CN107397722A - 注射用(s)-4-羟基-2-氧代-1-吡咯烷乙酰胺冻干粉及其制备方法 - Google Patents
注射用(s)-4-羟基-2-氧代-1-吡咯烷乙酰胺冻干粉及其制备方法 Download PDFInfo
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Abstract
本发明公开了一种注射用(S)‑4‑羟基‑2‑氧代‑1‑吡咯烷乙酰胺冻干粉及其制备方法；所述冻干粉含有以下重量百分比的原辅料：(S)‑4‑羟基‑2‑氧代‑1‑吡咯烷乙酰胺50%~57%，L‑丝氨酸20%~25%，甘露醇10%~17%，聚乙二醇2000 5%~7%，亚硫酸氢钠5%~10%，甲硫氨酸3%~6%。本发明利用特定的赋形剂组合，使得制备的(S)‑4‑羟基‑2‑氧代‑1‑吡咯烷乙酰胺冻干粉具有固定形状，在冻干制备过程中无干缩和鼓泡的现象，制备过程中杂质量增加较少，并且产品稳定性好，不溶性微粒显著减少减小，有利于提高药物使用的安全性，减少药物不良反应。
Description
技术领域
本发明属于制药领域，具体涉及一种注射用(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺冻干粉及其制备方法。
背景技术
左旋奥拉西坦化学名称为：(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺，为白色微晶状粉末，熔点135～136℃，旋光度-36°(C＝1.00in water)，左旋奥拉西坦的溶解性明显优于消旋体。化学结构式如下所示：
该药于1987年在意大利上市，上市的剂型为片剂，800mg；胶囊，800mg；注射液，1g/5ml。目前国内只有奥拉西坦胶囊和注射液上市，且所用主要活性成分均为外消旋体。叶雷等在公开号为CN 103735545A专利中提到左旋奥拉西坦对酒精中毒所致昏迷的促醒作用明显，而右旋奥拉西坦基本没有作用，左旋奥拉西坦的上述促醒效果为消旋奥拉西坦的2倍；左旋奥拉西坦对外伤、麻醉所致昏迷的促醒作用均显著。张峰等在公开号为CN 103599101A的专利中披露左旋奥拉西坦对液压及自由落体所致创伤性脑损伤大鼠学习记忆认知功能障碍均有明显的改善作用，其药效远高于右旋奥拉西坦。且200mg/kg左旋奥拉西坦与400mg/kg奥拉西坦的作用相当。药代动力学研究结果显示：左旋奥拉西坦和右旋奥拉西坦在比格犬体内无明显手性转化。比格犬单次静脉注射给予左旋和2倍剂量的消旋奥拉西坦后血浆中左旋奥拉西坦的主要药动学参数均无明显差异。安全药理、急毒、长毒等试验结果表明，在同等剂量水平下，左旋奥拉西坦与奥拉西坦对受试动物或细胞的毒性无明显差异。上述临床前的研究结果表明，左旋奥拉西坦是奥拉西坦体内发挥药效的主要活性成分，单独使用本品可降低临床使用剂量，降低潜在的毒副反应。
但是，现有的注射用(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺冻干粉存在无固定形状、不易形成骨架、易出现干缩和鼓泡现象，制备过程杂质增加明显，并且存在产品稳定性差的问题，临床使用前，需要溶入5％葡萄糖注射液或0.9％氯化钠注射液100～250ml中，制备成为静脉滴注溶液使用，制备成为静脉滴注溶液后，随着放置时间的延长其不溶性微粒增大增多，这就给临床的使用带来了很大的安全隐患。
发明内容
有鉴于此，本发明的目的在于提供一种注射用(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺冻干粉及其制备方法，具有固定形状、在冻干制备过程中无干缩和鼓泡的现象，制备过程中杂质量增加较少，并且产品稳定性好，制备成为静脉滴注溶液后，不溶性微粒减少。
为达到上述目的，本发明提供如下技术方案：
一种注射用(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺冻干粉，所述冻干粉含有以下重量百分比的原辅料：(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺50％～57％，L-丝氨酸20％～25％，甘露醇10％～17％，聚乙二醇20005％～7％，亚硫酸氢钠5％～10％，甲硫氨酸3％～6％。
进一步，所述冻干粉含有以下重量百分比的原辅料：(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺52％，L-丝氨酸21％，甘露醇11％，聚乙二醇2000 6％，亚硫酸氢钠6％，甲硫氨酸4％。
上述注射用(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺冻干粉的制备方法，包括以下步骤：
(1)浓配：将处方量的原辅料置于容器中，加入(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺10倍重量份的灭菌注射用水搅拌，溶解后，加入质量分数0.1％的针用活性炭，搅拌30min，随后用0.45微米的微孔滤膜滤过，收集滤液，备用；
(2)稀配：向滤液中加入灭菌注射用水至滤液体积的1000倍，用0.1mol/L的盐酸或0.1mol/L的氢氧化钠调节pH值至3.2～3.6，随后用0.22微米的微孔滤膜除菌过滤，取滤液合格后灌装分装于无菌玻璃瓶中，备用；
(3)冷冻干燥：将上述分装于无菌玻璃瓶中的药液置冷冻干燥机中冷冻干燥；
(4)轧盖：铝塑组合盖需经清洗后灭菌、干燥，然后进行轧盖，即得。
进一步，所述步骤(3)中，冷冻干燥的步骤为：迅速将温度冷冻至-40℃，整个过程保持180分钟；然后抽真空干燥，以15℃/小时升温至-10℃，-10℃恒温保持120分钟；以5℃/小时升温至0℃，0℃恒温320分钟；以5℃/小时升温至10℃，10℃恒温240分钟；以10℃/小时升温至30℃，30℃恒温60分钟，同时前箱真空降达到10Pa/10分时，冻干结束。
本发明的有益效果在于：
本发明利用特定的赋形剂组合，使得制备的(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺冻干粉具有固定形状，在冻干制备过程中无干缩和鼓泡的现象，制备过程中杂质量增加较少，并且产品稳定性好，溶入葡萄糖注射液或氯化钠注射液制备成为静脉滴注溶液后，不溶性微粒显著减少减小，有利于提高药物使用的安全性，减少药物不良反应。
具体实施方式
为了使本发明的目的、技术方案和有益效果更加清楚，下面将对本发明的优选实施例进行详细的描述。
实施例1
实施例1的注射用(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺冻干粉的处方如下表所示：
| 处方 | 重量百分比 |
| (S)-4-羟基-2-氧代-1-吡咯烷乙酰胺 | 50％ |
| L-丝氨酸 | 25％ |
| 甘露醇 | 12％ |
| 聚乙二醇2000 | 5％ |
| 亚硫酸氢钠 | 5％ |
| 甲硫氨酸 | 3％ |
实施例1的注射用(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺冻干粉的制备方法，包括以下步骤：
(1)浓配：将处方量的原辅料置于容器中，加入(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺10倍重量份的灭菌注射用水搅拌，溶解后，加入质量分数0.1％的针用活性炭，搅拌30min，随后用0.45微米的微孔滤膜滤过，收集滤液，备用；
(2)稀配：向滤液中加入灭菌注射用水至滤液体积的1000倍，用0.1mol/L的盐酸或0.1mol/L的氢氧化钠调节pH值至3.2～3.6，随后用0.22微米的微孔滤膜除菌过滤，取滤液合格后灌装分装于无菌玻璃瓶中，备用；
(3)冷冻干燥：将上述分装于无菌玻璃瓶中的药液置冷冻干燥机中，迅速将温度冷冻至-40℃，整个过程保持180分钟；然后抽真空干燥，以15℃/小时升温至-10℃，-10℃恒温保持120分钟；以5℃/小时升温至0℃，0℃恒温320分钟；以5℃/小时升温至10℃，10℃恒温240分钟；以10℃/小时升温至30℃，30℃恒温60分钟，同时前箱真空降达到10Pa/10分时，冻干结束；
(4)轧盖：铝塑组合盖需经清洗后灭菌、干燥，然后进行轧盖，即得。
实施例2
实施例2的注射用(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺冻干粉的处方如下表所示：
| 处方 | 重量百分比 |
| (S)-4-羟基-2-氧代-1-吡咯烷乙酰胺 | 52％ |
| L-丝氨酸 | 21％ |
| 甘露醇 | 11％ |
| 聚乙二醇2000 | 6％ |
| 亚硫酸氢钠 | 6％ |
| 甲硫氨酸 | 4％ |
实施例2的注射用(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺冻干粉的制备方法与实施例1相同。
实施例3
实施例3的注射用(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺冻干粉的处方如下表所示：
| 处方 | 重量百分比 |
| (S)-4-羟基-2-氧代-1-吡咯烷乙酰胺 | 51％ |
| L-丝氨酸 | 20％ |
| 甘露醇 | 10％ |
| 聚乙二醇2000 | 6％ |
| 亚硫酸氢钠 | 8％ |
| 甲硫氨酸 | 5％ |
实施例3的注射用(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺冻干粉的制备方法与实施例1相同。
对比例1
对比例1的注射用(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺冻干粉没有添加亚硫酸氢钠，其余组分及制备方法与实施例2相同。
对比例2
对比例2的注射用(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺冻干粉没有添加甲硫氨酸，其余组分及制备方法与实施例2相同。
一、性状考察：
将实施例1-3制得的注射用(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺冻干粉取样，对考察项目进行检验，考察项目：性状、可见异物、pH、有关物质、含量、无菌检查。
由性状考察结果可知，实施例1-3制得的注射用(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺冻干粉具有固定形状，在冻干制备过程中无干缩和鼓泡的现象，产品杂质少，各项指标符合生产要求。
二、不溶性微粒考察：
将实施例2和对比例1制得的注射用(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺冻干粉分别用250ml的0.9％氯化钠注射液和5％葡萄糖注射液稀释，制备成为静脉滴注溶液，参照中国药典2015年版第四部不溶性微粒检查法第一法(光阻法)，分别于0、4、8、12小时测定其不溶性微粒，计算每个标示装量中不容性微粒的个数，试验结果见下表：
由不溶性微粒考察结果可知，实施例2的产品稳定性明显优于对比例1，溶入葡萄糖注射液或氯化钠注射液制备成为静脉滴注溶液后，实施例2的不溶性微粒明显少于对比例1，随着放置时间的延长，实施例2的不溶性微粒几乎没有增加，而对比例1的不溶性微粒显著增大增多。
三、杂质增量考察：
将实施例2和对比例2的注射用(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺冻干粉在制备前后取样，检测其有关物质，考察制备过程对有关物质的影响，结果见下表：
| 供试品 | 制备前有关物质 | 制备后有关物质 | 制备过程有关物质增加量 |
| 实施例2 | 0.16％ | 0.18％ | 0.02％ |
| 对比例2 | 0.17％ | 0.29％ | 0.12％ |
由杂质增量考察结果可知，实施例2的产品在制备过程中杂质量增加明显少于对比例2。
最后说明的是，以上优选实施例仅用以说明本发明的技术方案而非限制，尽管通过上述优选实施例已经对本发明进行了详细的描述，但本领域技术人员应当理解，可以在形式上和细节上对其作出各种各样的改变，而不偏离本发明权利要求书所限定的范围。
Claims (4)
1.一种注射用(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺冻干粉，其特征在于：所述冻干粉含有以下重量百分比的原辅料：(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺50%~57%，L-丝氨酸20%~25%，甘露醇10%~17%，聚乙二醇2000 5%~7%，亚硫酸氢钠5%~10%，甲硫氨酸3%~6%。
2.根据权利要求1所述的注射用(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺冻干粉，其特征在于：所述冻干粉含有以下重量百分比的原辅料：(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺52%，L-丝氨酸21%，甘露醇11%，聚乙二醇2000 6%，亚硫酸氢钠6%，甲硫氨酸4%。
3.权利要求1或2所述的注射用(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺冻干粉的制备方法，其特征在于：包括以下步骤：
（1）浓配：将处方量的原辅料置于容器中，加入(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺10倍重量份的灭菌注射用水搅拌，溶解后，加入质量分数0.1%的针用活性炭，搅拌30min，随后用0.45微米的微孔滤膜滤过，收集滤液，备用；
（2）稀配：向滤液中加入灭菌注射用水至滤液体积的1000倍，用0.1mol/L的盐酸或0.1mol/L的氢氧化钠调节pH值至3.2~3.6，随后用0.22微米的微孔滤膜除菌过滤，取滤液合格后灌装分装于无菌玻璃瓶中，备用；
（2）冷冻干燥：将上述分装于无菌玻璃瓶中的药液置冷冻干燥机中冷冻干燥；
（3）轧盖：铝塑组合盖需经清洗后灭菌、干燥，然后进行轧盖，即得。
4.根据权利要求3所述的注射用(S)-4-羟基-2-氧代-1-吡咯烷乙酰胺冻干粉的制备方法，其特征在于：所述步骤（3）中，冷冻干燥的步骤为：迅速将温度冷冻至-40℃，整个过程保持180分钟；然后抽真空干燥，以15℃/小时升温至-10℃，-10℃恒温保持120分钟；以5℃/小时升温至0℃，0℃恒温320分钟；以5℃/小时升温至10℃，10℃恒温240分钟；以10℃/小时升温至30℃，30℃恒温60分钟，同时前箱真空降达到10Pa/10分时，冻干结束。
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| WO1993006826A1 (en) * | 1991-10-08 | 1993-04-15 | Smithkline Beecham Farmaceutici S.P.A. | Composition comprising s-oxiracetame for use as nootropic |
| CN101766597A (zh) * | 2008-12-31 | 2010-07-07 | 北京利乐生制药科技有限公司 | 一种以左旋奥拉西坦为活性成分的注射用制剂 |
| CN102872011A (zh) * | 2012-05-31 | 2013-01-16 | 北京阜康仁生物制药科技有限公司 | 包含(s)-4-羟基-2-氧代-1-吡咯烷乙酰胺的药物组合物 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO1993006826A1 (en) * | 1991-10-08 | 1993-04-15 | Smithkline Beecham Farmaceutici S.P.A. | Composition comprising s-oxiracetame for use as nootropic |
| CN101766597A (zh) * | 2008-12-31 | 2010-07-07 | 北京利乐生制药科技有限公司 | 一种以左旋奥拉西坦为活性成分的注射用制剂 |
| CN102872011A (zh) * | 2012-05-31 | 2013-01-16 | 北京阜康仁生物制药科技有限公司 | 包含(s)-4-羟基-2-氧代-1-吡咯烷乙酰胺的药物组合物 |
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