CN117379368A - 一种环磷腺苷葡胺注射液和制备方法 - Google Patents
一种环磷腺苷葡胺注射液和制备方法 Download PDFInfo
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Abstract
本发明属于医药制剂技术领域,具体涉及一种环磷腺苷葡胺注射液和制备方法,环磷腺苷葡胺注射液由如下重量百分含量组分组成,环磷腺苷0.77~1.28%,葡甲胺0.44~0.67%,余量为水,pH为5.5~7.0,本发明在保证具有较高有效成分的情况下,具有较好的稳定性和安全性。
Description
技术领域
本发明属于医药制剂技术领域,具体涉及一种环磷腺苷葡胺注射液和制备方法。
背景技术
环磷腺苷为参与调节细胞功能的第二信使物质,其作用非常广泛,注射大剂量的环磷腺苷,能使心肌收缩力增强,引起血压升高,心输出量增高,并能舒张平滑肌,扩张冠状动脉血管,改善肝功能,促进神经再生,抑制皮肤外层上皮细胞分裂及转化异常细胞的功能,促进呼吸链氧化酶的活性及改善心肌缺氧等。
葡甲胺易溶于水,通过增强环磷腺苷脂溶性,提高环磷腺苷纯度,使得环磷腺苷发挥最大程度的药理作用。
环磷腺昔微溶于水,在环磷腺中加入葡甲胺可增加其溶解性。环磷腺苷葡胺注射液为细胞信使,具有调节细胞多种功能,增强心肌收缩力,扩张心脑及外周血管,降低心肌耗氧量,改善心肌代谢等作用,并可促使受损窦房结功能的恢复。用于治疗病窦综合症,急性心肌炎,扩张型心肌病,冠心病心绞痛,各种病因所致的心力衰竭,对洋地黄不敏感或中毒的心衰患者疗效尤佳。
目前,环磷腺苷在临床上有粉针剂和水针剂。由于环磷腺苷微溶于水,配成水溶液时易析出,制成水针剂也比较困难;在环磷腺苷中加入葡甲胺能增加其溶解性,然而在环磷腺苷葡胺溶液中,随着保存时间的延长环磷腺苷葡胺会逐渐析出,使药液变质、浑浊,从而影响药品的疗效和用药的安全性。药企大都加入活性碳以去除环磷腺苷葡胺注射液里的热原,存在活性碳对注射液剂的潜在影响。
公开日为2005年2月16日,公开号为CN1579413A的发明专利申请公开了一种注射用环磷腺苷葡胺及其制备工艺就是采用此方法。但是冻干制剂的制备工艺非常复杂,复溶后有时也会有环磷腺苷葡胺会逐渐析出,使药液发生变质、浑浊。
公开号为CN102600070A的发明专利中公开了一种环磷腺苷葡胺组合物注射液及其制备方法,该环磷腺苷葡胺组合物注射液虽然澄明度良好、稳定性良好,但其在处方中引入了枸椽酸、氢氧化钠等pH调节剂和苯甲酸钠等助溶剂,从一定程度上给用药安全带来风险。
公开号为CN105055307A的发明专利中公开了具体涉及一种环磷腺苷葡胺注射液及其制备方法,该环磷腺苷葡胺组合物注射液虽然液澄明度好,稳定性好,但其未考虑温度过高的情况下,会对环磷腺苷葡甲胺的稳定性产生影响,杂质产生增长。
发明内容
本发明要解决的技术问题是提供一种环磷腺苷葡胺注射液和制备方法,在保证具有较高有效成分的情况下,具有较好的稳定性和安全性。
本发明实施例提供一种环磷腺苷葡胺注射液,由如下重量百分含量组分组成,环磷腺苷0.77~1.28%,葡甲胺0.44~0.67%,余量为水,pH为5.5~7.0。
优选的,由如下重量百分含量组分组成,环磷腺苷0.9~1.0%,葡甲胺0.5~0.6%,余量为水,pH为5.8~6.8。
本发明实施例提供一种所述环磷腺苷葡胺注射液的制备方法,步骤为,
将环磷腺苷和葡甲胺水溶液混合,所述葡甲胺水溶液的温度为40~100℃,然后冷却至30~40℃,加入剩余的水,过滤,得到环磷腺苷葡胺注射液。
优选的,所述葡甲胺水溶液的温度为40~60℃,优选为50℃。
优选的,葡甲胺水溶液中的水和所述剩余的水的重量比为9:1。
优选的,环磷腺苷和葡甲胺水溶液混合采用搅拌方式进行。
优选的,搅拌速度为10~60Hz。
优选的,搅拌时间为5~60min,优选30min。
优选的,过滤的滤膜为0.45μm、0.22μm滤膜,材质为PES材质。
优选的,过滤后,将过滤后的药液灌装在安瓿瓶(优选20ml以下的玻璃安培瓶或塑料安培瓶)中,将灌封后的产品进行灭菌和检漏,灭菌温度为100~121℃,优选为115℃,灭菌时间为8~60min,优选为50min。
本发明的有益效果是, 葡甲胺在水中的溶解度较大,其溶解过程受溶解过程参数的影响较小,环磷腺苷在水中的溶解度较小,虽然在葡甲胺溶液中的溶解度增大,但其溶解过程也相对缓慢,提高药液温度以加速环磷腺苷溶解,本发明在将环磷腺苷溶解即目视药液澄清后降温以保证药液稳定性。故选择合适工艺参数对保证环磷腺苷的溶解也很重要。
本发明不加入活性炭,采用从原辅料开始控制,在保证产品质量的同时,还降低了活性炭对注射剂的潜在风险。本发明的样品稳定性良好,加速试验期间样品澄清无色,未见晶体析出。本发明不加入其他辅料,保障用药安全。本发明控制配液温度,减少降解杂质的产生。
具体实施方式
实施例1稳定性加速试验
加入所配药液总体积90%的注射用水,加入葡甲胺9.0g,水浴加热至50℃搅拌至溶解。加入环磷腺苷21g,搅拌至溶解,目视原料药溶解后将药液冷却至40℃,加注射用水定容至2000g,搅匀。药液依次通过0.45μm和0.22μm滤膜。将过滤后的药液灌封在2ml玻璃安瓿瓶中。将灌封后的中间产品进行灭菌(115℃,50min),并放置在影响因素(高温60℃±2℃)下,检测样品的温度性,得到如表1所示的结果。
表1样品高温试验结果
测定结果表明,环磷腺苷葡胺注射液在高温60℃条件下放置30天,杂质总量有所增长(增长量为0.429),委托第三方对环磷腺苷葡胺注射液高温60℃30天样品进行液质检测,委托方给出结论为:产生机理为高温条件下环磷腺苷降解产生。综上可知,高温60℃条件下,环磷腺苷降解导致杂质总量有所增长,但是不会对样品的稳定性及安全性产生影响,增长幅度较小,故生产操作中控制配液温度是必要的。
实施例2
加入所配药液总体积90%的注射用水,加入葡甲胺0.9g,室温下用玻璃棒搅拌至澄清。加入环磷腺苷2.1g,用玻璃棒搅拌至澄清。目视原料药完全溶解后,加注射用水定容至200g,搅匀。药液依次通过0.45μm和0.22μm滤膜。配制后药液存放于配液温度下4h分别取样20ml,用于检测;然后将剩余药液置于室温条件下继续存放至配液完成后24h,于24h取样20ml,用于检测。
实施例3
加入所配药液总体积90%的注射用水,加入葡甲胺0.9g,水浴恒温至50℃,搅拌至溶解。加入环磷腺苷2.1g,搅拌至溶解。目视原料药完全溶解后,将药液冷却至40℃,加注射用水定容至200g,搅匀。药液依次通过0.45μm和0.22μm滤膜。配制后药液存放于配液温度下4h分别取样20ml,用于检测;然后将剩余药液置于室温条件下继续存放至配液完成后24h,于24h取样20ml,用于检测。
实施例4
加入所配药液总体积90%的注射用水,加入葡甲胺0.9g,水浴加热至60℃搅拌至溶解。加入环磷腺苷2.1g,搅拌至溶解,加注射用水定容至200g,搅匀。药液依次通过0.45μm和0.22μm滤膜。配制后药液存放于配液温度下4h分别取样20ml,用于检测;然后将剩余药液置于室温条件下继续存放至配液完成后24h,于24h取样20ml,用于检测。
实施例2-4的原料药溶解时间统计如表2所示,各样品的稳定性如表3所示。
表2不同配液温度原料药溶解时间统计表
表3实施例2~4环磷腺苷不同溶解方式对样品关键质量属性的影响
从表2可知,实施例2溶解时间长,实施例4溶解时间短,但有关物质均有所增长,可能会对产品安全性产生影响,实施例3溶解时间短,杂质总量无明显变化,故实施例3性能最优。
实施例5稳定性加速试验
加入所配药液总体积90%的注射用水,加入葡甲胺9g,水浴加热至50℃搅拌至溶解。加入环磷腺苷21g,搅拌至溶解,目视原料药溶解后将药液温度冷却至40℃,加注射用水定容至2000g,搅匀。药液依次通过0.45μm和0.22μm滤膜。将过滤后的药液灌封在2ml玻璃安瓿瓶中。将灌封后的产品进行灭菌(115℃,50min),并放置加速试验(40℃±2℃,75%±5%RH)。
表4加速试验结果
试验结果表明:3批生产放大样品于加速条件(40℃±2℃,75%±5%RH)放置6月,与0天结果比较,杂质总量有所增加(最大总杂增长量为0.267%)。但仍符合规定,样品无晶体析出,稳定性良好。热原结果均符合规定,不添加活性炭可行,减少了活性炭的潜在风险。
实施例6~7
将90%处方量的注射用水置于500ml烧杯中,加入1.8g的葡甲胺,水浴加热至50℃搅拌至溶解。加入4.2g的环磷腺苷,搅拌至环磷腺苷溶清,记录搅拌时间,将药液温度冷却至40℃。加水定容至400g。将药液分为两份,取一半未浸泡滤芯药液作为空白样品(实施例6),并取样30ml检测0h性状、pH和含量,将剩余药液浸泡PES滤芯(实施例7),2份样品分别于4h,8h,24h后取样。
表5过滤工艺研究试验结果
从表5可知,浸泡滤芯24h药液与同等条件下放置阴性样品相比,性状、含量、pH值、总杂均无明显差异,表明环磷腺苷葡胺注射液与PES滤芯无明显相容性问题,故暂定滤芯材质为PES。
实施例8~11
加入所配药液总体积90%的注射用水,加入葡甲胺,水浴加热至50℃搅拌至溶解。加入环磷腺苷,搅拌至溶解,目视原料药溶解后将药液温度冷却至40℃,加注射用水定容至200g,搅匀。药液依次通过0.45μm和0.22μm滤膜。将过滤后的药液灌封在2ml玻璃安瓿瓶中。将灌封后的产品进行灭菌(115℃,50min),
表6
试验结果表明:在相同制备方法的条件下,调整环磷腺苷或者葡甲胺的投料量使之不在本申请的保护范围内,样品pH将不符合规定,达不到产品质量要求。
所属领域的普通技术人员应当理解:以上任何实施例的讨论仅为示例性的,并非旨在暗示本申请的保护范围限于这些例子;在本申请的思路下,以上实施例或者不同实施例中的技术特征之间也可以进行组合,步骤可以以任意顺序实现,并存在如上所述的本申请中一个或多个实施例的不同方面的许多其它变化,为了简明它们没有在细节中提供。
本申请中一个或多个实施例旨在涵盖落入本申请的宽泛范围之内的所有这样的替换、修改和变型。因此,凡在本申请中一个或多个实施例的精神和原则之内,所做的任何省略、修改、等同替换、改进等,均应包含在本申请的保护范围之内。
Claims (10)
1.一种环磷腺苷葡胺注射液,其特征是,由如下重量百分含量组分组成,环磷腺苷0.77~1.28%,葡甲胺0.44~0.67%,余量为水,pH为5.5~7.0。
2.如权利要求1所述的环磷腺苷葡胺注射液,其特征是,由如下重量百分含量组分组成,环磷腺苷0.9~1.0%,葡甲胺0.5~0.6%,余量为水,pH为5.8~6.8。
3.一种如权利要求1或2所述的环磷腺苷葡胺注射液的制备方法,其特征是,步骤为,
将环磷腺苷和葡甲胺水溶液混合,所述葡甲胺水溶液的温度为40~100℃,然后冷却至30~40℃,加入剩余的水,过滤,得到环磷腺苷葡胺注射液。
4.如权利要求3所述的制备方法,其特征是,所述葡甲胺水溶液的温度为40~60℃。
5.如权利要求3所述的制备方法,其特征是,葡甲胺水溶液中的水和所述剩余的水的重量比为9:1。
6.如权利要求3、4或5所述的制备方法,其特征是,环磷腺苷和葡甲胺水溶液混合采用搅拌方式进行。
7.如权利要求6所述的制备方法,其特征是,搅拌速度为10~60Hz。
8.如权利要求6所述的制备方法,其特征是,搅拌时间为5~60min。
9.如权利要求3、4或5所述的制备方法,其特征是,过滤的滤膜为0.45μm、0.22μm滤膜。
10.如权利要求3、4或5所述的制备方法,其特征是,过滤后,将过滤后的药液灌装在安瓿瓶中,将灌封后的产品进行灭菌和检漏,灭菌温度为100~121℃。
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