CN114129511A - 一种具有改进稳定性的硫酸阿托品注射液 - Google Patents
一种具有改进稳定性的硫酸阿托品注射液 Download PDFInfo
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- HOBWAPHTEJGALG-JKCMADFCSA-N [(1r,5s)-8-methyl-8-azoniabicyclo[3.2.1]octan-3-yl] 3-hydroxy-2-phenylpropanoate;sulfate Chemical compound [O-]S([O-])(=O)=O.C([C@H]1CC[C@@H](C2)[NH+]1C)C2OC(=O)C(CO)C1=CC=CC=C1.C([C@H]1CC[C@@H](C2)[NH+]1C)C2OC(=O)C(CO)C1=CC=CC=C1 HOBWAPHTEJGALG-JKCMADFCSA-N 0.000 title claims abstract description 52
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Classifications
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
本发明提供了一种具有改进稳定性的硫酸阿托品注射液，属于药物制剂技术领域，包括硫酸阿托品0.5mg/ml，氯化钠9mg/ml，依地酸二钠0.1‑0.15mg/ml，盐酸适量，余量为注射用水。本发明的具有改进稳定性的硫酸阿托品注射液，克服了传统处方稳定性差的难题，能够大幅度降低杂质含量，大大提高硫酸阿托品注射液的稳定性。
Description
技术领域
本发明涉及一种具有改进稳定性的硫酸阿托品注射液，属于药物制剂技术领域。
技术背景
硫酸阿托品为抗胆碱能药，与M胆碱受体结合，对抗乙酰胆碱和其他拟胆碱药的毒蕈碱样作用。主要解除平滑肌的痉挛、抑制腺体分泌、解除迷走神经对心脏的抑制，使心跳加快、散大瞳孔，升高眼压；兴奋呼吸中枢。临床用于：抢救感染中毒性休克，解除有机磷农药中毒，阿斯综合症和内脏绞痛，也可用于麻醉前给药、散瞳或治疗角膜炎、虹膜炎等。与吗啡合用治疗肝、肾绞痛。
硫酸阿托品注射液，适应症包括：1.各种内脏绞痛，如胃肠绞痛及膀胱刺激症状。对胆绞痛、肾绞痛的疗效较差；2.全身麻醉前给药、严重盗汗和流涎症；3.迷走神经过度兴奋所致的窦房阻滞、房室阻滞等缓慢型心律失常，也可用于继发于窦房结功能低下而出现的室性异位节；4.抗休克；5.解救有机磷酸酯类中毒。
硫酸阿托品注射液的用法用量如下：1.皮下、肌内或静脉注射，成人常用量：每次0.3～0.5mg，一日0.5～3mg；极量：一次2mg。儿童皮下注射：每次0.01～0.02mg/kg，每日2～3次。静脉注射：用于治疗阿斯综合征，每次0.03～0.05mg/kg，必要时15分钟重复1次，直至面色潮红、循环好转、血压回升、延长间隔时间至血压稳定。2.抗心律失常，成人静脉注射0.5～1mg，按需可1～2小时一次，最大量为2mg。3.解毒：(1)用于锑剂引起的阿-斯综合征，静脉注射1～2mg，15～30分钟后再注射1mg，如患者无发作，按需每3～4小时皮下或肌内注射1mg；(2)用于有机磷中毒时，肌注或静注1～2mg(严重有机磷中毒时可加大5～10倍)，每10～20分钟重复，直到青紫消失，继续用药至病情稳定，然后用维持量，有时需2～3天；4.抗休克改善循环：成人一般按体重0.02～0.05mg/kg，用50％葡萄糖注射液稀释后静注或用葡萄糖水稀释后静滴；5.麻醉前用药，成人术前0.5～1小时，肌注0.5mg，小儿皮下注射用量为：体重3kg以下者为0.1mg，7～9kg为0.2mg，12～16kg为0.3mg，20～27kg为0.4mg，32kg以上为0.5mg。
不同剂量所致的不良反应大致如下：0.5mg，轻微心率减慢，略有口干及少汗；1mg，口干、心率加速、瞳孔轻度扩大；2mg，心悸、显著口干、瞳孔扩大，有时出现视物模糊；5mg，上述症状加重，并有语言不清、烦躁不安、皮肤干燥发热、小便困难、肠蠕动减少；10mg以上，上述症状更重，脉速而弱，中枢兴奋现象严重，呼吸加快加深，出现谵妄、幻觉、惊厥等；严重中毒时可由中枢兴奋转入抑制，产生昏迷和呼吸麻痹等，最低致死剂量成人约为80～130mg，儿童为10mg。发烧、速脉、腹泻和老年人慎用。
硫酸阿托品注射液为典型的M胆碱受体阻滞剂，除一般的抗M胆碱作用解除胃肠平滑肌痉挛、抑制腺体分泌、扩大瞳孔、升高眼压、视力调节麻痹、心率加快、支气管扩张等外，大剂量时能作用于血管平滑肌，扩张血管、解除痉挛性收缩，改善微循环。此外本品能兴奋或抑制中枢神经系统，具有一定的剂量依赖性。对心脏、肠和支气管平滑肌作用比其他颠茄生物碱更强而持久。
硫酸阿托品注射液肌注后15～20分钟，血药浓度峰值，口服为1～2小时，作用一般持续4～6小时，扩瞳时效更长。T1/2为3.7～4.3小时。主要通过肝细胞酶的水解代谢，约有13％～50％在12小时内以原形随尿排出。
现有的硫酸阿托品注射液包括：硫酸阿托品、氯化钠和盐酸，余量为注射用水；其缺点在于：硫酸阿托品注射液在生产过程中引入金属离子，风险较高，导致现有处方中，杂质含量偏高，特别是其中的杂质A和杂质C的含量偏高，导致硫酸阿托品注射液的稳定性降低。
因此，针对上述问题，提供一种具有改进稳定性的硫酸阿托品注射液，能够大幅度降低杂质含量，大大提高硫酸阿托品注射液的稳定性，就成为该技术领域急需解决的技术难题。
发明内容
本发明的目的是，提供一种具有改进稳定性的硫酸阿托品注射液，能够大幅度降低杂质含量，大大提高硫酸阿托品注射液的稳定性。
本发明的上述目的是通过以下技术方案达到的：
一种具有改进稳定性的硫酸阿托品注射液，包括硫酸阿托品0.5mg/ml，氯化钠9mg/ml，盐酸适量，依地酸二钠0.10-0.15mg/ml，余量为注射用水。
优选地，硫酸阿托品0.5mg/ml，氯化钠9mg/ml，盐酸适量，依地酸二钠0.1mg/ml，余量为注射用水。
优选地，所述具有改进稳定性的硫酸阿托品注射液的pH值至4.1±0.1。
优选地，所述具有改进稳定性的硫酸阿托品注射液的总杂质含量≤0.34％。
优选地，所述具有改进稳定性的硫酸阿托品注射液的杂质A含量≤0.07％。
优选地，所述具有改进稳定性的硫酸阿托品注射液的杂质C含量≤0.05％。
有益效果：
本发明的具有改进稳定性的硫酸阿托品注射液，能够大幅度降低杂质含量，大大提高硫酸阿托品注射液的稳定性。
下面通过具体实施例对本发明做进一步说明，但并不意味着对本发明保护范围的限制。
具体实施方式
除非特别说明，本发明实施例中所用原料、助剂或设备均为市场上可购之产品，其型号为本领域常规之型号；所用测试方法均为本领域的常规方法。
除非特别说明，本实施例中的比例或百分比均为重量单位。
实施例1
硫酸阿托品注射液(规格：1ml：0.5mg)，处方见下表1：
表1
| 名称 | 单剂量处方 | 作用 |
| 硫酸阿托品 | 0.5mg | 活性成分 |
| 氯化钠 | 9mg | 渗透压调节剂 |
| 依地酸二钠 | 0.1mg | 络合剂 |
| 0.1％盐酸溶液 | 0.02ml | pH调节剂 |
| 注射用水 | 稀释至1ml | 溶剂 |
制备方法：量取80％注射用水(配液温度为40℃)，依次加入处方量的依地酸二钠、硫酸阿托品、氯化钠，搅拌使溶解，采用0.1％(V/V)盐酸溶液，调节药液pH值至4.1±0.1，补加注射用水至全量，0.22μm滤膜过滤，灌装于安瓿中，封口，121℃、15min灭菌条件下灭菌。
实施例2
硫酸阿托品注射液(规格：1ml：0.5mg)处方见下表2：
表2
| 名称 | 单剂量处方 | 作用 |
| 硫酸阿托品 | 0.5mg | 活性成分 |
| 氯化钠 | 9mg | 渗透压调节剂 |
| 依地酸二钠 | 0.15mg | 络合剂 |
| 0.1％盐酸溶液 | 0.02ml | pH调节剂 |
| 注射用水 | 稀释至1ml | 溶剂 |
制备方法：量取80％注射用水(配液温度为40℃)，依次加入处方量的依地酸二钠、硫酸阿托品、氯化钠，搅拌使溶解，采用0.1％(V/V)盐酸溶液，调节药液pH值至4.1±0.1，补加注射用水至全量，0.22μm滤膜过滤，灌装于安瓿中，封口，121℃、15min灭菌条件下灭菌。
实施例3
硫酸阿托品注射液(规格：1ml：0.5mg)处方见下表3：
表3
| 名称 | 单剂量处方 | 作用 |
| 硫酸阿托品 | 0.5mg | 活性成分 |
| 氯化钠 | 9mg | 渗透压调节剂 |
| 依地酸二钠 | 0.05mg | 络合剂 |
| 0.1％盐酸溶液 | 0.02ml | pH调节剂 |
| 注射用水 | 稀释至1ml | 溶剂 |
制备方法：量取80％注射用水(配液温度为40℃)，依次加入处方量的依地酸二钠、硫酸阿托品、氯化钠，搅拌使溶解，采用0.1％(V/V)盐酸溶液，调节药液pH值至4.1±0.1，补加注射用水至全量，0.22μm滤膜过滤，灌装于安瓿中，封口，121℃、15min灭菌条件下灭菌。
对比例1
硫酸阿托品注射液(规格：1ml：0.5mg)处方见下表4：
表4
| 名称 | 单剂量处方 | 作用 |
| 硫酸阿托品 | 0.5mg | 活性成分 |
| 氯化钠 | 9mg | 渗透压调节剂 |
| 0.1％盐酸溶液 | 0.02ml | pH调节剂 |
| 注射用水 | 稀释至1ml | 溶剂 |
制备方法：量取80％注射用水(配液温度为40℃)，依次加入处方量的硫酸阿托品、氯化钠，搅拌使溶解，采用0.1％(V/V)盐酸溶液调节药液pH值至4.1±0.1，补加注射用水至全量，0.22μm滤膜过滤，灌装于安瓿中，封口，121℃、15min灭菌条件下灭菌。
应用实施例
将制备样品采用市售包装置于稳定性试验箱(40±2℃/75±5％RH)中，分别于0月、3月、6月取样后，采用欧洲药典硫酸阿托品有关物质方法高效液相色谱法，对有关物质进行检测，杂质A不得过0.5重量％，杂质C不得过2.0重量％，加速试验数据如下：
杂质A
(1R,3r,5S)-8-甲基-8-氮杂双环[3.2.1]-3-辛基2-苯基丙烯酸酯杂质C
(2RS)-3-羟基-2-苯基丙酸(托品酸)
对比例1的加速试验稳定性数据：
实施例1的加速试验稳定性数据：
实施例2的加速试验稳定性数据：
实施例3的加速试验稳定性数据：
通过对比例和实施例加速试验发现：具有改进稳定性的硫酸阿托品注射液加速试验杂质水平明显低于同时间点对比例杂质水平。依地酸二钠加入0.1mg处方样品和依地酸二钠加入0.15mg处方样品加速试验杂质水平明显低于同时间点依地酸二钠加入0.05mg处方样品，依地酸二钠加入0.10mg和0.15mg处方样品加速试验杂质水平相当；本发明人发现：单剂量处方中，依地酸二钠加入量为0.05mg时，不足以螯合引入的金属离子，依地酸二钠0.1mg以上的加入量时，才能满足螯合各种途径引入的金属离子，本着辅料用量尽量少的原则，故硫酸阿托品注射液中螯合剂依地酸二钠用量为0.1mg。
Claims (5)
1.一种具有改进稳定性的硫酸阿托品注射液，包括硫酸阿托品0.5mg/ml，氯化钠9mg/ml，依地酸二钠0.1-0.15mg/ml，盐酸适量，余量为注射用水。
2.根据权利要求1所述具有改进稳定性的硫酸阿托品注射液，其特征在于：所述具有改进稳定性的硫酸阿托品注射液的总杂质含量≤0.34重量％。
3.根据权利要求1所述具有改进稳定性的硫酸阿托品注射液，其特征在于：所述具有改进稳定性的硫酸阿托品注射液的杂质A含量≤0.07重量％。
4.根据权利要求1所述具有改进稳定性的硫酸阿托品注射液，其特征在于：所述具有改进稳定性的硫酸阿托品注射液的杂质C含量≤0.05重量％。
5.根据权利要求1所述具有改进稳定性的硫酸阿托品注射液，其特征在于：所述具有改进稳定性的硫酸阿托品注射液的pH值至4.1±0.1。
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104555869A (zh) * | 2013-10-21 | 2015-04-29 | 河南辅仁怀庆堂制药有限公司 | 硫酸阿托品注射液及其生产工艺 |
| US20180325888A1 (en) * | 2017-05-11 | 2018-11-15 | Nevakar Inc. | Atropine Pharmaceutical Compositions |
| CN109310687A (zh) * | 2016-05-25 | 2019-02-05 | 新加坡保健服务集团 | 含有阿托品的水性组合物 |
| CN113588817A (zh) * | 2021-07-20 | 2021-11-02 | 杭州赫尔斯科技有限公司 | 一种同时测定阿托品滴眼液中硫酸阿托品和EDTA-2Na含量的方法 |
-
2021
- 2021-12-07 CN CN202111484936.2A patent/CN114129511A/zh active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104555869A (zh) * | 2013-10-21 | 2015-04-29 | 河南辅仁怀庆堂制药有限公司 | 硫酸阿托品注射液及其生产工艺 |
| CN109310687A (zh) * | 2016-05-25 | 2019-02-05 | 新加坡保健服务集团 | 含有阿托品的水性组合物 |
| US20180325888A1 (en) * | 2017-05-11 | 2018-11-15 | Nevakar Inc. | Atropine Pharmaceutical Compositions |
| CN110621298A (zh) * | 2017-05-11 | 2019-12-27 | 内瓦卡有限公司 | 阿托品药物组合物 |
| CN113588817A (zh) * | 2021-07-20 | 2021-11-02 | 杭州赫尔斯科技有限公司 | 一种同时测定阿托品滴眼液中硫酸阿托品和EDTA-2Na含量的方法 |
Non-Patent Citations (1)
| Title |
|---|
| 济南军区后勤部卫生部编: "《医院制剂操作技术》", 31 December 1992, 山东科学技术出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115177584A (zh) * | 2022-07-14 | 2022-10-14 | 成都市海通药业有限公司 | 一种硫酸阿托品注射液的制备方法 |
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