Pharmaceutical preparation, its manufacturing method and tablet composition

Abstract

The present invention relates to a pharmaceutical formulation, a method for producing the same, and a tablet composition. The pharmaceutical formulation according to the present invention contains azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate as an active ingredient and microcrystalline cellulose as an excipient.

Description

[Technical Field]

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

[0002] Generally, to be considered as a candidate for drug development, a substance must possess not only favorable biological properties but also physical properties that enable its use as a pharmaceutical. However, even drugs with excellent activity often have difficulty in industrial application due to their poor formulation stability.

[0003] 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).

[0004] Therefore, the present inventors have endeavored to develop a stable pharmaceutical preparation of an imidazo[1,2-a]pyridine compound or a pharmaceutically acceptable salt thereof, and as a result have completed the present invention. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] Korean Patent No. 10-1777971 DETAILED DESCRIPTION OF THE INVENTION

[0006] (Problem to be solved by the invention) An object of the present invention is to provide a pharmaceutical preparation containing an imidazo[1,2-a]pyridine compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0007] Another object of the present invention is to provide a method for preparing said pharmaceutical formulation.

[0008] It is yet another object of the present invention to provide a tablet composition.

[0009] (Means for solving the problem) A pharmaceutical formulation for the purposes of the present invention comprises azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate as an active ingredient; and microcrystalline cellulose as an excipient.

[0010] 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)

[0011] 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 substance.

[0012] 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).

[0013] 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 more quickly than the free base of Compound 1, with a Cmax at least 11 times higher and an AUC at least 5 times higher.

[0014] Pharmacologically, the citrate salt of Compound 1 is powdery and has very high dispersion and adhesive properties. Due to these properties, at least a portion of the powder of the citrate salt of Compound 1 easily forms agglomerates and easily disperses irregularly even in a fine air current, making the handling of the citrate salt of Compound 1 very difficult. This is very different from the powder properties of the solid phase of Compound 1 (free base). Therefore, although the citrate salt of Compound 1 is a drug with superior bioavailability to Compound 1, it is very difficult to formulate it into a tablet that has good tabletability while maintaining pharmaceutically appropriate flowability.

[0015] According to the present invention, the citrate of Compound 1 can be stably formulated while preventing a decrease in the dissolution rate of the citrate of Compound 1. Furthermore, the pharmaceutical formulations according to the present invention can be produced in a stable form, and even in mass production, the active ingredient contained in each pharmaceutical formulation can be uniformly contained per unit formulation. Furthermore, the pharmaceutical formulations are physically stable due to low friability or abrasion, and are chemically stable even under changes in temperature and / or humidity and during storage. Furthermore, the pharmaceutical formulations of the present invention have excellent tableting properties, and tableting failures do not occur even when a direct compression process is used. Furthermore, the dissolution stability of the citrate of Compound 1 can be improved.

[0016] In one embodiment, the particle size D of the citrate salt of Compound 1 in the pharmaceutical formulation according to the invention 90 The thickness may be 60 μm or less, for example, 20 to 60 μm.

[0017] In one embodiment, in the pharmaceutical preparation according to the present invention, the weight ratio of the citrate salt of Compound 1 to microcrystalline cellulose may be 1:3.5 to 1:12.

[0018] This allows the citrate salt of Compound 1 to be stably formulated together with additives, ensuring that the active ingredient contained in each pharmaceutical preparation is uniformly contained per unit preparation, while preventing a decrease in the dissolution rate of the active ingredient in the preparation.

[0019] In one embodiment, the weight ratio of the citrate salt of Compound 1 to microcrystalline cellulose may be 1:5 to 1:9.

[0020] In one embodiment, the weight ratio of the citrate salt of Compound 1 to microcrystalline cellulose may be 1:6 to 1:7.

[0021] In one embodiment, the unit dosage form, i.e., the citrate salt of Compound 1, may be 5 to 50 mg per unit tablet, in which case the microcrystalline cellulose may be contained in an amount of 17.5 mg to 600 mg.

[0022] In one embodiment, a unit dosage form may contain 10 to 40 mg of the citrate salt of Compound 1 and 35 mg to 480 mg of microcrystalline cellulose.

[0023] In one embodiment, a unit dosage form may contain 20 mg of the citrate salt of Compound 1 and 70 mg to 240 mg of microcrystalline cellulose.

[0024] In one embodiment, a unit dosage form may contain 20 mg of the citrate salt of Compound 1 and 100 mg to 180 mg of microcrystalline cellulose.

[0025] In one embodiment, a unit dosage form may contain 20 mg of the citrate salt of Compound 1 and 130 mg to 140 mg of microcrystalline cellulose.

[0026] In one embodiment, the pharmaceutical formulation may include anhydrous lactose as an excipient.

[0027] In one embodiment, the weight ratio of the citrate salt of Compound 1 to anhydrous lactose may be 1:1 to 1:3.

[0028] In one embodiment, the weight ratio of the citrate salt of Compound 1 to anhydrous lactose may be 1:1.5 to 1:2.5.

[0029] In one embodiment, a unit dosage form may contain 10 to 30 mg of the citrate salt of Compound 1 and 10 to 45 mg of anhydrous lactose.

[0030] In one embodiment, a unit dosage form may contain 20 mg of the citrate salt of Compound 1 and 35 to 45 mg of anhydrous lactose.

[0031] In one embodiment, the particle size D of the anhydrous lactose contained in the pharmaceutical formulation 50 may be 110 to 130 μm.

[0032] In this specification, "particle size D x = Y (where X and Y are positive numbers) means that when particle size (particle diameter) distribution is represented by a cumulative curve, the particle size at the point where the particle size accumulates from 0 to X% (% is calculated based on number, volume, or weight) is Y. Therefore, particle size D 10 means the particle size at the 10% point on the cumulative curve of particle size distribution, and particle size D 50 means the particle size at the 50% point on the cumulative curve of particle size distribution, and particle size D 90can be defined as the particle size at the 90% point on the cumulative curve of the particle size distribution. The "particle size Dx" also differs depending on whether it represents the percentage of the total number of particles accumulated based on number, volume, or weight. Particle size Dx can be measured by laser diffraction, which considers particles as volume-equivalent spheres and records their diameters. When measuring particle size distribution using laser diffraction, the X value for particle size Dx represents the drug fraction calculated by volume average. Therefore, laser diffraction provides a volume-average particle size that is sensitive to particle volume, which can be considered the weight-average particle size when the density is constant. Volume-average particle size distribution can be measured using commercially available measurement devices based on laser diffraction and scattering methods based on Mie theory. For example, particle size can be measured using a Mastersizer laser diffraction device manufactured by Malvern Instruments.

[0033] In one embodiment, the particle size D 50 may be the average particle size.

[0034] In one embodiment, the microcrystalline cellulose used as an additive in the present invention has a particle size D 50 First microcrystalline cellulose with a particle size of 150-210 μm and particle size D 50 The second microcrystalline cellulose may have a particle size of 230 to 270 μm.

[0035] In one embodiment, the particle size D of the first microcrystalline cellulose 50 In this case, the particle size D of the second microcrystalline cellulose may be 160 to 200 μm or 170 to 190 μm. 50 may be 240 to 260 μm.

[0036] In one embodiment, the first microcrystalline cellulose is Vivapur® 12, Avicel® PH200, or the like, and the second microcrystalline cellulose is Vivapur® 200, or the like.

[0037] In one embodiment, the weight ratio of the first microcrystalline cellulose to the second microcrystalline cellulose may be 1:1 to 1:1.5.

[0038] In the present invention, by using the first and second microcrystalline celluloses in combination, it is possible to mix the active ingredient, Compound 1 citrate, and the additives very uniformly, and at the same time, it is possible to ensure excellent fluidity and tabletability of the mixture containing the active ingredient and the additives. Compared to the present invention, when the first microcrystalline cellulose or the second microcrystalline cellulose is used alone, or when the particle size D 50 When microcrystalline cellulose having a particle size of 130 μm or less is used, it is difficult to achieve a desirable formulation of a tablet containing the citrate salt of Compound 1 as an active ingredient in a mixture containing an active ingredient and an additive.

[0039] In the present invention, by including microcrystalline cellulose and / or anhydrous lactose that satisfy the above conditions as an additive to the citrate salt of Compound 1, the fluidity and tabletability of the composition for producing pharmaceutical formulations can be improved, the active ingredients contained in each pharmaceutical formulation can be uniformly distributed per unit formulation, the compressibility and disintegration of the pharmaceutical formulation can be improved, and the pharmaceutical formulation can be stable against temperature and / or humidity.

[0040] In one embodiment, the pharmaceutical formulation may contain pharmaceutically acceptable additives in addition to the active ingredient and additives. Examples of pharmaceutically acceptable additives include binders, disintegrants, lubricants, diluents, pH adjusters, solubilizers, surfactants, coating agents, etc., and two or more of these may be used in combination.

[0041] In one embodiment, the pharmaceutical formulation may contain a disintegrant and a lubricant in addition to the active ingredient and additives.

[0042] Examples of the disintegrants include starch or modified starches (e.g., sodium starch glycolate, corn starch, potato starch, or pregelatinized starch); clays (e.g., bentonite, montmorillonite, or veegum); celluloses (e.g., hydroxypropyl cellulose, carboxymethyl cellulose); algins (e.g., sodium alginate, alginic acid); cross-linked celluloses (e.g., croscarmellose sodium); gums (e.g., guar gum, xanthan gum); cross-linked polymers (e.g., crospovidone); and foaming agents (e.g., sodium bicarbonate, citric acid). These can be used alone or in combination.

[0043] Examples of the lubricant include calcium stearate, glyceryl monostearate, glyceryl monostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, talc, etc. These may be used alone or in combination of two or more.

[0044] In one embodiment, the lubricant of the present invention may contain sodium stearyl fumarate and magnesium stearate. Since the pharmaceutical formulation of the present invention contains sodium stearyl fumarate and magnesium stearate, the stability of the formulation and / or the stability of the formulation can be improved. In the pharmaceutical formulation of the present invention, the weight ratio of sodium stearyl fumarate to magnesium stearate may be 5:2 to 1:3. For example, in the pharmaceutical formulation of the present invention, the magnesium stearate may be 40 to 300 parts by weight per 100 parts by weight of sodium stearyl fumarate. In the pharmaceutical formulation of the present invention, the magnesium stearate may be 45 to 250 parts by weight per 100 parts by weight of sodium stearyl fumarate.

[0045] Examples of the coating agent include polyvinyl alcohol, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, polyvinyl acetate, polyethylene glycol, titanium dioxide, iron oxide, etc. Furthermore, examples of the product name Opadry (registered trademark) include Opadry White, Opadry Pink, Opadry Green, Opadry Orange, Opadry Blue, Opadry Yellow, Opadry Brown, etc. These can be used alone or in combination of two or more.

[0046] In one embodiment, the pharmaceutical formulation may be an oral formulation.

[0047] In one embodiment, the pharmaceutical formulation is an oral formulation, which may be a tablet.

[0048] In one embodiment, the tablet may be a plain tablet or a coated tablet. In this case, the plain tablet contains the active ingredient and additives, and the coating layer may contain a coating agent. Opadry Pink can be used as the coating agent.

[0049] In one embodiment, the pharmaceutical formulation may be a core tablet comprising the active ingredient and microcrystalline cellulose.

[0050] In one embodiment, the pharmaceutical preparation may be a coated tablet in which a core tablet containing the active ingredient and microcrystalline cellulose is coated with a coating layer.

[0051] The pharmaceutical formulation according to the present invention may include a tablet composition, which comprises the citrate salt of Compound 1 and microcrystalline cellulose. The components contained in the tablet composition are substantially the same as those described in the pharmaceutical formulation, and therefore, a detailed description thereof will be omitted.

[0052] The method for producing a pharmaceutical formulation according to the present invention comprises the steps of: mixing the citrate salt of Compound 1 and microcrystalline cellulose to produce a tablet composition; and

[0053] The method includes a step of producing tablets by compressing the tablet composition.

[0054] In the step of producing the tablet composition, the citrate salt of Compound 1 and microcrystalline cellulose can be mixed at a weight ratio of 1:3.5 to 1:12.

[0055] In the process of preparing the tablet composition, anhydrous lactose can be mixed together.

[0056] The microcrystalline cellulose of the tablet composition has a particle size of D 50 First microcrystalline cellulose with a particle size of 150-210 μm and particle size D 50 The second microcrystalline cellulose may contain 230 to 270 μm.

[0057] The tablet composition may further comprise a disintegrant and / or a lubricant.

[0058] The tableting composition obtained as described above overcomes the scattering and adhesive properties of the citrate salt of Compound 1, and can produce tablets with stable flowability and good physical compression properties. Tablets produced using this composition have a stable shape, are physically stable with low friability or abrasion, and are chemically stable against temperature and / or humidity and long-term storage. Furthermore, the citrate salt of Compound 1, the active ingredient of the tablets, has an excellent dissolution rate and dissolution stability.

[0059] The step of producing the tablet includes a step of compressing the tablet composition to obtain a core tablet. The step of obtaining the core tablet may be performed by a direct compression process.

[0060] The step of producing the tablet may include a step of compressing the tablet composition to obtain a core tablet; and a step of coating the core tablet to obtain a coated tablet.

[0061] (1) The pharmaceutical preparation 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 as an active ingredient; and microcrystalline cellulose as an additive.

[0062] (2) In the pharmaceutical preparation described in (1), the weight ratio of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate to microcrystalline cellulose may be 1:3.5 to 1:12.

[0063] (3) In the pharmaceutical composition according to (1) or (2), the content of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate per unit dosage form may be 5 to 50 mg.

[0064] (4) The pharmaceutical preparation according to any one of (1) to (3) above may contain anhydrous lactose as an additive.

[0065] (5) In the pharmaceutical preparation according to any one of (1) to (4), the microcrystalline cellulose has a particle size D 50 First microcrystalline cellulose with a particle size of 150-210 μm and particle size D 50 and second microcrystalline cellulose having a diameter of 230 to 270 μm.

[0066] (6) In the pharmaceutical preparation according to (5) above, the weight ratio of the first microcrystalline cellulose to the second microcrystalline cellulose may be 1:1 to 1:1.5.

[0067] (7) The pharmaceutical preparation according to any one of (1) to (6) above may contain sodium stearyl fumarate and magnesium stearate as lubricants.

[0068] (8) The pharmaceutical preparation according to claim 7, wherein the weight ratio of sodium stearyl fumarate to magnesium stearate is 5:2 to 1:3.

[0069] (9) The pharmaceutical preparation according to any one of (1) to (8) above may be a tablet.

[0070] (10) The pharmaceutical preparation according to any one of (1) to (9) above may be a compressed product produced by direct compression.

[0071] (11) A method for producing a pharmaceutical formulation according to the present invention includes the steps of: preparing a tablet 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 and microcrystalline cellulose as an additive; and compressing the tablet composition by direct compression to produce tablets.

[0072] (12) The pharmaceutical preparation according to any one of (1) to (10) above may be for the prevention or treatment of gastrointestinal inflammatory diseases or gastric acid-related diseases.

[0073] (13) The present invention provides use of a composition comprising azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo1,2-a]pyridin-6-yl}methanone citrate as an active ingredient and microcrystalline cellulose as an additive in the manufacture of the pharmaceutical preparation according to any one of (1) to (10) above for preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases.

[0074] (14) The present invention provides a method for preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases, which comprises administering the pharmaceutical preparation according to any one of (1) to (10) above to a subject.

[0075] (15) The present invention provides use of the pharmaceutical preparation according to any one of (1) to (10) above for preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases.

[0076] (Effects of the Invention) The pharmaceutical formulation, its manufacturing method, and tablet composition according to the present invention enable the pharmaceutical formulation to stably formulate azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate while preventing a decrease in its dissolution rate. Furthermore, the pharmaceutical formulation according to the present invention can be manufactured in a stable form, and even when manufactured in large quantities, the active ingredient contained in each pharmaceutical formulation can be uniformly contained per unit dosage form. Furthermore, the pharmaceutical formulation has low friability / abrasion and is physically stable, and is chemically stable even when subjected to changes in temperature and / or humidity and during long-term storage. Furthermore, azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate has excellent dissolution rate and dissolution stability.

[0077] Therefore, an oral pharmaceutical formulation containing azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-ylmethanone citrate as an active ingredient has significantly excellent bioavailability and can be highly effective in preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases. [Brief explanation of the drawings]

[0078] [Figure 1] 1 is a graph showing the dissolution characteristics over time of the tablet according to Example 1 of the present invention. [Example]

[0079] (Best Mode for Carrying Out the Invention) The present invention will be described in detail below with reference to examples. The following examples are intended to illustrate the present invention, but the present invention is not limited to these examples.

[0080] 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 according to the following method. Specifically, azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone was obtained according to 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 shown below.

[0081] 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).

[0082] Next, the azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone obtained above was mixed with an alcohol solvent (isopropyl alcohol, IPA), stirred, and then vacuum-dried at approximately 30°C to obtain a dried product. Approximately 10 g of the resulting dried product was collected and stirred with approximately 167 g of acetone. A solution of approximately 5 g of citric acid dissolved in approximately 33 g of acetone was slowly added to the mixture over 60 minutes and stirred at the same temperature for 1 hour. The reaction mixture was cooled to approximately 20-25°C and further stirred for 1 hour. The resulting solid was 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 citric acid obtained above are as follows.

[0083] 1 H NMR (400 MHz, MeOD); δ 7.90 (s, 1H), 7.06-7.15 (m, 3H), 6.77 (s, 1H), 4.50 (t, J=7.2 Hz, 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).

[0084] Examples 1 to 29: Tablet production Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6}ylmethanone citrate (citrate of Compound 1) obtained according to Preparation Example 1 above and ingredients in the amounts shown in Tables 1 to 6 below were weighed out to obtain a mixture so that the contents per unit tablet were as shown in Tables 1 to 6. The mixture was directly compressed to obtain tablets. The tableting pressure in the direct compression step was 500 to 600 kgf. The tablets were then coated using Opadry.

[0085] In the present invention, D is used as a raw material for tablets. 50 The first microcrystalline cellulose has a diameter of about 180 μm, and 50 The second microcrystalline cellulose with a diameter of about 250 μm was used. 50 The diameter was approximately 121 μm.

[0086] [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6]

[0087] Comparative Example: Tablet Production A comparative tablet composition was prepared that can be used to prepare tablets having the ingredients and contents shown in Table 7, similar to the ingredients and contents shown in Table 1, except that 20 mg of Compound 1 was used instead of the citrate salt of Compound 1.

[0088] In addition, a comparative tablet composition was prepared that can be used to prepare tablets having the ingredients and contents shown in Table 7, similar to the ingredients and contents shown in Table 1, except that 20 mg of the fumarate salt of Compound 1 was used instead of the citrate salt of Compound 1.

[0089] Each comparative tablet composition was directly compressed to obtain tablets according to Comparative Example 1 and Comparative Example 2. These were then coated using Opadry. In the direct compression step, it was confirmed that the tablets of Comparative Example 1 and Comparative Example 2 and the tablets of Example 1 could not be stably compressed at substantially the same compression pressure, and comparative tablets were produced by applying a compression pressure of 1000 kgf or more, specifically at least 1100 to 1200 kgf.

[0090] [Table 7]

[0091] Evaluation 1: Dissolution characteristics The dissolution rate of the active ingredient over time was measured under pH 1.2 conditions for the coated tablets obtained in Example 1. The dissolution test was carried out according to the following method, and the results are shown in Figure 1. TIFF2026503327000011.tif50164

[0092] 1, it was confirmed that the citrate salt of Compound 1 in the tablet according to the present invention was dissolved at a rate of about 80% or more within 10 minutes. This is a very good initial dissolution rate, and supports the fact that the tablet according to the present invention exhibits a good initial dissolution rate.

[0093] Evaluation 2: Acceleration conditions The uncoated tablets and coated tablets obtained in the same manner as in Example 1 were left in an acceleration chamber (40°C, 75% RH) and the change in LOD (loss on drying, in %) after 24 hours was measured. LOD was measured in accordance with the loss on drying test method of the Korean Pharmacopoeia.

[0094] The uncoated tablet according to the present invention was packed into a polyethylene container with a lid together with 1 g of silica gel, and the LOD (%) was measured. As a result, it was found that the value measured after 24 hours was almost the same as the initial value.

[0095] Rating 3: Harsh conditions The uncoated tablets and coated tablets obtained by the same process as in Example 1 were left under harsh conditions (60°C, 80% RH) for 2 weeks, and then the LOD (loss on dry weight) was measured. Furthermore, the changes in content, changes in impurities, and dissolution characteristics under harsh conditions were measured.

[0096] Each experiment was carried out as follows. TIFF2026503327000012.tif76164

[0097] The uncoated tablets according to the present invention were packaged in a lidded polyethylene container (without silica gel) and the LOD (%) was measured. As a result, it was confirmed that the difference between the initial value and the value measured after 2 weeks was significantly smaller than that of the uncoated tablets obtained in Comparative Examples 1 and 2. In other words, the uncoated tablets according to the present invention are stable tablets with extremely low hygroscopicity. On the other hand, the LOD (%) was similarly measured for uncoated tablets containing Compound 1 or its fumarate salt, and it was confirmed that the value significantly increased after 2 weeks.

[0098] The results of the content change of the uncoated tablet according to Example 1 of the present invention under severe conditions are as follows. [Table 8]

[0099] Referring to Table 8, it was found that the content after the first and second weeks did not change from the initial value. This confirmed that the uncoated tablets according to the present invention are very stable. Furthermore, when the change in content was measured similarly for the coated tablets according to the present invention, it was confirmed that the content did not change at least until the second week under harsh conditions.

[0100] The purity of the uncoated tablets according to the present invention was measured under harsh conditions to check for the generation of impurities, and it was found that the purity did not change substantially between the first and second weeks compared to the initial purity.

[0101] Furthermore, changes in dissolution rate under harsh conditions were confirmed, and dissolution rate measurements were performed at pH 1.2 and pH 4.0. As a result, it was found that the dissolution rates of the uncoated tablets and coated tablets according to the present invention at pH 1.2 and pH 4.0 were stable, with substantially no change compared to the initial dissolution rate, even after the first and second weeks under harsh conditions. For uncoated tablets containing the fumarate salt of Compound 1, changes in dissolution rate were similarly measured at pH 1.2 and pH 4.0 after storage under harsh conditions, and it was confirmed that the fumarate salt of Compound 1 showed a significantly higher change in dissolution rate. Therefore, it was confirmed that the tablets according to the present invention containing the citrate salt of Compound 1 as an active ingredient not only exhibited excellent dissolution rate, but also excellent dissolution stability.

[0102] Evaluation 4: Evaluation of content uniformity Tablets (coated tablets) according to Example 1 were produced according to the test method for uniformity of coated tablets in the general test method. The content of the citrate salt of Compound 1 in 10 tablets was measured and converted into a percentage relative to the initial content to evaluate the content uniformity. The results are shown in Table 9. [Table 9]

[0103] Referring to Table 9, the average value was 99.2% and the deviation was only 1.2%, that is, it was confirmed that the tablets (coated tablets) according to Example 1 had very good content uniformity.

[0104] While the present invention has been described above with reference to preferred embodiments, those skilled in the art will appreciate that various changes and modifications can be made thereto without departing from the spirit and scope of the invention as set forth in the following claims.

Claims

1. Azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate as the active ingredient; and microcrystalline cellulose as an additive; 10. A pharmaceutical formulation comprising:

2. 2. The pharmaceutical preparation according to claim 1, wherein the weight ratio of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate to microcrystalline cellulose is 1:3.5 to 1:

12.

3. 2. The pharmaceutical preparation according to claim 1, wherein the content of azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate per unit preparation is 5 to 50 mg.

4. 2. The pharmaceutical formulation of claim 1, which contains anhydrous lactose as an excipient.

5. Microcrystalline cellulose has a particle size of D 50 a first microcrystalline cellulose having a particle size D 50 2. The pharmaceutical formulation according to claim 1, comprising a second microcrystalline cellulose having a particle size of 230 to 270 μm.

6. 6. The pharmaceutical formulation according to claim 5, wherein the weight ratio of the first microcrystalline cellulose to the second microcrystalline cellulose is 1:1 to 1:1.

5.

7. 2. The pharmaceutical formulation of claim 1, comprising sodium stearyl fumarate and magnesium stearate as lubricants.

8. 8. The pharmaceutical preparation according to claim 7, wherein the weight ratio of sodium stearyl fumarate to magnesium stearate is 5:2 to 1:

3.

9. 2. The pharmaceutical preparation according to claim 1, wherein the pharmaceutical preparation is a tablet.

10. 10. The pharmaceutical preparation according to claim 9, wherein the pharmaceutical preparation is a compressed product produced by direct compression.

11. A process for producing a tablet composition comprising azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate as an active ingredient and microcrystalline cellulose as an additive: a step of directly compressing the tablet composition to produce tablets; A method for producing a pharmaceutical formulation comprising:

12. The pharmaceutical preparation according to claim 1, which is for the prevention or treatment of gastrointestinal inflammatory diseases or gastric acid-related diseases.

13. Use of a composition comprising azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo-1,2-a]pyridin-6-yl}methanone citrate as an active ingredient and microcrystalline cellulose as an additive in the manufacture of the pharmaceutical preparation according to any one of claims 1 to 10 for preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases.

14. A method for preventing or treating a gastrointestinal inflammatory disease or a gastric acid-related disease, comprising administering the pharmaceutical preparation according to any one of claims 1 to 10 to a subject.

15. Use of the pharmaceutical preparation according to any one of claims 1 to 10 for the prevention or treatment of gastrointestinal inflammatory diseases or gastric acid-related diseases.

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