Application of a composition containing cilostazol in preparing a drug for treating cerebrovascular disease

Abstract

The present invention relates to a composition containing cilostazol or a pharmaceutically acceptable salt thereof and edaravone, and its use in preparing a medicine for treating cerebrovascular disease, especially ischemic cerebrovascular disease.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceuticals and relates to the application of a cilostazol and edaravone composition in preparing a drug for treating cerebrovascular disease, particularly ischemic cerebrovascular disease. Background Art

[0002] Cerebrovascular disease (CVD) refers to brain lesions caused by various cerebrovascular diseases. According to the course of the disease, it can be divided into acute cerebrovascular disease (stroke) and chronic cerebrovascular disease. Acute cerebrovascular disease includes transient ischemic attack, cerebral thrombosis, cerebral embolism, hypertensive encephalopathy, cerebral hemorrhage and subarachnoid hemorrhage; chronic cerebrovascular disease includes cerebral arteriosclerosis, cerebrovascular dementia, cerebral artery steal syndrome, Parkinson's disease, etc. Ischemic stroke refers to the general term for brain tissue necrosis caused by stenosis or occlusion of the blood supply arteries (carotid artery and vertebral artery) of the brain and insufficient blood supply to the brain. There are four types of cerebral ischemia, namely transient ischemic attack (TIA), reversible neurological dysfunction (RIND), progressive stroke (SIE) and complete stroke (CS). TIA does not have cerebral infarction, while RIND, SIE and CS have different degrees of cerebral infarction.

[0003] Vinpocetine is an antiplatelet aggregation drug. It was first developed and synthesized by Otsuka Pharmaceutical Co., Ltd. in Japan and was launched in Japan in 1988. It was approved by the FDA in the United States in May 1999 and entered my country in 1996. Cilostazol is a selective phosphodiesterase 3 inhibitor (PDE3). The binding rate of cilostazol to plasma proteins is about 95%, and most of them exist in a relatively stable prototype. Cilostazol has a broad spectrum of pharmacological activity and has clinical value for many diseases, such as peripheral thrombotic diseases and intermittent claudication. In addition, cilostazol has antiplatelet and vasodilatory functions, which can prevent circulatory shock and recurrence of coronary artery stenosis. Studies have shown that PDE3 can inhibit the degradation of cAMP in the circulatory system and increase cAMP in platelets and vascular smooth muscle, which has an inhibitory effect on platelet formation and promotes the proliferation of vascular smooth muscle cells. Cilostazol mainly inhibits platelet degradation by affecting the following factors: arachidonic acid, adenosine diphosphate, adrenaline, collagen, and fibrinase. Some experts now believe that cilostazol can be recommended for patients with carotid artery thrombosis to treat or prevent cerebral ischemia. At the same time, PDE3 can inhibit the production of nitric oxide synthase (NOS), thereby reducing the production of nitric oxide (NO).

[0004] The structural formula of cilostazol is as follows:

[0005]

[0006] (Molecular formula C 20 H 27 N5O2; molecular weight 369.47)

[0007] Edaravone (chemical name: 3-methyl-1-phenyl-2-pyrazol-5-one) is a neuroprotective agent that has been marketed. Yakugaku Zasshi. 2004, 124(3): 99-111 ). Studies have shown that edaravone has antioxidant activity and can significantly improve the neurological deficit symptoms of animals with cerebral ischemia-reperfusion, reduce the infarct area, reduce the degree of brain damage, reduce brain edema, and inhibit lipid peroxidation in damaged brain tissue.

[0008]

[0009] Edaravone

[0010] (Molecular formula C 10 H 10 N2O, molecular weight 174.20)

[0011] The inventor of this patent found that administration of 1-15 mg / kg cilostazol or 1.67-8.33 mg / kg edaravone through the tail vein of rats with focal cerebral ischemia-reperfusion injury can significantly improve the neurological deficits and reduce the area of ​​cerebral infarction in MCAO rats; and the compound combination (mass ratio of cilostazol: edaravone 1:5-5:1) within the above dosage range can synergistically enhance the effect. Administration of 3.33-16.67 mg / kg cilostazol or 3.33-16.67 mg / kg edaravone through the tail vein of mice with focal cerebral ischemia-reperfusion injury can significantly improve the neurological deficits and reduce the area of ​​cerebral infarction in MCAO mice. Summary of the invention

[0012] The present invention aims to provide a pharmaceutical composition for use in preparing a drug for treating cerebrovascular diseases. The pharmaceutical composition contains cilostazol or a pharmaceutically acceptable salt thereof and edaravone. Furthermore, the combination of the drugs can synergistically increase the efficacy of treating cerebrovascular diseases.

[0013] The above-mentioned pharmaceutical composition is characterized in that the weight ratio of cilostazol or its pharmaceutically acceptable salt to edaravone is 1:10~10:1, preferably, the weight ratio is 1:5~10:1, preferably, the weight ratio is 1:10~5:1; preferably, the weight ratio is 1:5~5:1; preferably, the weight ratio is 1:2.5~2.5:1; and 1:1~2.5:1.

[0014] The drug combination of the present invention can be used to prepare cerebrovascular drugs. Among them, the cerebrovascular disease is preferably ischemic cerebrovascular disease, and ischemic stroke is further preferred.

[0015] The beneficial effect of the present invention is that the combination of cilostazol and edaravone has a synergistic effect of increasing the efficacy of cerebrovascular diseases according to the results of animal (rats, mice) efficacy tests. DETAILED DESCRIPTION

[0016] The following examples illustrate the present invention and should not be construed as limiting the present invention.

[0017] Example 1 Study on the protective effect of cilostazol and edaravone combination on focal cerebral ischemia-reperfusion injury

[0018] 1 Materials and methods

[0019] 1.1 Experimental animals

[0020] Sprague-Dawley (SD) rats, male, SPF grade, weighing 250-280 g.

[0021] Sample name factory batch number Cilostazol Shanghai Aladdin Biochemical Technology Co., Ltd. K1405071 Edaravone Jiangsu Tiansheng Pharmaceutical Co., Ltd. 20161103

[0022] 1.3 Experimental methods

[0023] 1.3.1 Animal grouping and drug administration

[0024] The experimental animals were divided into 4 groups: cilostazol group (1 mg / kg), edaravone group (5 mg / kg), cilostazol and edaravone combination group (6 mg / kg, cilostazol:edaravone = 1:5, cilostazol 1 mg / kg + edaravone 5 mg / kg) and model group. After the cerebral ischemia model was prepared, the animals were equally and blindly assigned to each group. The animals were intravenously administered once immediately after reperfusion, and the animals in the model group were given an equal volume of normal saline. The animals were killed 24 hours after cerebral ischemia, and the brain was removed, stained, and photographed to determine the range of cerebral infarction.

[0025] 1.3.2 Preparation of focal cerebral ischemia-reperfusion model

[0026] The rat focal cerebral ischemia-reperfusion model was prepared by internal carotid artery embolization. The rats were anesthetized and their limbs (the hind limbs were fixed above the knee joint, and the forelimbs were fixed below the wrist joint) and head were tied with rubber bands. The animals were fixed on the operating table in a supine position. The hair was shaved from the head to the chest with an animal shaver, and the skin was disinfected with alcohol. The neck was incised in the middle and the subcutaneous tissue was bluntly separated. The thin layer of fascia on the surface of the anterior cervical triangle was separated, and the lower edge of the lower side-claviohyoid muscle was lifted. The longitudinal pulsating artery parallel to this muscle was visible. The arterial shell was opened to expose the right carotid bifurcation. The right common carotid artery, external carotid artery, and internal carotid artery were separated. The vagus nerve was gently peeled off, and the external carotid artery was ligated and cut. The proximal end of the common carotid artery was clamped, and an incision was made from the distal end of the ligature of the external carotid artery. The embolization line was inserted through the bifurcation of the common carotid artery into the internal carotid artery, and then slowly inserted until there was slight resistance (about 20 mm from the bifurcation), blocking all blood supply to the middle cerebral artery. The suture was fixed slightly below the incision of the external carotid artery with silk thread, the silk thread clamped at the proximal end of the common carotid artery was loosened, the wound was covered with gauze soaked in sterile saline, and the rat was placed on a warming pad for warmth. After 2.0 h of right cerebral ischemia, the suture was gently pulled out, blood supply was restored for reperfusion, the external carotid artery was ligated with the silk thread that fixed the suture, the skin was sutured, and disinfected. The rat was placed in clean feed, and the general condition and breathing were observed until the rat woke up from anesthesia; food and water were added, and the rat was fed normally.

[0027] 1.3.3 Determination of cerebral infarction area

[0028] After the evaluation of the neurological deficit symptoms of the animals, they were killed with CO2, decapitated and the brains were removed. The olfactory bulbs, cerebellum and lower brain stem were removed, and the blood on the surface of the brain was rinsed with saline. The residual water on the surface was sucked off and placed at -20 ℃ for 20 min. After being taken out, a coronal section was immediately made vertically downward at the cross-line of vision plane, and a slice was cut every 2 mm backward. The brain slices were incubated in 1% TTC dye solution (37 ℃ for 30 min). Normal brain tissue was stained dark red, while ischemic brain tissue was pale. After being rinsed with saline, the brain slices were quickly arranged in a row from front to back, the residual water on the surface was sucked off, and photos were taken.

[0029] Calculation of cerebral infarction area: The photos were processed with Image J software, and the corresponding area of ​​the left brain and the non-infarct area of ​​the right brain were calculated according to the formula to obtain the percentage of infarction range.

[0030] Infarct volume calculation method:

[0031] V=t (A1+ A2+ A3+ ………+An)

[0032] t is the slice thickness, and A is the infarct area.

[0033] %I=100%×(VC-VL) / VC

[0034] %I is the percentage of infarct volume, VC is the brain volume of the control side (left cerebral hemisphere), and VL is the volume of the non-infarct area on the infarct side (right cerebral hemisphere).

[0035] 1.3.4 Synergistic analysis of the composition

[0036] According to the formula of Jin Zhengjun, q = E(a+b) / (Ea+ Eb- Ea×Eb), whether cilostazol and edaravone in the combination have synergistic effects is evaluated. In the formula, E(a+b) is the effective rate of the combined drug, and Ea and Eb are the effective rates of drug A (cilostazol) and drug B (edaravone) taken alone. E treatment group = (X 模型 -X 给药 ) / X 模型 , X is the range of cerebral infarction. If the q value is within the range of 0.85 to 1.15, it is a simple addition of the two drugs when used together, q value>1.15 is synergistic, and q value<0.85 indicates that the two drugs have an antagonistic effect when used together.

[0037] 1.4 Statistics

[0038] The experimental data were expressed as mean ± standard deviation (Mean ± SD). One-way ANOVA was used to analyze the differences among the groups, and the LSD method was used for inter-group comparison. P < 0.05 was defined as a significant difference.

[0039] 2 Experimental Results

[0040] The effects on the scope of cerebral infarction are shown in Table 1. The experimental results show that the administration of 5 mg / kg of edaravone and the combination (1 mg / kg of cilostazol + 5 mg / kg of edaravone) can significantly reduce the scope of cerebral infarction in animals (p=0.012, p=0.000), and the administration of 1 mg / kg of cilostazol has a tendency to improve cerebral ischemic injury, but there is no statistical difference (p=0.08). The synergistic calculation result q=1.33, indicating that the combination of the two drugs has a synergistic effect.

[0041] Group Number of animals Cerebral infarction area (%) Model Group 11 40.35±8.24 Cilostazol group 11 34.24 ± 7.25 Edaravone group 11 29.35±10.45* Cilostazol / edaravone 1:5 group 12 19.74±9.30***

[0042] Mean ± SD, * p < 0.05, *** p < 0.001, compared with the model group

[0043] Example 2 Study on the protective effect of cilostazol and edaravone combination on focal cerebral ischemia-reperfusion injury

[0044] 1 Materials and methods

[0045] 1.1 Experimental animals

[0046] Sprague-Dawley (SD) rats, male, SPF grade, weighing 250-280 g.

[0047] 1.2 Test Drugs

[0048] Cilostazol and edaravone are the same as those in Example 1.

[0049] 1.3 Experimental methods

[0050] The experimental animals were divided into 4 groups: cilostazol group (5 mg / kg), edaravone group (5 mg / kg), cilostazol and edaravone combination group (10 mg / kg, cilostazol:edaravone = 1:1, cilostazol 5 mg / kg + edaravone 5 mg / kg) and model group. After the cerebral ischemia model was prepared, the animals were equally and blindly assigned to each group. The animals were intravenously administered once immediately after reperfusion, and the animals in the model group were given an equal volume of normal saline. The animals were killed 24 hours after cerebral ischemia, and the brain was removed, stained, and photographed to determine the range of cerebral infarction.

[0051] The preparation of focal cerebral ischemia-reperfusion model, determination of cerebral infarction range, analysis of composition synergy and data statistical methods are the same as those in Example 1.

[0052] 2 Experimental Results

[0053] The effects on the scope of cerebral infarction are shown in Table 2. The experimental results show that the administration of cilostazol 5 mg / kg, edaravone 5 mg / kg and the combination (cilostazol 5 mg / kg + edaravone 5 mg / kg) can significantly reduce the scope of cerebral infarction in animals (p=0.025, p=0.008, p=0.000). The synergistic calculation result q=1.47, indicating that the combination of the two drugs has a synergistic effect.

[0054] Group Number of animals Cerebral infarction area (%) Model Group 11 40.50±8.51 Cilostazol group 12 32.59 ± 7.15* Edaravone group 11 29.49±9.06** Cilostazol / edaravone 1:1 group 12 15.82±7.43***

[0055] Mean ± SD, *p<0.05, **p<0.01, ***p<0.001, compared with the model group

[0056] Example 3 Study on the protective effect of cilostazol and edaravone combination on focal cerebral ischemia-reperfusion injury

[0057] 1 Materials and methods

[0058] 1.1 Experimental animals

[0059] Sprague-Dawley (SD) rats, male, SPF grade, weighing 250-280 g.

[0060] 1.2 Test Drugs

[0061] Cilostazol and edaravone are the same as those in Example 1.

[0062] 1.3 Experimental methods

[0063] The experimental animals were divided into 4 groups: cilostazol group (15 mg / kg), edaravone group (3 mg / kg), cilostazol and edaravone combination group (18 mg / kg, cilostazol:edaravone = 5:1, cilostazol 15 mg / kg + edaravone 3 mg / kg) and model group. After the cerebral ischemia model was prepared, the animals were equally and blindly assigned to each group. The animals were intravenously administered once immediately after reperfusion, and the animals in the model group were given an equal volume of normal saline. The animals were killed 24 hours after cerebral ischemia, and the brain was removed, stained, and photographed to determine the range of cerebral infarction.

[0064] The preparation of focal cerebral ischemia-reperfusion model, determination of cerebral infarction range, analysis of composition synergy and data statistical methods are the same as those in Example 1.

[0065] 2 Experimental Results

[0066] The effects on the scope of cerebral infarction are shown in Table 3. The experimental results show that the administration of 15 mg / kg of cilostazol, 3 mg / kg of edaravone and the combination (15 mg / kg of cilostazol + 3 mg / kg of edaravone) can significantly reduce the scope of cerebral infarction in animals (p=0.007, p=0.029, p=0.000). The synergistic calculation result q=1.38, indicating that the combination of the two drugs has a synergistic effect.

[0067] Group Number of animals Cerebral infarction area (%) Model Group 11 39.41±9.56 Cilostazol group 11 27.26 ± 9.74** Edaravone group 12 31.24±6.83* Cilostazol / edaravone 5:1 group 12 17.08±6.26***

[0068] Mean ± SD, *p<0.05, **p<0.01, ***p<0.001, compared with the model group

[0069] Example 4 Effects of Cilostazol / Edaravone (1:5, 1:2.5, 1:1) on Focal Cerebral Ischemia-Reperfusion Injury

[0070] 1 Materials and methods

[0071] 1.1 Experimental animals

[0072] Sprague-Dawley (SD) rats, male, SPF grade, weighing 250-280 g.

[0073] 1.2 Test Drugs

[0074] Cilostazol and edaravone are the same as those in Example 1.

[0075] 1.3 Experimental methods

[0076] The experimental animals were divided into a model group and three cilostazol / edaravone combination groups (1:5 group, cilostazol 1.67 mg / kg + edaravone 8.33 mg / kg; 1:2.5 group, cilostazol 2.86 mg / kg + edaravone 7.14 mg / kg; 1:1 group, cilostazol 5 mg / kg + edaravone 5 mg / kg. The total dose of each combination was 10 mg / kg.), a total of 4 groups. After the cerebral ischemia model was prepared, the animals were equally and blindly assigned to each group. The animals were intravenously administered once immediately after reperfusion, and the animals in the model group were given an equal volume of normal saline. The animals were killed 24 hours after cerebral ischemia, and the brain was removed, stained, and photographed to determine the range of cerebral infarction.

[0077] The preparation of focal cerebral ischemia-reperfusion model, determination of cerebral infarction range and data statistics method are the same as those in Example 1.

[0078] 2 Experimental Results

[0079] The effects on the scope of cerebral infarction are shown in Table 4. The experimental results show that the combination of cilostazol / edaravone at 1:5, 1:2.5 and 1:1 can significantly reduce the scope of cerebral infarction in animals (p<0.001).

[0080] Group Number of animals Cerebral infarction area (%) Model Group 12 38.75±8.79 Cilostazol / edaravone 1:5 group 12 21.91 ± 8.89*** Cilostazol / edaravone 1:2.5 group 12 19.46±9.39*** Cilostazol / edaravone 1:1 group 13 15.72±8.28***

[0081] Mean ± SD, *** p < 0.001, compared with the model group

[0082] Example 5 Effects of Cilostazol / Edaravone (1:1, 2.5:1, 5:1) on Focal Cerebral Ischemia-Reperfusion Injury

[0083] 1 Materials and methods

[0084] 1.1 Experimental animals

[0085] Sprague-Dawley (SD) rats, male, SPF grade, weighing 250-280 g.

[0086] 1.2 Test Drugs

[0087] Cilostazol and edaravone are the same as those in Example 1.

[0088] 1.3 Experimental methods

[0089] The experimental animals were divided into a model group and three cilostazol / edaravone combination groups (1:1 group, cilostazol 5 mg / kg + edaravone 5 mg / kg; 2.5:1 group, cilostazol 7.14 mg / kg + edaravone 2.86 mg / kg; 5:1 group, cilostazol 8.33 mg / kg + edaravone 1.67 mg / kg. The total dose of each combination was 10 mg / kg.), a total of 4 groups. After the cerebral ischemia model was prepared, the animals were equally and blindly assigned to each group. The animals were intravenously administered once immediately after reperfusion, and the animals in the model group were given an equal volume of normal saline. The animals were killed 24 hours after cerebral ischemia, and the brain was removed, stained, and photographed to determine the range of cerebral infarction.

[0090] The preparation of focal cerebral ischemia-reperfusion model, determination of cerebral infarction range and data statistics method are the same as those in Example 1.

[0091] 2 Experimental Results

[0092] The effects on the scope of cerebral infarction are shown in Table 5. The experimental results show that the combination of cilostazol / edaravone at 1:1, 2.5:1 and 5:1 can significantly reduce the scope of cerebral infarction in animals (p=0.000, p=0.000, p=0.001).

[0093] Group Number of animals Cerebral infarction area (%) Model Group 12 40.52±8.64 Cilostazol / edaravone 1:1 group 13 17.11± 8.94*** Cilostazol / edaravone 2.5:1 group 12 22.90±11.37*** Cilostazol / edaravone 5:1 group 12 24.54±12.10**

[0094] Mean ± SD, **p<0.01, ***p<0.001, compared with the model group

[0095] Example 6 Effects of Cilostazol / Edaravone (1:5, 1:2.5, 1:1) on Focal Cerebral Ischemia-Reperfusion Injury in Mice

[0096] 1 Materials and methods

[0097] 1.1 Experimental animals

[0098] C57BL / 6J mice, male, SPF grade, 8 weeks old.

[0099] 1.2 Test Drugs

[0100] Cilostazol and edaravone are the same as those in Example 1.

[0101] 1.3 Experimental methods

[0102] The experimental animals were divided into a model group and three cilostazol / edaravone combination groups (1:5 group, cilostazol 3.33 mg / kg + edaravone 16.67 mg / kg; 1:2.5 group, cilostazol 5.71 mg / kg + edaravone 14.29 mg / kg; 1:1 group, cilostazol 10 mg / kg + edaravone 10 mg / kg. The total dose of each combination was 20 mg / kg.), a total of 4 groups. After the cerebral ischemia model was prepared, the animals were equally and blindly assigned to each group. The animals were intravenously administered once immediately after reperfusion, and the animals in the model group were given an equal volume of normal saline. The animals were killed 24 hours after cerebral ischemia, and the brain was removed, stained, and photographed to determine the range of cerebral infarction.

[0103] Preparation of focal cerebral ischemia-reperfusion model: The focal cerebral ischemia-reperfusion model in mice was prepared by internal carotid artery embolization. The anesthetized mice were fixed in supine position on the operating table. The midline incision of the neck was performed, and the subcutaneous tissue was bluntly separated. The right common carotid artery, external carotid artery, and internal carotid artery were separated. The embolism line was inserted from the external carotid artery, passed through the bifurcation of the common carotid artery and entered the internal carotid artery, and then slowly inserted until there was slight resistance (about 10 mm from the bifurcation), blocking all blood supply to the middle cerebral artery. After 60 minutes of right cerebral ischemia, the embolism line was gently pulled out, and blood supply was restored for reperfusion. The mice were placed in clean feed, and their general condition and breathing were observed until they woke up from anesthesia; food and water were added, and they were fed normally.

[0104] The method for determining the extent of cerebral infarction and data statistics is the same as that in Example 1.

[0105] 2 Experimental Results

[0106] The effects on the scope of cerebral infarction are shown in Table 6. The experimental results show that the combination of cilostazol / edaravone at 1:5, 1:2.5 and 1:1 can significantly reduce the scope of cerebral infarction in animals (p<0.001, p<0.012, p<0.001).

[0107] Group Number of animals Cerebral infarction area (%) Model Group 12 36.24±9.46 Cilostazol / edaravone 1:5 group 13 22.49 ± 8.76*** Cilostazol / edaravone 1:2.5 group 12 21.12±11.04** Cilostazol / edaravone 1:1 group 13 16.75±8.44***

[0108] Mean ± SD, ** p < 0.01, *** p < 0.001, compared with the model group

[0109] Example 7 Effects of Cilostazol / Edaravone (1:1, 2.5:1, 5:1) on Focal Cerebral Ischemia-Reperfusion Injury in Mice

[0110] 1 Materials and methods

[0111] 1.1 Experimental animals

[0112] C57BL / 6J mice, male, SPF grade, 8 weeks old.

[0113] 1.2 Test Drugs

[0114] Cilostazol and edaravone are the same as those in Example 1.

[0115] 1.3 Experimental methods

[0116] The experimental animals were divided into a model group and three cilostazol / edaravone combination groups (1:1 group, cilostazol 10 mg / kg + edaravone 10 mg / kg; 2.5:1 group, cilostazol 14.29 mg / kg + edaravone 5.71 mg / kg; 5:1 group, cilostazol 16.67 mg / kg + edaravone 3.33 mg / kg. The total dose of each combination was 20 mg / kg.), a total of 4 groups. After the cerebral ischemia model was prepared, the animals were equally and blindly assigned to each group. The animals were intravenously administered once immediately after reperfusion, and the animals in the model group were given an equal volume of normal saline. The animals were killed 24 hours after cerebral ischemia, and the brain was removed, stained, and photographed to determine the range of cerebral infarction.

[0117] The preparation of the focal cerebral ischemia-reperfusion model was the same as in Example 6, and the determination of the cerebral infarction range and the data statistics method were the same as in Example 1.

[0118] 2 Experimental Results

[0119] The effects on the scope of cerebral infarction are shown in Table 7. The experimental results show that the combination of cilostazol / edaravone at 1:1, 2.5:1 and 5:1 can significantly reduce the scope of cerebral infarction in animals (p<0.001).

[0120] Group Number of animals Cerebral infarction area (%) Model Group 13 39.06±7.90 Cilostazol / edaravone 1:1 group 13 15.58± 8.95*** Cilostazol / edaravone 2.5:1 group 12 21.23±10.84*** Cilostazol / edaravone 5:1 group 12 23.88±11.90***

[0121] Mean ± SD, *** p < 0.001, compared with the model group.

Claims

1. Use of a composition in the preparation of a drug for treating cerebrovascular disease, the composition comprising a combination of cilostazol or a pharmaceutically acceptable salt thereof and edaravone; The weight ratio of cilostazol or its pharmaceutically acceptable salt to edaravone is 1:5 to 5:1; The cerebrovascular disease is ischemic stroke.

2. The use of the composition according to claim 1, characterized in that: The weight ratio of cilostazol or its pharmaceutically acceptable salt to edaravone is 1:2.5 to 2.5:

1.

3. The use of the composition according to claim 1, characterized in that: The weight ratio of cilostazol or its pharmaceutically acceptable salt to edaravone is 1:1 to 2.5:1.

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