Composition for prevention or treatment of ischemic stroke

Abstract

The present invention relates to a composition for preventing or treating ischemic stroke and, specifically, to a composition for preventing or treating ischemic stroke by administration to patients with moderate to severe ischemic stroke having a National Institutes of Health Stroke Scale (NIHSS) score of 7 or higher.

Description

[0001]

Description of the Invention

[0002]

Title of Invention

[0003] Composition for the prevention or treatment of ischemic stroke

[0004]

Technology Field

[0005] The present invention relates to a composition for the prevention or treatment of ischemic stroke, and specifically to a composition for preventing or treating ischemic stroke by administering it to patients with moderate to severe ischemic stroke with an NIHSS (National Institutes of Health Stroke Scale) score of 7 or higher.

[0006]

Background Techniques

[0007] Stroke is broadly classified into ischemic stroke (cerebral infarction) and hemorrhagic stroke (cerebral hemorrhage), with incidence rates of approximately 87% and 13%, respectively. The risk of stroke increases with age, particularly in patients over 64, and 75% of all strokes occur in these patients. According to the World Health Organization, stroke is the second leading cause of death, affecting 15 million people worldwide every year. Of these, 4.4 million people die, and 5 million suffer permanent disabilities.

[0008] According to the status of cerebrovascular disease treatment released by the Health Insurance Review and Assessment Service in 2023, there were a total of 634,177 stroke patients in 2022. Due to the aging phenomenon, this number increased by 7.1% compared to 2018, representing an annual average increase of 1.7%. Based on this, it is estimated that the number of stroke patients in Korea will increase to approximately 741,987 by 2032. Furthermore, over the past five years from 2018 to 2022, the age group with the highest increase in patients with cerebrovascular disease was those in their 20s and 30s for both men and women, accounting for approximately 34.7% (an annual average of about 7.7%), showing a prominent increasing trend in younger age groups following the elderly.

[0009] To date, the only drug available for clinical use in the treatment of acute ischemic stroke is recombinant tissue plasminogen activator (rtPA), which is defined as the standard treatment, and there are no other approved treatments as of 2024. rtPA is a treatment that dissolves blood clots to restore blood flow, and it has been used as the only treatment during the acute phase of stroke since a study by the National Institute of Neurological Disorders and Stroke (NINDS) demonstrated that administering it within 3 hours of the onset of stroke symptoms can improve the prognosis of patients with ischemic stroke. Recently, in addition to existing research results, favorable clinical outcomes were observed in the 3–4.5 hour administration group in the European Cooperation Acute Stroke Study (EC ASS)-III and the Safe Implementation of Thrombolysis in Stroke-Monitoring Study (SITS-MOST), leading to an extension of the indication for intravenous rtPA thrombolysis to 4.5 hours in the patient group. However, the risk of side effects such as bleeding and increased mortality caused by rtPA remains high, so the number of patients receiving rtPA within 4.5 hours is relatively limited.

[0010] Therefore, there is a growing need for new treatments that can overcome the limitations of existing treatments.

[0011]

Description of the Invention

[0012]

Technical Challenges

[0013] The present invention provides a composition comprising a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, to be administered in combination with a thrombolytic agent to a subject for the prevention or treatment of ischemic stroke, wherein the subject is a patient with moderate to severe ischemic stroke with an NIHSS score of 7 or higher.

[0014] The present invention provides a composition comprising a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and a thrombolytic agent, for co-administration of the same, to be administered to a subject to prevent or treat ischemic stroke, wherein the subject is a patient with moderate to severe ischemic stroke with an NIHSS score of 7 or higher.

[0015] The present invention provides a composition comprising a first composition comprising a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and a second composition comprising a thrombolytic agent, wherein the first composition and the second composition are administered in combination, and the composition is intended to prevent or treat ischemic stroke by administering the first composition and the second composition in combination to a subject, wherein the subject is a patient with moderate to severe ischemic stroke with an NIHSS score of 7 or higher.

[0016] The present invention provides a method for preventing or treating ischemic stroke by administering the composition of the present invention to a subject who is a patient with moderate to severe ischemic stroke with an NIHSS score of 7 or higher.

[0017] The present invention provides a use of the composition of the present invention for preventing or treating ischemic stroke by administering it to subjects who are patients with moderate to severe ischemic stroke with an NIHSS score of 7 or higher.

[0018] The present invention provides a use of the composition of the present invention for the manufacture of a drug to prevent or treat ischemic stroke by administering it to a subject who is a patient with moderate to severe ischemic stroke with an NIHSS score of 7 or higher.

[0019]

Technical Solution

[0020] Each description and embodiment disclosed in the present invention may be applied to other descriptions and embodiments thereof. That is, all combinations of the various elements disclosed in the present invention fall within the scope of the present invention. Furthermore, the scope of the present invention should not be considered limited by the specific descriptions provided below.

[0021] The present invention provides a composition comprising a compound represented by the following chemical formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, said composition for preventing or treating ischemic stroke by administering said composition to a subject.

[0022] [Chemical Formula 1]

[0023]

[0024] H

[0025] In embodiments of the present invention, the composition is a composition for preventing or treating ischemic stroke by administering it to a subject in combination with a thrombolytic agent.

[0026] In the embodiments of the present invention, the subject is a patient with moderate to severe ischemic stroke with an NIHSS (National Institutes of Health Stroke Scale) score of 7 or higher.

[0027] In the embodiments of the present invention, the composition of the present invention is a composition comprising a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and is intended to prevent or treat ischemic stroke by administering it in combination with a thrombolytic agent to a subject, wherein the subject is a patient with moderate to severe ischemic stroke with an NIHSS score of 7 or higher.

[0028] In the embodiments of the present invention, the composition of the present invention is a composition for administering a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and a thrombolytic agent in combination, to prevent or treat ischemic stroke by administering it to a subject, wherein the subject is a patient with moderate to severe ischemic stroke with an NIHSS score of 7 or higher.

[0029] In embodiments of the present invention, the composition of the present invention comprises a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and a thrombolytic agent, and is intended to be administered to a subject to prevent or treat ischemic stroke, wherein the subject is a patient with moderate to severe ischemic stroke with an NIHSS score of 7 or higher. In this case, the compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and the thrombolytic agent are administered in combination.

[0030] In this specification, the term "composition" may be used interchangeably with "combination." Specifically, when the present invention states that a composition comprises A and B, the composition may be interpreted to mean a composition comprising A and B; a combination comprising A and B as separate formulations (compositions); or a composition comprising said combination.

[0031] For example, in the present invention, a composition comprising a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof and a thrombolytic agent may comprise the compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof and a thrombolytic agent as separate preparations, or all of them in the form of a complex preparation.

[0032] In one embodiment of the present invention, the composition may each comprise a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof or a mixture thereof, and a thrombolytic agent as separate preparations.

[0033] For example, in embodiments of the present invention, a composition comprising a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and a thrombolytic agent may be a composition comprising a first composition comprising a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and a second composition comprising a thrombolytic agent, wherein the first composition and the second composition are administered in combination, and the composition is intended to prevent or treat ischemic stroke by administering the first composition and the second composition in combination to a subject, and the subject is a patient with moderate to severe ischemic stroke with an NIHSS score of 7 or higher. In one embodiment, the composition may be a kit, but is not limited thereto.

[0034] The NIHSS is a commonly used indicator for assessing the initial effects following a stroke. It consists of 14 items measuring level of consciousness, gaze, visual field, facial paralysis, limb muscle strength, ataxia, sensation, speech, dysarthria, neglect, and distal upper extremity movement. Scores are assigned to each item based on the patient's response, and the result is expressed as a total score calculated by summing these values. The NIHSS score (value) can indicate the severity of the stroke; the maximum total score is 42, signifying a critical condition, while the minimum value is 0, indicating no neurological impairment. Specifically, stroke severity based on the NIHSS score is classified as follows: 0 points: No Stroke Symptoms

[0035] 1–4 points: minor stroke

[0036] 5-15 points: Moderate stroke

[0037] 16-20 points: Moderate to severe stroke 21-42 points: Severe stroke

[0038] According to the composition of the present invention, a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof can be administered in combination with a thrombolytic agent to a subject with moderate to severe stroke (moderate and severe stroke) having an NIHSS score of 7 or higher to treat the ischemic stroke (cerebral infarction) of the subject and improve the prognosis of the subject, specifically to prevent, alleviate, or improve sequelae of stroke.

[0039] In addition, the composition of the present invention can minimize side effects caused by the administration of a thrombolytic agent, and accordingly, may be useful for the prevention, alleviation, improvement, or treatment of side effects caused by the administration of a thrombolytic agent. Side effects caused by the administration of the thrombolytic agent may include, but are not limited to, neurotoxicity due to reperfusion injury, increased inflammation, cerebral edema, vascular dysfunction, hemorrhage, and hemorrhagic risk. Specifically, the composition may be for the prevention, alleviation, improvement, or treatment of side effects caused by the administration of a thrombolytic agent comprising at least one selected from the group consisting of neurotoxicity, increased inflammation, cerebral edema, vascular dysfunction, hemorrhage, and hemorrhagic risk, but is not limited thereto.

[0040] According to the present invention, a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof is administered in combination with a thrombolytic agent to a subject with an NIHSS score of 7 or higher, thereby improving blood-brain barrier damage in the subject and significantly alleviating cerebral infarction damage caused by ischemia or reperfusion along with damage caused by the standard therapeutic agent, the thrombolytic agent, and maximizing the improvement of the subject's prognosis. That is, it is possible to minimize sequelae of stroke and minimize side effects caused by the administration of the thrombolytic agent.

[0041] In embodiments of the present invention, the subject may be an ischemic stroke patient receiving thrombolytic agent treatment. In embodiments of the present invention, the subject may be an ischemic stroke patient receiving at least one of thrombolytic agent treatment and mechanical thrombectomy treatment.

[0042] In embodiments of the present invention, the subject may be an ischemic stroke patient receiving thrombolytic therapy, or thrombolytic therapy and mechanical thrombectomy.

[0043] In the present invention, the term “patient receiving treatment” may be used interchangeably with “patient requiring treatment,” “patient needing treatment,” “patient who must receive treatment,” etc.

[0044] In embodiments of the present invention, thrombolytic agent treatment may include intravenous thrombolytic treatment, and mechanical thrombectomy may include intra-arterial thrombectomy, but is not necessarily limited thereto.

[0045] In one embodiment of the present invention, the composition of the present invention may be administered simultaneously or sequentially with intravascular thrombectomy (EVT), but is not necessarily limited thereto.

[0046] In one embodiment of the present invention, after performing intravascular thrombectomy, a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof or a composition containing the same (specifically a first composition) and a thrombolytic agent (specifically tenecteplase) or a composition containing the same (specifically a second composition) may be administered simultaneously, nearly simultaneously, or sequentially, but are not necessarily limited thereto.

[0047] In embodiments of the present invention, the subject may have an NIHSS score of 16 or higher. In embodiments of the present invention, the subject may be a moderate to severe ischemic stroke patient with an NIHSS score of 16 or higher who receives at least one of thrombolytic therapy and mechanical thrombectomy therapy.

[0048] The composition of the present invention exhibits excellent inhibitory effects on the increase in cerebral infarction volume and neurological and functional improvement effects in patients with moderate to severe ischemic stroke who have an NIHSS score of 16 or higher and receive at least one of thrombolytic therapy and mechanical thrombectomy therapy, and can treat cerebral infarction in patients with ischemic stroke, improve prognosis, and prevent, alleviate, or improve sequelae of stroke. In addition, it can prevent, alleviate, improve, or treat side effects caused by the administration of thrombolytic agents.

[0049] In embodiments of the present invention, the composition of the present invention may treat cerebral infarction in patients with ischemic stroke and prevent, alleviate, or improve sequelae. In addition, it may prevent, alleviate, improve, or treat side effects caused by the administration of thrombolytic agents.

[0050] In embodiments of the present invention, the composition of the present invention may inhibit the increase in the volume of cerebral infarction of a subject (a patient with ischemic stroke). That is, the composition of the present invention may reduce the volume of cerebral infarction of a subject (a patient with ischemic stroke).

[0051] In embodiments of the present invention, the composition of the present invention may result in a rate of increase in the volume of cerebral infarction of the subject within 5 days after administration to the subject of the present invention of 5% or less.

[0052] In embodiments of the present invention, the composition of the present invention may reduce the NIHSS score of the subject. Specifically, the composition of the present invention may reduce the NIHSS score of the subject after administration compared to before administration.

[0053] In embodiments of the present invention, the composition of the present invention may reduce the NIHSS score of the subject by about 9 to about 12 points compared to before administration after administration to the subject. In embodiments of the present invention, the composition may reduce the NIHSS score of the subject by about 9 points within 3 days after administration. In embodiments of the present invention, the composition may reduce the NIHSS score of the subject by about 9 points within 5 days after administration and by about 11 points within 28 days after administration. In embodiments of the present invention, the composition of the present invention may reduce the NIHSS score of the subject by about 12 points within 90 days after administration.

[0054] In the present invention, the term “approximately” may mean a range within or around a certain numerical value. For example, in the present invention, approximately a point may mean a range of a point, but is not necessarily limited thereto.

[0055] In embodiments of the present invention, the composition of the present invention may have a difference in NIHSS change amount of -3 to -4 points when the compound represented by Formula 1, its pharmaceutically acceptable salt, its hydrate or solvate, or a mixture thereof is not administered when the composition is administered to the subject.

[0056] In embodiments of the present invention, the composition of the present invention may increase the ratio of mRS 0 and 1 of the subject after administration.

[0057] In embodiments of the present invention, after administration of the composition of the present invention to the subject, at least 52.6% of the subject may have a 28-day mRS (modified Rankin Scale) score of 0 (no disability at all) and 1 (a condition in which mild disability remains but all daily tasks (jobs) and extracurricular activities can be performed without the help of others).

[0058] In embodiments of the present invention, after administration of the composition of the present invention to the subject, 52.6% or more of the subject may have an mRS score of 0 and 1 on day 28.

[0059] In embodiments of the present invention, after administration of the composition of the present invention to the subject, at least 36.8% of the subject may have an mRS score of 0 on day 28.

[0060] In embodiments of the present invention, the composition of the present invention may have a difference of 17.6% or more in the ratio of 0 and 1 points at day 28 compared to when the compound represented by Formula 1, its pharmaceutically acceptable salt, its hydrate or solvate, or a mixture thereof is not administered to the subject when the composition of the present invention is administered.

[0061] In embodiments of the present invention, the subject has an NIHSS score of 16 or higher, and when the composition is administered to the subject, the difference in the ratio from mRS 0 to 2 is 9.6% or higher compared to when the compound represented by Formula 1, its pharmaceutically acceptable salt, its hydrate or solvate, or mixture is not administered.

[0062] In embodiments of the present invention, the subject has an NIHSS score of 16 or higher, and when the composition is administered to the subject, the difference in the ratio of mRS 5 to 6 compared to when the compound represented by Formula 1, its pharmaceutically acceptable salt, its hydrate or solvate, or a mixture thereof is not administered may be 33% or lower.

[0063] The composition of the present invention may inhibit cerebral infarction when administered to a subject. The composition of the present invention may inhibit damage caused by ischemia when administered to a subject.

[0064] The composition of the present invention may minimize side effects associated with a thrombolytic agent without inhibiting the thrombolytic effect of the thrombolytic agent when administered to a subject. The composition of the present invention may minimize hemorrhagic risk associated with a thrombolytic agent without inhibiting the thrombolytic effect of the thrombolytic agent when administered to a subject.

[0065] The composition of the present invention may have a superior effect in inhibiting cerebral infarction when administered to a subject compared to the administration of a thrombolytic agent alone.

[0066] The composition of the present invention may have a superior anti-ischemic effect when administered to a subject compared to the administration of a thrombolytic agent alone.

[0067] The composition of the present invention may have excellent cell protective effects, including antioxidant and anti-inflammatory effects, when administered to a target.

[0068] Therefore, the composition of the present invention can be usefully used for the prevention and treatment of ischemic stroke or for enhancing the preventive and therapeutic effects of ischemic stroke, and can be usefully used for the prevention, alleviation, improvement, or treatment of side effects caused by the administration of thrombolytic agents.

[0069] In embodiments of the present invention, in the composition of the present invention, the compound represented by Formula 1, its pharmaceutically acceptable salt, its hydrate or solvate, or a mixture thereof and a thrombolytic agent may be administered together simultaneously, nearly simultaneously, or sequentially.

[0070] At this time, a thrombolytic agent (or a composition containing the same (specifically a second composition)) may be administered simultaneously, nearly simultaneously, or sequentially with the administration of a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof (or a composition containing the same (specifically a first composition)), or a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof (or a composition containing the same (specifically a first composition)) may be administered simultaneously, nearly simultaneously, or sequentially with the administration of a thrombolytic agent (or a composition containing the same (specifically a second composition)).

[0071] In the present invention, “simultaneously” may mean that two substances are administered simultaneously without a time difference, “sequentially” may mean that another substance is administered after the administration of one substance, and “almost simultaneously” may mean that another substance is administered immediately or quickly after the administration of one substance. In the present invention, “sequentially” may also be used in a comprehensive sense that includes “almost simultaneously.”

[0072] In embodiments of the present invention, a thrombolytic agent (or a composition containing the same (specifically a second composition)) may be administered (sequentially) in combination with the administration of a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof (or a composition containing the same (specifically a first composition)) simultaneously, immediately after administration, or within a certain time after administration.

[0073] In embodiments of the present invention, the composition of the present invention may be such that a thrombolytic agent (or a composition containing the same (specifically a second composition)) is administered (sequentially) immediately after administration of a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof (or a composition containing the same (specifically a first composition)).

[0074] In embodiments of the present invention, the composition of the present invention may be such that a thrombolytic agent (or a composition containing the same (specifically a second composition)) is administered (sequentially) within a certain time after administration of a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof (or a composition containing the same (specifically a first composition)).

[0075] In embodiments of the present invention, a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof (or a composition containing thereof (specifically, a first composition)) may be administered concurrently with the initiation of administration of a thrombolytic agent (or a composition containing the same (specifically, a second composition)).

[0076] In embodiments of the present invention, immediately (almost simultaneously) after administration of a thrombolytic agent (or a composition containing the same (specifically, a second composition)), a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof (or a composition containing the same (specifically, a first composition)) may be sequentially administered in combination. In embodiments of the present invention, within a certain time after administration of a thrombolytic agent (or a composition containing the same (specifically, a second composition)), specifically within 30 minutes, a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof (or a composition containing the same (specifically, a first composition)) may be sequentially administered in combination.

[0077] In the composition of the present invention, a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof (or a composition containing the same (specifically, a second composition)) is administered simultaneously with the start of administration of a thrombolytic agent (or a composition containing the same (specifically, a second composition)), or a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof (or a composition containing the same (specifically, a first composition)) is administered sequentially immediately (almost simultaneously) or within a certain time, specifically within 30 minutes, after the start of administration of the thrombolytic agent (or a composition containing the same (specifically, a second composition)), thereby allowing the thrombolytic agent and the compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof to be administered in combination to a subject.

[0078] In the present invention, a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof (or a composition containing the same (specifically, a first composition)) may be administered once or multiple times.

[0079] For example, (a) at the same time as the administration of a thrombolytic agent (or a composition containing the same (specifically, the second composition)), immediately after administration or within a certain time (specifically within 30 minutes), (b) a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof (or a composition containing the same (specifically, the first composition)) may be administered once or multiple times, but is not necessarily limited thereto.

[0080] For example, a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof (or a composition containing the same (specifically, the first composition)) may be administered simultaneously with the administration of a thrombolytic agent (or a composition containing the same (specifically, the second composition)), immediately after administration or within a certain time (specifically within 30 minutes), and after a single administration of the compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof (or a composition containing the same (specifically, the first composition)), the compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof (or a composition containing the same (specifically, the first composition)) may be administered again once or multiple times, but is not necessarily limited thereto.

[0081] In an embodiment of the present invention, a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof (or a composition containing the same (specifically, a first composition)) may be administered prior to the administration of a thrombolytic agent (or a composition containing the same (specifically, a second composition)), but is not necessarily limited thereto.

[0082] For example, a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof (or a composition containing the same (specifically, the second composition)) may be administered concomitantly before and / or simultaneously with the administration of the thrombolytic agent (or a composition containing the same (specifically, the second composition)), immediately after administration, or within a certain time after administration (specifically within 30 minutes), and in this case, the compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof (or a composition containing the same (specifically, the first composition)) may be administered multiple times, but is not necessarily limited thereto. Specifically, for example, (a) after administering a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof (or a composition containing the same (specifically, the first composition)), (b) a thrombolytic agent (or a composition containing the same (specifically, the second composition)) may be administered, and at this time, simultaneously with the thrombolytic agent, immediately after administration or within a certain time (specifically within 30 minutes), (c) a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof (or a composition containing the same (specifically, the first composition)) may be administered, and at this time, the compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof (or a composition containing the same (specifically, the first composition)) may be administered once or multiple times. However, it is not necessarily limited to this.

[0083] In the present invention, the compound represented by Formula 1 is known as otaplimastat, “N-[3-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)propyl]-N-(4-{[3-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)propyl]amino}butyl)acetamide (N-[3-(2,4-dioxo-1,4-dihydroquinazol in-3(2H)-yl)propyl ]amino}butyl )acetamide)”.

[0084] The "pharmaceuticalally acceptable salt" of the present invention may mean a salt commonly used in the pharmaceutical industry. In one embodiment of the present invention, the pharmaceutically acceptable salt of the compound represented by Formula 1 may be a hydrochloric acid salt, but is not necessarily limited thereto.

[0085] The “hydrate” of the present invention is a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof and water bonded by non-covalent intermolecular forces, and may contain stoichiometric or non-chemical stoichiometric amounts of water.

[0086] The “solvated water” of the present invention is a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof and a solvent other than water bonded by non-covalent intermolecular forces, and may contain the solvent in stoichiometric or non-chemical stoichiometric amounts.

[0087] In embodiments of the present invention, the thrombolytic agent may be at least one selected from the group consisting of alteplase, reteplase, tenecteplase, urokinase, pro-urokinase, streptokinase, anistreplase, desmoteplase, and saruplase, but is not necessarily limited thereto. In embodiments of the present invention, the thrombolytic agent may be a recombinant tissue plasminogen activator (rtPA).

[0088] In embodiments of the present invention, the thrombolytic agent may comprise at least one selected from the group consisting of alteplase and tenecteplase, but is not necessarily limited thereto.

[0089] The composition of the present invention may comprise 0.05 to 0.2 w / v% of a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof. Specifically, the composition of the present invention may comprise 0.08 w / v% of a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

[0090] In embodiments of the present invention, the composition of the present invention may comprise one or more selected from the group consisting of an isotonic agent, a pH adjuster, and an aqueous solvent. In this case, the pH adjuster may comprise a buffer.

[0091] In embodiments of the present invention, the composition of the present invention may comprise 0.5 to 1.5 w / v% of an isotonic agent.

[0092] In embodiments of the present invention, the pH adjuster may comprise 0.05 to 0.4 w / v%.

[0093] In embodiments of the present invention, the composition of the present invention may include an aqueous solvent.

[0094] In one embodiment of the present invention, the composition of the present invention may include 0.5 to 1.5 w / v% of an isotonic agent; 0.05 to 0.4 w / v% of a pH adjuster; and an aqueous solvent.

[0095] In embodiments of the present invention, for example, the isotonic agent may include sodium chloride, but is not necessarily limited thereto. For example, the pH adjusting agent may include hydrochloric acid, sodium hydroxide, sodium dihydrogen phosphate, sodium hydrogen phosphate, etc., but is not necessarily limited thereto.

[0096] In embodiments of the present invention, the composition of the present invention may include sodium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, and an aqueous solvent. In this case, the composition may further include hydrochloric acid, sodium hydroxide, etc., as needed. In embodiments of the present invention, the composition of the present invention may include 0.5 to 1.5 w / v% sodium chloride; 0.01 to 0.15 w / v% sodium dihydrogen phosphate; 0.05 to 0.2 w / v% disodium hydrogen phosphate; and an aqueous solvent. In this case, the composition may further include hydrochloric acid, sodium hydroxide, etc., as needed.

[0097] In one embodiment of the present invention, the composition of the present invention may comprise 0.82 w / v% sodium chloride; 0.0587 w / v% sodium dihydrogen phosphate; 0.09 w / v% disodium hydrogen phosphate; and an aqueous solvent. In this case, the composition may further comprise hydrochloric acid, sodium hydroxide, etc., as needed.

[0098] In embodiments of the present invention, the composition of the present invention (specifically the first composition) may comprise 0.05 to 0.2 w / v% of a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof; 0.5 to 1.5 w / v% of an isotonic agent; 0.05 to 0.4 w / v% of a pH adjuster; and an aqueous solvent.

[0099] In embodiments of the present invention, the composition of the present invention (specifically the first composition) may comprise a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, sodium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, and an aqueous solvent. In this case, the composition may further comprise hydrochloric acid, sodium hydroxide, etc., as needed.

[0100] In embodiments of the present invention, the composition of the present invention (specifically the first composition) may comprise 0.05 to 0.2 w / v% of a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof; 0.5 to 1.5 w / v% of sodium chloride; 0.01 to 0.15 w / v% of sodium dihydrogen phosphate; 0.05 to 0.2 w / v% of disodium hydrogen phosphate; and an aqueous solvent. In this case, the composition may further comprise hydrochloric acid, sodium hydroxide, etc., as needed.

[0101] In one embodiment of the present invention, the composition of the present invention (specifically the first composition) may comprise 0.08 w / v% of a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof; 0.82 w / v% of sodium chloride; 0.0587 w / v% of sodium dihydrogen phosphate; 0.09 w / v% of disodium hydrogen phosphate; and an aqueous solvent. In this case, the composition may further comprise hydrochloric acid, sodium hydroxide, etc., as needed. In the embodiments of the present invention, the sodium dihydrogen phosphate and disodium hydrogen phosphate may each be sodium dihydrogen phosphate dihydrate and disodium hydrogen phosphate anhydride, but are not limited thereto.

[0102] In one embodiment of the present invention, the aqueous solvent may be physiological saline or water for injection, but is not necessarily limited thereto. In the composition of the present invention, the aqueous solvent may be included in an appropriate amount to reach the desired liquid volume.

[0103] In embodiments of the present invention, the composition of the present invention may be an injectable composition or an intravenous fluid preparation.

[0104] In embodiments of the present invention, the composition of the present invention may be a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof administered at a concentration of 40 mg / 50 mL.

[0105] In embodiments of the present invention, the compound represented by Formula 1, its pharmaceutically acceptable salt, its hydrate or solvate, or a mixture thereof may be administered in a dose of 30 to 80 mg. In embodiments of the present invention, the compound represented by Formula 1, its pharmaceutically acceptable salt, its hydrate or solvate, or a mixture thereof may be administered in a dose of 40 mg, specifically in a single dose of 40 mg, but is not necessarily limited thereto. In embodiments of the present invention, the compound represented by Formula 1, its pharmaceutically acceptable salt, its hydrate or solvate, or a mixture thereof may be administered in a dose of 40 to 80 mg per day, specifically 80 mg per day, but is not necessarily limited thereto.

[0106] In embodiments of the present invention, when the thrombolytic agent is alteplase, the thrombolytic agent may be administered to the subject at a dose of 0.6 to 0.9 mg / kg, but is not necessarily limited thereto. For example, it may be administered at a dose of 0.9 mg / kg, but is not necessarily limited thereto. In this case, the maximum daily dose of alteplase allowed for patients with ischemic stroke may be 90 mg.

[0107] In embodiments of the present invention, when the thrombolytic agent is tenecteplase, the thrombolytic agent may be administered to the subject at a dose of 0.25 mg / kg, but is not necessarily limited thereto. For example, it may be administered at a dose of 15 mg when the weight of the ischemic stroke patient is less than 60 kg, 20 mg when it is 70 to 80 kg, and 25 mg when it is 90 kg or more, but is not necessarily limited thereto. In this case, the maximum daily dose of tenecteplase allowed for the ischemic stroke patient may be 25 mg.

[0108] In embodiments of the present invention, the composition of the present invention may be administered once, twice, three times, or more times per day. Specifically, the composition of the present invention may be administered once or twice per day, but is not necessarily limited thereto. In embodiments of the present invention, the compound represented by Formula 1, its pharmaceutically acceptable salt, its hydrate or solvate, or a mixture thereof (or a composition containing the same (specifically the first composition)) may be administered twice per day, but is not necessarily limited thereto.

[0109] In one embodiment of the present invention, the thrombolytic agent (or a composition containing the same (specifically, a second composition)) may be administered once a day, but is not necessarily limited thereto.

[0110] In embodiments of the present invention, the composition of the present invention may be administered for 1 day, 2 days, 3 days or more.

[0111] In one embodiment of the present invention, the compound represented by Formula 1, its pharmaceutically acceptable salt, its hydrate or solvate, or a mixture thereof (or a composition containing the same (specifically, the first composition)) may be administered for 3 days, but is not necessarily limited thereto.

[0112] In embodiments of the present invention, the composition of the present invention may be administered at 12-hour intervals.

[0113] In one embodiment of the present invention, in the composition of the present invention, the compound represented by Formula 1, the pharmaceutically acceptable salt thereof, the hydrate or solvate thereof, or a mixture thereof (or a composition containing the same (specifically, the first composition)) may be administered at 12-hour intervals.

[0114] In one embodiment of the present invention, the composition of the present invention is such that, simultaneously with the administration of a thrombolytic agent (or a composition containing the same (specifically, the second composition)), a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof (or a composition containing the same (specifically, the first composition)) is administered immediately after administration or within a certain time (specifically within 30 minutes), and the compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof (or a composition containing the same (specifically, the first composition)) may subsequently be administered twice a day at 12-hour intervals for a total of 6 times over 3 days, but is not necessarily limited thereto. In embodiments of the present invention, the composition may be administered intravenously.

[0115] In the present invention, “prevention” means any act of suppressing an ischemic stroke (cerebral infarction) in an individual or delaying the onset of cerebral infarction by administering a composition according to the present invention, or any act of suppressing or delaying sequelae of a stroke. In the present invention, “treatment” means any act of improving or beneficially changing the symptoms of an ischemic stroke (cerebral infarction) in an individual by administering a composition according to the present invention.

[0116] In the present invention, “administration” means introducing a specific substance to an individual in an appropriate manner.

[0117] In the present invention, “alleviation” and “improvement” refer to any act in which symptoms of stroke sequelae are improved or beneficially altered by the administration of a composition according to the present invention.

[0118] In the present invention, “composition” may refer to a pharmaceutical composition.

[0119] The present invention also provides a method for preventing or treating ischemic stroke in a subject by administering the composition of the present invention to a subject with an NIHSS score of 7 or higher.

[0120] The present invention also provides a method for preventing, alleviating, improving, or treating adverse effects caused by the administration of a thrombolytic agent by administering a composition of the present invention to a subject with an NIHSS score of 7 or higher. In this case, the compound represented by Formula 1, its pharmaceutically acceptable salt, its hydrate or solvate, or a mixture thereof, and the thrombolytic agent may be administered to the subject simultaneously, nearly simultaneously, or sequentially. In embodiments of the present invention, the compound represented by Formula 1, its pharmaceutically acceptable salt, its hydrate or solvate, or a mixture thereof may be administered nearly simultaneously or sequentially after the administration of the thrombolytic agent.

[0121] In embodiments of the present invention, a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof may be sequentially administered within a certain time after administration of a thrombolytic agent, specifically within 30 minutes.

[0122] The present invention also provides a use of the composition of the present invention for preventing or treating ischemic stroke in a subject by administering it to a subject with an NIHSS score of 7 or higher.

[0123] The present invention also provides a use of the composition of the present invention for manufacturing a drug to prevent or treat ischemic stroke in a subject by administering it to a subject with an NIHSS score of 7 or higher.

[0124] The present invention also provides a use of the composition of the present invention for the prevention, alleviation, improvement, or treatment of side effects caused by the administration of thrombolytic agents by administering it to subjects with an NIHSS score of 7 or higher.

[0125] The present invention provides a use of the composition of the present invention for the manufacture of a drug for the prevention, alleviation, improvement, or treatment of side effects caused by the administration of a thrombolytic agent, administered to subjects with an NIHSS score of 7 or higher.

[0126] In embodiments of the present invention, the present invention comprises the following items (1) to (30) regarding the composition, a method including administration thereof, and the use thereof.

[0127] (1) The present invention comprises a composition comprising a compound represented by the following chemical formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, wherein

[0128] It is intended to prevent or treat ischemic stroke by administering it to the subject in combination with a thrombolytic agent, and

[0129] The above-mentioned subject is a patient with moderate to severe ischemic stroke who has an NIHSS (National Institutes of Health Stroke Scale) score of 7 or higher, and provides a composition:

[0130] [Chemical Formula 1]

[0131]

[0132] H

[0133] (2) The present invention comprises a compound represented by the following formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof and a thrombolytic agent, and a composition for co-administering the same,

[0134] A composition is provided for the purpose of preventing or treating ischemic stroke by administering it to a subject, wherein the subject is a patient with moderate to severe ischemic stroke with an NIHSS score of 7 or higher:

[0135] [Chemical Formula 1]

[0136]

[0137] H

[0138] (3) The present invention comprises a first composition comprising a compound represented by the following chemical formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and a second composition comprising a thrombolytic agent, wherein

[0139] The first composition and the second composition are administered in combination, and

[0140] The above composition is intended to prevent or treat ischemic stroke by administering the first composition and the second composition in combination to a subject, and

[0141] The above subject provides a composition for patients with moderate to severe ischemic stroke who have an NIHSS score of 7 or higher:

[0142] [Chemical Formula 1]

[0143]

[0144] H

[0145] (4) In any one of (1) to (3), the subject may be an ischemic stroke patient with an NIHSS score of 16 or higher.

[0146] (5) In any one of (1) to (4), the subject may be an ischemic stroke patient receiving thrombolytic therapy.

[0147] (6) In any one of (1) to (5), the subject may be an ischemic stroke patient with an NIHSS score of 16 or higher who receives at least one of thrombolytic therapy and mechanical thrombectomy (endovascular therapy).

[0148] (7) In any one of (1) to (6), the subject may be an ischemic stroke patient with an NIHSS score of 16 or higher who is receiving thrombolytic therapy and mechanical thrombectomy.

[0149] (8) In any one of (1) to (7), the composition may be used to treat cerebral infarction in patients with ischemic stroke and to prevent, alleviate, improve, or treat sequelae.

[0150] (9) In any one of (1) to (8), the composition may reduce the rate of increase in the volume of cerebral infarction of the subject (patient with ischemic stroke) after administration.

[0151] (10) In any one of (1) to (9), the composition may reduce the NIHSS score of the subject after administration.

[0152] (11) In any one of (1) to (10), the composition may increase the ratio of the target body's mRS 0 and 1 point after administration.

[0153] (12) In any one of (1) to (11), the compound represented by Formula 1, the pharmaceutically acceptable salt thereof, the hydrate or solvate thereof, or a mixture thereof and the thrombolytic agent may be administered together at the same time, nearly at the same time, or sequentially. (13) In any one of (1) to (12), the content of the compound represented by Formula 1, the pharmaceutically acceptable salt thereof, the hydrate or solvate thereof, or a mixture thereof may be 0.08% w / v.

[0154] (14) In any one of (1) to (13), the composition may be administered once a day or twice a day.

[0155] (15) In any one of (1) to (14), the composition may be administered for 1 day, 2 days, 3 days or more.

[0156] (16) In any one of (1) to (15), the thrombolytic agent may be a recombinant tissue plasminogen activator (rtPA).

[0157] (17) In any one of (1) to (16), the thrombolytic agent may comprise at least one of alteplase and tenecteplase.

[0158] (18) (17) In this case, tenecteplase may be administered at a dose of 0.25 mg / kg. (19) (17) In this case, alteplase may be administered at a dose of 0.6 to 0.9 mg / kg.

[0159] (20) In any one of (1) to (19), the compound represented by Formula 1, the pharmaceutically acceptable salt thereof, the hydrate or solvate thereof, or a mixture thereof may be administered in an amount of 30 to 80 mg.

[0160] (21) In any one of (1) to (20), the composition may comprise one or more selected from the group consisting of an isotonic agent, a pH adjuster, and an aqueous solvent.

[0161] (22) In any one of (1) to (21), the composition may include sodium chloride, sodium dihydrogen phosphate, sodium hydrogen phosphate, and an aqueous solvent.

[0162] (23) In any one of (1) to (21), the composition may be for the prevention, alleviation, improvement, or treatment of side effects caused by the administration of a thrombolytic agent. (24) In (23), the side effects may include at least one selected from the group consisting of neurotoxicity due to reperfusion injury, increased inflammation, cerebral edema, vascular dysfunction, hemorrhage, and hemorrhagic risk.

[0163] (25) The present invention provides a method for preventing or treating ischemic stroke in a subject by administering any one of the compositions (1) to (24) to a subject with an NIHSS score of 7 or higher.

[0164] (26) The present invention provides the use of any one of (1) to (24) of a composition for preventing or treating ischemic stroke in a subject with an NIHSS score of 7 or higher by administering it to the subject.

[0165] (27) The present invention provides the use of any one of (1) to (24) of a composition for the manufacture of a drug to prevent or treat ischemic stroke in a subject with an NIHSS score of 7 or higher by administering it to the subject.

[0166] (28) The present invention provides a method for preventing, alleviating, improving, or treating side effects caused by the administration of a thrombolytic agent by administering any one of the compositions of (1) to (24) to a subject with an NIHSS score of 7 or higher.

[0167] (29) The present invention provides the use of any one of (1) to (24) for the prevention, alleviation, improvement, or treatment of side effects caused by the administration of a thrombolytic agent by administering it to a subject with an NIHSS score of 7 or higher.

[0168] (30) The present invention provides the use of any one of the compositions (1) to (24) for the manufacture of a drug for the prevention, alleviation, improvement, or treatment of side effects caused by the administration of a thrombolytic agent, administered to a subject with an NIHSS score of 7 or higher.

[0169] The details described above regarding the compositions of the present invention may be substantially applied to each composition of the present invention, a method for preventing or treating ischemic stroke by administering the composition of the present invention, and the use of the composition of the present invention, unless they are inconsistent with one another.

[0170] Embodiments of the present invention may be modified in various different forms, and the scope of the present invention is not limited to the embodiments described below. Furthermore, embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art. Moreover, throughout the specification, the term "comprising" any component means that, unless specifically stated otherwise, it does not exclude other components but may include additional components.

[0171]

Effects of the Invention

[0172] The composition of the present invention exhibits excellent inhibitory effects on the increase in cerebral infarction volume and neurological and functional improvement effects in patients with moderate to severe ischemic stroke receiving thrombolytic therapy or mechanical thrombectomy including endo-arterial treatment with NIHSS scores of 7 or 16 or higher, and can treat cerebral infarction in patients with ischemic stroke and improve prognosis. In other words, the composition of the present invention may be useful for the prevention or treatment of patients with ischemic stroke.

[0173]

Brief Description of the Drawing

[0174] Figure 1 is a figure showing the change in NIHSS scores (median) of the test group and placebo group compared to baseline in a group of patients with ischemic stroke (cerebral infarction) with an NIHSS score of less than 7 based on baseline NIHSS scores.

[0175] Figure 2 is a figure showing the change in NIHSS scores (median) of the test group and placebo group compared to baseline in a group of patients with ischemic stroke (cerebral infarction) with an NIHSS score of 7 or higher based on baseline NIHSS scores.

[0176] Figure 3 is a figure showing the change in NIHSS score (median) of the ischemic stroke (cerebral infarction) patient group with an NIHSS score of 7 or more based on baseline NIHSS score compared to the ischemic stroke (cerebral infarction) patient group with an NIHSS score of less than 7 based on baseline NIHSS score in the test group.

[0177] Figure 4 is a diagram comparing the functional improvement effect of the test group compared to the placebo group on day 28, divided into conditions where the baseline NIHSS score was less than 7 points and conditions where it was 7 points or higher.

[0178] Figure 5 is a figure showing the distribution of mRS scores at day 28 for the test group and placebo group relative to baseline in a group of patients with ischemic stroke (cerebral infarction) with an NIHSS score of 7 or higher based on baseline. Figure 6 is a figure showing the distribution of mRS scores at baseline for the test group and placebo group relative to baseline in a group of patients with ischemic stroke (cerebral infarction) with an NIHSS score of 16 or higher based on baseline and who underwent endovascular treatment after thrombolytic therapy.

[0179]

Form for carrying out the invention

[0180] The present invention will be explained in more detail below through embodiments. These embodiments are intended to illustrate the invention and the scope of the invention is not limited to these embodiments.

[0181] <Clinical Trial>

[0182] 1. Method

[0183] A clinical trial was conducted on a total of 226 patients with acute ischemic stroke using a composition containing the hydrochloric acid salt of the compound of Formula 1 of the present invention as the test drug, and water for injection containing an isotonic agent and a buffer agent, excluding the hydrochloric acid salt of the compound of Formula 1 from the test drug, as the placebo.

[0184] The test drug was prepared according to the composition listed in Table 1 below. Specifically, the hydrochloric acid salt of the compound of Formula 1 (the hydrochloric acid salt of the compound represented by Formula 1; the hydrochloric acid salt of the compound represented by Formula 1 was prepared and used according to the method described in Korean Patent 10-1075435) was added to water for injection and stirred to completely dissolve it. Then, sodium chloride was added as an isotonic agent, and a solution of sodium dihydrogen phosphate hydrate and anhydrous disodium hydrogen phosphate was added as a buffer agent. Afterward, additional water for injection was added to reach the target liquid volume (50 mL). Subsequently, the mixture was filtered using a filtration filter to prepare a composition containing the compound of Formula 1 (40 mg of the hydrochloric acid salt of the compound of Formula 1 / total liquid volume 50 mL).

[0185] [Table 1]

[0186] Ingredients % (w / v) Main component Hydrochloric acid salt of the compound of Chemical Formula 1 0.08 Isotonic agent Sodium chloride

[0187] 0.82

[0188]

[0189] Sodium Chloride (NaCl) sodium dihydrogen phosphate hydrate

[0190] Buffer agent low od um Phosphate Dihydrate rate Monobasic (NaH2PO4-2H2O) — 1 lya S io

[0191] Sodium hydrogen phosphate, anhydrous

[0192] Buffer Sodium Phosphate Dibasic Anhydrous (Na2HPO4) — 1 o Solvent for injection Water — 1 o

[0193]

[0194] A placebo with a total liquid volume of 50 mL was prepared using sodium chloride, sodium dihydrogen phosphate monohydrate, anhydrous disodium hydrogen phosphate, and water for injection in substantially the same manner as the test drug was prepared, except that the compound of Formula 1 of the present invention was excluded. Specifically, a solution was prepared by adding sodium chloride, sodium dihydrogen phosphate monohydrate, and anhydrous disodium hydrogen phosphate isotonic agents and buffers to water for injection, and then the placebo was prepared through a liquid volume control process in which water for injection was added to reach the target liquid volume (50 mL) and filtration.

[0195] When participating in the clinical trial, the investigational drug or placebo was administered along with standard treatment for ischemic stroke (cerebral infarction) (intravenous thrombolysis (IV Thrombolysis) and / or endovascular thrombectomy (EVT)).

[0196] The test drug and placebo were administered a total of 6 times over 3 days at a dosage and frequency of 2 times a day (80 mg / day of the hydrochloride of the compound of chemical formula 1 in the case of the test drug), regardless of endo-arterial thrombectomy treatment.

[0197] Specifically, in the patient conditions treated with intravenous thrombolysis alone as standard treatment, the investigational drug or placebo was administered along with the thrombolytic agent; specifically, the first investigational drug or placebo was intravenously infused over 30 minutes within 30 minutes of the start of administration of rtPA, the standard treatment for acute ischemic stroke. Following the first administration of the investigational drug or placebo, the investigational drug or placebo was administered twice daily at 12-hour intervals for a total of 6 doses over 3 days (80 mg / day of the compound of Formula 1 for the investigational drug). Alteplase (commercially available under the trade names Actilyse® or Activase®) was used for rtPA. rtPA was administered once at a dose of 0.9 mg / kg based on the patient's body weight and was limited to a maximum dose of 90 mg or less.

[0198] In the patient conditions for endovascular thrombectomy (EVT) treatment following intravenous thrombolysis as standard treatment, intravenous thrombolysis was performed using the same timing, administration cycle, and dosage of rtPA, the investigational drug, or the placebo as in the patient conditions for intravenous thrombolysis alone. In this case, endovascular thrombectomy was performed between the administration cycles of the investigational drug or the placebo after the first administration of the investigational drug or the placebo. Standard and widely used methods for endovascular thrombectomy included stent retriever thrombectomy, aspiration thrombectomy, and a combined technique of the two methods. Stent retriever thrombectomy is a treatment method that deploys a stent-shaped device at the site of the thrombus to capture and remove the clot, while aspiration thrombectomy is a method that removes the clot using suction force. The subjects for intra-arterial thrombectomy after intravenous thrombolysis were patients within 6 hours of the onset of cerebral infarction symptoms, or within 24 hours for selected patients with a small cerebral infarction area.

[0199] In this clinical trial, the group in which standard treatment and placebo were administered in combination was defined as the placebo group, and the group in which standard treatment and a composition containing the compound of Formula 1 were administered in combination was defined as the test group.

[0200] Test group (1) Thrombolytic therapy alone, test drug administration group

[0201] (2) Thrombolysis and thrombectomy treatment, test drug administration group

[0202] Placebo group (1) Thrombolytic therapy alone, placebo group

[0203]

[0204] (2) Thrombolysis and thrombectomy treatment, placebo group

[0205] The study and placebo groups of this clinical trial, including the subjects' NIHSS scores, are summarized as follows:

[0206] Test group (1) NIHSS score < 7, thrombolytic therapy alone, test drug administration group

[0207] (2) NIHSS score 7 or higher, thrombolytic therapy alone, test drug administration group

[0208] (3) NIHSS score of 16 or higher, thrombolytic and thrombectomy treatments, test drug administration group

[0209] Placebo group (1) NIHSS score < 7, thrombolytic therapy alone, placebo group

[0210]

[0211] (2) NIHSS score 7 or higher, thrombolysis monotherapy, placebo group

[0212]

[0213] (3) NIHSS score 16 or higher, thrombolytic and thrombectomy treatment, placebo group

[0214] The clinical trial was conducted using a double-blind, randomized, parallel design method in accordance with ICH-GCP, KGCP, and all applicable relevant regulations.

[0215] The subjects participating were patients who met the selection / exclusion criteria and agreed to participate in the clinical trial, who were able to receive standard treatment, such as thrombolytic therapy, within 4.5 hours of the onset of acute cerebral infarction symptoms, and who were determined to have no signs of hemorrhage through brain CT scan.

[0216] The main selection / exclusion criteria for participants are as follows:

[0217] [Major Selection Criteria]

[0218] 1) Patients with neurological deficits of NIHSS score 4 or higher

[0219] 2) Adults aged 19 to 85. (Those who were able to perform daily tasks and extracurricular activities with an mRS score of 0 or 1 prior to the onset of stroke)

[0220] 3) Those capable of undergoing brain MRI (DWI, GRE / SWI, FLAIR, MRA) imaging

[0221] [Major Exclusion Criteria]

[0222] 1) Those who were diagnosed with a myocardial infarction within 6 months of screening or had a severe arrhythmia causing clinical symptoms

[0223] 2) Patients with severe heart failure classified as Class I II or Class IV by the New York Heart Association (NYHA) heart failure classification

[0224] 3) Individuals who have been receiving continuous drug treatment for a respiratory disease (asthma, COPD, tuberculosis, etc.) for at least the past month at the time of screening.

[0225] 4) Persons undergoing dialysis or treatment for acute or chronic renal failure, nephropathy, etc. at the time of screening

[0226] 5) Patients who were diagnosed with cancer or received treatment for cancer within 6 months of the screening date, or who have recurrent or metastatic cancer.

[0227] 6) Pregnant and breastfeeding women

[0228] 7) Patients with acute ischemic cerebral infarction for whom administration of thrombolytic agents, the standard treatment, is impossible (patients for whom rtPA administration is impossible) (1) Method for evaluating neurological improvement effect

[0229] The neurological improvement effect on clinical trial subjects was evaluated using the modified National Institute of Health Stroke Scale (NIHSS), which is commonly used to assess the initial effect after a stroke.

[0230] The NIHSS measures a total of 14 items, including level of consciousness, gaze, visual field, facial paralysis, muscle strength of the limbs, ataxia, sensation, speech, dysarthria, neglect, and distal movement of the upper extremities. Scores are assigned to each item based on the patient's response and summed to represent a total score. The maximum NIHSS total score is 42, indicating a critical condition, while the minimum value is 0, indicating no neurological impairment. Additionally, the NIHSS score reflects the severity of the stroke: 1–4 points are classified as mild stroke, 4–15 points as moderate stroke, 16–20 points as moderate to severe stroke, and 21–42 points as severe stroke.

[0231] In this clinical trial, NIHSS was repeatedly assessed at baseline (before administration of the drug (rtPA and test drug / placebo)), Day 1 (the day administration began, Day 1), Day 2, Day 3, Day 4, Day 5, Day 28, and Day 90, respectively, to compare the neurological improvement effect over time between the placebo group and the test group based on the reduction in NIHSS scores relative to baseline. On Days 1, 2, and 3, NIHSS was assessed after the administration of the drug on each respective day was completed.

[0232] (2) Method for evaluating functional improvement effects

[0233] The functional improvement effect on clinical trial subjects was evaluated using the mRS (modified Rankin Scale), which is the most widely used prognostic indicator as a standard scale. The mRS is a functional outcome scale that can assess the long-term prognostic improvement effect after the onset of stroke. The mRS evaluation was assessed on a scale of 0 to 6 based on symptoms according to standard mRS evaluation criteria. 0 points indicate no disability at all; 1 point indicates a state where mild disability remains but all daily tasks (occupations) and extracurricular activities can be performed without the help of others; 2 points indicate a state where there is mild disability making it impossible to perform all general tasks (occupations) but independent daily living is possible, with higher mRA scores indicating progressively worsening disability; 3 points indicate a state with moderate disability where independent walking is impossible and assistive devices are required, and complex daily living activities are impossible; 4 points indicate a state with moderate to severe disability where walking and basic daily living are impossible without the help of others but one can be alone for several hours (4-5 hours); 5 points indicate a state with severe severe disability requiring continuous care, mostly bedridden, or requiring assistance with bowel and bladder control; and 6 points indicate a state of death. The maximum standard for functional improvement is set from 0 points, indicating no disability, to 1 point, indicating a state where mild sequelae of stroke remain but all daily tasks (occupations) and extracurricular activities performed before the stroke can be performed. In the case of patients who have undergone endovascular therapy, the condition is more remission-oriented, and the standard for functional improvement is set from 0 points to 2 points, indicating a state where, due to mild disability, all daily tasks (occupations) and extracurricular activities performed before the stroke cannot be performed but daily tasks and daily life can be managed independently without assistance.

[0234] (3) Method for evaluating the effect of suppressing cerebral infarction volume

[0235] As a surrogate marker for evaluating efficacy, the effect of suppressing stroke volume in clinical trial subjects was evaluated by measuring the stroke volume of clinical trial subjects using MRI (Magnetic Resonance Imaging) and then quantifying it. Specifically, MRI (Magnetic Resonance Imaging) was performed at baseline and on day 5, and the stroke volume was quantified using Image J software specialized for stroke volumetry. The stroke volume increase rate was calculated as the ratio of the stroke volume that increased or changed by day 5 to the quantified stroke volume at baseline.

[0236] 2. Results

[0237] (1) Neurological improvement effect in patients with acute ischemic stroke (cerebral infarction)

[0238] Based on baseline NIHSS scores, the neurological improvement effects were statistically compared and analyzed for the patient group with ischemic stroke (cerebral infarction) with a score of less than 7 and the patient group with moderate to severe ischemic stroke (cerebral infarction) with a score of 7 or higher. The results are shown in Table 2 and Figures 1, 2, and 3.[Table 2]

[0239] cerebral infarction patients treated with intravenous thrombolysis alone

[0240] Patients with a baseline NIHSS score of less than 7, or patients with a baseline NIHSS score of 7 or higher

[0241] Stroke Scale

[0242] (NIHSS) Difference in change in NIHSS between the test group (37) and the placebo group (43) and between the test group (30) and the placebo group (32) Median difference in change in NIHSS [95% Confidence Interval] P-value Median [95% Confidence Interval] : P-value Baseline 0.0 [-1.0, 0.0 0.416 2.0 [0.0, 5.0 0.098 Day 3 1.0 [0.0, 2.0 0.144 -3.0 [-6.0, 0.0 0.025 Day 5 1.0 [0.0, 2.0 0.102 -4.0 [-6.0, -1.0] 0.020 Day 28 0.0 [0.0, 1.0 0.249 -4.0 [-7.0, -1.0] 0.002

[0243]

[0244] Day 90 0.0 [0.0, 1.0] 0.224 -3.0 [-6.0, -1.0] 0.005 Table 2 shows the NIHSS scores of the test group versus the NIHSS scores of the placebo group at baseline, day 3, day 5, day 28, and day 90, specifically showing the median value and p-value for [NIHSS score of the test group] - [NIHSS score of the placebo group].

[0245] Figure 1 is a figure showing the change in NIHSS scores (median) of the test group and placebo group compared to baseline in a group of patients with ischemic stroke (cerebral infarction) with an NIHSS score of less than 7 based on baseline NIHSS scores.

[0246] Figure 2 is a figure showing the change in NIHSS scores (median) of the test group and placebo group compared to baseline in a group of patients with ischemic stroke (cerebral infarction) with an NIHSS score of 7 or higher based on baseline NIHSS scores.

[0247] Figure 3 is a figure showing the change in NIHSS score (median) of the ischemic stroke (cerebral infarction) patient group with an NIHSS score of 7 or more based on baseline NIHSS score compared to the ischemic stroke (cerebral infarction) patient group with an NIHSS score of less than 7 based on baseline NIHSS score in the test group.

[0248] Referring to Table 2 and Figures 1 and 2, in the patient group with ischemic stroke (cerebral infarction) with a baseline NIHSS score of less than 7, there was no statistical difference between the placebo group and the test group at all time points; however, in the patient group with moderate to severe ischemic stroke (cerebral infarction) with a score of 7 or higher, the decrease in NIHSS scores at days 3, 5, 28, and 90 was greater in the test group compared to the placebo group at all time points, and a statistically significant difference was observed (Day 3 p=0.025, Day 5 p=0.020, Day 28 p=0.002, Day 90 p=0.005). Additionally, referring to Figure 3, when analyzing the results in correspondence with the baseline NIHSS score within the same test group, ischemic stroke with a baseline NIHSS score of less than 7 Compared to the (cerebral infarction) patient group, a statistically significantly higher reduction in NIHSS was observed in the ischemic stroke (cerebral infarction) patient group with an NIHSS score of 7 or higher at baseline (median difference in NIHSS change at day 3 -7 points, p<0.001; median difference in NIHSS change at day 5 -7 points, p<0.001; median difference in NIHSS change at day 28 -7 points, p<0.001; median difference in NIHSS change at day 90 -8 points, p<0.001).

[0249] In particular, in the group of patients with moderate to severe ischemic stroke (cerebral infarction) with a score of 7 or higher, clinical improvement results were confirmed in the placebo group with a median change in NIHSS of -8.0 only after 90 days, whereas in the test group, clinical improvement results were rapidly reached with a median change in NIHSS of -9.0 in 3 days, and furthermore, it was confirmed that a change in NIHSS of -12.0 was observed on the 90th day.

[0250] In other words, for patients with ischemic stroke (cerebral infarction) with a baseline NIHSS score of less than 7, the neurological improvement effects in the test group and the placebo group were similar, so no difference was observed between the two groups; however, for patients with ischemic stroke (cerebral infarction) with a baseline NIHSS score of 7 or higher, neurological improvement results that significantly outperformed the placebo group at all time points, along with more rapid improvement results, could be observed.

[0251] Therefore, it can be confirmed that the composition of the present invention can demonstrate a rapid and significantly superior therapeutic and improvement effect for ischemic stroke compared to other patient groups and the placebo group in patients with ischemic stroke (cerebral infarction) with an NIHSS score of 7 or higher based on baseline time point.

[0252] (2) Functional improvement effect in patients with acute ischemic stroke (cerebral infarction)

[0253] Based on baseline NIHSS scores, the functional improvement effect was compared using the 28-day mRS scores in the patient group with ischemic stroke (cerebral infarction) with a score of less than 7 and the patient group with moderate to severe ischemic stroke (cerebral infarction) with a score of 7 or higher. The results are shown in Table 3 and Figures 4 and 5. [Table 3]

[0254] affection

[0255]

[0256] cerebral infarction patients treated with intravenous thrombolysis alone

[0257] The modified baseline NIHSS score is the baseline NIHSS score

[0258] Patients with less than 7 points Patients with 7 points or more

[0259] Lan Kin

[0260] Scale test group (28 people) and test group (28 people)

[0261] (mRS) Among the placebo group (30 people) Among the placebo group (30 people)

[0262] P-value Odds Ratio

[0263] (Ratio of 0 to 1 point) (Ratio of 0 to 1 point)

[0264] Day 28 -2.62% 0.859 0.90 17.63% 0.069 5.19

[0265]

[0266] * Odds Rat io , OR

[0267] Figure 4 is a diagram comparing the functional improvement effect of the test group compared to the placebo group on day 28, divided into conditions where the baseline NIHSS score was less than 7 points and conditions where it was 7 points or higher.

[0268] Figure 5 is a diagram showing the distribution of mRS scores at day 28 for the test group and placebo group relative to baseline in a group of patients with ischemic stroke (cerebral infarction) with an NIHSS score of 7 or higher based on baseline.

[0269] Referring to Table 3 and Figures 4 and 5, when examining the ratio of mRS 0-1 points, which is judged as a functional improvement effect, the benefit to functional improvement in the test group compared to the placebo group at day 28 was increased by approximately 5 times in ischemic stroke (cerebral infarction) patients with a baseline NIHSS score of 7 or higher compared to ischemic stroke (cerebral infarction) patients with a baseline NIHSS score of less than 7. In particular, at day 28, among the group of patients with ischemic stroke (cerebral infarction) with a baseline NIHSS score of less than 7, the placebo group was 63.3% and the test group was 60.7%, which were similar; however, among the group of patients with moderate to severe ischemic stroke (cerebral infarction) with an NIHSS score of 7 or higher, the placebo group was 35.0% and the test group was 52.6%, indicating a 17.6% benefit in functional improvement in the test group compared to the placebo group. This suggests a potential for approximately five times greater functional improvement compared to the placebo group.

[0270] Furthermore, in the placebo group, the proportion of mRS scores between 0 and 1 was significantly lower in the group of patients with a stroke severity of 7 or higher compared to the group with a score of less than 7. In contrast, the test group showed a similar proportion of 0-1 scores in the group with moderate or higher severity (7 or higher) as in the group with a score of less than 7; notably, the proportion of 0 scores, indicating no functional impairment, was actually higher in the group with a score of 7 or higher than in the group with a score of less than 7. Meanwhile, the mRS scores of the test and control groups were compared under the condition of patients with a baseline NIHSS score of 16 or higher who underwent endovascular therapy following thrombolytic treatment. The results are shown in Table 4 and Figure 6.

[0271] [Table 4]

[0272] cerebral infarction patients treated with endo-arterial thrombectomy after intravenous thrombolysis

[0273] (Patients with a baseline NIHSS score of 16 or higher)

[0274] Modified Functional Deterioration Rate (Ratio of scores from 5 to 6) Rankin Functional Improvement Rate (Ratio of scores from 0 to 2)

[0275] Scale Test Group and Test Group and (mRS) Placebo Group Functional Improvement Between Test Group and Placebo Group Difference in Rate of Functional Deterioration Between Placebo Group and Test Group Rate Difference Day 28 33.3% 42.9% 9.5% 33.3% 0.0% -33.3%

[0276]

[0277] Figure 6 is a diagram showing the distribution of mRS scores of the test group and placebo group relative to baseline in a group of ischemic stroke (cerebral infarction) patients who received endovascular treatment after thrombolytic therapy and had an NIHSS score of 16 or higher at baseline.

[0278] Referring to Table 4 and Figure 6, when examining the mRS 0-2 ratio, which is judged as the functional improvement effect in patients who underwent endovascular therapy, among ischemic stroke (cerebral infarction) patients who underwent endovascular therapy with an NIHSS score of 16 or higher at baseline on day 28, the placebo group showed 33.3% and the test group showed 42.9%, indicating a higher functional improvement effect in the test group compared to the placebo group. In particular, when looking at the ratio of deaths and patients with severe high-grade disability, the placebo group showed 33.3% and the test group showed 0.0%, confirming the beneficial effect of the test group.

[0279] (3) Effect of suppressing cerebral infarction volume in patients with acute ischemic stroke (cerebral infarction). Based on the NIHSS score at baseline, the difference between the cerebral infarction volume at baseline and the cerebral infarction volume at day 5 for the ischemic stroke (cerebral infarction) patient group with less than 7 points and the moderate to severe ischemic stroke (cerebral infarction) patient group with 7 points or more was calculated and compared. The increase in cerebral infarction volume and the suppression rate of cerebral infarction volume compared to the placebo group were calculated and compared. The results are shown in Table 5.

[0280] [Table 5]

[0281] cerebral infarction patients treated with intravenous thrombolysis alone

[0282] Patients with baseline NIHSS scores less than 7, patients with baseline NIHSS scores of 7 or higher, placebo group, study group, placebo group, study group (37 patients) (36 patients) (28 patients) (22 patients) Cerebral infarction at baseline

[0283] Volume 0.7 (0.3, 3.5) 2.1 (0.3, 6.2) 2.8 (1.2, 7.1) 6.6 (0.6, 24.4) [Median (Interquartile Range)]

[0284] From the baseline to the 5th day

[0285] Increased cerebral infarction volume 0.6 (0.0, 4.5) 1.7 (0.0, 3.5) 1.4 (0.0, 5.2) 0.2 (-0.5, 11.7) [Median (Interquartile Range)]

[0286] Cerebral infarction volume increase rate 3 30.4% 30.2% 44.5% 4.7% [Median (%)]

[0287] 0.7% 89.4% of cerebral infarction volume compared to placebo

[0288]

[0289] Inhibition rate (%)

[0290] a Percentage increase in cerebral infarction volume (%) = [Increased cerebral infarction volume from baseline to day 5 x 100 / Cerebral infarction volume at baseline]

[0291] Referring to Table 5, in patients with ischemic stroke (cerebral infarction) with a baseline NIHSS score of less than 7, the placebo group showed a 30.4% increase in cerebral infarction volume and the test group showed a 30.2% increase, resulting in a inhibition rate of 0.7% for cerebral infarction volume compared to the placebo group. On the other hand, in patients with moderate to severe ischemic stroke (cerebral infarction) with a baseline NIHSS score of 7 or higher, the placebo group showed a 44.5% increase in cerebral infarction volume and the test group showed a 4.7% increase, confirming that the test group demonstrated an 89.4% superior inhibition rate for cerebral infarction volume compared to the placebo group.

[0292] In addition, when the results were analyzed in correspondence with the baseline NIHSS scores in the same test group, the rate of increase in cerebral infarction volume was reduced by approximately 6 times in the group of ischemic stroke (cerebral infarction) patients with a baseline NIHSS score of 7 or higher compared to the group of ischemic stroke (cerebral infarction) patients with a baseline NIHSS score of less than 7. Therefore, through the above results, it can be confirmed that ischemic stroke (cerebral infarction) can be treated and prognosis improvement can be maximized by administering a composition containing the compound of Formula 1 according to the present invention in combination with a thrombolytic agent (rtPA).

[0293] In particular, through this clinical trial, it can be confirmed that when rtPA is used in combination with a composition containing Formula 1 of the present invention in a group of patients with moderate to severe ischemic stroke (cerebral infarction) with a baseline NIHSS score of 7 or higher—rather than in all acute ischemic stroke patients to whom standard treatment, thrombolytic agents, are applied—it shows unexpectedly significantly superior therapeutic effects and prognosis improvement compared to a group of ischemic stroke (cerebral infarction) patients with an NIHSS score of less than 7 and a placebo group. Specifically, in the patient group with a baseline NIHSS score of 7 or higher, the neurological improvement results based on the NIHSS score and the functional prognosis improvement results based on the mRS indicate that the combination therapy group of the compound of Formula 1 and a thrombolytic agent can demonstrate more rapid and maximized improvement in functional prognosis compared to the existing standard treatments, such as thrombolytic agent and rtPA monotherapy. Additionally, independently evaluated cerebral infarction volume imaging results confirmed that the treatment group showed a high inhibitory effect on the increase in cerebral infarction volume compared to the placebo group, similar to other results. However, in patients with a baseline NIHSS score of less than 7, the combination administration of the standard treatment rtPA and the compound of Formula 1 did not demonstrate differentiation compared to the placebo group.

[0294] That is, the composition according to the present invention showed consistent trend results in three independently evaluated evaluation variables (amount of change in NIHSS, mRS score, and cerebral infarction volume) in the patient group with an NIHSS score of 7 or higher, showing superior results compared to the patient group with a score of less than 7 and the placebo group. Therefore, it can be confirmed that the composition according to the present invention demonstrates unexpectedly and significantly superior therapeutic effects for ischemic stroke and maximized improvement of prognosis in the patient group with an NIHSS score of 7 or higher compared to the patient group with a score of less than 7 and the placebo group.

[0295] In addition, positive functional prognosis improvement results were shown in cerebral infarction patients who received endovascular therapy with an NIHSS score of 16 or higher based on baseline. Therefore, it can be confirmed that the composition of the present invention demonstrates excellent therapeutic effects for ischemic stroke and maximizes prognosis improvement not only in ischemic stroke (cerebral infarction) patients with an NIHSS score of 7 or higher, but also in ischemic stroke (cerebral infarction) patients with an NIHSS score of 16 or higher who received endovascular therapy.

Claims

【Scope of Claim】 【claim Paragraph 11 A composition comprising a compound represented by the following chemical formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, intended to be administered to a subject in combination with a thrombolytic agent to prevent or treat ischemic stroke, and The above subject is a patient with moderate to severe ischemic stroke who has an NIHSS (National Institutes of Health Stroke Scale) score of 7 or higher, and the composition: [Chemical Formula 1] H

2. A composition comprising a compound represented by the following chemical formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and a thrombolytic agent, for co-administration thereof, Composition: to be administered to a subject to prevent or treat ischemic stroke, wherein the subject is a patient with moderate to severe ischemic stroke with an NIHSS score of 7 or higher. [Chemical Formula 1]

3. A composition comprising a first composition comprising a compound represented by the following chemical formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and a second composition comprising a thrombolytic agent, The first composition and the second composition are administered in combination, and The above composition is intended to prevent or treat ischemic stroke by administering the first composition and the second composition in combination to a subject, and The above subject is a patient with moderate to severe ischemic stroke with an NIHSS score of 7 or higher, composition: [Chemical Formula 1]

4. A composition according to any one of claims 1 to 3, wherein the subject is an ischemic stroke patient with an NIHSS score of 16 or higher. 【claim Paragraph 5] A composition according to any one of claims 1 to 3, wherein the subject is an ischemic stroke patient receiving thrombolytic agent treatment. 【claim Paragraph 6] A composition according to any one of claims 1 to 3, wherein the subject is an ischemic stroke patient with an NIHSS score of 16 or higher who receives at least one of thrombolytic therapy and mechanical thrombectomy (endovascular therapy). [Claim] Paragraph 7] A composition according to any one of claims 1 to 3, wherein the subject is an ischemic stroke patient with an NIHSS score of 16 or higher who is receiving thrombolytic therapy and mechanical thrombectomy. 【claim Paragraph 8] A composition according to any one of claims 1 to 3, wherein the composition treats cerebral infarction in a patient with ischemic stroke and prevents, alleviates, improves, or treats sequelae. 【Claim this A composition according to any one of claims 1 to 3, wherein the composition reduces the rate of increase in cerebral infarction volume of a subject after administration.

10. A composition according to any one of claims 1 to 3, wherein the composition reduces the NIHSS score of the subject after administration.

11. A composition according to any one of claims 1 to 3, wherein the composition increases the ratio of mRS 0 and 1 of the subject after administration.

12. A composition according to any one of claims 1 to 3, wherein the compound represented by Formula 1, its pharmaceutically acceptable salt, its hydrate or solvate, or a mixture thereof, and the thrombolytic agent are administered sequentially or simultaneously in combination.

13. A composition according to any one of Claims 1 to 3, wherein the content of the compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof is 0.08% w / v.

14. A composition according to any one of claims 1 to 3, wherein the composition is administered once a day or twice a day.

15. A composition according to any one of claims 1 to 3, wherein the composition is administered for 1 day, 2 days, 3 days or more.

16. A composition according to any one of claims 1 to 3, wherein the thrombolytic agent is a recombinant tissue plasminogen activator (rtPA).

17. A composition according to any one of claims 1 to 3, wherein the thrombolytic agent comprises at least one of alteplase and tenecteplase.

18. In Clause 17, the composition is one in which tenecteplase is administered at 0.25 mg / kg. 【Claim 1 is A composition according to claim 17, wherein alteplase is administered at a dose of 0.6 to 0.9 mg / kg. [Claim Paragraph 20] A composition according to any one of claims 1 to 3, wherein the compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof is administered in an amount of 30 to 80 mg.

21. A composition according to any one of claims 1 to 3, wherein the composition comprises one or more selected from the group consisting of an isotonic agent, a pH adjuster, and an aqueous solvent.

22. A composition according to any one of claims 1 to 3, wherein the composition comprises sodium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, and an aqueous solvent.

23. A method of preventing or treating ischemic stroke in a subject by administering a composition of any one of claims 1 to 22 to a subject with an NIHSS score of 7 or higher.

24. Use of a composition of any one of claims 1 to 22 for preventing or treating ischemic stroke in a subject by administering it to a subject with an NIHSS score of 7 or higher.

25. Use of the composition of any one of claims 1 to 22 for the manufacture of a drug to prevent or treat ischemic stroke in a subject with an NIHSS score of 7 or higher.

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