A stable pharmaceutical composition

Abstract

A stable pharmaceutical composition belongs to the field of pharmaceutical technology. The pharmaceutical composition, whose active ingredients are edaravone and dextrorotatory borneol, can unexpectedly control the contents of its unique impurities SCR-756 and impurity SCR-757, thereby solving the problems of impurities and product quality being difficult to control and short storage period from the source.

Description

[0001] This application claims the priority of the prior application with patent application number 202010827343.0 and invention name “A stable pharmaceutical composition” filed by the applicant with the State Intellectual Property Office of China on August 17, 2020. The entire text of the prior application is incorporated into this application by reference. Technical Field

[0002] The invention belongs to the field of medical technology and relates to a stable pharmaceutical composition, in particular to a pharmaceutical composition whose active ingredients are edaravone (3-methyl-1-phenyl-2-pyrazol-5-one) and dextrorotatory borneol. Background Art

[0003] In the past 15 years, stroke is the second leading cause of death and long-term and serious neurological diseases in the world and the first in China. The Stroke Medical Quality Evaluation Study (CHINA QUEST) investigated the epidemiological status of acute stroke treatment in my country. The study showed that the average time from onset to hospital admission for ischemic stroke patients in my country was 20.1 hours, and a considerable number of patients arrived at the hospital after 24 hours. These patients have not received effective drug treatment. The edaravone injection, which is widely used in the clinic to treat acute ischemic stroke, clearly states in the instructions for use and dosage that the drug should be started within 24 hours after onset.

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

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

[0006] The invention provides a pharmaceutical composition, which comprises edaravone, dextrorotatory borneol, sodium pyrosulfite and a solvent, wherein the content of the sodium pyrosulfite is 0.95-1.05 mg / ml.

[0007] In some embodiments, the pharmaceutical composition comprises edaravone, dextrorotatory borneol, sodium metabisulfite, a cosolvent and a solvent, and the content of the sodium metabisulfite is 0.95 to 1.05 mg / ml.

[0008] In some embodiments, the content of sodium metabisulfite is 0.95-1.05 mg / ml, for example, 0.97-1.03 mg / ml, exemplified by 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, 1.05 mg / ml. In some embodiments, the content of sodium metabisulfite is 1.0 mg / ml.

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

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

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

[0013] According to the technical solution of the present invention, the content of dextrorotatory borneol 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 dextrorotatory borneol in the pharmaceutical composition is 0.5 mg / ml.

[0014] In some embodiments, the content of edaravone in the pharmaceutical composition is 2.0 mg / ml, the content of dextrorotatory borneol is 0.5 mg / ml, and the content of sodium metabisulfite is 1.0 mg / ml.

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

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

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

[0018] According to the technical solution of the present invention, the content of the co-solvent in the pharmaceutical composition is 0.01-0.15 ml / ml, for example, 0.03-0.12 ml / ml, exemplified by 0.05 ml / ml, 0.08 ml / ml, and 0.1 ml / ml.

[0019] In some embodiments, the content of edaravone in the pharmaceutical composition is 2.0 mg / ml, the content of dextrorotatory borneol is 0.5 mg / ml, the content of sodium metabisulfite is 1.0 mg / ml, and the content of propylene glycol is 0.08 ml / ml.

[0020] In some embodiments, the content of edaravone in the pharmaceutical composition is 2.0 mg / ml, the content of dextrorotatory borneol is 0.5 mg / ml, the content of sodium metabisulfite is 1.0 mg / ml, the content of propylene glycol is 0.08 ml / ml, 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 5 ml of solution, which contains 10 mg of edaravone, 2.5 mg of dextrorotatory borneol, 5 mg of sodium metabisulfite, 0.4 ml of propylene glycol, and the rest is water for injection.

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

[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%, less than 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%, less than 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, dextrorotatory borneol, sodium pyrosulfite, a cosolvent and a solvent, wherein the content of the sodium pyrosulfite 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 an amount of less than 0.3% by weight of the compound to be treated with edaravone.

[0030]

[0031] On the other hand, the present invention provides a pharmaceutical composition, comprising edaravone, dextrorotatory borneol, sodium pyrosulfite, a cosolvent and a solvent, wherein the content of the sodium pyrosulfite is 0.95 to 1.05 mg / ml, and the pharmaceutical composition further comprises a compound of formula II or a pharmaceutically acceptable salt thereof in an amount of less than 0.3% by weight of the compound to be treated with edaravone.

[0032]

[0033] On the other hand, the present invention provides a pharmaceutical composition, which comprises edaravone, dextrorotatory borneol, sodium metabisulfite, a cosolvent and a solvent, wherein the content of the sodium metabisulfite is 0.95 to 1.05 mg / ml, and the pharmaceutical composition further comprises the compound of formula I or a pharmaceutically acceptable salt thereof in an amount less than 0.3% by weight of the edaravone, and the compound of formula II or a pharmaceutically acceptable salt thereof in an amount less than 0.3% by weight of the edaravone.

[0034] The present invention also provides a compound represented by formula I or a pharmaceutically acceptable salt thereof,

[0035]

[0036] The present invention also provides a compound represented by formula II or a pharmaceutically acceptable salt thereof,

[0037]

[0038]

[0039] According to the technical solution 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.

[0040] The present invention also provides the use of the above-mentioned pharmaceutical composition in preparing a pharmaceutical preparation for treating cerebral stroke.

[0041] The present invention also provides use of the above-mentioned pharmaceutical composition in treating cerebral stroke.

[0042] The present invention also provides the above-mentioned pharmaceutical composition for treating cerebral stroke.

[0043] The present invention also provides use of the above-mentioned pharmaceutical composition in preparing a drug for treating amyotrophic lateral sclerosis or related disorders.

[0044] The present invention also provides use of the above pharmaceutical composition in treating amyotrophic lateral sclerosis or related disorders.

[0045] The present invention also provides the above pharmaceutical composition for treating amyotrophic lateral sclerosis or related disorders.

[0046] The present invention also provides a method for preventing and / or treating stroke, comprising administering a therapeutically effective amount of the pharmaceutical composition or pharmaceutical preparation to a subject, such as a human.

[0047] The present invention also provides a method for preventing and / or treating amyotrophic lateral sclerosis or related disorders, comprising administering a therapeutically effective amount of the pharmaceutical composition or pharmaceutical preparation to a subject, such as a human.

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

[0049] The present invention also provides the use of the compound represented by the above formula II or a pharmaceutically acceptable salt thereof in the quality control of the pharmaceutical composition or pharmaceutical preparation.

[0050] The present invention also provides a method for preparing a compound of formula I or its tautomer, characterized in that intermediate 2 is subjected to a reduction reaction to obtain a compound of formula I or its tautomer,

[0051]

[0052] The present invention also provides a method for preparing a compound of formula II or its tautomer, characterized in that intermediate 2 is subjected to a reduction reaction to obtain a compound of formula II or its tautomer,

[0053]

[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 a compound of formula I or its tautomer.

[0055] 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 a compound of formula II or its tautomer.

[0056] 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.

[0057] In some embodiments, the reducing agent is selected from sodium borohydride.

[0058] In some embodiments, the solvent is selected from protic solvents.

[0059] In some embodiments, the solvent is selected from one or more of water, methanol, ethanol, propanol, and isopropanol.

[0060] In some embodiments, the solvent is selected from methanol.

[0061] The present invention also provides a method for preparing intermediate 2, characterized in that intermediate 1 reacts with a sulfonating reagent to obtain intermediate 2,

[0062]

[0063] In some embodiments, the sulfonating agent is sulfur trioxide and / or an adduct of sulfur trioxide.

[0064] In some embodiments, the sulfonating agent is sulfur trioxide·dioxane adduct.

[0065] In some embodiments, the intermediate 1 can be prepared by the following reaction:

[0066]

[0067] Beneficial Effects of the Invention

[0068] The inventors found in the process of drug development that the pharmaceutical composition containing active ingredients edaravone and dextrorotatory borneol is prone to two novel impurities: impurity SCR-756 and impurity SCR-757. Once impurities SCR-756 and impurity SCR-757 are produced, their content usually exceeds the identification threshold of 0.1%, and the content of the two is difficult to control within a reasonable range. What is more complicated is that the stability test shows that the content of impurity SCR-756, impurity SCR-757 and total impurities of edaravone will increase with the increase of storage temperature and storage time. The conventional methods such as controlling temperature, pH value, cosolvent and preparation time in the process cannot effectively solve the above problems. The inventors unexpectedly found in a large number of experiments that the amount of sodium pyrosulfite has a great influence on the content of impurities SCR-756, impurity SCR-757 and total impurities in the pharmaceutical composition. If the amount of sodium pyrosulfite is too low or too high, impurities SCR-756, impurity SCR-757 and total impurities cannot be effectively controlled. Therefore, the present invention adds sodium metabisulfite and controls its dosage within a suitable range, thereby effectively solving technical problems such as impurities in the composition itself and product quality being difficult to control, and the impurity content increasing at a faster rate as the storage temperature increases or the storage period prolongs. In particular, the content of impurity SCR-756, impurity SCR-757 and total impurities of edaravone in the pharmaceutical composition can be unexpectedly controlled, solving the problems of impurities and product quality being difficult to control, short storage period, and drug safety from the source.

[0069] The term "tautomer" herein refers to structural isomers with different energies that can be converted to each other through a low energy barrier. If tautomerism is possible (such as in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (proton tautomers) (also known as protopictautomers) include interconversions through proton migration, such as keto-enol isomerization and imine-enamine isomerization. Unless otherwise indicated, all tautomeric forms of the compounds of the present invention are within the scope of the present invention.

[0070] Those skilled in the art will know that carbonyl compounds containing α-H have keto-enol tautomerism, and tautomers can be mutually converted and generally exist in equilibrium. Therefore, those skilled in the art will know that both Formula I and Formula II compounds of the present invention have tautomerism and tautomers can be mutually converted. In certain embodiments of the present invention, for the convenience of description and expression, compounds with tautomerism can be represented only by keto (such as Formula I or Formula II compounds), or can be represented only by enol (such as Formula I' or Formula II' compounds). Herein, compounds shown in Formula I or Formula II include both keto compounds and corresponding enol compounds.

[0071] BRIEF DESCRIPTION OF THE DRAWINGS

[0072] Figure 1 is the COSY spectrum of SCR-756;

[0073] Figure 2 is the HSQC spectrum of SCR-756;

[0074] Figure 3 is the HMBC spectrum of SCR-756;

[0075] Figure 4 is the COSY spectrum of SCR-757;

[0076] Figure 5 is the HSQC spectrum of SCR-757;

[0077] Figure 6 This is the HMBC spectrum of SCR-757. DETAILED DESCRIPTION

[0078] The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions and explanations 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 included in the scope that the present invention is intended to protect.

[0079] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0080] Example 1: Dosage of Sodium Pyrosulfite and Investigation of Related Substances

[0081] Propylene glycol is heated to 50-60°C, edaravone is added, and stirred until completely dissolved to obtain a drug solution; the drug solution is cooled to below 25°C, dextrorotatory borneol (structure: ), stir until completely dissolved. Add sodium metabisulfite to an appropriate amount of water below 25°C, stir until dissolved; slowly add the sodium metabisulfite solution to the drug solution while stirring, and continue to slowly add water to the prescribed amount. Use 0.1mol / L hydrochloric acid and sodium hydroxide solution to adjust the pH to 4.5±0.2, and finally add water to the prescribed amount, filter the drug solution, fill with nitrogen, and sterilize.

[0082] According to 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 prescriptions are shown in Table 1.

[0083] Table 1: Prescription of pharmaceutical compositions F1-F5

[0084] Prescription ingredients F1 F2 F3 F4 F5 Edaravone 10mg 10mg 10mg 10mg 10mg Borneol 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 Moderate Moderate Moderate Moderate Moderate Sodium hydroxide Moderate Moderate Moderate Moderate Moderate Water for injection Add to 5mL Add to 5mL Add to 5mL Add to 5mL Add to 5mL

[0085] The relevant substances of the pharmaceutical composition in Table 1 were analyzed, and the contents of impurity SCR-756, impurity SCR-757 and total impurities of edaravone were detected after the samples were placed at 60°C for 0 day and 10 days. The details are shown in Table 2.

[0086] Table 2: Content of impurity SCR-756, impurity SCR-757 and total impurities [1] Survey Results

[0087]

[0088]

[0089] Note: [1] “Content” refers to the weight ratio of impurity SCR-756, impurity SCR-757 and total impurities to edaravone in the pharmaceutical composition.

[0090] The analysis method of related substances is as follows: take an appropriate amount of sample, add solvent methanol-water (volume ratio 32:68) to dilute to a solution containing about 0.5 mg of edaravone per 1 mL, as the test solution; accurately measure an appropriate amount, dilute with solvent to a solution containing about 5 μg of edaravone per 1 mL, as the reference solution. Accurately weigh 5 mg of impurity reference substances SCR-756 and SCR-757 and place them in a 100 mL volumetric flask, add solvent to dissolve and dilute to the scale, shake well, and use as impurity stock solution; accurately weigh 10 mg of edaravone reference substance and place it in a 20 mL volumetric flask, add 5 mL of methanol to dissolve, add 1 mL of impurity stock solution, add solvent to dilute to the scale, shake well, and use as system suitability solution. According to the high performance liquid chromatography method (Chinese Pharmacopoeia 2015 Edition Part IV General Rules 0512), octadecylsilane bonded silica gel was used as the filler (Agilent Eclipse plus C18 4.6×150mm, 3.5μm); 0.5% triethylamine (pH adjusted to 6.3 with phosphoric acid) was used as mobile phase A, methanol was used as mobile phase B, and linear gradient elution was performed according to the following table; the detection wavelength was 248nm. Accurately measure 10μL of the system suitability solution and inject it into the liquid chromatograph, record the chromatogram, impurity SCR-756, impurity SCR-757 and edaravone peaked in turn, and the retention time of the edaravone peak was about 6 minutes. Accurately measure 10μL of the test solution and the control solution, respectively, inject them into the liquid chromatograph, and record the chromatogram.

[0091]

[0092]

[0093] Example 2

[0094] Heat propylene glycol to 50-60°C, add edaravone, stir until completely dissolved, and obtain a liquid medicine; cool the liquid medicine to below 25°C, add dextrorotatory borneol thereto, and stir until completely dissolved. Add an antioxidant (sodium pyrosulfite, sodium bisulfite, L-cysteine ​​hydrochloride, which can be used alone or in combination) to an appropriate amount of water below 25°C and stir until dissolved; slowly add the above antioxidant solution to the liquid medicine while stirring, and continue to slowly add water to the amount close to the prescription amount. Use 0.1 mol / L hydrochloric acid and sodium hydroxide solution to adjust the pH to 4.5±0.2, and finally add water to the prescribed amount (as shown in Table 3), filter the liquid medicine, fill it with nitrogen, and sterilize it. Focus on the properties of the samples and the impurities of edaravone, and the results are shown in Table 4.

[0095] Table 3

[0096] 3000 count meter Prescription 1 Prescription 2 Prescription 3 Edaravone(g) 30 30 30 Dextrorotatory Borneol(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 up to (L) 15 15 15

[0097] Table 4

[0098]

[0099]

[0100] The amounts of edaravone-related impurities in Prescriptions 1 and 2 are significantly lower than those in Prescription 3.

[0101] The analysis methods of relevant substances are as follows:

[0102] Determined by high performance liquid chromatography (Appendix VI E of Part II of the 2010 edition of the Chinese Pharmacopoeia), using octadecylsilane bonded silica gel as filler (Waters sunfire C18, 4.6×250 mm, 5.0 μm); using 0.02 mol / L ammonium acetate solution (adjusted to pH 4.0 with glacial acetic acid) as mobile phase A, acetonitrile as mobile phase B, and performing linear gradient elution as shown in the following table;

[0103] Detection wavelength: 254nm;

[0104] Flow rate: 1.0ml / min;

[0105] Injection volume: 20 μl;

[0106] Solvent: 0.02 mol / L ammonium acetate solution (adjust pH to 4.0 with glacial acetic acid)-acetonitrile (volume ratio 80:20);

[0107] Test solution: Take 5 ml of the product and place it in a 20 ml volumetric flask, add solvent to dilute to the mark, and you have it;

[0108] Control solution: Accurately measure 1 ml of the test solution and place it in a 200 ml volumetric flask, then add solvent to dilute to the mark.

[0109]

[0110] Example 3 Preparation of Compounds SCR-756 and SCR-757

[0111]

[0112] Synthesis steps:

[0113] (1) Preparation of Intermediate 1

[0114] 39.92g Na was added to 1.25L anhydrous ethanol in batches, kept stable at 25-40℃, and stirred at 50℃ until Na was completely dissolved and clarified; 250g edaravone solid was added in batches at 0-5℃ in a dark place away from light, and stirred to obtain a turbid liquid; N2 balloon was added for protection, and black plastic bag was used to avoid light; 203.11g chloroacetone was dissolved in 750mL anhydrous ethanol to form an ethanol solution, which was directly added to the dropping funnel; the above ethanol solution was added dropwise at -5-0℃, N2 balloon was used for protection, black plastic bag was used to avoid light, and stirred at 0-5℃ for 2h; TLC (petroleum ether: ethyl acetate = 1:1) monitored that most of the edaravone raw material was consumed; under stirring, the reaction solution was poured into 4L ice water; filtered, the filter cake was washed with 600mL*3 water, slurried with 200mL ethyl acetate, and 37g of intermediate 1 was obtained by filtration.

[0115] (2) Preparation of Intermediate 2

[0116] 37 g of intermediate 1 was added to a 3L three-necked flask, protected by a N2 balloon, 650 mL of dichloroethane and 325 mL of anhydrous dioxane were added through a feeding funnel, vacuumed, stirred until completely dissolved, 100 g of 4A molecular sieve and 69.41 g of sulfur trioxide·dioxane adduct were added in batches under stirring at 0-5°C, the temperature was raised to 100°C and reacted for 8 hours, the temperature was lowered to 25°C after 8 hours, filtered, the filter cake was rinsed twice with anhydrous dichloromethane, the filter cake and 600 mL of anhydrous dichloromethane were stirred and filtered to remove large particles of molecular sieve; the filtrate was stirred for 5 minutes, filtered again, the filter cake was rinsed twice with anhydrous dichloromethane to obtain a crude product, the crude product was slurried with ethanol, and 30 g of solid (intermediate 2) was obtained by filtration.

[0117] (3) Preparation of compounds SCR-756 and SCR-757

[0118] 30 g of intermediate 2 was added to a 2 L three-necked flask, protected by a N2 balloon, 600 mL of anhydrous MeOH was added through a feeding funnel, the flask was evacuated, and stirred in a dry ice bath, maintained at 0-5°C, 8.85 g of NaBH4 was added in batches, the reaction solution was stirred at 60°C for 3 h, the solvent was dried, and the solution was separated by HPLC (chromatographic column: YMC-Triart Prep C18250*50mm*10μm; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile]; acetonitrile%: 0%-28.5%, 19mins) to obtain compounds SCR-756 and SCR-757.

[0119] The structures of compounds SCR-756 and SCR-757 were confirmed by nuclear magnetic resonance.

[0120] Nuclear Magnetic Resonance Spectroscopy (NMR)

[0121] Instrument: BRUKER AV-400 NMR instrument

[0122] Solvent: DMSO-d6

[0123] Internal standard: TMS

[0124] Temperature: 300K.

[0125] The hydrogen spectrum and carbon spectrum NMR data of SCR-756 are shown in Table 5-1 and Table 5-2.

[0126]

[0127] Table 5-1: Hydrogen spectrum measurement results of SCR-756

[0128]

[0129]

[0130] Table 5-2: Carbon spectrum test results of SCR-756

[0131]

[0132] The hydrogen spectrum and carbon spectrum NMR data of SCR-757 are shown in Table 6-1 and Table 6-2.

[0133]

[0134] Table 6-1: Hydrogen spectrum measurement results of SCR-757

[0135]

[0136]

[0137] Table 6-2: Carbon spectrum test results of SCR-757

[0138]

[0139] In addition, the COSY spectra, HSQC spectra and HMBC spectra of SCR-756 and SCR-757 are shown in Figure 1 to Figure 6 .

[0140] The results show that SCR-756 has a structure as shown in Formula I, and SCR-757 has a structure as shown in Formula II.

[0141] The above is an explanation of the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises edaravone, dextrorotatory borneol, sodium pyrosulfite, propylene glycol and water for injection, wherein the content of the sodium pyrosulfite is 0.95-1.05 mg / ml, the content of edaravone in the pharmaceutical composition is 1.0-3.0 mg / ml, the content of dextrorotatory borneol in the pharmaceutical composition is 0.2-1.0 mg / ml, the content of the propylene glycol is 0.01-0.15 ml / ml, and the pharmaceutical composition further comprises a compound of formula I or a pharmaceutically acceptable salt thereof, the weight ratio of the compound of formula I or a pharmaceutically acceptable salt thereof to the edaravone is below 0.3%, and the pharmaceutical composition further contains a compound of formula II or a pharmaceutically acceptable salt thereof, the weight ratio of the compound of formula II or a pharmaceutically acceptable salt thereof to the edaravone is less than 0.3%; the weight ratio of edaravone, dextrorotatory borneol and sodium metabisulfite in the pharmaceutical composition is 4:1:

2.

2. The pharmaceutical composition according to claim 1, characterized in that The content of edaravone in the pharmaceutical composition is 1.5-2.5 mg / ml.

3. The pharmaceutical composition according to claim 1, characterized in that The content of edaravone is 2.0 mg / ml.

4. The pharmaceutical composition according to claim 1, characterized in that The content of dextrorotatory borneol in the pharmaceutical composition is 0.3-0.8 mg / ml.

5. The pharmaceutical composition according to claim 1, characterized in that The content of dextrorotatory borneol in the pharmaceutical composition is 0.5 mg / ml.

6. The pharmaceutical composition according to claim 1, characterized in that The content of the sodium pyrosulfite is 0.97-1.03 mg / ml.

7. The pharmaceutical composition according to claim 1, characterized in that The content of the sodium pyrosulfite is 1.0 mg / ml.

8. Use of the pharmaceutical composition according to any one of claims 1 to 7 in the preparation of a pharmaceutical preparation for treating stroke, amyotrophic lateral sclerosis or related disorders.

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