Norepinephrine bitartrate injection and preparation method thereof

Abstract

The invention belongs to the field of pharmaceutical preparations, and particularly relates to a norepinephrine bitartrate injection and a preparation method thereof, the injection comprises the following components: norepinephrine bitartrate, an amino acid antioxidant, N-(2-ethoxyl)-ethylenediamine triacetic acid trisodium salt, sodium chloride and the balance of water for injection, the technical problems that in the prior art, the content of norepinephrine bitartrate S-isomer impurities is high, and the content of sulfonated substance impurities caused by a sodium pyrosulfite antioxidant is high are solved. According to the present invention, the technical effect of simultaneous control of the norepinephrine bitartrate S-isomerous impurities, the oxide impurities and the sulfonate impurities in the norepinephrine bitartrate injection is achieved, the allergy risk caused by the use of sodium pyrosulfite is avoided, and the medication safety is increased.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceuticals, and in particular to a norepinephrine bitartrate injection and a preparation method thereof. Background Art

[0002] Norepinephrine bitartrate injection is used to treat hypotension caused by acute myocardial infarction, extracorporeal circulation, etc.; for shock, hypotension caused by insufficient blood volume, or hypotension after pheochromocytoma resection, this product is used as an auxiliary treatment to supplement blood volume during emergency treatment to restore blood pressure and temporarily maintain brain and coronary artery perfusion until the blood volume supplementation therapy takes effect; it can also be used for hypotension during intrathecal blockade and blood pressure maintenance after cardiac arrest resuscitation.

[0003] Norepinephrine bitartrate has isomerism, and the R configuration has pharmaceutical activity. Its chemical name is (R)-4-(2-amino-1-hydroxyethyl)-1,2-benzenediol bitartrate monohydrate, and its structure is shown in the following formula: .

[0004] The S-isomer of norepinephrine bitartrate has no pharmaceutical activity. If its content is not controlled, it will affect the final quality of the product and reduce the pharmacological activity of the product. Therefore, the S-isomer is usually controlled as an impurity in norepinephrine bitartrate injection.

[0005] In addition, norepinephrine bitartrate is easily oxidized, especially in the presence of oxygen. In the prior art, most norepinephrine bitartrate injections are packaged in glass ampoules, but glass ampoules produce glass chips when used, which endangers the health of patients. When packaged in vials, the residual oxygen in the product cannot be controlled, and oxidative impurities such as norepinephrine bitartrate will be produced, causing the color of the preparation to darken. In addition, light, heat, metal ions, etc. can all promote its oxidative degradation and produce oxidative impurities.

[0006] Hospira's norepinephrine bitartrate injection LEVOPHED uses sodium metabisulfite as an antioxidant, and the prescription is: norepinephrine bitartrate, sodium metabisulfite, sodium chloride, and the balance of water for injection; the injection has a pH value of 3.1 to 5.0, and is packaged in ampoules filled with nitrogen. The LEVOPHED package insert carries a warning label stating that sodium metabisulfite may cause allergic reactions, including anaphylactic shock and life-threatening or less severe asthma attacks. At the same time, the addition of sodium metabisulfite will also produce norepinephrine bitartrate sulfonate, i.e., sulfonate impurities. Therefore, sodium metabisulfite as an antioxidant will bring about drug safety issues.

[0007] CN102335123A, CN109394683A and CN115105466A still use sodium pyrosulfite as an antioxidant, but the preparation process and the amount of sodium pyrosulfite are adjusted, and sulfonated impurities are still produced in the injection. CN118217270A uses sodium formaldehyde sulfoxylate as an antioxidant, and the content of sulfonated impurities is lower than that using sodium pyrosulfite as an antioxidant, but a certain amount of sulfonated impurities still exist.

[0008] CN116327697A provides a norepinephrine bitartrate injection that can effectively control norepinephrine sulfonate and product color and its preparation method, comprising norepinephrine bitartrate as an active ingredient and disodium edetate, L-cysteine, sodium chloride, hydrochloric acid and water as auxiliary materials, which can effectively control norepinephrine sulfonate impurities and other oxidative impurities and product color. CN 118490634 A provides a stable norepinephrine bitartrate injection, characterized in that it is composed of the following raw materials in mass percentage: 0.2% norepinephrine bitartrate, 0.8% sodium chloride, 0.05-0.1% antioxidant and the balance water; wherein the antioxidant is vitamin C and sodium L-cysteine ​​hydrochloride. The use of sodium L-cysteine ​​hydrochloride and vitamin C as antioxidants instead of sodium pyrosulfite can effectively reduce the content of related impurities, inhibit the degradation of norepinephrine bitartrate, and also avoid the generation of sulfonated impurities. No metal ion chelating agent such as disodium edetate is added separately. The synergistic effect of sodium L-cysteine ​​hydrochloride and vitamin C is used to ensure that the preparation has good stability.

[0009] In summary, the prior art has not paid attention to the technical problem of controlling the content of the S-isomer of norepinephrine bitartrate in norepinephrine bitartrate injection. Summary of the invention

[0010] The first object of the present invention is to provide a sodium pyrosulfite-free noradrenaline bitartrate injection. The present invention can reduce the content of oxide impurities, sulfonate impurities and S-isomer impurities in the prior art noradrenaline bitartrate injection, avoid color changes in the preparation, and increase the stability of the preparation. It can also reduce the potential allergic risk caused by the use of sodium pyrosulfite and increase the safety of medication.

[0011] Another object of the present invention is to provide a method for preparing the above injection.

[0012] Another object of the present invention is to provide an application of a metal ion chelator in controlling the impurity content of the S-isomer of norepinephrine bitartrate in norepinephrine bitartrate injection. Preferably, the metal ion chelator is trisodium salt of N-(2-hydroxyethyl)-ethylenediaminetriacetic acid. More preferably, the content of trisodium salt of N-(2-hydroxyethyl)-ethylenediaminetriacetic acid is 0.01-0.15%.

[0013] The invention provides a norepinephrine bitartrate injection, comprising the following components: norepinephrine bitartrate, an amino acid antioxidant, N-(2-hydroxyethyl)-ethylenediaminetriacetic acid trisodium salt, sodium chloride and water for injection; the pH value of the injection is 3.0-5.0.

[0014] The invention provides a norepinephrine bitartrate injection, which comprises the following components in percentage by mass: 0.2-0.3% of norepinephrine bitartrate, 0.01-0.15% of an amino acid antioxidant, 0.01-0.15% of trisodium N-(2-hydroxyethyl)-ethylenediaminetriacetic acid, 0.7-0.9% of sodium chloride and water for injection, wherein the pH value of the injection is 3.0-5.0.

[0015] The invention provides a norepinephrine bitartrate injection, which is composed of the following components in percentage by mass: 0.2-0.3% of norepinephrine bitartrate, 0.01-0.15% of an amino acid antioxidant, 0.01-0.15% of trisodium N-(2-hydroxyethyl)-ethylenediaminetriacetic acid, 0.7-0.9% of sodium chloride and the balance of water for injection, and the pH value of the injection is 3.0-5.0.

[0016] Preferably, the amount of amino acid antioxidant is 0.025-0.1%, and the amount of N-(2-hydroxyethyl)-ethylenediaminetriacetic acid trisodium salt is 0.025-0.1%. More preferably, the amount of amino acid antioxidant is 0.05%, and the amount of N-(2-hydroxyethyl)-ethylenediaminetriacetic acid trisodium salt is 0.05%.

[0017] Preferably, in the norepinephrine bitartrate injection, the amino acid antioxidant and N-(2-hydroxyethyl)-ethylenediaminetriacetic acid trisodium salt are used in a ratio of 1:1.

[0018] Preferably, the norepinephrine bitartrate injection is composed of the following components in mass percentage: 0.2-0.3% norepinephrine bitartrate, 0.025-0.1% amino acid antioxidant, 0.025-0.1% N-(2-hydroxyethyl)-ethylenediaminetriacetic acid trisodium salt, 0.7-0.9% sodium chloride and the balance water for injection; the pH value of the injection is 3.0-5.0.

[0019] More preferably, the norepinephrine bitartrate injection is composed of the following components in percentage by mass: 0.2% norepinephrine bitartrate, 0.05% amino acid antioxidant, 0.05% N-(2-hydroxyethyl)-ethylenediaminetriacetic acid trisodium salt, 0.8% sodium chloride, and the balance water for injection; the pH value of the injection is 3.0-5.0.

[0020] More preferably, the norepinephrine bitartrate injection contains 8 mg of norepinephrine bitartrate, 2 mg of amino acid antioxidant, 2 mg of N-(2-hydroxyethyl)-ethylenediaminetriacetic acid trisodium salt and 32 mg of sodium chloride in 4 mL of aqueous solution; the pH value of the injection is 3.0-5.0.

[0021] Preferably, the amino acid antioxidant is selected from one or more of glycine, cysteine, phenylalanine, methionine, arginine and leucine. More preferably, the amino acid antioxidant is glycine.

[0022] The present invention provides a method for preparing norepinephrine bitartrate injection, comprising the following steps: (1) Liquid preparation: Add cooled water for injection into a container, fill with nitrogen, add norepinephrine bitartrate, amino acid antioxidant, N-(2-hydroxyethyl)-ethylenediaminetriacetic acid trisodium salt and sodium chloride into the water for injection, stir until dissolved, and make up to volume with water for injection; (2) Filling and sterilization: Filter the solution prepared in step (1), then fill it into a vial, fill it with nitrogen, and sterilize it at 121° C. for 15 min.

[0023] The invention solves the technical problems in the prior art that the impurity content of the S-isomer of norepinephrine bitartrate in the norepinephrine bitartrate injection is high, the impurity content of the sulfonate brought by the sodium pyrosulfite antioxidant is high, and the like, and achieves the technical effect of simultaneously controlling the impurities of the S-isomer of norepinephrine bitartrate, oxide impurities and sulfonate impurities in the norepinephrine bitartrate injection, avoiding the allergic risk brought by the use of sodium pyrosulfite, and increasing the safety of medication.

[0024] The beneficial effects of the present invention are as follows: (1) The present invention achieves effective control of the impurity content of the S-isomer of norepinephrine bitartrate by adding trisodium salt of N-(2-hydroxyethyl)-ethylenediaminetriacetic acid to the norepinephrine bitartrate injection. (2) The present invention adopts amino acids as antioxidants, avoids the use of sodium pyrosulfite as an antioxidant to produce norepinephrine bitartrate sulfonate impurities, and achieves excellent antioxidant effect. DETAILED DESCRIPTION

[0025] The present invention is described in detail below in conjunction with embodiments, which are intended to explain rather than limit the technical solutions of the present invention.

[0026] The test materials and instruments used in the present invention are shown in Tables 1 to 3.

[0027] Table 1 Raw materials and auxiliary materials.

[0028]

[0029] Table 2 Vial packaging materials.

[0030]

[0031] Table 3 Test instruments.

[0032]

[0033] Investigation of the sensitivity of I to metal ions.

[0034] During the preparation process, the norepinephrine bitartrate injection will come into contact with metal equipment and will be affected by metal ions. Therefore, the present invention investigates the sensitivity of the injection to metal ions. The prescriptions of Investigation Examples 1 to 5 are shown in Table 4 below.

[0035] Table 4 Prescriptions for Investigation Examples 1 to 5.

[0036]

[0037] The preparation methods of Investigation Examples 1 to 5 are as follows: (1) Preparation: Add 3 mL of cooled water for injection into a container and fill it with nitrogen. Weigh each component according to the prescription amount in Table 4 and add it to the water for injection, stir until dissolved, and then make up to 4 mL with water for injection. Iron ions are provided by ferric chloride solution, aluminum ions are provided by aluminum chloride solution, magnesium ions are provided by magnesium chloride solution, and barium ions are provided by barium chloride solution; (2) Filling and sterilization: Filter the solution prepared in step (1), then fill it into a vial, fill it with nitrogen, and sterilize it at 121° C. for 15 min.

[0038] The samples were placed at a high temperature of 60°C and a light intensity of 4500±500lx for 10 days and then tested after 30 days. The contents of norepinephrine bitartrate and norepinephrine bitartrate S-isomer (hereinafter referred to as S-isomer) are shown in Table 5.

[0039] Table 5 Contents of norepinephrine bitartrate and S-isomer (%).

[0040]

[0041] Iron ions and aluminum ions have a significant effect on the S-isomer content, especially aluminum ions, which have a greater effect on the S-isomer content, while magnesium ions and barium ions have a smaller effect on the S-isomer content. At the same time, high temperature will increase the S-isomer impurity content.

[0042] II. Effect of metal ion chelators on the S-isomer content in formulations.

[0043] In order to reduce the influence of metal ions on the quality of norepinephrine bitartrate injection and control the content of S-isomer in the finished product, the present invention investigates the influence of different metal ion chelators on the content of S-isomer in the preparation.

[0044] The prescriptions of Example 1 and Comparative Examples 1-6 are shown in Table 6.

[0045] Table 6 Prescriptions of Example 1 and Comparative Examples 1 to 6.

[0046]

[0047] The preparation methods of Example 1 and Comparative Examples 1 to 6 are as follows: (1) Preparation: Add 3 mL of cooled water for injection into a container and fill it with nitrogen. Weigh each component according to the prescription amount in Table 6 and add it to the water for injection, stir until dissolved, and then make up to 4 mL with water for injection; (2) Filling and sterilization: Filter the solution prepared in step (1), then fill it into a vial, fill it with nitrogen, and sterilize it at 121° C. for 15 min.

[0048] The pH value of the product prepared above was tested, as shown in Table 7. The samples were placed under high temperature of 60°C and light of 4500±500lx for 10 days and 30 days, and then the samples were tested. The contents of norepinephrine bitartrate and S-isomer are shown in Table 7.

[0049] Table 7 Contents of norepinephrine bitartrate and S-isomer (%).

[0050]

[0051] As can be seen from the above table, chelating agents such as N-(2-hydroxyethyl)-ethylenediaminetriacetic acid trisodium salt, EDTA·2Na, EDTA·2Na·Ca, sodium citrate, sodium tartrate, boric acid and gallic acid can reduce the content of norepinephrine bitartrate S-isomer in the preparation, especially N-(2-hydroxyethyl)-ethylenediaminetriacetic acid trisodium salt can significantly reduce the content of S-isomer.

[0052] The present invention investigates the influence of the content of trisodium salt of N-(2-hydroxyethyl)-ethylenediaminetriacetic acid on the content of S-isomer in the preparation.

[0053] The prescriptions of Examples 2 to 7 are shown in Table 8, and the preparation methods are the same as those of Example 1.

[0054] Table 8 Prescriptions for Examples 2 to 7.

[0055]

[0056] The pH value of the product prepared above was tested, as shown in Table 9. The samples were placed under high temperature of 60°C and light of 4500±500lx for 10 days and 30 days, and then the samples were tested. The contents of norepinephrine bitartrate and S-isomer are shown in Table 9.

[0057] Table 9 Contents of norepinephrine bitartrate and S-isomer (%).

[0058]

[0059] As can be seen from the above table, when the content of trisodium salt of N-(2-hydroxyethyl)-ethylenediaminetriacetic acid is 0.01-0.15% (Example 1, Example 3, Example 4, Example 5, Example 6), there is a significant inhibitory effect on the production of S-isomers, and Examples 2 and 7 have a certain inhibitory effect on the production of S-isomers.

[0060] Investigation on the content of oxidized impurities and sulfonated impurities in III injection.

[0061] Norepinephrine bitartrate is easily oxidized to produce oxidative impurities, but the sodium pyrosulfite used in the prior art reacts with norepinephrine bitartrate to produce sulfonated impurities, which can cause allergic reactions. After analysis, it was found that the cause of the generation of sulfonated impurities is that norepinephrine bitartrate reacts with antioxidants with sulfonate groups. Therefore, in order to avoid sulfonated impurities and provide drug safety, the present invention investigates the antioxidant effect of amino acid antioxidants.

[0062] The prescriptions of Example 1, Example 8-Example 12 and Comparative Example 7 are shown in Table 10, and the preparation method is the same as that of Example 1.

[0063] Table 10 Prescriptions of Example 1, Examples 8-12 and Comparative Example 7.

[0064]

[0065] The pH value of the product prepared above was tested, as shown in Table 11. The prepared samples were placed at a high temperature of 60°C and a light of 4500±500lx for 10 days and 30 days, and then the samples were tested. The contents of related substances in the norepinephrine bitartrate injection of Example 1, Example 8-Example 12 and Comparative Example 7 are shown in Table 11.

[0066] Table 11 Contents of related substances in Example 1, Examples 8-12 and Comparative Example 7 (%)

[0067]

[0068] As can be seen from the above table, the use of amino acid antioxidants avoids the use of sodium metabisulfite in norepinephrine bitartrate injection, thereby avoiding the production of norepinephrine bitartrate sulfonate impurities and the allergic reactions that may be caused by sodium metabisulfite, and achieves better antioxidant effects and less total impurity content than using sodium metabisulfite as an antioxidant.

[0069] The present invention also investigates the influence of the content of amino acid antioxidant on the content of related substances in norepinephrine bitartrate injection.

[0070] The prescriptions of Examples 13 to 18 are shown in Table 12, and the preparation methods are the same as those of Example 1.

[0071] Table 12 Prescriptions for Examples 13 to 18.

[0072]

[0073] The pH value of the product prepared above was tested, as shown in Table 13. The prepared samples were placed at a high temperature of 60°C and a light of 4500±500lx for 10 days and 30 days, and then the samples were tested. The contents of related substances in Example 13-Example 18 Norepinephrine bitartrate injection are shown in Table 13.

[0074] Table 13 Contents of related substances in Examples 13 to 18 (%).

[0075]

[0076] It can be seen from the above table that when the content of amino acid antioxidant is 0.01-0.15% (Example 1, Example 14, Example 15, Example 16, Example 17), the oxidative impurity norepinephrine bitartrate injection and the total impurity content can be effectively reduced.

[0077] The embodiments described above are merely descriptions of preferred implementation modes of the present invention and are not intended to limit the scope of the present invention. Without departing from the design spirit of the present invention, various modifications and improvements made to the technical solutions of the present invention by ordinary technicians in this field should all fall within the protection scope determined by the claims of the present invention.

Claims

1. A norepinephrine bitartrate injection, characterized in that: The injection consists of the following components in percentage by mass: 0.2-0.3% of norepinephrine bitartrate, 0.01-0.15% of amino acid antioxidant, 0.01-0.15% of N-(2-hydroxyethyl)-ethylenediaminetriacetic acid trisodium salt, 0.7-0.9% of sodium chloride and the balance of water for injection, and the pH value of the injection is 3.0-5.

0.

2. The norepinephrine bitartrate injection according to claim 1, characterized in that: The dosage of the amino acid antioxidant is 0.025-0.1%, and the dosage of the trisodium salt of N-(2-hydroxyethyl)-ethylenediaminetriacetic acid is 0.025-0.1%.

3. The norepinephrine bitartrate injection according to claim 2, characterized in that: The dosage of the amino acid antioxidant is 0.05%, and the dosage of the trisodium salt of N-(2-hydroxyethyl)-ethylenediaminetriacetic acid is 0.05%.

4. The norepinephrine bitartrate injection according to any one of claims 1 to 3, characterized in that: The amino acid antioxidant and N-(2-hydroxyethyl)-ethylenediaminetriacetic acid trisodium salt are used in a ratio of 1:

1.

5. The norepinephrine bitartrate injection according to any one of claims 1 to 3, characterized in that: The amino acid antioxidant is selected from one or more of glycine, cysteine, phenylalanine, methionine, arginine and leucine.

6. The norepinephrine bitartrate injection according to any one of claims 1 to 3, wherein the amino acid antioxidant is glycine.

7. The norepinephrine bitartrate injection according to any one of claims 1 to 3, characterized in that: 4 mL of aqueous solution contains 8 mg of norepinephrine bitartrate, 2 mg of amino acid antioxidant, 2 mg of N-(2-hydroxyethyl)-ethylenediaminetriacetic acid trisodium salt and 32 mg of sodium chloride; the pH value of the injection is 3.0-5.

0.

8. The norepinephrine bitartrate injection according to any one of claims 1 to 3, characterized in that: Prepared by the following steps: (1) Liquid preparation: Add cooled water for injection into a container, fill with nitrogen, add norepinephrine bitartrate, amino acid antioxidant, N-(2-hydroxyethyl)-ethylenediaminetriacetic acid trisodium salt and sodium chloride into the water for injection, stir until dissolved, and then make up to volume with water for injection; (2) Filling and sterilization: Filter the solution prepared in step (1), then fill it into a vial, fill it with nitrogen, and sterilize it at 121° C. for 15 min.

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