WO2022037537A1 - 一种稳定的药物组合物 - Google Patents

一种稳定的药物组合物 Download PDF

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WO2022037537A1
WO2022037537A1 PCT/CN2021/112813 CN2021112813W WO2022037537A1 WO 2022037537 A1 WO2022037537 A1 WO 2022037537A1 CN 2021112813 W CN2021112813 W CN 2021112813W WO 2022037537 A1 WO2022037537 A1 WO 2022037537A1
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pharmaceutical composition
edaravone
formula
compound
scr
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PCT/CN2021/112813
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English (en)
French (fr)
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钱勇
王霞
朱溪
刘存存
王峰
任晋生
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先声药业有限公司
江苏先声药业有限公司
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Priority to AU2021329765A priority Critical patent/AU2021329765A1/en
Priority to BR112023002684A priority patent/BR112023002684A2/pt
Priority to EP21857631.2A priority patent/EP4176868A1/en
Priority to CN202180056592.7A priority patent/CN116472035A/zh
Priority to US18/041,764 priority patent/US20230364059A1/en
Priority to JP2023512045A priority patent/JP2023539573A/ja
Priority to CA3188671A priority patent/CA3188671A1/en
Publication of WO2022037537A1 publication Critical patent/WO2022037537A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/18—One oxygen or sulfur atom
    • C07D231/20—One oxygen atom attached in position 3 or 5
    • C07D231/22—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms
    • C07D231/24—One oxygen atom attached in position 3 or 5 with aryl radicals attached to ring nitrogen atoms having sulfone or sulfonic acid radicals in the molecule

Definitions

  • the invention belongs to the technical field of medicine, and relates to a stable pharmaceutical composition, in particular to the active ingredients of edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) and Pharmaceutical compositions of dextrose.
  • CHINA QUEST Stroke Medical Quality Assessment Study
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising edaravone, d-camphenol, sodium metabisulfite and a solvent, wherein the content of the sodium metabisulfite is 0.95-1.05 mg/ml.
  • the pharmaceutical composition comprises edaravone, d-camphenol, sodium metabisulfite, a cosolvent and a solvent, and the content of the sodium metabisulfite is 0.95-1.05 mg/ml.
  • the content of sodium metabisulfite is 0.95-1.05 mg/ml, such as 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, 1.05 mg/mL.
  • the sodium metabisulfite is present at 1.0 mg/ml.
  • the weight ratio of edaravone and d-camphenol in the pharmaceutical composition is 1:1 to 4:1, eg, 2:1, 2.5:1, 3:1, or 3.5:1 .
  • the weight ratio of edaravone to d-camphenol in the pharmaceutical composition is 4:1.
  • the weight ratio of edaravone, d-camphenol, and sodium metabisulfite in the pharmaceutical composition is 4:1:2.
  • 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 amount of edaravone in the pharmaceutical composition is 2.0 mg/ml.
  • the content of d-camphenol in the pharmaceutical composition is 0.2-1.0 mg/ml, for example, 0.3-0.8 mg/ml. In some embodiments, the amount of d-camphenol in the pharmaceutical composition is 0.5 mg/ml.
  • the pharmaceutical composition contains edaravone at 2.0 mg/ml, d-camphenol at 0.5 mg/ml, and sodium metabisulfite at 1.0 mg/ml.
  • the co-solvent is selected from propylene glycol, ethanol, or tert-butanol.
  • the solvent is selected from water for injection.
  • the co-solvent and solvent are propylene glycol and water for injection, respectively.
  • 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, exemplarily 0.05 ml/ml, 0.08 ml/ml, 0.1 ml/ml ml.
  • the content of edaravone in the pharmaceutical composition is 2.0 mg/ml
  • the content of d-camphenol 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.
  • the content of edaravone in the pharmaceutical composition is 2.0 mg/ml
  • the content of d-camphenol 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
  • the balance is water for injection.
  • the dose (single dose) of the pharmaceutical composition is a 5 ml solution, which contains 10 mg of edaravone, 2.5 mg of d-camphenol, 5 mg of sodium metabisulfite, propylene glycol 0.4 ml, the rest is water for injection.
  • the active ingredients of the pharmaceutical composition are edaravone and d-camphenol.
  • the pharmaceutical composition may also contain a compound of formula I or a pharmaceutically acceptable salt thereof,
  • the weight ratio of the compound of formula I or its pharmaceutically acceptable salt to the edaravone is below 0.3%, for example below 0.29%, below 0.28%, below 0.27%, below 0.26%, below 0.25% or less, 0.2% or less, 0.15% or less, 0.1% or less.
  • the pharmaceutical composition may also contain a compound of formula II or a pharmaceutically acceptable salt thereof,
  • 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%, 0.25% or less, 0.2% or less, 0.15% or less, 0.1% or less.
  • the present invention provides a pharmaceutical composition
  • the pharmaceutical composition comprises edaravone, d-camphenol, sodium metabisulfite, a cosolvent and a solvent, and the content of the sodium metabisulfite is 0.95-1.05 mg/ ml
  • the pharmaceutical composition further contains the compound of formula I or a pharmaceutically acceptable salt thereof in a weight ratio of 0.3% or less to the edaravone
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising edaravone, d-camphenol, sodium metabisulfite, a cosolvent and a solvent, and the content of the sodium metabisulfite is 0.95-1.05 mg/ milliliters, the pharmaceutical composition further contains a compound of formula II or a pharmaceutically acceptable salt thereof in a weight ratio of 0.3% or less to the edaravone,
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising edaravone, d-camphenol, sodium metabisulfite, a cosolvent and a solvent, and the content of the sodium metabisulfite is 0.95-1.05 mg/ Milliliter
  • the pharmaceutical composition further comprises the compound of formula I or a pharmaceutically acceptable salt thereof in a weight ratio of 0.3% to the Edaravone, and the weight ratio to the Edaravone in 0.3% or less of the compound of formula II or a pharmaceutically acceptable salt thereof.
  • the present invention also provides the compound shown in formula I or a pharmaceutically acceptable salt thereof,
  • the present invention also provides a compound represented by formula II or a pharmaceutically acceptable salt thereof,
  • the pharmaceutically acceptable salt is an alkali metal salt, such as potassium salt, sodium salt or lithium salt.
  • the present invention also provides the application of the above-mentioned pharmaceutical composition in the preparation of a pharmaceutical preparation for treating cerebral apoplexy.
  • the present invention also provides the use of the above-mentioned pharmaceutical composition in the treatment of stroke.
  • the present invention also provides the above-mentioned pharmaceutical composition for treating cerebral apoplexy.
  • the present invention also provides the application of the above-mentioned pharmaceutical composition in preparing a medicine for treating amyotrophic lateral sclerosis or related disorders.
  • the present invention also provides the use of the above-mentioned pharmaceutical composition in the treatment of amyotrophic lateral sclerosis or related disorders.
  • the present invention also provides the above pharmaceutical composition for the treatment of amyotrophic lateral sclerosis or related disorders.
  • 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.
  • the present invention also provides a method of preventing and/or treating amyotrophic lateral sclerosis or a related disorder, comprising administering a therapeutically effective amount of a pharmaceutical composition or pharmaceutical formulation to a subject, eg, a human.
  • 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.
  • 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.
  • the present invention also provides a preparation method of the compound of formula I or its tautomer, characterized in that, the compound of formula I or its tautomer is obtained by reducing the intermediate 2,
  • the present invention also provides a method for preparing the compound of formula II or its tautomer, characterized in that the intermediate 2 is subjected to a reduction reaction to obtain the compound of formula II or its tautomer,
  • the compound of formula I or its tautomer is obtained by reacting the intermediate 2 in the presence of a reducing agent and a solvent.
  • the compound of formula II or its tautomer is obtained by reacting the intermediate 2 in the presence of a reducing agent and a solvent.
  • the reducing agent is selected from the group consisting of sodium borohydride, potassium borohydride, lithium borohydride, zinc borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, and/or lithium cyanoborohydride.
  • the reducing agent is selected from sodium borohydride.
  • the solvent is selected from protic solvents.
  • the solvent is selected from one or more of water, methanol, ethanol, propanol, and isopropanol.
  • the solvent is selected from methanol.
  • the present invention also provides a method for preparing intermediate 2, characterized in that, intermediate 1 is reacted with a sulfonating reagent to obtain intermediate 2,
  • the sulfonating reagent is sulfur trioxide and/or an adduct of sulfur trioxide.
  • the sulfonating reagent is a sulfur trioxide ⁇ dioxane adduct.
  • the intermediate 1 can be prepared by the following reaction,
  • the stability test shows that impurities SCR-756, impurities SCR-757 and Yida
  • the content of total impurities in lavone will increase with the increase of storage temperature and storage time, and the above problems cannot be effectively solved by conventional methods such as controlling temperature, pH value, co-solvent and preparation time in the process link.
  • the inventor unexpectedly found in a large number of tests that the amount of sodium metabisulfite has a great influence on the content of impurities SCR-756, impurity SCR-757 and total impurities in the pharmaceutical composition, the amount of sodium metabisulfite is too low or too high, the impurity SCR-756 -756, impurity SCR-757 and total impurities could not be effectively controlled.
  • sodium metabisulfite is added and its dosage is controlled within a suitable range, thereby effectively solving the problem that impurities existing in the composition itself and product quality are difficult to control, and the impurity content increases with the increase of storage temperature or the extension of storage period. Acceleration and other technical problems, especially the content of impurities SCR-756, impurity SCR-757 and edaravone total impurities in the pharmaceutical composition can be unexpectedly controlled, and the impurity and product quality are difficult to control and storage period from the source. short-term, medication safety and other issues.
  • tautomer herein refers to structural isomers of different energies that are interconvertible through a low energy barrier. A chemical equilibrium of tautomers can be achieved if tautomerism is possible (eg, in solution).
  • proton tautomers also known as prototro pictautomers
  • proton tautomers include interconversions by migration of protons, 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.
  • ⁇ -H-containing carbonyl compounds have keto-enol tautomerism, and tautomers can be interconverted and generally exist in equilibrium. Therefore, those skilled in the art should know that the compounds of formula I and formula II of the present invention all have tautomerism and the tautomers can be converted into each other.
  • compounds with tautomerism can be represented only by ketone formula (such as compounds of formula I or formula II), or only by enol formula (such as formula I' or the compound of formula II').
  • the compounds represented by formula I or formula II include both keto compounds and corresponding enol compounds.
  • Figure 1 is the COSY spectrum of SCR-756
  • Figure 2 is the HSQC spectrum of SCR-756
  • Figure 3 is the HMBC spectrum of SCR-756
  • Figure 4 is the COSY spectrum of SCR-757
  • Figure 5 is the HSQC spectrum of SCR-757
  • Figure 6 is the HMBC spectrum of SCR-757.
  • Embodiment 1 the consumption of sodium metabisulfite and the investigation of related substances
  • Propylene glycol is heated to 50 ⁇ 60 °C, add Edaravone, stir until completely dissolved, obtain medicinal liquid; Cool medicinal liquid to below 25 °C, add d-camphenol (structure: ) and stir until completely dissolved.
  • the pharmaceutical compositions with the contents of 0.5 mg/mL, 0.8 mg/mL, 1.0 mg/mL, 1.2 mg/mL and 1.5 mg/mL of sodium metabisulfite were prepared and obtained, and their specific prescriptions were shown in Table 1. Show.
  • composition refers to the weight ratio of impurity SCR-756, impurity SCR-757 and total impurities relative to Edaravone in the pharmaceutical composition.
  • the analysis method for related substances is as follows: take an appropriate amount of the sample, dilute it with solvent methanol-water (volume ratio 32:68) to prepare 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 prepare a solution containing about 5 ⁇ g of edaravone per 1 mL, as a control solution.
  • the propylene glycol is heated to 50-60°C, edaravone is added, stirred until completely dissolved to obtain a medicinal solution; the medicinal solution is cooled to below 25°C, d-camphenol is added thereto, and stirred until completely dissolved.
  • antioxidants sodium metabisulfite, sodium bisulfite, L-cysteine hydrochloride, which can be used alone or in combination
  • Add the oxidant solution to the medicinal solution and continue to slowly add water to the prescribed amount.
  • formulations 1 and 2 had significantly lower amounts of edaravone-related impurities.
  • Solvent 0.02mol/L ammonium acetate solution (adjust pH to 4.0 with glacial acetic acid)-acetonitrile (volume ratio is 80:20);
  • Test solution take 5ml of this product and put it in a 20ml measuring bottle, dilute the solvent to the mark, and get it;
  • Control solution Precisely measure 1ml of the test solution and place it in a 200ml volumetric flask, add solvent and dilute to the mark.
  • compound SCR-756 and compound SCR-757 were confirmed by nuclear magnetic resonance.
  • SCR-756 has the structure shown in formula I
  • SCR-757 has the structure shown in formula II.

Abstract

一种稳定的药物组合物，其属于医药技术领域，该活性成分为依达拉奉和右旋莰醇的药物组合物能够出乎意料地控制其特有的杂质SCR-756和杂质SCR-757的含量，从源头上解决了杂质和产品质量难以控制、存储期限短等问题。

Description

一种稳定的药物组合物
本申请要求申请人于2020年8月17日向中国国家知识产权局提交的专利申请号为202010827343.0，发明名称为“一种稳定的药物组合物”的在先申请的优先权。所述在先申请的全文通过引用的方式结合于本申请中。
技术领域
本发明属于医药技术领域，涉及一种稳定的药物组合物，具体而言，涉及活性成分为依达拉奉(3-甲基-1-苯基-2-吡唑啉-5-酮)和右旋莰醇的药物组合物。
背景技术
在过去的15年中脑卒中是世界范围内第二位、中国第一位导致死亡和引发长期且严重的神经系统疾病的原因。脑卒中医疗质量评估研究(CHINA QUEST)调查了我国急性脑卒中治疗现状的流行病学情况。研究表明，我国缺血性脑卒中患者从发病到医院时间平均为20.1小时，有相当数量的患者到医院时间在24小时之后，这部分患者尚未得到有效的药物治疗，在临床上广泛用于治疗急性缺血性脑卒中的依达拉奉注射液，其说明书的用法用量部分明确记载了在发病后24小时内开始给药。
同时，对药品质量的控制也逐渐成为药物开发中的重点和难点。
因此，提供一种治疗时间窗长、治疗效果显著、稳定性好、用药安全性高的依达拉奉药物组合物成为本领域亟待解决的技术问题。
发明内容
本发明提供了一种药物组合物，所述药物组合物包含依达拉奉、右旋莰醇、焦亚硫酸钠和溶剂，所述焦亚硫酸钠的含量为0.95～1.05毫克/毫升。
在一些实施方案中，所述药物组合物包含依达拉奉、右旋莰醇、焦亚硫酸钠、助溶剂和溶剂，所述焦亚硫酸钠的含量为0.95～1.05毫克/毫升。
在一些实施方案中，焦亚硫酸钠的含量为0.95～1.05毫克/毫升，例如为 0.97～1.03毫克/毫升，示例性为0.95毫克/毫升、0.96毫克/毫升、0.97毫克/毫升、0.98毫克/毫升、0.99毫克/毫升、1.0毫克/毫升、1.01毫克/毫升、1.02毫克/毫升、1.03毫克/毫升、1.04毫克/毫升、1.05毫克/毫升。在一些实施方案中，所述焦亚硫酸钠的含量为1.0毫克/毫升。
在一些实施方案中，所述药物组合物中依达拉奉和右旋莰醇的重量比为1∶1～4∶1，例如为2∶1、2.5∶1、3∶1或3.5∶1。
在一些实施方案中，所述药物组合物中依达拉奉和右旋莰醇的重量比为4∶1。
在一些实施方案中，所述药物组合物中依达拉奉、右旋莰醇和焦亚硫酸钠的重量比为4∶1∶2。
根据本发明的技术方案，所述药物组合物中依达拉奉的含量为1.0-3.0毫克/毫升，例如为1.5-2.5毫克/毫升。在一些实施方案中，所述药物组合物中依达拉奉的含量为2.0毫克/毫升。
根据本发明的技术方案，所述药物组合物中右旋莰醇的含量为0.2-1.0毫克/毫升，例如0.3-0.8毫克/毫升。在一些实施方案中，所述药物组合物中右旋莰醇的含量为0.5毫克/毫升。
在一些实施方案中，所述药物组合物中依达拉奉的含量为2.0毫克/毫升，右旋莰醇的含量为0.5毫克/毫升，焦亚硫酸钠的含量为1.0毫克/毫升。
在一些实施方案中，所述助溶剂选自丙二醇、乙醇或叔丁醇。
在一些实施方案中，所述溶剂选自注射用水。
在一些实施方案中，所述助溶剂和溶剂分别为丙二醇和注射用水。
根据本发明的技术方案，所述药物组合物中助溶剂的含量为0.01-0.15毫升/毫升，例如为0.03-0.12毫升/毫升，示例性为0.05毫升/毫升、0.08毫升/毫升、0.1毫升/毫升。
在一些实施方案中，所述药物组合物中依达拉奉的含量为2.0毫克/毫升，右旋莰醇的含量为0.5毫克/毫升，焦亚硫酸钠的含量为1.0毫克/毫升，丙二醇的含量0.08毫升/毫升。
在一些实施方案中，所述药物组合物中依达拉奉的含量为2.0毫克/毫升，右旋莰醇的含量为0.5毫克/毫升，焦亚硫酸钠的含量为1.0毫克/毫升，丙二醇的含量0.08毫升/毫升，余量为注射用水。
根据本发明示例性的实施方案，所述药物组合物的剂量(单剂量)为5毫升溶液，其中含有依达拉奉10毫克，右旋莰醇2.5毫克，焦亚硫酸钠的含量为5毫克，丙二醇0.4毫升，其余为注射用水。
根据本发明的技术方案，所述药物组合物的活性成分为依达拉奉和右旋莰醇。
根据本发明的技术方案，所述药物组合物中还可以含有式I化合物或其药学上可接受的盐，
Figure PCTCN2021112813-appb-000001
进一步的，所述式I化合物或其药学上可接受的盐与所述依达拉奉的重量比在0.3％以下，例如在0.29％以下、0.28％以下、0.27％、0.26％以下、0.25％以下、0.2％以下、0.15％以下、0.1％以下。
根据本发明的技术方案，所述药物组合物中还可以含有式II化合物或其药学上可接受的盐，
Figure PCTCN2021112813-appb-000002
进一步的，所述式II化合物或其药学上可接受的盐与所述依达拉奉的重量比在0.3％以下，例如在0.29％以下、0.28％以下、0.27％、0.26％以下、0.25％以下、0.2％以下、0.15％以下、0.1％以下。
另一方面，本发明提供了一种药物组合物，所述药物组合物包含依达拉奉、 右旋莰醇、焦亚硫酸钠、助溶剂和溶剂，所述焦亚硫酸钠的含量为0.95～1.05毫克/毫升，所述药物组合物还含有与所述依达拉奉的重量比在0.3％以下的式I化合物或其药学上可接受的盐，
Figure PCTCN2021112813-appb-000003
另一方面，本发明提供了一种药物组合物，所述药物组合物包含依达拉奉、右旋莰醇、焦亚硫酸钠、助溶剂和溶剂，所述焦亚硫酸钠的含量为0.95～1.05毫克/毫升，所述药物组合物还含有与所述依达拉奉的重量比在0.3％以下的式II化合物或其药学上可接受的盐，
Figure PCTCN2021112813-appb-000004
另一方面，本发明提供了一种药物组合物，所述药物组合物包含依达拉奉、右旋莰醇、焦亚硫酸钠、助溶剂和溶剂，所述焦亚硫酸钠的含量为0.95～1.05毫克/毫升，所述药物组合物还包含与所述依达拉奉的重量比在0.3％以下的所述式I化合物或其药学上可接受的盐，和与所述依达拉奉的重量比在0.3％以下的所述式II化合物或其药学上可接受的盐。
本发明还提供了式I所示的化合物或其药学上可接受的盐，
Figure PCTCN2021112813-appb-000005
本发明还提供了式II所示的化合物或其药学上可接受的盐，
Figure PCTCN2021112813-appb-000006
Figure PCTCN2021112813-appb-000007
根据本发明的技术方案，所述药学上可接受的盐为碱金属盐，例如钾盐、钠盐或锂盐。
本发明还提供上述药物组合物在制备治疗脑卒中药物制剂中的应用。
本发明还提供上述药物组合物在治疗脑卒中方面的用途。
本发明还提供治疗脑卒中的上述药物组合物。
本发明还提供上述药物组合物在制备治疗肌萎缩性侧索硬化症或相关障碍的药物中的应用。
本发明还提供上述药物组合物在治疗肌萎缩性侧索硬化症或相关障碍的用途。
本发明还提供治疗肌萎缩性侧索硬化症或相关障碍的上述药物组合物。
本发明还提供一种预防和/或治疗脑卒中的方法，包括将治疗有效量的药物组合物或药物制剂给予治疗对象，例如人。
本发明还提供一种预防和/或治疗肌萎缩性侧索硬化症或相关障碍的方法，包括将治疗有效量的药物组合物或药物制剂给予治疗对象，例如人。
本发明还提供上述式I所示的化合物或其药学上可接受的盐在所述药物组合物或药物制剂质量控制中的应用。
本发明还提供上述式II所示的化合物或其药学上可接受的盐在所述药物组合物或药物制剂质量控制中的应用。
本发明还提供式I化合物或其互变异构体的制备方法，其特征在于，中间体2经还原反应得到式I化合物或其互变异构体，
Figure PCTCN2021112813-appb-000008
本发明还提供式II化合物或其互变异构体的制备方法，其特征在于，中间体 2经还原反应得到式II化合物或其互变异构体，
Figure PCTCN2021112813-appb-000009
根据本发明的技术方案，中间体2在还原剂和溶剂的存在下，经反应得到式I化合物或其互变异构体。
根据本发明的技术方案，中间体2在还原剂和溶剂的存在下，经反应得到式II化合物或其互变异构体。
在一些实施方案中，所述还原剂选自硼氢化钠、硼氢化钾、硼氢化锂、硼氢化锌、氰基硼氢化钠、三乙酰氧基硼氢化钠和/或氰基硼氢化锂。
在一些实施方案中，所述还原剂选自硼氢化钠。
在一些实施方案中，所述溶剂选自质子性溶剂。
在一些实施方案中，所述溶剂选自水、甲醇、乙醇、丙醇和异丙醇中的一种或多种。
在一些实施方案中，所述溶剂选自甲醇。
本发明还提供中间体2的制备方法，其特征在于，中间体1与磺化试剂反应得到中间体2，
Figure PCTCN2021112813-appb-000010
在一些实施方案中，所述磺化试剂为三氧化硫和/或三氧化硫的加合物。
在一些实施方案中，所述磺化试剂为三氧化硫·二氧六环加合物。
在一些实施方案中，所述中间体1可经以下反应制备得到，
Figure PCTCN2021112813-appb-000011
本发明的有益效果
发明人在药物开发过程中发现，含有活性成分依达拉奉和右旋莰醇的药物组合物容易出现两种结构新颖的杂质：杂质SCR-756和杂质SCR-757，杂质SCR-756和杂质SCR-757一旦产生，其含量通常就会超过鉴定阈值0.1％，二者含量很难被控制在合理范围内，更加复杂的是，稳定性试验表明杂质SCR-756、杂质SCR-757以及依达拉奉总杂质的含量会随着存储温度的升高及存储时间的延长而增长速率加快，且在工艺环节通过控制温度、pH值、助溶剂及配制时间等常规方法无法有效解决上述问题。而发明人在大量的试验中出人意料地发现焦亚硫酸钠的用量对药物组合物中杂质SCR-756、杂质SCR-757和总杂质的含量影响较大，焦亚硫酸钠的用量过低或过高，杂质SCR-756、杂质SCR-757和总杂质均无法得到有效控制。故本发明通加入焦亚硫酸钠并将其用量控制在合适范围内，从而有效解决了组合物自身存在的杂质和产品质量较难控制、杂质含量随着存储温度升高或存储期的延长而增长速率加快等技术问题，尤其能够出乎意料地控制该药物组合物中杂质SCR-756、杂质SCR-757以及依达拉奉总杂质的含量，从源头上解决了杂质和产品质量难以控制、存储期限短、用药安全性等问题。
本文术语“互变异构体”是指具有不同能量的可通过低能垒(low energy barrier)互相转化的结构异构体。若互变异构是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称为质子转移互变异构体(prototro pictautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。除非另外指出，本发明化合物的所有互变异构体形式都在本发明的范围之内。
本领域技术人员应当知道，含α-H的羰基化合物存在酮式-烯醇式互变异构现象，互变异构体能够相互转化且一般以平衡形式存在。因此本领域技术人员应当知道，本发明式I及式II化合物均存在互变异构现象且互变异构体之间能够相互转化。在本发明某些实施方案中，为方便描述和表达，存在互变异构现象的化合物可以仅以酮式(如式I或式II化合物)来表示，也可以仅以烯醇式(如式I’或式II’化合物)来表示。本文中，式I或式II所示化合物既包含酮式化合物，也包含对应的烯醇式化合物。
Figure PCTCN2021112813-appb-000012
附图说明
图1为SCR-756的COSY谱；
图2为SCR-756的HSQC谱；
图3为SCR-756的HMBC谱；
图4为SCR-757的COSY谱；
图5为SCR-757的HSQC谱；
图6为SCR-757的HMBC谱。
具体实施方式
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
实施例1：焦亚硫酸钠的用量和有关物质的考察
将丙二醇加热至50～60℃，加入依达拉奉，搅拌至完全溶解，得到药液；将药液降温至25℃以下，向其中加入右旋莰醇(结构为
Figure PCTCN2021112813-appb-000013
)，搅拌至完全溶解。将焦亚硫酸钠加入适量25℃以下的水中，搅拌至溶解；边搅拌边缓慢将焦亚硫酸钠溶液加入药液中，继续缓慢加水至近处方量。用0.1mol/L的盐酸和氢氧化钠溶液调节pH至4.5±0.2，最终加水定容至处方量，药液过滤、充氮灌封、灭菌。
按照以上方法，制备并获得焦亚硫酸钠的含量分别为0.5mg/mL、0.8mg/mL、1.0mg/mL、1.2mg/mL、1.5mg/mL的药物组合物，其具体的处方如表1所示。
表1：药物组合物F1-F5的处方情况
处方组分 F1 F2 F3 F4 F5
依达拉奉 10mg 10mg 10mg 10mg 10mg
右旋莰醇 2.5mg 2.5mg 2.5mg 2.5mg 2.5mg
丙二醇(供注射用) 0.4mL 0.4mL 0.4mL 0.4mL 0.4mL
焦亚硫酸钠 2.5mg 4mg 5mg 6mg 7.5mg
盐酸 适量 适量 适量 适量 适量
氢氧化钠 适量 适量 适量 适量 适量
注射用水 加至5mL 加至5mL 加至5mL 加至5mL 加至5mL
对表1中的药物组合物的有关物质进行分析，分别检测样品在温度为60℃条件下0天及放置10天后其杂质SCR-756、杂质SCR-757和依达拉奉总杂的含量情况。具体如表2所示。
表2：杂质SCR-756、杂质SCR-757和总杂的含量 [1]考察结果
Figure PCTCN2021112813-appb-000014
Figure PCTCN2021112813-appb-000015
注：[1]“含量”指杂质SCR-756、杂质SCR-757和总杂相对于药物组合物中依达拉奉的重量比。
有关物质分析方法为：取样品适量，加溶剂甲醇-水(体积比32∶68)稀释制成每1mL中约含依达拉奉0.5mg的溶液，作为供试品溶液；精密量取适量，用溶剂稀释制成每1mL中约含依达拉奉5μg的溶液，作为对照溶液。精密称取杂质对照品SCR-756 5mg、SCR-757 5mg置于100mL量瓶中，加溶剂超声使溶解并稀释至刻度，摇匀，作为杂质贮备液；另精密称取依达拉奉对照品10mg置于20mL量瓶中，加甲醇5mL使溶解，加入杂质贮备液1mL，加溶剂稀释至刻度，摇匀，作为系统适用性溶液。按照高效液相色谱法(中国药典2015年版四部通则0512)试验，用十八烷基硅烷键合硅胶为填充剂(Agilent Eclipse plus C18 4.6×150mm，3.5μm)；以0.5％三乙胺(用磷酸调节pH值至6.3)为流动相A，甲醇为流动相B，按下表进行线性梯度洗脱；检测波长为248nm。精密量取系统适用性溶液10μL注入液相色谱仪，记录色谱图，杂质SCR-756、杂质SCR-757和依达拉奉依次出峰，依达拉奉峰的保留时间约为6分钟。精密量取供试品溶液与对照溶液各10μL，分别注入液相色谱仪，记录色谱图。
Figure PCTCN2021112813-appb-000016
Figure PCTCN2021112813-appb-000017
实施例2
将丙二醇加热至50～60℃，加入依达拉奉，搅拌至完全溶解，得到药液；将药液降温至25℃以下，向其中加入右旋莰醇，搅拌至完全溶解。将抗氧化剂(焦亚硫酸钠、亚硫酸氢钠、L-半胱氨酸盐酸盐，可单用或两种联用)加入适量25℃以下的水中，搅拌至溶解；边搅拌边缓慢将上述抗氧化剂溶液加入药液中，继续缓慢加水至近处方量。用0.1mol/L的盐酸和氢氧化钠溶液调节pH至4.5±0.2，最终加水定容至处方量(如表3所示)，药液过滤、充氮灌封、灭菌。重点考察样品的性状及依达拉奉杂质情况，结果如表4所示。
表3
3000支量计 处方1 处方2 处方3
依达拉奉(g) 30 30 30
右旋莰醇(g) 7.5 7.5 7.5
焦亚硫酸钠(g) 15 15 -
亚硫酸氢钠(g) - - 15
L-半胱氨酸盐酸盐(g) - 7.5 7.5
丙二醇(L) 1.2 1.2 1.2
注射用水至(L) 15 15 15
表4
Figure PCTCN2021112813-appb-000018
Figure PCTCN2021112813-appb-000019
处方1、2相对于处方3，其依达拉奉相关杂质的量明显更低。
有关物质分析方法如下：
按照高效液相色谱法(中国药典2010年版二部附录VI E)测定，用十八烷基硅烷键合硅胶为填充剂(Waters sunfire C18，4.6×250mm，5.0μm)；以0.02mol/L醋酸铵溶液(用冰醋酸调节pH值至4.0)为流动相A，乙腈为流动相B，按下表进行线性梯度洗脱；
检测波长：254nm；
流速：1.0ml/min；
进样量：20μl；
溶剂：0.02mol/L醋酸铵溶液(用冰醋酸调节pH值至4.0)-乙腈(体积比为80∶20)；
供试品溶液：取本品5ml置20ml量瓶中，加溶剂稀至刻度，即得；
对照溶液：精密量取供试品溶液1ml置200ml量瓶中，加溶剂稀至刻度，即得。
Figure PCTCN2021112813-appb-000020
实施例3化合物SCR-756及SCR-757的制备
Figure PCTCN2021112813-appb-000021
合成步骤：
(1)中间体1的制备
将39.92g Na分批次加入到1.25L无水乙醇中，保持稳定在25～40℃，50℃搅拌至Na完全溶解澄清；避光黑暗处，0～5℃分批加入250g依达拉奉固体，搅拌得浑浊液体；加N 2气球保护，黑色塑料袋避光；203.11g氯丙酮溶解于750mL无水乙醇成乙醇溶液，直接加到滴液漏斗；-5～0℃滴加上述乙醇溶液，N 2气球保护，黑色塑料袋避光，在0～5℃搅拌2h；TLC(石油醚∶乙酸乙酯＝1∶1)监测到大部分依达拉奉原料消耗完；搅拌状态下，反应液倒入4L冰水中；过滤，滤饼用水600mL*3洗涤，用乙酸乙酯200mL打浆，过滤得中间体1共37g。
(2)中间体2的制备
将37g的中间体1加入到3L三颈瓶中，N2气球保护，通过加料漏斗加入650mL二氯乙烷和325mL无水二氧六环，抽真空，搅拌至完全溶解，在0-5℃搅拌状态下依次分批次加入100g 4A型分子筛和69.41g的三氧化硫·二氧六环加合物，升温到100℃反应8个小时，8h后降温到25℃，过滤，用无水二氯甲烷淋洗滤饼两遍，将滤饼和600mL无水二氯甲烷搅拌过滤去除大颗粒的分子筛；滤液搅拌5分钟，再过滤，用无水二氯甲烷淋洗滤饼两遍得到粗品，粗品用乙醇打浆，过滤得到30g固体(中间体2)。
(3)化合物SCR-756及SCR-757的制备
将30g中间体2加入到2L三颈瓶中，N 2气球保护，通过加料漏斗加入600mL无水MeOH，抽真空，干冰浴下搅拌，保持0-5℃，分批加入8.85g的NaBH 4，反应液在60℃搅拌3h后旋干溶剂，通过HPLC分离(色谱柱：YMC-Triart Prep C18 250*50mm*10μm；流动相：[水(0.1％三氟乙酸)-乙腈]；乙腈％：0％-28.5％，19mins)得到化合物SCR-756和化合物SCR-757。
通过核磁共振对化合物SCR-756和化合物SCR-757的结构进行确证。
核磁共振谱(NMR)
仪器：BRUKER AV-400型核磁共振仪
溶剂：DMSO-d 6
内标：TMS
温度：300K。
SCR-756的氢谱、碳谱核磁数据如表5-1和表5-2所示。
Figure PCTCN2021112813-appb-000022
表5-1：SCR-756的氢谱测定结果
Figure PCTCN2021112813-appb-000023
Figure PCTCN2021112813-appb-000024
表5-2：SCR-756的碳谱测定结果
Figure PCTCN2021112813-appb-000025
SCR-757的氢谱、碳谱核磁数据如表6-1和表6-2所示。
Figure PCTCN2021112813-appb-000026
表6-1：SCR-757的氢谱测定结果
Figure PCTCN2021112813-appb-000027
Figure PCTCN2021112813-appb-000028
表6-2：SCR-757的碳谱测定结果
Figure PCTCN2021112813-appb-000029
另外，SCR-756和SCR-757的COSY谱、HSQC谱和HMBC谱分别见图1～图6。
结果表明，SCR-756具有如式I所示的结构，SCR-757具有如式II所示的结构。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。

Claims (10)

  1. 一种药物组合物，其特征在于，所述药物组合物包含依达拉奉、右旋莰醇、焦亚硫酸钠和溶剂，所述焦亚硫酸钠的含量为0.95～1.05毫克/毫升；
    优选地，所述药物组合物包含依达拉奉、右旋莰醇、焦亚硫酸钠、助溶剂和溶剂，所述焦亚硫酸钠的含量为0.95～1.05毫克/毫升。
  2. 根据权利要求1所述的药物组合物，其特征在于，所述依达拉奉和右旋莰醇的重量比为1∶1～4∶1；
    优选地，所述依达拉奉和右旋莰醇的重量比为4∶1；
    优选地，所述药物组合物中依达拉奉、右旋莰醇和焦亚硫酸钠的重量比为4∶1∶2。
  3. 根据权利要求1或2所述的药物组合物，其特征在于，所述药物组合物中依达拉奉的含量为1.0-3.0毫克/毫升；优选地，所述依达拉奉的含量为2.0毫克/毫升；
    优选地，所述药物组合物中右旋莰醇的含量为0.2-1.0毫克/毫升；优选为0.5毫克/毫升；
    优选地，所述焦亚硫酸钠的含量为0.97～1.03毫克/毫升；还优选所述焦亚硫酸钠的含量为1.0毫克/毫升；
    优选地，所述助溶剂和溶剂分别为丙二醇和注射用水。
  4. 根据权利要求1-3任一项所述的药物组合物，其特征在于，所述药物组合物中还含有式I化合物或其药学上可接受的盐，
    Figure PCTCN2021112813-appb-100001
    优选地，所述式I化合物或其药学上可接受的盐与所述依达拉奉的重量比在0.3％以下。
  5. 根据权利要求1-4任一项所述的药物组合物，其特征在于，所述药物组合物中还含有式II化合物或其药学上可接受的盐；
    Figure PCTCN2021112813-appb-100002
    优选地，所述式II化合物或其药学上可接受的盐与所述依达拉奉的重量比在0.3％以下。
  6. 根据权利要求1-5任一项所述的药物组合物，其特征在于，所述药物组合物包含与所述依达拉奉的重量比在0.3％以下的式I化合物或其药学上可接受的盐和与所述依达拉奉的重量比在0.3％以下的式II化合物或其药学上可接受的盐。
  7. 式I所示的化合物或其药学上可接受的盐，
    Figure PCTCN2021112813-appb-100003
  8. 式II所示的化合物或其药学上可接受的盐，
    Figure PCTCN2021112813-appb-100004
  9. 权利要求1-6任一项所述药物组合物在制备治疗脑卒中、肌萎缩性侧索硬化症或相关障碍的药物制剂中的应用。
  10. 权利要求7所述式I所示的化合物或其药学上可接受的盐，和/或权利要求8所述式II所示的化合物或其药学上可接受的盐，在权利要求1-6任一项所述药物组合物或药物制剂质量控制中的应用。
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