WO2022222630A1 - 一种复方电解质注射液及其制备方法 - Google Patents

一种复方电解质注射液及其制备方法 Download PDF

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WO2022222630A1
WO2022222630A1 PCT/CN2022/079881 CN2022079881W WO2022222630A1 WO 2022222630 A1 WO2022222630 A1 WO 2022222630A1 CN 2022079881 W CN2022079881 W CN 2022079881W WO 2022222630 A1 WO2022222630 A1 WO 2022222630A1
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compound electrolyte
electrolyte injection
injection
preparation
chloride
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PCT/CN2022/079881
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English (en)
French (fr)
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刘晓娟
张泽慧
王博
金佳鑫
张金葆
杨学杰
苏燕
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石家庄四药有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J3/00—Devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/14—Alkali metal chlorides; Alkaline earth metal chlorides
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis

Definitions

  • the application relates to the technical field of pharmaceutical preparations, in particular to a compound electrolyte injection and a preparation method thereof.
  • Compound Electrolyte Injection (II) is a compound preparation, is an isotonic electrolyte solution, the electrolyte concentration is compatible with the plasma electrolyte concentration, it is used for the treatment of isotonic dehydration accompanied or expected to appear acidosis, and to supplement the loss of extracellular fluid , to maintain normal osmotic pressure between extracellular and intracellular.
  • Compound Electrolyte Injection (II) contains potassium, calcium, magnesium, chloride and other ions in similar proportions to those in human plasma. When used for extracellular fluid loss replacement therapy, it will not cause electrolytes.
  • Imbalance, edema or increased intracranial pressure, the acetate and malate it contains can effectively avoid the occurrence of dilution acidosis, and the components do not contain lactate, which does not affect the use of lactic acid as a monitoring indicator of hypoxia, and does not It will cause the accumulation of lactic acid in the patient's body, and will not increase the body burden of those with shock and liver insufficiency. Therefore, Compound Electrolyte Injection (II) plays an important role in emergency treatment and sign maintenance for patients undergoing major surgeries such as neurointensive care unit (ICU), neurosurgery, and hemorrhagic shock, and also has unique advantages in clinical volume therapy.
  • ICU neurointensive care unit
  • hemorrhagic shock also has unique advantages in clinical volume therapy.
  • the preparation process of compound electrolyte injection (II) needs to add activated carbon to remove the heat source, but this also introduces some impurities and insoluble particles, which brings risks to the application safety of the injection; and the existing preparation process is generally
  • the two-step preparation method of concentrated preparation and diluted preparation increases the contact between the medicinal liquid and the concentrated preparation tank, concentrated preparation pipeline and titanium rod filter, which increases the safety risk of microbial contamination, and the process is complicated, which is more likely to cause the process of electrolyte composition.
  • the compound electrolyte injection (II) prepared by the existing process has a high impurity content and a variety of types, and the impurity increases significantly during the storage process.
  • Concentrated preparation is for raw materials with poor quality or many dissolved impurities, first dissolve the materials with a small amount of solvent, then filter out the impurities, and then add the solvent to obtain a solution.
  • Diluted preparation is a solution prepared by adding the required amount of solvent at one time with a better quality raw material drug.
  • the present application provides a compound electrolyte injection and a preparation method thereof.
  • a preparation method of compound electrolyte injection comprising the following steps:
  • Step a adding the L-malic acid, magnesium chloride, sodium chloride, potassium chloride, calcium chloride, sodium acetate and sodium hydroxide of the recipe quantity to the water for injection of the preparation total volume 70-80% in sequence, stirring Dissolve, heat to boiling, keep for 10min-20min, get compound electrolyte liquid;
  • step b water for injection is added to the compound electrolyte liquid to make up the total volume, filtered through a multi-stage polyethersulfone filter element with decreasing pore size in turn, filled and sterilized to obtain compound electrolyte injection.
  • step a the sodium hydroxide is added in the form of an aqueous sodium hydroxide solution.
  • the concentration of the sodium hydroxide aqueous solution is 2mol/L, and the addition amount of the sodium hydroxide aqueous solution is 1.875mL-3.125mL per 1000mL of the compound electrolyte injection.
  • the application chooses to add sodium hydroxide in the form of sodium hydroxide aqueous solution, which can avoid local over-alkali caused by direct input of materials, which leads to the degradation of L-malic acid and the increase of impurity content; at the same time, it can also avoid calcium ions or magnesium ions.
  • the ions form hydroxide precipitation, causing the problem of turbidity of the medicinal solution.
  • the addition amount of the sodium hydroxide aqueous solution in the present application can make the pH of the medicinal solution in the range of 5.1-5.9, no additional pH adjustment is required, operation steps are saved, and production efficiency is improved.
  • the multi-stage polyethersulfone filter is filtered by a second-stage polyethersulfone filter, wherein the pore size of the first-stage polyethersulfone filter is 0.45 ⁇ m, and the second-stage polyethersulfone filter is 0.45 ⁇ m.
  • the pore size of the filter element is 0.2 ⁇ m.
  • the application uses multi-stage polyethersulfone filter elements with specific pore sizes to filter in sequence, which can ensure that the content of bacteria and endotoxin in the product is qualified, reduce the introduction of process impurities, and reduce the content of impurities in the product, which is beneficial to the improvement of product stability, and in the production process.
  • No activated carbon is used in the compound electrolyte injection, which not only reduces the loss of electrolyte components in the compound electrolyte injection, but also reduces the risk of introducing insoluble particles. At the same time, it also reduces the pollution to the production clean area and reduces the pressure on environmental protection.
  • the filling is performed using a multi-layer co-extruded film infusion bag.
  • the compound electrolyte injection in this application adopts a multi-layer co-extruded film infusion bag, which can reduce the introduction of insoluble particles, reduce the pollution of the compound electrolyte injection caused by microorganisms, and is convenient to open and not easily broken, which is conducive to product transportation and preservation.
  • the sterilization method is constant temperature sterilization at 121° C. for 12-15 minutes.
  • the application adopts a terminal sterilization process, which greatly improves the sterilization level and sterilization efficiency of the product.
  • the temperature of the water for injection is 65-75°C.
  • the present application also provides a compound electrolyte injection (II), which is prepared by the preparation method of the compound electrolyte injection (II) described in any one of the above.
  • each 1000mL of the compound electrolyte injection includes: L-malic acid 0.65g-0.70g, sodium chloride 6.5g-7.0g, potassium chloride 0.28g-0.30g, calcium chloride 0.35g g-0.38g, magnesium chloride 0.19g-0.21g, sodium acetate 3.0g-3.5g and sodium hydroxide 0.15g-0.25g.
  • the pH of the compound electrolyte injection is 5.1-5.9.
  • the multi-stage polyethersulfone filter element filtration is a two-stage polyethersulfone filter element filtration, specifically, a polyethersulfone pleated filter element filtration.
  • the formulation amount mentioned in this application refers to the amount of each component in the formulation of the formulation.
  • the terminal sterilization process mentioned in this application refers to sterilization by moist heat sterilization after the medicine is potted and sealed on the basis of controlling the amount of microbial contamination.
  • the total volume of preparation in this application refers to the total volume of compound electrolyte injection prepared, and the water for injection with 70-80% of the total volume of preparation refers to the amount of water for injection that is the total volume of compound electrolyte injection. 70-80%.
  • the preparation method of compound electrolyte injection (II) provided by this application can effectively reduce the impurities in compound electrolyte injection according to the specific material adding sequence and the method of heating and boiling the medicinal liquid for 10-20min. It can effectively reduce the impurity content, and the impurities removed by boiling will not be regenerated during the whole storage process, which effectively improves the stability of compound electrolyte injection (II). , to avoid the defect of introducing impurities and insoluble particles in the traditional process of adding activated carbon to remove the heat source, and improving the safety of the product.
  • the present application achieves the purpose of preparing compound electrolyte injection (II) with low impurity content and high storage stability by a one-step preparation method through a specific material addition sequence and a heating and boiling method.
  • the production steps of concentration, mixing, rinsing and coarse filtration not only reduce the contact between the medicinal liquid and the preparation system, reduce the risk of microbial contamination during the production process, but also avoid the process loss of electrolyte components;
  • the sulfone filter element filtration method ensures that the visible foreign matter and insoluble particles of the product can be qualified, reduces the introduction of impurities, significantly simplifies the production steps, reduces the production cost, and has extremely high promotion value.
  • the present application prepares the compound electrolyte injection (II) with significantly reduced types and contents of impurities through a one-step preparation method, and significantly improves the storage stability of the compound electrolyte injection.
  • the impurity content in Compound Electrolyte Injection (II) did not increase significantly.
  • the one-step preparation method also greatly simplifies the production process, improves the production efficiency, reduces the production cost, facilitates the realization of industrialized production, and has broad application prospects.
  • This embodiment provides a compound electrolyte injection (II), and the prescription amount is shown in the following table:
  • Step a add 700mL of fresh water for injection in the preparation tank, add L-malic acid, magnesium chloride, sodium chloride, potassium chloride, calcium chloride, sodium acetate and sodium hydroxide aqueous solution of the recipe in sequence, stir and dissolve , heated to boiling and kept for 15min to obtain compound electrolyte liquid;
  • Step b adding water for injection to the compound electrolyte medicinal solution to make up the total volume, filtering through polyethersulfone pleated filter elements with pore diameters of 0.45 ⁇ m and 0.2 ⁇ m in turn, and filling the filtered medicinal solution into a multi-layer co-extrusion infusion bag , seal the multi-layer co-extrusion infusion bag, sterilize in a water bath at a constant temperature of 121°C for 12 minutes, inspect by light, and package to obtain compound electrolyte injection (II).
  • This embodiment provides a compound electrolyte injection (II), and the prescription amount is shown in the following table:
  • Step a add 750mL of fresh water for injection in the preparation tank, add L-malic acid, magnesium chloride, sodium chloride, potassium chloride, calcium chloride, sodium acetate and sodium hydroxide aqueous solution of the recipe in sequence, stir and dissolve , heated to boiling and kept for 10min to obtain compound electrolyte liquid;
  • Step b adding water for injection to the compound electrolyte medicinal solution to make up the total volume, filtering through polyethersulfone pleated filter elements with pore diameters of 0.45 ⁇ m and 0.2 ⁇ m in turn, and filling the filtered medicinal solution into a multi-layer co-extrusion infusion bag , seal the multi-layer co-extrusion infusion bag, sterilize in a water bath at a constant temperature of 121° C. for 13 minutes, inspect by light, and package to obtain compound electrolyte injection (II).
  • This embodiment provides a compound electrolyte injection (II), and the prescription amount is shown in the following table:
  • Step a add 800mL of fresh water for injection in the preparation tank, add L-malic acid, magnesium chloride, sodium chloride, potassium chloride, calcium chloride, sodium acetate and sodium hydroxide aqueous solution of the recipe in sequence, stir and dissolve , heated to boiling and kept for 20min to obtain compound electrolyte liquid;
  • Step b adding water for injection to the compound electrolyte medicinal solution to make up the total volume, filtering through polyethersulfone pleated filter elements with pore diameters of 0.45 ⁇ m and 0.2 ⁇ m in turn, and filling the filtered medicinal solution into a multi-layer co-extrusion infusion bag , seal the multi-layer co-extruded infusion bag, sterilize in a water bath at a constant temperature of 121°C for 15 minutes, light inspection, and package to obtain compound electrolyte injection (II).
  • This comparative example provides a compound electrolyte injection (II), the prescription amount of which is shown in the following table:
  • Step a add 500mL of fresh water for injection in the concentrated preparation tank, add the L-malic acid, magnesium chloride, sodium chloride, potassium chloride, calcium chloride and sodium acetate of the recipe quantity, stir and dissolve, get the medicinal liquid, and add the medicinal liquid to the medicine.
  • Step b inject the compound electrolyte concentrated solution into the dilute preparation tank, rinse the concentrated preparation tank with water for injection, and transport the flushing water to the dilute preparation tank after filtering, and then add water for injection to the dilute preparation tank to prepare the total volume , filter the solution in the dilute preparation tank, fill the filtered solution into a multi-layer co-extrusion infusion bag, seal the multi-layer co-extrusion infusion bag, sterilize in a water bath at a constant temperature of 121 ° C for 12 minutes, light inspection, and package to obtain compound electrolytes Injection (II).
  • This comparative example provides a compound electrolyte injection (II), and its recipe quantity is exactly the same as that of Example 1, the only difference is that the order of adding the materials in the preparation method is different, and the specific preparation steps are as follows:
  • Step a add 700mL of fresh water for injection in the preparation tank, add magnesium chloride, sodium chloride, potassium chloride, calcium chloride, L-malic acid, sodium hydroxide aqueous solution and sodium acetate in the prescribed amount in sequence, and stir and dissolve. , heated to boiling and kept for 15min to obtain compound electrolyte liquid;
  • Step b adding water for injection to the compound electrolyte medicinal solution to make up the total volume, filtering through polyethersulfone pleated filter elements with pore diameters of 0.45 ⁇ m and 0.2 ⁇ m in turn, and filling the filtered medicinal solution into a multi-layer co-extrusion infusion bag , seal the multi-layer co-extrusion infusion bag, sterilize in a water bath at a constant temperature of 121°C for 12 minutes, inspect by light, and package to obtain compound electrolyte injection (II).
  • This comparative example provides a compound electrolyte injection (II), the prescription amount is exactly the same as that of Example 1. The only difference is that the heating and boiling time in the preparation method is different, and the specific preparation steps are as follows:
  • Step a add 700mL of fresh water for injection in the preparation tank, add L-malic acid, magnesium chloride, sodium chloride, potassium chloride, calcium chloride, sodium acetate and sodium hydroxide aqueous solution of the recipe in sequence, stir and dissolve , heated to boiling and kept for 40min to obtain compound electrolyte liquid;
  • Step b adding water for injection to the compound electrolyte medicinal solution to make up the total volume, filtering through polyethersulfone pleated filter elements with pore diameters of 0.45 ⁇ m and 0.2 ⁇ m in turn, and filling the filtered medicinal solution into a multi-layer co-extrusion infusion bag , seal the multi-layer co-extrusion infusion bag, sterilize in a water bath at a constant temperature of 121°C for 12 minutes, inspect by light, and package to obtain compound electrolyte injection (II).
  • HPLC high performance liquid chromatography
  • Chromatographic column C18 chromatographic column
  • Detection wavelength 205 ⁇ 225nm
  • Injection volume 80 ⁇ L
  • the peak time of L-malic acid is 6.0 ⁇ 8.0min
  • the peak time of tartaric acid (2,3-dihydroxysuccinic acid) is 5.5 ⁇ 7.5min
  • fumaric acid The peak time of fumaric acid
  • the peak time of maleic acid maleic acid is 9.5 ⁇ 12.0min.
  • the largest unknown single impurity refers to the impurity with the largest content among the unknown impurities;
  • the other unknown total impurities refers to the sum of all unknown impurities except tartaric acid and maleic acid.

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Abstract

一种复方电解质注射液及其制备方法。其制备方法为：将处方量的L-苹果酸、氯化镁、氯化钠、氯化钾、氯化钙、醋酸钠和氢氧化钠按顺序依次加入配制总体积量70-80％的注射用水中，搅拌溶解，加热至沸，保持10min-20min，补加注射用水至配制总体积量，经过孔径依次减小的多级聚醚砜滤芯过滤，灌装，灭菌，得复方电解质注射液。本申请通过一步配制法制备得到了杂质种类、含量均明显降低的复方电解质注射液(II)，显著提高了注射液的存储稳定性。在稳定性考察试验中，复方电解质注射液(II)中杂质含量增加不明显。

Description

一种复方电解质注射液及其制备方法
本专利申请要求于2021年04月22日提交的中国专利申请No.CN202110434877.1的优先权。在先申请的公开内容通过整体引用并入本申请。
技术领域
本申请涉及药物制剂技术领域，尤其涉及一种复方电解质注射液及其制备方法。
 背景技术
复方电解质注射液（Ⅱ）为复方制剂，是一种等渗性电解质溶液，电解质浓度与血浆电解质浓度相适合，用于治疗伴随或预期出现酸中毒的等渗性脱水，补充细胞外液的丢失，以维持细胞外和细胞内之间正常的渗透压。复方电解质注射液（Ⅱ）含有的钾、钙、镁、氯等离子成分和人体血浆中的钾、钙、镁、氯等离子成分比例相近，在用于细胞外液丢失替代治疗时，不会引起电解质失衡、水肿或颅内压升高，其含有的醋酸根和苹果酸根可有效避免稀释性酸中毒的发生，且组分中不含有乳酸根，不影响以乳酸作为缺氧状态的监测指标，不会引起患者体内乳酸蓄积，不会增加休克和肝功能不全者的机体负担。因此，复方电解质注射液（Ⅱ）在神经重症监护病房（ICU）、神经外科、失血性休克等重大手术患者的急救及体征维持中起到重要作用，在临床容量治疗方面也具有独特的优势。
目前，复方电解质注射液（Ⅱ）的制备工艺中需要加入活性炭以脱除热源，但是由此也会引入一些杂质和不溶性微粒，给注射剂的应用安全性带来风险；且现有制备工艺一般是采用浓配和稀配两步配制法，增加了药液与浓配罐、浓配管路以及钛棒过滤器的接触，增加了微生物污染的安全风险，且工序复杂，更容易造成电解质成分的工序损耗，生产时间也较长；除此之外，现有工艺制备的复方电解质注射液（Ⅱ）杂质含量高、种类多，在存储过程中杂质增长明显。因此，研发一种生产工艺简单且存储稳定性高的复方电解质注射液（Ⅱ），对提高患者的用药安全及降低生产成本具有十分重要的意义。浓配就是针对质量较差或者溶解杂质多的原料，先用少量溶剂将物料溶解，然后滤除杂质，再加入溶剂所得到的溶液。稀配就是质量较好的原料药物，一次性加入所需量的溶剂配得的溶液。
 技术问题
针对现有的复方电解质注射液（Ⅱ）存在的杂质含量高、种类多，以及长期存储过程杂质增多明显，生产工艺复杂的问题，本申请提供一种复方电解质注射液及其制备方法。
 技术解决方案
为解决上述技术问题，本申请提供的技术方案是：
一种复方电解质注射液的制备方法，包括如下步骤：
步骤a，将处方量的L-苹果酸、氯化镁、氯化钠、氯化钾、氯化钙、醋酸钠和氢氧化钠按顺序依次加入配制总体积量70-80%的注射用水中，搅拌溶解，加热至沸，保持10min-20min，得复方电解质药液；
步骤b，向所述复方电解质药液中补加注射用水至配制总体积量，经过孔径依次减小的多级聚醚砜滤芯过滤，灌装，灭菌，得复方电解质注射液。
本申请中所述复方电解质注射液为复方电解质注射液（Ⅱ）。在其中一个实施例中，步骤a中，所述氢氧化钠以氢氧化钠水溶液的形式加入。
进一步优选的，步骤a中，所述氢氧化钠水溶液的浓度为2mol/L，氢氧化钠水溶液的加入量为每1000mL所述复方电解质注射液中加入1.875mL-3.125mL。
本申请选择将氢氧化钠以氢氧化钠水溶液的形式加入，可避免物料直接投入造成的局部过碱，从而导致L-苹果酸降解，杂质含量增加的问题；同时，也能避免钙离子或者镁离子形成氢氧化物沉淀，造成药液浑浊问题的发生。
本申请中氢氧化钠水溶液的加入量可以使药液的pH在5.1-5.9范围内，无需额外调节pH，节省了操作步骤，提高了生产效率。
在其中一个实施例中，步骤b中，所述多级聚醚砜滤芯过滤为二级聚醚砜滤芯过滤，其中，第一级聚醚砜滤芯的孔径为0.45μm，第二级聚醚砜滤芯的孔径为0.2μm。
本申请采用特定孔径的多级聚醚砜滤芯依次过滤，可保证产品细菌、内毒素含量合格，减少工艺杂质的引入，降低产品中杂质的含量，有利于产品稳定性的提高，且在生产过程中不采用活性炭，不但减少了复方电解质注射液中电解质成分的损耗，也减少了不溶性微粒引入的风险，同时，也降低了对生产洁净区的污染，减轻了环保压力。
在其中一个实施例中，所述灌装采用多层共挤膜输液袋进行灌装。
本申请中复方电解质注射液采用多层共挤膜输液袋，可以减少不溶性微粒的引入，降低微生物对复方电解质注射液造成的污染，且开启方便，不易破碎，有利于产品运输保存。
在其中一个实施例中，所述灭菌的方式为121℃恒温灭菌12-15min。
本申请采用终端灭菌工艺，大大提高了产品的无菌水平和灭菌效率。
在其中一个实施例中，步骤a和步骤b中，所述注射用水的温度为65-75℃。
本申请还提供一种复方电解质注射液（Ⅱ），由上述任一项所述的复方电解质注射液（Ⅱ）的制备方法制备得到。
在其中一个实施例中，每1000mL所述复方电解质注射液中包括：L-苹果酸0.65g-0.70g，氯化钠6.5g-7.0g，氯化钾0.28g-0.30g，氯化钙0.35g-0.38g，氯化镁0.19g-0.21g，醋酸钠3.0g-3.5g和氢氧化钠0.15g-0.25g。
在其中一个实施例中，所述复方电解质注射液的pH为5.1-5.9。
所述多级聚醚砜滤芯过滤为二级聚醚砜滤芯过滤，具体可为聚醚砜折叠滤芯过滤。
本申请中所述处方量是指制剂处方中各组分的量。
本申请中所述终端灭菌工艺（terminal sterilization process）是指在控制微生物污染量的基础上，在药品灌封后，通过湿热灭菌方式除菌。
本申请中所述配制总体积量是指配制的复方电解质注射液的总体积量，所述配制总体积量70-80%的注射用水是指注射用水的量是复方电解质注射液的总体积量的70-80%。
可以理解的是，本申请中公开的数值范围可以是范围区间的任意值；公开的数值仅是较优的选择。当然，在其他实施例中，还可以采用其他数值，并不局限于此。
 有益效果
相对于现有技术，本申请提供的复方电解质注射液（Ⅱ）的制备方法，按照特定的物料加入顺序并配合将药液加热煮沸10-20min的方法，有效减少了复方电解质注射液中的杂质种类，且有效降低了杂质含量，经煮沸去除的杂质在整个存储过程中均不会再产生，有效提高了复方电解质注射液（Ⅱ）的稳定性；且配合多级聚醚砜滤芯过滤的方法，避免了传统工艺加入活性炭去除热源会引入杂质和不溶性微粒的缺陷，提高了产品的安全性。本申请通过特定的物料加入顺序以及加热煮沸的方法，实现了一步配制法制备杂质含量少、储存稳定性高的复方电解质注射液（Ⅱ）的目的，同时，省去了浓配系统预处理、浓配、打料、冲洗和粗滤等生产步骤，既减少了药液与配制系统的接触，降低了生产过程中微生物污染的风险，也避免了电解质成分的工序损耗；且经多级聚醚砜滤芯过滤的方法保证了产品可见异物、不溶性微粒能达到合格，减少了杂质的引入，显著简化了生产步骤，降低了生产成本，具有极高的推广价值。
本申请通过一步配制方法制备得到了杂质种类、含量均明显降低的复方电解质注射液（Ⅱ），显著提高了复方电解质注射液的存储稳定性。在稳定性考察试验中，复方电解质注射液（Ⅱ）中杂质含量增加不明显。同时，该一步配制方法还极大地简化了生产工艺，提高了生产效率，降低了生产成本，便于实现工业化生产，具有广阔的应用前景。
本申请的实施方式
为了使本申请的目的、技术方案及优点更加清楚明白，以下结合实施例，对本申请进行进一步详细说明。应当理解，此处所描述的具体实施例仅仅用以解释本申请，并不用于限定本申请。
为了更好的说明本申请，下面通过实施例做进一步的举例说明。
实施例1
本实施例提供一种复方电解质注射液（Ⅱ），处方量如下表所示：
L-苹果酸                   0.68g
氯化钠                     6.8g
氯化钾                     0.29g
氯化钙                     0.38g
氯化镁                     0.19g
醋酸钠                     3.5g
2mol/L氢氧化钠水溶液      2.5mL
注射用水至1L。
上述复方电解质注射液（Ⅱ）的制备方法如下：
步骤a，在配制罐中加入700mL的新鲜注射用水，按顺序依次加入处方量的L-苹果酸、氯化镁、氯化钠、氯化钾、氯化钙、醋酸钠和氢氧化钠水溶液，搅拌溶解，加热至沸，保持15min，得复方电解质药液；
步骤b，向复方电解质药液中补加注射用水至配制总体积量，依次通过孔径为0.45μm和0.2μm的聚醚砜折叠滤芯过滤，灌装过滤后的药液至多层共挤输液袋中，将多层共挤输液袋封口，121℃恒温12min水浴灭菌，灯检，包装，得复方电解质注射液（Ⅱ）。
实施例2
本实施例提供一种复方电解质注射液（Ⅱ），处方量如下表所示：
L-苹果酸                   0.70g
氯化钠                     7.0g
氯化钾                     0.28g
氯化钙                     0.35g
氯化镁                     0.20g
醋酸钠                     3.2g
2mol/L氢氧化钠水溶液       1.875mL
注射用水至1L。
上述复方电解质注射液（Ⅱ）的制备方法如下：
步骤a，在配制罐中加入750mL的新鲜注射用水，按顺序依次加入处方量的L-苹果酸、氯化镁、氯化钠、氯化钾、氯化钙、醋酸钠和氢氧化钠水溶液，搅拌溶解，加热至沸，保持10min，得复方电解质药液；
步骤b，向复方电解质药液中补加注射用水至配制总体积量，依次通过孔径为0.45μm和0.2μm的聚醚砜折叠滤芯过滤，灌装过滤后的药液至多层共挤输液袋中，将多层共挤输液袋封口，121℃恒温13min水浴灭菌，灯检，包装，得复方电解质注射液（Ⅱ）。
实施例3
本实施例提供一种复方电解质注射液（Ⅱ），处方量如下表所示：
L-苹果酸                   0.65g
氯化钠                     6.5g
氯化钾                     0.30g
氯化钙                     0.36g
氯化镁                     0.21g
醋酸钠                     3.0g
2mol/L氢氧化钠水溶液       3.125mL
注射用水至1L。
上述复方电解质注射液（Ⅱ）的制备方法如下：
步骤a，在配制罐中加入800mL的新鲜注射用水，按顺序依次加入处方量的L-苹果酸、氯化镁、氯化钠、氯化钾、氯化钙、醋酸钠和氢氧化钠水溶液，搅拌溶解，加热至沸，保持20min，得复方电解质药液；
步骤b，向复方电解质药液中补加注射用水至配制总体积量，依次通过孔径为0.45μm和0.2μm的聚醚砜折叠滤芯过滤，灌装过滤后的药液至多层共挤输液袋中，将多层共挤输液袋封口，121℃恒温15min水浴灭菌，灯检，包装，得复方电解质注射液（Ⅱ）。
对比例1
本对比例提供一种复方电解质注射液（Ⅱ），其处方量如下表所示：
L-苹果酸                   0.68g
氯化钠                     6.8g
氯化钾                     0.29g
氯化钙                     0.38g
氯化镁                     0.19g
醋酸钠                     3.5g
氢氧化钠                   0.2g
注射用水至1L。
上述复方电解质注射液（Ⅱ）的制备方法如下：
步骤a，在浓配罐中加入500mL的新鲜注射用水，加入处方量的L-苹果酸、氯化镁、氯化钠、氯化钾、氯化钙和醋酸钠，搅拌溶解，得药液，向药液中加入处方量的氢氧化钠调节药液的pH至5.3-5.7，然后向药液中投入活性炭0.1g，搅拌吸附10min，过滤脱除活性炭，得复方电解质浓配液；
步骤b，将复方电解质浓配液注入稀配罐中，用注射用水冲洗浓配罐，冲洗水经过滤后输送至稀配罐中，然后向稀配罐中补加注射用水至配制总体积量，将稀配罐中的溶液进行过滤，灌装过滤后的溶液至多层共挤输液袋中，将多层共挤输液袋封口，121℃恒温12min水浴灭菌，灯检，包装，得复方电解质注射液（Ⅱ）。
对比例2
本对比例提供一种复方电解质注射液（Ⅱ），其处方量与实施例1完全相同，不同的仅是制备方法中物料的加入顺序不同，具体制备步骤如下：
步骤a，在配制罐中加入700mL的新鲜注射用水，按顺序依次加入处方量的氯化镁、氯化钠、氯化钾、氯化钙、L-苹果酸、氢氧化钠水溶液和醋酸钠，搅拌溶解，加热至沸，保持15min，得复方电解质药液；
步骤b，向复方电解质药液中补加注射用水至配制总体积量，依次通过孔径为0.45μm和0.2μm的聚醚砜折叠滤芯过滤，灌装过滤后的药液至多层共挤输液袋中，将多层共挤输液袋封口，121℃恒温12min水浴灭菌，灯检，包装，得复方电解质注射液（Ⅱ）。
对比例3
本对比例提供一种复方电解质注射液（Ⅱ），处方量与实施例1完全相同。不同的仅是制备方法中加热煮沸的时间不同，具体制备步骤如下：
步骤a，在配制罐中加入700mL的新鲜注射用水，按顺序依次加入处方量的L-苹果酸、氯化镁、氯化钠、氯化钾、氯化钙、醋酸钠和氢氧化钠水溶液，搅拌溶解，加热至沸，保持40min，得复方电解质药液；
步骤b，向复方电解质药液中补加注射用水至配制总体积量，依次通过孔径为0.45μm和0.2μm的聚醚砜折叠滤芯过滤，灌装过滤后的药液至多层共挤输液袋中，将多层共挤输液袋封口，121℃恒温12min水浴灭菌，灯检，包装，得复方电解质注射液（Ⅱ）。
质量检测
有关物质检测方法采用高效液相色谱法（HPLC），实验参数为：
色谱柱：C18色谱柱；
流动相：20mmol/L磷酸二氢钠水溶液；
检测波长：205~225nm；
进样量：80µL；
流速：0.5~1.5mL/min；
柱温：30~40℃。
其中，L-苹果酸（L-羟基丁二酸）的出峰时间为6.0~8.0min，酒石酸（2,3-二羟基丁二酸）的出峰时间为5.5~7.5min，富马酸（反丁烯二酸）的出峰时间为12~14.5min，马来酸（顺丁烯二酸）的出峰时间为9.5~12.0min。
除有关物质外，其他检测项目按照《中国药典》（2010年版），对实施例1-3以及对比例1-3制备的复方电解质注射液（Ⅱ）产品进行质量检测和稳定性试验，结果如表1-2所示。
表1 实施例1-3试验结果
Figure dest_path_image001
表2 对比例1-3试验结果
Figure dest_path_image002
其中，最大未知单杂是指未知杂质中含量最大的杂质；其他未知总杂是指除酒石酸和马来酸之外的所有未知杂质的总和。
由上述试验数据可以看出，与对比例1-3相比，本申请实施例1-3制备的复方电解质注射液中杂质种类及含量更低，且稳定性更高，在加速6个月以及长期24个月试验过程中杂质含量增加均明显低于对比例1-3，且杂质种类没有增加，这证明本申请实施例制备的复方电解质注射液具有更好的稳定性和安全性，从而更有利于提高临床应用的安全性。
以上所述仅为本申请的较佳实施例而已，并不用以限制本申请，凡在本申请的精神和原则之内所作的任何修改、等同替换或改进等，均应包含在本申请的保护范围之内。

Claims (10)

  1. 一种复方电解质注射液的制备方法，其特征在于，包括如下步骤：
    步骤a，将处方量的L-苹果酸、氯化镁、氯化钠、氯化钾、氯化钙、醋酸钠和氢氧化钠按顺序依次加入配制总体积量70-80%的注射用水中，搅拌溶解，加热至沸，保持10min-20min，得复方电解质药液；
    步骤b，向所述复方电解质药液中补加注射用水至配制总体积量，经过孔径依次减小的多级聚醚砜滤芯过滤，灌装，灭菌，得复方电解质注射液。
  2. 如权利要求1所述的复方电解质注射液的制备方法，其特征在于，步骤a中，所述氢氧化钠以氢氧化钠水溶液的形式加入。
  3. 如权利要求2所述的复方电解质注射液的制备方法，其特征在于，步骤a中，所述氢氧化钠水溶液的浓度为2mol/L，加入量为每1000mL所述复方电解质注射液中加入1.875mL-3.125mL。
  4. 如权利要求1所述的复方电解质注射液的制备方法，其特征在于，所述多级聚醚砜滤芯过滤为二级聚醚砜滤芯过滤，其中，第一级聚醚砜滤芯的孔径为0.45μm，第二级聚醚砜滤芯的孔径为0.2μm。
  5. 如权利要求1所述的复方电解质注射液的制备方法，其特征在于，所述灌装采用多层共挤膜输液袋进行灌装。
  6. 如权利要求1所述的复方电解质注射液的制备方法，其特征在于，所述灭菌的方式为121℃恒温灭菌12-15min。
  7. 如权利要求1所述的复方电解质注射液的制备方法，其特征在于，步骤a和步骤b中，所述注射用水的温度为65-75℃。
  8. 一种复方电解质注射液，其特征在于，由权利要求1-7任一项所述的复方电解质注射液的制备方法制备得到。
  9. 如权利要求8所述的复方电解质注射液，其特征在于，每1000mL所述复方电解质注射液中包括：L-苹果酸0.65g-0.70g，氯化钠6.5g-7.0g，氯化钾0.28g-0.30g，氯化钙0.35g-0.38g，氯化镁0.19g-0.21g，醋酸钠3.0g-3.5g和氢氧化钠0.15g-0.25g。
  10. 如权利要求9所述的复方电解质注射液，其特征在于，所述复方电解质注射液的pH为5.1-5.9。
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