Injectable composition, pharmaceutical preparation containing the same, and method for producing the same

Abstract

The present invention relates to an injectable composition, a pharmaceutical formulation containing the same, and a method for producing the same. The injectable composition according to the present invention comprises azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate and SBE-β-CD as active ingredients.

Description

[Technical Field]

[0001] The present invention relates to an injectable composition containing an imidazo[1,2-a]pyridine compound or a salt thereof, a pharmaceutical preparation containing the same, and a method for producing the same. [Background technology]

[0002] In general, candidate substances (drugs) must have not only desirable biological properties but also physical properties that enable their use as pharmaceuticals, which is why the possibility of developing the substance as a pharmaceutical is being considered. However, despite their excellent activity, they often have low stability from a pharmaceutical viewpoint, making their application to industrialization difficult.

[0003] Among various types of formulations, injectables are particularly required to have high solubility in the injection solvent because they are injected into the body in a liquid state. However, many drugs are poorly soluble, and their solubility and stability decrease depending on the pH, making them difficult to prepare as injections. To solve these problems, it is necessary to select an appropriate injection solvent and add sufficient amounts of additives such as solubilizers and stabilizers. However, too many additives can reduce stability and productivity, or cause pain when injected into the body. Therefore, it is extremely difficult to develop a formulation that is both stable and suitable for injection.

[0004] On the other hand, imidazo[1,2-a]pyridine compounds or pharmaceutically acceptable salts thereof are medicinal materials for preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases such as peptic ulcers, gastroduodenal ulcers, gastritis, gastroesophageal reflux disease (GERD), and non-erosive gastroesophageal reflux disease (NERD).

[0005] Therefore, the present inventors have made great efforts to develop an extremely stable injectable formulation having excellent solubility and stability for an imidazo[1,2-a]pyridine compound or a pharmaceutically acceptable salt thereof, and have completed the present invention. [Prior art documents] [Patent documents]

[0006] [Patent Document 1] Korean Patent No. 10-1777971 DETAILED DESCRIPTION OF THE INVENTION

[0007] (Problem to be solved by the invention) One object of the present invention is to provide an injectable composition having excellent solubility and / or stability, which contains an imidazo[1,2-a]pyridine compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0008] Another object of the present invention is to provide a pharmaceutical formulation comprising said injectable composition.

[0009] It is yet another object of the present invention to provide a kit comprising said pharmaceutical formulation.

[0010] It is yet another object of the present invention to provide a method for preparing said injectable composition or pharmaceutical formulation.

[0011] (Means for solving the problem) An injectable composition for one purpose of the present invention comprises, as active ingredients, azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate; and sulfobutylether-β-cyclodextrin (hereinafter, SBE-β-CD).

[0012] In the present invention, azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone is compound 1 represented by the following formula (1). [ka] (1)

[0013] The active ingredient of the present invention is the citrate salt of Compound 1 represented by the above formula (1), and hereinafter, "azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt" and "citrate salt of Compound 1" refer to the same entity.

[0014] The citrate salt of Compound 1 is represented by the following formula (2): [ka] (2) (wherein n may be 0.3 to 1.3, for example, 0.5 to 1).

[0015] The citrate salt of Compound 1, which is the active ingredient of the present invention, exhibits significantly better bioavailability than the free base of Compound 1, and is a drug that exhibits excellent efficacy in the prevention or treatment of gastrointestinal inflammatory diseases or gastric acid-related diseases. Specifically, when orally administered, the citrate salt of Compound 1 reaches its maximum blood concentration in a shorter time than the free base of Compound 1, with a Cmax that is significantly 11 times higher and an AUC that is 5 times higher.

[0016] The citrate salt of Compound 1 exhibits excellent solubility at pH levels below 3, but exhibits significantly lower solubility (less than 1.5 mg / mL) at pH levels above 3, particularly above pH 3.3. However, the injectable composition of the present invention can improve the solubility and stability of the citrate salt of Compound 1 even at pH levels above 3 by using SBE-β-CD in combination with the citrate salt of Compound 1.

[0017] The addition of 2-hydroxypropyl-β-cyclodextrin (HP-β-CD) and polyethylene glycol to the citrate salt of Compound 1 does not improve the solubility of the citrate salt of Compound 1 at pH 3 or higher, and polysorbates such as Tween 80 may not improve the stability of the citrate salt of Compound 1. In contrast, the injectable composition of the present invention contains SBE-β-CD, which can improve the solubility and stability of the citrate salt of Compound 1 at pH 3 or higher.

[0018] If the content of the citrate salt of Compound 1 is less than 1 mg / mL, a large amount of injection solution must be administered to achieve a sufficient therapeutic effect, which may make administration difficult.

[0019] In one embodiment, the citrate salt of Compound 1 may be contained in an amount of 1 to 10 wt% relative to 100 wt% of the total solid content of the injectable composition. When the injectable composition is in a liquid phase, 100 wt% of the solid content refers to the total weight of the components excluding the injection solvent being 100%. When the injectable composition is in a solid phase, 100 wt% of the solid content refers to the total weight of the injectable composition being 100%.

[0020] If the content of the citrate of Compound 1 is less than 1 wt% based on 100 wt% of the total solid content of the injectable composition, a large amount of injection solution must be administered to achieve a sufficient therapeutic effect, which may make administration difficult.Furthermore, if the content of the citrate of Compound 1 is more than 10 wt% based on 100 wt% of the total solid content of the injectable composition, it may be difficult to sufficiently dissolve the citrate of Compound 1, and it may be prone to precipitation.

[0021] In one embodiment, the citrate salt of Compound 1 may be contained in an amount of 1 mg to 30 mg, for example, 5 mg to 30 mg, per unit dosage form of the injectable composition.

[0022] In the present invention, SBE-β-CD may be a solubilizing agent that improves the solubility of the citrate salt of Compound 1 at pH 3 or higher and / or a stabilizer that prevents the citrate salt of Compound 1 from precipitating.

[0023] In the present invention, SBE-β-CD may be a compound represented by the following formula (3) (sulfobutylether-β-cyclodextrin sodium), which has a form in which sodium is added to sulfobutylether-β-cyclodextrin. [ka] (3)

[0024] In one embodiment, in the injectable composition according to the present invention, the weight ratio of the citrate salt of Compound 1 to SBE-β-CD may be 1:5 to 1:60, or 1:10 to 1:60.

[0025] In one embodiment, the injectable composition according to the present invention may comprise a citrate salt of Compound 1, SBE-β-CD, and a pH adjuster. In this case, the pH adjuster may be any pH adjuster that is conventionally used to adjust pH in the preparation of injectable compositions, such as sodium hydroxide, without any particular limitation.

[0026] In the present invention, the injectable composition containing the citrate salt of Compound 1 and SBE-β-CD does not need to contain any additives other than a pH adjuster, and may further contain, optionally, an isotonicity agent, a buffer, an osmotic agent, etc. commonly used in the art, but is not limited to these.

[0027] In one embodiment, the injectable composition according to the present invention comprises the citrate salt of Compound 1, SBE-β-CD, and albumin. In the present invention, albumin, when used in combination with the citrate salt of Compound 1 and SBE-β-CD, can improve the solubility and stability of the citrate salt of Compound 1 even at pH 3 or higher.

[0028] Albumin in the present invention can include recombinant albumin or albumin purified from human plasma.

[0029] In one embodiment, the albumin may be from 1 mg to 60 mg per unit dosage form of the injectable composition.

[0030] In one embodiment, the albumin may be present in an amount of 0.1 to 10% by weight, for example, 0.2 to 7% by weight, 0.25 to 7% by weight, 0.28 to 6.9% by weight, or 0.29 to 6.8% by weight, relative to 100% by weight of the total solid content of the injectable composition.

[0031] In one embodiment, when the injectable composition is a liquid-phase injection containing an injection solvent, the albumin content is 105 mg to 1560 mg, specifically 106 mg to 1553 mg, per 100 mL of the injectable composition.

[0032] In one embodiment, the weight ratio of SBE-β-CD to albumin may be 7:1 to 300:1.

[0033] In one embodiment, the injectable composition according to the present invention may comprise a citrate salt of Compound 1; SBE-β-CD; and two or more selected from albumin, lysine, and arginine.

[0034] In one embodiment, the injectable composition according to the present invention comprises the citrate salt of Compound 1; SBE-β-CD; and a lyophilizing agent.

[0035] Examples of the lyophilizing agent include mannitol and trehalose, which can be used alone or in combination. The lyophilizing agent, when used in combination with SBE-β-CD, can further improve the stability of the citrate salt of Compound 1, thereby improving the stability of the solid content of the injectable composition or the lyophilized product.

[0036] In one embodiment, the injectable composition according to the present invention may comprise a citrate salt of Compound 1; SBE-β-CD; and at least one of mannitol and trehalose.

[0037] In one embodiment, an injectable composition according to the present invention comprises the citrate salt of Compound 1, SBE-β-CD, albumin, and a lyophilizing agent. The lyophilizing agent, together with SBE-β-CD and albumin, can further improve the stability of the citrate salt of Compound 1.

[0038] In an embodiment, the injectable composition according to the present invention may comprise a citrate salt of Compound 1; SBE-β-CD; albumin; and at least one of mannitol and trehalose.

[0039] In one embodiment, the weight ratio of the citrate salt of Compound 1 to the lyophilizing agent may be 1:5 to 1:10. For example, the weight ratio of the citrate salt of Compound 1 to the lyophilizing agent may be 1:7 to 1:8.

[0040] Injectable compositions according to the invention may be in liquid or solid phase.

[0041] In one embodiment, the injectable composition according to the present invention may comprise the citrate salt of Compound 1, SBE-β-CD, and an aqueous medium. In this case, the aqueous medium may be an injection solvent, and examples of the injection solvent include, but are not limited to, water for injection, saline injection, Ringer's solution, etc., and specifically, water for injection.

[0042] In embodiments, an injectable composition according to the present invention may be clear and colorless.

[0043] The pH of the injectable composition according to the present invention may be equal to or higher than 3. Injectables with a pH of less than 3 induce pain upon administration and increase the amount of decomposition products of the citrate salt of Compound 1, which is the active ingredient. Therefore, in consideration of safety and stability, it is preferable that the pH be at least 3.

[0044] In one embodiment, the pH of the injectable composition according to the present invention may be 3 or more and 4.9 or less, or may be 3 or more, 3.5 or more, 3.7 or more, 3.75 or more, 3.8 or more, 3.95 or more, or 4 or more, or may be 4.9 or less, 4.7 or less, or 4 or less. For example, the pH of the injectable composition according to the present invention may be 3 to 4.7, 3.5 to 4.9, 3.5 to 4.7, 3.5 to 4, 3.7 to 4, 3.75 to 4.7, 3.75 to 3.95, 4 to 4.7, 4 to 4.9, 3.75 to 4.9, or 3.75 to 4.

[0045] In one embodiment, the injectable composition according to the present invention may be a liquid containing the citrate salt of Compound 1 and SBE-β-CD.

[0046] In one embodiment, the injectable composition according to the present invention may be a liquid containing the citrate salt of Compound 1, SBE-β-CD, and albumin.

[0047] In one embodiment, the injectable composition according to the present invention may be a clear, colorless liquid containing the citrate salt of Compound 1, SBE-β-CD, and an aqueous medium, and having a pH of 3 or more and 4.9 or less.

[0048] In one embodiment, the injectable composition according to the present invention may be a colorless, transparent liquid containing the citrate salt of Compound 1, SBE-β-CD, albumin, and an injection solvent, and having a pH of 3 or more and 4.9 or less, for example, a pH of 3.75 to 4.9.

[0049] In one embodiment, the injectable composition according to the present invention may be a solid powder. A liquid injectable composition may be dried to form a powder. Drying may be performed by a conventional drying process, such as lyophilization, rotary evaporation, spray drying, or fluid phase drying. In one embodiment, the injectable composition according to the present invention may be a lyophilizate.

[0050] In one embodiment, the injectable composition according to the present invention may be a dry product containing the citrate salt of Compound 1 and SBE-β-CD.

[0051] In one embodiment, the injectable composition according to the present invention may be a dry product containing the citrate salt of Compound 1, SBE-β-CD, and a lyophilizing agent.

[0052] In one embodiment, the injectable composition according to the present invention may be a dry product containing the citrate salt of Compound 1, SBE-β-CD, and albumin.

[0053] In one embodiment, the injectable composition according to the present invention may be a dry product containing the citrate salt of Compound 1, SBE-β-CD, albumin, and a lyophilizing agent.

[0054] For another object of the present invention, a pharmaceutical formulation comprises the citrate salt of Compound 1 and SBE-β-CD.

[0055] In one embodiment, the pharmaceutical preparation according to the present invention may be an injection containing the citrate salt of Compound 1 and SBE-β-CD. In this case, the injection may contain an injection solvent.

[0056] The injection according to the present invention has excellent solubility of the active ingredient and excellent stability against temperature and / or humidity.

[0057] In an embodiment, the pharmaceutical preparation according to the present invention may be an injection containing the citrate salt of Compound 1, SBE-β-CD, and albumin. In this case, the injection may contain an injection solvent.

[0058] In one embodiment, the pH of the injection containing the citrate salt of Compound 1 and SBE-β-CD may be 3 or more and 4.9 or less.

[0059] In one embodiment, the pH of the injection containing the citrate salt of Compound 1 and SBE-β-CD may be 3.75 or higher and lower than 4, or 4 or higher and lower than 4.9.

[0060] In one embodiment, the pharmaceutical formulation according to the present invention may be a lyophilized product containing the citrate salt of Compound 1 and SBE-β-CD. In this case, the lyophilized product may contain mannitol and / or trehalose.

[0061] In one embodiment, the pharmaceutical formulation according to the present invention may be a lyophilized product containing the citrate salt of Compound 1, SBE-β-CD, and albumin. In this case, the lyophilized product may contain mannitol and / or trehalose.

[0062] The freeze-dried product of the present invention has excellent stability against temperature and / or humidity, allowing it to be stored for a long period of time, and can be easily made into an injection by dissolving it in an injection solvent, which is an aqueous medium. In this case, the pH of the resulting injection may be 3 or more and 4.9 or less, 3 or more and 4.7 or less, 3.75 or more and 4.9 or less, or 3.75 or more and 4.7 or less.

[0063] In one embodiment, the method for producing an injectable composition according to the present invention comprises the step of mixing the citrate salt of Compound 1, SBE-β-CD, and an aqueous medium. For example, this step can be carried out by adding SBE-β-CD to an aqueous medium, and then mixing the citrate salt of Compound 1 with an aqueous SBE-β-CD solution. The pH of the solution obtained by mixing the citrate salt of Compound 1, SBE-β-CD, and an aqueous medium may be 3 to 4.9, specifically 3.5 to 4 or 3.75 to 3.95.

[0064] The liquid mixture containing the citrate salt of Compound 1 and SBE-β-CD may be an injectable preparation according to the present invention. The pH of the injectable preparation may be 3 to 4.9, specifically 3.5 to 4, or 3.75 to 3.95.

[0065] The freeze-dried product according to the present invention can be produced through a step of freeze-drying the liquid phase mixture.

[0066] In one embodiment, the method for producing an injectable composition according to the present invention comprises the steps of mixing the citrate salt of compound 1, SBE-β-CD, albumin, and an aqueous medium. For example, the steps may include mixing the citrate salt of compound 1 and SBE-β-CD with an aqueous medium; and adding albumin to a mixed solution containing the citrate salt of compound 1 and SBE-β-CD. The pH of the solution obtained by mixing the citrate salt of compound 1, SBE-β-CD, albumin, and an aqueous medium may be 3 or 4.9 to 4.9, specifically 4 to 4.9, or 4 to 4.7.

[0067] The liquid mixture containing the citrate salt of Compound 1, SBE-β-CD, and albumin, or the liquid mixture further containing a pH adjuster, may be an injectable preparation according to the present invention. The pH of the injectable preparation may be 3 to 4.7, specifically 4 to 4.9 or 4 to 4.7.

[0068] The production method may further comprise the step of adding mannitol and / or trehalose to the liquid phase mixture.

[0069] The method may further include a step of drying the liquid mixture containing mannitol and / or trehalose. The drying step may be performed through a freeze-drying process, thereby producing the freeze-dried product according to the present invention.

[0070] The freeze-dried product can be redissolved in an aqueous medium such as an injection solvent to form a liquid-phase injection. Even when the freeze-dried product is used as a liquid-phase injection, it can be redissolved to form a colorless and transparent product. In this case, the pH of the liquid-phase injection may be 3 to 4.9.

[0071] The kit according to the invention comprises a lyophilisate containing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate and sulfobutylether-β-cyclodextrin (SBE-β-CD) as active ingredients; and an injection solvent.

[0072] The lyophilized product contained in the kit is substantially the same as that described above, and therefore a detailed description thereof will be omitted.

[0073] The injection solvent contained in the kit is substantially the same as the aqueous medium described above, and therefore, a detailed description thereof will be omitted.

[0074] In the kit, the freeze-dried product and the injection solvent may be contained in separate containers to constitute one kit.

[0075] (1) The injectable composition according to the present invention comprises, as active ingredients, azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate; and sulfobutylether-β-cyclodextrin (SBE-β-CD).

[0076] (2) The injectable composition according to (1) above may further contain albumin.

[0077] (3) The injectable composition according to (1) or (2) above may further contain mannitol or trehalose as a lyophilizing agent.

[0078] (4) The injectable composition according to any one of (1) to (3) above may further contain albumin as a solubilizing agent; and mannitol or trehalose as a lyophilizing agent.

[0079] (5) The injectable composition according to any one of (1) to (4) above may be in a liquid phase having a pH of 3 or more and 4.9 or less.

[0080] (6) The injectable composition according to any one of (1) to (5) above may be a colorless, transparent liquid phase having a pH of 3 to 3.95.

[0081] (7) The injectable composition according to any one of (1) to (6) above may be a colorless, transparent liquid phase having a pH of 4 to 4.9.

[0082] (8) The injectable composition according to any one of (1) to (4) above may be in the form of a solid freeze-dried product.

[0083] (9) A pharmaceutical formulation according to the present invention comprises, as active ingredients, azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate; and sulfobutylether-β-cyclodextrin (SBE-β-CD).

[0084] (10) The pharmaceutical preparation according to (9) above may further contain albumin.

[0085] (11) The pharmaceutical formulation according to (9) or (10) above may further contain mannitol or trehalose as a lyophilizing agent.

[0086] (12) The pharmaceutical preparation according to any one of (9) to (11) above may further contain albumin; and mannitol or trehalose as a lyophilizing agent.

[0087] (13) The pharmaceutical preparation according to any one of (9) to (12) above may be an injection or a lyophilized product.

[0088] (14) A method for producing an injectable composition according to the present invention includes the steps of mixing sulfobutylether-β-cyclodextrin (SBE-β-CD) with an aqueous medium to produce an SBE-β-CD solution; and mixing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate with the SBE-β-CD solution.

[0089] (15) In the manufacturing method described in (14) above, a colorless, transparent solution can be obtained in the step of mixing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate.

[0090] (16) The production method according to (14) or (15) above may further include a step of mixing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate and then mixing albumin.

[0091] (17) The production method described in (16) above may further include a step of drying the solution containing albumin.

[0092] (18) The production method according to (16) or (17) above may further comprise the steps of adding mannitol or trehalose to the albumin-mixed solution; and drying the solution to which mannitol or trehalose has been added.

[0093] (19) The pH of the solution obtained in the step of mixing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate in the production method according to any one of (14) to (18) above may be 3 to 4.9.

[0094] (20) In the production method according to any one of (16) to (19) above, the solution mixed with the albumin may have a pH of 4 to 4.7.

[0095] (21) In the production method according to any one of (16) to (20), the solution mixed with the albumin has a pH of 4 to 4.9, and the production method can further include a step of drying the solution mixed with the albumin.

[0096] (22) The injectable composition according to any one of (1) to (8) above may be a pharmaceutical composition for preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases.

[0097] (23) The present invention provides a method for preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases, comprising a therapeutically effective amount of the injectable composition according to any one of (1) to (8) above.

[0098] (24) The present invention provides use of the injectable composition according to any one of (1) to (8) above for the manufacture of a medicament for preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases.

[0099] (25) The present invention provides use of the injectable composition according to any one of (1) to (8) above for preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases.

[0100] (Effects of the Invention) The injectable composition, pharmaceutical formulation containing the same, and method for producing the same according to the present invention can ensure excellent solubility and stability of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate. Furthermore, the injectable composition according to the present invention maintains stability without degradation even under high temperature, high humidity, and / or long-term harsh conditions, thereby providing an injectable preparation with excellent long-term storage stability. A lyophilized product that can be easily produced as an injectable preparation can also be provided.

[0101] Therefore, an injectable composition containing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate as an active ingredient, which has significantly excellent bioavailability, can exhibit excellent effects in preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases. [Brief explanation of the drawings]

[0102] [Figure 1] FIG. 1 is a photograph showing the properties of a freeze-dried product according to an embodiment of the present invention. [Example]

[0103] (Best Mode for Carrying Out the Invention) The present invention will be described in more detail below. The following examples are provided to illustrate the present invention, but are not intended to limit the scope of the present invention.

[0104] Preparation Example 1: Preparation of citrate salt of Compound 1 Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate was obtained by the following steps. Specifically, azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone was obtained by the method described in Patent Document 1. The NMR analysis results of the obtained azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone are as follows:

[0105] 1 H NMR (400 MHz, CDCl3); δ 7.63(d, J=1.2 Hz, 1H), 7.13(dd, J =8.4, 6.8 Hz, 1H), 7.06-7.04(m, 2H), 6.42(d, J= 1.2 Hz, 1H), 4.86-4.84(m, 1H), 4.41-4.28(m, 4H), 4.37(d, J =4.4 Hz, 2H), 3.75-3.69(m, 1H), 2.43-2.34(m, 13H).

[0106] Next, the resulting azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone was mixed with an alcohol solvent (isopropyl alcohol, IPA), stirred, and then vacuum-dried at approximately 30°C to 35°C to obtain a dried product. Approximately 10 g of this product was collected and stirred with approximately 167 g of acetone. A solution of approximately 5 g of citric acid in approximately 33 g of acetone was slowly added dropwise over 60 minutes and stirred at the same temperature for 1 hour. The resulting mixture was cooled to approximately 20°C to 25°C and stirred for an additional hour. The resulting solid was then filtered, washed with acetone, and vacuum-dried to obtain azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate. The NMR analysis results of the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate obtained above are as follows.

[0107] 1 H NMR(400MHz, MeOD); δ 7.90(s, 1H), 7.06-7.15(m, 3H), 6.77(s, 1H), 4.50(t, J=7.2Hz, 2H), 4.45(s, 2H), 4.24(t, J=7.2Hz, 2H), 2.80(d, J=15.6Hz, 2H), 2.70(d, J=12.0, 2H), 2.39-2.44(m, 11H), 2.35(s, 3H).

[0108] Examples 1 to 35: Preparation of injections Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate (citrate of Compound 1) obtained according to Preparation Example 1, SBE-β-CD, and 10% albumin or mannitol were weighed out in the amounts shown in Tables 1 to 4 below, mixed with a predetermined amount of water for injection, and thoroughly stirred to completely dissolve. The pH and properties of the obtained solutions are also shown in Tables 1 to 4 below.

[0109] In the case of the injectable preparations containing albumin in the examples shown in Tables 1 to 4 below, the citrate salt of Compound 1, SBE-β-CD, and optionally mannitol were mixed with water for injection and thoroughly stirred, and then 10% albumin was added at the content shown in Tables 1 to 4 and stirred. [Table 1] [Table 2] [Table 3] [Table 4]

[0110] Referring to Tables 1 to 4 above, it was confirmed that the injections obtained in Examples 1 to 35 were all obtained as colorless, transparent solutions.

[0111] The citrate salt of Compound 1 can give a clear solution without SBE-β-CD at pH below 3, but its solubility may decrease rapidly at pH above 3. The presence of SBE-β-CD may enable the citrate salt of Compound 1 to exhibit excellent solubility in the pH range of 3 to 4.7. The use of various known solubilizing agents may not improve the solubility of the citrate salt of Compound 1 at pH above 3. However, it was confirmed that the addition of albumin and / or mannitol may improve the solubility of the citrate salt with SBE-β-CD.

[0112] Examples 36 to 52: Preparation of freeze-dried products Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate (the citrate salt of Compound 1) obtained according to Preparation Example 1, SBE-β-CD, and 10% albumin were weighed out in the amounts shown in Table 5 below, mixed with a predetermined amount of water for injection, and thoroughly stirred to completely dissolve the mixture to obtain a colorless, clear solution. Alternatively, mannitol or trehalose was further added to the mixture to obtain an injectable composition for lyophilization. The resulting solution was then filtered through a 0.22 μm membrane filter and filled into a cleaned and sterilized sealable vial. The vial was then lyophilized to produce lyophilized products according to Examples 36 to 43 of the present invention.

[0113] In the case of the injectable preparations containing albumin in the examples in Table 5 below, the citrate salt of Compound 1, SBE-β-CD, and optionally mannitol or trehalose were mixed with water for injection and thoroughly stirred, and then 10% albumin was added in the amount shown in Table 5 and stirred.

[0114] In addition, the liquid phase injectable compositions (Examples 2 to 5, 8 to 11 and 35) prepared according to Tables 1 to 4 were freeze-dried using essentially the same steps as above, such as filtration and washing, to produce freeze-dried products according to Examples 44 to 52 of the present invention. [Table 5]

[0115] The photograph in Figure 1 shows the properties of each freeze-dried product produced according to Examples 36 to 52 of the present invention. Referring to Figure 1, it was confirmed that the freeze-dried products produced according to Examples 36 to 52 of the present invention were stably obtained as sufficient amounts of white solids.

[0116] Evaluation 1: Solution stability The stability of each injection according to the examples of the present invention was confirmed on days 4 and 7. Specifically, the changes in appearance and stability were confirmed using HPLC at temperatures of 40°C, 25°C, and 4°C. The HPLC conditions were as follows: Column: C18 (4.6 mm x 150 mm, 3 μm) Mobile phase: A = 0.1% TFA aqueous solution / B = acetonitrile Mobile phase flow rate: 1.0mL / min Detector: UV absorption spectrophotometer 254 nm Mobile phase distribution over time TIFF2026505092000010.tif39155

[0117] As a result, it was confirmed that the injections of Examples 3, 4, 12, 13, 17-19, 23-25, 28, and 7 of the present invention did not change in properties even after at least 5 days under refrigerated / room temperature / high temperature conditions.

[0118] Furthermore, the HPLC analysis results of the injections according to Examples 1, 2, 3, 4, 5, 6 and 35 of the present invention after 7 days showed a purity of at least 99.5%, confirming that the injections were indeed maintained stably without decomposition.

[0119] Considering that injections are generally stored in a refrigerator, the storage stability at 4°C was confirmed. The injections according to the present invention shown in Tables 1 to 4 maintained their initial colorless and transparent state for at least 4 days or more under refrigerated storage, demonstrating excellent stability under refrigerated storage and storage stability.

[0120] Evaluation 2: Stability of the lyophilized product The storage stability of each freeze-dried product according to the present invention was evaluated under harsh conditions (60°C, 80% RH) for 2 weeks and 4 weeks, and the results are shown in Table 6 below. [Table 6]

[0121] The freeze-dried product according to the present invention was stably obtained as a white solid, and it was confirmed that it maintained its state without discoloration or change in properties even after 4 weeks. In particular, the HPLC analysis results showed that it was 99% or more, confirming that it was not actually decomposed but was maintained stably. This confirmed that the freeze-dried product according to the present invention has excellent stability.

[0122] The freeze-dried product was stored at 60°C for 4 weeks, and its properties and stability were confirmed. When the freeze-dried product was redissolved in 1 mL of distilled water after 4 weeks, a colorless, transparent solution was obtained. The pH of the resulting solution was confirmed to be in the range of 3 to 4.9.

[0123] Furthermore, the freeze-dried product of Example 41, which had been stored at 4°C and whose properties and stability had been confirmed after 4 weeks, was redissolved in 1 mL of distilled water, yielding a colorless, transparent solution.

[0124] Although the present invention has been described herein with reference to preferred embodiments, those skilled in the art will recognize that the invention is capable of various changes and modifications without departing from the spirit and scope thereof, as set forth in the following claims.

Claims

1. The active ingredients are azetidine-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone citrate; and Sulfobutyl ether-β-cyclodextrin (SBE-β-CD) An injectable composition containing the following:

2. The injectable composition according to claim 1, further comprising albumin.

3. The injectable composition according to claim 1, further comprising mannitol or trehalose as a freeze-drying agent.

4. Albumin as a solubilizing agent; and Mannitol or trehalose as a freeze-drying agent The injectable composition according to claim 1, further comprising:

5. The injectable composition according to claim 1 or 2, wherein the pH of the liquid phase is 3 or more and 4.9 or less.

6. The injectable composition according to claim 1, wherein the pH is 3 to 3.95 and the liquid phase is colorless and transparent.

7. The injectable composition according to claim 2, wherein the pH is 4 to 4.9 and the liquid phase is colorless and transparent.

8. The injectable composition according to any one of claims 1 to 4, wherein the solid phase is a freeze-dried product.

9. The active ingredients are azetidine-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone citrate; and Sulfobutyl ether-β-cyclodextrin (SBE-β-CD) A pharmaceutical preparation containing the above.

10. The pharmaceutical preparation according to claim 9, further comprising albumin.

11. The pharmaceutical preparation according to claim 9, further comprising mannitol or trehalose as a freeze-drying agent.

12. Albumin; and Mannitol or trehalose as a freeze-drying agent A pharmaceutical preparation according to claim 9, further comprising:

13. A pharmaceutical preparation according to any one of claims 9 to 12, which is an injectable preparation or a lyophilized product.

14. A step of preparing an SBE-β-CD solution by mixing sulfobutyl ether-β-cyclodextrin (SBE-β-CD) with an aqueous medium; and The step of mixing azetidine-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone citrate with the aforementioned SBE-β-CD solution. A method for producing an injectable composition containing the above.

15. A method for producing an injectable composition according to claim 14, wherein a colorless and transparent solution is obtained by the step of mixing azetidine-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone citrate.

16. A method for producing an injectable composition according to claim 14, further comprising the steps of mixing azetidine-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone citrate, and then mixing in albumin.

17. A method for producing an injectable composition according to claim 16, further comprising the step of drying a solution mixed with albumin.

18. The step of adding mannitol or trehalose to a solution containing albumin; and The process of drying the solution to which the mannitol or trehalose has been added. A method for producing an injectable composition according to claim 14, further comprising:

19. A method for producing an injectable composition according to claim 14, wherein the pH of the solution obtained in the step of mixing azetidine-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridine-6-yl}methanone citrate is 3 to 4.

9.

20. A method for producing an injectable composition according to claim 16, wherein the pH of the solution mixed with the albumin is 4 to 4.

7.

21. The pH of the solution containing the aforementioned albumin is 4 to 4.

9. A method for producing an injectable composition according to claim 16, further comprising the step of drying the solution containing the albumin.

22. The injectable composition according to claim 1, wherein the injectable composition is a pharmaceutical composition for the prevention or treatment of gastrointestinal inflammatory disease or gastric acid-related disease.

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