A medicinal injection and a preparation method thereof

Abstract

The application provides a preparation method of a medicinal injection, and the injection contains edaravone 2 mg / ml, dextrohydrotalcid 0.5 mg / ml, propylene glycol 0.08 ml / ml and sodium pyrosulfite 1.0 mg / ml. In the preparation process, the prescription amount of 60%-85% propylene glycol and the prescription amount of 5%-25% water are first injected into a preparation tank in a volume ratio, heated to 50-60 DEG C, and then edaravone is added and stirred to dissolve, and then dextrohydrotalcid dissolved in the remaining prescription amount of propylene glycol is added, and then water close to the constant volume is added, and then the temperature is reduced to below 25 DEG C, and then sodium pyrosulfite is added, and then the pH value is adjusted to 4.0-5.0, and then the constant volume is adjusted to the full amount. The preparation method of the edaravone dextrohydrotalcid injection solves the problem that the raw material is easily precipitated in the preparation process by matching the specific proportion of the auxiliary materials with the preparation steps, and the preparation process has low requirements on the industrialization preparation tank, is convenient for industrialization operation, and has low manufacturing cost.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a method for preparing edaravone dexborneol injection. Background Technology

[0002] Stroke has become a disease that poses a significant threat to human health. It can not only cause death but also lead to long-term disability and shorten life expectancy. Ischemic stroke is the most common type and a major cause of long-term disability. In particular, acute ischemic stroke is a significant factor contributing to death, disability, and shortened life expectancy worldwide, posing a particularly great threat to middle-aged and elderly people.

[0003] Edaravone and dexborneol injection, developed by Simcere Pharmaceutical and approved for marketing in 2020, has become an innovative drug for the treatment of stroke globally. It contains two active ingredients, edaravone and dexborneol, and is indicated for improving neurological deficits and daily living ability impairments caused by acute ischemic stroke. Clinical trials have shown that it can extend the stroke treatment window to 48 hours after onset and significantly improve patients' neurological function recovery.

[0004] Edaravone and dexborneol, when prepared as an injection, are suitable for emergency treatment. However, their active ingredients have poor water solubility. Edaravone is very slightly soluble or almost insoluble in water, while dexborneol is almost insoluble and has a low melting point and is volatile. Edaravone and dexborneol injections are concentrated solutions, with edaravone at a concentration of 2 mg / ml and dexborneol at 0.5 mg / ml. Preparing an aqueous solution for such poorly water-soluble active ingredients presents a challenge. Although the excipient propylene glycol improves solubility to some extent, numerous problems still exist in the preparation process.

[0005] CN116472035A discloses a pharmaceutical composition of edaravone and dextroborneol, and describes a preparation method as follows: propylene glycol is heated to 50-60°C, edaravone is added, and the mixture is stirred until completely dissolved to obtain a pharmaceutical solution. The solution is then cooled to below 25°C, and dextroborneol is added and stirred until completely dissolved. While stirring, sodium metabisulfite solution is slowly added to the solution, and water is continued to be slowly added until the volume is close to the prescription amount. However, this preparation method is prone to the problem of active pharmaceutical ingredient precipitation during actual operation. Furthermore, in this patent, propylene glycol accounts for approximately 8% of the prescription amount, and the initial stirring volume for directly dissolving edaravone in propylene glycol is extremely low. The minimum stirring volume in typical production mixing tanks is approximately 10%~15%, posing a challenge to scale-up production stirring.

[0006] CN119770422A discloses a process for preparing edaravone dexborneol solution. The process involves dissolving edaravone in a heated organic solvent (propylene glycol, polyethylene glycol, ethanol), cooling the solution to no higher than 30°C, adding dexborneol to dissolve the edaravone, and then adding water and an antioxidant to the solution for further mixing. However, in practice, the addition of water and an antioxidant during mixing can easily lead to the precipitation of the active pharmaceutical ingredient. Summary of the Invention

[0007] In view of the above-mentioned shortcomings in the prior art, the main objective of the present invention is to provide a method for preparing edaravone dexborneol injection, which solves the problem of easy precipitation of raw materials during the preparation process by combining excipients in a specific ratio with the preparation steps. Furthermore, the preparation process has low requirements for industrial-scale dispensing tanks, is convenient for industrial-scale operation, and has low manufacturing costs.

[0008] The present invention discloses a method for preparing edaravone dexborneol injection, wherein the injection comprises edaravone, dexborneol, propylene glycol, and sodium metabisulfite. In the preparation process, 60%-85% of the prescribed amount of propylene glycol and 5%-25% of the prescribed amount of water are first injected into a mixing tank by volume ratio. The mixture is heated to 50-60°C, edaravone is added and stirred until dissolved, then dexborneol, previously dissolved in the remaining prescribed amount of propylene glycol, is added. After stirring evenly, water is added to near the fixed volume. The mixture is then cooled to below 25°C, sodium metabisulfite is added, the pH is adjusted to 4.0-5.0, and the volume is brought to the final volume. During the preparation process, no precipitation occurs in the edaravone dexborneol injection.

[0009] In a preferred embodiment of the present invention, the edaravone-dexborneol injection has an edaravone concentration of 1.0-3.0 mg / ml, a dexborneol concentration of 0.1-1.0 mg / ml, a sodium metabisulfite concentration of 0.5-1.5 mg / ml, and a propylene glycol concentration of 0.05-0.10 ml / ml; preferably, the concentrations are edaravone 2 mg / ml, dexborneol 0.5 mg / ml, propylene glycol 0.08 ml / ml, and sodium metabisulfite 1.0 mg / ml.

[0010] In the preferred embodiment of the present invention, the preparation method includes the following steps:

[0011] (1) Pour 60%-85% of the prescribed amount of propylene glycol and 5%-25% of the prescribed amount of water into a mixing tank and heat to 50-60℃;

[0012] (2) Keep the temperature at 50-60℃, add edaravone and stir to dissolve and mix evenly;

[0013] (3) Cool the solution from step (2) to 40-50°C, add dextromethorphanol that has been dissolved in the remaining amount of propylene glycol in the prescription, and stir until dissolved and mixed evenly;

[0014] (4) Add water to a volume close to the set volume, the water being preheated to 35-45°C;

[0015] (5) Cool down to below 25°C, add sodium metabisulfite and mix it evenly, adjust the pH value to 4.0-5.0, and make up to the full volume.

[0016] Preferably, the preparation process is operated under an inert gas atmosphere, and further, an inert gas is introduced before the operation of step (1). In some embodiments, the inert gas is nitrogen. Further, during the preparation process, the dissolved oxygen of the drug solution is ≤2 mg / L and the headspace residual oxygen is ≤2%.

[0017] Preferably, in step (1), the volume of the solution is ≥ 10% of the volume of the mixing tank.

[0018] Preferably, in step (5), hydrochloric acid and / or sodium hydroxide are used to adjust the pH value.

[0019] Preferably, the preparation method further includes step (6): filtering the drug solution from step (5), filling it with nitrogen, and sterilizing it. In some specific embodiments, the filtration in step (6) is carried out using 0.45μm and 0.22μm filter cartridges in sequence. The sterilization method includes, but is not limited to, autoclaving, flowing steam sterilization, boiling sterilization, filtration sterilization, and gas sterilization. In some specific embodiments, the sterilization process is autoclaving, and the sterilization parameters are 121±5℃ and 10±5min.

[0020] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0021] 1. By using specific proportions of excipients in different steps, this invention can control the precipitation of poorly water-soluble active pharmaceutical ingredients edaravone and dexborneol during the preparation process, thus maintaining the stability of the drug solution. Furthermore, the preparation method is compatible with commonly used industrial dispensing tanks, is easy to operate, and is particularly suitable for large-scale industrial production.

[0022] 2. This invention further optimizes the solution temperature for adding dexborneol, thereby preventing the precipitation of edaravone and dexborneol during the preparation process and avoiding the loss of low-melting-point dexborneol through volatilization, thus ensuring the stability of the dexborneol content.

[0023] 3. The present invention further optimizes the temperature at which the remaining water is added, thereby reducing the operation time while controlling the precipitation of edaravone and dexborneol during the preparation process. Detailed Implementation

[0024] The present invention is further illustrated below by way of embodiments, but these embodiments are not intended to limit the invention to the scope of the embodiments described. All other embodiments obtained by those skilled in the art based on the embodiments of this application without inventive effort are within the scope of protection of this application.

[0025] Unless otherwise stated, all other reagents and raw materials used in this invention are commercially available.

[0026] For methods of determining edaravone content and related substances, refer to CN116472035A.

[0027] The methods for determining the content of dextromethorphanol and related substances are based on the 2025 edition of the Chinese Pharmacopoeia and related records.

[0028] The following comparative examples and embodiments were prepared according to the following formulation table 1.

[0029] Table 1 Prescription Table

[0030]

[0031] Comparative Example 1

[0032] (1) In an inert gas atmosphere, inject 90% of the prescribed amount of propylene glycol into the mixing tank, heat the propylene glycol to 60°C, add edaravone into the mixing tank, and stir to dissolve it completely.

[0033] (2) Add propylene glycol to the remaining amount in the clean container, and add dextromethorphan while stirring until completely dissolved;

[0034] (3) Cool the solution in the mixing tank to 50°C, add the dextromethorphan solution to the mixing tank, and stir to make the solution uniform;

[0035] (4) While maintaining stirring, slowly add water for injection to the mixing tank until it is close to the fixed volume, and stir to mix it evenly.

[0036] (5) Cool the solution to below 25°C, add the prescribed amount of sodium metabisulfite and stir until completely dissolved; adjust the pH of the solution to 4.0-5.0 with hydrochloric acid and / or sodium hydroxide, and bring the volume to the maximum.

[0037] (6) Use 0.45μm and 0.22μm filter elements for nitrogen pressurization filtration, nitrogen filling and sealing, and sterilization.

[0038] Comparative Example 2

[0039] (1) In an inert gas atmosphere, inject the prescribed amount of propylene glycol into the mixing tank, heat the propylene glycol to 60°C, add edaravone into the mixing tank, and stir to dissolve it completely.

[0040] (2) Cool down to 30°C, add dextromethorphan while stirring, and stir until completely dissolved;

[0041] (3) While maintaining stirring, slowly add water for injection to the mixing tank until it is close to the fixed volume, and stir to make it evenly mixed;

[0042] (4) Add the prescribed amount of sodium metabisulfite and stir until completely dissolved; adjust the pH of the solution to 4.0-5.0 using hydrochloric acid and / or sodium hydroxide, and bring the volume to the final volume;

[0043] (5) Use 0.45μm and 0.22μm filter elements for nitrogen pressurization filtration, nitrogen filling and sealing, and sterilization.

[0044] Comparative Example 3

[0045] The preparation method is basically the same as in Example 1, except that the solution in the mixing tank is cooled to 30°C before the dextromethorphan solution is added to the mixing tank.

[0046] Comparative Example 4

[0047] The preparation method is basically the same as in Example 1, except that the temperature of the mixing tank is maintained at 70°C, edaravone is added to the mixing tank and stirred to dissolve it completely; the solution in the mixing tank is cooled to 60°C, dextromethorphan solution is added to the mixing tank and stirred to make the drug solution uniform.

[0048] Evaluation of the compatibility between the preparation process of Example 1 and commercially available production-type liquid preparation tanks

[0049] Based on the volume of commercially available dispensing tanks, i.e. the maximum production batch, it is difficult to find a suitable dispensing tank for the initial dispensing volume prepared according to the reference formulation. Even if the tank is full for production, it will no longer meet the requirements after reducing the batch size, indicating poor compatibility.

[0050] Table 2. Compatibility Assessment of Preparation Process with Commercially Available Production-Type Dispensing Tanks

[0051]

[0052] Example 1

[0053] (1) In an inert gas atmosphere, inject 75% of the prescribed amount of propylene glycol and 25% of the prescribed amount (calculated according to the fixed volume) of water for injection into the mixing tank, mix them evenly and heat to 60°C;

[0054] (2) Keep the solution temperature in the mixing tank at 60°C, add edaravone into the mixing tank, and stir to dissolve it completely;

[0055] (3) Cool the solution from step (2) to 50°C, add dextromethorphanol that has been dissolved in the remaining amount of propylene glycol in the prescription, and stir until dissolved;

[0056] (4) While maintaining stirring, add water to the mixing tank until it is close to the fixed volume (water temperature 35-45℃), and stir to make it evenly mixed;

[0057] (5) Cool down to below 25°C, add sodium metabisulfite and stir until completely dissolved, then add hydrochloric acid and / or sodium hydroxide to adjust the pH of the solution to 4.0-5.0, and bring the volume to the total volume;

[0058] (6) Use 0.45μm and 0.22μm filter elements for nitrogen pressurization filtration, nitrogen filling and sealing, and sterilization.

[0059] The dissolved oxygen in the solution during the entire preparation process is ≤2 mg / L, and the residual oxygen in the headspace during the filling process is ≤2%.

[0060] Example 2

[0061] The preparation method is basically the same as in Example 1, except that in step (1), 85% of the prescribed amount of propylene glycol and 15% of the prescribed amount of water for injection are added to the solution preparation vessel, the dissolution temperature of edaravone is 50°C, and the temperature of the drug solution when dexborneol is added in step (3) is 40°C.

[0062] Example 3

[0063] The preparation method is basically the same as in Example 1, except that step (1) is to add 60% of the prescribed amount of propylene glycol and 8% of the prescribed amount of water for injection to the mixing tank.

[0064] Test Example 1

[0065] The preparation methods of the comparative examples and embodiments described above were followed, and the preparation process data are as follows:

[0066] Table 3 Preparation process data

[0067]

[0068] Test Example 2

[0069] The samples prepared in the comparative examples and the embodiments described above were measured, and the results are as follows:

[0070] Table 4 Sample Measurement Results

[0071]

Claims

1. A method for preparing a pharmaceutical injection solution, characterized by, The medicine injection solution comprises edaravone 2mg / ml, dextrohydrotalcid 0.5mg / ml, propylene glycol 0.08ml / ml, sodium pyrosulfite 1.0mg / ml, and the preparation method comprises the following steps: (1) inject prescription amount of 60%-85% propylene glycol and prescription amount of 5%-25% water into a solution tank to obtain a solution, and heat to 50-60℃; (2) keep the temperature at 50-60℃, add edaravone and stir to dissolve and mix uniformly; (3) cool the solution in step (2) to 40-50℃, add dextrohydrotalcid which is previously dissolved in the remaining prescription amount of propylene glycol, and stir to dissolve and mix uniformly; (4) add water close to the constant volume, and the water is preheated to 35-45℃; (5) cool to below 25℃, add sodium pyrosulfite and mix uniformly, adjust the pH value to 4.0-5.0, and make up to the full amount.

2. The production method according to claim 1, characterized by, The preparation process is operated in an inert gas atmosphere.

3. The preparation method according to claim 2, characterized in that, The preparation method is pre-filled with inert gas before step (1) is operated.

4. The production method according to claim 3, characterized by, In the preparation process, the dissolved oxygen of the solution is ≤2mg / L and the headspace residual oxygen is ≤2%.

5. The method of any one of claims 2-4, wherein, In step (1), the volume of the solution is ≥10% of the volume of the solution tank.

6. The method of claim 1, wherein, In step (5), hydrochloric acid and / or sodium hydroxide is used to adjust the pH value.

7. The method of any one of claims 2-4, wherein, The preparation method further comprises step (6): filter the solution in step (5), fill with nitrogen, seal, and sterilize.

8. The preparation method according to claim 7, characterized in that, The filtration in step (6) is sequentially filtered by 0.45μm and 0.22μm filter cartridges.

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