A stable pharmaceutical composition

Abstract

The application belongs to the technical field of medicine, and discloses a stable pharmaceutical composition. The pharmaceutical composition with active ingredients of edaravone and dextrocamphor can unexpectedly control the content of specific impurities SCR-756 and impurities SCR-757, and solves the problems of difficult control of impurities and product quality, short storage period and the like from the source.

Description

[0001] This application claims priority to the earlier application filed by the applicant with the State Intellectual Property Office on August 17, 2020, with patent application number 202010827343.0 and entitled "A Stable Pharmaceutical Composition". The entire contents of the earlier application are incorporated herein by reference. Technical Field

[0002] This invention belongs to the field of pharmaceutical technology and relates to a stable pharmaceutical composition, specifically, a pharmaceutical composition in which the active ingredients are edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) and dextroborneol. Background Technology

[0003] Over the past 15 years, stroke has been the second leading cause of death worldwide and the leading cause of long-term and severe neurological disorders in China. A stroke medical quality assessment study investigated the epidemiological situation of acute stroke treatment in my country. The study showed that the average time from symptom onset to hospital arrival for ischemic stroke patients in my country is 20.1 hours, with a significant number arriving at the hospital after 24 hours. These patients have not yet received effective drug treatment. Edaravone injection, widely used clinically to treat acute ischemic stroke, clearly states in its instructions that administration should begin within 24 hours of symptom onset.

[0004] Meanwhile, controlling drug quality has gradually become a key focus and challenge in drug development.

[0005] Therefore, providing an edaravone drug composition with a long therapeutic window, significant therapeutic effect, good stability, and high drug safety has become an urgent technical problem to be solved in this field. Summary of the Invention

[0006] The present invention provides a pharmaceutical composition comprising edaravone, dextroborneol, sodium metabisulfite and a solvent, wherein the sodium metabisulfite content is 0.95–1.05 mg / mL.

[0007] In some embodiments, the pharmaceutical composition comprises edaravone, dextroborneol, sodium metabisulfite, a solubilizer, and a solvent, wherein the sodium metabisulfite content is 0.95–1.05 mg / mL.

[0008] In some embodiments, the sodium metabisulfite content is 0.95–1.05 mg / mL, for example 0.97–1.03 mg / mL, exemplarily 0.95 mg / mL, 0.96 mg / mL, 0.97 mg / mL, 0.98 mg / mL, 0.99 mg / mL, 1.0 mg / mL, 1.01 mg / mL, 1.02 mg / mL, 1.03 mg / mL, 1.04 mg / mL, and 1.05 mg / mL. In some embodiments, the sodium metabisulfite content is 1.0 mg / mL.

[0009] In some embodiments, the weight ratio of edaravone to dextroborneol in the pharmaceutical composition is 1:1 to 4:1, for example, 2:1, 2.5:1, 3:1 or 3.5:1.

[0010] In some embodiments, the weight ratio of edaravone to dextroborneol in the pharmaceutical composition is 4:1.

[0011] In some embodiments, the weight ratio of edaravone, dextroborneol, and sodium metabisulfite in the pharmaceutical composition is 4:1:2.

[0012] According to the technical solution of the present invention, the edaravone content in the pharmaceutical composition is 1.0-3.0 mg / mL, for example, 1.5-2.5 mg / mL. In some embodiments, the edaravone content in the pharmaceutical composition is 2.0 mg / mL.

[0013] According to the technical solution of the present invention, the content of dextroborneol in the pharmaceutical composition is 0.2-1.0 mg / mL, for example, 0.3-0.8 mg / mL. In some embodiments, the content of dextroborneol in the pharmaceutical composition is 0.5 mg / mL.

[0014] In some embodiments, the pharmaceutical composition contains 2.0 mg / mL of edaravone, 0.5 mg / mL of dextroborneol, and 1.0 mg / mL of sodium metabisulfite.

[0015] In some embodiments, the co-solvent is selected from propylene glycol, ethanol, or tert-butanol.

[0016] In some embodiments, the solvent is selected from water for injection.

[0017] In some embodiments, the cosolvent and the solvent are propylene glycol and water for injection, respectively.

[0018] According to the technical solution of the present invention, the content of the cosolvent in the pharmaceutical composition is 0.01-0.15 ml / ml, for example 0.03-0.12 ml / ml, and exemplary values ​​are 0.05 ml / ml, 0.08 ml / ml, and 0.1 ml / ml.

[0019] In some embodiments, the pharmaceutical composition contains 2.0 mg / mL edaravone, 0.5 mg / mL dextroborneol, 1.0 mg / mL sodium metabisulfite, and 0.08 mL / mL propylene glycol.

[0020] In some embodiments, the pharmaceutical composition contains 2.0 mg / mL edaravone, 0.5 mg / mL dextroborneol, 1.0 mg / mL sodium metabisulfite, 0.08 mL / mL propylene glycol, and the balance is water for injection.

[0021] According to an exemplary embodiment of the present invention, the dosage (single dose) of the pharmaceutical composition is a 5 mL solution containing 10 mg of edaravone, 2.5 mg of dextroborneol, 5 mg of sodium metabisulfite, 0.4 mL of propylene glycol, and the remainder being water for injection.

[0022] According to the technical solution of the present invention, the active ingredients of the pharmaceutical composition are edaravone and dextroborneol.

[0023] According to the technical solution of the present invention, the pharmaceutical composition may further contain a compound of formula I or a pharmaceutically acceptable salt thereof.

[0024]

[0025] Furthermore, the weight ratio of the compound of Formula I or its pharmaceutically acceptable salt to the edaravone is less than 0.3%, for example less than 0.29%, less than 0.28%, 0.27%, less than 0.26%, less than 0.25%, less than 0.2%, less than 0.15%, or less than 0.1%.

[0026] According to the technical solution of the present invention, the pharmaceutical composition may further contain a compound of formula II or a pharmaceutically acceptable salt thereof.

[0027]

[0028] Furthermore, the weight ratio of the compound of Formula II or its pharmaceutically acceptable salt to the edaravone is less than 0.3%, for example less than 0.29%, less than 0.28%, 0.27%, less than 0.26%, less than 0.25%, less than 0.2%, less than 0.15%, or less than 0.1%.

[0029] On the other hand, the present invention provides a pharmaceutical composition comprising edaravone, dextroborneol, sodium metabisulfite, a solubilizer, and a solvent, wherein the sodium metabisulfite content is 0.95–1.05 mg / mL, and the pharmaceutical composition further comprises a compound of formula I or a pharmaceutically acceptable salt thereof in a weight ratio of less than 0.3% to the edaravone.

[0030]

[0031] On the other hand, the present invention provides a pharmaceutical composition comprising edaravone, dextroborneol, sodium metabisulfite, a solubilizer, and a solvent, wherein the sodium metabisulfite content is 0.95–1.05 mg / mL, and the pharmaceutical composition further comprises a compound of formula II or a pharmaceutically acceptable salt thereof in a weight ratio of less than 0.3% to the edaravone.

[0032]

[0033] On the other hand, the present invention provides a pharmaceutical composition comprising edaravone, dextroborneol, sodium metabisulfite, a solubilizer, and a solvent, wherein the sodium metabisulfite content is 0.95 to 1.05 mg / mL, and the pharmaceutical composition further comprises a compound of formula I or a pharmaceutically acceptable salt thereof in a weight ratio of less than 0.3% to the edaravone, and a compound of formula II or a pharmaceutically acceptable salt thereof in a weight ratio of less than 0.3% to the edaravone.

[0034] The present invention also provides compounds of formula I or pharmaceutically acceptable salts thereof.

[0035]

[0036] The present invention also provides compounds represented by Formula II or pharmaceutically acceptable salts thereof.

[0037]

[0038] According to the technical solution of the present invention, the pharmaceutically acceptable salt is an alkali metal salt, such as a potassium salt, sodium salt, or lithium salt.

[0039] The present invention also provides the use of the above-described pharmaceutical composition in the preparation of a pharmaceutical formulation for treating stroke.

[0040] The present invention also provides the use of the above-described pharmaceutical composition in the treatment of stroke.

[0041] The present invention also provides the above-described pharmaceutical composition for treating stroke.

[0042] The present invention also provides the use of the above-described pharmaceutical composition in the preparation of a medicament for treating amyotrophic lateral sclerosis or related disorders.

[0043] The present invention also provides the use of the above-described pharmaceutical composition in the treatment of amyotrophic lateral sclerosis or related disorders.

[0044] The present invention also provides the above-mentioned pharmaceutical composition for treating amyotrophic lateral sclerosis or related disorders.

[0045] The present invention also provides a method for preventing and / or treating stroke, comprising administering a therapeutically effective amount of a pharmaceutical composition or pharmaceutical preparation to a subject, such as a human.

[0046] The present invention also provides a method for preventing and / or treating amyotrophic lateral sclerosis (ALS) or related disorders, comprising administering a therapeutically effective amount of a pharmaceutical composition or pharmaceutical preparation to a subject, such as a human.

[0047] The present invention also provides the use of the compound represented by Formula I above, or a pharmaceutically acceptable salt thereof, in the quality control of the pharmaceutical composition or pharmaceutical preparation.

[0048] The present invention also provides the use of the compound represented by Formula II above or a pharmaceutically acceptable salt thereof in the quality control of the pharmaceutical composition or pharmaceutical preparation.

[0049] This invention also provides a method for preparing a compound of formula I or its tautomers, characterized in that intermediate 2 is reduced to obtain a compound of formula I or its tautomers.

[0050]

[0051] This invention also provides a method for preparing a compound of formula II or its tautomers, characterized in that intermediate 2 is reduced to obtain a compound of formula II or its tautomers.

[0052]

[0053] According to the technical solution of the present invention, intermediate 2 is reacted in the presence of a reducing agent and a solvent to obtain compound of formula I or its tautomer.

[0054] According to the technical solution of the present invention, intermediate 2 is reacted in the presence of a reducing agent and a solvent to obtain compound of formula II or its tautomer.

[0055] In some embodiments, the reducing agent is selected from sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and / or lithium cyanoborohydride.

[0056] In some embodiments, the reducing agent is selected from sodium borohydride.

[0057] In some embodiments, the solvent is selected from protic solvents.

[0058] In some embodiments, the solvent is selected from one or more of water, methanol, ethanol, propanol, and isopropanol.

[0059] In some embodiments, the solvent is selected from methanol.

[0060] The present invention also provides a method for preparing intermediate 2, characterized in that intermediate 1 is reacted with a sulfonating agent to obtain intermediate 2.

[0061]

[0062] In some embodiments, the sulfonating agent is sulfur trioxide and / or an adduct of sulfur trioxide.

[0063] In some embodiments, the sulfonating agent is a sulfur trioxide-dioxane adduct.

[0064] In some embodiments, intermediate 1 can be prepared by the following reaction:

[0065]

[0066] Beneficial effects of the present invention

[0067] During drug development, the inventors discovered that drug compositions containing the active ingredients edaravone and dextroborneol are prone to two novel impurities: impurity SCR-756 and impurity SCR-757. Once formed, the content of impurities SCR-756 and SCR-757 typically exceeds the identification threshold of 0.1%, making it difficult to control their levels within a reasonable range. Further complicating matters, stability tests showed that the content of impurities SCR-756, SCR-757, and total edaravone impurities increases at an accelerated rate with increasing storage temperature and time. Conventional methods such as controlling temperature, pH, co-solvents, and preparation time in the manufacturing process are ineffective in addressing these issues. Unexpectedly, through extensive testing, the inventors discovered that the dosage of sodium metabisulfite significantly affects the content of impurities SCR-756, SCR-757, and total impurities in the drug composition. Both excessively low and excessively high dosages of sodium metabisulfite result in the inability to effectively control these impurities. Therefore, by adding sodium metabisulfite and controlling its dosage within a suitable range, this invention effectively solves the technical problems of difficult control of impurities in the composition and product quality, and the accelerated increase rate of impurity content with increasing storage temperature or extended storage period. In particular, it can unexpectedly control the content of impurities SCR-756, SCR-757 and total edaravone impurities in the drug composition, thus solving the problems of difficult control of impurities and product quality, short storage period and drug safety from the source.

[0068] The term "tautomer" in this document refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerization is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also known as prototro pictautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Unless otherwise stated, all tautomer forms of the compounds of this invention are within the scope of this invention.

[0069] Those skilled in the art will understand that carbonyl compounds containing α-H exhibit keto-enol tautomerism, and the tautomers can interconvert and generally exist in equilibrium. Therefore, those skilled in the art will understand that the compounds of Formula I and Formula II of this invention exhibit tautomerism, and the tautomers can interconvert. In some embodiments of this invention, for ease of description and expression, compounds exhibiting tautomerism may be represented solely by their keto form (such as compounds of Formula I or II) or solely by their enol form (such as compounds of Formula I' or II'). In this document, the compounds represented by Formula I or Formula II include both keto compounds and their corresponding enol compounds.

[0070] Attached Figure Description

[0071] Figure 1 The COSY spectrum of SCR-756;

[0072] Figure 2 The HSQC spectrum of SCR-756;

[0073] Figure 3 The HMBC spectrum of SCR-756;

[0074] Figure 4 The COSY spectrum of SCR-757;

[0075] Figure 5 The HSQC spectrum of SCR-757;

[0076] Figure 6 The HMBC spectrum of SCR-757. Detailed Implementation

[0077] The technical solution of the present invention will be further described in detail below with reference to specific embodiments. It should be understood that the following embodiments are merely illustrative and explanatory of the present invention, and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are covered within the scope of protection intended by the present invention.

[0078] Unless otherwise stated, the raw materials and reagents used in the following examples are commercially available products or can be prepared by known methods.

[0079] Example 1: Dosage of sodium metabisulfite and investigation of related substances

[0080] Propylene glycol is heated to 50–60°C, edaravone is added, and the mixture is stirred until completely dissolved to obtain a drug solution. The solution is then cooled to below 25°C, and dextrorotatory camphor (structure: [structure not provided]) is added. Stir until completely dissolved. Add sodium metabisulfite to an appropriate amount of water below 25°C and stir until dissolved. While stirring, slowly add the sodium metabisulfite solution to the drug solution, and continue to slowly add water to near the prescribed volume. Adjust the pH to 4.5±0.2 with 0.1mol / L hydrochloric acid and sodium hydroxide solution, and finally add water to bring the volume to the prescribed volume. Filter the drug solution, fill it with nitrogen, and sterilize it.

[0081] Following the above method, pharmaceutical compositions with sodium metabisulfite contents of 0.5 mg / mL, 0.8 mg / mL, 1.0 mg / mL, 1.2 mg / mL, and 1.5 mg / mL were prepared and obtained, and their specific formulations are shown in Table 1.

[0082] Table 1: Formulation details of pharmaceutical compositions F1-F5

[0083] Prescription components F1 F2 F3 F4 F5 Idaravon 10mg 10mg 10mg 10mg 10mg Dextrorotatory camphor 2.5mg 2.5mg 2.5mg 2.5mg 2.5mg Propylene glycol (for injection) 0.4mL 0.4mL 0.4mL 0.4mL 0.4mL Sodium metabisulfite 2.5mg 4mg 5mg 6mg 7.5mg hydrochloric acid Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Sodium hydroxide Appropriate amount Appropriate amount Appropriate amount Appropriate amount Appropriate amount Water for Injection Add to 5mL Add to 5mL Add to 5mL Add to 5mL Add to 5mL

[0084] Related substances of the pharmaceutical compositions in Table 1 were analyzed, and the contents of impurities SCR-756, SCR-757, and total edaravone impurities were detected after 0 days and 10 days of storage at 60°C. Details are shown in Table 2.

[0085] Table 2: Content of impurities SCR-756, SCR-757 and total impurities [1] Investigation results

[0086]

[0087]

[0088] Note: [1] "Content" refers to the weight ratio of impurity SCR-756, impurity SCR-757 and total impurities relative to edaravone in the pharmaceutical composition.

[0089] The relevant substances analysis method is as follows: Take an appropriate amount of sample and dilute it with methanol-water (volume ratio 32:68) to prepare a solution containing approximately 0.5 mg of edaravone per mL, which is used as the test solution; accurately measure an appropriate amount and dilute it with solvent to prepare a solution containing approximately 5 μg of edaravone per mL, which is used as the control solution. Accurately weigh 65 mg and 75 mg of impurity reference standards SCR-75 and place them in a 100 mL volumetric flask, add solvent, sonicate to dissolve and dilute to the mark, and shake well to prepare the impurity stock solution; separately, accurately weigh 10 mg of edaravone reference standard and place it in a 20 mL volumetric flask, add 5 mL of methanol to dissolve it, add 1 mL of the impurity stock solution, dilute to the mark with solvent, and shake well to prepare the system suitability solution. The test was performed according to the high-performance liquid chromatography (HPLC) method (Chinese Pharmacopoeia 2015 Edition, Part IV, General Chapter 0512), using octadecylsilane-bonded silica gel as the stationary phase (Agilent Eclipse plus C18 4.6×150mm, 3.5μm); mobile phase A was 0.5% triethylamine (adjusted to pH 6.3 with phosphoric acid), and mobile phase B was methanol, with linear gradient elution performed according to the table below; the detection wavelength was 248nm. 10μL of the system suitability solution was accurately injected into the HPLC system, and the chromatogram was recorded. Impurities SCR-756, SCR-757, and edaravone eluted sequentially, with the edaravone peak retaining for approximately 6 minutes. 10μL each of the test solution and the control solution were accurately injected into the HPLC system separately, and the chromatograms were recorded.

[0090]

[0091]

[0092] Example 2

[0093] Propylene glycol was heated to 50–60°C, edaravone was added, and the mixture was stirred until completely dissolved to obtain a drug solution. The drug solution was then cooled to below 25°C, and dextrorotatory camphene was added, stirring until completely dissolved. Antioxidants (sodium metabisulfite, sodium bisulfite, and L-cysteine ​​hydrochloride, either alone or in combination) were added to an appropriate amount of water below 25°C and stirred until dissolved. While stirring, the antioxidant solution was slowly added to the drug solution, and water was continued to be added slowly until the volume was close to the prescription volume. The pH was adjusted to 4.5 ± 0.2 using 0.1 mol / L hydrochloric acid and sodium hydroxide solution, and finally, water was added to bring the volume to the prescription volume (as shown in Table 3). The drug solution was filtered, nitrogen-filled, and sterilized. The properties of the sample and the presence of edaravone impurities were investigated, and the results are shown in Table 4.

[0094] Table 3

[0095] 3000 pieces Prescription 1 Prescription 2 Prescription 3 Edaravone (g) 30 30 30 Dextrorotatory camphor (g) 7.5 7.5 7.5 Sodium metabisulfite (g) 15 15 - Sodium bisulfite (g) - - 15 L-cysteine ​​hydrochloride (g) - 7.5 7.5 Propylene glycol (L) 1.2 1.2 1.2 Water for injection to (L) 15 15 15

[0096] Table 4

[0097]

[0098]

[0099] Compared to prescription 3, prescriptions 1 and 2 contain significantly lower levels of edaravone-related impurities.

[0100] The relevant material analysis methods are as follows:

[0101] The determination was performed according to high performance liquid chromatography (Appendix VIE, Part II, Chinese Pharmacopoeia 2010 Edition), using octadecylsilane-bonded silica gel as the stationary phase (Waters Sunfire C18, 4.6 × 250 mm, 5.0 μm); with 0.02 mol / L ammonium acetate solution (adjusted to pH 4.0 with glacial acetic acid) as mobile phase A and acetonitrile as mobile phase B, linear gradient elution was performed according to the table below;

[0102] Detection wavelength: 254nm;

[0103] Flow rate: 1.0 ml / min;

[0104] Injection volume: 20 μl;

[0105] Solvent: 0.02 mol / L ammonium acetate solution (adjusted to pH 4.0 with glacial acetic acid) - acetonitrile (volume ratio 80:20);

[0106] Test solution: Take 5 ml of this product and place it in a 20 ml volumetric flask, dilute with solvent to the mark, and you have the test solution.

[0107] Control solution: Accurately measure 1 ml of the test solution and place it in a 200 ml volumetric flask. Dilute to the mark with solvent.

[0108]

[0109] Example 3 Preparation of compounds SCR-756 and SCR-757

[0110]

[0111] Synthesis steps:

[0112] (1) Preparation of intermediate 1

[0113] 39.92 g of Na was added in batches to 1.25 L of anhydrous ethanol, and the mixture was kept stable at 25–40 °C. The mixture was stirred at 50 °C until the Na was completely dissolved and clear. In the dark, protected from light, 250 g of edaravone solid was added in batches at 0–5 °C, and the mixture was stirred to obtain a turbid liquid. The mixture was protected with an N2 balloon and a black plastic bag to prevent light exposure. 203.11 g of chloroacetone was dissolved in 750 mL of anhydrous ethanol to form an ethanol solution, which was added directly to a dropping funnel. The above ethanol solution was added dropwise at -5–0 °C, protected with an N2 balloon and a black plastic bag to prevent light exposure, and the mixture was stirred at 0–5 °C for 2 h. TLC (petroleum ether:ethyl acetate = 1:1) showed that most of the edaravone raw material was consumed. The reaction mixture was poured into 4 L of ice water while stirring. The mixture was filtered, and the filter cake was washed with 600 mL of water three times. The mixture was then slurried with 200 mL of ethyl acetate and filtered to obtain intermediate 1, totaling 37 g.

[0114] (2) Preparation of intermediate 2

[0115] 37g of intermediate 1 was added to a 3L three-necked flask under N2 balloon protection. 650mL of dichloroethane and 325mL of anhydrous dioxane were added through a feeding funnel. Vacuum was applied, and the mixture was stirred until completely dissolved. 100g of type 4A molecular sieve and 69.41g of sulfur trioxide-dioxane adduct were added in batches while stirring at 0-5℃. The mixture was heated to 100℃ and reacted for 8 hours. After 8 hours, the temperature was lowered to 25℃, and the mixture was filtered. The filter cake was washed twice with anhydrous dichloromethane. The filter cake and 600mL of anhydrous dichloromethane were stirred and filtered to remove large molecular sieve particles. The filtrate was stirred for 5 minutes, filtered again, and the filter cake was washed twice with anhydrous dichloromethane to obtain the crude product. The crude product was slurried with ethanol and filtered to obtain 30g of solid (intermediate 2).

[0116] (3) Preparation of compounds SCR-756 and SCR-757

[0117] 30 g of intermediate 2 was added to a 2 L three-necked flask, protected by an N2 balloon. 600 mL of anhydrous MeOH was added through a feeding funnel. The mixture was then vacuumed and stirred under a dry ice bath at 0-5 °C. 8.85 g of NaBH4 was added in portions. The reaction mixture was stirred at 60 °C for 3 h, and the solvent was evaporated. The compounds SCR-756 and SCR-757 were obtained by HPLC separation (column: YMC-Triart Prep C18 250*50 mm*10 μm; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile]; acetonitrile %: 0%-28.5%, 19 mins).

[0118] The structures of compounds SCR-756 and SCR-757 were confirmed by nuclear magnetic resonance.

[0119] Nuclear magnetic resonance spectroscopy (NMR)

[0120] Instrument: BRUKER AV-400 nuclear magnetic resonance spectrometer

[0121] Solvent: DMSO-d6

[0122] Internal Standard: TMS

[0123] Temperature: 300K.

[0124] The proton NMR and carbon NMR data of SCR-756 are shown in Tables 5-1 and 5-2.

[0125]

[0126] Table 5-1: 1H NMR Spectroscopy Results of SCR-756

[0127]

[0128]

[0129] Table 5-2: Carbon Spectroscopy Results of SCR-756

[0130]

[0131] The proton NMR and carbon NMR data of SCR-757 are shown in Tables 6-1 and 6-2.

[0132]

[0133] Table 6-1: 1H NMR Spectroscopy Results of SCR-757

[0134]

[0135]

[0136] Table 6-2: Carbon Spectroscopy Results of SCR-757

[0137]

[0138] In addition, the COSY, HSQC, and HMBC spectra of SCR-756 and SCR-757 can be found in [link to relevant documentation]. Figures 1-6 .

[0139] The results show that SCR-756 has the structure shown in Formula I, and SCR-757 has the structure shown in Formula II.

[0140] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A pharmaceutical composition, characterized in that, The pharmaceutical composition comprises edaravone, dextroborneol, sodium metabisulfite, a solubilizer, and a solvent, wherein the solubilizer and the solvent are propylene glycol and water for injection, respectively, and the sodium metabisulfite content is 0.95~1.05 mg / mL; The pharmaceutical composition also contains the formula compound Or a pharmaceutically acceptable salt thereof, the formula The pharmaceutical composition contains a compound or a pharmaceutically acceptable salt thereof in a weight ratio of less than 0.3% to edaravone, and further comprises the formula... Compound I Or a pharmaceutically acceptable salt thereof, the formula The weight ratio of compound I or a pharmaceutically acceptable salt thereof to edaravone is less than 0.3%; The pharmaceutical composition contains edaravone at a concentration of 1.5-2.5 mg / mL; The content of dextrorotatory camphor in the pharmaceutical composition is 0.3-0.8 mg / mL.

2. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition contains 2.0 mg / mL of edaravone.

3. The pharmaceutical composition according to claim 1, characterized in that, The content of dextrorotatory camphor in the pharmaceutical composition is 0.5 mg / mL.

4. The pharmaceutical composition according to claim 1, characterized in that, The pharmaceutical composition contains 2.0 mg / mL of edaravone and 0.5 mg / mL of dextromethorphan.

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