Stable pharmaceutical composition

Abstract

A stable pharmaceutical composition, which belongs to the field of pharmaceutical technology and whose active ingredients are edaravone and dexborneol, can unexpectedly control the contents of its specific impurities SCR-756 and SCR-757, thereby fundamentally resolving the problems of difficulty in controlling impurities and product quality, short storage period, etc.

Description

Detailed Description of the Invention

[0001] This application claims priority based on a previous application filed by the applicant with the China National Intellectual Property Administration on August 17, 2020, with a patent application number of 202010827343.0 and an invention title of "Stable Pharmaceutical Composition". The entire content of the previous application is incorporated into this application by reference.

[0002] 〔Technical Field〕 The present invention belongs to the field of pharmaceutical technology and relates to a stable pharmaceutical composition. Specifically, it relates to a pharmaceutical composition in which the active ingredients are edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) and dexborneol.

[0003] 〔Background Art〕 In the past 15 years, stroke has ranked second in the world and first in China as a cause of death and long-term and severe neurological diseases. The China Quality Evaluation of Stroke Treatment (CHINA QUEST) investigated the epidemiological situation of the current treatment status of acute stroke in China. According to the research, the average time from onset to hospital for ischemic stroke patients in China is 20.1 hours, and a considerable number of patients arrive at the hospital after 24 hours. This part of the patients have not yet received effective drug treatment. Edaravone injection, which is clinically widely used in the treatment of acute ischemic stroke, clearly states in the usage and dosage section of its instruction manual that administration should be started within 24 hours after onset.

[0004] At the same time, the management of drug quality has gradually become the focus and difficulty in pharmaceutical development.

[0005] Therefore, providing an edaravone pharmaceutical composition with a long treatment time window, significant treatment effect, excellent stability, and high dosing safety has become an urgent technical problem to be solved in this field.

[0006] 〔Summary of the Invention〕 The present invention provides a pharmaceutical composition comprising edaravone, dexborneol, sodium pyrosulfite, and a solvent, wherein the sodium pyrosulfite content is 0.95 to 1.05 milligrams / milliliter.

[0007] In some embodiments, the pharmaceutical composition comprises edaravone, dexborneol, sodium pyrosulfite, a cosolvent, and a solvent, wherein the sodium pyrosulfite content is 0.95 to 1.05 milligrams / milliliter.

[0008] In some embodiments, the sodium pyrosulfite content is 0.95 to 1.05 milligrams / milliliter, for example, 0.97 to 1.03 milligrams / milliliter, and exemplary values ​​include 0.95 milligrams / milliliter, 0.96 milligrams / milliliter, 0.97 milligrams / milliliter, 0.98 milligrams / milliliter, 0.99 milligrams / milliliter, 1.0 milligrams / milliliter, 1.01 milligrams / milliliter, 1.02 milligrams / milliliter, 1.03 milligrams / milliliter, 1.04 milligrams / milliliter, and 1.05 milligrams / milliliter. In some embodiments, the sodium pyrosulfite content is 1.0 milligram / milliliter.

[0009] In some embodiments, the weight ratio of edaravone to dexborneol 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 dexborneol in the pharmaceutical composition is 4:1.

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

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

[0013] According to the technical proposal of the present invention, the content of dexborneol in the pharmaceutical composition is 0.2 to 1.0 milligrams / milliliter, for example, 0.3 to 0.8 milligrams / milliliter. In some embodiments, the content of dexborneol in the pharmaceutical composition is 0.5 milligrams / milliliter.

[0014] In some embodiments, the pharmaceutical composition contains 2.0 milligrams / milliliter of edaravone, 0.5 milligrams / milliliter of dexborneol, and 1.0 milligram / milliliter of sodium pyrosulfite.

[0015] In some embodiments, the cosolvent is selected from propylene glycol, ethanol, or t-butanol.

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

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

[0018] According to the technical proposal of the present invention, the cosolvent content in the pharmaceutical composition is 0.01 to 0.15 milliliters / milliliter, for example, 0.03 to 0.12 milliliters / milliliter, and exemplary, 0.05 milliliters / milliliter, 0.08 milliliters / milliliter, and 0.1 milliliters / milliliter.

[0019] In some embodiments, the pharmaceutical composition contains 2.0 milligrams / milliliter of edaravone, 0.5 milligrams / milliliter of dexborneol, 1.0 milligram / milliliter of sodium pyrosulfite, and 0.08 milliliters / milliliter of propylene glycol.

[0020] In some embodiments, the pharmaceutical composition contains 2.0 milligrams / milliliter of edaravone, 0.5 milligrams / milliliter of dexborneol, 1.0 milligram / milliliter of sodium pyrosulfite, 0.08 milliliters / milliliter of propylene glycol, and the remainder is water for injection.

[0021] According to an exemplary embodiment of the present invention, the dose (single dose) of the pharmaceutical composition is 5 milliliters of solution, the solution containing 10 milligrams of edaravone, 2.5 milligrams of dexborneol, 5 milligrams of sodium pyrosulfite, 0.4 milliliters of propylene glycol, and the remainder being water for injection.

[0022] According to the proposed technology of the present invention, the active ingredients of the pharmaceutical composition are edaravone and dexborneol.

[0023] According to the proposed technology of the present invention, the pharmaceutical composition is of formula I:

[0024] [ka]

[0025] The compound indicated by or a pharmaceutically acceptable salt thereof may further be included.

[0026] Furthermore, the weight ratio of the compound of Formula I or its pharmaceutically acceptable salt to edaravone is 0.3% or less, for example, 0.29% or less, 0.28% or less, 0.27%, 0.26% or less, 0.25% or less, 0.2% or less, 0.15% or less, 0.1% or less.

[0027] According to the technical solution of the present invention, the pharmaceutical composition has Formula II:

[0028]

Chemical formula

[0029] It may further contain a compound represented by or its pharmaceutically acceptable salt.

[0030] Furthermore, the weight ratio of the compound of Formula II or its pharmaceutically acceptable salt to edaravone is 0.3% or less, for example, 0.29% or less, 0.28% or less, 0.27%, 0.26% or less, 0.25% or less, 0.2% or less, 0.15% or less, 0.1% or less.

[0031] In another aspect, the present invention provides a pharmaceutical composition, which contains edaravone, dexborneol, sodium pyrosulfite, a co-solvent, and a solvent. The content of the sodium pyrosulfite is 0.95 - 1.05 milligrams / milliliter, and the pharmaceutical composition further contains a compound represented by Formula I:

[0032]

Chemical formula

[0035] [ka]

[0036] The compound indicated by or a pharmaceutically acceptable salt thereof further comprises

[0037] In another embodiment, the present invention provides a pharmaceutical composition comprising edaravone, dexborneol, sodium pyrosulfite, a cosolvent, and a solvent, wherein the sodium pyrosulfite content is 0.95 to 1.05 milligrams / milliliter, and the pharmaceutical composition further comprises a compound of formula I or a pharmaceutically acceptable salt thereof in a weight ratio of 0.3% or less with respect to edaravone, and a compound of formula II or a pharmaceutically acceptable salt thereof in a weight ratio of 0.3% or less with respect to edaravone.

[0038] This invention relates to formula I:

[0039] [ka]

[0040] Further, the compound shown or a pharmaceutically acceptable salt thereof is provided.

[0041] This invention relates to formula II:

[0042] [ka]

[0043] Further, the compound shown or a pharmaceutically acceptable salt thereof is provided.

[0044] According to the technical proposal of the present invention, the pharmaceutically acceptable salt is an alkali metal salt, such as a potassium salt, a sodium salt, or a lithium salt.

[0045] The present invention further provides applications of the above-mentioned pharmaceutical composition in the manufacture of pharmaceutical formulations for treating stroke.

[0046] The present invention further provides the above-mentioned pharmaceutical composition for use in the treatment of stroke.

[0047] The present invention further provides the above-mentioned pharmaceutical composition for treating stroke.

[0048] The present invention further provides applications of the above-mentioned pharmaceutical composition in the manufacture of agents for treating amyotrophic lateral sclerosis or related disorders.

[0049] The present invention further provides the use of the above-mentioned pharmaceutical composition in the treatment of amyotrophic lateral sclerosis or related disorders.

[0050] The present invention further provides the above-mentioned pharmaceutical composition for treating amyotrophic lateral sclerosis or related disorders.

[0051] The present invention further provides a method for preventing and / or treating stroke, the method comprising administering a therapeutically effective amount of a pharmaceutical composition or pharmaceutical preparation to a target for treatment, for example, a human being.

[0052] The present invention provides a method for preventing and / or treating amyotrophic lateral sclerosis or related disorders, the method comprising administering a therapeutically effective amount of a pharmaceutical composition or pharmaceutical preparation to a target for treatment, for example, a human.

[0053] The present invention further provides applications of the compound shown in Formula I above or a pharmaceutically acceptable salt thereof in the quality control of the pharmaceutical composition or pharmaceutical preparation.

[0054] The present invention further provides applications of the compound shown in Formula II above or a pharmaceutically acceptable salt thereof in the quality control of the pharmaceutical composition or pharmaceutical preparation.

[0055] The present invention further provides a method for producing a compound of formula I or its tautomer, characterized by performing a reduction reaction on intermediate 2 to obtain a compound of formula I or its tautomer.

[0056] [ka]

[0057] The present invention further provides a method for producing a compound of formula II or its tautomer, characterized by performing a reduction reaction on intermediate 2 to obtain a compound of formula II or its tautomer.

[0058] [ka]

[0059] According to the technical method of the present invention, intermediate 2 is reacted in the presence of a reducing agent and a solvent to obtain the compound of formula I or its tautomer.

[0060] According to the technical method of the present invention, intermediate 2 is reacted in the presence of a reducing agent and a solvent to obtain the compound of formula II or its tautomer.

[0061] 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.

[0062] In some embodiments, the reducing agent is selected from sodium borohydride.

[0063] In some embodiments, the solvent is selected from protic solvents.

[0064] In some embodiments, the solvent is one or more selected from water, methanol, ethanol, propanol, and isopropanol.

[0065] In some embodiments, the solvent is selected from methanol.

[0066] The present invention further provides a method for producing intermediate 2, characterized by reacting intermediate 1 with a sulfonating reagent to obtain intermediate 2.

[0067] [ka]

[0068] In some embodiments, the sulfonating reagent is sulfur trioxide and / or an adduct of sulfur trioxide.

[0069] In some embodiments, the sulfonating reagent is a sulfur trioxide-dioxane adduct.

[0070] In some embodiments, the intermediate 1 is obtained by the following reaction.

[0071] [ka]

[0072] [Beneficial effects] The inventors discovered that in the pharmaceutical development process, pharmaceutical compositions containing the active ingredients edaravone and dexborneol are prone to the appearance of two novel impurities, SCR-756 and SCR-757. Once formed, the content of SCR-756 and SCR-757 typically exceeds the identification threshold of 0.1%, making it difficult to control their content within a reasonable range. Furthermore, stability tests revealed that the content of SCR-756, SCR-757, and the total edaravone impurities increases rapidly with increasing storage temperature and extended storage time. This indicates that the above problem cannot be effectively solved by conventional methods such as controlling temperature, pH value, co-solvent, and blending time during the process. In contrast, the inventors, through extensive testing, unexpectedly discovered that the dosage of sodium pyrosulfite significantly affects the content of impurities SCR-756, SCR-757, and total impurities in the pharmaceutical composition, and that if the dosage of sodium pyrosulfite is too low or too high, the content of impurities SCR-756, SCR-757, and total impurities cannot be effectively controlled. Therefore, the present invention effectively solves technical problems such as difficulty in controlling impurities present in the composition itself and product quality, and the rate at which impurity content increases with rising storage temperature or extended storage period, by adding sodium pyrosulfite and controlling its dosage within an appropriate range. In particular, it is possible to unexpectedly control the content of impurities SCR-756, SCR-757, and edaravone (total impurity) in the pharmaceutical composition, fundamentally solving problems such as difficulty in controlling impurities and product quality, short shelf life, and low administration safety.

[0073] In this specification, the term "tautomer" refers to structural isomers of different energies that are interconvertible across a low-energy barrier. When tautomerism is possible (for example, in solution), chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton transfer, such as ketoenol isomerization and imine enamine isomerization. Unless otherwise specified, all tautomer forms of the compounds of the present invention are within the scope of the invention.

[0074] As those skilled in the art will know, α-H-containing carbonyl compounds exhibit keto-enol tautomerism, and the tautomers are interconvertible and generally exist in equilibrium forms. Therefore, as those skilled in the art will know, both compounds of formula I and formula II of the present invention exhibit tautomerism, and the tautomers are interconvertible. In some embodiments of the present invention, for ease of description and expression, compounds exhibiting tautomerism may be represented only in keto form (e.g., compounds of formula I or formula II) or only in enol form (e.g., compounds of formula I' or formula II'). In this specification, compounds represented by formula I or formula II include both keto compounds and their corresponding enol compounds.

[0075] [ka]

[0076] [Brief explanation of the drawing] [Figure 1] This is the COSY spectrum of SCR-756.

[0077] [Figure 2] This is the HSQC spectrum of SCR-756.

[0078] [Figure 3] This is the HMBC spectrum of SCR-756.

[0079] [Figure 4] This is the COSY spectrum of SCR-757.

[0080] [Figure 5] This is the HSQC spectrum of SCR-757.

[0081] [Figure 6] This is the HMBC spectrum of SCR-757.

[0082] [Modes for carrying out the invention] The following describes the technical aspects of the present invention in more detail, linking them to specific embodiments. It should be understood that the following embodiments are merely illustrative examples for illustrating and interpreting the present invention, and should not be interpreted as limiting the scope of protection of the present invention. Any technology realized based on the above-described aspects of the present invention falls within the scope of protection of the present invention.

[0083] Unless otherwise specified, the raw materials and reagents used in the following examples are either commercially available or can be manufactured by known methods.

[0084] Example 1: Consideration of the dosage of sodium pyrosulfite and related substances Propylene glycol is heated to 50-60°C, edaravone is added, and the mixture is stirred until completely dissolved to obtain the chemical solution. The chemical solution is then cooled to below 25°C, and dexborneol (structure is

[0085] [ka]

[0086] The following was added and stirred until completely dissolved: Sodium pyrosulfite was added to an appropriate amount of water below 25°C and stirred until completely dissolved, and the sodium pyrosulfite solution was slowly added to the drug solution while stirring, and water was slowly added until it reached nearly the prescribed volume. The pH was adjusted to 4.5±0.2 with 0.1 mol / L hydrochloric acid and sodium hydroxide solution, and finally water was added to reach the prescribed volume, the drug solution was filtered, filled with nitrogen and sealed by injection, and sterilized.

[0087] By the above method, pharmaceutical compositions with sodium pyrosulfite content of 0.5 mg / mL, 0.8 mg / mL, 1.0 mg / mL, 1.2 mg / mL, and 1.5 mg / mL were produced, and their specific formulations are shown in Table 1.

[0088] [Table 1]

[0089] The relevant substances in the pharmaceutical compositions listed in Table 1 were analyzed, and the content of impurities SCR-756, SCR-757, and total edaravone impurities in the samples after being left at 60°C for 0 and 10 days was detected. The specific results are shown in Table 2.

[0090] [Table 2]

[0091] The analytical method for the related substances was as follows: an appropriate amount of sample was taken, diluted with methanol-water (volume ratio 32:68) to prepare a solution containing approximately 0.5 mg of edaravone per 1 mL, which was used as the test solution. A precise amount was weighed out and diluted with solvent to prepare a solution containing approximately 5 μg of edaravone per 1 mL, which was used as the control solution. 5 mg each of impurity control samples SCR-756 and SCR-757 were precisely weighed out, placed in a 100 mL volumetric flask, dissolved with solvent using ultrasound, diluted to scale, and shaken well to prepare the impurity storage solution. Additionally, 10 mg of edaravone control sample was precisely weighed out, placed in a 20 mL volumetric flask, dissolved with 5 mL of methanol, 1 mL of the impurity storage solution was added, diluted with solvent to scale, and shaken well to prepare the system-compatible solution. According to the high-performance liquid chromatography (Chinese Pharmacopoeia 2015 Edition, General Rules for Four Parts 0512) test, octadecylsilane-bound silica gel was used as the packing material (Agilent Eclipse plus C18 4.6×150 mm, 3.5 μm), 0.5% triethylamine (pH adjusted to 6.3 with phosphoric acid) was used as mobile phase A, and methanol as mobile phase B. Linear gradient elution was performed according to the table below, with a detection wavelength of 248 nm. 10 μL of system-compatible solution was precisely measured and injected into the liquid chromatograph, and the chromatogram was recorded. Impurities SCR-756, SCR-757, and edaravone appeared as peaks in that order, and the retention time of the edaravone peak was approximately 6 minutes. 10 μL of the test solution and the control solution were precisely measured and injected into the liquid chromatograph, and the chromatograms were recorded.

[0092] [Table 3]

[0093] Example 2 Propylene glycol was heated to 50-60°C, edaravone was added, and the mixture was stirred until completely dissolved to obtain the drug solution. The drug solution was then cooled to below 25°C, and dexborneol was added and stirred until completely dissolved. An appropriate amount of antioxidant (sodium pyrosulfite, sodium bisulfite, L-cysteine ​​hydrochloride, can be used alone or in combination) was added to water below 25°C and stirred until dissolved. The antioxidant solution was slowly added to the drug solution while stirring, and water was slowly added until the volume was close to the prescribed amount. The pH was adjusted to 4.5±0.2 with 0.1 mol / L hydrochloric acid and sodium hydroxide solution, and finally water was added to reach the prescribed volume (as shown in Table 3). The drug solution was filtered, filled with nitrogen, injected and sealed, and sterilized. The properties of the sample and the status of edaravone impurities were examined in detail, and the results are shown in Table 4.

[0094] [Table 4]

[0095] [Table 5]

[0096] Formulations 1 and 2 contain significantly lower amounts of edaravone-related impurities compared to Formulation 3.

[0097] The analytical methods for the related substances are as follows: According to the high-performance liquid chromatography assay (Appendix VI E, Part 2, 2010 edition of the Chinese Pharmacopoeia), octadecylsilane-conjugated silica gel was used as the packing material (Waters Sunfire C18, 4.6 × 250 mm, 5.0 μm), a 0.02 mol / L ammonium acetate solution (pH adjusted to 4.0 with glacial acetic acid) was used as mobile phase A, and acetonitrile was used as mobile phase B. Linear gradient elution was performed according to the table below. Detection wavelength: 254 nm; Flow rate: 1.0ml / min; Sample volume: 20 μl; Solvent: 0.02 mol / L ammonium acetate solution (pH adjusted to 4.0 with glacial acetic acid) - acetonitrile (volume ratio 80:20); Test solution: Take 5 ml of this product, place it in a 20 ml volumetric flask, add solvent, and dilute until it reaches the scale. Control solution: This can be obtained by accurately measuring 1 ml of the test solution, placing it in a 200 ml volumetric flask, and diluting it to the scale by adding solvent.

[0098] [Table 6]

[0099] Example 3: Preparation of compounds SCR-756 and SCR-757

[0100] [ka]

[0101] Synthesis step: (1) Production of intermediate 1 39.92g of Na was divided and added to 1.25L of anhydrous ethanol, maintained at 25-40°C, stirred at 50°C until the Na was completely dissolved and the solution was clear, added in a dark place where light could not penetrate, 250g of edaravone solid was divided and added at 0-5°C, stirred to obtain a cloudy liquid, protected with an N2 balloon, and covered with a black plastic bag to avoid light, and 203.11g of chloroacetone was dissolved in 750mL of anhydrous ethanol to obtain an ethanol solution, which was added directly to the dropping hopper, and the above ethanol solution was added dropwise at -5-0°C, protected with an N2 balloon, and covered with a black plastic bag to avoid light, stirred at 0-5°C for 2 hours, monitoring that most of the edaravone raw material had been consumed by TLC (petroleum ether:ethyl acetate = 1:1), and while stirring, the reaction mixture was poured into 4L of ice water, filtered, the filtered cake was washed with 600mL*3 of water, beaten with 200mL of ethyl acetate, filtered to obtain a total of 37g of intermediate 1.

[0102] (2) Production of intermediate 2 37 g of intermediate 1 was placed in a 3 L three-necked flask, protected with an N2 balloon, and 650 mL of dichloroethane and 325 mL of anhydrous dioxane were added using a hopper. Vacuum was applied and the mixture was stirred until completely dissolved. At a stirring temperature of 0-5°C, 100 g of type 4A molecular sieve and 69.41 g of sulfur trioxide-dioxane adduct were added in portions. The mixture was heated to 100°C and reacted for 8 hours. After 8 hours, the mixture was cooled to 25°C, filtered, and the filter cake was washed twice with anhydrous dichloromethane. The filter cake and 600 mL of anhydrous dichloromethane were stirred and filtered to remove large molecular sieve particles. The filtrate was stirred for 5 minutes and then filtered. The filter cake was washed twice with anhydrous dichloromethane to obtain a crude product. The crude product was beaten with ethanol and filtered to obtain 30 g of solid (intermediate 2).

[0103] (3) Production of compounds SCR-756 and SCR-757 Add 30g of intermediate 2 to a 2L three-necked flask, protect with an N2 balloon, add 600mL of anhydrous MeOH using a hopper, create a vacuum, and stir in a dry ice bath, then 0-5 o The mixture was maintained in 1C, 8.85 g of NaBH4 was added in fractions, and the reaction mixture was stirred at 60°C for 3 hours. After that, the solvent was spin-dried, and compounds SCR-756 and SCR-757 were obtained by HPLC isolation (chromatographic column: YMC-Triart Prep C18 250*50 mm*10 μm, mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile], acetonitrile %: 0%~28.5%, 19 mins).

[0104] The structures of compounds SCR-756 and SCR-757 were verified using nuclear magnetic resonance.

[0105] Nuclear magnetic resonance (NMR) spectrum Instrument: BRUKER AV-400 Nuclear Magnetic Resonance Spectrometer Solvent: DMSO-d6 Internal standard: TMS Temperature: 300K.

[0106] The hydrogen spectrum, carbon spectrum, and nuclear magnetic data for SCR-756 are shown in Tables 5-1 and 5-2.

[0107] [ka]

[0108] [Table 7]

[0109] [Table 8]

[0110] The hydrogen spectrum, carbon spectrum, and nuclear magnetic data for SCR-757 are shown in Tables 6-1 and 6-2.

[0111] [ka]

[0112] [Table 9]

[0113] [Table 10]

[0114] Furthermore, the COSY, HSQC, and HMBC spectra of SCR-756 and SCR-757 are shown in Figures 1 to 6, respectively.

[0115] As a result, it was found that SCR-756 has the structure shown in formula I, and SCR-757 has the structure shown in formula II.

[0116] Embodiments of the present invention have been described above. However, the present invention is not limited to the embodiments described above. Any modifications, equivalent changes, improvements, etc., made without departing from the spirit and principles of the present invention should be included in the claims of the present invention. [Brief explanation of the drawing]

[0117] [Figure 1] This is the COSY spectrum of the SCR-756. [Figure 2] This is the HSQC spectrum of SCR-756. [Figure 3] This is the HMBC spectrum of SCR-756. [Figure 4] This is the COSY spectrum of the SCR-757. [Figure 5] This is the HSQC spectrum of SCR-757. [Figure 6] This is the HMBC spectrum of the SCR-757.

Claims

1. A pharmaceutical composition comprising 1.0 to 3.0 milligrams / milliliter of edaravone, 0.2 to 1.0 milligrams / milliliter of dexborneol, 0.95 to 1.05 milligrams / milliliter of sodium pyrosulfite, propylene glycol, and water for injection, The active ingredients of the aforementioned pharmaceutical composition are edaravone and dexborneol. The structural formula of the aforementioned dexborneol is, 【Chemistry 1】 A pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, characterized in that the weight ratio of edaravone to dexborneol is 1:1 to 4:

1.

3. The pharmaceutical composition according to claim 1, characterized in that the weight ratio of edaravone to dexborneol is 4:

1.

4. The pharmaceutical composition according to claim 1, characterized in that the weight ratio of edaravone, dexborneol, and sodium pyrosulfite in the pharmaceutical composition is 4:1:

2.

5. The edaravone content in the aforementioned pharmaceutical composition is 2.0 milligrams / milliliter, and / or, The content of dexborneol in the pharmaceutical composition is 0.2 to 1.0 milligrams / milliliter, and / or The pharmaceutical composition according to any one of claims 1 to 4, characterized in that the sodium pyrosulfite content is 0.97 to 1.03 milligrams / milliliter.

6. The pharmaceutical composition contains 0.5 milligrams / milliliter and / or, The pharmaceutical composition according to claim 5, characterized in that the sodium pyrosulfite content is 1.0 milligram / milliliter.

7. The aforementioned pharmaceutical composition contains formula I: 【Chemistry 2】 The pharmaceutical composition according to any one of claims 1 to 6, further comprising a compound represented by or a pharmaceutically acceptable salt thereof.

8. The pharmaceutical composition according to claim 7, characterized in that the weight ratio of the compound of formula I or a pharmaceutically acceptable salt thereof to edaravone is 0.3% or less.

9. The aforementioned pharmaceutical composition contains Formula II: 【Transformation 3】 The pharmaceutical composition according to any one of claims 1 to 8, further comprising a compound represented by or a pharmaceutically acceptable salt thereof.

10. The pharmaceutical composition according to claim 9, characterized in that the weight ratio of the compound of formula II or a pharmaceutically acceptable salt thereof to edaravone is 0.3% or less.

11. Formula I: 【Chemistry 4】 The compound indicated by or a pharmaceutically acceptable salt thereof.

12. Formula II: 【Transformation 5】 The compound indicated by or a pharmaceutically acceptable salt thereof.

13. Use of the pharmaceutical composition according to any one of claims 1 to 10 in the manufacture of a pharmaceutical formulation for the treatment of stroke or amyotrophic lateral sclerosis.

14. Use of the compound represented by Formula I as described in claim 11 or a pharmaceutically acceptable salt thereof and / or the compound represented by Formula II as described in claim 12 or a pharmaceutically acceptable salt thereof in quality control of the pharmaceutical composition or pharmaceutical preparation according to any one of claims 1 to 10.

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