WO2022007831A1 - Utilisation médicale de composition - Google Patents

Utilisation médicale de composition Download PDF

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Publication number
WO2022007831A1
WO2022007831A1 PCT/CN2021/104932 CN2021104932W WO2022007831A1 WO 2022007831 A1 WO2022007831 A1 WO 2022007831A1 CN 2021104932 W CN2021104932 W CN 2021104932W WO 2022007831 A1 WO2022007831 A1 WO 2022007831A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
edaravone
use according
stroke
dexbornol
Prior art date
Application number
PCT/CN2021/104932
Other languages
English (en)
Chinese (zh)
Inventor
冯晓飞
诸舜伟
刘存存
王峰
任晋生
Original Assignee
先声药业有限公司
江苏先声药业有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 先声药业有限公司, 江苏先声药业有限公司 filed Critical 先声药业有限公司
Publication of WO2022007831A1 publication Critical patent/WO2022007831A1/fr

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Classifications

    • 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
    • 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

Definitions

  • the present invention relates to the medicinal use of a composition, furthermore, the present invention relates to the use of a composition in preparing a medicament for treating stroke in patients.
  • stroke is the second leading cause of death worldwide and the first cause of long-term and serious neurological disease in China.
  • risk factors for stroke.
  • the more common risk factors mainly include blood pressure, blood sugar, cholesterol level, body mass index, smoking, physical activity and diet. These risk factors are strongly associated with stroke.
  • stroke patients with a history of underlying diseases may have higher morbidity, mortality, recurrence, and disability rates.
  • drugs that have actually been confirmed for the acute and subacute stages of cerebral ischemia cannot fully meet the needs of clinical applications, especially those with multiple diseases or disease history.
  • Clinical needs of patients with ischemic stroke (such as history of hypertension, hyperlipidemia, diabetes, heart disease, etc.).
  • the present invention provides a method for treating stroke in patients with a history of heart disease.
  • the present invention specifically relates to the use of a composition in preparing a medicine for treating stroke in patients, characterized in that the composition comprises edaravone (3-methyl-1-phenyl-2-pyrazoline- 5-keto) and Dexborneol (also known as Dexborneol) in the patient with a history of heart disease.
  • edaravone 3-methyl-1-phenyl-2-pyrazoline- 5-keto
  • Dexborneol also known as Dexborneol
  • the present invention relates to the use of a composition for the treatment of stroke in patients, characterized in that the composition comprises edaravone and dexbornol, and the patient has a history of heart disease.
  • the present invention relates to a composition for treating cerebral apoplexy in a patient, characterized in that the composition comprises edaravone and dexbornol, and the patient has a history of heart disease.
  • the present invention relates to a method for treating stroke in a patient, the method comprising administering to the patient a therapeutically effective dose of a composition comprising edaravone and dexbornol, and the patient has a cardiac medical history.
  • 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 stroke is ischemic stroke.
  • the stroke is acute ischemic stroke.
  • Beneficial effects of the present invention We unexpectedly found that the edaravone and dexcamphenol composition of the present invention has achieved significant curative effect on stroke patients with a history of heart disease, especially for acute ischemic stroke complicated with heart disease The patients are provided with more effective therapeutic drugs and treatment plans to meet the urgent clinical needs of stroke patients with heart disease.
  • 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.
  • the pharmacodynamics and safety of edaravone dexbornol injection group or edaravone group injection were studied.
  • each subgroup was included according to the following diagnostic criteria, and the subgroups of patients were randomly assigned in an approximately 1:1 ratio to receive edaravone dexbornol injection or edaravone injection Treatment was continued for 14 days and followed up to day 90.
  • 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).
  • Acute ischemic stroke patients with a history of heart disease indicate that the subject has heart-related diseases before or at the time of enrollment, including but not limited to coronary heart disease, rheumatic heart disease, acute/chronic heart failure, hypertrophic Cardiomyopathy, dilated cardiomyopathy, myocarditis, etc.
  • the total cholesterol in the fasting serum of the subjects exceeds 5.72 mmol/L, and the triglyceride exceeds 1.70 mmol/L. L; or subjects currently using lipid-lowering drugs whose serum total cholesterol and triglyceride do not exceed the above standards (total cholesterol does not exceed 5.72 mmol/L and triglyceride does not exceed 1.70 mmol/L); and Diagnosis criteria of "Guidelines for the Prevention and Treatment of Dyslipidemia in Adults in China" (2016 Revised Edition).
  • 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 Edaravone control 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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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne l'utilisation d'une composition dans la préparation d'un médicament pour le traitement d'un accident vasculaire cérébral chez un patient. La composition comprend de l'édaravone et du dexbornéol, et le patient a un historique de maladie cardiaque.
PCT/CN2021/104932 2020-07-08 2021-07-07 Utilisation médicale de composition WO2022007831A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202010653989 2020-07-08
CN202010653989.1 2020-07-08

Publications (1)

Publication Number Publication Date
WO2022007831A1 true WO2022007831A1 (fr) 2022-01-13

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/104932 WO2022007831A1 (fr) 2020-07-08 2021-07-07 Utilisation médicale de composition

Country Status (2)

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TW (1) TW202214232A (fr)
WO (1) WO2022007831A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101524352A (zh) * 2008-03-04 2009-09-09 江苏先声药物研究有限公司 一种含有3-甲基-1-苯基-2-吡唑啉-5-酮的组合物
CN102485223A (zh) * 2010-12-01 2012-06-06 江苏先声药物研究有限公司 一种药物组合物及其在制备治疗脑血管病药物中的应用
CN102579432A (zh) * 2011-01-12 2012-07-18 江苏先声药物研究有限公司 3-甲基-1-苯基-2-吡唑啉-5-酮与2-莰醇组合物的新应用
CN107773545A (zh) * 2016-08-29 2018-03-09 烟台益诺依生物医药科技有限公司 依达拉奉与(+)‑2‑莰醇的舌下用药物组合物

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101524352A (zh) * 2008-03-04 2009-09-09 江苏先声药物研究有限公司 一种含有3-甲基-1-苯基-2-吡唑啉-5-酮的组合物
CN102485223A (zh) * 2010-12-01 2012-06-06 江苏先声药物研究有限公司 一种药物组合物及其在制备治疗脑血管病药物中的应用
CN102579432A (zh) * 2011-01-12 2012-07-18 江苏先声药物研究有限公司 3-甲基-1-苯基-2-吡唑啉-5-酮与2-莰醇组合物的新应用
CN107773545A (zh) * 2016-08-29 2018-03-09 烟台益诺依生物医药科技有限公司 依达拉奉与(+)‑2‑莰醇的舌下用药物组合物

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