Preparation method of potassium magnesium aspartate preparation for improving drug safety

Abstract

The invention discloses a preparation method of a potassium magnesium aspartate preparation for improving drug safety. The method comprises the following steps: filling argon into a medicine solution subjected to argon filling protection treatment, filling and sealing, and sterilizing. According to the invention, the step of argon filling protection is added in the preparation process, so that the thermosensitive reaction of the medicine is effectively prevented, and the stability and safety of the medicine are improved; meanwhile, through high-temperature sterilization treatment, bacteria and microorganisms are killed, and the sterility of the injection is guaranteed; in addition, by using potassium aspartate and magnesium aspartate as main components, the finished injection has the advantages of obvious treatment effect, convenience in use and the like. Therefore, the method has good application value and popularization prospect.

Description

Technical Field

[0001] The present invention belongs to the field of pharmaceutical preparations, and particularly relates to the preparation of potassium magnesium aspartate preparations. Background Art

[0002] Potassium magnesium aspartate is a mixture of potassium aspartate and magnesium aspartate. Aspartic acid is a precursor of oxaloacetic acid in the body and plays an important role in the tricarboxylic acid cycle. Potassium magnesium aspartate also participates in the ornithine cycle, promotes the metabolism of ammonia and carbon dioxide, generates urea, and reduces the content of ammonia and carbon dioxide in the blood. Aspartic acid has a strong affinity for cells and can serve as a carrier for potassium ions, enabling potassium ions to enter cells, promoting cell depolarization and cell metabolism, and maintaining their normal functions. Magnesium ions are essential substances for glycogen formation and high-energy phosphates, and can enhance the efficacy of potassium aspartate. Magnesium ions and potassium ions are important cations in cells, which play important roles in the functions of many enzymes, can bind macromolecules to subcellular structures, and are related to the mechanism of muscle contraction. The contractility of cardiomyocytes is affected by the concentration ratio of potassium, calcium, and sodium inside and outside the cells. Potassium magnesium aspartate can maintain myocardial contractility, improve myocardial contractile function, reduce oxygen consumption, promote fibrinolysis, and reduce blood viscosity.

[0003] Potassium magnesium aspartate is in the form of an injection, which is a commonly used pharmaceutical dosage form in clinical practice. Since it directly enters the human body, quality control of its preparation process is particularly important. How to ensure the stability of the injection during the preparation process and improve its therapeutic effect at the same time is an urgent problem to be solved. Summary of the Invention

[0004] The object of the present invention is to provide a method for preparing potassium magnesium aspartate injection to improve drug safety. The method includes the following steps:

[0005] (1) Dissolve potassium aspartate and magnesium aspartate in a solvent to form a drug solution;

[0006] (2) Filter the drug solution obtained in step (1) to remove impurities therein;

[0007] (3) Perform argon gas protection treatment on the filtered drug solution. By controlling the flow rate and pressure of argon gas, make argon gas fully contact with the drug solution to prevent drug oxidation and thermosensitive reactions from occurring;

[0008] (4) Fill and seal the drug solution treated with argon gas protection with argon gas and perform sterilization treatment;

[0009] (5) Sterilize by moist heat at 121 °C to obtain the finished injection.

[0010] According to one aspect of the present invention, the solvent in step (1) is water for injection.

[0011] According to one aspect of the present invention, in the above step (3), the flow rate of argon is controlled at 2 - 5 liters per minute, and the pressure is controlled at 0.2 - 0.5 MPa.

[0012] According to one aspect of the present invention, in the above step (5), the temperature for moist heat sterilization is 121 °C, the sterilization time is 12 min, and the F0 value is greater than or equal to 12.

[0013] According to one aspect of the present invention, the concentration of potassium aspartate in the above finished injection is 50 g / L, and the concentration of magnesium aspartate is 50 g / L.

[0014] According to one aspect of the present invention, the above method for preparing potassium magnesium aspartate injection may further include the following amounts of raw and auxiliary materials:

[0015] Potassium aspartate 50 g (calculated as anhydrous substance)

[0016] Magnesium aspartate 50 g (calculated as anhydrous substance)

[0017] Water for injection is added to 1000 ml

[0018] The preparation steps are as follows:

[0019] 1. Take 80% of the prescription volume of water for injection, add the prescribed amount of magnesium aspartate, and stir to dissolve;

[0020] 2. Add the prescribed amount of potassium aspartate and stir to dissolve;

[0021] 3. Add water for injection to make up the volume to the prescribed amount. Stir evenly;

[0022] 4. Filter using a 0.22 μm polyethersulfone membrane filter;

[0023] 5. Fill with argon and seal. Use 10 ml medium borosilicate glass ampoules, with a filling volume of 10 ml, and control the residual oxygen below 1.0%;

[0024] 6. Perform moist heat sterilization at a sterilization temperature of 121 °C and a sterilization time of 12 min.

[0025] 7. Conduct leak detection, lamp inspection, and packaging. Description of the Drawings

[0026] Figure 1 Chromatogram of related substances in Example 1 of the present invention;

[0027] Figure 2 Chromatogram of related substances in Example 2 of the present invention;

[0028] Figure 3 Chromatogram of related substances in Example 3 of the present invention;

[0029] Figure 4Relevant substance chromatogram in Example 4 of the present invention. Detailed implementation mode

[0030] Example 1

[0031] Take 80% of the prescription volume of water for injection, cool it to 30 - 40 °C, add 50 g of magnesium aspartate, stir at a speed of 300 rpm, and stir until dissolved. Add 50 g of potassium aspartate, stir at a speed of 300 rpm, and stir until dissolved. Add water for injection to make the volume up to 1000 ml, and stir evenly. Filter with a 0.22 μm polyethersulfone membrane filter. The filtration temperature is 20 - 40 °C. Use 10 ml medium borosilicate glass ampoules, with a filling volume of 10 ml, and seal with an OKFKJ - 300 oxyhydrogen flame sealing machine. Sterilize by moist heat, with a sterilization temperature of 121 °C and a sterilization time of 12 min. The relevant substance chromatogram of the finished product is as Figure 1 .

[0032] Example 2

[0033] Take 80% of the prescription volume of water for injection, cool it to 30 - 40 °C, add 50 g of magnesium aspartate, stir at a speed of 300 rpm, and stir until dissolved. Add 50 g of potassium aspartate, stir at a speed of 300 rpm, and stir until dissolved. Add water for injection to make the volume up to 1000 ml. Stir evenly. Filter with a 0.22 μm polyethersulfone membrane filter. The filtration temperature is 20 - 40 °C. Use 10 ml medium borosilicate glass ampoules, with a filling volume of 10 ml. Seal with an OKFKJ - 300 oxyhydrogen flame sealing machine. Seal with carbon dioxide filling, with a residual oxygen of 0.8%. Sterilize by moist heat, with a sterilization temperature of 121 °C and a sterilization time of 12 min. The relevant substance chromatogram of the finished product is as Figure 2 .

[0034] Example 3

[0035] Take 80% of the prescription volume of water for injection, cool it to 30 - 40 °C, add 50 g of magnesium aspartate, stir at a speed of 300 rpm, and stir until dissolved. Add 50 g of potassium aspartate, stir at a speed of 300 rpm, and stir until dissolved. Add water for injection to make the volume up to 1000 ml. Stir evenly. Filter with a 0.22 μm polyethersulfone membrane filter. The filtration temperature is 20 - 40 °C. Use 10 ml medium borosilicate glass ampoules, with a filling volume of 10 ml. Seal with an OKFKJ - 300 oxyhydrogen flame sealing machine. Seal with nitrogen filling, with a residual oxygen of 0.9%. Sterilize by moist heat, with a sterilization temperature of 121 °C and a sterilization time of 12 min. The relevant substance chromatogram of the finished product is as Figure 3 .

[0036] Example 4

[0037] Take 80% of the prescription volume of water for injection, cool it down to 30 - 40 °C, add 50 g of magnesium aspartate, stir at a speed of 300 rpm, and stir until dissolved. Add 50 g of potassium aspartate, stir at a speed of 300 rpm, and stir until dissolved. Add water for injection to make up to 1000 ml. Stir evenly. Filter using a 0.22 μm polyethersulfone filter membrane. The filtration temperature is 20 - 40 °C. 10 ml medium-borosilicate glass ampoules, with a filling volume of 10 ml. Seal using an OKFKJ-300 oxyhydrogen flame sealing machine. Fill with argon gas for sealing, with a residual oxygen of 0.9%. Sterilize by moist heat, with a sterilization temperature of 121 °C and a sterilization time of 12 min. The chromatogram of related substances of the finished product is as Figure 4 .

[0038] Sample batch number Sealing condition Residual oxygen Fumaric acid Maleic acid Malic acid Example 1 Without inert gas 20.5％ 10.543％ 0.832％ 0.129％ Example 2 Filled with carbon dioxide 0.8％ 13.607％ 1.046％ 0.136％ Example 3 Filled with nitrogen 0.9％ 4.141％ 0.274％ 0.151％ Example 4 Filled with argon 0.9％ 1.658％ 0.076％ 0.141％

[0039] (Note: The calculation of related substances is based on area normalization, not the actual content percentage)

[0040] The test results of related substances show that after sterilization of the product without inert gas passing, the fumaric acid reaches 10%, the maleic acid exceeds 0.8%, and the maleic acid exceeds the standard limit of 0.3%. After sterilization with carbon dioxide gas filling, the increase in related substances is more significant, the fumaric acid reaches 13%, and the maleic acid reaches 1.0%. It may be that carbon dioxide causes the pH of the solution to decrease, affecting stability. After sterilization with nitrogen gas filling, the fumaric acid is about 4% and the maleic acid is about 0.27%, slightly lower than the limit of 0.3%. For the sample sterilized with argon gas filling, the fumaric acid is 1.6% and the maleic acid is only 0.076%, and the stability is significantly improved.

[0041] The data of related substances of the sterilized samples show that after argon gas filling, the related substances of the sterilized samples are significantly reduced. Sealing with argon gas filling can significantly improve the sterilization stability of potassium magnesium aspartate injection.

[0042] In the present invention, by adding a step of argon gas filling protection during the preparation process, the occurrence of drug thermal sensitivity reaction is effectively prevented, and the stability and safety of the drug are improved; at the same time, through high-temperature sterilization treatment, bacteria and microorganisms are killed, ensuring the sterility of the injection; in addition, by using potassium aspartate and magnesium aspartate as the main components, the finished injection has the advantages of obvious therapeutic effect and convenient use. Therefore, the present invention has good application value and popularization prospect.

[0043] It should be noted that the above preferred embodiments are only used to illustrate the technical concept and characteristics of the present invention, and their purpose is to enable those skilled in the art to understand the content of the present invention and implement it accordingly, and cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit and essence of the present invention should be covered within the protection scope of the present invention.

Claims

1. A preparation method of potassium magnesium aspartate injection for improving drug safety, characterized in that, The method includes the following steps: (1) Potassium aspartate, magnesium aspartate are dissolved in a solvent to form a drug solution; (2) The drug solution obtained in step (1) is filtered to remove impurities therein; (3) The filtered drug solution is subjected to argon gas protection treatment. By controlling the flow rate and pressure of argon gas, the argon gas is made to fully contact with the drug solution to prevent drug oxidation and thermosensitive reaction from occurring; (4) The drug solution treated with argon gas protection is filled and sealed with argon gas and then sterilized; (5) Sterilized by moist heat at 121 °C to obtain the finished injection.

2. The preparation method of potassium magnesium aspartate injection according to claim 1, wherein, The solvent described in step (1) is water for injection.

3. The preparation method of potassium magnesium aspartate injection according to claim 2, characterized in that, In step (3), the flow rate of the argon gas is controlled at 2 - 5 L / min, and the pressure is controlled at 0.2 - 0.5 MPa.

4. The preparation method of potassium magnesium aspartate injection according to claim 3, characterized in that, In step (5), the moist heat sterilization temperature is 121 °C, the sterilization time is 12 min, and the F0 value is greater than or equal to 12.

5. The preparation method of potassium magnesium aspartate injection according to claim 4, characterized in that, In the finished injection described, the concentration of potassium aspartate is 50 g / L, and the concentration of magnesium aspartate is 50 g / L.

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