Composition comprising quinazoline-2,4-dione derivative

Abstract

The present invention relates to a composition for co-administration with a thrombolytic agent, comprising a quinazoline-2,4-dione derivative, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof. Specifically, the present invention relates to a composition comprising a compound represented by Formula 1 for co-administration with a thrombolytic agent, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, a method for preventing or treating thromboembolic disease using the same, a method for preventing, alleviating, improving, or treating side effects caused by the administration of a thrombolytic agent, and the use thereof.

Description

Technology Field

[0001] The present invention relates to a composition for co-administration with a thrombolytic agent, comprising a quinazoline-2,4-dione derivative, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof. Specifically, the present invention relates to a composition comprising a compound represented by Formula 1 for co-administration with a thrombolytic agent, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, a method for preventing or treating thromboembolic disease using the same, a method for preventing, alleviating, improving, or treating side effects caused by the administration of a thrombolytic agent, and the use thereof. Background Technology

[0003] When vascular tissue is injured, blood leaks out of the vessel, and a blood clot forms in the tissue surrounding the injury to stop the bleeding. Blood clots that stop bleeding localized to the site of injury are a normal part of the wound healing process and are essential for survival. In contrast, if a blood clot is abnormally present within a blood vessel, it will block blood flow if not removed. Blocking blood flow leads to fatal thromboembolic diseases such as stroke, pulmonary embolism, and myocardial infarction, which cause tissue necrosis due to hypoxia.

[0004] Thromboembolic disease is a very serious condition with a high incidence rate, leading to the development of various treatments. Thrombolytics are direct therapeutic agents that dissolve blood clots, with tissue-type plasminogen activator (tPA) and urokinase being representative examples. These thrombolytics all cleave plasminogen in the body to activate it into plasmin, and the activated plasmin then breaks down blood clots to produce a therapeutic effect.

[0005] Plasmin is a protein-degrading enzyme found in the blood. Normally, it exists in the body as a precursor (plasminogen) (an inactive protein) in the blood, but is converted into plasmin capable of degrading fibrin by an activating agent. When fibrin is produced in the body, it acts to stop bleeding; however, if excessive fibrin is produced and blocks blood vessels, plasmin acts to restore normal blood flow.

[0006] Conventionally, blood clots were dissolved using plasminogen activators, but conventional thrombolytics have the disadvantage of requiring administration within 3 to 4.5 hours (narrow time window), having side effects that limited their use to only 5% of all patients, and having limited efficacy (8-32%) in large embolisms. Additionally, there are issues such as the occurrence of cerebral hemorrhage (0.5–6%), a mortality rate of over 8.8%, and reperfusion injury. Furthermore, there are problems with strict administration conditions and high difficulty of administration (intravenous infusion 30 minutes after a 10% intravenous bolus injection). In other words, conventional plasminogen activator thrombolytics require rapid administration, have limited efficacy in large embolisms, and their use is restricted due to side effects such as reperfusion injury and high difficulty of administration.

[0007] Recently, approval for tenecteplase, a third-generation thrombolytic agent that has partially resolved the issue, as a treatment for ischemic stroke is underway, primarily in Europe. However, according to various clinical trials, tenecteplase is not yet free from the side effects characteristic of thrombolytic agents. In particular, since the potential risk of bleeding is still reported as a major side effect of tenecteplase, there is a need for new technological solutions that can effectively suppress the risk of bleeding while maintaining the excellent pharmacological activity of tenecteplase. The problem to be solved

[0009] The present invention provides a composition for co-administration with tenecteplase, comprising a quinazolin-2,4-dione derivative, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

[0010] The present invention provides a composition comprising a quinazolin-2,4-dione derivative, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof and tenecteplase.

[0011] The present invention provides a method for preventing or treating thromboembolic diseases using the composition of the present invention.

[0012] The present invention provides a method for preventing, alleviating, improving, or treating side effects caused by the administration of a thrombolytic agent using the composition of the present invention.

[0013] The present invention provides a use of the composition of the present invention for the prevention or treatment of thromboembolic diseases.

[0014] The present invention provides a use of the composition of the present invention for preventing, alleviating, improving, or treating side effects caused by the administration of a thrombolytic agent.

[0015] The present invention provides a use of the composition of the present invention for the manufacture of a drug for the prevention or treatment of thromboembolic diseases.

[0016] The present invention provides a use of the composition of the present invention for the manufacture of a drug to prevent, alleviate, improve, or treat side effects caused by the administration of a thrombolytic agent. means of solving the problem

[0018] 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.

[0020] The present invention provides a composition comprising a quinazoline-2,4-dione derivative, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

[0021] In the present invention, the quinazolin-2,4-dione derivative may be otaplimastat.

[0022] Otap-limastat is a compound represented by the following chemical formula 1, which is “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-dihydroquinazolin-3(2H)-yl)propyl]-N-(4-{[3-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)propyl]amino}butyl)acetamide)”.

[0023] [Chemical Formula 1]

[0024]

[0025] That is, 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.

[0026] 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 hydrochloride salt, but is not necessarily limited thereto.

[0027] 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-stoichiometric amounts of water.

[0028] The “solvent” 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-stoichiometric amounts.

[0029] In embodiments of the present invention, the composition may be intended for co-administration with a thrombolytic agent.

[0030] 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.

[0031] In embodiments of the present invention, the thrombolytic agent may be a recombinant tissue plasminogen activator (rtPA).

[0032] In embodiments of the present invention, the thrombolytic agent may include at least one of alteplase and tenecteplase, but is not necessarily limited thereto.

[0033] In one embodiment of the present invention, the thrombolytic agent may be tenecteplase.

[0034] In one embodiment of the present invention, the composition of the present invention may comprise a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and may be a composition for co-administration with tenecteplase.

[0035] In embodiments of the present invention, the composition may be 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.

[0036] The above composition 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.

[0037] In embodiments of the present invention, the composition may be a composition comprising a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof and tenecteplase.

[0038] In embodiments of the present invention, the composition is a composition for co-administering a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof and tenecteplase.

[0039] In this specification, the term "composition" may be used interchangeably with "combination." Specifically, where 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.

[0040] 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 (specifically tenecteplase) may comprise the compound represented by Formula 1, the pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and a thrombolytic agent (specifically tenecteplase) as separate preparations, or all of them in the form of a complex preparation.

[0041] 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 (specifically tenecteplase) as separate preparations.

[0042] Specifically, 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 (specifically tenecteplase) 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 (tenecteplase). For example, the composition may be a kit, but is not necessarily limited thereto.

[0043] In the compositions 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)) and the thrombolytic agent (specifically tenecteplase) (or a composition containing the same (specifically the second composition)) may each be administered concurrently, nearly concurrently, or sequentially.

[0044] At this time, a thrombolytic agent (or a composition containing the same (specifically a second composition)) may be administered simultaneously, almost 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 second composition)) may be administered simultaneously, almost simultaneously, or sequentially with the administration of a thrombolytic agent (or a composition containing the same).

[0045] In the present invention, "simultaneously" may mean that two substances are administered at the same time without a time difference, "sequentially" may mean that one substance is administered after another substance is administered, 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."

[0046] In embodiments of the present invention, 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 the first composition)) may be administered simultaneously with the administration of a thrombolytic agent (specifically tenecteplase) (or a composition containing the same (specifically the second composition)) immediately after administration or within a certain time after administration (sequentially) co-administered.

[0047] In embodiments of the present invention, the composition of the present invention may be such that a thrombolytic agent (specifically tenecteplase) (or a composition containing the same (specifically a second composition)) is administered (sequentially) in combination 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)).

[0048] In embodiments of the present invention, the composition of the present invention may be such that a thrombolytic agent (specifically tenecteplase) (or a composition containing the same (specifically a second composition)) is (sequentially) administered in combination 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)).

[0049] In embodiments of the present invention, the composition of the present invention may be such that a thrombolytic agent (specifically tenecteplase) (or a composition containing the same (specifically a second composition)) is (sequentially) co-administered within 3 hours 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)).

[0050] Or, in embodiments of the present invention, the composition of the present invention may be such that, simultaneously with the administration of the thrombolytic agent (specifically tenecteplase) (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 sequentially administered immediately after administration or within a certain time after administration.

[0051] 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 the first composition)) may be sequentially administered within a certain time after administration of the thrombolytic agent (specifically tenecteplase) (or a composition containing the same (specifically the second composition)).

[0052] In embodiments of the present invention, the composition of the present invention may be for the prevention or treatment of thromboembolic disease.

[0053] The above-mentioned thromboembolic disease refers to a disease in which a blood clot detaches from its original location and travels through the bloodstream (as an embolus) to block blood vessels, causing tissue ischemia and organ damage.

[0054] In embodiments of the present invention, the thromboembolic disease is selected from the group consisting of (acute) ischemic stroke, transient ischemic attack, ischemic myocardial infarction, unstable angina pectoris, peripheral artery thrombosis, mesenteric artery thrombosis, renal artery thrombosis, deep vein thrombosis (DVT), pulmonary embolism (PE), upper extremity vein thrombosis, portal vein thrombosis, hepatic vein thrombosis (Budd-Chiari syndrome), cerebral venous sinus thrombosis (CVST), retinal vein occlusion, atrial fibrillation-related embolism, left ventricular thrombosis after myocardial infarction, heart valve disease-related embolism, artificial heart valve-related thromboembolism, endocarditis-related embolism, disseminated intravascular coagulation (DIC), antiphospholipid syndrome (APS), cancer-related thromboembolism, pregnancy / puerperal thromboembolism, and drug-induced thromboembolism. There may be at least one, but it is not necessarily limited to this.

[0055] In embodiments of the present invention, the thromboembolic disease may be at least one selected from the group consisting of ischemic myocardial infarction, pulmonary embolism, and (acute) ischemic stroke. In one embodiment of the present invention, the thromboembolic disease may be (acute) ischemic stroke.

[0056] In addition, in the embodiments of the present invention, the composition of the present invention may be for the prevention or treatment of side effects caused by the administration of a thrombolytic agent.

[0057] Tenecteplase is a third-generation thrombolytic agent that offers increased convenience as it can be administered as a single bolus intravenous injection, and has the advantage of sustained thrombolytic effect due to its long half-life and suitability for emergency situations. However, it is reported that tenecteplase is not free from the side effects characteristic of thrombolytic agents, such as limited efficacy in large embolisms and limited use due to reperfusion injury and high difficulty of administration, and in particular, there is a problem in that the risk of bleeding is reported as a major side effect.

[0058] The composition of the present invention is a composition for administering in combination a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and a thrombolytic agent (specifically tenecteplase). According to the present invention, by administering in combination (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 (specifically tenecteplase), not only can thromboembolic disease be prevented or treated, but side effects and sequelae associated with the use of the thrombolytic agent can also be minimized, thereby maximizing the improvement of the prognosis.

[0059] Specifically, 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 can be safely administered in combination with a thrombolytic agent (specifically tenecteplase) without any inhibitory effect on the thrombolytic effect of tenecteplase, thereby increasing the therapeutic effect. At the same time, the risk of hemorrhagic activity caused by the thrombolytic agent (specifically tenecteplase) can be further reduced, and sequelae can be prevented, alleviated, and improved, ultimately increasing the rate of improvement in the patient's prognosis. In addition, rapid treatment application in combination with a thrombolytic agent (specifically tenecteplase) may be possible in emergency situations.

[0060] In particular, according to the present invention, compared to the administration of tenecteplase alone, by combining a compound represented by Formula 1 according to the present invention, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof with a thrombolytic agent (specifically tenecteplase), damage to the blood-brain barrier can be improved and damage caused by standard therapeutic agents, such as thrombolytic agents, as well as damage caused by ischemia or reperfusion, can be significantly alleviated and a superior anti-ischemic effect can be exhibited.

[0061] Accordingly, the composition of the present invention may be very useful for the prevention or treatment of thromboembolic diseases, e.g., ischemic myocardial infarction, pulmonary embolism and (acute) ischemic stroke (AIS), and may be useful for the prevention, alleviation, improvement, or treatment of side effects caused by the administration of thrombolytic agents.

[0062] Side effects caused by the administration of the above-mentioned thrombolytic agent may include, but are not limited to, neurotoxicity due to reperfusion injury, increased inflammation, cerebral edema, vascular dysfunction, hemorrhage, and hemorrhagic risk.

[0063] Specifically, the composition of the present invention may inhibit the increase in cerebral infarction volume in a subject requiring it (e.g., a subject suffering from (acute) ischemic stroke). That is, the composition of the present invention may reduce cerebral infarction volume when administered to a subject.

[0064] The composition of the present invention may inhibit cerebral infarction when administered to a subject.

[0065] The composition of the present invention may inhibit damage caused by ischemia when administered to a subject.

[0066] The composition of the present invention may minimize side effects associated with the thrombolytic agent without inhibiting the thrombolytic effect of the thrombolytic agent when administered to a subject.

[0067] The composition of the present invention may minimize side effects associated with tenecteplase without reducing the thrombolytic effect of tenecteplase when administered to a subject.

[0068] The composition of the present invention may minimize neurotoxicity, increased inflammation, cerebral edema, vascular dysfunction, hemorrhage, and hemorrhagic risk caused by reperfusion injury due to the thrombolytic agent without inhibiting the thrombolytic effect of the thrombolytic agent when administered to a subject.

[0069] The composition of the present invention may minimize neurotoxicity, increased inflammation, cerebral edema, vascular dysfunction, hemorrhage, and hemorrhagic risk caused by reperfusion injury due to tenecteplase without inhibiting the thrombolytic effect of tenecteplase when administered to a subject.

[0070] 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.

[0071] The composition of the present invention may have a superior cerebral infarction inhibitory effect when administered to a subject compared to tenecteplase alone.

[0072] 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.

[0073] The composition of the present invention may have a superior anti-ischemic effect when administered to a subject compared to tenecteplase alone.

[0074] The composition of the present invention may have excellent cell protective effects, including antioxidant and anti-inflammatory properties, when administered to a subject.

[0075] Therefore, the composition of the present invention can be usefully used for the prevention and treatment of thromboembolic diseases or for enhancing the preventive and therapeutic effects of thromboembolic diseases, and can be usefully used for the prevention, alleviation, improvement, or treatment of side effects caused by the administration of thrombolytic agents.

[0076] 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 a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof in an amount of 0.05 to 0.2 w / v%, 0.06 to 0.2 w / v%, 0.07 to 0.2 w / v%, 0.08 to 0.2 w / v%, 0.05 to 0.15 w / v%, 0.06 to 0.15 w / v%, 0.07 to 0.15 w / v%, 0.08 to 0.15 w / v%, 0.05 to 0.1 w / v%, 0.06 to 0.1 w / v%, 0.07 to 0.1 w / v%, or 0.08 to 0.1 w / v%. More 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.

[0077] 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.

[0078] In embodiments of the present invention, the composition of the present invention may include a compound of Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, an isotonic agent, a pH adjuster, and a solvent.

[0079] In the present invention, the term "pH adjuster" may include buffers. Specifically, the term "pH adjuster" encompasses all substances added to adjust or maintain the pH of a composition within a desired range. This includes not only acids or bases that immediately change the pH of the composition, but also buffers, buffer solutions, etc., that perform the function of maintaining a constant pH of the composition by resisting the influx of external acids, bases, etc., or environmental changes.

[0080] In embodiments of the present invention, the composition comprising the compound of Formula 1 of the present invention, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof may have a pH of 5 or higher and less than 8, specifically a pH of 6 or higher and less than 8, but is not necessarily limited thereto.

[0081] In the embodiments of the present invention, a pH adjuster may be used without limitation as long as it is capable of preparing the composition of the present invention at a pH of 5 or higher and / or maintaining the pH of the composition of the present invention at a pH of 5 or higher and less than 8 for a certain period of time.

[0082] In embodiments of the present invention, the pH adjuster may be one or more selected from the group consisting of phosphoric acid, phosphate, phosphate hydrate, acetic acid, acetate, citric acid, citric acid hydrate, citrate, citrate hydrate, succinic acid, lactic acid, histidine, histidine salt, tris(hydroxymethyl)aminomethane (Tris), tris(hydroxymethyl)aminomethane (Tris) salt, methanesulfonic acid, sulfonic acid, hydrochloric acid, nitric acid, sulfuric acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium bicarbonate, sodium carbonate, sodium carbonate hydrate, diethanolamine, meglumine, tromethamine, edetic acid, and pentetic acid, but is not limited thereto.

[0083] In embodiments of the present invention, the pH adjuster may be one or more selected from the group consisting of phosphoric acid, phosphate, phosphate hydrate, acetic acid, acetic acid, citric acid, citric acid hydrate, citrate, tris(hydroxymethyl)aminomethane (Tris), salt of tris(hydroxymethyl)aminomethane (Tris), 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES), hydrochloric acid, and sodium hydroxide.

[0084] Specifically, the pH adjuster may be one or more selected from the group consisting of sodium dihydrogen phosphate, hydrate of sodium dihydrogen phosphate (e.g., sodium dihydrogen phosphate dihydrate, etc.), disodium hydrogen phosphate (e.g., anhydrous disodium hydrogen phosphate), hydrate of disodium hydrogen phosphate, acetic acid, sodium acetate, citric acid, sodium citrate, hydrochloride of tris(hydroxymethyl)aminomethane (Tris-HCl), 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES), hydrochloric acid, and sodium hydroxide. For example, the pH adjuster may be hydrochloric acid and sodium hydroxide; or sodium dihydrogen phosphate dihydrate and anhydrous disodium hydrogen phosphate; or citric acid and sodium citrate; or sodium dihydrogen phosphate and disodium hydrogen phosphate; or acetic acid and sodium acetate. or tris(hydroxymethyl)aminomethane hydrochloride (Tris-HCl); or 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES) and sodium hydroxide.

[0085] In the present invention, "isotonic agent" refers to a substance added to adjust the osmotic pressure of a composition to be substantially the same as the osmotic pressure of a biological sample (e.g., blood, serum, tears, etc.).

[0086] In embodiments of the present invention, the isotonic agent may be sodium chloride (NaCl).

[0087] Specifically, in one embodiment of the present invention, the isotonic agent is sodium chloride, and the pH adjuster may be hydrochloric acid and sodium hydroxide; or sodium dihydrogen phosphate dihydrate and anhydrous disodium hydrogen phosphate; or citric acid and sodium citrate; or sodium dihydrogen phosphate and disodium hydrogen phosphate; or acetic acid and sodium acetate; or hydrochloride of tris(hydroxymethyl)aminomethane (Tris-HCl); or 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES) and sodium hydroxide. For example, the composition of the present invention 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 a solvent.

[0088] Preferably, the sodium dihydrogen phosphate and disodium hydrogen phosphate may be sodium dihydrogen phosphate dihydrate and disodium hydrogen phosphate anhydrous, respectively, but are not limited thereto. 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. Specifically, the composition of the present invention may contain 0.5 to 1.5 w / v%, 0.6 to 1.5 w / v%, 0.7 to 1.5 w / v%, 0.8 to 1.5 w / v%, 0.5 to 1.2 w / v%, 0.6 to 1.2 w / v%, 0.7 to 1.2 w / v%, 0.8 to 1.2 w / v%, 0.5 to 1.0 w / v%, 0.6 to 1.0 w / v%, 0.7 to 1.0 w / v%, or 0.8 to 1.0 w / v%.

[0089] In embodiments of the present invention, the composition of the present invention may include an appropriate amount of a pH adjuster to achieve a pH of 5 or higher and less than 8. For example, the composition of the present invention may include a pH adjuster in an amount of 0.01 to 0.4 w / v%. Specifically, the composition of the present invention may include a pH adjuster in an amount of 0.01 to 0.4 w / v%, 0.01 to 0.3 w / v%, 0.01 to 0.25 w / v%, 0.01 to 0.2 w / v%, 0.01 to 0.18 w / v%, or 0.01 to 0.15 w / v%.

[0090] In embodiments of the present invention, the composition of the present invention may comprise 0.05 to 0.4 w / v% of a pH adjuster.

[0091] In embodiments of the present invention, the composition of the present invention may include an aqueous solvent.

[0092] In one embodiment of the present invention, the composition of the present invention may comprise 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.

[0093] In this case, the isotonic agent may include sodium chloride, etc., but is not necessarily limited thereto. For example, the pH adjuster may include hydrochloric acid, sodium hydroxide, sodium dihydrogen phosphate, disodium hydrogen phosphate, etc., but is not necessarily limited thereto.

[0094] 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.

[0095] In embodiments of the present invention, the composition of the present invention may comprise 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 comprise hydrochloric acid, sodium hydroxide, etc., as needed.

[0096] 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.

[0097] 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.

[0098] 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.

[0099] 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 the remainder being an aqueous solvent. In this case, the composition may further comprise hydrochloric acid, sodium hydroxide, etc., as needed.

[0100] 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 the remainder being an aqueous solvent. In this case, the composition may further comprise hydrochloric acid, sodium hydroxide, etc., as needed.

[0101] In embodiments of the present invention, the sodium dihydrogen phosphate and disodium hydrogen phosphate may each be sodium dihydrogen phosphate dihydrate and disodium hydrogen phosphate anhydrous, but are not limited thereto.

[0102] In one embodiment of the present invention, the aqueous solvent may be physiological saline, water for injection, etc., 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. The water for injection may be used without particular limitation as long as it is water for injection generally used to dissolve, suspend, or emulsify the composition, and preferably, physiological saline, glucose water for injection, xylitol water for injection, D-mannitol water for injection, fructose water for injection, dextran 40 water for injection, dextran 70 water for injection, amino acid water for injection, Ringer's solution, lactic acid-Ringer's solution, etc. may be used.

[0103] In the embodiments of the present invention, the composition of the present invention may be an injectable composition or an intravenous preparation. The injectable composition may be a liquid (e.g., aqueous injectable, non-aqueous injectable, concentrated injectable, etc.), a suspension (e.g., suspension injectable, liposomal injectable, etc.), an emulsion (e.g., emulsion injectable, etc.), or a preparation that is dissolved upon use (e.g., freeze-dried powder), but is not limited thereto.

[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 in a dose of 80 mg per day, but is not necessarily limited thereto.

[0106] In the embodiments of the present invention, tenecteplase may be administered at a dose of 0.25 mg / kg when administered to humans, but is not necessarily limited thereto.

[0107] In embodiments of the present invention, the thrombolytic agent may be administered in a dose of 10 to 50 mg, but is not necessarily limited thereto. For example, if the composition is for the prevention or treatment of thromboembolic disease, tenecteplase may be administered in a dose of 10 to 50 mg, specifically 20 to 40 mg or 25 to 40 mg, but is not necessarily limited thereto. For example, if the composition is for the prevention or treatment of ischemic stroke, tenecteplase may be administered in a maximum daily dose of 25 mg, but is not necessarily limited thereto.

[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.

[0109] 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 twice a day, but is not necessarily limited thereto.

[0110] In one embodiment of the present invention, the thrombolytic agent (specifically tenecteplase) (or a composition containing the same (specifically the second composition)) may be administered once a day, but is not necessarily limited thereto. Specifically, the thrombolytic agent (specifically tenecteplase) (or a composition containing the same (specifically the second composition)) may be administered only once, but is not necessarily limited thereto.

[0111] In embodiments of the present invention, the composition of the present invention may be administered for 1 day, 2 days, 3 days or more.

[0112] In one embodiment of the present invention, 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 for 3 days, but is not necessarily limited thereto.

[0113] In embodiments of the present invention, the composition of the present invention may be administered at 12-hour intervals, but is not necessarily limited thereto.

[0114] 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, but is not necessarily limited thereto.

[0115] In embodiments of the present invention, the composition may be administered intravenously.

[0116] In embodiments of the present invention, the composition of the present invention may be administered within 3 to 6 hours after the occurrence of ischemia (embolism), but is not necessarily limited thereto.

[0117] In embodiments 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 within 3 hours after the occurrence of ischemia (embolism), but is not necessarily limited thereto.

[0118] In embodiments of the present invention, the thrombolytic agent (specifically tenecteplase) (or a composition containing the same (specifically the second composition)) may be administered within 6 hours after the occurrence of ischemia, but is not necessarily limited thereto.

[0119] Ischemia is a condition in which the blood flow into a tissue or organ is partially or completely blocked, resulting in insufficient supply of oxygen and nutrients to the affected area and impaired removal of metabolic waste products, thereby causing dysfunction in cell metabolism. In the present invention, ischemia may specifically include acute ischemic stroke caused by a thrombus or embolus.

[0120] The composition of the present invention can be used alone or in combination with methods using surgery, hormone therapy, drug therapy, and biological response modifiers for the prevention and treatment of thromboembolic diseases or to enhance the effect of preventing and treating thromboembolic diseases.

[0121] In the embodiments of the present invention, the administration of the composition of the present invention may be combined with endovascular thrombectomy (EVT), but is not necessarily limited thereto.

[0122] In one embodiment of the present invention, the composition of the present invention may be administered simultaneously or sequentially with endovascular thrombectomy (EVT), but is not necessarily limited thereto.

[0123] In one embodiment of the present invention, after performing endovascular thrombectomy, a thrombolytic agent (specifically tenecteplase) or a composition containing the same (specifically the second composition) and 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, nearly simultaneously, or sequentially, but are not necessarily limited thereto.

[0124] In one 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, the first composition) may be administered simultaneously, nearly simultaneously, or sequentially with a thrombolytic agent (specifically, tenecteplase) or a composition containing the same (specifically, the second composition), and then endovascular thrombectomy may be performed, but is not necessarily limited thereto.

[0125] In one embodiment of the present invention, endovascular thrombectomy may be performed after administering a thrombolytic agent (specifically tenecteplase) or a composition containing the same (specifically the second composition) simultaneously with the 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), immediately after administration or within a certain time after administration (e.g., within 3 hours), but is not necessarily limited thereto.

[0126] In one embodiment of the present invention, an intravascular thrombectomy may be performed after administering a thrombolytic agent (specifically tenecteplase) or a composition containing the same (specifically the second composition) and 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), but is not necessarily limited thereto.

[0127] In one embodiment of the present invention, intravascular thrombectomy may be performed 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 second composition) simultaneously with the administration of a thrombolytic agent (specifically tenecteplase) or a composition containing the same (specifically the second composition), immediately after administration, or within a certain time after administration, but is not necessarily limited thereto.

[0128] Mechanical vascular ablation (endovascular thrombectomy (EVT)) is a treatment method that directly removes blocked blood vessels through mechanical procedures. While it offers the advantages of a long treatment window (8 hours after ischemia) and a low risk of side effects, it has the limitation that its application is restricted to large vessels (LVO). In other words, while thrombi in large vessels can be mechanically removed via EVT, it is difficult to resolve microvessels or distal thrombi that are hard to access with EVT.

[0129] According to the present invention, the composition of the present invention can be used in combination with mechanical thrombectomy before or after administration thereof, thereby exhibiting a superior preventive or therapeutic effect against thromboembolic disease, and can prevent, alleviate, improve, or treat sequelae, side effects, etc. of the subject.

[0130] That is, the composition of the present invention can demonstrate significant efficacy in both chemical therapy and mechanical therapy (bridging therapy) for the treatment of ischemic stroke.

[0131] In the present invention, "prevention" means any act of suppressing thromboembolic disease in a subject or delaying the onset of thromboembolic disease by administering a composition according to the present invention, or any act of suppressing or delaying sequelae caused by thromboembolic disease or side effects caused by the administration of a thrombolytic agent.

[0132] In the present invention, "treatment" means any act in which the symptoms of a subject's thromboembolic disease are improved or beneficially altered by the administration of a composition according to the present invention.

[0133] In the present invention, "administration" means introducing a specific substance to a subject by an appropriate method.

[0134] In the present invention, "alleviation" and "improvement" refer to any act in which sequelae symptoms of thromboembolic disease or side effects symptoms of thrombolytic agent administration are improved or beneficially altered by the administration of the composition according to the present invention.

[0135] In the present invention, "object" refers to all animals, including humans, rats, mice, and livestock, that have developed or may develop a disease; specifically, it may be mammals including humans, but is not necessarily limited thereto.

[0136] In the present invention, "composition" may refer to a pharmaceutical composition.

[0137] The present invention also provides a kit for the prevention and treatment of thromboembolic diseases 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.

[0138] The present invention also provides a kit for the prevention and treatment of thromboembolic diseases 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.

[0139] The present invention also provides a method for preventing or treating thromboembolic disease comprising administering the composition of the present invention to a subject in need thereof.

[0140] Specifically, the present invention provides a method for preventing or treating thromboembolic disease comprising administering a composition of the present invention, comprising a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, in combination with a thrombolytic agent to a subject in need thereof.

[0141] Specifically, the present invention provides a method for preventing or treating thromboembolic disease comprising administering to a subject in need the composition of the present invention, 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.

[0142] More specifically, the present invention provides a method for preventing or treating thromboembolic disease comprising administering to a subject in need 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.

[0143] In embodiments of the present invention, the thromboembolic disease may be one or more selected from the group consisting of ischemic myocardial infarction, pulmonary embolism and acute ischemic stroke (AIS), but is not necessarily limited thereto.

[0144] In embodiments of the present invention, the thrombolytic agent may be tenecteplase.

[0145] In embodiments of the present invention, in the method, a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof and tenecteplase are administered in combination. Specifically, 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 in combination with tenecteplase or a composition containing the same (specifically a second composition).

[0146] In the embodiments of the present invention, the compound represented by Formula 1 in the composition of the present invention, the pharmaceutically acceptable salt thereof, the hydrate or solvate thereof, or a mixture thereof and tenecteplase may each be administered together at the same time, almost simultaneously (immediately after administration), or sequentially (within a certain time after administration).

[0147] Specifically, 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 tenecteplase or a composition containing the same (specifically, a second composition) may each be administered in combination, simultaneously, nearly simultaneously (immediately after administration), or sequentially (within a certain time after administration).

[0148] In embodiments 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) and a thrombolytic agent (specifically, tenecteplase) or a composition containing the same (specifically, the second composition) may be administered in combination sequentially.

[0149] In embodiments of the present invention, the thrombolytic agent (specifically tenecteplase) or the composition containing the same (specifically the second composition) may be sequentially administered after administration of 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).

[0150] In embodiments of the present invention, the thrombolytic agent (specifically tenecteplase) or the composition containing it (specifically the second composition) may be sequentially administered within 3 hours after administration of 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).

[0151] In embodiments of the present invention, after administering the thrombolytic agent (specifically tenecteplase) 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) may be sequentially administered in combination.

[0152] In one embodiment of the present invention, the method may comprise administering an effective amount 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) and an effective amount of tenecteplase or a composition containing the same (specifically, a second composition) to a subject requiring the same.

[0153] In embodiments of the present invention, the method may be used for the prevention and treatment of thromboembolic disease or to enhance the effect of preventing and treating thromboembolic disease, either by administering the composition of the present invention alone or in combination with methods using surgery, hormone therapy, drug therapy, and biological response modifiers.

[0154] In the embodiments of the present invention, the administration of the composition of the present invention may be combined with endovascular thrombectomy (EVT), but is not necessarily limited thereto.

[0155] In one embodiment of the present invention, in the method, the administration of the composition of the present invention may be combined with endovascular thrombectomy (EVT) simultaneously or sequentially, but is not necessarily limited thereto.

[0156] In one embodiment of the present invention, after performing endovascular thrombectomy, a thrombolytic agent (specifically tenecteplase) or a composition containing the same (specifically the second composition) and 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, nearly simultaneously, or sequentially, but are not necessarily limited thereto.

[0157] In one 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, the first composition) may be administered simultaneously, nearly simultaneously, or sequentially with a thrombolytic agent (specifically, tenecteplase) or a composition containing the same (specifically, the second composition), and then endovascular thrombectomy may be performed, but is not necessarily limited thereto.

[0158] In one embodiment of the present invention, endovascular thrombectomy may be performed after administering a thrombolytic agent (specifically tenecteplase) or a composition containing the same (specifically the second composition) simultaneously with the 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), immediately after administration or within a certain time after administration (e.g., within 3 hours), but is not necessarily limited thereto.

[0159] In one embodiment of the present invention, an intravascular thrombectomy may be performed after administering a thrombolytic agent (specifically tenecteplase) or a composition containing the same (specifically the second composition) and 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), but is not necessarily limited thereto.

[0160] In one embodiment of the present invention, after administering a thrombolytic agent (specifically tenecteplase) or a composition containing the same (specifically the 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 the first composition) may be sequentially administered, and then an intravascular thrombectomy may be performed, but is not necessarily limited thereto.

[0161] The present invention also provides a use of the composition of the present invention for the prevention or treatment of thromboembolic diseases.

[0162] The present invention also provides a use of the composition of the present invention for the manufacture of a drug for the prevention or treatment of thromboembolic diseases.

[0163] The present invention also provides a method for preventing, alleviating, improving, or treating side effects caused by the administration of a thrombolytic agent, comprising administering a composition of the present invention.

[0164] 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 a thrombolytic agent.

[0165] The present invention also 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.

[0167] The details described above regarding the compositions and methods of the present invention may be applied substantially identically to each composition, each method, and each use of the present invention, provided that they do not contradict one another.

[0169] 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. Effects of the invention

[0171] The composition according to the present invention exhibits an excellent anti-ischemic effect while minimizing side effects caused by the administration of a thrombolytic agent, and can be usefully used for the prevention, alleviation, improvement, or treatment of side effects caused by the administration of a thrombolytic agent, or for the prevention or treatment of thromboembolic diseases. Brief explanation of the drawing

[0173] Figure 1a is a diagram showing the administration group and time of administration in the evaluation of the combined efficacy of compound 1 and tenecteplase in a rat embolic stroke model. Figure 1b is a diagram showing the lethality and hemoglobin levels for each group in a rat embolic stroke model. Figure 1c is a diagram showing the quantified cerebral infarction patterns, cerebral infarction volume and edema, and behavioral evaluation scores by group in a rat embolic stroke model. Figure 2a is a diagram showing the thrombolytic pattern according to tenecteplase concentration. Figure 2b is a diagram showing the quantified spectrophotometric values ​​according to tenecteplase concentration. Figure 3a is a diagram showing the tenecteplase-induced thrombolysis pattern according to the concentration of compound 1. Figure 3b is a diagram showing the quantified spectrophotometric values ​​according to the concentration of compound 1. Specific details for implementing the invention

[0174] The present invention will be explained in more detail below through examples. These examples are intended to illustrate the invention and the scope of the invention is not limited to these examples.

[0176] Experimental Example 1: Evaluation of the combined efficacy of Compound 1 and TNK (tenecteplase) in a rat embolic stroke model

[0178] Induction of an Embolic Stroke Model - Induction of an Embolic Middle Cerebral Artery Occlusion (MCAO) Model

[0179] To prepare the embolism, blood from the femoral artery of a donor rat (SD rat) was collected in a polyethylene tube (PE-50, Intramedic, DK) and stored at room temperature for 2 hours, followed by storage at 4°C for 22 hours to produce a clot. The clot was washed 2 to 3 times with physiological saline and then gently injected into the internal carotid artery (ICA) of the rat via the external carotid artery (ECA) using a 100 μl Hamilton syringe and a surgical microscope (Carl Zeiss, Inc., Thornwood, NY). The injected clot landed in the middle cerebral artery (MCA) according to the anatomical location of the animal (rat), inducing an ischemic stroke caused by middle cerebral artery ischemia (MCAO).

[0180] Drug administration

[0181] In an embolic middle cerebral artery ischemic stroke rat model, Compound 1 (hydrochloride of the compound represented by Chemical Formula 1; the hydrochloride of the compound represented by Chemical Formula 1 was prepared and used according to the method described in Korean Patent 10-1075435) was dissolved in sterile physiological saline and administered intravenously over 1 minute at a dose of 3 mg / kg, and then tenecteplase was administered over 30 minutes at a dose of 1.5 mg / kg (rat dose) at 6 hours after inducing ischemia (Compound 1 + Tenecteplase combination administration group). The control group was administered only sterile physiological saline at 3 hours after inducing ischemia, and the tenecteplase monotherapy group was administered only tenecteplase at 6 hours after ischemia without administration of Compound 1 (see Fig. 1a).

[0182] Measurement of cerebral infarction and edema volume

[0183] Twenty-four hours after embolic induction of middle cerebral artery ischemia, rats were sacrificed and damaged brain tissue was excised. The excised brain was sectioned into six segments and stained in 2,3,5-triphenyltetrazolium chloride (TTC) solution at room temperature for 30 minutes to visually distinguish between the infarcted and normal regions. The cross-sectional area of ​​the infarcted region was measured by distinguishing between cortical and subcutaneous structures within the damaged brain hemisphere using the image analysis program (TOMORO ScopeEye 3.5), and the edema volume (%) was calculated using the following formula:

[0184] Volume of edema (%) = [(VI - VC) / VC] × 100

[0185] Here, VI represents the volume of the damaged hemisphere (the hemisphere where the cerebral infarction occurred due to the injection of the blood clot), and VC represents the volume of the undamaged hemisphere (the hemisphere opposite to the hemisphere where the cerebral infarction occurred).

[0186] The total corrected infarct volume was quantified by integrating six slices after cerebral edema correction. The corrected infarct volume (IVC, mm³) was calculated as follows:

[0187] Corrected Infarct Volume (IVC) = IVd Х (VC / VI)

[0188] Here, IVd represents the infarct volume of the damaged hemisphere measured directly.

[0189] The percentage of infarct volume relative to total brain volume was calculated using the following formula:

[0190] Infarct volume (%) = IVC / VW × 100

[0191] Here, VW represents the total brain volume.

[0192] Quantitative determination of intracerebral hemorrhage

[0193] Cerebral hemisphere tissues were obtained from rats that had undergone complete cardiac perfusion to remove intravascular blood. Subsequently, 0, 2, 4, 8, 16, and 32 μl of allogeneic blood were added stepwise to each hemisphere sample. After centrifugation at 13,000 RPM for 30 minutes, the hemoglobin of the blood exposed into the tissue was quantified by reacting with Drabkin reagent (Sigma-Aldrich, CA). The quantified hemoglobin information was displayed as a standard curve using a spectrophotometer (SpectraMAX190, Molecular Devices, CA) at 540 nm, and this standard curve was used to quantify the amount of hemorrhage (μL) exposed in the cerebral hemispheres of each diseased animal.

[0194] Evaluation of behavioral indicators

[0195] Behavioral indicators were scored by evaluating the behavioral characteristics of diseased animals according to the following table (Score, Animal behavioral characteristics)

[0196]

[0197] result

[0198] Referring to Fig. 1b, in an ischemic stroke (embolic middle cerebral artery ischemia) model, the group administered tenecteplase alone showed a mortality rate similar to that of the control group at 24 hours after ischemia induction, and it was confirmed that the amount of hemoglobin in brain tissue, reflecting hemorrhagic side effects, was approximately twice that of the control group. On the other hand, the group administered tenecteplase + Compound 1 showed the lowest mortality rate, and it was confirmed that the amount of hemoglobin was also reduced compared to the group administered tenecteplase alone (Fig. 1b). (In the mortality graph of Fig. 1b, (15), (16), and (19) represent the number of animals used in the study for each group.)

[0199] Brain tissues damaged by ischemia may experience cell damage due to the recirculation of blood flow (reperfusion injury), and in particular, side effects such as cerebral hemorrhage may occur due to damage to vascular endothelial tissue caused by tenecteplase (TNK).

[0200] However, according to the above results, it can be confirmed that by administering compound 1 and tenecteplase together according to the present invention, both the lethality rate and hemorrhagic side effects were suppressed compared to the group administered tenecteplase alone, and thus, it can be confirmed that the composition of the present invention can minimize side effects such as death or hemorrhagic side effects, and side effects that may be caused by the administration of thrombolytic agents.

[0201] In addition, referring to Fig. 1c, in an ischemic stroke model, the group administered tenecteplase alone showed a tendency for approximately 35% reduction in cerebral infarction volume compared to the control group (control: 21.74%, tenecteplase: 14.22%), confirming the inhibitory effect of tenecteplase on ischemic damage. Furthermore, the group administered in combination with tenecteplase + Compound 1 induced approximately 52% inhibition of cerebral infarction compared to the control group (control: 21.74%, tenecteplase + Compound 1: 10.59%). In other words, in an ischemic stroke model, a more improved trend of cerebral infarction inhibition was observed with the combination administration of tenecteplase + Compound 1 compared to tenecteplase alone (Fig. 1c).

[0202] Accordingly, it can be seen that by administering compound 1 and tenecteplase together according to the present invention, a superior cerebral infarction inhibitory effect can be achieved compared to the administration of tenecteplase alone, and a superior effect can be achieved in the prevention or treatment of ischemic stroke.

[0204] From the above results, it can be confirmed that by administering compound 1 and tenecteplase in combination according to the present invention, side effects such as death or hemorrhagic side effects, and side effects that may be caused by the administration of thrombolytic agents, can be minimized, and improved inhibition of cerebral infarction can be shown compared to the group administered tenecteplase alone. In other words, it can be confirmed that the composition of the present invention minimizes side effects and shows excellent effects on infarction, so it can be usefully used for the prevention or treatment of thromboembolic diseases, including ischemic stroke.

[0206] Experimental Example 2: Clot lysis assay

[0208] To determine whether compound 1 affects the intrinsic thrombolytic effect of tenecteplase when compound 1 is administered in combination with tenecteplase, the effect of compound 1 on tenecteplase was confirmed using an artificially produced blood clot.

[0209] Production of blood clots

[0210] Arterial blood was collected from the femoral artery of a rat (SD rat), 200 μL of aPTT (activated partial thromboplastin time) reagent was added to 300 μL of the collected blood, followed by the addition of 200 μL of calcium chloride (CaCl2), and then incubated at 37°C for 10 minutes to obtain a stable fibrin-rich clot.

[0211] Dissolution and evaluation of thrombosis

[0212] Preliminary test: Arterial blood was collected from the femoral artery of a rat (SD rat) in a 1.5 mL tube without anticoagulant, and the pure blood clot formed by natural coagulation was left at room temperature (20-25℃) for 30 minutes to 2 hours. Tenecteplase diluted in normal saline was then added at concentrations of 0, 50, 500, 1000, and 2000 ng / ml, with 200 μL of each dose, and incubated at 37℃ for 20 minutes. Based on the thrombolytic pattern of tenecteplase at different concentrations measured by optical density, the appropriate concentration of tenecteplase to be used in the main test was determined.

[0213] Main test: After mixing tenecteplase at concentrations set in the preliminary test with compound 1 at different concentrations, the mixture was treated with prepared fibrin thrombi to determine whether the thrombolytic reaction of tenecteplase was affected by compound 1.

[0214] Specifically, each mixture of 500 ng / mL tenecteplase and Compound 1 at concentrations of 0, 5, 10, 15, and 20 μM was placed into tubes containing fibrin thrombi, and after incubation at 37°C for 20 minutes, the thrombolytic profiles of each group were evaluated using the supernatant.

[0215] Evaluation was performed by placing the obtained supernatant into a spectrophotometer and measuring the optical density value under 405 nm conditions, and was continuously monitored and recorded until complete thrombolysis was achieved in the wells containing each drug.

[0217] result

[0218] As a result of the test, no group was identified in all compound 1 treatment groups that showed an effect on thrombolysis by tenecteplase (Figs. 2a, 2b, 3a, and 3b).

[0220] Accordingly, it was confirmed that even when compound 1 and tenecteplase are administered together according to the present invention, the thrombolytic effect of tenecteplase can be fully exerted without interference between the drugs.

[0222] Experimental Example 3: Evaluation of the Efficacy of Compound 1 in Chemical and Mechanical Thrombolysis

[0224] To confirm the effects of Compound 1 under chemical and mechanical thrombectomy conditions, changes in anti-ischemic efficacy were evaluated after co-treatment with Tenecteplase (TNK) and Compound 1 in a transient middle cerebral artery occlusion (tMCAO) model capable of mimicking mechanical thrombectomy (EVT), after blocking blood flow in the middle cerebral artery for a certain period of time using a silicone-coated filament.

[0226] From the foregoing description, those skilled in the art to which the present invention pertains will understand that the present invention may be implemented in other specific forms without altering its technical concept or essential features. In this regard, the embodiments described above should be understood as illustrative in all respects and not restrictive. The scope of the present invention should be interpreted as including all modifications or variations derived from the meaning and scope of the claims set forth below and their equivalents, rather than from the detailed description above.

Claims

Claim 1 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 for co-administration with tenecteplase: [Chemical Formula 1] . Claim 2 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 tenecteplase: [Chemical Formula 1] . Claim 3 A composition according to claim 1 or 2, wherein a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof and tenecteplase are administered together. Claim 4 A composition according to claim 1 or 2, wherein the composition is for the prevention or treatment of thromboembolic disease. Claim 5 A composition according to claim 1 or 2, wherein the composition comprises at least one selected from the group consisting of ischemic myocardial infarction, pulmonary embolism, and acute ischemic stroke, for the prevention or treatment of thromboembolic diseases. Claim 6 A composition according to claim 1 or 2, wherein the composition is for preventing, alleviating, improving, or treating side effects caused by the administration of a thrombolytic agent. Claim 7 A composition according to claim 1 or 2, wherein the compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof and tenecteplase are each administered together, either simultaneously or sequentially. Claim 8 A composition according to claim 1 or 2, wherein the composition comprises 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. Claim 9 A composition according to claim 8, wherein 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 are each administered in combination, either simultaneously or sequentially. Claim 10 A composition according to claim 1 or 2, wherein the content of the compound represented by Formula 1, the pharmaceutically acceptable salt thereof, the hydrate or solvate thereof, or a mixture thereof is 0.05 to 0.2 w / v%. Claim 11 A composition according to claim 1 or 2, 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. Claim 12 A composition according to claim 1 or 2, 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. Claim 13 A composition according to claim 1 or 2, wherein the tenecteplase is administered in an amount of 10 to 50 mg. Claim 14 A composition according to claim 1 or 2, wherein the tenecteplase is administered at a dose of 0.25 mg / kg. Claim 15 A composition according to claim 1 or 2, wherein the composition reduces the volume of a cerebral infarction. Claim 16 A composition according to claim 1 or 2, wherein the composition alleviates side effects caused by the administration of a thrombolytic agent. Claim 17 A composition according to claim 1 or 2, wherein the composition comprises at least one selected from the group consisting of neurotoxicity, increased inflammation, cerebral edema, vascular dysfunction, hemorrhage, and hemorrhagic risk, for the prevention, alleviation, improvement, or treatment of side effects caused by the administration of a thrombolytic agent. Claim 18 A composition according to claim 1 or 2, wherein the composition reduces the risk of hemorrhagic activity caused by the administration of a thrombolytic agent. Claim 19 A composition according to claim 1 or 2, wherein the composition is administered after mechanical thrombectomy. Claim 20 A composition according to claim 1 or 2, wherein the composition is administered once, twice, three times, or more times per day. Claim 21 A composition according to claim 1 or 2, wherein the composition is administered for 1 day, 2 days, 3 days or more. Claim 22 A composition according to either claim 1 or 2, wherein the composition comprises one or more selected from the group consisting of an isotonic agent, a pH adjuster, and an aqueous solvent. Claim 23 A composition according to either claim 1 or 2, wherein the composition comprises sodium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, and an aqueous solvent.

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