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, having a pH of 5 or higher and a pH of less than 8, and a method for preparing the same. The composition according to the present invention can maintain a transparent liquid state without pH change or precipitation even during long-term storage regardless of the storage container, and can be usefully utilized as an injectable composition or an intravenous fluid preparation.

Description

Technology Field

[0001] 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 for preparing the same. Specifically, it relates 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 for preparing the same. Background Technology

[0002] When vascular tissue is injured, blood leaks out of the vessel, and a blood clot forms in the tissue surrounding the injury to stop the bleeding. Blood clots that stop bleeding localized to the site of injury are a normal part of the wound healing process and are essential for survival. In contrast, if a blood clot is abnormally present within a blood vessel, it will block blood flow if not removed. Blocking blood flow leads to fatal thromboembolic diseases such as stroke, pulmonary embolism, and myocardial infarction, which cause tissue necrosis due to hypoxia.

[0003] 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 into injectable compositions or fluid preparations and store them for a long period.

[0004] 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. The problem to be solved

[0005] The present invention provides a composition having a pH of 5 or higher and less than 8, comprising a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

[0006] The present invention provides a method for preparing a composition having a pH of 5 or higher and less than 8, comprising a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof. means of solving the problem

[0007] 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.

[0009] The composition of the present invention comprises a quinazoline-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.

[0010] In the present invention, the quinazolin-2,4-dione derivative may be otaplimastat.

[0011] Otap-limastat is a compound represented by the following chemical formula 1, which is “N-[3-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)propyl]-N-(4-{[3-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)propyl]amino}butyl)acetamide (N-[3-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)propyl]-N-(4-{[3-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)propyl]amino}butyl)acetamide)”.

[0012] [Chemical Formula 1]

[0013] .

[0014] 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.

[0015] The "pharmaceuticalally acceptable salt" of the present invention may mean a salt commonly used in the pharmaceutical industry. In one embodiment of the present invention, the pharmaceutically acceptable salt of the compound represented by Formula 1 may be a hydrochloride salt, but is not necessarily limited thereto.

[0016] 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 salt of a compound represented by Formula 1.

[0017] The “hydrate” of the present invention is a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof and water bonded by non-covalent intermolecular forces, and may contain stoichiometric or non-stoichiometric amounts of water.

[0018] The “solvent” of the present invention is a compound represented by Formula 1 or a pharmaceutically acceptable salt thereof and a solvent other than water bonded by non-covalent intermolecular forces, and may contain the solvent in stoichiometric or non-stoichiometric amounts.

[0019] 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 the embodiments of the present invention, the composition of the present invention may have a pH of 6 or higher and less than 8.

[0020] 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 ℃ for 2 to 24 months based on the pH immediately after preparation.

[0021] In the embodiments of the present invention, the change in pH of the composition of the present invention may be within 1.0 (±1.0) after storage at 1 to 30 ℃ for 2 months based on the pH immediately after preparation.

[0022] In the embodiments of the present invention, the composition of the present invention may have a change in pH of 1.0 (±1.0) after storage at 1 to 30°C for 18 months based on the pH immediately after preparation.

[0023] In the embodiments of the present invention, the composition of the present invention may have a change in pH of 1.0 (±1.0) after storage at 1 to 30°C for 24 months based on the pH immediately after preparation.

[0024] The above "change in pH" refers to the value calculated by the following mathematical formula I:

[0025] [Mathematical Formula I]

[0026] Change in pH = |pH (immediately after preparation) - pH (after n months of storage)|

[0027] *n means an integer greater than or equal to 2.

[0028] 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 photostability 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 impurities 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.

[0029] In the present invention, "stability of the composition" refers to physical and chemical stability, such as, for example, stability of appearance, storage stability, pH stability, container suitability, etc.

[0030] The composition of the present invention can maintain its properties, pH, etc., even during long-term storage, and the amount of impurities generated can be kept low.

[0031] The composition of the present invention may be suitable for all of the following conditions 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)): practical volume, appearance, pH, content of active ingredients, osmotic pressure, impurities (individual unknown impurities, total impurities, etc.), insoluble foreign matter, insoluble fine particles, etc.

[0032] 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.

[0033] 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.

[0034] In the present invention, the term "pH adjuster" may include buffers. Specifically, the term "pH adjuster" encompasses all substances added to adjust or maintain the pH of a composition within a desired range. This includes not only acids or bases that immediately change the pH of the composition, but also buffers, buffer solutions, etc., that perform the function of maintaining a constant pH of the composition by resisting the influx of external acids, bases, etc., or environmental changes.

[0035] In the embodiments of the present invention, a pH adjuster may be used without limitation as long as it is capable of preparing the composition of the present invention at a pH of 5 or higher and / or maintaining the pH of the composition of the present invention at a pH of 5 or higher and less than 8 for a certain period of time.

[0036] In embodiments of the present invention, the pH adjuster may be one or more selected from the group consisting of phosphoric acid, phosphate, phosphate hydrate, acetic acid, acetate, citric acid, citric acid hydrate, citrate, citrate hydrate, succinic acid, lactic acid, histidine, histidine salt, tris(hydroxymethyl)aminomethane (Tris), tris(hydroxymethyl)aminomethane (Tris) salt, methanesulfonic acid, sulfonic acid, hydrochloric acid, nitric acid, sulfuric acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium bicarbonate, sodium carbonate, sodium carbonate hydrate, diethanolamine, meglumine, tromethamine, edetic acid, and pentetic acid, but is not limited thereto.

[0037] In embodiments of the present invention, the pH adjuster may be one or more selected from the group consisting of phosphoric acid, phosphate, phosphate hydrate, acetic acid, acetic acid, citric acid, citric acid hydrate, citrate, tris(hydroxymethyl)aminomethane (Tris), salt of tris(hydroxymethyl)aminomethane (Tris), 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES), hydrochloric acid, and sodium hydroxide.

[0038] Specifically, the pH adjuster may be one or more selected from the group consisting of sodium dihydrogen phosphate, hydrate of sodium dihydrogen phosphate (e.g., sodium dihydrogen phosphate dihydrate, etc.), disodium hydrogen phosphate (e.g., anhydrous disodium hydrogen phosphate), hydrate of disodium hydrogen phosphate, acetic acid, sodium acetate, citric acid, sodium citrate, hydrochloride of tris(hydroxymethyl)aminomethane (Tris-HCl), 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES), hydrochloric acid, and sodium hydroxide. For example, the pH adjuster may be hydrochloric acid and sodium hydroxide; or sodium dihydrogen phosphate dihydrate and anhydrous disodium hydrogen phosphate; or citric acid and sodium citrate; or sodium dihydrogen phosphate and disodium hydrogen phosphate; or acetic acid and sodium acetate. or tris(hydroxymethyl)aminomethane hydrochloride (Tris-HCl); or 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES) and sodium hydroxide.

[0039] In the present invention, "isotonic agent" refers to a substance added to adjust the osmotic pressure of a composition to be substantially the same as the osmotic pressure of a biological sample (e.g., blood, serum, tears, etc.).

[0040] In embodiments of the present invention, the isotonic agent may be sodium chloride (NaCl).

[0041] Specifically, in one embodiment of the present invention, the isotonic agent is sodium chloride, and the pH adjuster may be hydrochloric acid and sodium hydroxide; or sodium dihydrogen phosphate dihydrate and anhydrous disodium hydrogen phosphate; or citric acid and sodium citrate; or sodium dihydrogen phosphate and disodium hydrogen phosphate; or acetic acid and sodium acetate; or hydrochloride of tris(hydroxymethyl)aminomethane (Tris-HCl); or 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES) and sodium hydroxide. For example, the composition of the present invention may comprise a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, sodium chloride, sodium dihydrogen phosphate, disodium hydrogen phosphate, and a solvent.

[0042] Preferably, the sodium dihydrogen phosphate and disodium hydrogen phosphate may be sodium dihydrogen phosphate dihydrate and disodium hydrogen phosphate anhydrous, respectively, but are not limited thereto.

[0043] In the present invention, "solvent" refers to a medium for dissolving, dispersing, or suspending the main components and additives within the composition to form a specific phase.

[0044] In the 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 can be used as long as it is water for injection generally used to dissolve, suspend, or emulsify a 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.

[0045] In embodiments of the present invention, the composition may be an injectable composition or an aqueous formulation. 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 formulation that is dissolved for use (e.g., freeze-dried powder), but is not limited thereto.

[0046] 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.

[0051] 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 disodium hydrogen phosphate may be sodium dihydrogen phosphate dihydrate and disodium hydrogen phosphate anhydrous, respectively, but are not limited thereto.

[0052] In the embodiments of the present invention, the aqueous solvent in the composition of the present invention may be included in an appropriate amount to reach a desired liquid volume.

[0053] The composition of the present invention may be a colorless, transparent solution.

[0054] 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).

[0055] The composition of the present invention can be stably maintained regardless of the packaging container.

[0056] In other words, the composition of the present invention can exhibit excellent stability when stored not only in glass containers but also in plastic containers. Specifically, the composition can be maintained stably in plastic containers; for example, it can maintain a colorless, transparent liquid state without sedimentation for a long period of time even when stored in a plastic container.

[0057] In embodiments of the present invention, the composition may be stored in a colorless transparent multilayer film plastic container. For example, the plastic container may be a plastic bag, and specifically, may be a colorless transparent polypropylene container (bag).

[0058] The composition of the present invention can be maintained stably for a long period of time when stored, for example, the pH of the composition can be maintained at a pH of 5 or higher and less than a pH of 8.

[0059] In embodiments of the present invention, the composition can be maintained stably for a long period of time when stored at room temperature, for example, the pH of the composition can be maintained at a pH of 5 or higher and less than pH 8.

[0060] In embodiments of the present invention, the composition can be maintained stably for 24 months when stored at 1 to 30°C, 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 in 55 to 65% RH.

[0061] 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.

[0062] 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.

[0063] 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 maintain a colorless, transparent liquid state without precipitation.

[0064] In embodiments of the present invention, the composition can be maintained stably for 24 months when stored at 1 to 30°C, for example, and 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.

[0065] The composition of the present invention can maintain 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 an extended period.

[0066] 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 disodium hydrogen phosphate; and an appropriate amount of a solvent. Preferably, the sodium dihydrogen phosphate and disodium hydrogen phosphate may be sodium dihydrogen phosphate dihydrate and disodium hydrogen phosphate anhydrous, respectively, but are not limited thereto.

[0067] 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.

[0069] The method for preparing the above composition of the present invention is,

[0070] (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

[0071] (b) includes the step of adding an isotonic agent to the solution prepared in (a).

[0072] In the embodiments of the present invention,

[0073] The above manufacturing method may further include the step of adding a pH adjuster (c) after step (a) and before step (b); simultaneously with step (b); or after step (b).

[0074] Specifically, the above manufacturing method is,

[0075] (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;

[0076] (b) a step of adding an isotonic agent to the solution prepared in (a); and

[0077] (c) may include the step of adding a pH adjuster to the solution prepared in (b).

[0078] In embodiments of the present invention, the manufacturing method is,

[0079] (d) A step of adding more solvent to the solution prepared in (c); and / or

[0080] (e) may further include a step of filtering the solution prepared in (c) or (d).

[0081] In embodiments of the present invention, the manufacturing method is,

[0082] (f) a step of filling a packaging container with the composition prepared in (c), (d), or (e); and

[0083] (g) A sealing step may be further included.

[0084] In embodiments of the present invention, the manufacturing method is,

[0085] (h) The composition may further include a step of sterilizing it.

[0086] 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.

[0087] 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.

[0088] In embodiments of the present invention, the pH adjuster 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 adjuster 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.

[0089] In embodiments of the present invention, the isotonic agent may be sodium chloride (NaCl).

[0090] In embodiments of the present invention, the pH adjuster may be one or more selected from the group consisting of phosphoric acid, phosphate, phosphate hydrate, acetic acid, acetate, citric acid, citric acid hydrate, citrate, citrate hydrate, succinic acid, lactic acid, histidine, histidine salt, tris(hydroxymethyl)aminomethane (Tris), tris(hydroxymethyl)aminomethane (Tris) salt, methanesulfonic acid, sulfonic acid, hydrochloric acid, nitric acid, sulfuric acid, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium bicarbonate, sodium carbonate, sodium carbonate hydrate, diethanolamine, meglumine, tromethamine, edetic acid, and pentetic acid, but is not limited thereto.

[0091] In embodiments of the present invention, the pH adjuster may be one or more selected from the group consisting of phosphoric acid, phosphate, phosphate hydrate, acetic acid, acetic acid, citric acid, citric acid hydrate, citrate, tris(hydroxymethyl)aminomethane (Tris), salt of tris(hydroxymethyl)aminomethane (Tris), 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES), hydrochloric acid, and sodium hydroxide.

[0092] Specifically, the pH adjuster may be one or more selected from the group consisting of sodium dihydrogen phosphate, hydrate of sodium dihydrogen phosphate (e.g., sodium dihydrogen phosphate dihydrate, etc.), disodium hydrogen phosphate (e.g., anhydrous disodium hydrogen phosphate), hydrate of disodium hydrogen phosphate, acetic acid, sodium acetate, citric acid, sodium citrate, hydrochloride of tris(hydroxymethyl)aminomethane (Tris-HCl), 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES), hydrochloric acid, and sodium hydroxide. For example, the pH adjuster may be hydrochloric acid and sodium hydroxide; or sodium dihydrogen phosphate dihydrate and anhydrous disodium hydrogen phosphate; or citric acid and sodium citrate; or sodium dihydrogen phosphate and disodium hydrogen phosphate; or acetic acid and sodium acetate. or tris(hydroxymethyl)aminomethane hydrochloride (Tris-HCl); or 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES) and sodium hydroxide.

[0093] 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.

[0094] 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.

[0095] The composition prepared 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.

[0096] The composition of the present invention may be for the prevention or treatment of thromboembolic diseases, for example, ischemic stroke (cerebral infarction).

[0097] 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.

[0098] The present invention provides the use of the above composition for the prevention or treatment of thromboembolic diseases, e.g., ischemic stroke (cerebral infarction).

[0099] The present invention provides a use for preventing, alleviating, improving, or treating side effects caused by the administration of a thrombolytic agent of the above composition.

[0100] 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).

[0101] 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.

[0102] 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.

[0103] 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.

[0104] 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 thereof.

[0105] In the present invention, "thromboembolic disease" is blood clot Detach from this original location and through the bloodstream ( embolism (as) move and block blood vessels, tissue ischemia It refers to a disease that causes internal organ damage.

[0106] 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 artery thrombosis, mesenteric artery thrombosis, renal artery thrombosis, deep vein thrombosis (DVT), pulmonary embolism (PE), upper extremity vein thrombosis, portal vein thrombosis, hepatic vein thrombosis (Budd-Chiari syndrome), cerebral venous sinus thrombosis (CVST), retinal vein occlusion, atrial fibrillation-related embolism, left ventricular thrombosis after myocardial infarction, heart valve disease-related embolism, artificial heart valve-related thromboembolism, endocarditis-related embolism, disseminated intravascular coagulation (DIC), antiphospholipid syndrome (APS), cancer-related thromboembolism, pregnancy / puerperal thromboembolism, and drug-induced thromboembolism. It may be at least one selected from the formed group, but is not necessarily limited thereto.

[0107] 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.

[0108] 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 side effects caused by the administration of a thrombolytic agent, by administering a composition according to the present invention.

[0109] In the present invention, “treatment” means any act in which the symptoms of an individual’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.

[0110] In the present invention, “administration” means introducing a specific substance to an individual by an appropriate method.

[0111] In the present invention, “alleviation” and “improvement” refer to any act in which sequelae symptoms of thromboembolic disease or side effects symptoms of thrombolytic agent administration are improved or beneficially altered by the administration of the composition according to the present invention.

[0112] In the present invention, “individual” refers to all animals, including humans, rats, mice, and livestock, that have developed or may develop a disease; specifically, it may be mammals including humans, but is not limited thereto.

[0113] In the present invention, the term “therapeutic effective dose” refers to an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment and that does not cause side effects. This amount may be determined by a person skilled in the art based on factors including the patient’s gender, age, weight, health status, type and severity of the disease, 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 simultaneously, and other factors well known in the medical field. It is preferable to apply a specific therapeutic effective dose for a specific patient differently based on various factors and similar factors well known in the medical field, including the specific composition (such as the type and degree of response to be achieved and whether other preparations are used in some cases), the patient’s age, weight, general health status, gender and diet, time of administration, route of administration and elimination rate of the composition, duration of treatment, and drugs used with or simultaneously with the specific composition.

[0115] The details described above regarding the compositions and methods of the present invention may be applied substantially identically to each composition, each method, and each use of the present invention, provided that they do not contradict one another.

[0117] Embodiments of the present invention may be modified in various different forms, and the scope of the present invention is not limited to the embodiments described below. Furthermore, embodiments of the present invention are provided to more completely explain the present invention to those skilled in the art. Moreover, throughout the specification, the term "comprising" any component means that, unless specifically stated otherwise, it does not exclude other components but may include additional components. Effects of the invention

[0118] The composition according to the present invention can maintain a transparent liquid state without pH change or precipitation even during long-term storage, regardless of the storage container, and can be usefully utilized as an injectable composition or an intravenous fluid preparation. Brief explanation of the drawing

[0119] Figure 1 shows the results of the characterization evaluation under severe stability conditions (50°C, 75% RH, 2 months) of 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 physical evaluation at the 2-month mark under severe stability conditions (50°C, 75% RH) after manufacturing Examples 9 to 13. Specific details for implementing the invention

[0120] The present invention will be explained in more detail below through examples. These examples are intended to illustrate the invention and the scope of the invention is not limited to these examples.

[0122] Examples 1 to 3: Preparation of injectable compositions containing quinazoline-2,4-dione compounds

[0123] An injectable preparation containing a quinazoline-2,4-dione compound was prepared according to the composition of Table 1 below. Specifically, the quinazoline-2,4-dione compound (hydrochloride of the compound of Chemical Formula 1; the hydrochloride of the compound represented by Chemical Formula 1 was prepared and used according to the method described in Korean Patent No. 10-1075435) was added to water for injection and stirred to completely dissolve it, after which sodium chloride was added and stirred. After confirming the state of dissolution, 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 additional water for injection was added to reach the target liquid volume (50 mL). Subsequently, filtration was performed using a filtration filter, the mixture was filled into a glass vial, and the preparation was completed by performing an autoclave process (40 mg hydrochloride of the compound of Chemical Formula 1 / total liquid volume 50 mL).

[0124]

[0126] Experimental Example 1: Evaluation of Appearance

[0127] 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 quinazoline-2,4-dione compound according to pH. As a result of the test at the 2-month mark under harsh stability conditions (50°C, 75% RH), it was confirmed that the injectable containing the quinazoline-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.

[0128]

[0129] Accordingly, 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.

[0130] In addition, to determine compliance with the appearance criteria when the pH exceeds this range, an injectable formulation containing a quinazoline-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 harsh 2-month test under harsh stability conditions (50°C, 75% RH), it was confirmed that the quinazoline-2,4-dione compound injectable formulation did not meet the appearance criteria because a precipitate was formed when the pH was 8 or higher (see Figure 1 and Table 3).

[0131]

[0133] Experimental Example 2: Accelerated Stability Test

[0134] Since there is a possibility of changes in pH and appearance of the injectable containing the quinazoline-2,4-dione compound, 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℃, 75% RH, 3 months, 6 months).

[0135]

[0136] *A (Accelerated stability test): Accelerated stability test (40 ℃ / 75% RH)

[0137] *Appearance test standard: The liquid is clear and free of clearly visible insoluble foreign matter.

[0139] Examples 4 to 8: Preparation of injectable compositions containing quinazoline-2,4-dione compounds

[0140] An injectable preparation containing a quinazoline-2,4-dione compound was prepared according to the composition listed in Table 5 below. Specifically, the quinazoline-2,4-dione compound (hydrochloride of the compound of Chemical Formula 1) was added to sterile water for injection and stirred to completely dissolve it, after which sodium chloride was added and stirred. After confirming the dissolution state, sodium dihydrogen phosphate dihydrate, disodium hydrogen phosphate, and anhydrous water were added to adjust the pH as pH regulators and buffers, and additional sterile water for injection was added to reach the target liquid volume (50 mL). Subsequently, the preparation was filtered using a filtration filter to produce an injectable preparation containing the quinazoline-2,4-dione compound (40 mg hydrochloride of the compound of Chemical Formula 1 / total liquid volume 50 mL). The prepared injectable preparation was filled into glass vials or plastic containers (infusion bags) by changing the material and type of material as shown in Table 6 below. After filling, the process of autoclaving was carried out.

[0141]

[0142]

[0144] Experimental Example 3: Evaluation of the Effect of Storage Container

[0145] 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.

[0146] 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℃ / 60% RH, 24 months) and an accelerated stability test (40℃ / 75% RH, 6 months), and evaluated all items including practical volume, physical properties, pH, content, osmotic pressure, insoluble foreign matter, insoluble fine particles, impurities, reduction in practical volume, and moisture loss rate. In particular, the pH stability and physical properties examined in Example 3 were selected as the primary subjects for comparison and review.

[0147]

[0148] *A (Accelerated stability test): Accelerated stability test (40℃ / 75% RH)

[0149] *L(long-term stability test): Long-term stability test (25℃ / 60% RH)

[0151] As a result, all of Examples 4 to 8 showed suitable results within the pH range of 5 to 8 based on pH test results, 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.

[0152] In other words, when the pH range of the composition of the present invention is limited to pH 5 or higher and pH 8 or lower, significant results can be obtained in terms of stability. Additionally, it can be seen that when a buffer is selected and used among pH adjusters, pH stabilization is more effective and pH can be stabilized without significant fluctuations.

[0154] Experimental Example 4: Stability Evaluation

[0155] 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℃ / 75% RH, 3 months, 6 months), severe stability (50℃ / 75% RH, 2 months), and long-term stability (25℃ / 60% RH, 18 months, 24 months) are shown in Table 9 below.

[0156]

[0157]

[0158] *A (Accelerated stability test): Accelerated stability test (40℃ / 75% RH)

[0159] *S(Stress stability test): Harsh stability test (50℃ / 75% RH)

[0160] *L(long-term stability test): Long-term stability test (25℃ / 60% RH)

[0161] *Appearance test standard: The liquid is clear and free of clearly visible insoluble foreign matter.

[0162] Insoluble particulate matter test standards: 10 µm or larger: 6,000 particles / container or less, 25 µm or larger: 600 particles / container or less

[0163] Practical Dose Test Standards for Injectables (USP) <697> ): Must be greater than or equal to the indicated amount (50 mL or more)

[0164] *Osmotic pressure test standards (USP) <785> ): 230 to 370 mOsm / kg

[0165] Insoluble Foreign Matter Test Standards (USP) <790> The liquid must be clear and free of clearly visible insoluble foreign matter.

[0167] 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.

[0169] Examples 9 to 13: Preparation of injectable compositions containing quinazoline-2,4-dione compounds according to the type of pH adjuster (buffer).

[0170] Examples 9 to 13 prepared injectable compositions containing quinazoline-2,4-dione compounds with the compositions of Tables 10 and 11 below by changing only the pH adjuster (buffer) in the compositions listed in Table 5 above.

[0171] Specifically, the quinazoline-2,4-dione compound (hydrochloride of the compound represented by Chemical Formula 1) was added to sterile water for injection and stirred to completely dissolve it; subsequently, sodium chloride was added as an isotonic agent and stirred further. Afterward, appropriate amounts of the pH adjusters (buffers) listed in Tables 10 and 11 below were added to adjust the pH of the composition to a pH of 5 or higher and less than 8, more specifically to around pH 7. After adding additional sterile water for injection to reach the target liquid volume (50 mL), the solution was filtered using a filtration filter to prepare the quinazoline-2,4-dione compound injectable (40 mg hydrochloride of the compound of Chemical Formula 1 / total liquid volume 50 mL). The prepared solution was filled into a glass vial. After filling, the process of autoclaving was carried out.

[0172] No differences in pH and characteristics were observed depending on whether the above sterilization process was applied.

[0173]

[0174] (Component content relative to total liquid volume) Unit: % w / v)

[0175]

[0177] Experimental Example 5: Evaluation of pH and physical stability according to the type of pH adjuster (buffer)

[0178] For the quinazoline-2,4-dione compound injectable compositions prepared in Examples 9 to 13, a stability test was performed to evaluate pH stability and whether the properties were maintained according to the type of pH adjuster (buffer).

[0179] 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 Fig. 2 and Table 12).

[0180] Stability tests were performed under long-term conditions (25℃ / 60% RH, 2 months), refrigeration conditions (5℃, 2 months), and harsh conditions (50℃ / 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 a sterilization process was applied.

[0181]

[0182] *L(long-term stability test): Long-term stability test (25℃ / 60% RH)

[0183] *R(Refrigerated stability test): Refrigeration stability test (5℃)

[0184] *S(Stress stability test): Harsh stability test (50℃ / 75% RH)

[0186] As a result, the compositions to which the pH adjusters (buffers) of Examples 9 to 13 were applied maintained an overall stable pH from immediately after preparation until 2 months later, and exhibited the best pH stability, particularly in the pH range of 5 or higher and less than 8. No color change or formation of insoluble foreign matter was observed regardless of storage conditions.

[0188] 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.

[0190] From the foregoing description, those skilled in the art to which the present invention pertains will understand that the present invention may be implemented in other specific forms without altering its technical concept or essential features. In this regard, the embodiments described above should be understood as illustrative in all respects and not restrictive. The scope of the present invention should be interpreted as including all modifications or variations derived from the meaning and scope of the claims set forth below and their equivalents, rather than from the detailed description above.

Claims

Claim 1 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] . Claim 2 A composition according to claim 1, wherein the pH of the composition is pH 6 or higher and less than pH 8. Claim 3 The composition according to claim 1, wherein the change in pH after storage at 1 to 30 ℃ for 2 months, based on the pH immediately after manufacturing, is within 1.0 (±1.0). Claim 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. Claim 5 A composition according to claim 4, wherein the pH adjuster is one or more selected from the group consisting of phosphoric acid, phosphate, phosphate hydrate, acetic acid, acetate, citric acid, citric acid hydrate, citrate, citrate hydrate, succinic acid, lactic acid, histidine, histidine salt, tris(hydroxymethyl)aminomethane (Tris), 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. Claim 6 A composition according to claim 4, wherein the pH adjuster is one or more selected from the group consisting of phosphoric acid, phosphate, phosphate hydrate, acetic acid, acetate, citric acid, citric acid hydrate, citrate, tris(hydroxymethyl)aminomethane (Tris), salt of tris(hydroxymethyl)aminomethane (Tris), 4-(2-hydroxyethyl)-1-piperazine ethanesulfonic acid (HEPES), hydrochloric acid, and sodium hydroxide. Claim 7 A composition according to paragraph 4, wherein the solvent is sterile physiological saline or water for injection. Claim 8 In claim 1, the composition is an injectable composition or an intravenous fluid preparation. Claim 9 In claim 1, the composition is a colorless, transparent liquid. Claim 10 A composition according to claim 1, 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. Claim 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 included in the composition at an amount of 0.05 to 0.2 w / v%. Claim 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%. Claim 13 A composition according to claim 4, wherein the pH adjuster in the composition is included in an amount of 0.01 to 0.4 w / v%. Claim 14 The composition according to 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. Claim 15 The composition according to 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 room temperature. Claim 16 The composition according to 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 1 to 30 ℃. Claim 17 The composition according to claim 1, wherein the composition has stability such that the pH is maintained at pH 5 or higher and less than pH 8 when stored in a plastic container. Claim 18 A composition according to claim 1, wherein the composition has long-term storage stability, maintaining a colorless, transparent liquid state without precipitation for a long period. Claim 19 The composition according to 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. Claim 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 ℃. Claim 21 The composition according to claim 1, wherein the composition has stability that maintains a colorless, transparent liquid state without precipitation when stored in a plastic container. Claim 22 A method for preparing a composition having a pH of 5 or higher and less than 8, comprising a compound represented by Formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, 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): [Formula 1] . Claim 23 In paragraph 22, the above manufacturing method further comprises the step of adding a pH adjuster (c).

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