Composition comprising quinazoline-2,4-dione derivative

Abstract

The present invention relates to a composition for co-administration with a thrombolytic agent, the composition 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 for co-administration with a thrombolytic agent, the composition comprising a compound represented by chemical formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof; a method for preventing or treating thromboembolic diseases, using same; a method for preventing, alleviating, ameliorating or treating side effects caused by administration of a thrombolytic agent; and use thereof.

Description

[0001]

Description of the Invention

[0002]

Title of Invention

[0003] Composition containing quinazoline-2,4-dione derivatives

[0004]

Technology Field

[0005] The present invention relates to a composition for co-administration with a thrombolytic agent, comprising a quinazolin-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.

[0006]

Background Techniques

[0007] 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 injury site 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.

[0008] Thromboembolic diseases are very serious and have a high incidence rate, leading to the development of various treatments. Thrombolytic agents are direct therapeutic agents that dissolve blood clots, with alteplase (t-issue-type plasminogen activator, tPA) and urokinase being representative examples. These thrombolytic agents 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.

[0009] Plasmin is a protein-degrading enzyme found in the blood. Normally, it exists in the body in the form of a precursor (plasminogen) (an inactive protein) and 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 generated and blocks blood vessels, plasmin acts to restore normal blood flow.

[0010] Conventionally, blood clots were dissolved using plasminogen activators, but conventional thrombolytic agents have the disadvantage of requiring administration within 3-4 to 5 hours (narrow time window), having side effects that limited their use to only 5% of all patients, and having limited efficacy (8-32%) for 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 (10% intravenous bolus followed by 30-minute intravenous infusion). In other words, conventional plasminogen activator thrombolytic agents must be administered within a short period, have limited efficacy for large embolisms, and their use is restricted due to side effects such as reperfusion injury and high difficulty of administration.

[0011] 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.

[0012]

Description of the Invention

[0013]

Technical Challenges

[0014] 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.

[0015] 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. The present invention provides a method for preventing or treating thromboembolic disease using the composition of the present invention.

[0016] 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.

[0017] The present invention provides a use of the composition of the present invention for the prevention or treatment of thromboembolic diseases.

[0018] 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.

[0019] 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.

[0020] 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.

[0021]

Technical Solution

[0022] 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.

[0023] 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.

[0024] In the present invention, the quinazolin-2,4-dione derivative may be otapl imastat.

[0025] O-Taplimastat is "N-[3-(2,4-dioxo-1,4-dihydroquinazol-3(2H)-yl)propyl]-N-(4-{[3-(2,4-dioxo-1,4-dihydroquinazol-3(2H)-yl)propyl]amino}butyl)acetamide (N-[3-(2,4-dioxo-1,4-dihydroquinazol in-3(2H)-yl)propyl ]—N—(4—{[3—(2,4—dioxo—1,4—dihydroquinazol in—3(2H)—yl)propyl]amino}butyl)acetamide", which is a compound represented by the following chemical formula 1. [Chemical Formula 1]

[0026]

[0027] H

[0028] 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.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] In embodiments of the present invention, the composition may be intended for co-administration with a thrombolytic agent.

[0033] 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).

[0034] In embodiments of the present invention, the thrombolytic agent may comprise at least one of alteplase and tenecteplase, but is not necessarily limited thereto.

[0035] In one embodiment of the present invention, the thrombolytic agent may be Tenectepla.

[0036] In one embodiment 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 may be a composition for co-administration with tenecteplase.

[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 a thrombolytic agent.

[0038] The above 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 a thrombolytic agent.

[0039] 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.

[0040] 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.

[0041] 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.

[0042] 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, a 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.

[0043] 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.

[0044] 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.

[0045] 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.

[0046] 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 second 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)). 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 "nearly simultaneously" means after the administration of one substance Immediately, another substance may be administered quickly after administration. In the present invention, "sequentially" may be used in a comprehensive sense including "almost simultaneously."

[0047] In embodiments of the present invention, a thrombolytic agent (specifically tenecteplase) (or a composition containing the same (specifically a second composition)) may be administered (sequentially) concurrently 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)) of the composition of the present invention, immediately after administration or within a certain time after administration.

[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 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)).

[0049] In embodiments of the present invention, the composition of the present invention may be one in which a thrombolytic agent (specifically tenecteplase) (or a composition containing the same (specifically a second composition)) is administered (sequentially) 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)).

[0050] 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 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 a first composition)). 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 a second composition)), immediately after administration or within a certain time after administration, 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 a first composition)) Water may be administered in combination in sequence.

[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 a 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 a 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 (acute) ischemic stroke, transient ischemic attack, ischemic myocardial infarction, unstable angina pectoris, peripheral arterial 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 pulsatile 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. It may be at least one selected from the group consisting of postpartum thromboembolism and drug-induced thromboembolism, but is not necessarily limited thereto.

[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 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 sustaining thrombolytic effects and being beneficial in emergency situations due to its long half-life. 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 the side effects of 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 co-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). According to the present invention, by co-administering (using) 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 and, at the same time, further reducing the hemorrhagic risk caused by the thrombolytic agent (specifically tenecteplase), and preventing, alleviating, and improving sequelae, 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 cerebral infarction 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. The composition of the present invention may inhibit damage caused by ischemia when administered to a subject.

[0065] 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.

[0066] The composition of the present invention may minimize side effects associated with tenecteplase without impairing the thrombolytic effect of tenecteplase when administered to a subject. The composition of the present invention may minimize neurotoxicity, increased inflammation, cerebral edema, vascular dysfunction, hemorrhage, and hemorrhagic risk caused by reperfusion injury associated with the thrombolytic agent without impairing the thrombolytic effect of the thrombolytic agent when administered to a subject.

[0067] 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. 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.

[0068] The composition of the present invention may have a superior effect in inhibiting cerebral infarction when administered to a target body compared to administration of tenecteplase alone.

[0069] 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.

[0070] The composition of the present invention may have a superior anti-ischemic effect when administered to a target body compared to the administration of tenecteplase alone.

[0071] The composition of the present invention may have excellent cell protective effects, including antioxidant and anti-inflammatory effects, when administered to a target.

[0072] 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.

[0073] 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.

[0074] 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. In embodiments of the present invention, the composition of the present invention may comprise 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.

[0075] In the present invention, "pH adjusting agent" may include a buffer. Specifically, the "pH adjusting agent" encompasses all substances added to adjust or maintain the pH of a composition to a desired range, including 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 the pH of the composition constant by resisting the inflow of external acids, bases, etc. or environmental changes.

[0076] In embodiments of the present invention, a 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 a pH of less than 8, specifically a pH of 6 or higher and a pH of less than 8, but is not necessarily limited thereto.

[0077] In embodiments of the present invention, a pH adjusting agent 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.

[0078] In embodiments of the present invention, the pH adjusting agent is phosphoric acid, phosphate salt, hydrate of phosphate salt, acetic acid, acetate, citric acid, hydrate of citric acid, hydrate of citrate salt, hydrate of citrate salt, succinic acid, lactic acid, histidine, histidine salt, tris(hydroxymethyl)aminomethane (Tris),

[0079] It may be one or more selected from the group consisting of salts of tris(hydroxymethyl)aminomethane (Tris), 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.

[0080] In embodiments of the present invention, the pH adjusting agent is phosphoric acid, phosphate salt, hydrate of phosphate salt, acetic acid, acetate, citric acid, hydrate of citric acid, citrate salt, tris(hydroxymethyl)aminomethane (Tris),

[0081] It may be one or more selected from the group consisting of the salt of tris(hydroxymethyl)aminomethane (Tris), 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES), hydrochloric acid, and sodium hydroxide.

[0082] Specifically, the pH adjusting agent may be one or more selected from the group consisting of sodium dihydrogen phosphate, sodium dihydrogen phosphate hydrate (e.g., sodium dihydrogen phosphate dihydrate, etc.), sodium hydrogen phosphate (e.g., sodium hydrogen phosphate anhydride), sodium hydrogen phosphate hydrate, acetic acid, sodium acetate, citric acid, sodium citrate, hydrochloric acid salt of tris(hydroxymethyl)aminomethane (Tris-HC1), 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES), hydrochloric acid, and sodium hydroxide. For example, the pH adjusting agent may be hydrochloric acid and sodium hydroxide; or sodium dihydrogen phosphate dihydrate and sodium hydrogen phosphate anhydride; 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 (Tri-HC1); or 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES) and sodium hydroxide.

[0083] In the present invention, "isotonic agent" refers to a substance added to adjust the osmotic pressure of the composition to be substantially the same as the osmotic pressure of a biological sample (e.g., blood, serum, tears, etc.).

[0084] In embodiments of the present invention, the isotonic agent may be sodium chloride (NaCl). Specifically, in one embodiment of the present invention, the isotonic agent is sodium chloride, and the pH adjusting agent may be hydrochloric acid and sodium hydroxide; or sodium dihydrogen phosphate dihydrate and sodium hydrogen phosphate anhydride; or citric acid and sodium citrate; or sodium dihydrogen phosphate and sodium hydrogen phosphate; or acetic acid and sodium acetate; or hydrochloric acid salt of tris(hydroxymethyl)aminomethane (Tri-HC1); or 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES) and sodium hydroxide. For example, the composition of the present invention may include 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.

[0085] Preferably, the sodium dihydrogen phosphate and the sodium hydrogen phosphate may be sodium dihydrogen phosphate dihydrate and sodium hydrogen phosphate anhydrous, respectively, but are not limited thereto. In embodiments of the present invention, the composition of the present invention may contain 0.5 to 1.5 w / v% of an isotonic agent. Specifically, the composition of the present invention may include 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%.

[0086] In embodiments of the present invention, the composition of the present invention may include an appropriate amount of a pH adjusting agent to achieve a pH of 5 or higher and less than 8. For example, the composition of the present invention may include a pH adjusting agent in an amount of 0.01 to 0.4 w / v%. Specifically, the composition of the present invention may include a pH adjusting agent 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%.

[0087] 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.

[0088] In embodiments of the present invention, the composition of the present invention may include an aqueous solvent.

[0089] 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.

[0090] At this time, the above-mentioned topical agent may include sodium chloride, etc., 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.

[0091] In embodiments of the present invention, the composition of the present invention may include sodium chloride, sodium dihydrogen phosphate, sodium hydrogen phosphate, and an aqueous solvent. In this case, the composition may further include hydrochloric acid, sodium hydroxide, etc., as needed.

[0092] 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. 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.

[0093] 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.

[0094] 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.

[0095] 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.

[0096] 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.

[0097] In embodiments of the present invention, the sodium dihydrogen phosphate and the sodium hydrogen phosphate may be sodium dihydrogen phosphate dihydrate and sodium hydrogen phosphate anhydrous, respectively, but are not limited thereto. In one embodiment of the present invention, the aqueous solvent may be physiological saline, water for injection, etc., but is not necessarily limited thereto. The aqueous solvent may be included in an appropriate amount to reach the desired liquid volume in the composition of the present invention. 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.

[0098] In 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 for use (e.g., freeze-dried powder, etc.), but is not limited thereto.

[0099] 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.

[0100] 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.

[0101] In 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. In embodiments of the present invention, the thrombolytic agent may be administered at 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 at 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 at a maximum daily dose of 25 mg, but is not necessarily limited thereto.

[0102] 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.

[0103] 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.

[0104] In one embodiment of the present invention, the thrombolytic agent (specifically tenecteplase) (or a composition containing the same (specifically a 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 a second composition)) may be administered only once, but is not necessarily limited thereto.

[0105] In embodiments of the present invention, the composition of the present invention may be administered for 1 day, 2 days, 3 days or more.

[0106] 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.

[0107] 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. In one embodiment of the present invention, in the composition 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 at 12-hour intervals, but is not necessarily limited thereto.

[0108] In embodiments of the present invention, the composition may be administered intravenously. 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.

[0109] In embodiments 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 within 3 hours after the occurrence of ischemia (embolism), but is not necessarily limited thereto.

[0110] In embodiments of the present invention, the thrombolytic agent (specifically tenecteplase) (or a composition containing the same (specifically a second composition)) may be administered within 6 hours after the occurrence of ischemia, but is not necessarily limited thereto.

[0111] 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.

[0112] The composition of the present invention can be used alone or in combination with methods using surgery, hormone therapy, drug therapy, and biological response modulators for the prevention and treatment of thromboembolic diseases or to enhance the preventive and therapeutic effects of thromboembolic diseases.

[0113] In 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. In one embodiment of the present invention, 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.

[0114] In one embodiment of the present invention, after performing endovascular thrombectomy, a thrombolytic agent (specifically tenecteplase) or a composition containing the same (specifically a 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 a first composition) may be administered simultaneously, nearly simultaneously, or sequentially, but are not necessarily limited thereto.

[0115] 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, a first composition) may be administered simultaneously, nearly simultaneously, or sequentially with a thrombolytic agent (specifically, tenecteplase) or a composition containing the same (specifically, a second composition), and then an intravascular thrombectomy may be performed, but is not necessarily limited thereto.

[0116] 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 a second composition) simultaneously with, immediately after, or within a certain time after administration (e.g., within 3 hours) of 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 a first composition). However, the procedure is not necessarily limited thereto.

[0117] 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 a 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 a first composition) simultaneously, nearly simultaneously, or sequentially, but is not necessarily limited thereto. In one embodiment of the present invention, endovascular 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 a second composition) simultaneously with the administration of a thrombolytic agent (specifically tenecteplase) or a composition containing the same (specifically a second composition), immediately after administration, or within a certain time after administration. While it may be performed, it is not necessarily limited to this. Mechanical vascular ablation (endovascular thrombectomy (EVT)) is a treatment method that directly removes blocked blood vessels through mechanical procedures. It has the advantages of a long treatment window (8 hours after ischemia) and a low risk of side effects, but 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.

[0118] 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.

[0119] That is, the composition of the present invention can show significant efficacy in both chemical therapy and mechanical therapy (bridging therapy) for the treatment of ischemic stroke.

[0120] 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 of thromboembolic disease or side effects caused by the administration of a thrombolytic agent.

[0121] In the present invention, "treatment" refers to any act in which the symptoms of a thromboembolic disease of a subject are improved or beneficially altered by the administration of a composition according to the present invention.

[0122] In the present invention, "administration" means introducing a specific substance to a subject in an appropriate manner. In the present invention, "alleviation" and "improvement" refer to any act in which symptoms of sequelae caused by thromboembolic disease or symptoms of side effects caused by the administration of a thrombolytic agent are improved or beneficially altered by the administration of a composition according to the present invention.

[0123] In the present invention, "object body" refers to all animals, including humans, rats, mice, and livestock, that have developed or may develop a disease, and specifically may be mammals including humans, but is not necessarily limited thereto.

[0124] In the present invention, "composition" may refer to a pharmaceutical composition.

[0125] 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.

[0126] 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.

[0127] 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.

[0128] 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.

[0129] Specifically, the present invention provides a method for preventing or treating thromboembolic disease comprising administering to a subject in need 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, and a thrombolytic agent.

[0130] 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.

[0131] 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.

[0132] In embodiments of the present invention, the thrombolytic agent may be tenecteplase. 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).

[0133] In embodiments of the present invention, the compound represented by Formula 1 in the composition of the present invention, its pharmaceutically acceptable salt, its hydrate or solvate, or a mixture thereof and tenecteplase may each be administered concurrently, nearly concurrently (immediately after administration), or sequentially (within a certain time after administration).

[0134] 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).

[0135] 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, a first composition) and a thrombolytic agent (specifically, tenecteplase) or a composition containing the same (specifically, a second composition) may be administered in combination sequentially. In embodiments of the present invention, after administration of 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, a first composition), the thrombolytic agent (specifically, tenecteplase) or a composition containing the same (specifically, a second composition) may be administered in combination sequentially.

[0136] 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, its pharmaceutically acceptable salt, its hydrate or solvate, or a mixture thereof or a composition containing the same (specifically the first composition).

[0137] In embodiments of the present invention, after administering the thrombolytic agent (specifically tenecteplase) 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.

[0138] 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.

[0139] 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 prevention and treatment of 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 modulators.

[0140] In 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. 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.

[0141] In one embodiment of the present invention, after performing endovascular thrombectomy, a thrombolytic agent (specifically tenecteplase) or a composition containing the same (specifically a 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 a first composition) may be administered simultaneously, nearly simultaneously, or sequentially, but are not necessarily limited thereto.

[0142] 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, a first composition) may be administered simultaneously, nearly simultaneously, or sequentially with a thrombolytic agent (specifically, tenecteplase) or a composition containing the same (specifically, a second composition), and then an intravascular thrombectomy may be performed, but is not necessarily limited thereto.

[0143] 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 a second composition) simultaneously with, immediately after, or within a certain time after administration (e.g., within 3 hours) of 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 a first composition). However, the procedure is not necessarily limited thereto.

[0144] 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 a 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 a first composition) simultaneously, nearly simultaneously, or sequentially, but is not necessarily limited thereto. 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 a second composition) (specifically within 30 minutes) and then sequentially 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 a first composition), but is not necessarily It is not limited to this.

[0145] The present invention also provides a use of the composition of the present invention for the prevention or treatment of thromboembolic diseases.

[0146] 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.

[0147] 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. The present invention also provides a use of a composition of the present invention for preventing, alleviating, improving, or treating side effects caused by the administration of a thrombolytic agent.

[0148] 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.

[0149] 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.

[0150] (1) The present invention provides a composition comprising a compound represented by the following formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, intended for co-administration with tenecteplase:

[0151] [Chemical Formula 1]

[0152]

[0153] H(2) The present invention provides a composition comprising a compound represented by the following formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof and tenecteplase:

[0154] [Chemical Formula 1]

[0155]

[0156] (3) In (1) or (2), the compound represented by Formula 1, the pharmaceutically acceptable salt thereof, the hydrate or solvate thereof, or a mixture thereof and tenecteplase may be administered together.

[0157] (4) In any one of (1) to (3), the composition may be used for the prevention or treatment of thromboembolic disease.

[0158] (5) In any one of (1) to (4), the composition may be for the prevention or treatment of thromboembolic diseases, including at least one selected from the group consisting of ischemic myocardial infarction, pulmonary embolism and acute ischemic stroke.

[0159] (6) In any one of (1) to (5), the composition may be used for the prevention, alleviation, improvement, or treatment of side effects caused by the administration of a thrombolytic agent.

[0160] (7) In any one of (1) to (6), the compound represented by Formula 1, the pharmaceutically acceptable salt thereof, the hydrate or solvate thereof, or a mixture thereof and tenecteplase may be administered together, either simultaneously or sequentially.

[0161] (8) In any one of (1) to (7), the composition may comprise 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.

[0162] (9) In any one of (1) to (8), 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 may be administered together, either simultaneously or sequentially.

[0163] (10) In any one of (1) to (9), 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 0.05 to 0.2 w / v%.

[0164] (11) In any one of (1) to (10), 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.

[0165] (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 may be administered in an amount of 30 to 80 mg.

[0166] (13) In any one of (1) to (12), the tenecteplase may be administered in an amount of 10 to 50 mg.

[0167] (14) In any one of (1) to (13), the tenecteplase may be administered at a dose of 0.25 mg / kg.

[0168] (15) In any one of (1) to (14), the composition may reduce the volume of the cerebral infarction.

[0169] (16) In any one of (1) to (15), the composition may be one that alleviates side effects caused by the administration of a thrombolytic agent.

[0170] (17) In any one of (1) to (16), 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.

[0171] (18) In any one of (1) to (17), the composition may reduce the risk of hemorrhagic activity caused by the administration of a thrombolytic agent.

[0172] (19) In any one of (1) to (18), the composition may be administered after mechanical thrombectomy.

[0173] (20) In any one of (1) to (19), the composition may be administered once, twice, three times or more times per day. (21) In any one of (1) to (20), the composition may be administered for one day, two days, three days or more.

[0174] (22) In any one of (1) to (21), the composition may comprise one or more selected from the group consisting of an isotonic agent, a pH adjuster, and an aqueous solvent.

[0175] (23) In any one of (1) to (22), the composition may include sodium chloride, sodium dihydrogen phosphate, sodium hydrogen phosphate, and an aqueous solvent.

[0176] (24) The present invention provides a method for preventing or treating thromboembolic disease, comprising administering a composition according to any one of (1) to (23) to a subject who requires it.

[0177] (25) The present invention provides a method for preventing, alleviating, improving, or treating side effects caused by the administration of a thrombolytic agent, comprising administering a composition according to any one of (1) to (23) to a subject who requires it.

[0178] (26) (24) or (25) in the above method, the compound represented by Formula 1, the pharmaceutically acceptable salt thereof, the hydrate or solvate thereof, or a mixture thereof and tenecteplase may each be administered together, either simultaneously or sequentially.

[0179] (27) The present invention provides a use of a composition according to any one of (1) to (23) for the prevention or treatment of thromboembolic disease.

[0180] (28) The present invention provides a use of a composition according to any one of (1) to (23) for the manufacture of a drug for the prevention or treatment of thromboembolic disease.

[0181] (29) The present invention provides a use of a composition according to any one of (1) to (23) for the prevention, alleviation, improvement, or treatment of side effects caused by the administration of a thrombolytic agent.

[0182] (30) The present invention provides a use of a composition according to any one of (1) to (23) for the manufacture of a drug for the prevention, alleviation, improvement, or treatment of side effects caused by the administration of a thrombolytic agent. The details described above regarding the compositions and methods of the present invention may be applied substantially the same to each composition, each method, and use of the present invention, unless they are inconsistent with one another.

[0183] 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.

[0184]

Effects of the Invention

[0185] 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.

[0186]

Brief Description of the Drawing

[0187] Figure la 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.

[0188] Figure lb shows the lethality and hemoglobin levels for each group in a rat embolic stroke model.

[0189] 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.

[0190] Figure 2a is a diagram showing the thrombolytic pattern according to tenecteplase concentration. Figure 2b is a diagram showing the spectrophotometric values ​​quantified according to tenecteplase concentration.

[0191] 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.

[0192]

Form for carrying out the invention

[0193] 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.

[0194] Experimental Example 1: Evaluation of the combined efficacy of Compound 1 and TNK (tenecteplase) in a rat embolic stroke model

[0195] Induction of an embolic stroke model - Induction of an embolic middle cerebral artery occlusion (MCAO) model

[0196] 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 produced clot was washed 2 to 3 times with physiological saline and then gently injected into the internal carotid artery (ICA) via the external carotid artery (ECA) of the rat using a 100-ill 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).

[0197] Drug administration

[0198] In a rat model of embolic middle cerebral artery ischemic stroke, Compound 1 (hydrochloride salt of the compound represented by Chemical Formula 1; the hydrochloride salt of the compound represented by Chemical Formula 1 was prepared and used according to the method described in Republic of Korea 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. la).

[0199] Measurement of cerebral infarction and edema volume

[0200] 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 in the damaged brain hemisphere using the image analysis program (TOMORO ScopeEye 3.5), and the volume (%) of edema was calculated using the following formula:

[0201] Volume of edema (%) = [ (VI - VO / VC] X 100

[0202] Here, VI represents the volume of the damaged hemisphere (the hemisphere where the cerebral infarction occurred due to the injection of the thrombus), and VC represents the volume of the undamaged hemisphere (the hemisphere opposite to the hemisphere where the cerebral infarction occurred).

[0203] Total corrected infarct volume was quantified by integrating 6 slices after correction for cerebral edema. Corrected infarct volume (IVC, mm²) 3 ) calculated as follows:

[0204] Corrected Infarct Volume (IVC) = IVd x (VC / VI)

[0205] Here, IVd represents the directly measured infarct volume of the damaged hemisphere. The percentage of infarct volume relative to total brain volume was calculated using the following formula: Infarct Volume (%) = IVC / VW X 100

[0206] Here, W represents the total brain volume.

[0207] Quantitative determination of intracerebral hemorrhage

[0208] After obtaining cerebral hemisphere tissues from rats that had undergone complete cardiac perfusion to remove intravascular blood, 0, 2, 4, 8, 16, and 32 volcanic

[0209] Evaluation of behavioral indicators

[0210] Behavioral indicators were scored by evaluating the behavioral characteristics of diseased animals according to the following table (Score, Animal behavioral characteristics)

[0211] 0, no apparent defects;

[0212] 1, unable to fully extend the left front leg;

[0213] 2, Decrease in gripping strength of the left foreleg when the tail is pulled;

[0214] 3, voluntary movement in all directions; turn left only when tail is pulled; 4, voluntary left turn or walking;

[0215] 5. Walk only when stimulated;

[0216] 6, Unresponsive to stimuli and reduced level of consciousness;

[0217] 7, death

[0218]

[0219] result

[0220] Referring to Fig. lb, 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 cerebral 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 tenecteplase alone group (Fig. lb). (In the mortality graph of Fig. lb, (15), (16), and (19) represent the number of animals used in the study for each group.)

[0221] Brain tissues damaged by ischemia may experience cell damage due to the re-perfusion of blood flow (reperfusion injury), and in particular, side effects such as cerebral hemorrhage resulting from damage to vascular endothelial tissue caused by tenecteplase (TNK) may occur.

[0222] 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 tenecteplase-alone administration group, 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.

[0223] 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. Additionally, the group administered tenecteplase + compound 1 showed 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, an improved tendency for inhibition of cerebral infarction was confirmed with the combined administration of tenecteplase + compound 1 compared to the administration of tenecteplase alone (Fig. 1C).

[0224] Therefore, 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.

[0225] 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.

[0226] Experimental Example 2: Clot lysis assay

[0227] 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 examined using an artificially produced blood clot.

[0228] Arterial blood was collected from the femoral artery of a thrombus-producing rat (SD rat), and 300 µl of the collected blood was added with an aPTT (activated partial thromboplastin time) of approximately 200 yL and 200 yL of calcium chloride (CaCl2) in sequence, followed by incubation at 37 °C for 10 minutes to obtain a stable fibrin-rich clot.

[0229] Dissolution and evaluation of thrombosis

[0230] Preliminary test: Arterial blood was collected from the femoral artery of a rat (SD rat) in a 1.5 mL tube without anticoagulant, and left to naturally coagulate at room temperature (20-25 °C) for 30 minutes to 2 hours. Tenecteplase diluted in normal saline was then applied to the formed pure blood clots at concentrations of 0, 50, 500, 1000, and 2000 ng / ml, each in 200 yL, and incubated at 37 °C for 20 minutes. Based on the thrombolytic patterns of tenecteplase at different concentrations measured by optical density, the appropriate concentration of tenecteplase to be used in this test was determined. Main test: After mixing tenecteplase at a concentration set through a 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.

[0231] Specifically, each mixture of 500 ng / mL tenecteplase and Compound 1 at 0, 5, 10, 15, and 20 yM was placed into a tube containing fibrin thrombus, and after incubation at 37° for 20 minutes, the thrombolytic pattern of each group was evaluated using the supernatant. The 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.

[0232] result

[0233] 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).

[0234] Therefore, it was confirmed that the thrombolytic effect of tenecteplase can be fully exerted without interference between the drugs by co-administering Compound 1 and tenecteplase according to the present invention. Experimental Example 3: Evaluation of the efficacy of Compound 1 in chemical and mechanical thrombolytic removal procedures

[0235] 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 aortic 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.

[0236] 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

【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 for co-administration with tenecteplase: [Chemical Formula 1]

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 tenecteplase: [Chemical Formula 1] H

3. 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 administered in combination.

4. The composition of Claim 1 or 2, wherein the composition is for the prevention or treatment of thromboembolic diseases. 【claim Paragraph 5] A composition for the prevention or treatment of thromboembolic diseases, wherein the composition comprises at least one selected from the group consisting of ischemic myocardial infarction, pulmonary embolism, and acute ischemic stroke. 【claim Paragraph 6] A composition according to claim 1 or 2, wherein the composition is for the prevention, alleviation, improvement, or treatment of side effects caused by the administration of a thrombolytic agent. 【claim Paragraph 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 in combination, either simultaneously or sequentially. 【claim Paragraph 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 this 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 together, either simultaneously or sequentially.

10. 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 0.05 to 0.2 w / v%.

11. A composition according to claim 1 or 2, wherein the content of the compound represented by Formula 1, its pharmaceutically acceptable salt, its hydrate or solvate, or a mixture thereof is 0.08% w / v.

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.

13. A composition according to claim 1 or 2, wherein the tenecteplase is administered in an amount of 10 to 50 mg.

14. A composition according to claim 1 or 2, wherein the tenecteplase is administered at a dose of 0.25 mg / kg.

15. A composition according to claim 1 or 2, wherein the composition reduces the volume of a cerebral infarction.

16. The composition of Claim 1 or 2, wherein the composition alleviates side effects caused by the administration of a thrombolytic agent.

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.

18. A composition according to claim 1 or 2, wherein the composition reduces the hemorrhagic risk caused by the administration of a thrombolytic agent. 【Claim 1 is A composition according to claim 1 or 2, wherein the composition is administered after mechanical thrombectomy.

20. A composition according to claim 1 or 2, wherein the composition is administered once, twice, three times, or more times per day.

21. A composition according to claim 1 or 2, wherein the composition is administered for 1 day, 2 days, 3 days or more.

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] Paragraph 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.

24. A method for the prevention or treatment of thromboembolic disease comprising administering a composition according to any one of claims 1 to 23 to a subject requiring the same.

25. A method for preventing, alleviating, improving, or treating side effects caused by the administration of a thrombolytic agent, comprising administering a composition according to any one of claims 1 to 23 to a subject requiring the same.

26. A method according to claim 24 or 25, 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 in combination, either simultaneously or sequentially.

27. Use of a composition according to any one of claims 1 to 23 for the prevention or treatment of thromboembolic diseases.

28. Use of a composition according to any one of claims 1 to 23 for the manufacture of a drug for the prevention or treatment of thromboembolic diseases. [Claim 2 Use of a composition according to any one of Claims 1 to 23 for the prevention, alleviation, improvement, or treatment of side effects caused by the administration of a thrombolytic agent.]

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