Composition comprising quinazoline-2,4-dione derivative

Abstract

The present invention relates to: a composition comprising a quinazoline-2,4-dione derivative, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and having a pH of at least 5 and less than 8; and a method for preparing same. The composition according to the present invention can maintain a transparent liquid state without pH changes and precipitation, even during long-term storage and regardless of a storage container, and thus can be effectively used as an injectable composition or an infusion preparation.

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 comprising a quinazolin-2,4-dione derivative, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and a method of preparing the same, specifically to an injectable composition and an intravenous formulation comprising a quinazolin-2,4-dione derivative, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and a method of preparing the same.

[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 disease is a very serious disease with a high incidence rate, and various treatments have been developed. However, these drugs have very low stability under specific pH environments, making it difficult to dissolve them as injectable formulations or fluid preparations and store them for a long period.

[0009] Accordingly, there was a need for research on injectable compositions or fluid preparations that are suitable for in vivo administration and stably maintain active ingredients without changes in pH or properties even under long-term storage, refrigeration, acceleration, or harsh conditions.

Description of the Invention

[0010]

Technical Challenges

[0011] The present invention provides a composition having a pH of 5 or higher and a pH of less than 8, comprising a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof. The present invention provides a method for preparing a composition having a pH of 5 or higher and a pH of less than 8, comprising a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

[0012]

Technical Solution

[0013] 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.

[0014] The composition of the present invention comprises a quinazolin-2,4-dione derivative, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and the pH is pH 5 or higher and pH less than 8.

[0015] In the present invention, the quinazolin-2,4-dione derivative may be otaplimastat.

[0016] 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.

[0017] [Chemical Formula 1]

[0018]

[0019] H

[0020] 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 has a pH of 5 or higher and less than 8. The "pharmaceutically 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.

[0021] In embodiments of the present invention, the composition of the present invention may be a salt of a compound represented by Formula 1. For example, it may be a hydrochloric acid salt of a compound represented by Formula 1.

[0022] 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.

[0023] 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.

[0024] The composition of the present invention may have a pH of 5 or higher and less than 8. Specifically, the composition of the present invention may have a pH of 5 or higher and less than 8, 5.1 or higher and less than 8, 5.2 or higher and less than 8, 5.3 or higher and less than 8, 5.4 or higher and less than 8, 5.5 or higher and less than 8, 5.6 or higher and less than 8, 5.7 or higher and less than 8, 5.8 or higher and less than 8, 5.9 or higher and less than 8, or 6 or higher and less than 8. More specifically, in embodiments of the present invention, the composition of the present invention may have a pH of 6 or higher and less than 8.

[0025] In embodiments of the present invention, the composition of the present invention may have a change in pH of 1.0 (1.0) or less after storage at 1 to 30 °C for 2 to 24 months based on the pH immediately after preparation.

[0026] In the embodiments of the present invention, the composition of the present invention may have a change in pH of 1.0 (1.0) or less after storage at 1 to 30 °C for 2 months based on the pH immediately after preparation.

[0027] In embodiments of the present invention, the composition of the present invention may have a change in pH of 1.0 (± 1.0) or less after storage at 1 to 30 °C for 18 months based on the pH immediately after preparation. In embodiments of the present invention, the composition of the present invention may have a change in pH of 1.0 (± 1.0) or less after storage at 1 to 30 °C for 24 months based on the pH immediately after preparation. The "change in pH" refers to a value calculated by the following mathematical formula I:

[0028] [Mathematical Formula I]

[0029] Change in pH = | pH (immediately after preparation) - pH (after n months of storage) |

[0030] *n means an integer greater than or equal to 2.

[0031] The composition of the present invention can exhibit excellent stability and maintain its properties within a pH range of 5 to 8, but if the pH is less than 5, the light stability of the compound represented by Formula 1, its pharmaceutically acceptable salt, its hydrate or solvate, or a mixture thereof may decrease, and the decomposition of the compound and the generation of related substances may increase; and if the pH is 8 or higher, problems such as the formation of precipitates and changes in properties may occur. In addition, the composition of the present invention can maintain a stable pH without significant fluctuations in pH even during long-term storage.

[0032] In the present invention, "stability of the composition" refers to physical and chemical stability, for example, stability of appearance, storage stability, pH stability, suitability of the container, etc.

[0033] The composition of the present invention can maintain its properties, pH, etc., even during long-term storage, and the amount of flexible substances generated can be kept low.

[0034] The composition of the present invention may be suitable for all practical amounts, appearance, pH, content of active ingredients, osmotic pressure, impurities (individual unknown impurities, total impurities, etc.), insoluble foreign substances, insoluble fine particles, etc. after storage for a certain period (e.g., 2 months or more) under specific conditions (e.g., cold stability (4-5°C), accelerated stability (40°C / 75% RH), severe stability (50°C / 75% RH), and long-term stability (25°C / 60% RH)).

[0035] In embodiments of the present invention, the composition of the present invention may further include one or more selected from the group consisting of an isotonic agent, a pH adjuster, and a solvent.

[0036] 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.

[0037] In the present invention, "pH adjusting agent" may include a buffer. Specifically, the term "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., which perform the function of maintaining the pH of the composition constant by resisting the inflow of external acids, bases, etc., or environmental changes.

[0038] In embodiments of the present invention, a pH adjusting agent may be used without limitation if 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.

[0039] In embodiments of the present invention, the pH adjusting agent may be one or more selected from the group consisting of phosphoric acid, phosphate salt, hydrate of phosphate salt, acetic acid, acetate, citric acid, hydrate of citric acid, citrate salt, hydrate of citrate salt, succinic acid, lactic acid, histidine, histidine salt, tris(hydroxymethyl)aminomethane (Tris), salt 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, hydrate of sodium carbonate, diethanolamine, meglumine, tromethamine, edetic acid, and pentetic acid, but is not limited thereto.

[0040] In embodiments of the present invention, the pH adjusting agent may be one or more selected from the group consisting of phosphoric acid, phosphate salt, hydrate of phosphate salt, acetic acid, acetate, citric acid, hydrate of citric acid, citrate salt, tris(hydroxymethyl)aminomethane (Tris), salt of tris(hydroxymethyl)aminomethane (Tris), 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES), hydrochloric acid, and sodium hydroxide.

[0041] Specifically, the pH adjuster 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 adjuster 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 (Tris-HC1); or 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES) and sodium hydroxide. 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.).

[0042] 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 citrate 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 (Tris-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 Chemical Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, sodium chloride, sodium dihydrogen phosphate, sodium hydrogen phosphate, and a solvent.

[0043] 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.

[0044] In the present invention, "solvent" refers to a medium for dissolving, dispersing, or suspending the main components and additives in the composition to form a certain phase.

[0045] In embodiments of the present invention, the solvent may be an aqueous solvent. Specifically, the solvent may be sterile physiological saline or water for injection. The water for injection is not particularly limited and may be used as long as it is water for injection generally used to dissolve, suspend, or emulsify the composition. 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.

[0046] In embodiments of the present invention, the composition 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), but is not limited thereto. In embodiments of the present invention, the composition of the present invention may contain 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. Preferably, 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%.

[0047] In embodiments of the present invention, the composition of the present invention may contain an isotonic agent in an amount of 0.5 to 1.5 w / v%. Preferably, 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%.

[0048] 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%. Preferably, 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%.

[0049] In embodiments of the present invention, 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; 0.5 to 1.5 w / v% of an isotonic agent; a pH adjuster and a solvent.

[0050] In embodiments of the present invention, 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; 0.5 to 1.5 w / v% of an isotonic agent; 0.01 to 0.4 w / v% of a pH adjuster; and a solvent. In embodiments of the present invention, 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; 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 a solvent. 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.

[0051] In embodiments of the present invention, an aqueous solvent may be included in an appropriate amount in the composition of the present invention to reach a desired liquid amount.

[0052] The composition of the present invention may be a colorless, transparent solution.

[0053] The composition of the present invention may be capable of being stored in a glass container or a plastic container. For example, the composition may be capable of being stored in an ampoule, vial, pre-filled syringe, or plastic container (e.g., an IV bag).

[0054] The composition of the present invention can be maintained stably regardless of the packaging container. That is, the composition of the present invention can exhibit excellent stability when stored in plastic containers as well as glass containers. Specifically, the composition can be maintained stably in plastic containers, and, for example, can maintain a colorless, transparent liquid state without sedimentation for a long period of time even when stored in plastic containers. In embodiments of the present invention, the composition can be stored in a colorless, transparent multilayer film plastic container. For example, the plastic container may be a plastic bag, and specifically, a colorless, transparent polypropylene container (bag).

[0055] The composition of the present invention can be maintained stably for a long period of time during storage, and, for example, the pH of the composition can be maintained at a pH of 5 or higher and less than a pH of 8.

[0056] In embodiments of the present invention, the composition can be maintained stably for a long period of time when stored at room temperature, and, for example, the pH of the composition can be maintained at a pH of 5 or higher and less than pH 8.

[0057] In embodiments of the present invention, the composition can be maintained stably for 24 months when stored at 1 to 30°C, and, for example, the pH of the composition can be maintained at a pH of 5 or higher and less than pH 8 for 2 to 24 months from the date of manufacture. Specifically, the composition can be maintained stably at a pH of 5 or higher and less than pH 8 for 2 to 24 months when stored at 1 to 30°C at 55 to 65% RH.

[0058] The composition of the present invention can maintain a stable pH and properties regardless of the packaging container, and can also maintain stability even when stored for a long period. Specifically, the composition of the present invention can maintain a pH of 5 or higher and less than 8 for a long period even when stored in a plastic container at room temperature.

[0059] The composition of the present invention can be maintained stably for a long period of time during storage, and, for example, can maintain a colorless, transparent liquid state without precipitation.

[0060] In embodiments of the present invention, the composition can be maintained stably for a long period of time when stored at room temperature, and, for example, can be maintained in a colorless, transparent liquid state without precipitation.

[0061] In embodiments of the present invention, the composition can be maintained stably for 24 months when stored at 1 to 30°C, and, for example, can be maintained in a colorless, transparent liquid state without precipitation for 2 to 24 months from the date of manufacture. Specifically, the composition can be maintained stably in a colorless, transparent liquid state without precipitation for 2 to 24 months when stored at 1 to 30°C at 55 to 65% RH.

[0062] The composition of the present invention can maintain a stable pH and properties regardless of the packaging container, and can also maintain stability even when stored for a long period. Specifically, the composition of the present invention can maintain a colorless, transparent liquid state without precipitation for a long period even when stored in a plastic container at room temperature for a long period.

[0063] A composition according to one embodiment 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; 0.82 w / v% of sodium chloride; 0.0587 w / v% of sodium dihydrogen phosphate; 0.09 w / v% of sodium hydrogen phosphate; and an appropriate amount of a solvent. Preferably, the sodium dihydrogen phosphate and the sodium hydrogen phosphate may be sodium dihydrogen phosphate dihydrate and sodium hydrogen phosphate anhydride, respectively, but are not limited thereto.

[0064] 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 may not include other additives other than an isotonic agent and a pH adjuster, but may additionally optionally include stabilizers, surfactants, preservatives, etc. commonly used in the art without limitation.

[0065] The method for manufacturing the above composition of the present invention is,

[0066] (a) a step of stirring and dissolving a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof in a solvent; and

[0067] (b) includes the step of adding an isotonic agent to the solution prepared in (a).

[0068] In embodiments of the present invention,

[0069] The above manufacturing method may further include the step of adding a pH adjusting agent (c) after step (a) and before step (b); simultaneously with step (b); or after step (b). Specifically, the above manufacturing method comprises:

[0070] (a) a step of dissolving a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof in a solvent;

[0071] (b) A step of adding an isotonic agent to the solution prepared in (a); and

[0072] (c) The method may include the step of adding a pH adjusting agent to the solution prepared in (b). In embodiments of the present invention, the manufacturing method comprises:

[0073] (d) A step of adding more solvent to the solution prepared in (c); and / or

[0074] (e) The method may further include a step of filtering the solution prepared in (c) or (d). In embodiments of the present invention, the manufacturing method is,

[0075] (f) a step of filling a packaging container with the composition prepared in (c), (d), or (e); and

[0076] (g) A sealing step may be further included.

[0077] In embodiments of the present invention, the manufacturing method is,

[0078] (h) It may further include a step of sterilizing the composition.

[0079] 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 included 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% with respect to the total composition content.

[0080] In embodiments of the present invention, the isotonic agent may be included in an amount of 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% based on the total composition content.

[0081] In embodiments of the present invention, the pH adjusting agent may be included in an appropriate amount relative to the total composition content to adjust the pH of the composition to pH 5 or higher and less than pH 8. The pH adjusting agent may be included 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% relative to the total composition content.

[0082] In embodiments of the present invention, the isotonic agent may be sodium chloride (NaCl).

[0083] In embodiments of the present invention, the pH adjusting agent may be one or more selected from the group consisting of phosphoric acid, phosphate salt, hydrate of phosphate salt, acetic acid, acetate, citric acid, hydrate of citric acid, citrate salt, hydrate of citrate salt, succinic acid, lactic acid, histidine, histidine salt, tris(hydroxymethyl)aminomethane (Tris), salt 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, hydrate of sodium carbonate, diethanolamine, meglumine, tromethamine, edetic acid, and pentetic acid, but is not limited thereto.

[0084] In embodiments of the present invention, the pH adjusting agent may be one or more selected from the group consisting of phosphoric acid, phosphate salt, hydrate of phosphate salt, acetic acid, acetate, citric acid, hydrate of citric acid, citrate salt, tris(hydroxymethyl)aminomethane (Tris), salt of tris(hydroxymethyl)aminomethane (Tris), 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES), hydrochloric acid, and sodium hydroxide.

[0085] 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 (Tris-HC1); or 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES) and sodium hydroxide.

[0086] In embodiments of the present invention, the solvent may be an aqueous solvent. Specifically, the solvent may be sterile physiological saline or water for injection.

[0087] In embodiments of the present invention, the composition prepared by the above manufacturing method may have a pH of 5 or higher and less than 8. Specifically, the pH may be 5 or higher and less than 8, 5.1 or higher and less than 8, 5.2 or higher and less than 8, 5.3 or higher and less than 8, 5.4 or higher and less than 8, 5.5 or higher and less than 8, 5.6 or higher and less than 8, 5.7 or higher and less than 8, 5.8 or higher and less than 8, 5.9 or higher and less than 8, or 6 or higher and less than 8. More specifically, the composition may have a pH of 6 or higher and less than 8.

[0088] The composition produced by the manufacturing method according to the present invention has a pH of 5 or higher and less than 8, and the pH and properties can be maintained stably regardless of the packaging container, and can be maintained stably even when stored for a long period of time.

[0089] The composition of the present invention may be for the prevention or treatment of thromboembolic diseases, for example, ischemic stroke (cerebral infarction).

[0090] The composition of the present invention may be for the prevention, alleviation, improvement, or treatment of side effects caused by the administration of a thrombolytic agent.

[0091] The present invention provides the use of the above composition for the prevention or treatment of thromboembolic diseases, e.g., ischemic stroke (cerebral infarction).

[0092] The present invention provides a use for the prevention, alleviation, improvement, or treatment of side effects caused by the administration of a thrombolytic agent of the above composition. The present invention provides a use of the above composition for the manufacture of a drug for the prevention or treatment of thromboembolic diseases, e.g., ischemic stroke (cerebral infarction).

[0093] The present invention provides a use of the above composition for the manufacture of a drug for the prevention, alleviation, improvement, or treatment of side effects caused by the administration of a thrombolytic agent.

[0094] The present invention provides a method for preventing or treating thromboembolic diseases, e.g., ischemic stroke (cerebral infarction), comprising administering the above composition to an individual in need thereof.

[0095] The present invention provides a method for preventing, alleviating, improving, or treating side effects caused by the administration of a thrombolytic agent, comprising administering the above composition to an individual in need thereof.

[0096] In embodiments of the present invention, the administration may be the administration of the composition in a therapeutically effective amount to an individual in need of it.

[0097] In the present invention, "thromboembolic disease" refers to a disease in which a blood clot detaches from its original location and moves through the bloodstream (as an embolus) to block blood vessels, causing tissue ischemia and organ damage.

[0098] In embodiments of the present invention, the thromboembolic disease is (acute) ischemic stroke (cerebral infarction), 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 It may be at least one selected from the group consisting of thromboembolism, pregnancy / puerperal thromboembolism, and drug-induced thromboembolism, but is not necessarily limited thereto.

[0099] 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. In the present invention, “prevention” means any act of suppressing a thromboembolic disease in an individual, e.g., ischemic stroke (cerebral infarction), or side effects caused by the administration of a thrombolytic agent, or delaying the onset of a thromboembolic disease, e.g., ischemic stroke (cerebral infarction), or the occurrence of side effects caused by the administration of a thrombolytic agent, by administering a composition according to the present invention.

[0100] In the present invention, “treatment” means any act in which the symptoms of a person’s thromboembolic disease, e.g., ischemic stroke (cerebral infarction), or 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.

[0101] In the present invention, “administration” means introducing a specific substance to an individual by an appropriate method.

[0102] 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 a composition according to the present invention.

[0103] In the present invention, “individual” means all animals, including humans, rats, mice, livestock, etc., that have developed or may develop a disease, and specifically may be mammals including humans, but is not limited thereto.

[0104] In the present invention, “therapeutic effective amount” means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment and that does not cause side effects, and this can be determined by a person skilled in the art based on factors including the patient’s gender, age, weight, health condition, type of disease, severity, drug activity, sensitivity to the drug, method of administration, time of administration, route of administration, elimination rate, duration of treatment, drugs used in combination or concurrently, and other factors well known in the medical field. It is desirable to apply a specific therapeutically effective dose for a specific patient differently depending on various factors including the specific composition, the type and degree of response to be achieved, whether a different agent is used in some cases, the patient's age, weight, general health condition, gender and diet, time of administration, route of administration and excretion rate of the composition, duration of treatment, drugs used together or simultaneously with the specific composition, and similar factors well known in the pharmaceutical field. The present invention includes the following items (1) to (31) regarding the composition, the method of manufacturing the same, the use of the same, and a treatment method including the administration of the same.

[0105] (1) The present invention provides a composition having a pH of 5 or higher and a pH of less than 8, comprising a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof:

[0106] [Chemical Formula 1]

[0107]

[0108] (2) In the above (1), the pH of the composition may be pH 6 or higher and pH 8 or lower.

[0109] (3) In the above (1) or (2), the composition may have a change in pH of 1.0 (1.0) or less after storage at 1 to 30 °C for 2 months based on the pH immediately after manufacturing.

[0110] (4) In any one of (1) to (3) above, the composition may further include one or more selected from the group consisting of an isotonic agent, a pH adjuster, and a solvent.

[0111] (5) In any one of (1) to (4) above, the compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof; an isotonic agent; a pH adjusting agent; and a solvent may be included.

[0112] (6) In any one of (1) to (5) above, the pH adjusting agent may be one or more selected from the group consisting of phosphoric acid, phosphate salt, phosphate salt hydrate, acetic acid, acetate, citric acid, citric acid hydrate, citrate salt, citrate salt 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.

[0113] (7) In any one of (1) to (6) above, the pH adjusting agent may be one or more selected from the group consisting of phosphoric acid, phosphate salt, phosphate salt hydrate, acetic acid, acetate, citric acid, citric acid hydrate, citric acid salt, tris(hydroxymethyl)aminomethane (Tris), tris(hydroxymethyl)aminomethane (Tris) salt, 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES), hydrochloric acid, and sodium hydroxide.

[0114] (8) In any one of (1) to (7) above, the solvent may be sterile physiological saline or water for injection.

[0115] (9) In any one of (1) to (8) above, the composition may be an injectable composition or a fluid preparation.

[0116] (10) In any one of (1) to (9) above, the composition may be a colorless, transparent liquid.

[0117] (11) In any one of (1) to (10) above, the compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof may be included in the composition in an amount of 0.05 to 0.2 w / v%.

[0118] (12) In any one of (1) to (11) above, the isotonic agent in the composition may be included in an amount of 0.5 to 1.5 w / v%.

[0119] (13) In any one of (1) to (12) above, the pH adjusting agent in the composition may be included in an amount of 0.01 to 0.4 w / v%.

[0120] (14) In any one of (1) to (13) above, the composition may have long-term storage stability in which the pH is maintained at pH 5 or higher and pH 8 or lower for a long period of time.

[0121] (15) In any one of (1) to (14) above, the composition may have long-term storage stability in which the pH is maintained at pH 5 or higher and pH 8 or lower for a long period when stored at room temperature. (16) In any one of (1) to (15) above, the composition may have long-term storage stability in which the pH is maintained at pH 5 or higher and pH 8 or lower for a long period when stored at 1 to 30 °C.

[0122] (17) In any one of (1) to (16) above, the composition may have stability such that the pH is maintained at pH 5 or higher and less than pH 8 when stored in a plastic container.

[0123] (18) In any one of (1) to (17) above, the composition may have long-term storage stability, maintaining a colorless, transparent liquid state without precipitation for a long period of time.

[0124] (19) In any one of (1) to (18) above, the composition may have long-term storage stability, maintaining a colorless, transparent liquid state without precipitation for a long period when stored at room temperature.

[0125] (20) In any one of (1) to (19) above, the composition may have long-term storage stability, maintaining a colorless, transparent liquid state without precipitation for a long period when stored at 1 to 30 °C.

[0126] (21) In any one of (1) to (20) above, the composition may have stability that maintains a colorless, transparent liquid state without precipitation when stored in a plastic container.

[0127] (22) The present invention comprises the steps of: (a) stirring and dissolving a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof in a solvent; and

[0128] (b) A method for preparing a composition having a pH of 5 or higher and a pH of less than 8, or a composition according to (1) to (22), comprising the step of adding an isotonic agent to the solution prepared in (a):

[0129] [Chemical Formula 1]

[0130]

[0131] H

[0132] (23) In the above (22), the manufacturing method is

[0133] (c) It may further include a step of adding a pH adjuster.

[0134] (24) A composition according to one of (1) to (21) above; or a composition prepared by the method according to (22) or (23) above may be for the prevention or treatment of thromboembolic diseases, e.g., ischemic stroke (cerebral infarction).

[0135] (25) A composition according to one of (1) to (21) above; or a composition prepared by the method according to (22) or (23) above may be for the prevention, alleviation, improvement, or treatment of side effects caused by the administration of a thrombolytic agent.

[0136] (26) The present invention provides a composition according to one of (1) to (21); or a composition prepared by the method according to (22) or (23) for the prevention or treatment of thromboembolic diseases, e.g., ischemic stroke (cerebral infarction).

[0137] (27) The present invention provides a use for preventing, alleviating, improving, or treating side effects caused by the administration of a thrombolytic agent of a composition according to one of (1) to (21); or a composition prepared by the method according to (22) or (23).

[0138] (28) The present invention provides a composition according to one of (1) to (21) for the prevention or treatment of thromboembolic diseases, e.g., ischemic stroke (cerebral infarction); or a composition prepared by the method according to (22) or (23).

[0139] (29) The present invention provides a composition according to one of (1) to (21) above for the prevention, alleviation, improvement, or treatment of side effects caused by the administration of a thrombolytic agent; or a composition prepared by the method according to (22) or (23) above.

[0140] (30) The present invention provides a method for preventing or treating thromboembolic disease, e.g., ischemic stroke (cerebral infarction), comprising administering a composition according to one of (1) to (21); or a composition prepared by the method according to (22) or (23) to an individual in need thereof.

[0141] (31) The present invention provides a method for preventing, alleviating, improving, or treating side effects caused by the administration of a thrombolytic agent, comprising administering the above composition to an individual who needs it.

[0142] 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 they do not contradict one another.

[0143] 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, the 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

[0144] The composition according to the present invention can maintain a transparent liquid state without pH change or precipitation even when stored for a long period, regardless of the storage container, and can be usefully utilized as an injectable composition or an intravenous preparation.

[0145]

Brief Description of the Drawing

[0146] Figure 1 shows the results of the property evaluation under severe stability conditions (50°C, 75% RH, 2 months) for Examples 1, 2, and 3 (pH 5, 6, and 7) and Comparative Examples 1 and 2 (pH 8 and 9). Figure 2 shows the results of the property evaluation at the 2-month mark under severe stability conditions (50°C, 75% RH) after manufacturing for Examples 9 to 13.

[0147]

Form for carrying out the invention

[0148] The present invention will be explained in more detail below through examples. These examples are intended to illustrate the present invention, and the scope of the present invention is not limited to these examples. Examples 1 to 3: Preparation of an injectable composition comprising a quinazolin-2,4-dione compound

[0149] An injection containing a quinazolin-2,4-dione compound according to the composition of Table 1 below was prepared. Specifically, the quinazolin-2,4-dione compound (hydrochloride of the compound of Formula 1, the hydrochloride of the compound represented by Formula 1 was prepared and used according to the method described in Korean Patent 10-1075435) was added to injection water, stirred to completely dissolve it, then sodium chloride was added and stirred. After confirming the dissolved state, hydrochloric acid and sodium hydroxide were added to adjust the pH to pH 5 (Example 1), pH 6 (Example 2), and pH 7 (Example 3), respectively, and then additional injection water was added to reach the target liquid volume (50 mL). Subsequently, filtration was carried out using a filter, filled into glass vials, and a high-pressure sterilization process was carried out to complete the preparation (40 mg of the hydrochloride of the compound of Formula 1 / total liquid volume 50 mL).

[0150] [Table 1]

[0151] Component content in total liquid volume Component Function

[0152] (% w / v) Hydrochloride of the compound of Formula 1 Main component 0.08%

[0153] Sodium Chloride

[0154] Isotonic agent 0.9%

[0155] Sodium Chloride (NaCl )

[0156] Sodium Hydroxide

[0157] pH adjustment appropriate amount

[0158] Sodium Hydroxide (NaOH)

[0159] Hydrochloric acid

[0160] pH adjustment appropriate amount Hydrochloric acid (HC1 )

[0161] Injection water Solvent appropriate amount

[0162] Total 100%

[0163] Filling and packaging container glass vial

[0164]

[0165] Experimental Example 1: Evaluation of Appearance

[0166] Generally, since injectable solutions filled in vials may undergo changes in appearance depending on pH, an in vitro test was conducted to evaluate the solution stability of an injectable containing a quinazolin-2,4-dione compound according to pH. As a result of the harsh 2-month test under harsh stability conditions (50°C, 75% RH), it was confirmed that the injectable containing the quinazolin-2,4-dione compound met the appearance criteria when the pH was between 5 and 8 (see Fig. 1). These test results can be confirmed through the results in Table 2 below.

[0167] [Table 2]

[0168] Classification pH Value Packaging Container USP Type Appearance Test Results

[0169] Example 1 pH 5 suitable

[0170] glass vial

[0171] Example 2 pH 6 suitable

[0172] (Glass Vial)

[0173] Example 3 pH 7 suitable

[0174]

[0175] Therefore, it was confirmed that the composition of the present invention meets the physical criteria when the pH is 5 or higher and less than 8.

[0176] In addition, to determine whether the product meets the appearance criteria when the pH exceeds this range, an injectable product containing a quinazolin-2,4-dione compound with a pH of 8 or higher was prepared using substantially the same process as in Examples 1 to 3, and an in vitro test was conducted. As a result of the test at the 2-month mark under severe stability conditions (50°C, 75% RH), it was confirmed that the quinazolin-2,4-dione compound injectable product did not meet the appearance criteria because a precipitate was formed when the pH was 8 or higher (see Figure 1 and Table 3).

[0177] [Table 3]

[0178] Classification pH Value Packaging Container USP Type Appearance Test Results Comparison Example 1 pH 8 Glass Vial Unsuitable (Precipitate Formation) Comparison Example 2 pH 9 (Glass Vial) Unsuitable (Precipitate Formation)

[0179]

[0180] Experimental Example 2: Accelerated Stability Test

[0181] Since there is a possibility of changes in pH and appearance of the injectable containing quinazolin-2,4-dione compounds, an accelerated stability test was conducted to verify these issues. As shown in the results of Table 4 below, the composition of Example 3 contained in the prepared vial filling container was found to have suitable appearance and pH (within the pH range of 5 to 8) as a result of the stability test under accelerated stability conditions (40 °C, 75% RH, 3 months, 6 months).

[0182] [Table 4]

[0183] Test Item Immediately after manufacture (Initial) A3M A6M

[0184] Appearance suitability suitability suitability

[0185] pH suitable suitable suitable

[0186]

[0187] *A (Accelerated stability test): Accelerated stability test (40 °C / 75% RH) *Appearance test criteria: The liquid is clear and there are no visible insoluble foreign substances.

[0188] Examples 4 to 8: Preparation of an injection composition containing a quinazoline-2,4-dione compound

[0189] An injection containing a quinazoline-2,4-dione compound was prepared according to the composition shown in Table 5 below. Specifically, the quinazoline-2,4-dione compound (hydrochloride of the compound of Formula 1) was added to the injection water, stirred until completely dissolved, and then sodium chloride was added and stirred. After confirming the dissolution state, sodium dihydrogen phosphate dihydrate and disodium hydrogen phosphate anhydrous were added as pH adjusters and buffers to adjust the pH, and injection water was further added to reach the target liquid volume (50 mL). Subsequently, filtration was performed using a filter to prepare an injection containing a quinazoline-2,4-dione compound (40 mg of the hydrochloride of the compound of Formula 1 / total liquid volume 50 mL). The prepared injection was filled into a glass vial or a plastic container (aqueous solution bag) by changing the material and type of material as shown in Table 6 below. After filling, a high-pressure sterilization process was carried out.

[0190] [Table 5] ​​​​​​​​​​​​​​​​​​​(Buffer)

[0198]

[0199] Sodium Phosphate Dihydrate

[0200] Monobasic

[0201] (NaH2P04-2H20)

[0202] Sodium hydrogen phosphate, anhydrous

[0203] Sodium Phosphate Dibasic pH Adjuster

[0204] Appropriate amount Anhydrous (buffer)

[0205] (Na2HP04)

[0206] Appropriate amount of solution for injection

[0207] Total 100%

[0208]

[0209] [Table 6]

[0210] Classification Material Type USP Type Material Material Country of Manufacture Internal Processing USP Type Soda-Lime (Soda- Example 3 Glass Vial Korea No III 1 ime)

[0211] Example 4 Borosilicate Korean Acid-treated Glass Vial USP Type I

[0212] Example 5 (Borosi 1 icate) also O! SiO2 coated polypropylene < 50

[0213] Example 6 Korean multilayer film (Polypropylene < 50)

[0214] Polypropylene < 50

[0215] Styrene-Ethylene / Buta

[0216] diene copolymer

[0217] plastic

[0218] Example 7 (Polypropylene < 50 Korea multilayer film container USP <661>

[0219] Styrene (sap bag)

[0220] ethyl ene / But ad i ene

[0221] Copolymer

[0222] Polymer packaging material

[0223] Example 8 (Polymeric multilayer film packaging material)

[0224]

[0225] Experimental Example 3: Evaluation of the Effect of Storage Container

[0226] As a result of conducting accelerated stability tests on the glass vial packaging containers used in Experimental Example 1 and Examples 1 to 3, it was confirmed through Table 2 that the packaging containers met the test standards. However, since the internal surface treatment material may affect product quality due to the characteristics of glass vials, additional tests were conducted to evaluate the impact based on the material and type of the packaging.

[0227] As a result of conducting stability tests (tests for pH and physical suitability) in accordance with the material expansion list, the results presented in Table 7 below were obtained. This stability test included a long-term stability test (25°C / 60% RH, 24 months) and an accelerated stability test (40°C / 75% RH, 6 months), and evaluated all items including practical weight, physical properties, pH, content, osmotic pressure, insoluble foreign matter, insoluble fine particles, impurities, reduction in practical weight, and moisture loss rate. In particular, the pH stability and physical properties examined in Example 3 were selected as the main subjects for review, and the results were compared and reviewed.

[0228] [Table 7]

[0229] pH

[0230] Classification Composition Classification Material Type Immediately After Manufacturing

[0231] A6M L24M (Initial)

[0232] Example 3 pH Adjuster Glass Vial pH 7.10 pH 6.90 pH 7.85 pH Adjuster

[0233] Example 4 pH 6.91 pH 6.85 pH 6.85 (buffer)

[0234] glass vial

[0235] pH adjuster

[0236] Example 5 pH 6.93 pH 6.85 pH 6.85 (buffer)

[0237] pH adjuster

[0238] Example 6 pH 6.91 pH 6.85 pH 6.86 (buffer)

[0239] pH adjuster plastic container

[0240] Example 7 pH 6.84 pH 6.89 pH 6.88 (Buffer) (Infusion bag)

[0241] pH adjuster

[0242] Example 8 pH 6.84 pH 6.88 pH 6.88 (buffer)

[0243]

[0244] *A (Accelerated stability test): Accelerated stability test (40°C / 75% RH) *L (Long-term stability test): Long-term stability test (25°C / 60% RH) As a result, all of Examples 4 to 8 showed suitable results within the pH range of 5 to 8, consistent with the test results of Example 3. In addition, it was confirmed that pH variability was significantly reduced in these examples compared to Example 3.

[0245] In other words, it can be seen that significant results in stability can be obtained when the pH range of the composition of the present invention is limited to pH 5 or higher and pH less than 8, and also that when a buffer is selected and used among pH adjusting agents, it is more effective for pH stabilization and can stabilize the pH without significant fluctuations.

[0246] Experimental Example 4: Stability Evaluation

[0247] Among Examples 6, 7, and 8 using plastic containers (fluid bags), the stability of Example 7, which showed the best stability in all test results, was confirmed, and the final packaging container of Example 7 is shown in Table 8, and the data for accelerated stability (40°C / 75% RH, 3 months, 6 months), severe stability (50°C / 75% RH, 2 months), and long-term stability (25°C / 60% RH, 18 months, 24 months) are shown in Table 9 below.

[0248] [Table 8]

[0249] Primary packaging container: Transparent plastic bag (Non-PVC Bag (Polypropylene)), rubber stopper Secondary packaging container: Aluminum bag (Aluminum PE Foi 1)

[0250]

[0251] [Table 9]

[0252] Example 7 Stability Test Results

[0253] Immediately after manufacturing

[0254] Test Items A3M A6M S2M L18M L24M (Initial)

[0255] Practical Amount Suitable Suitable Suitable Suitable Suitable Appearance Suitable Suitable Suitable Suitable Suitable pH 6.84 6.89 6.89 6.88 6.88 6.88 Content 101.7 100.7 103.3 98.4 101.6 101.1

[0256]

[0257] Osmotic pressure suitable suitable suitable suitable suitable suitable individual unknown

[0258] 0.02% 0.06% 0.11% 0.07% 0.07% 0.09% Flexible material Flexible material

[0259] Total flexible matter 0.21% 0.42% 0.77% 0.71% 0.31% 0.39% Insoluble foreign matter Water Suitable Suitable Suitable Suitable Suitable Suitable Insoluble particulates

[0260] Fit Fit Fit Fit Fit Fit Fit (10 @ or more / 25 / mi or more)

[0261]

[0262] *A (Accelerated stability test): Accelerated stability test (40°C / 75% RH) *S (Stress stability test): Stress stability test (50°C / 75% RH)

[0263] *L( long-term stability test) : Long-term stability test (25°C / 60% RH)

[0264] *Appearance Test Criteria: The liquid is clear and free of clearly visible insoluble foreign matter. *Insoluble Particulate Test Criteria: 10 oz or larger: 6,000 particles / container or less; 25 oz or larger: 600 particles / container or less

[0265] Practical Dose Test Standards for Injections (USP) <697> ) : Must be greater than the indicated volume (50 mL or more)

[0266] *Osmotic pressure test standards (USP) <785> ) : 230 to 370 mOsm / kg

[0267] Insoluble Foreign Water Testing Standards (USP) <790> ) : The liquid must be clear and free of clearly visible insoluble foreign matter.

[0268] As a result, Example 7 maintained an overall stable pH in all accelerated stability, harsh stability, and long-term stability tests, and it was confirmed that the physical properties also met the criteria.

[0269] Examples 9 to 13: Preparation of injectable compositions containing quinazolin-2,4-dione compounds according to the type of pH adjusting agent (buffer)

[0270] Examples 9 to 13 prepared injectable compositions containing a quinazolin-2,4-dione compound with the compositions of Tables 10 and 11 below by changing only the pH adjusting agent (buffer) in the compositions listed in Table 5 above. Specifically, the quinazolin-2,4-dione compound (hydrochloric acid salt of the compound represented by Chemical Formula 1) was added to water for injection and stirred to completely dissolve it, after which sodium chloride was added as an isotonic agent and stirred further. Subsequently, an appropriate amount of the pH adjusting agent (buffer) listed in Tables 10 and 11 below was added to each to adjust the pH of the composition to pH 5 or higher and pH less than 8, more specifically to pH 7. After adding water for injection to reach the target volume (50 mL), the solution was filtered using a filtration filter to prepare the quinazoline-2,4-dione compound injection (40 mg hydrochloride salt of the compound of Formula 1 / total volume 50 mL). The prepared solution was filled into a glass vial. After filling, the process of autoclaving was performed.

[0271] No differences in pH and characteristics were observed depending on whether the above sterilization process was applied. [Table 1

[0272] Examples Example Examples Example Examples Example Functional Components

[0273] 9 10 11 12 13 Main component Hydrochloric acid salt of compound of Chemical Formula 1 0.08% 0.08% 0.08% 0.08% 0.08% Appearing topic Sodium chloride 0.82% 0.82% 0.82% 0.82% 0.82% Citric acid appropriate amount - - - - Sodium citrate

[0274] Appropriate amount - - - - (Tr isodium Citrate)

[0275] Sodium dihydrogen phosphate hydrate - appropriate amount - - - (NaH2P04-2H2O)

[0276] Sodium hydrogen phosphate, anhydrous

[0277] pH adjuster - - - 2 4 Optimal amount - (Na HPO )

[0278] (Slowdown agent) Acetic acid - - appropriate amount - - Sodium acetate - - appropriate amount - - (Sodium Acetate)

[0279] Tris- Hydrochloric Acid Buffer - - - Appropriate Amount - HEPES - - - - Appropriate Amount Sodium Hydroxide - - - - Appropriate Amount Solvent Water for Injection Appropriate Amount Appropriate Amount Appropriate Amount Total 100% 100% 100% 100% 100%

[0280]

[0281] (Ingredient content relative to total liquid volume: % w / v)

[0282] [Table 11]

[0283] pH adjuster

[0284] Example composition

[0285] (Buffer)

[0286] Citric acid (Citric acid) 10 Sodium citrate Example 9 Citric acid buffer

[0287] (Tr isodium citrate)

[0288] Sodium dihydrogen phosphate (NaH2P04) + disodium hydrogen phosphate Example 10 Phosphate buffer

[0289] (Na2HPO4)

[0290] Acetic acid 10 Sodium acetate (Sodium Example 11 Acetic acid buffer)

[0291] acetate)

[0292] Tris(hydroxymethyl)aminomethane Example 12 Hydrochloride salt of Tris-hydrochloride buffer (Tris(hydroxymethyl)aminomethane) (Tris-HCl)

[0293] Example 13 HEPES buffer HEPES + sodium hydroxide (NaOH)

[0294]

[0295] Experimental Example 5: Evaluation of pH and physical stability according to the type of pH adjusting agent (buffer). For the quinazolin-2,4-dione compound injectable compositions prepared in Examples 9 to 13, a stability test was performed to evaluate pH stability and physical stability depending on the type of pH adjusting agent (buffer).

[0296] Each composition was evaluated for pH and appearance (whether it was colorless and transparent and whether there was a visible presence of insoluble foreign matter) immediately after preparation (Initial) and at 2 months after preparation (see Figure 2 and Table 12).

[0297] Stability tests were performed under long-term conditions (25 °C / 60% RH, 2 months), refrigerated conditions (5 °C, 2 months), and harsh conditions (50 °C / 75% RH, 2 months) as shown in Table 12 below, and the test results according to each storage condition showed the same trend. In addition, no changes in pH or differences in appearance were observed depending on whether the sterilization process was applied.

[0298] [Table 12]

[0299] Immediately after manufacturing

[0300] Classification pH Adjusters (Buffers) L2M R2M S2M

[0301] (Initial)

[0302]

[0303] Example 9 Citric Acid Buffer Approx. 5.04 Approx. 5.13 Approx. 5.12 Approx. 5.36 Example 10 Phosphate Buffer Approx. 6.90 Approx. 6.91 Approx. 6.90 Approx. 6.88 Example 11 Acetic Acid Buffer Approx. 5.39 Approx. 5.39 Approx. 5.41 Approx. 5.36 Example 12 Tris-Hydrochloride Buffer Approx. 5.31 Approx. 5.71 Approx. 5.71 Approx. 5.64 Example 13 HEPES Buffer Approx. 6.89 Approx. 7.09 Approx. 7.09 Approx. 6.85

[0304]

[0305] *L (long-term stability test): Long-term stability test (25°C / 60% RH) *R (Refrigerated stability test): Refrigerated stability test (5°C)

[0306] *S(Stress stability test): Harsh stability test (50°C / 75% RH)

[0307] As a result, the compositions to which the pH adjusting agent (buffer) of Examples 9 to 13 was applied maintained an overall stable pH from immediately after preparation until 2 months later, and exhibited the best pH stability, particularly in the range of pH 5 or higher and less than 8. No color change or formation of insoluble foreign matter was observed regardless of storage conditions.

[0308] Therefore, it was confirmed that the injectable composition of the present invention exhibits excellent physical stability when the pH is maintained at 5 or higher and less than 8.

[0309] 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 11 A composition comprising a compound represented by Chemical Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, having a pH of 5 or higher and less than 8: [Chemical Formula 1]

2. The composition of claim 1, wherein the pH of the composition is pH 6 or higher and less than pH 8.

3. A composition according to claim 1, wherein the change in pH after storage at 1 to 30 °C for 2 months, based on the pH immediately after manufacturing, is within 1.0 (1.0).

4. A composition according to claim 1, further comprising one or more selected from the group consisting of an isotonic agent, a pH adjuster, and a solvent.

5. In claim 4, the pH adjusting agent is a composition comprising one or more selected from the group consisting of phosphoric acid, phosphate salt, phosphate salt hydrate, acetic acid, acetate, citric acid, citric acid hydrate, citrate salt, citrate salt hydrate, succinic acid, lactic acid, histidine, histidine salt, tris(hydroxymethyl)aminomethane (Tris), salt 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.

6. The composition of Claim 4, wherein the pH adjusting agent is one or more selected from the group consisting of phosphoric acid, phosphate salt, hydrate of phosphate salt, acetic acid, acetate, citric acid, hydrate of citric acid, citrate salt, tris(hydroxymethyl)aminomethane (Tris), salt of tris(hydroxymethyl)aminomethane (Tris), 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES), hydrochloric acid, and sodium hydroxide.

7. A composition according to claim 4, wherein the solvent is sterile physiological saline or water for injection.

8. In claim 1, the composition is a composition that is an injectable composition or an intravenous fluid preparation. 【Claim this In claim 1, the composition is a colorless, transparent liquid.

10. A composition comprising: a compound represented by 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.

11. A composition according to claim 1, wherein the compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof is contained in the composition at an amount of 0.05 to 0.2 w / v%.

12. A composition according to claim 4, wherein the isotonic agent in the composition is included in an amount of 0.5 to 1.5 w / v%.

13. A composition according to claim 4, wherein the pH adjusting agent in the composition is included in an amount of 0.01 to 0.4 w / v%.

14. In claim 1, the composition has long-term storage stability in which the pH is maintained at pH 5 or higher and less than pH 8 for a long period.

15. The composition of Claim 1, wherein the composition has long-term storage stability in which the pH is maintained at pH 5 or higher and pH 8 or lower for a long period when stored at room temperature.

16. The composition of claim 1, wherein the composition has long-term storage stability in which the pH is maintained at pH 5 or higher and less than pH 8 for a long period when stored at 1 to 30 °C.

17. In claim 1, the composition has stability such that when stored in a plastic container, the pH is maintained at pH 5 or higher and less than pH 8.

18. In claim 1, the composition has long-term storage stability, maintaining a colorless, transparent liquid state without precipitation for a long period. 【Claim 1 is The composition of claim 1, wherein the composition has long-term storage stability, maintaining a colorless, transparent liquid state without precipitation for a long period when stored at room temperature.

20. The composition of claim 1, wherein the composition has long-term storage stability, maintaining a colorless, transparent liquid state without precipitation for a long period when stored at 1 to 30 °C.

21. In claim 1, the composition has the stability to maintain a colorless, transparent liquid state without precipitation when stored in a plastic container.

22. A method for preparing a composition having a pH of 5 or higher and less than 8, comprising: (a) stirring and dissolving a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof in a solvent; and (b) adding an isotonic agent to the solution prepared in (a); wherein the composition comprises a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof. [Chemical Formula 1] H

23. In Clause 22, the above manufacturing method is (c) A method of manufacturing that further comprises the step of adding a pH adjusting agent.

24. In claim 1, the composition is a composition intended for the prevention or treatment of thromboembolic disease.

25. In claim 1, the composition is intended for the prevention, alleviation, improvement, or treatment of side effects caused by the administration of a thrombolytic agent.

26. Use of the composition according to Claim 1 for the prevention or treatment of thromboembolic diseases.

27. Use for the prevention, alleviation, improvement, or treatment of side effects caused by the administration of a thrombolytic agent of the composition according to Paragraph 1.

28. Use of the composition according to claim 1 for the manufacture of a drug for the prevention or treatment of thromboembolic diseases. 【Claim 2 Use of the composition according to claim 1 for the manufacture of a drug for the prevention, alleviation, improvement, or treatment of side effects caused by the administration of a thrombolytic agent.

30. A method for the prevention or treatment of thromboembolic disease comprising administering the composition according to paragraph 1 to an individual in need thereof. 【claim [Clause 31] A method for preventing, alleviating, improving, or treating side effects caused by the administration of a thrombolytic agent, comprising administering the composition according to Clause 1 to an individual in need thereof.

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