WO2022007833A1 - 一种组合物在治疗脑卒中的用途 - Google Patents

一种组合物在治疗脑卒中的用途 Download PDF

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WO2022007833A1
WO2022007833A1 PCT/CN2021/104934 CN2021104934W WO2022007833A1 WO 2022007833 A1 WO2022007833 A1 WO 2022007833A1 CN 2021104934 W CN2021104934 W CN 2021104934W WO 2022007833 A1 WO2022007833 A1 WO 2022007833A1
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composition
edaravone
use according
stroke
hours
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French (fr)
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冯晓飞
诸舜伟
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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    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular 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

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  • the present invention relates to the use of a composition, furthermore, the present invention relates to the use of a composition in the preparation of a medicament for treating cerebral apoplexy.
  • the main methods of specific treatment for acute ischemic stroke are: First, improve cerebral blood circulation, perform vascular recanalization, and quickly reflow to save the ischemic penumbra , Thrombolytic therapy is currently the most important measure to restore blood flow; second, neuroprotection, reducing reperfusion injury, inhibiting the ischemic cascade to reduce neurological deficits, the currently effective neuroprotective agent proven by clinical trials is Yida Rabon. Although multiple clinical evidences show that patients can benefit from thrombolytic therapy, the short treatment time window and bleeding risk make most patients still unable to receive effective treatment.
  • the present invention relates to the use of a composition in the treatment of stroke, characterized in that the composition comprises edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) and Dexborneol (Dexborneol, also known as dexborneol), its treatment time window is 24-48 hours.
  • the present invention relates to the use of a composition in the preparation of a medicament for treating stroke, characterized in that the composition comprises edaravone and dexbornol, and the treatment time window is 24-48 hours.
  • the present invention relates to a composition for treating cerebral apoplexy, which is characterized in that the composition comprises edaravone and dexbornol, and the treatment time window is 24-48 hours.
  • the present invention relates to a method for treating cerebral apoplexy, which comprises administering a composition of therapeutically effective dose to a patient, characterized in that, the composition comprises edaravone and dexbornol, and its treatment time window is 24 -48 hours.
  • the weight ratio of edaravone to dexbornol in the composition is 1:1-8:1, 1:1-7:1, 1:1-6:1, 1:1 ⁇ 5:1, 1:1 ⁇ 4:1, 1:1 ⁇ 3:1, 1:1 ⁇ 2:1 or 1:1 ⁇ 1.5:1.
  • the weight ratio of edaravone to dexbornol in the composition is 1:1 to 5:1.
  • the weight ratio of edaravone to dexbornol in the composition is 1:1 to 4:1.
  • the weight ratio of edaravone to dexbornol in the composition is 4:1.
  • the plasma exposure ratio of edaravone to dexbornol in the patient is 1:1-8:1, 1:1-7 :1, 1:1 ⁇ 6:1, 1:1 ⁇ 5:1, 1:1 ⁇ 4:1, 1:1 ⁇ 3:1, 1:1 ⁇ 2:1 or 1:1 ⁇ 1.5:1 , preferably 1:1 to 5:1, more preferably 4:1.
  • the composition is administered 1-3 times daily for 3-21 consecutive days.
  • the composition is administered every 12 hours, twice a day, for 14 consecutive days.
  • the dose of edaravone administered in the composition is 10-30 mg/time.
  • the dose of edaravone administered in the composition is 10 mg/time.
  • the dose of edaravone administered in the composition is 20 mg/time.
  • the dose of edaravone administered in the composition is 30 mg/time.
  • the composition further comprises a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable adjuvant is selected from one or more of antioxidants, co-solvents or solvents.
  • the pharmaceutically acceptable adjuvant is selected from antioxidants, cosolvents or solvents.
  • the antioxidant is sodium metabisulfite.
  • the co-solvent is propylene glycol.
  • the solvent is water for injection.
  • the treatment time window of 24-48 hours refers to administration of the composition of the present invention to a patient within 24-48 hours after the onset of stroke.
  • the proportion of patients with an mRS score of ⁇ 1 on day 90 is greater than 60%, preferably greater than 65%, more preferably greater than 67%, following administration in a treatment time window of 24-48 hours .
  • the stroke is ischemic stroke.
  • the stroke is acute ischemic stroke.
  • Beneficial effects of the present invention when the treatment time window of the composition of the present invention is 24-48 hours, its therapeutic effect on stroke is significant, suggesting that the treatment time window of the composition of the present invention can be expanded to 48 hours, and for most of the patients exceeding thrombolysis Stroke patients within the treatment time window are particularly important treatment methods, and the composition of the present invention is of great significance for the treatment of these patients.
  • test objectives derived from clinical trials
  • test methods derived from test objectives, test methods and test results are as follows.
  • a multi-center, randomized double-blind, positive drug (edaravone injection) controlled phase III clinical trial was carried out, and 1200 patients with acute ischemic stroke with an onset time of ⁇ 48 hours were selected and randomly assigned to enter the hospital according to a ratio of about 1:1.
  • Pharmacodynamics and safety studies were conducted in the edaravone dexbornol injection group or the edaravone group.
  • the clinical trial also conducted a systematic study on the treatment time window of edaravone and dexbornol injection, in which 764 subjects who met the inclusion criteria received edaravone within 24 to 48 hours of the onset time.
  • Dexcamphenol injection or edaravone injection were continuously treated for 14 days and followed up to the 90th day.
  • the main criteria for subjects to be selected are age 35-80 years old, male or female, diagnosed as ischemic stroke (cerebral infarction) according to the Fourth National Cerebrovascular Disease Academic Conference "Key Points of Diagnosis of Various Cerebrovascular Diseases", and have a clear diagnosis of ischemic stroke (cerebral infarction).
  • Test drug name Edaravone Dexbornol Injection
  • 5mL 10mg (Edaravone 10mg);
  • test drug and the positive control drug are identical in color and shape.
  • the two groups of drugs have identical packaging and batch numbers, and the packaging and batch numbers are uniformly marked.
  • Each randomized subject will be assigned 1 large box of medicine, containing 14 small boxes, for a course of 14 days of medication, 1 small box per day, each small box contains 6 bottles of medicine, each use 3 bottles of medicine in a small box are administered once every 12 hours, 2 times a day.
  • the specific medicine packaging specifications and quantities are shown in the following table:
  • Test group Number of small boxes Each small box of medicines consists of Edaravone and Dexbornol Injection Group 14 6 bottles
  • the subjects were randomly divided into groups, and the subjects in the experimental group received edaravone dexbornol injection 37.5 mg intravenously, twice a day for 14 consecutive days; subjects in the control group received edaravone injection 30mg, intravenous injection, 2 times a day for 14 consecutive days. Dosage adjustment is not allowed during the study period, and the cumulative delay in dosing cannot exceed 2 days. During the study period, the use of neuroprotective agents and thrombolytic drugs listed in the "Chinese Guidelines for the Diagnosis and Treatment of Acute Ischemic Stroke" (2010 edition) was prohibited.
  • Edaravone and Dexbornol Injection group before use, add 3 vials of medicine in a small box to 100 mL of 0.9% sodium chloride injection to dilute and infuse intravenously, finish the drip within 30 minutes, two times a day. times, 12 hours apart each time, for 14 consecutive days.
  • Edaravone group The administration method is the same as that of the experimental drug Edaravone Dexbornol Injection. Before use, add 3 vials of medicine in 1 small box to 100 mL of 0.9% sodium chloride injection to dilute and infuse intravenously, within 30 minutes, twice a day, 12 hours apart each time, for 14 consecutive days .
  • the primary efficacy endpoint was the proportion of patients with an mRS score ⁇ 1 on day 90 of treatment.
  • the overall outcome scale was assessed using the Modified Rankin Scale (mRS) for the overall assessment of disability and disability. Principles" recommended primary endpoint.
  • the mRS score is currently the most widely used functional outcome scale in stroke clinical trials, ranging from 0 for no symptoms to 5 for severe disability, with an additional 6 points added to indicate death in some trials.
  • an mRS score of 0 to 1 is generally chosen as the criterion for judging that subjects have no disability after a stroke, and some clinical trials choose an mRS score of 0 to 2 as the criterion.
  • the mRS score of 0-1 was selected as the criterion.
  • Table 1 The test results are shown in Table 1.

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Abstract

一种组合物在制备治疗脑卒中药物中的用途，所述组合物包含依达拉奉和右莰醇。

Description

一种组合物在治疗脑卒中的用途 技术领域
本发明涉及一种组合物的用途，进一步地，本发明涉及一种组合物在制备治疗脑卒中药物中的用途。
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。
根据“中国急性缺血性脑卒中诊治指南2014”，急性缺血性脑卒中特异性治疗的主要手段为：第一，改善脑血循环，进行血管再通，迅速复流以挽救缺血半暗带，溶栓治疗是目前最重要的恢复血流措施；第二，神经保护，减少再灌注损伤、抑制缺血级联反应以减轻神经功能缺损，目前被临床试验证实有效的神经保护剂为依达拉奉。虽然多项临床证据表明患者可以通过溶栓治疗得到显著获益，但短暂的治疗时间窗和出血风险导致大部分的患者仍然无法得到有效治疗，有些地方如中国，卒中患者发病3小时内到达医院的患者比例仅为21.3％。近20多年来国际上进行了多种神经保护剂研究，基础研究和动物实验结果十分令人鼓舞，但临床试验尚未取得满意结果。神经保护剂的疗效与安全性尚需开展更多高质量临床试验进一步证实。脑卒中医疗质量评估研究(CHINA QUEST)表明，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。由此可见，依达拉奉注射液存在治疗时间窗较短、临床应用受限等问题。
发明内容
本发明涉及一种组合物在治疗脑卒中的用途，其特征在于，所述的组合物包含依达拉奉(3-甲基-1-苯基-2-吡唑啉-5-酮)和右莰醇(Dexborneol，也称右旋莰醇)，其治疗时间窗为24-48小时。
本发明涉及一种组合物在制备治疗脑卒中药物中的用途，其特征在于，所述的组合物包含依达拉奉和右莰醇，其治疗时间窗为24-48小时。
本发明涉及一种治疗脑卒中的组合物，其特征在于，所述的组合物包含依达拉奉和右莰醇，其治疗时间窗为24-48小时。
本发明涉及一种治疗脑卒中的方法，该方法包含给以患者治疗上有效剂量的组合物，其特征在于，所述的组合物包含依达拉奉和右莰醇，其治疗时间窗为24-48小时。
在一些实施方案中，所述组合物中依达拉奉和右莰醇的重量比为1:1～8:1、1:1～7:1、1:1～6:1、1:1～5:1、1:1～4:1、1:1～3:1、1:1～2:1或1:1～1.5:1。
在一些实施方案中，所述组合物中依达拉奉和右莰醇的重量比为1:1～5:1。
在一些实施方案中，所述组合物中依达拉奉和右莰醇的重量比为1:1～4:1。
在一些实施方案中，所述组合物中依达拉奉和右莰醇的重量比为4:1。
在一些实施方案中，向有此需要的患者施用所述组合物后，所述患者体内依达拉奉和右莰醇的血浆暴露量比为1:1～8:1、1:1～7:1、1:1～6:1、1:1～5:1、1:1～4:1、1:1～3:1、1:1～2:1或1:1～1.5:1，优选为1:1～5:1，更优选为4:1。
在一些实施方案中，所述组合物每日给药1-3次，连续给药3-21天。
在一些实施方案中，所述组合物每12小时给药一次，每日给药2次，连续给药14天。
在一些实施方案中，所述组合物中依达拉奉的给药剂量为10-30毫克/一次。
在一些实施方案中，所述组合物中依达拉奉的给药剂量为10毫克/一次。
在一些实施方案中，所述组合物中依达拉奉的给药剂量为20毫克/一次。
在一些实施方案中，所述组合物中依达拉奉的给药剂量为30毫克/一次。
在一些实施方案中，所述组合物还包含药学上可接受的辅料。
在一些实施方案中，所述药学上可接受的辅料选自抗氧化剂、助溶剂或溶剂中的一种或多种。
在一些实施方案中，所述药学上可接受的辅料选自抗氧化剂、助溶剂或溶剂。
在一些实施方案中，所述抗氧化剂为焦亚硫酸钠。
在一些实施方案中，所述助溶剂为丙二醇。
在一些实施方案中，所述溶剂为注射用水。
在一些实施方案中，所述治疗时间窗24-48小时是指距脑卒中发病后24-48小时内给予患者本发明所述的组合物。
在一些实施方案中，在治疗时间窗24-48小时给药后，第90天mRS评分≤1分的患者比例达到60％以上，优选地，达到65％以上，更优选地，达到67％以上。
在一些实施方案中，所述脑卒中为缺血性脑卒中。
在一些实施方案中，所述脑卒中为急性缺血性脑卒中。
本发明的有益效果：本发明的组合物治疗时间窗为24-48小时时，其治疗脑卒中疗效显著，提示本发明的组合物的治疗时间窗可扩大至48小时，对于大部分超过溶栓治疗时间窗的脑卒中患者是尤为重要的治疗手段，本发明的组合物对于这部分患者治疗意义重大。
具体实施方式
以下实施例详细说明发明的技术方案，但本发明的保护范围包括但不限于此。
实施例
本发明实施例方法和数据来源于临床试验，其试验目的、试验方法和试验结果如下。
试验目的：依达拉奉右莰醇注射液的治疗时间窗研究
开展了多中心、随机双盲、阳性药(依达拉奉注射液)对照的III期临床试验,入选1200例发病时间≤48h的急性缺血性卒中患者，按照约1:1比例随机分配进入依达拉奉右莰醇注射液组或依达拉奉组进行药效学及安全性研究。同时，该临床试验还对依达拉奉右莰醇注射液的治疗时间窗进行了系统研究，其中符合入组标准的764名受试者在发病时间24～48小时内接受了依达拉奉右莰醇注射液或依达拉奉注射液连续治疗14天并随访至第90天。
受试者入选标准：
受试者入选的主要标准为年龄35～80岁，男性或女性，根据第四届全国脑血管病学术会议《各类脑血管病诊断要点》诊断为缺血性卒中(脑梗塞)，有明确神经系统定位体征，神经功能缺损评分：4≤NIHSS≤24，并且NIHSS第五项上肢和第六项下肢评分之和≥2分；排除已经接受过静脉溶栓、动脉溶栓和神经保护药物治疗的受试者。
药物规格与来源：
1)试验药品名称：依达拉奉右莰醇注射液；
规格：5mL:12.5mg(依达拉奉10mg、右莰醇2.5mg)，辅料成分为焦亚硫酸钠、丙二醇和注射用水；其中右莰醇的结构为
Figure PCTCN2021104934-appb-000001
保存条件：避光，密封，在阴凉处(不超过20℃)保存；
生产单位：南京先声东元制药有限公司
2)阳性对照药品名称：依达拉奉注射液；
规格：5mL:10mg(依达拉奉10mg)；
保存条件：避光，密封，在阴凉处(不超过20℃)保存；
生产单位：南京先声东元制药有限公司
试验药与阳性对照药在颜色、形状方面完全相同，为保证盲法，两组药物包装、批号均完全相同，包装批号统一标注。每例随机化入组的受试者将分配1个大盒药物，内装14个小盒，用于一个疗程14天的用药，每天1小盒，每小盒内含6瓶药物，每次使用1个小盒内的3瓶药物，每12h给药1次，一日2次，具体药物分装规格及数量见下表：
试验组别 小盒数量 每个小盒药物组成
依达拉奉右莰醇注射液组 14 6瓶
依达拉奉对照组 14 6瓶
试验方法：
对受试者进行随机分组，试验组受试者接受依达拉奉右莰醇注射液37.5mg，静脉注射，每日2次，连续14天；对照组受试者接受依达拉奉注射液30mg，静脉注射，每日2次，连续14天。研究期间不允许调整剂量，累计推迟给药时间不能超过2天。研究期间禁止使用《中国急性缺血性卒中诊治指南》2010年版列出的神经保护剂和溶栓药物。
更为具体的，本临床试验两组的给药方案如下：
依达拉奉右莰醇注射液组：临用前将1个小盒内的3瓶药物加入到100mL的0.9％氯化钠注射液中稀释后静脉滴注，30分钟内滴完，一天两次，每次间隔12小时，连续14天。
依达拉奉组：给药方法与试验药依达拉奉右莰醇注射液相同。临用前将1个小盒内的3瓶药物加入到100mL的0.9％氯化钠注射液中稀释后静脉滴注，30分钟内滴完，一天两次，每次间隔12小时，连续14天。
评价指标：
主要疗效终点为治疗第90天mRS评分≤1分的患者比例。
整体结局量表评定采用对残疾和残障的总体评定的改良Rankin评分量表(ModifiedRankinScale，mRS)，此研究终点也是国家食品药品监督管理总局发布的“急性缺血性脑卒中治疗药物临床试验技术指导原则”推荐的主要终点指标。mRS评分是目前脑卒中临床试验采用最多的功能结局评估量表，等级分为从0分的没有症状到5分的重度残疾，在某些试验中会增加额外的6分表示死亡。在临床试验中，一般选择mRS评分0～1分为判定受试者发生脑卒中后没有残疾的标准，也有部分临床试验选择mRS评分0～2分为判定标准。本申请试验选择mRS评分0～1分为判定标准。试验结果参见表1。
表1治疗第90天的mRS评分情况
Figure PCTCN2021104934-appb-000002
Figure PCTCN2021104934-appb-000003
表1的结果显示，依达拉奉右莰醇注射液在脑卒中发病时间24～48小时内给药仍然有良好的治疗效果，且其效果优于依达拉奉注射液。

Claims (14)

  1. 一种组合物在制备治疗脑卒中药物中的用途，其特征在于，所述的组合物包含依达拉奉和右莰醇，其治疗时间窗为24-48小时。
  2. 根据权利要求1所述的用途，其特征在于，所述组合物中依达拉奉和右莰醇的重量比为1:1～8:1、1:1～7:1、1:1～6:1、1:1～5:1、1:1～4:1、1:1～3:1、1:1～2:1、1:1～1.5:1、1:4～1:1、1:3～1:1、1:2～1:1或1:1.5～1:1，优选为1:1～5:1。
  3. 根据权利要求1所述的用途，其特征在于，所述组合物中依达拉奉和右莰醇的重量比为4:1。
  4. 根据权利要求1所述的用途，其特征在于，所述组合物每日给药1-3次，连续给药3-21天。
  5. 根据权利要求1所述的用途，其特征在于，所述组合物每12小时给药一次，每日给药2次，连续给药14天。
  6. 根据权利要求1所述的用途，其特征在于，所述组合物中依达拉奉的给药剂量为10-30毫克/一次。
  7. 根据权利要求1所述的用途，其特征在于，所述组合物中依达拉奉的给药剂量为10毫克/一次、20毫克/一次或30毫克/一次。
  8. 根据权利要求1所述的用途，其特征在于，所述组合物还包含药学上可接受的辅料。
  9. 根据权利要求8所述的用途，其特征在于，所述药学上可接受的辅料选自焦亚硫酸钠、丙二醇和注射用水。
  10. 根据权利要求1所述的用途，其特征在于，所述治疗时间窗24-48小时是指距脑卒中发病后24-48小时内给予患者所述组合物。
  11. 根据权利要求1-10任一项所述的用途，其特征在于，所述脑卒中为缺血性脑卒中。
  12. 根据权利要求1-10任一项所述的用途，其特征在于，所述脑卒中为急性缺血性脑卒中。
  13. 一种治疗脑卒中的方法，所述方法包括向有此需要的受试者施用包含依达拉奉和右莰醇的组合物，所述施用是在所述脑卒中发生后24-48小时。
  14. 根据权利要求13所述的方法，其特征在于，施用所述组合物后，所述患者体内依达拉奉和右莰醇的血浆暴露量比为1:1～8:1、1:1～7:1、1:1～6:1、1:1～5:1、1:1～4:1、1:1～3:1、1:1～2:1或1:1～1.5:1，优选为1:1～5:1，更优选为4:1。
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