CN115300465A - 一种注射用尼可地尔冻干粉针剂及其制备方法 - Google Patents
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Abstract
本发明提供了一种注射用尼可地尔冻干粉针剂及其生产工艺。其中生产工艺采用程序降温预冻和/或缓慢升温干燥的方式对样品进行冷冻干燥。本发明提供了制备室温稳定性良好的注射用尼可地尔冻干粉针剂的工艺,大大提高了该制剂运输与贮存的方便性,并降低由于运输和贮存过程中因温控异常带来的用药安全隐患。
Description
技术领域
本发明属于医药制剂技术领域,更具体地,涉及一种注射用冻干粉针剂;特别涉及一种注射用尼可地尔冻干粉针剂及其生产工艺。
背景技术
尼可地尔,化学名硝酸乙氧烟酰胺,属硝酸酯类化合物,是由N-2(2- 羟乙基)烟酰胺维生素和有机硝酸酯的部分结构连接而成的化合物,它同时也是一种ATP敏感性钾通道开放剂。与硝酸酯一样,尼可地尔可激活细胞质鸟苷酸环化酶,从而导致细胞内环磷酸鸟苷升高和细胞内钙的降低,同时引起血管平滑肌松弛。作为一种钾通道开放剂,尼可地尔增加了钾离子从细胞内的流出,静息膜电位负值增大,动作电位缩短,钙的内流减少,细胞内钙水平下降,导致血管平滑肌松弛和血管舒张(间接的钙通道阻断作用),减少了ATP的消耗。临床研究证实,它适用于各类型心绞痛,包括劳力型心绞痛和痉挛性心绞痛,而且能显著减少心血管事件发生风险,改善预后。
由于尼可地尔在高温高湿条件下稳定性较差,目前上市剂型主要为片剂和冻干粉针剂。已知尼可地尔即使制备为冻干粉针剂,现在市售的产品也只能在10℃条件下储藏,有效期仅为2年。
因此,急需开发一种制备方法以提高尼可地尔冻干粉针剂室温条件下的稳定性,方便该制剂的运输和贮存,并降低由于运输和贮存过程中因温控异常带来的用药安全隐患。
发明内容
本发明旨在提供一种简单、稳定性好的注射用尼可地尔冻干粉针剂及其生产工艺,提高了尼可地尔冻干粉针剂室温条件下的稳定性。
在本发明的第一个方面,提供了一种尼可地尔冻干粉针剂的生产工艺,包括冷冻干燥的步骤,所述冷冻干燥的步骤包括程序降温预冻和缓慢升温干燥。
本发明的第二个方面,提供了一种由本发明第一个方面制备而得到的尼可地尔冻干粉针剂。
本发明提供的尼可地尔冻干粉针剂及其生产工艺简单,安全性高,降低了尼可地尔冻干粉针剂在贮藏期间的杂质降解程度,提高了尼可地尔冻干粉针剂的稳定性。
具体实施方式
在本发明的第一方面,在一具体实施方案中,所述的程序降温预冻是通过以下方式进行的,缓慢降温1~10℃,优选地,为3℃~5℃,降温时长不少于1h,优选地,为1h~2h;降至目标温度后,温度维持时长不少于1h,优选地,为2h~3h;循环前述步骤降温至-15℃~-25℃范围后,0.5h~3h降温至-40℃,温度维持时间不少于1h,优选地,温度维持时间为2h~3h;
在一具体实施方案中,所述的缓慢升温干燥包括一期干燥和二期干燥,所述一期干燥的程序为:10h~24h缓慢升温至-15℃~-5℃,优选地,为-10℃,维持不少于10h,其中升温时长优选10h~15h,维持时间优选15h~18h;
和/或,所述的二期干燥的温度为20℃~40℃,优选30℃,维持时长为 4h-20h,优选地,为8h-12h;
在一具体实施方案中,程序降温预冻之前还包括隔板预冷过程,所述隔板预冷的温度为5~10℃,优选地,为5℃。
本发明还提供了上述注射用尼可地尔冻干粉针剂的生产工艺,其包括以下步骤:
步骤一:将甘露醇、枸橼酸钠、尼可地尔顺序溶解到95%处方体积量的 5℃~10℃注射用水中,溶解结束后用注射用水定容形成混合溶液。
步骤二:将步骤一所得的混合溶液除菌过滤、灌装、半加塞,形成样品溶液。
步骤三:按照如下工艺进行冷冻干燥;
i)隔板预冷:隔板预冷至5~10℃,优选地,为5℃;
ii)程序降温预冻阶段:将步骤二的样品溶液放入冻干机后,缓慢降温 1~10℃,优选地,为3℃-5℃,降温时间不少于1h,优选地,为1h~2h;降至目标温度后维持时长不少于1h,优选地,为2h~3h;循环前述步骤降温至 -15℃~-25℃范围后,0.5h~3h降温至-40℃,温度维持时间不少于1h,优选地为2h~3h;
iii)一期干燥阶段:10h~24h缓慢升温至-15℃~-5℃,维持不少于10h;
iv)二期干燥阶段:干燥温度为20℃~40℃,维持4h~20h。
步骤四:充氮,全压塞,出箱,轧盖。
本发明还提供了一种由上述注射用尼可地尔冻干粉针的生产工艺制备得到的注射用尼可地尔冻干粉针。
本发明的有益效果如下:
本发明通过药液冻干时采用缓慢梯度降温预冻和缓慢升温干燥的方式制备了室温稳定性良好的注射用尼可地尔冻干粉针剂,大大提高了该制剂运输与贮存的方便性,并降低由于运输和贮存过程中因温控异常带来的用药安全隐患。
实施例
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
实施例1
处方组成如下表1所示:
表1
步骤一:将甘露醇、枸橼酸钠、尼可地尔顺序溶解到处方体积量95%的 5℃~10℃注射用水中,溶解结束后用注射用水定容形成混合溶液。
步骤二:将步骤一所得混合溶液除菌过滤,灌装,半加塞,形成样品溶液;
步骤三:按照如下工艺进行冷冻干燥;
i)隔板预冷:隔板预冷至5℃;
ii)程序降温预冻阶段:将步骤二的样品溶液放入冻干机后,1h降温至 0℃,降温结束后维持2h;1h降温至-5℃,降温结束后维持2h;1h降温至-10℃,降温结束后维持2h;1h降温至-15℃,降温结束后维持2h;1h降温至-20℃,降温结束后维持2h;1h降温至-40℃,维持2h;
iii)一期干燥阶段:10h缓慢升温至-10℃,维持15h;
iv)二期干燥阶段:干燥温度为30℃,维持10h。
步骤四:充氮,全压塞,出箱,轧盖。
实施例2
处方组成与实施例1相同。
步骤一:将甘露醇、枸橼酸钠、尼可地尔顺序溶解到95%处方体积量的 5℃~10℃注射用水中,溶解结束后用注射用水定容形成混合溶液;
步骤二:将步骤一所得的混合溶液除菌过滤,灌装,半加塞,形成样品溶液;
步骤三:按照如下工艺进行冷冻干燥;
i)隔板预冷:隔板预冷至5℃;
ii)程序降温预冻阶段:将步骤二的样品溶液放入冻干机后,2h降温至 0℃,降温结束后维持3h,2h降温至-5℃,降温结束后维持3h,2h降温至-10℃,降温结束后维持3h,2h降温至-15℃,降温结束后维持3h,2h降温至-20℃,降温结束后维持4h,2h降温至-40℃,维持3h;
iii)一期干燥阶段:10h缓慢升温至-10℃,维持15h;
iv)二期干燥阶段:干燥温度为30℃,维持10h。
步骤四:冻干结束后充氮,全压塞,出箱,轧盖。
对比例1
处方组成与实施例1相同。
步骤一:将甘露醇、枸橼酸钠、尼可地尔顺序溶解到95%处方体积量的 5℃~10℃注射用水中,溶解结束后用注射用水定容形成混合溶液。
步骤二:将步骤一所得的混合溶液药液除菌过滤,灌装,半加塞,形成样品溶液。
步骤三:按照如下工艺进行冷冻干燥;
i)隔板预冷:隔板预冷至5℃;
ii)预冻阶段:将步骤二的样品溶液放入冻干机后,0.5h降温至-40℃,降温结束后维持3h;
iii)一期干燥阶段:10h缓慢升温至-10℃,维持15h;
iv)二期干燥阶段:干燥温度为30℃,维持10h。
步骤四:冻干结束后充氮,全压塞,出箱,轧盖。
对比例2
处方组成与实施例1相同。
步骤一:将甘露醇、枸橼酸钠、尼可地尔顺序溶解到95%处方体积量的 5℃~10℃注射用水中,溶解结束后用注射用水定容形成混合溶液。
步骤二:将步骤一所得的混合溶液除菌过滤,灌装,半加塞,形成样品溶液;
步骤三:按照如下工艺进行冷冻干燥;
i)隔板预冷:隔板预冷至5℃;
ii)程序降温预冻阶段:将步骤二的样品溶液放入冻干机后,0.25h降温至-5℃,降温结束后维持0.5h,0.25h降温至-10℃,降温结束后维持0.5h,0.25h降温至-15℃,降温结束后维持0.5h,0.25h降温至-20℃,降温结束后维持0.5h,0.25h降温至-40℃,维持2h;
iii)一期干燥阶段:10h缓慢升温至-10℃,维持15h;
iv)二期干燥阶段:干燥温度为30℃,维持10h。
步骤四:冻干结束后充氮,全压塞,出箱,轧盖。
对比例3
处方组成与实施例1相同。
步骤一:将甘露醇、枸橼酸钠、尼可地尔顺序溶解到95%处方体积量的 5℃~10℃注射用水中,溶解结束后用注射用水定容形成混合溶液。
步骤二:将步骤一所得的混合溶液除菌过滤,灌装,半加塞,形成样品溶液;
步骤三:按照如下工艺进行冷冻干燥;
i)隔板预冷:隔板预冷至5℃;
ii)程序降温预冻阶段:将步骤二的样品溶液放入冻干机后,0.25h降温至-10℃,降温结束后维持3h,0.25h降温至-25℃,降温结束后维持3h,0.25h 降温至-40℃,维持3h;
iii)一期干燥阶段:0.25h缓慢升温至-6℃,维持4h;
iv)二期干燥阶段:12h升温至0℃后维持6h,0.25h升温至15℃后维持 20h。
步骤四:冻干结束后充氮,全压塞,出箱,轧盖。
制剂稳定性实验
参比制剂:将市售注射用尼可地尔冻干粉针剂(规格:48mg,中外制药株式会社)在2~8℃条件下保存,在使用时取出。
将实施例1-2、对比例1-3和参比制剂样品置于40℃±2℃,75%±5%条件下进行加速稳定性考察,分别于第1、2、3、6个月末取样,进行样品的检测。
检测结果如下:
通过40℃加速条件的对比结果可知,经过梯度降温预冻和缓慢升温干燥的冻干工艺制备的样品(实施例1和实施例2)稳定性明显提高。市售制剂要求效期内总杂含量不得高于0.5%,参比制剂加速3月时总杂质含量已接近限度。对比例1和对比例2采用较快的预冻速度,制备的样品稳定性很差,尤其是对比例1采用常规的预冻工艺,加速一个月总杂质含量就已超标,对比例2将预冻速度稍微降低,虽然稳定性有提高的趋势,但是仍不能满足要求。对比例3冻干工艺将预冻降温温度跨度调整为15℃,而一期干燥时快速升温至-6℃并仅维持了4h后又继续升温,导致一期干燥速率过快,样品出现分层,上部产生一层与块状冻干粉分层的薄膜,同时由于对比例3的二期干燥温度仅为15℃,故冻干结束后样品水分含量较高,超过了参比制剂对水分的控制限度3%,40℃加速2月产品的有关物质也超过了限度要求。
将实施例1-2、对比例1-3和参考制剂样品置于25℃±2℃,60%±5%条件下进行长期稳定性考察,分别于第3、6、12个月末取样,进行样品的检测。检测结果如下:
通过对各工艺制备样品的长期稳定性考察,发现采用梯度降温预冻和缓慢升温干燥的冻干工艺制备的样品长期12个月时,总杂质水平约为0.25%,明显低于0.5%的限度要求,推测该工艺制备的冻干粉针剂可以满足室温储存2年的需求。参比制剂长期12个月时,总杂质含量接近限度,对比例1 和对比例2样品稳定性较差。由此结果可知,注射用尼可地尔冻干粉针剂的稳定性受冻干工艺影响明显。
Claims (5)
1.一种制备尼可地尔冻干粉针剂的方法,其特征在于,包括冷冻干燥的步骤,所述冷冻干燥的步骤包括程序降温预冻阶段和/或缓慢升温干燥。
2.根据权利要求1所述的方法,其特征在于,所述的程序降温预冻阶段是通过以下方式进行的,
缓慢降温1~10℃,优选地,为3℃~5℃,降温时长不少于1h,优选地,为1h~2h;降至目标温度后,温度维持时长不少于1h,优选地,为2h~3h;循环前述步骤降温至-15℃~-25℃范围后,0.5h~3h降温至-40℃,温度维持时间不少于1h,优选地,温度维持时间为2h~3h;
和/或,所述缓慢升温干燥包括一期干燥和二期干燥,所述一期干燥的程序为:10h~24h缓慢升温至-15℃~-5℃,优选地,为-10℃,维持时间不少于10h;其中升温时长优选10h~15h,维持时间优选15h~18h;
和/或,所述的二期干燥的温度为20℃~40℃,优选30℃,维持时长为4h-20h,优选地,为8h-12h。
3.根据权利要求2所述的方法,其特征在于,所述程序降温预冻之前还包括隔板预冷过程,所述隔板预冷的温度为5~10℃,优选地,为5℃。
4.根据权利要求3所述的方法,其特征在于,包括以下步骤:
步骤一:将甘露醇、枸橼酸钠、尼可地尔顺序溶解到95%处方体积量的5℃~10℃注射用水中,溶解结束后用注射用水定容形成混合溶液;
步骤二:将步骤一所得的混合溶液除菌过滤、灌装、半加塞,形成样品溶液;
步骤三:按照如下工艺进行冷冻干燥;
i)隔板预冷:隔板预冷至5~10℃,优选地,为5℃;
ii)程序降温预冻阶段:将所述样品溶液放入冻干机后,缓慢降温1~10℃,优选地,为3℃~5℃,降温时间不少于1h,优选地,为1h~2h;降至目标温度后维持时长不少于1h,优选地,为2h~3h;循环前述步骤降温至-15℃~-25℃范围后,0.5h~3h降温至-40℃,温度维持时间不少于1h,优选地,为2h~3h;
iii)一期干燥阶段:10h~24h缓慢升温至-15℃~-5℃,温度维持不少于10h;
iv)二期干燥阶段:干燥温度为20℃~40℃,维持4h~20h;
步骤四:充氮,全压塞,出箱,轧盖。
5.一种由权利要求1~4任一项所述的方法而制备得到的尼可地尔冻干粉针剂。
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