CN102784098A - 丙戊酸镁注射液及其制备工艺 - Google Patents
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Abstract
本发明涉及一种抗癫痫药，具体是丙戊酸镁注射液及其制备工艺。丙戊酸镁由下列物质制备而成(按重量百分比计)：丙戊酸镁0.5～10％，氯化铵0～5.0％，枸橼酸0～5.0％，注射用水89～99.9％，乙醇0～95％，丙二醇0～95％。其制备工艺是：将丙戊酸镁溶于注射用水或乙醇中，加入氯化铵和枸橼酸，使溶解后，加入适量活性炭，于60～90℃保温约30分钟，抽滤，滤液根据含量要求再添加注射用水或乙醇或丙二醇，再用微孔滤膜过滤，在氮气流下灌封成2～100ml/支或瓶，最后用100℃流通蒸汽灭菌30分钟即可。按人体药用注射剂澄明度、pH值、渗透压、异常毒性试验，溶血试验、稳定性试验等项目，本发明的产品均符合人体使用要求。动物药代动力学试验表明本品吸收快，并很快进入脑组织。
Description
技术领域：
本发明涉及一种抗癫痫药，具体是丙戊酸镁注射液及其制备工艺。
背景技术：
丙戊酸类系列药物属广谱抗癫痫药，以其疗效确切，作用稳定，毒副反应少而被推为抗癫痫首选药物。国内外文献资料和有关临床试验表明，丙戊酸镁具有抗偏头痛用途，比苯噻啶疗效好；抗躁狂疗效与碳酸锂相似，但副作用比碳酸锂少；丙戊酸镁还具有抗心律不齐，抗焦虑、抗艾滋病、抗癌等作用，极具发展潜力。丙戊酸镁现市场销售只有片剂、缓释片剂，对于癫痫持续状态、急性偏头痛，急性躁狂、心律不齐必须起效迅速，现国内外用的是进口丙成酸钠注射液。临床已证实丙戊酸镁疗效优于丙戊酸钠，硫酸镁就用于抗惊厥，抗偏头痛和抗心律不齐。
发明内容：
本发明的目的就是提供一种丙戊酸镁注射液及其制备工艺，使丙戊酸镁能及时用于治疗癫痫持续状态、急性偏头痛、急性躁狂，心律不齐等患者。
本发明的技术方案是：丙戊酸镁注射液是由下列物质制备而成(按重量百分比计)
根据上述技术方案，丙戊酸镁为白色粉末，分子量310.71，分子式为C16H30O4Mg，化学结构式为：
其在稀酸中略溶，在水及乙醇中微溶。氯化铵为无机盐，在此作为稳定剂使用。丙戊酸镁注射液澄明度易出问题，究其原因是易生成碳酸镁和氢氧化镁沉淀的影响，氯化铵一是调节药液的PH值，二是铵离子可以与某些杂质离子结合，从而使丙戊酸镁注射液不产生沉淀。枸橼酸用于调节溶液的pH值。注射用水和乙醇、丙二醇作为溶剂用。
本发明提供的丙戊酸镁注射液的制备工艺是：将丙戊酸镁溶于注射用水中，加入氯化铵和枸橼酸，使溶解后，加入适量活性炭。于60～90℃保温10～60分钟，抽滤，滤液根据含量再添加注射用水或乙醇或丙二醇，再用微孔滤膜过滤，在氮气流下灌封成2～500ml/支或瓶，最后用100℃以上流通蒸汽灭菌10～60分钟即可。
附图说明：
图1丙戊酸镁注射液一次腹腔注射大白鼠血与脑组织血药浓度-时间曲线
图2丙戊酸镁注射液多次腹腔注射大白鼠血与脑组织血药浓度-时间曲线
具体实施方式：下面通过实例对本发明进一步说明：
实施例：
将丙戊酸镁20g置于400ml新鲜放冷的注射用水中，搅拌，待溶后，补加注射用水550ml，加入氯化铵4g，使溶后，加活性碳5g，70～80℃保温20分钟后，抽滤，测含量，根据含量补加注射用水至全量，混匀，用微孔滤膜过滤，在氮气流下灌封成10ml/支。最后用100℃流通蒸汽灭菌30分钟。
按上实施列配制多批样品，按规定检查澄明度、含量、pH值、渗透压均符合规定。pH值为7.0～8.5，符合注射剂pH应控制在pH4～9范围的一般要求。注射剂要有一定的渗透压，其渗透压要求与血浆的渗透压(正常范围内280～310mos/L，平均为298mos/L)相等或接近。取丙戊酸镁注射液适量，在FM-4冰点渗透压计(上海医科大学仪器厂生产)进行渗透压测定，测得渗透压值为285～308mosm/L，均符合要求。无菌检查，热原检查，安全性试验，稳定性试验等结果均符合注射剂的一般质量要求。
急性毒性试验：丙戊酸镁注射液小鼠静脉注射iv LD50为214.70±22.93mg/kg；腹腔注射ip LD50为417.20±59.71mg/kg，应属毒性较低的药品。
异常毒性试验：丙戊酸镁注射液分别对小鼠静脉、腹腔、皮下、口服0.5ml/只四种不同徐径给药，均无死亡和不良反应出现。
体外溶血试验：丙戊酸镁注射液体外溶血试验无论肉眼观察还是显微镜镜检均未见该药对红细胞有溶血作用。
单次ip丙戊酸镁150mg/kg后，大白鼠的血、脑组织中VPA浓度-时间曲线如图1。VPA在血、脑组织中的药代动力学参数如表1。ip后VPA很快被吸收，达峰时间为0.23h，同时VPA进入脑内的速度亦快，达峰时间为0.26h。如图1所示，由于VPA的肠肝循环产生第二峰浓度，可通过AUC2-12来估计VPA的肠肝循环的情况。
表1单次i.p实验血、脑组织中VPA的药代动力学参数
注：Ke：消除速率常数 Vd：表现颁容积 Tmax：达峰时间
Cmax：峰浓度 Cl：总清除率 C2max：第二峰浓度
AUC2-12：2h-12h曲线下面积
多次(每天一次，连续7天)腹腔注射后大白鼠的血、脑组织VPA浓度-时间曲线如图2，VPA在血、脑组织中的药代动力学参数如表2。
表2多次i.p实验血、脑组织中VPA的药代动力学参数
给药后2h所得总浓度以及游离浓度如表3。
表3给药后2h测得血中VPA总浓度与游离VPA浓度(μg/ml)
Claims (2)
1.丙戊酸镁注射液其特征是在于制得的注射液以下述重量配比的物质为原料制成：
2.一种制备权利要求1所述的现戊酸注射液的制备工艺其特征是：将丙戊酸镁溶于注射注射用水或乙醇或丙二醇中，加入氯化铵和枸椽酸，使溶解后，加入适量活性炭，于60～90℃，保温10～60分钟，抽滤，滤液根据含量要求再添加注射用水或乙醇或丙二醇，再用微孔滤膜过滤，在氮气流下灌封成2～500ml/支或瓶，最后用100℃以上流通蒸汽灭菌10～60分钟即成。
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104027301A (zh) * | 2013-03-05 | 2014-09-10 | 肖云彩 | 一种奥拉西坦组合物注射液 |
| CN105326784A (zh) * | 2014-08-08 | 2016-02-17 | 四川科瑞德制药有限公司 | 一种丙戊酸钠注射液 |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1732974A (zh) * | 2005-08-31 | 2006-02-15 | 杨喜鸿 | 果糖二磷酸钠和镁盐的组合药物 |
| WO2010074662A1 (ru) * | 2008-12-22 | 2010-07-01 | Sokyrko Oleg Sergeevich | Противоопухолевое средство, способ его получения и способ его стабилизации |
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| CN1732974A (zh) * | 2005-08-31 | 2006-02-15 | 杨喜鸿 | 果糖二磷酸钠和镁盐的组合药物 |
| WO2010074662A1 (ru) * | 2008-12-22 | 2010-07-01 | Sokyrko Oleg Sergeevich | Противоопухолевое средство, способ его получения и способ его стабилизации |
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| Title |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104027301A (zh) * | 2013-03-05 | 2014-09-10 | 肖云彩 | 一种奥拉西坦组合物注射液 |
| CN104027301B (zh) * | 2013-03-05 | 2017-05-10 | 肖云彩 | 一种奥拉西坦组合物注射液 |
| CN105326784A (zh) * | 2014-08-08 | 2016-02-17 | 四川科瑞德制药有限公司 | 一种丙戊酸钠注射液 |
| CN105326784B (zh) * | 2014-08-08 | 2018-06-26 | 四川科瑞德制药股份有限公司 | 一种丙戊酸钠注射液 |
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