Edaravone dextrocylol injection and preparation method thereof

Abstract

This invention belongs to the field of pharmaceutical preparation technology, specifically relating to an edaravone dexborneol injection and its preparation method. The injection provided by this invention comprises edaravone, dexborneol, a pH adjuster, an antioxidant, and water for injection. The antioxidant is a combination of sodium metabisulfite or sodium bisulfite and gentianic acid. The injection provided by this invention maintains good sample stability during production, sterilization, and storage, has low impurity content, meets the relevant requirements for drug quality and efficacy, and is suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to an edaravone dexborneol injection and its preparation method. Background Technology

[0002] Edaravone, a novel and potent free radical scavenger and effective neuroprotective agent, was developed by Mitsubishi Pharmaceutical Co., Ltd. of Japan and first marketed in 2001. It is an effective first-line treatment for ischemic stroke. Edaravone's chemical name is 3-methyl-1-phenyl-2-pyrazolino-5-one, and its dextroborneol chemical name is [1R,2S,4R]-1,7,7-trimethyl-bicyclo[2.2.1]hepta-2-ol. Their chemical structures are as follows:

[0003]

[0004] CN200980100527.9 discloses the use of a specific ratio composition of edaravone and (+)-2-borneol injection in the preparation of drugs for treating cerebrovascular diseases, especially ischemic cerebrovascular diseases.

[0005] CN201510751056.5 provides an edaravone and (+)2-camphenol liniment and its preparation method. The edaravone and (+)2-camphenol liniment comprises edaravone, (+)2-camphenol, a cosolvent, an antioxidant, and a solvent. The cosolvent is selected from one or more alcohol solvents such as ethanol, isopropanol, ethylene glycol, propylene glycol, glycerol, or polyethylene glycol. The antioxidant includes one or more water-soluble antioxidants such as sodium sulfite, sodium bisulfite, sodium metabisulfite, sodium thiosulfate, and ascorbic acid. The solvent is water.

[0006] CN201610761890.7 discloses a sublingual administration formulation of edaravone and (+)-2-borneol, and its preparation method. The sublingual administration formulation includes edaravone, (+)-2-borneol, excipients, fillers, binders, disintegrants, lubricants, etc. Sublingual administration formulations can avoid the first-pass effect in the liver, and have advantages such as good sample stability, ease of transportation, and convenient use.

[0007] WO2022037537A1 discloses a stable pharmaceutical composition whose active ingredients are edaravone and dextroborneol. This composition unexpectedly controls the content of its characteristic impurities SCR-756 and SCR-757, fundamentally solving problems such as difficulty in controlling impurities and product quality, and short shelf life. The pharmaceutical composition comprises edaravone, dextroborneol, sodium metabisulfite, and a solvent.

[0008] CN202310567786.4 discloses a nasal thermosensitive in-situ gel containing edaravone and borneol inclusion complex, which is made with edaravone and borneol inclusion complex as active substances, temperature-sensitive gel material, solubilizer and water.

[0009] In addition, Wang Shengli et al. disclosed the generation process of six impurities in edaravone injection and synthesized them in "Synthesis of Edaravone Related Substances. China Pharmaceutical Industry Journal, 2018, 49(5), 595-599".

[0010] Among them, edaravone dexborneol concentrated solution for injection was developed by Simcere Pharmaceutical Co., Ltd., and is used to improve neurological symptoms, daily living activities and functional impairment caused by acute ischemic stroke.

[0011] Because edaravone is prone to degradation through redox reactions in solution, and dextroborneol has very low solubility in water and is easily volatile, the commonly used antioxidants for this product are sodium metabisulfite, sodium bisulfite, and cysteine. However, these three antioxidants react with edaravone to form new impurities, and the amount of impurities increases with the amount of antioxidant used.

[0012] Therefore, selecting a suitable antioxidant has become both a challenge and a key focus of this product's research. Summary of the Invention

[0013] The purpose of this invention is to provide an edaravone dexborneol injection and its preparation method. This injection has low impurity content, maintains good product stability during storage, and ensures product quality.

[0014] Specifically, the present invention is achieved through the following technical solution:

[0015] An edaravone dexborneol injection, the active ingredients being edaravone and dexborneol, the excipients containing a solubilizer, pH adjuster, and antioxidant, and the solvent being water for injection.

[0016] Preferably, the active ingredients are edaravone and dexborneol, with an edaravone:dexborneol weight ratio of 1:1 to 4:1. A ratio of 4:1 is preferred.

[0017] Preferably, the content of edaravone, an active ingredient in the injection solution, is 1-3 mg / ml; more preferably, the content of edaravone, an active ingredient in the injection solution, is 2 mg / ml.

[0018] Preferably, the content of the active ingredient dexborneol in the injection solution is 0.2-1.0 mg / ml; more preferably, the content of dexborneol is 0.5 mg / ml.

[0019] Preferably, the co-solvent is one or more of propylene glycol and ethanol; preferably, propylene glycol has a concentration of 6.4% to 9.6% ml / ml in the injection solution.

[0020] Preferably, the antioxidant is a combination of sodium metabisulfite or sodium bisulfite and gentianic acid, wherein the concentration of sodium metabisulfite or sodium bisulfite is 0.6–1 mg / ml, and the concentration of gentianic acid is 0.3–0.6 mg / ml. More preferably, the concentration of sodium metabisulfite or sodium bisulfite is 0.8–0.9 mg / ml, and the concentration of gentianic acid is 0.3%–0.4 mg / ml.

[0021] Preferably, the pH adjuster is one or more of disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydroxide, hydrochloric acid, and phosphoric acid, adjusting the pH of the injection solution to 3.0-5.0.

[0022] In a preferred embodiment, the injection solution contains 2 mg / ml of the active ingredient edaravone, 0.5 mg / ml of dextromethorphanol, 0.9 mg / ml of sodium metabisulfite or sodium bisulfite, 0.4 mg / ml of gentianic acid, and 8% ml / ml of propylene glycol.

[0023] Preferably, the preparation process of the above-mentioned edaravone dexborneol injection is as follows: propylene glycol is heated to 50-60°C, the prescribed amount of edaravone is added, and the mixture is stirred until completely dissolved to obtain a drug solution; the drug solution is cooled to below 25°C, the prescribed amount of dexborneol is added, and the mixture is stirred until completely dissolved; water is added to near the prescribed volume, the prescribed amount of antioxidant is added, the mixture is stirred to dissolve, the pH value is adjusted, water is added to a final volume, the mixture is stirred evenly, nitrogen is filled into vials, nitrogen is filled, and sterilization is performed.

[0024] Preferred sterilization conditions: autoclaving at 121℃ for 15-20 minutes.

[0025] Beneficial effects: The inventors were pleasantly surprised to find that the addition of the antioxidant gentianic acid to the formula, which works synergistically with sodium pyrosulfate or sodium bisulfite, and whose dosage is controlled within a reasonable and safe range, effectively solved the technical problem that the content of impurities in the composition increases rapidly with increasing temperature (especially high-temperature sterilization) or long-term storage; it can better improve the stability of the product, effectively solve the impurity problem, and make the medication safer. Detailed Implementation

[0026] The following are specific embodiments of the present invention, which further describe the technical solutions of the present invention. However, those skilled in the art should understand that the present invention is not limited to these embodiments and the preparation methods used. Moreover, those skilled in the art can make equivalent substitutions, combinations, improvements, or modifications to the present invention based on the description therein, but all of these will be included within the scope of the present invention.

[0027] All operations not described in detail in this invention are routine operations.

[0028] Impurity I: 4,4'-bis-(3-methyl-1-phenyl-5-pyrazolone)

[0029]

[0030] Impurity III: 5,5',5''-trimethyl-2,2',2''-triphenyl-2,2'',4,4''-tetrahydro-3H,3''H-[4,4':4',4''-tripyrazole]-3,3',3''(2'H)-trione

[0031]

[0032] Impurity IV: 2-(3-methyl-5-carbonyl-1-phenyl-4,5-dihydro-1H-pyrazol-4-yl)-2-sulfonic acid propionic acid

[0033]

[0034] Impurity V: 2-(3-methyl-5-carbonyl-1-phenyl-4,5-dihydro-1H-pyrazol-4-yl)propane-2-sulfonic acid

[0035]

[0036] Impurity VIII: (1S,2R) / (1R,2S)-2-hydroxy-1-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazolin-4-yl)prop-1-sulfonic acid

[0037]

[0038] Impurity IX: (1S,2S) / (1R,2S)-2-hydroxy-1-(5-hydroxy-3-methyl-1-phenyl-1H-pyrazolin-4-yl)prop-1-sulfonic acid

[0039]

[0040] Example 1:

[0041]

[0042]

[0043] Based on the above prescription, a concentrated solution of edaravone dexborneol for injection was prepared, and its antioxidant properties were investigated.

[0044] Preparation process: Propylene glycol is heated to 50-60℃, and the prescribed amount of edaravone is added. The mixture is stirred until completely dissolved to obtain a drug solution. The solution is then cooled to below 25℃, and the prescribed amount of dextroborneol is added. The mixture is stirred until completely dissolved, and then 90% of the prescribed amount of water for injection is added. The prescribed amounts of sodium metabisulfite, thioglycerol, citric acid, sodium citrate, gentian acid, sodium bisulfite, and disodium edetate are added separately, stirred until dissolved, and the pH is adjusted to approximately 4.0. Water is added to a final volume of 200 ml, stirred thoroughly, and the solution is filled into vials under nitrogen. The vials are then sterilized at 121℃ for 15 minutes. The samples are then subjected to high-temperature (60℃) testing.

[0045] Results: No precipitation was observed on day 0. Prescriptions 2, 3, 4, 5, and 11 showed significant precipitation after being placed at high temperature for 10 days. Other prescriptions showed no precipitation after being placed at high temperature for 10 days.

[0046] The results of related substances (%) of edaravone in prescriptions 1, 6-10, and 12 are as follows:

[0047]

[0048]

[0049] The results of other related substances (%) for prescriptions 1, 6-10, and 12 are as follows:

[0050]

[0051] Formulas without sodium metabisulfite or sodium bisulfite showed significant precipitation after 10 days of high-temperature storage. The related substances in formulas 6 and 7 increased significantly after 10 days, while formula 10 showed relatively smaller impurities compared to other formulas. Dextroborneol and phenylhydrazine showed no significant change after 10 days compared to 0 days; therefore, subsequent investigations will focus on the combination of sodium metabisulfite / sodium bisulfite and gentianic acid, and on edaravone-related substances.

[0052] Implement column 2

[0053]

[0054] Based on the above prescription, prepare a concentrated solution of edaravone dexborneol for injection and select the appropriate antioxidant concentration.

[0055] Preparation process: Propylene glycol was heated to 50-60℃, and the prescribed amount of edaravone was added. The mixture was stirred until completely dissolved to obtain a drug solution. The solution was then cooled to below 25℃, and the prescribed amount of dextroborneol was added. The mixture was stirred until completely dissolved, and approximately 90% of the prescribed amount of water for injection was added. The prescribed amounts of sodium metabisulfite / sodium bisulfite and gentianic acid were added, and the mixture was stirred until dissolved. The pH was adjusted to 4.0. The volume was brought to a final volume, nitrogen was added, and the solution was filled into ampoules and nitrogen-filled. The ampoules were sterilized at 121℃ for 15 minutes. The results were investigated at a high temperature (60℃).

[0056] The results of related substances (%) of edaravone in prescriptions 13-21 are as follows:

[0057]

[0058]

[0059] The results for other related substances (%) in prescriptions 13-21 are as follows:

[0060]

[0061]

[0062] Based on the above results, a combination of 0.06–1% sodium metabisulfite (or sodium bisulfite of equal concentration) and 0.03–0.06% gentianic acid was selected as the final concentration of the antioxidant combination.

[0063] Implement column 3

[0064]

[0065] Preparation process: Heat propylene glycol to 50-60℃, add the prescribed amount of edaravone, and stir until completely dissolved to obtain a drug solution; cool the drug solution to below 25℃, add the prescribed amount of dextromethorphanol, stir until completely dissolved, add approximately 90% of the prescribed amount of water for injection, add sodium metabisulfite and gentian acid respectively, stir to dissolve, adjust the pH according to the prescription, add water to 200ml, stir evenly, fill with nitrogen, fill into ampoules, fill with nitrogen, and sterilize at 121℃ for 15min.

[0066] The results of the investigation of the relevant substances at high temperature (60℃) are shown in the table below:

[0067] The results of the related substances (%) of edaravone in prescriptions 22-30 are as follows:

[0068]

[0069] The results for other relevant substances (%) in prescriptions 22-30 are as follows:

[0070]

[0071]

[0072] Based on the above results, the results for related substances were better in the pH range of 2.5-5.0. Considering the irritation of low pH to the human body, a pH range of 3.0-5.0 was selected, with phosphoric acid and / or sodium hydroxide preferred as pH adjusters.

[0073] Example 4:

[0074] Samples were prepared according to prescription 26 and divided into 6 portions: no sterilization, sterilization at 115℃ for 30 minutes, sterilization at 121℃ for 8 minutes, sterilization at 121℃ for 15 minutes, sterilization at 121℃ for 20 minutes, and sterilization at 121℃ for 30 minutes. The samples were placed under the influence of high temperature (60℃) and light (4500lx±500lx) to investigate the different sterilization conditions. The results are as follows:

[0075]

[0076] After sterilization, the levels of related substances increased slightly compared to before sterilization, but all were within acceptable limits. Sterilization at 121℃ for 15-20 minutes did not affect the formulation's influencing factors for 30 days. Considering both sterilization effectiveness and the increase in related substances, a higher level of aseptic assurance was achieved through overkill sterilization.

Claims

1. An edaravone dexborneol injection, characterized in that, The active ingredients are edaravone and dextroborneol. The excipients include solubilizers, pH adjusters, and antioxidants. The solvent is water for injection.

2. The injection solution according to claim 1, characterized in that, The active ingredients are edaravone and dexborneol, with the weight ratio of edaravone to dexborneol being 1:1 to 4:

1.

3. The injection solution according to claim 1, characterized in that, The co-solvent is one or both of propylene glycol and ethanol, preferably propylene glycol.

4. The injection solution according to claim 1, characterized in that, The antioxidant is sodium metabisulfite or a combination of sodium bisulfite and gentianic acid.

5. The injection solution according to claim 1, characterized in that, The pH adjuster is one or more of disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium hydroxide, hydrochloric acid, and phosphoric acid.

6. The injection solution according to claim 1, characterized in that, The content of the active ingredient edaravone in the injection solution is 1-3 mg / ml; preferably, the content of the active ingredient edaravone in the injection solution is 2 mg / ml; the content of the active ingredient dexborneol in the injection solution is 0.2-1.0 mg / ml; preferably, the content of dexborneol is 0.5 mg / ml.

7. The injection solution according to claim 3, characterized in that, The concentration of propylene glycol in the injection solution is 6.4% to 9.6% ml / ml.

8. The injection solution according to claim 4, characterized in that, The concentration of sodium metabisulfite or sodium bisulfite is 0.6–1 mg / ml, and the concentration of gentianic acid is 0.3–0.6 mg / ml.

9. The injection solution according to claim 1, characterized in that, The pH of the injection solution is 3.0–5.0.

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