Application of cilostazol-containing compositions to cerebrovascular diseases

Abstract

The present invention provides the application of a composition containing cilostazol or a pharma- ceutical acceptable salt thereof and edaravone in the preparation of a drug for treating cerebrovascular disease, particularly ischemic cerebrovascular disease. As shown in the experimental results, neurological deficits in MCAO rats can be significantly improved and the area of ​​cerebral infarction can be reduced by administering 1-15 mg / kg of cilostazol or 1.67-8.33 mg / kg of edaravone to the tail vein for focal cerebral ischemia-reperfusion injury in rats, and a synergistic effect can be achieved by combining drugs within the above dose range (cilostazol:edaravone is 1:5-5:1 by mass ratio). In addition, neurological deficits can be significantly improved and the area of ​​cerebral infarction can be reduced by administering 3.33-16.67 mg / kg of cilostazol or 3.33-16.67 mg / kg of edaravone to the tail vein for focal cerebral ischemia-reperfusion injury in mice.

Description

[Technical Field]

[0001] [Cross reference] This application claims priority from China Patent Application No. 202110122555.3, entitled "Application of a composition containing cilostazol to cerebrovascular disease," filed with the State Intellectual Property Administration of China on January 29, 2021, the entire contents of which are incorporated herein by reference.

[0002] The present invention belongs to the field of pharmacy and relates to the application of a composition of cilostazol and edaravone in the preparation of a medicament for treating cerebrovascular diseases, especially ischemic cerebrovascular diseases. [Background technology]

[0003] Cerebrovascular disease (CVD) refers to brain lesions caused by various cerebrovascular diseases and can be divided into acute cerebrovascular disease (stroke) and chronic cerebrovascular disease depending on the pathogenesis. Acute cerebrovascular diseases include transient ischemic attack, cerebral thrombosis, cerebral embolism, hypertensive encephalopathy, cerebral hemorrhage, and subarachnoid hemorrhage. Chronic cerebrovascular diseases include cerebral arteriosclerosis, vascular dementia, cerebral steal syndrome, and Parkinson's disease. Ischemic stroke is a general term for necrosis of brain tissue caused by stenosis or occlusion of the arteries supplying blood to the brain (carotid arteries and vertebral arteries) or by insufficient blood supply to the brain. Cerebral ischemia includes four types: transient ischemic attack (TIA), reversible ischemic neurological deficit (RIND), progressive stroke (SIE), and complete stroke (CS). No cerebral infarction was observed in TIA, but cerebral infarction of varying degrees was observed in RIND, SIE, and CS.

[0004] Cilostazol is a drug used to inhibit platelet aggregation. It was first developed and synthesized by Otsuka Pharmaceutical Co., Ltd. in Japan and launched in Japan in 1988. It received US FDA approval in May 1999 and was imported to China in 1996. Cilostazol is a selective inhibitor of type 3 phosphodiesterase 3 (PDE3). Its plasma protein binding rate is approximately 95%, and most of its products exist as relatively stable prototypes. Cilostazol has broad pharmacological activity and is clinically valuable for many diseases, including peripheral thrombotic disease and intermittent claudication. Furthermore, cilostazol's antiplatelet and vasodilatory effects can prevent circulatory shock and coronary restenosis. Studies have shown that PDE3 inhibits the degradation of cAMP in the circulatory system, increasing cAMP levels in platelets and vascular smooth muscle cells, suppressing platelet formation and promoting vascular smooth muscle cell proliferation. Cilostazol inhibits platelet degradation mainly by affecting factors such as arachidonic acid, adenosine diphosphate, epinephrine, collagen, and fibrinase. Cilostazol treatment is currently recommended by experts for patients with carotid artery thrombosis, which can treat or prevent cerebral ischemia. PDE3 also inhibits the production of nitric oxide synthase (NOS), thereby reducing the production of nitric oxide (NO).

[0005] The structural formula of cilostazol is as follows:

[0006] [ka]

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

[0008] [ka]

[0009] As described above, providing the application of a composition of cilostazol and edaravone to the treatment of cerebrovascular diseases, particularly ischemic cerebrovascular diseases, is of great practical significance. Summary of the Invention [Problem to be solved by the invention]

[0010] The present invention aims to provide a pharmaceutical composition containing cilostazol or a pharmaceutically acceptable salt thereof and edaravone for use in the preparation of a therapeutic drug for cerebrovascular diseases. The combined use of these drugs can synergistically enhance the therapeutic effect for cerebrovascular diseases. [Means for solving the problem]

[0011] In order to achieve the object of the present invention, the present invention provides the following technical solutions:

[0012] According to a first aspect, the present invention provides a composition comprising the following components: Component (I) is cilostazol, a derivative thereof, a pharmaceutically acceptable salt thereof or a prodrug molecule thereof; and a composition containing edaravone or a component (II) which is a drug containing edaravone as an active ingredient.

[0013] In some specific embodiments of the present invention, the weight ratio of the component (I) to the component (II) is 1:10 to 10:1.

[0014] In some specific embodiments of the present invention, the weight ratio of the component (I) to the component (II) is 1:10 to 5:1.

[0015] In some specific embodiments of the present invention, the weight ratio of the component (I) to the component (II) is 1:5 to 10:1.

[0016] In some specific embodiments of the present invention, the weight ratio of the component (I) to the component (II) is 1:5 to 5:1.

[0017] In some specific embodiments of the present invention, the weight ratio of the component (I) to the component (II) is 1:2.5 to 2.5:1.

[0018] In some specific embodiments of the present invention, the weight ratio of the component (I) to the component (II) is 1:1 to 2.5:1.

[0019] In some specific embodiments of the present invention, the weight ratio of component (I) to component (II) is 1:1, 5:1, 2.5:1, 1:2.5, and / or 1:5.

[0020] In addition, according to a second aspect, the present invention provides a pharmaceutical agent comprising the above composition and a pharmaceutically acceptable additive.

[0021] Furthermore, according to a third aspect, the present invention provides a use of the composition or the medicament in the preparation of a medicament for the prevention and / or treatment of cerebrovascular disease, comprising: Preferably, the cerebrovascular disease is an ischemic cerebrovascular disease, Preferably, the use is also provided wherein the ischemic cerebrovascular disease is ischemic stroke.

[0022] The pharmaceutical combination of the present invention can be used to prepare drugs for cerebrovascular disease, preferably ischemic cerebrovascular disease, more preferably ischemic stroke. [Effects of the Invention]

[0023] In the present invention, as shown by the results of efficacy tests in animals (rats and mice), the combined use of cilostazol and edaravone has the advantageous effect of synergistically increasing the efficacy against cerebrovascular diseases.

[0024] The experimental results of the present invention have revealed that intravenous administration of 1-15 mg / kg of cilostazol or 1.67-8.33 mg / kg of edaravone into the tail vein of a rat model of focal cerebral ischemia-reperfusion injury significantly improves neurological deficits and reduces the area of ​​cerebral infarction in MCAO rats, and that a synergistic effect can be achieved by combining drugs within the above dose range (cilostazol:edaravone mass ratio of 1:5 to 5:1). In mice with focal cerebral ischemia-reperfusion injury, intravenous administration of 3.33-16.67 mg / kg of cilostazol or 3.33-16.67 mg / kg of edaravone into the tail vein significantly improves neurological deficits and reduces the area of ​​cerebral infarction. DETAILED DESCRIPTION OF THE INVENTION

[0025] The present invention discloses the application of a composition containing cilostazol to cerebrovascular diseases, and those skilled in the art can realize the present invention by appropriately modifying the process parameters based on the contents of this specification. It should be noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included in the present invention. Although the method and application of the present invention have been described using preferred embodiments, it is clear that those skilled in the art can modify or make appropriate changes and combinations of the method and application described herein to implement and apply the technology of the present invention without departing from the content, spirit, and scope of the present invention.

[0026] All of the raw materials and reagents used in the application of the cilostazol-containing composition of the present invention to cerebrovascular diseases can be purchased from the market. [Example]

[0027] The present invention will now be further described with reference to the following examples.

[0028] Example 1 Study on the protective effect of a composition of cilostazol and edaravone on focal cerebral ischemia-reperfusion injury 1

[0029] 1. Materials and Methods 1.1 Animals Sprague-Dawley (SD) rats, male, SPF grade, weighing 250-280g.

[0030] 1.2 Test drug

[0031] [Table 1]

[0032] 1.3 Experimental Method 1.3.1 Animal Grouping and Dosing The test animals were divided into four groups: a cilostazol group (1 mg / kg), an edaravone group (5 mg / kg), a cilostazol and edaravone composition group (6 mg / kg, cilostazol:edaravone ratio 1:5, cilostazol 1 mg / kg + edaravone 5 mg / kg), and a model group. After the cerebral ischemia model was established, the animals were assigned to each group with equal probability using a single-blind method. The animals received a single intravenous dose of the drug immediately after reperfusion, while the animals in the model group received an equal volume of saline. Twenty-four hours after cerebral ischemia, the animals were sacrificed, and the brains were removed, stained, and photographed to measure the extent of cerebral infarction.

[0033] 1.3.2 Creation of a focal cerebral ischemia-reperfusion model A rat model of focal cerebral ischemia-reperfusion was created using the intracarotid artery suture method. The limbs and head of an anesthetized rat were tied with rubber bands (hind limbs above the knee joint, forelimbs below the wrist joint). The animal was then placed supine on the operating table. The hair from the head to the chest was shaved with an animal shaver, and the skin was disinfected with alcohol. A midline neck incision was made, and the subcutaneous tissue was bluntly dissected. A thin fascia on the surface of the anterior cervical triangle was dissected, and the inferior end of the clavicle-hyoid muscle was exposed. The arterial shell was opened, exposing the right carotid bifurcation. The right common carotid artery, external carotid artery, and internal carotid artery were then dissected. The vagus nerve was gently dissected, and the external carotid artery was ligated and transected. The proximal end of the common carotid artery was occluded, and an incision was made distal to the external carotid artery ligature. An embolic line was inserted through the common carotid artery bifurcation and into the internal carotid artery. It was then slowly advanced until resistance was felt (approximately 20 mm from the bifurcation), completely blocking the blood supply to the middle cerebral artery. The embolic line was slightly secured below the incision in the external carotid artery with a thread, and the occluding thread 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 heating pad to maintain warmth. After 2.0 hours of cerebral ischemia on the right side, the blood supply was restored by slowly withdrawing the embolic line, allowing for reperfusion. The external carotid artery was ligated with the secured embolic line thread, and the skin was sutured and disinfected. The rats were placed on clean feed and monitored for normal behavior and breathing until they recovered from anesthesia. They were provided with food and water and housed in the usual manner.

[0034] 1.3.3 Measurement of cerebral infarction area After evaluating the animals for neurological deficits, they were sacrificed by CO2 decapitation. The brains were then removed, and the olfactory bulbs, cerebellum, and lower brainstem were removed. The brains were washed with saline to remove blood and absorb any remaining surface water. The brains were then placed at -20°C for 20 minutes. Immediately after removal, coronal sections were cut at 2 mm intervals in a cross-section perpendicular to the viewing plane and stained in 1% TTC solution (37°C for 30 minutes). Normal brain tissue stained dark red, while ischemic brain tissue stained lightly. After washing with saline, the brain sections were quickly arranged in a line from front to back, the remaining surface water was absorbed, the surfaces were allowed to dry, and then photographed.

[0035] Calculation of the area of ​​cerebral infarction: The photographs were processed using Image J software, and the corresponding area of ​​the left brain and the area of ​​the non-infarcted region of the right brain were calculated according to the following formula, and the percentage of the infarcted area was calculated.

[0036] How to calculate infarct volume: V=t(A1+A2+A3+……+An) where t is the thickness of the slice and A is the infarct area.

[0037] %I = 100% × (VC-VL) / VC where %I is the percentage of infarct volume, VC is the brain volume on the target side (left hemisphere), and VL is the volume of the non-infarcted region on the infarcted side (right hemisphere).

[0038] 1.3.4 Analysis of synergistic properties of the composition According to Kim Jeong-gyun's formula, q = E(a + b) / (Ea + Eb - Ea × Eb), the synergistic effect of cilostazol and edaravone in the composition was evaluated. In the formula, E(a + b) is the efficacy rate of the combined drug, and Ea and Eb are the efficacy rates of drug A (cilostazol) and drug B (edaravone) when administered alone, respectively. E administration group = (X モデル -X 投与 ) / X モデル , where X is the value of the cerebral infarction range. If the q value is within the range of 0.85 to 1.15, it indicates that the combination of the two drugs has a simple additive effect; if the q value is greater than 1.15, it indicates that the combination of the two drugs has a synergistic effect; and if the q value is less than 0.85, it indicates that the combination of the two drugs has an antagonistic effect.

[0039] 1.4 Data Statistics The experimental data were expressed as mean ± standard deviation (Mean ± SD). Differences between groups were analyzed by one-way analysis of variance, and comparisons between groups were tested using the LSD method. P < 0.05 was defined as significant.

[0040] 2. Experimental Results The effects on the extent of cerebral infarction are shown in Table 1. The experimental results showed that administration of edaravone 5 mg / kg and the composition (cilostazol 1 mg / kg + edaravone 5 mg / kg) significantly reduced the extent of cerebral infarction in animals (p=0.012, p=0.000), and administration of cilostazol 1 mg / kg showed a tendency to improve cerebral ischemic damage, but there was no statistical difference (p=0.08). The synergy calculation result was q=1.33, indicating that the combination of the two drugs produced a synergistic effect.

[0041] [Table 2]

[0042] Example 2 Study 2 on the protective effect of a composition of cilostazol and edaravone on focal cerebral ischemia-reperfusion injury

[0043] 1. Materials and Methods 1.1 Animals Sprague-Dawley (SD) rats, male, SPF grade, weighing 250-280g.

[0044] 1.2 Test Drug Cilostazol and edaravone were the same as in Example 1.

[0045] 1.3 Experimental Method The test animals were divided into four groups: a cilostazol group (5 mg / kg), an edaravone group (5 mg / kg), a cilostazol and edaravone composition group (10 mg / kg, cilostazol:edaravone ratio 1:1, cilostazol 5 mg / kg + edaravone 5 mg / kg), and a model group. After the cerebral ischemia model was established, the animals were assigned to each group with equal probability using a single-blind method. The animals received a single intravenous dose of the drug immediately after reperfusion, while the animals in the model group received an equal volume of saline. Twenty-four hours after cerebral ischemia, the animals were sacrificed, and the brains were removed, stained, and photographed to measure the extent of cerebral infarction.

[0046] The methods for creating a focal cerebral ischemia-reperfusion model, measuring the extent of cerebral infarction, analyzing the synergistic effect of the compositions, and statistically analyzing the data were the same as in Example 1.

[0047] 2. Experimental Results The effect on the extent of cerebral infarction is shown in Table 2. The experimental results showed that the administration of cilostazol 5 mg / kg, edaravone 5 mg / kg, and the composition (cilostazol 5 mg / kg + edaravone 5 mg / kg) could significantly reduce the extent of cerebral infarction in animals (p=0.025, p=0.008, p=0.000). The synergy calculation result was q=1.47, indicating that the combination of the two drugs produced a synergistic effect.

[0048] [Table 3]

[0049] Example 3 Study 3: Protective effect of a composition of cilostazol and edaravone on focal cerebral ischemia-reperfusion injury

[0050] 1. Materials and Methods 1.1 Animals Sprague-Dawley (SD) rats, male, SPF grade, weighing 250-280g.

[0051] 1.2 Test Drug Cilostazol and edaravone were the same as in Example 1.

[0052] 1.3 Experimental Method The test animals were divided into four groups: a cilostazol group (15 mg / kg), an edaravone group (3 mg / kg), a cilostazol and edaravone composition group (18 mg / kg, cilostazol:edaravone ratio 5:1, cilostazol 15 mg / kg + edaravone 3 mg / kg), and a model group. After creating the cerebral ischemia model, animals were assigned to each group with equal probability using a single-blind method. The animals received a single intravenous dose of the drug immediately after reperfusion, while animals in the model group received an equal volume of saline. Twenty-four hours after cerebral ischemia, the animals were sacrificed, and the brains were removed, stained, and photographed to measure the extent of cerebral infarction.

[0053] The methods for creating a focal cerebral ischemia-reperfusion model, measuring the extent of cerebral infarction, analyzing the synergistic effect of the compositions, and statistically analyzing the data were the same as in Example 1.

[0054] 2. Experimental Results The effect on the extent of cerebral infarction is shown in Table 3. The experimental results showed that the administration of cilostazol 15 mg / kg, edaravone 3 mg / kg, and the composition (cilostazol 15 mg / kg + edaravone 3 mg / kg) could significantly reduce the extent of cerebral infarction in animals (p=0.007, p=0.029, p=0.000). The synergy calculation result was q=1.38, indicating that the combination of the two drugs produced a synergistic effect.

[0055] [Table 4]

[0056] Example 4 Effect of cilostazol / edaravone (1:5, 1:2.5, 1:1) on focal cerebral ischemia-reperfusion injury

[0057] 1. Materials and Methods 1.1 Animals Sprague-Dawley (SD) rats, male, SPF grade, weighing 250-280g.

[0058] 1.2 Test Drug Cilostazol and edaravone were the same as in Example 1.

[0059] 1.3 Experimental Method The test animals were divided into four groups: a model group and three cilostazol / edaravone composition 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 administered dose of each composition was 10 mg / kg). After the cerebral ischemia model was established, the animals were assigned to each group with equal probability using a single-blind method. The animals received a single intravenous dose of the drug immediately after reperfusion, while the animals in the model group received an equal volume of saline. 24 hours after cerebral ischemia, the animals were sacrificed, and the brains were removed, stained, and photographed to measure the extent of cerebral infarction.

[0060] The methods for creating the focal cerebral ischemia-reperfusion model, measuring the extent of cerebral infarction, and statistically analyzing the data were the same as in Example 1.

[0061] 2. Experimental Results The effect on the extent of cerebral infarction is shown in Table 4. The experimental results showed that the combined administration of cilostazol / edaravone at 1:5, 1:2.5 and 1:1 could significantly reduce the extent of cerebral embolism in animals (p<0.001).

[0062] [Table 5]

[0063] Example 5 Effect of cilostazol / edaravone (1:1, 2.5:1, 5:1) on focal cerebral ischemia-reperfusion injury

[0064] 1. Materials and Methods 1.1 Animals Sprague-Dawley (SD) rats, male, SPF grade, weighing 250-280g.

[0065] 1.2 Test Drug Cilostazol and edaravone were the same as in Example 1.

[0066] 1.3 Experimental Method The test animals were divided into four groups: a model group and three cilostazol / edaravone composition 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 administered dose of each composition was 10 mg / kg). After the cerebral ischemia model was established, the animals were assigned to each group with equal probability using a single-blind method. The animals received a single intravenous dose of the drug immediately after reperfusion, while the animals in the model group received an equal volume of saline. 24 hours after cerebral ischemia, the animals were sacrificed, and the brains were removed, stained, and photographed to measure the extent of cerebral infarction.

[0067] The methods for creating the focal cerebral ischemia-reperfusion model, measuring the extent of cerebral infarction, and statistically analyzing the data were the same as in Example 1.

[0068] 2. Experimental Results The effect on the extent of cerebral infarction is shown in Table 5. The experimental results showed that the combined administration of cilostazol / edaravone at 1:1, 2.5:1 and 5:1 could significantly reduce the extent of cerebral embolism in animals (p=0.000, p=0.000, p=0.001).

[0069] [Table 6]

[0070] Example 6 Effect of cilostazol / edaravone (1:5, 1:2.5, 1:1) on focal cerebral ischemia-reperfusion injury in mice

[0071] 1. Materials and Methods 1.1 Animals C57BL / 6J mice, male, SPF grade, 8 weeks old.

[0072] 1.2 Test Drug Cilostazol and edaravone were the same as in Example 1.

[0073] 1.3 Experimental Method The test animals were divided into four groups: a model group and three cilostazol / edaravone composition 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 administered dose of each composition was 20 mg / kg). After the cerebral ischemia model was established, the animals were assigned to each group with equal probability using a single-blind method. The animals received a single intravenous dose of the drug immediately after reperfusion, while the animals in the model group received an equal volume of saline. 24 hours after cerebral ischemia, the animals were sacrificed, and the brains were removed, stained, and photographed to measure the extent of cerebral infarction.

[0074] A focal cerebral ischemia-reperfusion model was established in mice using the internal carotid artery suture method. Anesthetized mice were placed supine on the operating table. A midline incision was made in the neck, and the subcutaneous tissue was bluntly dissected. The right common carotid, external carotid, and internal carotid arteries were dissected. An embolic catheter was inserted through the external carotid artery, passing through the bifurcation of the common carotid artery and into the internal carotid artery. It was then slowly inserted until resistance was felt (approximately 10 mm from the bifurcation), completely blocking the blood supply to the middle cerebral artery. After 60 min of right-sided cerebral ischemia, the embolic catheter was slowly withdrawn to restore blood supply and allow reperfusion. Mice were placed on clean feed and observed for normal behavior and breathing until they recovered from anesthesia. Food and water were provided and housed according to conventional procedures.

[0075] The methods for measuring the extent of cerebral embolism and statistically analyzing the data were the same as in Example 1.

[0076] 2. Experimental Results The effect on the extent of cerebral infarction is shown in Table 6. The experimental results showed that the combined administration of cilostazol / edaravone at 1:5, 1:2.5 and 1:1 could significantly reduce the extent of cerebral embolism in animals (p<0.001, p<0.012, p<0.001).

[0077] [Table 7]

[0078] Example 7 Effect of cilostazol / edaravone (1:1, 2.5:1, 5:1) on focal cerebral ischemia-reperfusion injury in mice

[0079] 1. Materials and Methods 1.1 Animals C57BL / 6J mice, male, SPF grade, 8 weeks old.

[0080] 1.2 Test Drug Cilostazol and edaravone were the same as in Example 1.

[0081] 1.3 Experimental Method The test animals were divided into four groups: a model group and three cilostazol / edaravone composition 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 administered dose of each composition was 20 mg / kg). After the cerebral ischemia model was established, the animals were assigned to each group with equal probability using a single-blind method. The animals received a single intravenous dose of the drug immediately after reperfusion, while the animals in the model group received an equal volume of normal saline. 24 hours after cerebral ischemia, the animals were sacrificed, and the brains were removed, stained, and photographed to measure the extent of cerebral infarction.

[0082] The focal cerebral ischemia-reperfusion model was prepared in the same manner as in Example 6, and the methods for measuring the extent of cerebral embolism and statistically analyzing the data were the same as in Example 1.

[0083] 2. Experimental Results The effect on the extent of cerebral infarction is shown in Table 7. The experimental results showed that the combined administration of cilostazol / edaravone 1:1, 2.5:1 and 5:1 could significantly reduce the extent of cerebral embolism in animals (p<0.001).

[0084] [Table 8]

[0085] The application of the composition containing cilostazol provided by the present invention to cerebrovascular disease has been described in detail above. The principles and embodiments of the present invention are explained in this specification using specific examples, and the explanations in the above examples are only used to understand the method and gist of the present invention. It should be noted that those skilled in the art may make several improvements and modifications to the present invention without departing from the principles of the present invention, and these improvements and modifications are also within the patentable scope of the present invention.

Claims

1. Component (I) is cilostazol or a pharmaceutically acceptable salt thereof; and a component (II) which is edaravone or a drug containing edaravone as an active ingredient, A composition for preventing and / or treating cerebrovascular diseases, characterized in that the weight ratio of component (I) to component (II) is 1:2.5 to 2.5:

1.

2. 2. The composition according to claim 1, wherein the weight ratio of said component (I) to said component (II) is 1:1 to 2.5:

1.

3. The composition of claim 1, wherein the weight ratio of component (I) to component (II) is 1:1, 2.5:1, or 1:2.

5.

4. A drug for preventing and / or treating cerebrovascular disease, comprising the composition according to any one of claims 1 to 3 and a pharmaceutically acceptable additive.

5. Use of the composition according to any one of claims 1 to 3 or the agent according to claim 4 in the preparation of a medicament for preventing and / or treating cerebrovascular diseases.

6. The use according to claim 5, wherein the cerebrovascular disease is an ischemic cerebrovascular disease.

7. The use according to claim 6, wherein the ischemic cerebrovascular disease is ischemic stroke.

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