WO2019242039A1 - 一种低杂质水平的罗库溴铵注射液的制备方法 - Google Patents

一种低杂质水平的罗库溴铵注射液的制备方法 Download PDF

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WO2019242039A1
WO2019242039A1 PCT/CN2018/093566 CN2018093566W WO2019242039A1 WO 2019242039 A1 WO2019242039 A1 WO 2019242039A1 CN 2018093566 W CN2018093566 W CN 2018093566W WO 2019242039 A1 WO2019242039 A1 WO 2019242039A1
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solution
rocuronium bromide
injection
acetic acid
add
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PCT/CN2018/093566
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French (fr)
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汤征
王小镒
周亚兵
杜芳
张鑫
周敏
周敏慧
丁云晖
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上药东英（江苏）药业有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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

Definitions

  • the invention belongs to the technical field of medicine, and particularly relates to a method for preparing rocuronium bromide injection with low impurity level.
  • the original research company of rocuronium bromide injection is the Dutch company Oganon.
  • the product description published by the company contains 10 mg rocuronium bromide, 2 mg of sodium acetate, and sodium chloride adjusted to isotonicity, glacial acetic acid or hydrogen Sodium oxide adjusted the pH of the chemical solution to 4.0.
  • the preparation method of rocuronium injection is not disclosed.
  • CN102048684 discloses a method for preparing rocuronium bromide injection, which is prepared as follows: a. Cooling water for injection to room temperature; b. Preparing an acetate-sodium acetate buffer solution; c. Measuring water for injection for cooling to room temperature, Add acetic acid-sodium acetate buffer and mix well; d. Add sodium chloride and stir until completely dissolved; put rocuronium bromide in it and adjust the pH to 4.0e with 1mol / L acetic acid. Add activated carbon and stir at room temperature 30min, the determination of the content of decarbonized and filtered intermediates; add water for injection until the labeled amount meets the standard f. Filter through a 0.22 microporous filter to sterilize, fill and sterilize. In this preparation method, a buffer solution needs to be prepared in advance, the preparation process is cumbersome, and decolorization and heat removal are required by adding activated carbon.
  • CN101643412 discloses a preparation method of stable rocuronium bromide injection for intravenous administration, which is characterized by a buffer system containing a therapeutically effective amount of rocuronium bromide, citric acid or acetate having a pH value of 3.8 to 4.0. , Metal chelator, and 0.1% activated carbon adsorption heat source.
  • This preparation method requires the use of a metal chelating agent to stabilize the preparation, and also requires decolorization and heat removal by adding activated carbon.
  • CN102860980 discloses a preparation precaution for rocuronium bromide injection.
  • the preparation process is as follows: a. Weigh about 2000g of water for injection below 25 ° C, mix with sodium acetate to dissolve it, mix well, and adjust the pH of the solution to 3.8 to 4.2 with glacial acetic acid. B. Add the prescribed amount of rocuronium bromide to the a solution, stir to dissolve, and add water for injection to 2850ml; c. After adjusting the pH of the b solution to 3.8 ⁇ 4.2 with glacial acetic acid, add an appropriate amount of chlorinated Sodium adjusts the solution to isotonicity; dc solution is supplemented with water for injection to 3000ge.
  • the present invention provides a method for preparing rocuronium bromide injection with low impurity level.
  • a method for preparing low-impurity rocuronium bromide injection each 1000ml of the injection contains the following components: 8-12g rocuronium bromide, 1-5g sodium acetate, an appropriate amount of glacial acetic acid or hydrogen Sodium oxide and sodium chloride, including the following steps:
  • step b adjust the pH of the solution in step a to 3.0 ⁇ 0.1 with acetic acid;
  • step d Add a prescribed amount of sodium acetate and an appropriate amount of sodium chloride to the solution in step c above, and adjust the pH to 3.0 ⁇ 0.1 with acetic acid or sodium hydroxide;
  • the bacterial endotoxin of rocuronium bromide raw material in the prepared rocuronium bromide injection does not exceed 0.2EU / g
  • the bacterial endotoxin of sodium chloride and sodium acetate does not exceed 2.5EU / g.
  • nitrogen aeration has been used in the preparation process of the preparation process to control the residual oxygen concentration in the solution ⁇ 5.0%.
  • the preparation process does not include an activated carbon adsorption pyrogen step.
  • Rocuronium bromide injection is subject to its own stability during storage and transportation.
  • the content of impurity C will increase with time.
  • the release standard of impurity C is 0.5%.
  • the impurity C content level was reduced to 0.1% as much as possible to ensure that the impurities of rocuronium bromide injection did not exceed the standard during the validity period (shelf life standard: 1.5%).
  • the bacterial endotoxin of the raw materials and auxiliary materials is controlled, it is not necessary to add activated carbon to perform pyrogen removal operation in the prescription process, and the bacterial endotoxin of the finished rocuronium bromide injection is still qualified.
  • lowering the temperature of the pharmaceutical solution, removing the dissolved oxygen in the solution by nitrogen aeration, and lowering the pH of the solution during preparation all help to reduce the content of impurities C and help improve the stability of rocuronium bromide injection. .
  • the preparation process does not need to add activated carbon for adsorption and heat removal, and the endotoxin of the final product also meets the standard requirements.
  • the main degradation impurity of rocuronium bromide is impurity C.
  • Rocuronium bromide is unstable under high temperature conditions. If it is treated at 121 °C for 20 minutes, the impurity content of impurity C will increase by 3 times.
  • Rocuronium bromide is stable under acidic conditions. After treatment with 1 mol / L hydrochloric acid, the content of impurity C does not change significantly, but it is unstable under alkaline conditions, and the content of impurity C increases significantly. Therefore, in the preparation process, lowering the pH of the solution is beneficial to ensure the stability of rocuronium bromide injection.
  • Rocuronium bromide is unstable under oxidation conditions. Under the condition of 30% H 2 O 2 , the content of impurity C increases greatly, so during the preparation process, the residual oxygen content in the solution can be controlled by nitrogen aeration Lower rocuronium injection.
  • the present invention provides a method for preparing rocuronium bromide injection with a low impurity level.
  • Each 1000ml of the injection contains the following components: 10 g rocuronium bromide, 2 g sodium acetate, and an appropriate amount of glacial acetic acid or hydroxide Sodium and sodium chloride, the preparation method includes the following steps:
  • step b adjust the pH of the solution in step a to 3.0 ⁇ 0.1 with acetic acid;
  • step d Add a prescribed amount of sodium acetate and an appropriate amount of sodium chloride to the solution in step c above, and adjust the pH to 3.0 ⁇ 0.1 with acetic acid or sodium hydroxide;
  • the bacterial endotoxin of rocuronium bromide raw material does not exceed 0.2 EU / g, and the bacterial endotoxin of sodium chloride and sodium acetate does not exceed 2.5 EU / g.
  • the pH of the final solution is 3.9 to 4.1, and 3.3 mg / ml sodium chloride needs to be added to achieve isotonicity.
  • the preparation method is as follows: Measure about 850 g of water for injection cooled to below 25 ° C, adjust the pH to 3.9 to 4.1 with glacial acetic acid to obtain solution A, add the prescribed amount of rocuronium bromide to solution A, and stir Dissolve to obtain solution B, add the prescribed amount of sodium acetate and sodium chloride to solution B, adjust the pH of solution B to 3.9 to 4.1 with glacial acetic acid, and add water for injection to 1000.0 g to obtain solution C; pass solution C over 0.2 ⁇ m After the polyvinylidene fluoride film, 5ml was filled.
  • the preparation method is as follows: Measure about 850 g of water for injection cooled to below 25 ° C, cool the solution to 8-12 ° C, and adjust the pH to 3.9 to 4.1 with glacial acetic acid to obtain solution A. Sulfonium bromide was added to solution A, stirred and dissolved to obtain solution B. Prescribed amounts of sodium acetate and sodium chloride were added to solution B, and the pH of solution B was adjusted to 3.9 to 4.1 with glacial acetic acid, and water for injection was added to 1000.0 g to obtain a solution. C; 5 ml of solution C was passed through a 0.2 ⁇ m polyvinylidene fluoride film.
  • the preparation method is as follows: Measure about 850 g of water for injection cooled to below 25 ° C, cool the solution to 8-12 ° C, adjust the pH to 2.9-3.1 with glacial acetic acid to obtain solution A, and add the prescribed amount of Luo Sulfonium bromide was added to solution A, stirred and dissolved to obtain solution B. The prescribed amounts of sodium acetate and sodium chloride were added to solution B. The pH of solution B was adjusted to 2.9 to 3.1 with glacial acetic acid, and water for injection was added to 1000.0 g. Or adjust the solution B pH to 3.9-4.1 with sodium hydroxide to obtain solution C; after passing solution C through a 0.2 ⁇ m polyvinylidene fluoride film, fill 5 ml.
  • the preparation method is as follows: Measure about 850g of water for injection cooled to below 25 ° C, cool the solution to 8-12 ° C, and adjust the pH to 2.9-3.1 with glacial acetic acid to obtain solution A. Sulfonium bromide was added to solution A and stirred to dissolve to obtain solution B. Prescribed amounts of sodium acetate and sodium chloride were added to solution B. The pH of solution B was adjusted to 2.9 to 3.1 with glacial acetic acid, and water for injection was added to 1000.0 g. The acetic acid or sodium hydroxide was used to adjust the solution B pH to 3.9 to 4.1, 0.1% activated carbon was added, and the mixture was stirred for 30 min. The solution was decarbonized through a titanium rod to obtain a solution C. After the solution C was passed through a 0.2 ⁇ m polyvinylidene fluoride film, 5 ml was filled.
  • the preparation method is as follows: Measure about 850 g of water for injection cooled to below 25 ° C, measure the temperature to 8-12 ° C with nitrogen aeration, and cool the solution to 8-12 ° C. Adjust the pH to 2.9-3.1 with glacial acetic acid to obtain solution A. Add the prescribed amount of rocuronium bromide to solution A, stir and dissolve to obtain solution B. Add the prescribed amounts of sodium acetate and sodium chloride to solution B, adjust the solution B pH to 2.9-3.1 with glacial acetic acid, and add water for injection to 1000.0 g.
  • the pH of the solution B was adjusted to 3.9-4.1 with glacial acetic acid or sodium hydroxide to obtain solution C, and the nitrogen aeration was stopped; after passing the solution C through a 0.2 ⁇ m polyvinylidene fluoride film, 5 ml was filled.

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Abstract

一种罗库溴铵注射液的制备方法，采用降低配制溶液的温度、氮气曝气、控制原料内毒素含量、降低药液pH的方式，制备中无需进行活性炭除热源，即可获得低杂质水平的罗库溴铵注射液。

Description

一种低杂质水平的罗库溴铵注射液的制备方法 技术领域
本发明属于医药技术领域，具体涉及一种低杂质水平的罗库溴铵注射液的制备方法。
背景技术
罗库溴铵注射液的原研公司为荷兰欧加农公司，其公布的产品说明书，其处方成分为每ml含罗库溴铵10mg，醋酸钠2mg，氯化钠调节至等渗，冰醋酸或氢氧化钠调节药液的pH为4.0。但未公开罗库溴铵注射液的制备方法。
CN102048684公开了一种罗库溴铵注射液的制备方法，其制备过程如下：a.将注射用水冷却至室温；b.配制醋酸-醋酸钠缓冲液；c.量取冷至室温的注射用水，加醋酸-醋酸钠缓冲液，混合均匀；d.取氯化钠加入，搅拌至完全溶解；将罗库溴铵放入其中，用1mol/L醋酸调节pH至4.0e.加入活性炭，室温下搅拌30min，脱碳滤过中间体含量的测定；补加注射用水至标示量符合标准f.经0.22微孔滤膜过滤除菌，灌装灭菌。此制备方法中，需预先配制缓冲液，配制工序繁琐，还需通过加入活性炭进行脱色、除热源。
CN101643412公开了一种稳定的供静脉给药的罗库溴铵注射液的制备方法，其特征是含有治疗有效量的罗库溴铵、pH值3.8～4.0的柠檬酸或醋酸盐的缓冲体系、金属螯合剂，并用0.1％活性炭吸附热源。此制备方法需使用金属螯合剂稳定制剂，且也需要通过加入活性炭进行脱色、除热源。
CN102860980公开了一种罗库溴铵注射的制备防范，其制备过程如下：a.称取25℃以下的注射用水约2000g，加醋酸钠溶解后混合均匀，用冰醋酸调节溶液pH至3.8～4.2；b.将处方量的罗库溴铵加入上述a溶液中，搅拌使溶解， 补加注射用水至2850ml；c.用冰醋酸调节b溶液的pH值至3.8～4.2后，加入适量的氯化钠调节溶液至等渗；d.c溶液中补加注射用水至3000ge.经0.22μm的聚醚砜滤膜过滤，灌装灭菌，得到每1ml含罗库溴铵5mg的罗库溴铵注射液。此制备方法需要进行终端灭菌，但罗库溴铵在高温下不稳定性，在终端灭菌过程中会增加杂质含量。
发明内容
发明目的：为了解决现有技术的不足，本发明提供了一种低杂质水平的罗库溴铵注射液的制备方法。
技术方案：一种低杂质水平的罗库溴铵注射液的制备方法，每1000ml注射液含有一下重量的组分：8-12g罗库溴铵，1-5g醋酸钠，适量的冰醋酸或氢氧化钠和氯化钠，包括以下步骤：
a.向配制容器中加入处方量85％的注射用水，氮气曝气，冷却上述溶液8-12℃；
b.用乙酸调节a步骤中的溶液的pH至3.0±0.1；
c.处方量的罗库溴铵加入上述b步骤中的溶液，搅拌使溶解；
d.将处方量的乙酸钠和适量氯化钠加入上述c步骤中的溶液，用乙酸或氢氧化钠调节pH至3.0±0.1；
e.补加注射用水至最终溶液重量，用乙酸或氢氧化钠调节pH至3.5-4.3，停止氮气曝气；
f.经0.2μm的聚偏氟乙烯膜过滤，灌装加塞，得到每1ml含10mg罗库溴铵的罗库溴铵注射液。
作为优化：制备的罗库溴铵注射液中罗库溴铵原料的细菌内毒素不超过0.2EU/g，氯化钠和醋酸钠的细菌内毒素不超过2.5EU/g。
作为优化：制备过程的配制工序中一直采用氮气曝气处理，控制溶液中的残留氧浓度≤5.0％。
作为优化：制备过程中不含活性炭吸附热原步骤。
有益效果：罗库溴铵注射液在储存运输的过程中，受限于自身稳定性的原因，杂质C的含量会随时间的推移而增加，杂质C的放行标准为0.5％，本发明在罗库溴铵的注射液的制备过程中尽可能降低杂质C含量水平至0.1％，保证了罗库溴铵注射液在有效期内杂质不超标(货架期标准：1.5％)。
本发明中，当控制好原料及辅料的细菌内毒素时，处方工艺中并不需要加入活性炭进行除热原操作，所得成品的罗库溴铵注射液的细菌内毒素仍是合格的。
本发明中，降低配制药液的温度，氮气曝气除去溶液中的溶解氧以及降低配制时的溶液pH均有助于降低杂质C的含量，有助于提高罗库溴铵注射液的稳定性。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述，以使本领域的技术人员能够更好的理解本发明的优点和特征，从而对本发明的保护范围做出更为清楚的界定。本发明所描述的实施例仅仅是本发明一部分实施例，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的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。
实施例
经过研究发现：
1、当严格控制原辅料中的细菌内毒素时，制备工程无需再加入活性炭进行吸附除热源，最终的产品的内毒素也是符合标准要求的。
2、罗库溴铵的主要降解杂质是杂质C，罗库溴铵在高温条件下不稳定，121 ℃处理20min，杂质C的杂质含量会增加3倍。
3、罗库溴铵在酸性条件下稳定，1mol/L的盐酸处理后，杂质C的含量没有明显变化，而在碱性条件下不稳定，杂质C的含量大幅增加。所以在配制过程中，降低溶液的pH有利于保证罗库溴铵注射液的稳定性。
4、罗库溴铵在氧化条件下不稳定，30％H 2O 2条件下，杂质C的含量大幅增加，所以在配制过程中，通过氮气曝气控制溶液中的残氧量可以得到杂质含量较低的罗库溴铵注射液。
因此，本发明提供了一种低杂质水平的罗库溴铵注射液的制备方法，每1000ml注射液含有一下重量的组分：10g罗库溴铵，2g醋酸钠，适量的冰醋酸或氢氧化钠和氯化钠，制备方法包括以下步骤：
a.向配制容器中加入处方量85％的注射用水，氮气曝气，冷却上述溶液8-12℃；
b.用乙酸调节a步骤中的溶液的pH至3.0±0.1；
c.处方量的罗库溴铵加入上述b步骤中的溶液，搅拌使溶解；
d.将处方量的乙酸钠和适量氯化钠加入上述c步骤中的溶液，用乙酸或氢氧化钠调节pH至3.0±0.1；
e.补加注射用水至最终溶液重量，用乙酸或氢氧化钠调节pH至3.9-4.1，停止氮气曝气；
f.经0.2μm的聚偏氟乙烯膜过滤，灌装加塞，得到每1ml含10mg罗库溴铵的罗库溴铵注射液。
根据本发明的罗库溴铵注射液，罗库溴铵原料的细菌内毒素不超过0.2EU/g，氯化钠和醋酸钠的细菌内毒素不超过2.5EU/g。
最终溶液的pH为3.9～4.1，需要加入3.3mg/ml氯化钠才能达到等渗。
对比实施例1：
表1 对比实施例1中的注射液的成分和用量
成分 用量
罗库溴铵 10.0
醋酸钠 2.0
冰醋酸 适量
氯化钠 3.3
氢氧化钠 适量
注射用水 适量
总量 1000.0
根据上表1，制备方法为：量取冷却至25℃以下的注射用用水约850g，用冰醋酸调节pH至3.9～4.1，得到溶液A，将处方量的罗库溴铵加入A溶液，搅拌溶解，得到溶液B，将处方量的乙酸钠和氯化钠加入溶液B，用冰醋酸调节溶液BpH至3.9～4.1，补加注射用水至1000.0g，得到溶液C；将溶液C过0.2μm的聚偏氟乙烯膜后，灌装5ml。
对比实施例2：
表2 对比实施例2中的注射液的成分和用量
成分 用量
罗库溴铵 10.0
醋酸钠 2.0
冰醋酸 适量
氯化钠 3.3
氢氧化钠 适量
注射用水 适量
总量 1000.0
根据上表2，制备方法为：量取冷却至25℃以下的注射用用水约850g，冷却溶液至8-12℃，用冰醋酸调节pH至3.9～4.1，得到溶液A，将处方量的罗库溴铵加入A溶液，搅拌溶解，得到溶液B，将处方量的乙酸钠和氯化钠加入溶液B，用冰醋酸调节溶液B pH至3.9～4.1，补加注射用水至1000.0g，得到溶液C； 将溶液C过0.2μm的聚偏氟乙烯膜后，灌装5ml。
对比实施例3：
表3 对比实施例3中的注射液的成分和用量
成分 用量
罗库溴铵 10.0
醋酸钠 2.0
冰醋酸 适量
氯化钠 3.3
氢氧化钠 适量
注射用水 适量
总量 1000.0
根据上表3，制备方法为：量取冷却至25℃以下的注射用用水约850g，冷却溶液至8-12℃，用冰醋酸调节pH至2.9～3.1，得到溶液A，将处方量的罗库溴铵加入A溶液，搅拌溶解，得到溶液B，将处方量的乙酸钠和氯化钠加入溶液B，用冰醋酸调节溶液BpH至2.9～3.1，补加注射用水至1000.0g，用冰醋酸或氢氧化钠调节溶液BpH至3.9～4.1得到溶液C；将溶液C过0.2μm的聚偏氟乙烯膜后，灌装5ml。
对比实施例4：
表4 对比实施例4中的注射液的成分和用量
成分 用量
罗库溴铵 10.0
醋酸钠 2.0
冰醋酸 适量
氯化钠 3.3
氢氧化钠 适量
注射用水 适量
总量 1000.0
根据上表4，制备方法为：量取冷却至25℃以下的注射用用水约850g，冷却溶液至8-12℃，用冰醋酸调节pH至2.9～3.1，得到溶液A，将处方量的罗库 溴铵加入A溶液，搅拌溶解，得到溶液B，将处方量的乙酸钠和氯化钠加入溶液B，用冰醋酸调节溶液B pH至2.9～3.1，补加注射用水至1000.0g，用冰醋酸或氢氧化钠调节溶液BpH至3.9～4.1，加入0.1％的活性炭，搅拌30min，过钛棒脱碳，得到溶液C，将溶液C过0.2μm的聚偏氟乙烯膜后，灌装5ml。
实施例1：
表5 实施例1中的注射液的成分和用量
成分 用量
罗库溴铵 10.0
醋酸钠 2.0
冰醋酸 适量
氯化钠 3.3
氢氧化钠 适量
注射用水 适量
总量 1000.0
根据上表5，制备方法为：量取冷却至25℃以下的注射用用水约850g，氮气曝气，冷却溶液至8-12℃，用冰醋酸调节pH至2.9～3.1，得到溶液A，将处方量的罗库溴铵加入A溶液，搅拌溶解，得到溶液B，将处方量的乙酸钠和氯化钠加入溶液B，用冰醋酸调节溶液BpH至2.9～3.1，补加注射用水至1000.0g，用冰醋酸或氢氧化钠调节溶液B的pH至3.9～4.1得到溶液C，停止氮气曝气；将溶液C过0.2μm的聚偏氟乙烯膜后，灌装5ml。
根据2015年版中国药典1143细菌内毒素检测法，检测对比实施例1、对比实施例2、对比实施例3、对比实施例4、实施例1罗库溴铵注射液的细菌内毒素，同时将上述样品进行影响因素考察，采用EP9.0的有关物质方法检测有关物质。
表6 内毒素检验结果
Figure PCTCN2018093566-appb-000001
表7 有关物质检验结果
Figure PCTCN2018093566-appb-000002
根据表6结果，当控制好原料及辅料的细菌内毒素时，处方工艺中并不需要加入活性炭进行除热原操作，所得成品的罗库溴铵注射液的细菌内毒素仍是合格的。根据表7的结果，降低配制药液的温度，氮气曝气除去溶液中的溶解氧以及降低配制时的溶液pH均有助于降低杂质C的含量，有助于提高罗库溴铵注射液的稳定性。

Claims (4)

  1. 一种低杂质水平的罗库溴铵注射液的制备方法，每1000ml注射液含有一下重量的组分：8-12g罗库溴铵，1-5g醋酸钠，适量的冰醋酸或氢氧化钠和氯化钠，其特征在于：包括以下步骤：
    a.向配制容器中加入处方量85％的注射用水，氮气曝气，冷却上述溶液8-12℃；
    b.用乙酸调节a步骤中的溶液的pH至3.0±0.1；
    c.处方量的罗库溴铵加入上述b步骤中的溶液，搅拌使溶解；
    d.将处方量的乙酸钠和适量氯化钠加入上述c步骤中的溶液，用乙酸或氢氧化钠调节pH至3.0±0.1；
    e.补加注射用水至最终溶液重量，用乙酸或氢氧化钠调节pH至3.5-4.4，停止氮气曝气；
    f.经0.2μm的聚偏氟乙烯膜过滤，灌装加塞，得到每1ml含10mg罗库溴铵的罗库溴铵注射液。
  2. 根据权利要求1所述的低杂质水平的罗库溴铵注射液的制备方法，其特征在于：制备的罗库溴铵注射液中罗库溴铵原料的细菌内毒素不超过0.2EU/g，氯化钠和醋酸钠的细菌内毒素不超过2.5EU/g。
  3. 根据权利要求1所述的低杂质水平的罗库溴铵注射液的制备方法，其特征在于：制备过程的配制工序中一直采用氮气曝气处理，控制溶液中的残留氧浓度≤5.0％。
  4. 根据权利要求1所述的低杂质水平的罗库溴铵注射液的制备方法，其特征在于：制备过程中不含活性炭吸附热原步骤。
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CN110876718A (zh) * 2019-12-10 2020-03-13 湖南洞庭药业股份有限公司 氨甲环酸注射液及其制备方法
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Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102048684A (zh) * 2009-11-06 2011-05-11 华北制药集团制剂有限公司 一种罗库溴铵注射液的制备方法
WO2012145888A1 (zh) * 2011-04-25 2012-11-01 浙江华海药业股份有限公司 一种罗库溴铵的纯化方法
CN102860980A (zh) * 2012-09-22 2013-01-09 浙江华海药业股份有限公司 一种罗库溴铵注射液的制备方法
CN102949339A (zh) * 2012-11-28 2013-03-06 天津红日药业股份有限公司 一种含有罗库溴铵的注射剂
CN103462885A (zh) * 2013-09-11 2013-12-25 河北凯盛医药科技有限公司 一种稳定的罗库溴铵注射液制剂及其制备方法
JP2016121073A (ja) * 2014-12-24 2016-07-07 ニプロ株式会社 注射剤用医薬組成物の製造方法
CN107073007A (zh) * 2014-06-26 2017-08-18 丸石制药株式会社 具有改进的稳定性的罗库溴铵制剂

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102048684A (zh) * 2009-11-06 2011-05-11 华北制药集团制剂有限公司 一种罗库溴铵注射液的制备方法
WO2012145888A1 (zh) * 2011-04-25 2012-11-01 浙江华海药业股份有限公司 一种罗库溴铵的纯化方法
CN102860980A (zh) * 2012-09-22 2013-01-09 浙江华海药业股份有限公司 一种罗库溴铵注射液的制备方法
CN102949339A (zh) * 2012-11-28 2013-03-06 天津红日药业股份有限公司 一种含有罗库溴铵的注射剂
CN103462885A (zh) * 2013-09-11 2013-12-25 河北凯盛医药科技有限公司 一种稳定的罗库溴铵注射液制剂及其制备方法
CN107073007A (zh) * 2014-06-26 2017-08-18 丸石制药株式会社 具有改进的稳定性的罗库溴铵制剂
JP2016121073A (ja) * 2014-12-24 2016-07-07 ニプロ株式会社 注射剤用医薬組成物の製造方法

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