CN113476411A - 注射用盐酸地尔硫卓冻干粉针剂及其制备方法 - Google Patents
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Abstract
本发明提供一种注射用盐酸地尔硫卓冻干粉针剂及其制备方法,属于药物制备技术领域,所述制备方法是取注射用水加入1.15~1.73重量份枸橼酸和3.47~4.27重量份枸橼酸钠溶解后,再加入6~8重量份甘露醇和1~2重量份盐酸地尔硫卓溶解,然后经调节pH值、脱色、除菌过滤、冻干,即得所述注射用盐酸地尔硫卓冻干粉针剂。本发明通过添加枸橼酸和枸橼酸钠,能够有效抑制盐酸地尔硫卓在制备粉针剂过程中发生水解,维持盐酸地尔硫卓的稳定性,提高所制注射用盐酸地尔硫卓冻干粉针剂的品质。
Description
技术领域
本发明涉及冻干粉针剂的制备,尤其涉及一种注射用盐酸地尔硫卓冻干粉针剂及其制备方法。
背景技术
盐酸地尔硫卓是一种钙离子通道阻滞剂,主要通过阻断心肌和血管平滑肌细胞膜上的钙通道功能,抑制细胞外的钙离子水平,从而调节心血管功能。盐酸地尔硫卓能够使血管平滑肌松弛,周围血管阻力下降,血压降低;其还具有负性肌力作用,可以减慢窦房结和房室结的传导。盐酸地尔硫卓也可以有效扩张心外膜和心内膜下的冠状动脉,缓解自发性心绞痛或由冠状动脉痉挛所致的心绞痛。盐酸地尔硫卓能够通过减慢心率、降低血压、减少心肌需氧量,从而增加运动耐量、缓解劳力型心绞痛。临床上,盐酸地尔硫卓主要用于治疗冠状动脉痉挛引起的心绞痛、劳力型心绞痛及高血压。
目前,盐酸地尔硫卓的剂型主要包括冻干粉针剂、片剂、胶囊剂等,临床上使用最多的剂型为冻干粉针剂。但在制备冻干粉针剂的过程中,需先将盐酸地尔硫卓在水中溶解,再冻干。然而,盐酸地尔硫卓结构式中具有在水中易断裂的酰胺键和酯键,导致其在水中不稳定,易发生水解,进而影响成品品质,使其在复溶过程中出现不溶杂质(即药典中规定的有关物质的一部分),进一步导致成品存在可见异物、不溶性微粒、澄清度不合格等问题。
发明内容
针对上述问题,本发明提供一种注射用盐酸地尔硫卓冻干粉针剂及其制备方法。
为实现上述目的,本发明所采用的技术方案为:
一种注射用盐酸地尔硫卓冻干粉针剂,以重量份数计,制成所述注射用盐酸地尔硫卓冻干粉针剂的有效成分的原料包括:盐酸地尔硫卓1~2份、甘露醇6~8份、枸橼酸1.15~1.73份和枸橼酸钠3.47~4.27份。
一种注射用盐酸地尔硫卓冻干粉针剂的制备方法,是取注射用水加入枸橼酸和枸橼酸钠溶解后,再加入甘露醇和盐酸地尔硫卓溶解,然后经调节pH值、脱色、除菌过滤、冻干,即得所述注射用盐酸地尔硫卓冻干粉针剂。
进一步的,所述盐酸地尔硫卓与注射用水的重量体积比为1g:150~200mL。
进一步的,所述盐酸地尔硫卓的溶解温度为25~40℃。
进一步的,所述冻干的过程是先于-42~-38℃预冻2~4h,再以2~3℃/h升温至-5~0℃进行升华干燥12~18h,然后以2~3℃/h升温进行25~30℃经解析干燥3~5h。
进一步的,所述升华干燥和解析干燥的压力均为10~20Pa。
进一步的,所述pH值调节至5.0~5.6。
进一步的,所述调节pH值的调节剂为盐酸或氢氧化钠水溶液。
进一步的,所述除菌过滤是先经0.22μm一次过滤器过滤,再经0.22μm二次终端除菌过滤。
进一步的,所述脱色的温度为25~40℃、时间为20~40min。
本发明的注射用盐酸地尔硫卓冻干粉针剂及其制备方法的有益效果为:
针对盐酸地尔硫卓易水解的现象,通过多次实验研究发现,盐酸地尔硫卓在不同pH值的水溶液中溶解,其水解程度有所不同,维持水溶液的pH值在5.0~5.6之间,能够抑制盐酸地尔硫卓结构式中的酰胺键和酯键发生水解,进而减少有关物质的产生;本发明通过添加枸橼酸和枸橼酸钠,能够有效抑制盐酸地尔硫卓在制备粉针剂过程中发生水解,维持盐酸地尔硫卓的稳定性,提高所制注射用盐酸地尔硫卓冻干粉针剂的品质;
同时,研究还发现,水溶液中的枸橼酸和枸橼酸钠还可以促进盐酸地尔硫卓溶解;在盐酸地尔硫卓溶解过程中无需加入助溶剂或升温即可完全溶解,而盐酸地尔硫卓的溶解过程在较低温度下进行,能够进一步抑制了盐酸地尔硫卓发生水解,提高所制注射用盐酸地尔硫卓冻干粉针剂的品质。
具体实施方式
下面对本发明实施例中的技术方案进行清楚、完整地描述。在下面的描述中阐述了很多具体细节以便于充分理解本发明,但是本发明还可以采用其他不同于在此描述的其它方式来实施,本领域技术人员可以在不违背本发明内涵的情况下做类似推广,因此本发明不受下面公开的具体实施例的限制。
实施例1一种注射用盐酸地尔硫卓冻干粉针剂的制备方法
本实施例为一种注射用盐酸地尔硫卓冻干粉针剂的制备方法,具体制备过程包括依次进行的以下步骤:
1)取注射用水煮沸放冷备用;
取2000mL煮沸后的注射用水,加入15.3g枸橼酸和37.4g枸橼酸钠,室温搅拌至完全溶解,过滤除去不溶杂质,得枸橼酸缓冲液,此时枸橼酸缓冲液的pH值为5.2;
2)枸橼酸缓冲液略加热或降温,维持枸橼酸缓冲液的温度为30℃,依次加入70g甘露醇和10g地尔硫卓,维持30℃搅拌至完全溶解呈澄明溶液,滴加少量20wt%的氢氧化钠水溶液调节pH值至5.2,再加入1g针用活性炭于30℃搅拌脱色30min,过滤除碳,然后经0.22μm一次过滤器过滤,再经0.22μm二次终端除菌过滤,有效去除细菌微生物,得无菌药液;
3)将无菌药液按所需规格进行分装,半加塞,再移入预冷至-40℃的冻干机中,-40℃预冻3h,然后抽真空使箱内压力为15Pa后,以2.5℃/h升温至-5℃,进行升华干燥15h,继续保持箱内压力为15Pa,再以2.5℃/h升温至25℃,进行解析干燥4h。
干燥完成后,真空条件下压全塞,出箱,目检,包装,即得注射用盐酸地尔硫卓冻干粉针剂(规格:盐酸地尔硫卓10mg)。
实施例2~6注射用盐酸地尔硫卓冻干粉针剂的制备方法
实施例2~6分别为一种注射用盐酸地尔硫卓冻干粉针剂的制备方法,它们的步骤与实施例1基本相同,不同之处仅在于工艺参数的不同,具体详见表1:
表1实施例2~6中各项工艺参数一览表(规格:盐酸地尔硫卓10mg)
实施例2~6其它部分的内容,与实施例6相同。
实施例1~6制备的注射用盐酸地尔硫卓冻干粉针剂稳定性好、主药含量高、杂质少,且成品表面平整,外观良好,复溶性优良。
实验例1注射用盐酸地尔硫卓冻干粉针剂的性能测定
对比例1~3为实施例1中注射用盐酸地尔硫卓冻干粉针剂(规格:盐酸地尔硫卓10mg)制备过程的对比试验,区别仅在于:
对比例1中枸橼酸的用量为10g,枸橼酸钠的用量为30g,在盐酸地尔硫卓溶解过程中,溶解速度变慢,30℃无法完全溶解,需升温至43.4℃才完全溶解,可见枸橼酸和枸橼酸钠的用量降低,会影响盐酸地尔硫卓的溶解温度,说明枸橼酸和枸橼酸钠能够促进盐酸地尔硫卓溶解;
对比例2中枸橼酸的用量为20g,枸橼酸钠的用量为45g;
对比例3中盐酸地尔硫卓的溶解温度为50℃;
对比例4采用授权公告号CN100563633C中公开的制备方法制备注射用盐酸地尔硫卓冻干粉针剂(规格:盐酸地尔硫卓10mg);
S1)稳定性检测
取实施例1~6和对比例1~4制备的注射用盐酸地尔硫卓冻干粉针剂,分别于40±2℃、RH75±5%的条件下放置24个月,期间分别于第1、3、6、12和24个月取样,按稳定性检查项目检测,并与0天数据比较。
依据《中国药典》2015版第二部中规定的样品性状、含量、澄清度、有关物质(包含盐酸地尔硫卓的水解产物)等指标及测定方法,对注射用盐酸地尔硫卓冻干粉针剂进行检测,具体检测结果见下表:
表2检测结果一览表
由表2可以看出,在实验开始(0天)时,实施例1~6制备的注射用盐酸地尔硫卓冻干粉针剂的有关物质含量明显低于对比例1~4,且对比例1~3中制备的注射用盐酸地尔硫卓冻干粉针剂的有关物质含量也低于对比例4,可见在制备过程中加入枸橼酸和枸橼酸钠能够抑制有关物质产生;同时在实验开始(0天)时,对比例1中制备的注射用盐酸地尔硫卓冻干粉针剂的有关物质含量也明显低于对比例3,说明温度升高也会使注射用盐酸地尔硫卓冻干粉针剂中有关物质增加;
表2中还可以看出,实施例1~6制备的注射用盐酸地尔硫卓冻干粉针剂的稳定性明显优于对比例1~4,且杂质含量更少。
上述实验说明,本发明的工艺参数更利于注射用盐酸地尔硫卓冻干粉针剂的制备和储存。
S2)复溶性检测
取实施例1~6和对比例1~4中制备的注射用盐酸地尔硫卓冻干粉针剂(规格:盐酸地尔硫卓10mg),加5mL灭菌生理盐水溶解,并观察其溶解速度,发现实施例1~6和对比例1~4中制备的注射用盐酸地尔硫卓冻干粉针剂均全部快速溶解,说明本发明制备的注射用盐酸地尔硫卓冻干粉针剂复溶性良好。
显然,所描述的实施例仅仅是本发明的一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做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。
Claims (10)
1.一种注射用盐酸地尔硫卓冻干粉针剂,其特征在于,以重量份数计,制成所述注射用盐酸地尔硫卓冻干粉针剂的有效成分的原料包括:盐酸地尔硫卓1~2份、甘露醇6~8份、枸橼酸1.15~1.73份和枸橼酸钠3.47~4.27份。
2.权利要求1所述的注射用盐酸地尔硫卓冻干粉针剂的制备方法,其特征在于,所述制备方法是取注射用水加入枸橼酸和枸橼酸钠溶解后,再加入甘露醇和盐酸地尔硫卓溶解,然后经调节pH值、脱色、除菌过滤、冻干,即得所述注射用盐酸地尔硫卓冻干粉针剂。
3.根据权利要求2所述的注射用盐酸地尔硫卓冻干粉针剂的制备方法,其特征在于,所述盐酸地尔硫卓与注射用水的重量体积比为1g:150~200mL。
4.根据权利要求2或3所述的注射用盐酸地尔硫卓冻干粉针剂的制备方法,其特征在于,所述盐酸地尔硫卓的溶解温度为25~40℃。
5.根据权利要求2或3所述的注射用盐酸地尔硫卓冻干粉针剂的制备方法,其特征在于,所述冻干的过程是先于-42~-38℃预冻2~4h,再以2~3℃/h升温至-5~0℃进行升华干燥12~18h,然后以2~3℃/h升温至25~30℃进行解析干燥3~5h。
6.根据权利要求5所述的注射用盐酸地尔硫卓冻干粉针剂的制备方法,其特征在于,所述升华干燥和解析干燥的压力均为10~20Pa。
7.根据权利要求2、3或6所述的注射用盐酸地尔硫卓冻干粉针剂的制备方法,其特征在于,所述pH值调节至5.0~5.6。
8.根据权利要求2、3或6所述的注射用盐酸地尔硫卓冻干粉针剂的制备方法,其特征在于,所述调节pH值的调节剂为盐酸或氢氧化钠水溶液。
9.根据权利要求2、3或6所述的注射用盐酸地尔硫卓冻干粉针剂的制备方法,其特征在于,所述除菌过滤是先经0.22μm一次过滤器过滤,再经0.22μm二次终端除菌过滤。
10.根据权利要求2、3或6所述的注射用盐酸地尔硫卓冻干粉针剂的制备方法,其特征在于,所述脱色的温度为25~40℃、时间为20~40min。
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