WO2022007831A1

WO2022007831A1 - Medical use of composition

Info

Publication number: WO2022007831A1
Application number: PCT/CN2021/104932
Authority: WO
Inventors: 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: 2020-07-08
Filing date: 2021-07-07
Publication date: 2022-01-13
Also published as: TW202214232A

Abstract

Use of a composition in the preparation of a medicament for treating cerebral stroke in a patient. The composition comprises Edaravone and Dexborneol, and the patient has a heart disease history.

Description

Medicinal use of a composition

technical field

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.

Background technique

In the past 15 years, stroke is the second leading cause of death worldwide and the first cause of long-term and serious neurological disease in China. There are many 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. In addition, stroke patients with a history of underlying diseases may have higher morbidity, mortality, recurrence, and disability rates. Although a large number of drugs are clinically used in the treatment of stroke, the 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.).

SUMMARY OF THE INVENTION

In order to solve the above problems, 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.

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.

In some embodiments, 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.

In some embodiments, the weight ratio of edaravone to dexbornol in the composition is 1:1 to 5:1.

In some embodiments, the weight ratio of edaravone to dexbornol in the composition is 1:1 to 4:1.

In some embodiments, the weight ratio of edaravone to dexbornol in the composition is 4:1.

In some embodiments, following administration of the composition to a patient in need thereof, 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.

In some embodiments, the composition is administered 1-3 times daily for 3-21 consecutive days.

In some embodiments, the composition is administered every 12 hours, twice a day, for 14 consecutive days.

In some embodiments, the dose of edaravone administered in the composition is 10-30 mg/time.

In some embodiments, the dose of edaravone administered in the composition is 10 mg/time.

In some embodiments, the dose of edaravone administered in the composition is 20 mg/time.

In some embodiments, the dose of edaravone administered in the composition is 30 mg/time.

In some embodiments, the composition further comprises a pharmaceutically acceptable excipient.

In some embodiments, the pharmaceutically acceptable adjuvant is selected from one or more of antioxidants, co-solvents or solvents.

In some embodiments, the pharmaceutically acceptable adjuvant is selected from antioxidants, cosolvents or solvents.

In some embodiments, the antioxidant is sodium metabisulfite.

In some embodiments, the co-solvent is propylene glycol.

In some embodiments, the solvent is water for injection.

In some embodiments, the stroke is ischemic stroke.

In some embodiments, 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.

detailed description

The following examples illustrate the technical solutions of the invention in detail, but the protection scope of the present invention includes but is not limited thereto.

Example

The methods and data in the embodiments of the present invention are derived from clinical trials, and the test objectives, test methods and test results are as follows.

Objective: Subgroup efficacy study of edaravone and dexbornol injection in stroke patients with a history of underlying diseases

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. To study and analyze the efficacy of edaravone dexbornol injection in the treatment of acute ischemic stroke patients with a history of underlying diseases. Among the selected 1200 stroke patients, 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.

Subject inclusion criteria:

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). Nervous system localization signs, neurological deficit score: 4≤NIHSS≤24, and the sum of the NIHSS item 5 upper limb and sixth lower limb score ≥ 2; have received intravenous thrombolysis, arterial thrombolysis and neuroprotective drug treatment are excluded subjects.

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.

Among the above selected subjects, if they meet the following conditions, they are considered to have a history of hyperlipidemia: before or during the enrollment period, 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).

Drug Specifications and Sources:

1) Test drug name: Edaravone Dexbornol Injection;

Specifications: 5mL: 12.5mg (Edaravone 10mg, (+)-2-camphenol 2.5mg), the excipients are sodium metabisulfite, propylene glycol and water for injection; the structure of dexcamphenol is

Storage conditions: dark, sealed and stored in a cool place (not more than 20 ℃);

Production unit: Nanjing Simcere TECO Pharmaceutical Co., Ltd.

2) Name of positive control drug: Edaravone injection;

Specifications: 5mL: 10mg (Edaravone 10mg);

Production unit: Nanjing Simcere TECO Pharmaceutical Co., Ltd.

The test drug and the positive control drug are identical in color and shape. In order to ensure blindness, 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:

试验组别Test group	小盒数量Number of small boxes	每个小盒药物组成Each small box of medicines consists of
依达拉奉右莰醇注射液组Edaravone and Dexbornol Injection Group	1414	6瓶6 bottles
依达拉奉对照组Edaravone control group	1414	6瓶6 bottles

experiment method:

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.

More specifically, the dosing regimens of the two groups in this clinical trial are as follows:

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 .

Evaluation indicators:

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. In clinical 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. In this application, the mRS score of 0-1 was selected as the criterion. The test results are shown in Table 1.

Table 1 mRS score on the 90th day of treatment

The results in Table 1 show that the therapeutic effect of edaravone injection on stroke patients with a history of heart disease is significantly inferior to that on stroke patients without a history of heart disease, and the mRS scores on the 90th day were 35.8% and 62.1%, respectively. . The use of edaravone dexbornol injection can significantly improve the treatment effect of stroke patients with a history of heart disease, from 35.8% to 57.0%, compared with edaravone injection, an increase of 59.2% (100% *(57.0-35.8)/35.8=59.2%). For stroke patients with a history of hyperlipidemia, there is no significant difference between edaravone and dexborneol injection and edaravone injection. The above results show that edaravone dexbornol has a good therapeutic effect on stroke patients with a history of heart disease, and its effect is better than that of edaravone injection.

Claims

A use of a composition for preparing a medicament for treating stroke in a patient, characterized in that the composition comprises edaravone and dexbornol, and the patient has a history of heart disease.
The use according to claim 1, wherein the weight ratio of edaravone to dexcamphenol 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, preferably 1:1～ 5:1.
The use according to claim 1, wherein the weight ratio of edaravone and dexbornol in the composition is 4:1.
The use according to claim 1, wherein the composition is administered 1-3 times a day for 3-21 consecutive days.
The use according to claim 1, wherein the composition is administered once every 12 hours, twice a day, for 14 consecutive days.
The use according to claim 1, wherein the administration dose of edaravone in the composition is 10-30 mg/time.
The use according to claim 1, wherein the administration dose of edaravone in the composition is 10 mg/time, 20 mg/time or 30 mg/time.
The use according to claim 1, wherein the composition further comprises a pharmaceutically acceptable auxiliary material.
The use according to claim 8, wherein the pharmaceutically acceptable adjuvant is selected from the group consisting of sodium metabisulfite, propylene glycol and water for injection.
The use according to any one of claims 1-9, wherein the stroke is ischemic stroke.
The use according to any one of claims 1-9, wherein the stroke is acute ischemic stroke.
A method of treating stroke, the method comprising administering a composition comprising edaravone and dexbornol to a patient in need thereof, the patient having a history of cardiac disease.
The method of claim 12, wherein after administration of the composition, 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.