Concentrated solution for edaravone dextroborneol injection and preparation method thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to a concentrated solution for injection of edaravone dextroborneol and a preparation method of the concentrated solution. According to the invention, the sulfonic acid antioxidant and the amino acid antioxidant are compounded and added into the edaravone dextroborneol injection solution, so that a synergistic effect is generated on inhibition of compound oxidative degradation of edaravone dextroborneol, and the prepared edaravone dextroborneol injection concentrated solution has high stability in accelerated and long-term stability tests; related substances grow slowly, the content of main components is not obviously reduced, the appearance of the solution is almost unchanged, and the validity period of the product is obviously prolonged. The preparation method provided by the invention is stable in process and easy for industrial production, and ensures the consistency of batch-to-batch quality through the combination of nitrogen charging protection and a specific antioxidant system.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical preparation technology, and in particular to a concentrated solution of edaravone dexborneol for injection and its preparation method. Background Technology

[0002] Ischemic stroke is one of the leading causes of disability and death worldwide. Edaravone is a free radical scavenger, and dextromethorphan has anti-inflammatory effects. The combination of these two drugs has shown synergistic neuroprotective effects in clinical practice and has become an important drug for the treatment of acute ischemic stroke.

[0003] However, the stability of this compound formulation has been a technical bottleneck restricting its product quality and shelf life. Both the pyrazolone ring and the dextroborneol structure in the edaravone molecule are highly sensitive to oxidation. In liquid formulations, especially in the presence of dissolved oxygen and trace metal ions, the active ingredient is prone to oxidative degradation, leading to increased levels of related substances (particularly oxidative degradation products), darker solution color, and decreased main component content. This not only affects efficacy but may also introduce unknown safety risks.

[0004] Existing technologies typically employ the addition of a single antioxidant to improve the stability of injectable solutions. For example, CN116472035B discloses an edaravone-dexborneol injection using sodium metabisulfite as an antioxidant. However, during research and development and long-term stability studies, the inventors discovered that for this specific compound system of edaravone and dexborneol, the traditional single antioxidant approach has limited effectiveness. Sulfite antioxidants may be completely consumed during long-term storage and are not effective in inhibiting oxidation reactions catalyzed by trace metal ions; while using metal ion chelating agents alone (such as disodium edetate) cannot effectively remove free oxygen and free radicals from the solution.

[0005] Therefore, there is an urgent need in this field to develop a stabilization technology that can effectively and synergistically inhibit the oxidative degradation of edaravone dexborneol in the long term, so as to improve the quality, safety and commercial value of this important drug. Summary of the Invention

[0006] The purpose of this invention is to overcome the shortcomings of the existing technology and provide a concentrated solution of edaravone dexborneol for injection with excellent stability.

[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows: In a first aspect, the present invention provides a concentrated solution of edaravone and dexborneol for injection, comprising the following components: edaravone, dexborneol, a complex antioxidant system, and a pharmaceutically acceptable solvent for injection; wherein the mass ratio of edaravone to dexborneol is edaravone:dexborneol = (1-5):1; and the complex antioxidant system comprises sulfonic acid antioxidants and amino acid antioxidants.

[0008] To address the critical stability challenge of edaravone-dexborneol combination formulations during storage due to easy oxidative degradation, this invention, through extensive research, discovered that adding sulfonic acid antioxidants and amino acid antioxidants to the edaravone-dexborneol injection solution can form an antioxidant stabilizing system. This system produces a synergistic effect of "1+1>2" in inhibiting the oxidative degradation of the edaravone-dexborneol combination, significantly improving the stability of the injection solution.

[0009] The edaravone dexborneol concentrated solution for injection prepared in this invention showed slow growth of related substances, no significant decrease in the content of the main component, and almost no change in the appearance of the solution in accelerated and long-term stability tests, and the product shelf life was significantly extended.

[0010] Preferably, the sulfonic acid antioxidant includes at least one of sodium metabisulfite, sodium bisulfite, sodium sulfite, sodium thiosulfate, and sodium formaldehyde sulfite.

[0011] More preferably, the sulfonic acid antioxidant is sodium bisulfite (NaHSO3).

[0012] Preferably, the amino acid antioxidant includes at least one of cysteine, cysteine ​​hydrochloride, methionine, glutamic acid, and aspartic acid.

[0013] More preferably, the amino acid antioxidant is cysteine ​​hydrochloride (L-Cys·HCl).

[0014] Preferably, the mass ratio of the sulfonic acid antioxidant to the amino acid antioxidant is sulfonic acid antioxidant : amino acid antioxidant = (1-10) : (1-10).

[0015] Preferably, the mass ratio of the sulfonic acid antioxidant to the amino acid antioxidant is sulfonic acid antioxidant : amino acid antioxidant = (1-5) : (1-5).

[0016] More preferably, the mass ratio of the sulfonic acid antioxidant to the amino acid antioxidant is sulfonic acid antioxidant: amino acid antioxidant = (1-2): (1-2).

[0017] Preferably, the composite antioxidant system accounts for 0.01%-0.5% of the total weight of the edaravone dexborneol concentrated solution for injection.

[0018] More preferably, the composite antioxidant system accounts for 0.05%-0.3% of the total weight of the edaravone dexborneol concentrated solution for injection.

[0019] Preferably, the edaravone dexborneol injection concentrate further comprises a metal ion chelating agent.

[0020] Chelating agents can complex trace metal ions that may be present in the solution. These ions are catalysts for oxidation reactions, thereby further improving the stability of the system.

[0021] Preferably, the metal ion chelating agent includes at least one of edetate, edetate salt, or their hydrates.

[0022] Preferably, the pH value of the concentrated edaravone dexborneol injection solution is 4.0-6.0. This pH range is beneficial to the co-stability of the active ingredient and the antioxidant system.

[0023] Preferably, the concentration of edaravone in the edaravone-dexborneol injection concentrate is 2 mg / mL, and the concentration of dexborneol is 0.5 mg / mL.

[0024] In a second aspect, the present invention provides a method for preparing the above-mentioned concentrated solution of edaravone dexborneol for injection, comprising the following steps: (1) under a nitrogen-protected environment, edaravone, dexborneol, and a complex antioxidant system are dissolved in a pharmaceutically acceptable injectable solvent, or edaravone, dexborneol, a complex antioxidant system, and a metal ion chelating agent are dissolved in a pharmaceutically acceptable injectable solvent. (2) Adjust the pH to 4-6, filter, and obtain the concentrated solution of edaravone dexborneol for injection.

[0025] This invention describes a method for preparing an injection solution by co-formulating the composite antioxidant stabilizing system with the active ingredients under nitrogen-protected conditions. This method minimizes the amount of oxygen introduced during production and works synergistically with the composite antioxidant to control oxidation at its source.

[0026] Preferably, nitrogen purging is implemented throughout the preparation process or in key steps to ensure that the dissolved oxygen content in the solution is below 2 ppm.

[0027] Thirdly, the present invention provides a pharmaceutical composition for treating ischemic stroke, comprising the above-mentioned concentrated solution of edaravone dexborneol for injection.

[0028] Preferably, the concentrated edaravone dexborneol injection solution is filled using ampoules, vials, or pre-filled syringes; the container is made of light-proof or amber-colored material.

[0029] The beneficial effects of this invention are as follows: This invention combines sulfonic acid antioxidants and amino acid antioxidants into the injection solution of edaravone dexborneol, resulting in a synergistic effect of "1+1>2" in inhibiting the oxidative degradation of edaravone dexborneol, and significantly improving its stability.

[0030] The edaravone dexborneol concentrated solution for injection prepared in this invention showed slow growth of related substances, no significant decrease in the content of the main component, and almost no change in the appearance of the solution in accelerated and long-term stability tests, and the product shelf life was significantly extended.

[0031] This invention can effectively control the content of specific unknown degradation products at extremely low levels, thereby improving product purity and medication safety, and resulting in better quality control.

[0032] The preparation method provided by this invention is stable and easy to industrialize. By combining nitrogen protection with a specific antioxidant system, batch-to-batch quality consistency is ensured. Attached Figure Description

[0033] Figure 1 The image shows a high-performance liquid chromatogram of edaravone-related substances in the edaravone dexborneol injection prepared in Example 1. Detailed Implementation

[0034] To better illustrate the purpose, technical solution, and advantages of this invention, the invention will be further described below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the invention and should not be construed as limiting the scope of protection of this invention. All technologies implemented based on the above content of this invention are covered within the scope of protection intended by this invention.

[0035] Unless otherwise specified, the experimental methods used in this invention are conventional methods, and the materials and reagents used are commercially available products that can be obtained through commercial channels.

[0036] Example 1: An embodiment of the edaravone dexborneol concentrated solution for injection of the present invention; the formulation of the edaravone dexborneol concentrated solution for injection is shown in Table 1.

[0037] Table 1 The preparation method of the edaravone dexborneol concentrated solution for injection includes the following steps: (1) Replace the air in the mixing tank with high-purity nitrogen to maintain a nitrogen protective atmosphere. Take about 800 mL of boiled and cooled water for injection, add cysteine ​​hydrochloride and sodium bisulfite, stir until completely dissolved to obtain a mixed solution; (2) Add edaravone and dexborneol to propylene glycol and stir until completely dissolved; then add the mixed solution, add water for injection to bring the total volume to 1000 mL, and slowly adjust the pH to 5.0±0.1 with 1 mol / L sodium hydroxide solution, stirring thoroughly until homogeneous; filter through a 0.22 μm microporous membrane; under nitrogen protection, fill the filtrate into 5 mL ampoules, and immediately seal with nitrogen. Perform sterilization and leak testing to obtain the concentrated edaravone and dexborneol injection solution.

[0038] Example 2: This invention provides an embodiment of the concentrated edaravone dexborneol injection solution. The only difference between this embodiment and Example 1 is that the dosage of the composite antioxidant system is adjusted: sodium bisulfite 0.25g and cysteine ​​hydrochloride 0.25g. The dosage and preparation method of the remaining components are the same as in Example 1.

[0039] Example 3: This invention provides an embodiment of the concentrated edaravone dexborneol injection solution. The only difference between this embodiment and Example 1 is that the dosage of the composite antioxidant system is adjusted: sodium bisulfite 0.25 g and cysteine ​​hydrochloride 2.5 g. The dosage and preparation method of the remaining components are the same as in Example 1.

[0040] Example 4: This invention provides an embodiment of the concentrated edaravone dexborneol injection solution. The only difference between this embodiment and Embodiment 1 is that the dosage of the composite antioxidant system is adjusted: sodium bisulfite 2.5g and cysteine ​​hydrochloride 2.5g. The dosage and preparation method of the remaining components are the same as in Embodiment 1.

[0041] Example 5: This invention provides an embodiment of the concentrated edaravone dexborneol injection solution. The only difference between this embodiment and Example 1 is that the dosage of the composite antioxidant system is adjusted: sodium bisulfite 0.25g and cysteine ​​hydrochloride 1.25g. The dosage and preparation method of the remaining components are the same as in Example 1.

[0042] Example 6: This invention provides an embodiment of the concentrated edaravone dexborneol injection solution. The only difference between this embodiment and Embodiment 1 is that the dosage of the composite antioxidant system is adjusted: sodium bisulfite 1.25g and cysteine ​​hydrochloride 0.25g. The dosage and preparation method of the remaining components are the same as in Embodiment 1.

[0043] Example 7: This invention provides an embodiment of the concentrated edaravone dexborneol injection solution. The only difference between this embodiment and Embodiment 1 is that the dosage of the composite antioxidant system is adjusted: sodium bisulfite 1.0g and cysteine ​​hydrochloride 0.5g. The dosage and preparation method of the remaining components are the same as in Embodiment 1.

[0044] Example 8: This invention provides an embodiment of the concentrated edaravone dexborneol injection solution. The only difference between this embodiment and Embodiment 1 is that the dosage of the composite antioxidant system is adjusted: sodium bisulfite 0.5g and cysteine ​​hydrochloride 1.0g. The dosage and preparation method of the remaining components are the same as in Embodiment 1.

[0045] Example 9: This invention provides an embodiment of the concentrated edaravone and dexborneol injection solution. The difference between this embodiment and Embodiment 7 is that the dosage of the main components is adjusted: edaravone 0.5g and dexborneol 0.5g. The dosage and preparation method of the other components are the same as in Embodiment 7.

[0046] Example 10: This invention provides an embodiment of the concentrated edaravone and dexborneol injection solution. The difference between this embodiment and Embodiment 7 is that the dosage of the main component system is adjusted: edaravone 2.5g and dexborneol 0.5g. The dosage and preparation method of the other components are the same as in Embodiment 7.

[0047] Example 11: This invention provides an embodiment of the concentrated edaravone dexborneol injection solution. The difference between this embodiment and Embodiment 1 is that the dosage of the complex antioxidant system was adjusted: sodium bisulfite 1.0 g, cysteine ​​hydrochloride 0.3 g, and the metal chelating agent disodium edetate 0.5 g was added. The dosages of the remaining components are the same as in Embodiment 1.

[0048] The preparation method of the concentrated edaravone dexborneol injection solution differs from that in Example 1 in that: in step (1), disodium edetate, cysteine ​​hydrochloride, and sodium bisulfite are added and stirred until completely dissolved to obtain a mixed solution. The rest is the same as in Example 1.

[0049] Comparative Example 1: This invention provides a comparative example of a concentrated solution of edaravone dexborneol for injection. The only difference between this comparative example and Example 7 is that sodium bisulfite and cysteine ​​hydrochloride are not added, while the amounts and preparation methods of the remaining components are the same as in Example 7.

[0050] Comparative Example 2: This invention provides a comparative example of a concentrated solution of edaravone dexborneol for injection. The only difference between this comparative example and Example 7 is that cysteine ​​hydrochloride is not added, while the amounts and preparation methods of the remaining components are the same as in Example 7.

[0051] Comparative Example 3: This invention provides a comparative example of a concentrated solution of edaravone dexborneol for injection. The only difference between this comparative example and Example 7 is that sodium bisulfite is not added, while the amounts and preparation methods of the remaining components are the same as in Example 7.

[0052] Comparative Example 4: This invention provides a comparative example of a concentrated solution of edaravone dexborneol for injection. The only difference between this comparative example and Example 7 is that the dosage of the composite antioxidant system was adjusted: sodium bisulfite 1.9g and cysteine ​​hydrochloride 0.1g. The dosage and preparation method of the remaining components are the same as in Example 7.

[0053] Comparative Example 5: This invention provides a comparative example of a concentrated edaravone and dexborneol injection solution. The only difference between this comparative example and Example 7 is that the amount of the main component system was adjusted: edaravone 4g and dexborneol 0.5g. The amounts and preparation methods of the other components are the same as in Example 7.

[0054] Comparative Example 6: This invention relates to a comparative example of a concentrated edaravone dexborneol injection solution; the comparative example is a commercially available concentrated edaravone dexborneol injection solution (manufacturer: Simcere Pharmaceutical Co., Ltd., batch number 181-240302).

[0055] Test example: The quality indicators in this test case include edaravone-related substances, content, and properties.

[0056] The detection method for edaravone-related substances in this test example is as follows: Determined according to the high performance liquid chromatography method (General Rule 0512).

[0057] Solvent: Methanol aqueous solution (methanol:water = 32:68).

[0058] Test solution: Accurately measure 5 mL of this product and place it in a 20 mL volumetric flask. Add solvent to dissolve and dilute to the mark, then shake well.

[0059] Control solution: Accurately measure 1 mL of the test solution and place it in a 100 mL volumetric flask. Dilute to the mark with solvent and shake well.

[0060] System suitability solution: Take appropriate amounts of edaravone and impurity X reference standard, dissolve and dilute them with solvent to prepare a mixed solution containing approximately 0.5 μg of each per 1 mL.

[0061] Sensitivity solution: Weigh an appropriate amount of edaravone reference standard accurately, dissolve and dilute it in solvent to prepare a solution containing approximately 0.15 μg per ml.

[0062] Chromatographic conditions: Octadecylsilane-bonded silica gel was used as the stationary phase (Agilent Eclipse plus C18, 4.6mm*150mm, 3.5μm or equivalent column); 0.5% triethylamine solution (adjusted to pH 6.3 with phosphoric acid) was used as mobile phase A, and methanol was used as mobile phase B.

[0063] Perform gradient elution according to the table below; flow rate is 1.0 mL per minute; column temperature is 30℃; detection wavelength is 248 nm; injection volume is 10 µL.

[0064] Table 2 System suitability requirements: In the sensitivity solution chromatogram, the signal-to-noise ratio of the edaravone peak should be greater than 10; the resolution between the impurity X peak and the edaravone peak should be not less than 1.5.

[0065] Limits: If there is a chromatographic peak in the chromatogram of the test solution with the same retention time as the impurity X peak, its peak area shall not be greater than the area of ​​the main peak of the control solution (0.1%), the area of ​​any other single impurity peak shall not be greater than 6 times (0.6%) the area of ​​the main peak of the control solution, and the sum of the areas of all impurity peaks shall not be greater than 12 times (1.2%) the area of ​​the main peak of the control solution.

[0066] Assay: Accurately measure the test solution and the control solution, inject them separately into the liquid chromatograph, and record the chromatograms.

[0067] The method for detecting edaravone content in this test example is as follows: The content was determined according to the high performance liquid chromatography method (General Rule 0512).

[0068] Solvent: Methanol aqueous solution (methanol:water = 32:68).

[0069] Test solution: Accurately measure 1 mL of this product and place it in a 100 mL volumetric flask. Dilute to the mark with solvent and shake well.

[0070] Reference solution: Weigh an appropriate amount of edaravone reference standard accurately, dissolve it in solvent and dilute quantitatively to prepare a solution containing approximately 20 μg of edaravone per 1 mL, and shake well.

[0071] For system suitability solutions, chromatographic conditions, and system suitability requirements, please refer to the section on related substances.

[0072] Assay: Accurately measure the test solution and reference solution, inject them separately into the liquid chromatograph, and record the chromatograms. Calculate the results based on peak area using the external standard method.

[0073] The results of each test sample after 3 months of accelerated testing (temperature 40℃±2℃, relative humidity 75%±5%) are shown in Table 3. The high-performance liquid chromatogram of edaravone-related substances in the edaravone dexborneol injection prepared in Example 1 is shown in Table 3. Figure 1 As shown.

[0074] Table 3: Comparison of key quality indicators after 3 months of accelerated testing (temperature 40℃±2℃, relative humidity 75%±5%) The above results show that the edaravone dexborneol concentrated solution for injection prepared in the embodiments of the present invention maintains excellent stability in all aspects. In particular, in accelerated and long-term stability tests, the related substances increase slowly, the content of the main component does not decrease significantly, the appearance of the solution is almost unchanged, and the product shelf life is significantly extended (related substances <0.5%, impurities X <0.1%).

[0075] Compared with Example 1, the ratio of sodium bisulfite and cysteine ​​hydrochloride in Comparative Example 4 exceeded the specific range of the present invention, resulting in a significant decrease in antioxidant effect. Related substances were detected at 0.76%, and impurities were detected at 0.45%.

[0076] Examples 1-8 demonstrated superior stability compared to commercially available edaravone dexborneol injection concentrate (Comparative Example 6), with Examples 3, 5, 7, and 8 showing exceptional performance in controlling the critical oxidative degradation impurity X (<0.05%). Example 11 showed that the addition of a chelating agent further optimized the results.

[0077] Therefore, this invention, through extensive experiments, has for the first time discovered and verified that the combined use of sodium bisulfite and cysteine ​​hydrochloride within a specific ratio range exhibits a synergistic antioxidant protective effect on edaravone-dexborneol compound injection. This specific combination significantly inhibits oxidative degradation and controls the formation of potentially toxic impurities, thus solving the long-standing stability bottleneck problem of this important formulation.

[0078] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and are not intended to limit the scope of protection of the present invention. Although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications or equivalent substitutions can be made to the technical solutions of the present invention without departing from the essence and scope of the technical solutions of the present invention.

Claims

1. A concentrated solution for injection of edaravone dexpanthenol, characterized in that, The preparation comprises the following components: edaravone, dextromethorphan, a composite antioxidant system, and a pharmaceutically acceptable solvent for injection; the mass ratio of the edaravone and the dextromethorphan is edaravone:dextromethorphan=(1-5):1; the composite antioxidant system comprises at least one of a sulfonic acid antioxidant and an amino acid antioxidant.

2. The concentrated idarucic acid dexpanthenol injection solution as set forth in claim 1, characterized by The sulfonic acid antioxidant comprises at least one of sodium pyrosulfite, sodium bisulfite, sodium sulfite, sodium thiosulfate, and formaldehyde-sodium bisulfite.

3. The concentrated edaravone dexpanthenol injection solution as set forth in claim 1, characterized by, The amino acid antioxidant comprises at least one of cysteine, cysteine hydrochloride, methionine, glutamic acid, and aspartic acid.

4. The concentrated edaravone dexpanthenol injection solution as set forth in claim 1, characterized by The mass ratio of the sulfonic acid antioxidant and the amino acid antioxidant is sulfonic acid antioxidant:amino acid antioxidant=(1-10):(1-10).

5. The concentrated edaravone dexpanthenol injection solution as set forth in claim 1, characterized by, The composite antioxidant system accounts for 0.01%-0.5% of the total weight of the edaravone-dextromethorphan injection concentrated solution.

6. The concentrated edaravone dexpanthenol injection solution as set forth in claim 1, characterized by, The edaravone-dextromethorphan injection concentrated solution further comprises a metal ion chelating agent.

7. The concentrated edaravone dexpanthenol injection solution as set forth in claim 6, characterized by The metal ion chelating agent comprises at least one of edetic acid, an edetic acid salt, or a hydrate thereof.

8. The concentrated edaravone dexpanthenol injection solution as set forth in claim 1, characterized by, The pH value of the edaravone-dextromethorphan injection concentrated solution is 4.0-6.

0.

9. A method for preparing the idarucic acid right isopropyl alcohol injection concentrated solution according to any one of claims 1 to 8, characterized by, The preparation comprises the following steps: (1) under a nitrogen protection environment, dissolving edaravone, dextromethorphan, and a composite antioxidant system in a pharmaceutically acceptable solvent for injection, or dissolving edaravone, dextromethorphan, a composite antioxidant system, and a metal ion chelating agent in a pharmaceutically acceptable solvent for injection; (2) adjusting the pH value to 4-6, filtering, and obtaining the edaravone-dextromethorphan injection concentrated solution.

10. A pharmaceutical composition for treating ischemic stroke, comprising, The preparation comprises the edaravone-dextromethorphan injection concentrated solution of any one of claims 1-8.

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