内迅速降温至-30℃～-40℃，物料变为表面凹凸不平、内部有大量贯通孔隙的松散冰状结构；
C、升华干燥：开启真空系统，控制真空度缓慢上升，30min内使得真空度达到20Pa；开启加热，使得物料的温度在2-4h内由-30℃～-40℃缓慢升温至0~10℃，此时物料变为松散的粉末，维持在该温度下2-5h；
D、解析干燥：将上述物料粉末在0.5~1.5h内迅速升温到40-45℃，并维持在该温度下0.5~1h，关闭真空系统，使得压力缓慢恢复到常压，得到物料的冻干粉末；
E、封装：在干燥环境下，将上述冻干后的产品迅速装填到密闭容器中，并迅速抽真空或通入氮气后进行密封包装。
本发明还提供一种注射用哌拉西林钠舒巴坦钠组合物在制备治疗细菌感染的药物中的用途。
与现有技术比，本发明提供的注射用哌拉西林钠舒巴坦钠组合物及其制备方法，具有以下优点：
1、稳定性好：本发明提供的哌拉西林钠舒巴坦钠的药物组合物，是将其包裹和吸附在纳米粒载体材料中，其活性成分得到有效保护，故稳定性较优市售品更优。加速6月和长期 稳定性考察结果也表明溶液颜色、pH值、有关物质、含量均没有明显变化，包封率小，极大地提高了药物稳定性。
2、复溶性好：冷冻干燥技术的采用有效的避免了聚合材料的降解、药物泄露或药物降解，使药品保存条件范围更广，并且冷冻干燥前加入赋形剂使本品的复溶性好，复溶后药物各种理化性质与冻干前基本相同。
3、制备方法简便：在配方中已经加入了冻干保护基，无需加入额外的有机试剂，经冷冻干燥即可制得。
具体实施方式
下面结合具体实施方式对本发明作进一步的详细描述。但不应将此理解为本发明上述主题的范围仅限于下述实施例。
实施例1 注射用粉针剂及其制备
配方：
哌拉西林钠 400g；
舒巴坦钠 100g；
聚氰基丙烯酸烷基酯 200g；
聚乙烯吡咯烷酮（PVP） 60g；
海藻糖 500g；
甘氨酸 500g；
吐温80 100g。
将哌拉西林钠和舒巴坦钠依次加入2.5L注射用水中，常温搅拌溶解后加入聚氰基丙烯酸烷基酯、吐温80和PVP，继续搅拌3h，加入海藻糖和甘氨酸，补加0.5L注射用水，搅拌至完全溶解，调节pH至5-7，0.22μm滤膜无菌过滤；将滤液分装至灭菌后的西林瓶中。
将上述物料放入冻干机，开启制冷，1h内迅速降温至-40℃，料液变为块状结构。将上述块状物料在3h内升温至-10℃，然后在0.5h内迅速降温至-40℃，物料变为表面凹凸不平、内部有大量贯通孔隙的松散冰状结构。开启真空系统，控制真空度缓慢上升，30min内使得真空度达到10Pa。开启加热，使物料的温度在3h内由-40℃缓慢升温至10℃，此时物料变为松散的粉末，维持在该温度下3h。将上述物料粉末在1h内迅速升温到45℃，并维持在该温度下1h，关闭真空系统，使得压力缓慢恢复到常压，以无菌胶塞封口，再用无菌铝盖进行扎盖密封即得。
实施例2 粒径检测
取实施例1的注射剂，加水溶解成每1ml含1mg克哌拉西林钠的溶液，用激光散射粒度仪测定。
结果：实施例1制备的哌拉西林钠舒巴坦钠注射剂呈微球状，粒径分布均匀，全部粒径介于50-120nm之间。
实施例3：包封率检测
将哌拉西林钠舒巴坦钠的注射剂加水溶解成每1ml含哌拉西林钠1mg的溶液，以5000r/min的速度离心25min，取上清液1ml，用甲醇溶解，测定哌拉西林钠的含量。
包封率=微球内的药量/（微球内的药量+介质中的药量）×100%
结果：实施例1制备的注射剂的包封率，介于88%-95%之间。
实施例4：复溶性考察
随机选取实施例1中的注射剂8瓶，编号1-8，物理混合后的样品编号9，按临床用药的溶解方法，分别注入10ml注射用水，在漩涡混合器上震摇，以溶解完全澄明为指标，计算溶解速度
| 样品 | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 |
| 溶解时间/秒 | 16 | 17 | 15 | 15 | 17 | 16 | 16 | 15 | 29 |
实验结果表明本发明的注射剂的复溶速度明显优于直接分装的注射剂。
实施例5：稳定性考察
将实施例1制备的样品（编号为A）和原料直接混合分装的注射剂（编号为B）分别置于高温40℃、相对湿度75%±5%条件下6个月，进行加速考察。
实验表明，加速实验6个月时，直接分装的注射剂性状变为淡黄色粉末，pH下降明显，含量降低较多；而本发明制备的注射剂外观性状、pH、含量均无明显变化，从而证明了本发明注射剂的稳定性更加突出。
Claims (1)
1.一种注射用哌拉西林钠舒巴坦钠组合物的制备方法，其特征在于：
所述组合物中各组分的重量份数为：
哌拉西林钠 4重量份；
舒巴坦钠 1重量份；
聚氰基丙烯酸烷基酯 2-6重量份；
聚乙烯吡咯烷酮 0.5-1重量份；
海藻糖 5-10重量份；
甘氨酸 5-10重量份；
吐温 1-2重量份；
其制备方法包括如下步骤：
(1)按配方比例称取各组分；
(2)将哌拉西林钠和舒巴坦钠依次加入注射用水中，搅拌溶解后加入聚氰基丙烯酸烷基酯、吐温和聚乙烯吡咯烷酮，继续搅拌3h，加入海藻糖和甘氨酸至完全溶解，调节pH至5-7，0.22μm滤膜无菌过滤；
(3)分装，冷冻干燥；
所述聚氰基丙烯酸烷基酯选自聚氰基丙烯酸甲酯，聚氰基丙烯酸乙酯，聚氰基丙烯酸丙酯，聚氰基丙烯酸正丁酯，聚氰基丙烯酸异丁酯中的一种；
所述冷冻干燥的方法包括如下步骤：
A、产品的预冻：将待干燥的料液稀释到质量浓度为20~35%，1~2h内迅速降温至-30℃～-40℃，料液变为块状结构；
B、退火：将上述块状物料在4-5h内升温至-10~0℃，然后在0.5-1h内迅速降温至-30℃～-40℃，物料变为表面凹凸不平、内部有大量贯通孔隙的松散冰状结构；
C、升华干燥：开启真空系统，控制真空度缓慢上升，30min内使得真空度达到20Pa；开启加热，使得物料的温度在2-4h内由-30℃～-40℃缓慢升温至0~10℃，此时物料变为松散的粉末，维持在该温度下2-5h；
D、解析干燥：将上述物料粉末在0.5~1.5h内迅速升温到40-45℃，并维持在该温度下0.5~1h，关闭真空系统，使得压力缓慢恢复到常压，得到物料的冻干粉末；
E、封装：在干燥环境下，将上述冻干后的产品迅速装填到密闭容器中，并迅速抽真空或通入氮气后进行密封包装。
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| CN101632671A (zh) * | 2009-08-18 | 2010-01-27 | 海南永田药物研究院有限公司 | 一种哌拉西林钠舒巴坦钠药物组合物混悬粉针剂及其新应用 |
| CN103054818A (zh) * | 2013-01-28 | 2013-04-24 | 苏州二叶制药有限公司 | 一种优质高效的冷冻干燥技术 |
| CN103271925A (zh) * | 2013-06-05 | 2013-09-04 | 重庆福安药业集团庆余堂制药有限公司 | 注射用头孢美唑钠克拉维酸钾药物组合物 |
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| CN101632671A (zh) * | 2009-08-18 | 2010-01-27 | 海南永田药物研究院有限公司 | 一种哌拉西林钠舒巴坦钠药物组合物混悬粉针剂及其新应用 |
| CN103054818A (zh) * | 2013-01-28 | 2013-04-24 | 苏州二叶制药有限公司 | 一种优质高效的冷冻干燥技术 |
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