Stable pharmaceutical composition

Abstract

The invention belongs to the technical field of medicines, and discloses a stable pharmaceutical composition. According to the pharmaceutical composition with the active ingredients of edaravone and dextroborneol, the content of the specific impurity SCR-756 and impurity SCR-757 of edaravone and dextroborneol can be controlled unexpectedly, and the problems that the quality of the impurities and the product is difficult to control, and the storage life is short are solved from the source.

Description

[0001] This application claims the priority of a prior application with the patent application number 202010827343.0 and the invention title "A Stable Pharmaceutical Composition" submitted by the applicant to the China National Intellectual Property Administration on August 17, 2020. The full text of the prior application is incorporated into this application by reference. Technical Field

[0002] The present invention belongs to the field of pharmaceutical technology and relates to a stable pharmaceutical composition. Specifically, it relates to a pharmaceutical composition with edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) and dextrorbornol as active ingredients. Background Art

[0003] The China Quality Evaluation of Stroke Therapy (CHINA QUEST) investigated the epidemiological situation of the current treatment status of acute stroke in China. The research shows that the average time from the onset of ischemic stroke in Chinese patients to the hospital is 20.1 hours, and a considerable number of patients arrive at the hospital more than 24 hours after the onset. These patients have not received effective drug treatment. For the edaravone injection widely used clinically to treat acute ischemic stroke, the usage and dosage section of its instruction manual clearly states that administration should be started within 24 hours after the 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 treatment effect, good stability, and high drug safety has become an urgent technical problem in this field. Summary of the Invention

[0006] The present invention provides a pharmaceutical composition, which comprises edaravone, dextrorbornol, sodium metabisulfite, and a solvent, and the content of sodium metabisulfite is 0.95 - 1.05 mg / ml.

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

[0008] In some embodiments, the content of sodium metabisulfite is 0.95 to 1.05 mg / mL, for example, 0.97 to 1.03 mg / mL, and 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, 1.05 mg / mL. In some embodiments, the content of the sodium metabisulfite is 1.0 mg / mL.

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

[0011] In some embodiments, the weight ratio of edaravone, dextrancamphor 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 dextrancamphor 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 dextrancamphor 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 dextrancamphor 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-butanol.

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

[0017] In some embodiments, the co-solvent 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 exemplarily 0.05 ml / ml, 0.08 ml / ml, 0.1 ml / ml.

[0019] In some embodiments, the content of edaravone in the pharmaceutical composition is 2.0 mg / ml, the content of dextrancamphor alcohol 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 dextrancamphor alcohol 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 dose (single dose) of the pharmaceutical composition is 5 ml of solution, which contains 10 mg of edaravone, 2.5 mg of dextrancamphor alcohol, the content of sodium metabisulfite is 5 mg, 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 dextrancamphor alcohol.

[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 a pharmaceutically acceptable salt thereof to the edaravone is below 0.3%, for example, below 0.29%, below 0.28%, 0.27%, below 0.26%, below 0.25%, below 0.2%, below 0.15%, below 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 a pharmaceutically acceptable salt thereof to the edaravone is below 0.3%, for example, below 0.29%, below 0.28%, 0.27%, below 0.26%, below 0.25%, below 0.2%, below 0.15%, below 0.1%.

[0029] On the other hand, the present invention provides a pharmaceutical composition, which comprises edaravone, dextronicamphor, sodium metabisulfite, a co-solvent and a solvent. The content of the sodium metabisulfite is 0.95 to 1.05 mg / mL. The pharmaceutical composition further contains a compound of formula I or a pharmaceutically acceptable salt thereof, with a weight ratio to edaravone of less than 0.3%.

[0030]

[0031] On the other hand, the present invention provides a pharmaceutical composition, which comprises edaravone, dextronicamphor, sodium metabisulfite, a co-solvent and a solvent. The content of the sodium metabisulfite is 0.95 to 1.05 mg / mL. The pharmaceutical composition further contains a compound of formula II or a pharmaceutically acceptable salt thereof, with a weight ratio to edaravone of less than 0.3%.

[0032]

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

[0034] The present invention also provides a compound of formula I or a pharmaceutically acceptable salt thereof.

[0035]

[0036] The present invention also provides a compound of formula II or a pharmaceutically acceptable salt thereof.

[0037]

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

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

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

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

[0042] The present invention also provides the use of the above-mentioned 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-mentioned 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 the pharmaceutical composition or pharmaceutical preparation to a subject to be treated, such as a human.

[0046] 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 to be treated, such as a human.

[0047] The present invention also provides the use of the compound shown in the above formula I 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 shown in the above formula II or a pharmaceutically acceptable salt thereof in the quality control of the pharmaceutical composition or pharmaceutical preparation.

[0049] The present invention also provides a method for preparing the compound of formula I or a tautomer thereof, which is characterized in that the compound of formula I or a tautomer thereof is obtained by subjecting intermediate 2 to a reduction reaction.

[0050]

[0051] The present invention also provides a method for preparing the compound of formula II or a tautomer thereof, which is characterized in that the compound of formula II or a tautomer thereof is obtained by subjecting intermediate 2 to a reduction reaction.

[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 the compound of formula I or a tautomer thereof.

[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 the compound of formula II or a tautomer thereof.

[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 reacts 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 sulfur trioxide - dioxane adduct.

[0064] In some embodiments, intermediate 1 can be prepared through the following reaction.

[0065]

[0066] Advantages of the present invention

[0067] During the drug development process, the inventors found that a pharmaceutical composition containing the active ingredients edaravone and dextrancamphor easily produced two novel impurities: impurity SCR-756 and impurity SCR-757. Once generated, the contents of impurity SCR-756 and impurity SCR-757 usually exceeded the identification threshold of 0.1%, and it was difficult to control their contents within a reasonable range. Moreover, stability tests showed that the contents of impurity SCR-756, impurity SCR-757, and the total impurities of edaravone increased at an accelerated rate with the increase in storage temperature and the extension of storage time, and these problems could not be effectively solved by conventional methods such as controlling temperature, pH value, cosolvent, and formulation time in the process. However, the inventors unexpectedly found in a large number of experiments that the dosage of sodium metabisulfite had a great influence on the contents of impurity SCR-756, impurity SCR-757, and total impurities in the pharmaceutical composition. If the dosage of sodium metabisulfite was too low or too high, impurity SCR-756, impurity SCR-757, and total impurities could not be effectively controlled. Therefore, the present invention effectively solves the technical problems such as the difficult control of impurities and product quality existing in the composition itself, and the accelerated growth rate of impurity content with the increase in storage temperature or the extension of storage period by adding sodium metabisulfite and controlling its dosage within a suitable range. In particular, it can unexpectedly control the contents of impurity SCR-756, impurity SCR-757, and the total impurities of edaravone in the pharmaceutical composition, and solves the problems of difficult control of impurities and product quality, short storage period, and drug safety from the source.

[0068] As used herein, the term "tautomer" refers to structural isomers that can be interconverted through a low energy barrier and have different energies. If tautomerism is possible (e.g., in solution), a chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions that occur 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.

[0069] Those skilled in the art should be aware that carbonyl compounds containing α-H exhibit keto-enol tautomerism, and the tautomers can interconvert and generally exist in an equilibrium form. Therefore, those skilled in the art should know that the compounds of Formula I and Formula II of the present invention both exhibit tautomerism and the tautomers can interconvert. In certain embodiments of the present invention, for the convenience of description and expression, the compounds exhibiting tautomerism can be represented only in the keto form (such as the compounds of Formula I or Formula II), or can be represented only in the enol form (such as the compounds of Formula I' or Formula II'). In this article, the compounds represented by Formula I or Formula II include both keto compounds and the corresponding enol compounds.

[0070] BRIEF DESCRIPTION OF THE DRAWINGS

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

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

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

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

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

[0076] Figure 6 is the HMBC spectrum of SCR-757. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0077] The technical solutions 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 for illustrative explanation of the present invention and should not be construed as limiting the protection scope 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 specified, the raw materials and reagents used in the following embodiments are commercially available products or can be prepared by known methods.

[0079] Example 1: Investigation of the dosage of sodium metabisulfite and related substances

[0080] Heat propylene glycol to 50-60°C, add edaravone, and stir until completely dissolved to obtain a medicinal solution; cool the medicinal solution to below 25°C, and add dextronicamphor (the structure is ) Stir until completely dissolved. Add sodium metabisulfite to an appropriate amount of water below 25°C and stir until dissolved; slowly add the sodium metabisulfite solution to the medicinal liquid while stirring, and continue to slowly add water until close to the prescription volume. Adjust the pH to 4.5 ± 0.2 with 0.1 mol / L hydrochloric acid and sodium hydroxide solution, and finally add water to a fixed volume to the prescription volume. Filter the medicinal liquid, fill with nitrogen, seal, and sterilize.

[0081] According to the above method, prepare and obtain pharmaceutical compositions with the contents of sodium metabisulfite being 0.5 mg / mL, 0.8 mg / mL, 1.0 mg / mL, 1.2 mg / mL, and 1.5 mg / mL respectively. The specific prescriptions are shown in Table 1.

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

[0083] Prescription Components F1 F2 F3 F4 F5 Edaravone 10 mg 10 mg 10 mg 10 mg 10 mg Dextrancamphorol 2.5 mg 2.5 mg 2.5 mg 2.5 mg 2.5 mg Propylene Glycol (for injection) 0.4 mL 0.4 mL 0.4 mL 0.4 mL 0.4 mL Sodium Pyrosulfite 2.5 mg 4 mg 5 mg 6 mg 7.5 mg Hydrochloric Acid Q.S. Q.S. Q.S. Q.S. Q.S. Sodium Hydroxide Q.S. Q.S. Q.S. Q.S. Q.S. Water for Injection Up to 5 mL Up to 5 mL Up to 5 mL Up to 5 mL Up to 5 mL

[0084] Analyze the related substances of the pharmaceutical compositions in Table 1, and detect the contents of impurity SCR - 756, impurity SCR - 757, and the total impurity of edaravone in the samples at 0 day and after storage for 10 days at a temperature of 60°C. The specific results are shown in Table 2.

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

[0086]

[0087]

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

[0089] The method for related substances analysis is as follows: Take an appropriate amount of the sample, dilute it with methanol-water (volume ratio 32:68) solvent to prepare a solution containing about 0.5 mg of edaravone per 1 mL as the test solution; accurately measure an appropriate amount and dilute it with the solvent to prepare a solution containing about 5 μg of edaravone per 1 mL as the control solution. Accurately weigh 5 mg of impurity reference substance SCR-756 and 5 mg of SCR-757 and place them in a 100 mL volumetric flask, add the solvent, ultrasonically dissolve and dilute to the mark, shake well to obtain the impurity stock solution; separately accurately weigh 10 mg of edaravone reference substance 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, and dilute to the mark with the solvent, shake well to obtain the system suitability solution. According to the high performance liquid chromatography method (General Principles 0512, Volume IV, Chinese Pharmacopoeia 2015 Edition), use octadecylsilane chemically bonded silica gel as the filler (Agilent Eclipse plus C18 4.6×150 mm, 3.5 μm); use 0.5% triethylamine (adjust the pH value to 6.3 with phosphoric acid) as mobile phase A and methanol as mobile phase B, and perform linear gradient elution according to the following table; the detection wavelength is 248 nm. Accurately measure 10 μL of the system suitability solution and inject it into the liquid chromatograph, record the chromatogram, and impurities SCR-756, SCR-757 and edaravone elute in sequence, and the retention time of the edaravone peak is about 6 minutes. Accurately measure 10 μL of the test solution and the control solution respectively, inject them into the liquid chromatograph, and record the chromatogram.

[0090]

[0091]

[0092] Example 2

[0093] Heat propylene glycol to 50 - 60 °C, add edaravone, and stir until completely dissolved to obtain the medicinal solution; cool the medicinal solution to below 25 °C, add dextrorotatory borneol to it, and stir until completely dissolved. Add the antioxidant (sodium metabisulfite, sodium bisulfite, L-cysteine hydrochloride, which can be used alone or in combination of two) to an appropriate amount of water below 25 °C, and stir until dissolved; slowly add the above antioxidant solution to the medicinal solution while stirring, and continue to slowly add water to near the prescription amount. Adjust the pH to 4.5 ± 0.2 with 0.1 mol / L hydrochloric acid and sodium hydroxide solution, and finally add water to make up to the prescription amount (as shown in Table 3), filter the medicinal solution, fill with nitrogen, seal, and sterilize. Focus on investigating the properties of the sample and the edaravone impurities, and the results are shown in Table 4.

[0094] Table 3

[0095] Calculated for 3000 Vials Prescription 1 Prescription 2 Prescription 3 Edaravone (g) 30 30 30 Dextrancamphorol (g) 7.5 7.5 7.5 Sodium Pyrosulfite (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

[0096] Table 4

[0097]

[0098]

[0099] For Formulations 1 and 2, the amount of edaravone-related impurities is significantly lower than that of Formulation 3.

[0100] The related substances analysis method is as follows:

[0101] Determined by high performance liquid chromatography (Appendix VI E, Part II of Chinese Pharmacopoeia 2010 Edition), using octadecylsilane chemically bonded silica gel as the filler (Waters sunfire C18, 4.6×250mm, 5.0μm); using 0.02mol / L ammonium acetate solution (adjusted to pH 4.0 with glacial acetic acid) as mobile phase A and acetonitrile as mobile phase B, and performing linear gradient elution according to the following table;

[0102] Detection wavelength: 254nm;

[0103] Flow rate: 1.0ml / min;

[0104] Injection volume: 20μl;

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

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

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

[0108]

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

[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 absolute ethanol, and the temperature was kept stable at 25 - 40 °C. Then it was stirred at 50 °C until the Na was completely dissolved and clarified. In the dark and away from light, 250 g of edaravone solid was added in batches at 0 - 5 °C, and stirred to obtain a turbid liquid. Protected by an N₂ balloon and shielded from light with a black plastic bag, 203.11 g of chloroacetone was dissolved in 750 mL of absolute ethanol to form an ethanol solution, which was directly added to a dropping funnel. The above ethanol solution was added dropwise at -5 - 0 °C, protected by an N₂ balloon and shielded from light with a black plastic bag, and stirred at 0 - 5 °C for 2 h. 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 4 L of ice water. It was filtered, the filter cake was washed with 600 mL of water * 3, slurried with 200 mL of ethyl acetate, and filtered to obtain 37 g of Intermediate 1 in total.

[0114] (2) Preparation of Intermediate 2

[0115] 37 g of Intermediate 1 was added to a 3 L three-necked flask, protected by an N₂ balloon. 650 mL of dichloroethane and 325 mL of absolute dioxane were added through a feeding funnel. The mixture was evacuated and stirred until completely dissolved. Under stirring at 0 - 5 °C, 100 g of 4A molecular sieve and 69.41 g of sulfur trioxide·dioxane adduct were added in batches. The temperature was raised to 100 °C and reacted for 8 hours. After 8 h, the temperature was lowered to 25 °C, filtered, and 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, then filtered, and the filter cake was rinsed twice with anhydrous dichloromethane to obtain the crude product. The crude product was slurried with ethanol and filtered to obtain 30 g 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 evacuated and stirred in a dry ice bath, maintaining 0 - 5 °C. 8.85 g of NaBH₄ was added in batches. After the reaction solution was stirred at 60 °C for 3 h, the solvent was rotary evaporated. It was separated by HPLC (chromatographic column: YMC-Triart Prep C18 250*50mm*10μm; mobile phase: [water (0.1% trifluoroacetic acid) - acetonitrile]; acetonitrile%: 0% - 28.5%, 19 mins) to obtain Compound SCR-756 and Compound SCR-757.

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

[0119] Nuclear Magnetic Resonance Spectrum (NMR)

[0120] Instrument: BRUKER AV-400 Nuclear Magnetic Resonance Spectrometer

[0121] Solvent: DMSO-d6

[0122] Internal standard: TMS

[0123] Temperature: 300K.

[0124] The 1H NMR and 13C NMR data of SCR-756 are shown in Table 5-1 and Table 5-2.

[0125]

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

[0127]

[0128]

[0129] Table 5-2: Results of 13C NMR Determination of SCR-756

[0130]

[0131] The 1H NMR and 13C NMR data of SCR-757 are shown in Table 6-1 and Table 6-2.

[0132]

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

[0134]

[0135]

[0136] Table 6-2: Results of 13C NMR Determination of SCR-757

[0137]

[0138] In addition, the COSY spectrum, HSQC spectrum and HMBC spectrum of SCR-756 and SCR-757 are shown in 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 replacements, improvements, etc. made within the spirit and principle of the present invention shall be included within the protection scope of the present invention.

Claims

1. A pharmaceutical composition, characterized in that, The pharmaceutical composition contains edaravone, dextronicamphor, sodium metabisulfite and a solvent, and the content of the sodium metabisulfite is 0.95 - 1.05 mg / ml; Preferably, the pharmaceutical composition contains edaravone, dextronicamphor, sodium metabisulfite, a cosolvent and a solvent, and the content of the sodium metabisulfite is 0.95 - 1.05 mg / ml.

2. The pharmaceutical composition according to claim 1, wherein The weight ratio of edaravone to dextronicamphor is 1:1 - 4:1; Preferably, the weight ratio of edaravone to dextronicamphor is 4:1; Preferably, the weight ratio of edaravone, dextronicamphor and sodium metabisulfite in the pharmaceutical composition is 4:1:

2.

3. The pharmaceutical composition according to claim 1 or 2, characterized in that, The content of edaravone in the pharmaceutical composition is 1.0 - 3.0 mg / ml; preferably, the content of edaravone is 2.0 mg / ml; Preferably, the content of dextronicamphor in the pharmaceutical composition is 0.2 - 1.0 mg / ml; preferably 0.5 mg / ml; Preferably, the content of the sodium metabisulfite is 0.97 - 1.03 mg / ml; more preferably, the content of the sodium metabisulfite is 1.0 mg / ml; Preferably, the cosolvent and the solvent are propylene glycol and water for injection, respectively.

4. The pharmaceutical composition according to any one of claims 1-3, characterized in that, The pharmaceutical composition further contains a compound of formula I or a pharmaceutically acceptable salt thereof, Preferably, the weight ratio of the compound of formula I or a pharmaceutically acceptable salt thereof to edaravone is below 0.3%.

5. The pharmaceutical composition according to any one of claims 1-4, characterized in that, The pharmaceutical composition further contains a compound of formula II or a pharmaceutically acceptable salt thereof; Preferably, the weight ratio of the compound of formula II or a pharmaceutically acceptable salt thereof to edaravone is below 0.3%.

6. The pharmaceutical composition according to any one of claims 1-5, characterized in that, The pharmaceutical composition contains a compound of formula I or a pharmaceutically acceptable salt thereof with a weight ratio to edaravone below 0.3% and a compound of formula II or a pharmaceutically acceptable salt thereof with a weight ratio to edaravone below 0.3%.

7. The compound of formula I or a pharmaceutically acceptable salt thereof, 8. The compound of formula II or a pharmaceutically acceptable salt thereof, 9. Use of the pharmaceutical composition according to any one of claims 1 - 6 in the preparation of a pharmaceutical preparation for treating stroke, amyotrophic lateral sclerosis or related disorders.

10. Use of the compound of formula I or a pharmaceutically acceptable salt thereof according to claim 7, and / or the compound of formula II or a pharmaceutically acceptable salt thereof according to claim 8, in the quality control of the pharmaceutical composition or pharmaceutical preparation according to any one of claims 1 - 6.

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