Pharmaceutical preparation, preparation method thereof and tablet composition

Abstract

The invention relates to a pharmaceutical preparation, a preparation method thereof and a tablet composition. The pharmaceutical formulation according to the present invention comprises azetidine-1-yl {8-[(2, 6-dimethylbenzyl) amino]-2, 3-dimethylimidazo [1, 2-a] pyridin-6-yl} ketone citrate as an active ingredient and microcrystalline cellulose as an excipient.

Description

TECHNICAL FIELD

[0001] The present application relates to a pharmaceutical preparation comprising an imidazo[1,2-a]pyridine compound or a salt thereof, a method for preparing the same, and a composition for tableting. BACKGROUND

[0002] Generally, in order to be considered as a candidate for development as a pharmaceutical agent, a substance must have desired biological properties as well as physical properties that enable it to be used pharmaceutically. However, even if a drug has excellent activity, it is often difficult to apply it to industrialization due to poor formulation stability thereof.

[0003] Meanwhile, the imidazo[1,2-a]pyridine compound or a pharmaceutically acceptable salt thereof is a drug material for preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases such as peptic ulcer, gastroduodenal ulcer, gastritis, gastroesophageal reflux disease (GERD), nonerosive reflux disease (NERD), etc.

[0004] Accordingly, the present inventors have endeavored to develop a stable pharmaceutical preparation for the imidazo[1,2-a]pyridine compound or a pharmaceutically acceptable salt thereof, and now have completed the present application.

[0005] [Prior Literature]

[0006] [Patent Literature]

[0007] (Patent Literature 1) Korean Patent No. 10-1777971 SUMMARY

[0008] TECHNICAL PROBLEM

[0009] An object of the present application is to provide a pharmaceutical preparation comprising an imidazo[1,2-a]pyridine compound or a pharmaceutically acceptable salt thereof as an active ingredient.

[0010] Another object of the present application is to provide a method for preparing a pharmaceutical preparation.

[0011] Still another object of the present application is to provide a composition for tableting.

[0012] SOLUTION TO THE TECHNICAL PROBLEM

[0013] The pharmaceutical preparation for one object of the present application 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.

[0014] In the present application, azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone is a compound 1 represented by the following formula 1

[0015] [Formula 1]

[0016]

[0017] The active ingredient in the present application is a citrate salt of the compound 1 represented by formula 1, and hereinafter, "azetidin-1-yl{8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate" and "the citrate salt of the compound 1" are intended to mean the same medicament.

[0018] The citrate salt of the compound 1 can be represented by the following formula 2.

[0019] [Formula 2]

[0020]

[0021] In the above formula 2, n can be 0.3 to 1.3, for example, n can be 0.5 to 1.

[0022] The citrate salt of the compound 1, which is the active ingredient of the present application, is a medicament that exhibits remarkably superior bioavailability compared to the compound 1 free base and is very effective in preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases. Specifically, when the citrate salt of the compound 1 is orally administered, it reaches the peak blood concentration faster than the compound 1 free base, in which Cmax is at least 11 times higher and AUC is at least 5 times higher.

[0023] Pharmacologically-physically, the citrate salt of the compound 1 is in a powder form, and has very high dispersibility, and even has tackiness. Due to these properties, at least a part of the powder of the citrate salt of the compound 1 easily forms agglomerates and is easily irregularly dispersed even in a fine air stream, making the handling of the citrate salt of the compound 1 very difficult. This is very different from the powder properties of the solid phase of the compound 1 (free base). Therefore, even though the citrate salt of the compound 1 is a medicament having better bioavailability than the compound 1, it is difficult to formulate to have good compressibility while having pharmaceutically sufficient flowability.

[0024] According to the present application, the citrate salt of Compound 1 can be stably formulated while preventing a decrease in the dissolution rate of the citrate salt of Compound 1. In addition, the pharmaceutical preparation according to the present application can be prepared in a stable shape, and when prepared on a large scale, the active ingredient contained in each pharmaceutical preparation can be uniformly contained in each unit preparation. In addition, the pharmaceutical preparation is physically stable due to low friability or attrition, and chemically stable, without change, in the case of temperature and / or humidity and long-term storage. In addition, the pharmaceutical preparation has excellent tabletability such that tabletting failure does not occur even when direct tabletting is used. In addition, the dissolution stability of the citrate salt of Compound 1 can be improved.

[0025] In one embodiment, the particle size D10 of the pharmaceutical preparation of the citrate salt of Compound 1 according to the present application can be 10 μm or less, for example, 1 μm to 10 μm. 90 may be 60 μm or less, for example, 20 μm to 60 μm.

[0026] In one embodiment, in the pharmaceutical preparation according to the present application, the weight ratio of the citrate salt of Compound 1 to microcrystalline cellulose can be 1:3.5 to 1:12.

[0027] Accordingly, the citrate salt of Compound 1 can be stably formulated with excipients while ensuring that the active ingredient contained in each pharmaceutical preparation is uniformly contained in each unit preparation and preventing a decrease in the dissolution rate of the active ingredient in the preparation.

[0028] In one embodiment, the weight ratio of the citrate salt of Compound 1 to microcrystalline cellulose can be 1:5 to 1:9.

[0029] In one embodiment, the weight ratio of the citrate salt of Compound 1 to microcrystalline cellulose can be 1:6 to 1:7.

[0030] In one embodiment, each unit tablet can contain the unit preparation, i.e., the citrate salt of Compound 1, in an amount of 5 mg to 50 mg. In this case, microcrystalline cellulose can be contained in an amount of 17.5 mg to 600 mg.

[0031] In one embodiment, the unit preparation can contain 10 mg to 40 mg of the citrate salt of Compound 1 and 35 mg to 480 mg of microcrystalline cellulose.

[0032] In one embodiment, the unit preparation can contain 20 mg of the citrate salt of Compound 1 and 70 mg to 240 mg of microcrystalline cellulose.

[0033] In one embodiment, the unit preparation can contain 20 mg of the citrate salt of Compound 1 and 100 mg to 180 mg of microcrystalline cellulose.

[0034] In an embodiment, the unit formulation can comprise 20 mg of citrate salt of Compound 1 and 130 mg to 140 mg of microcrystalline cellulose.

[0035] In an embodiment, the pharmaceutical formulation can comprise anhydrous lactose as an excipient.

[0036] In an embodiment, the weight ratio of the citrate salt of Compound 1 to anhydrous lactose can be 1 : 1 to 1 : 3.

[0037] In an embodiment, the weight ratio of the citrate salt of Compound 1 to anhydrous lactose can be 1 : 1 to 1 : 3.

[0038] In an embodiment, the unit formulation can comprise 10 mg to 30 mg of citrate salt of Compound 1 and 10 mg to 45 mg of anhydrous lactose.

[0039] In an embodiment, the unit formulation can comprise 20 mg of citrate salt of Compound 1 and 35 mg to 45 mg of anhydrous lactose.

[0040] In an embodiment, the particle size D 50 may be 110 pm to 130 pm.

[0041] As used herein, “particle size D X = Y (where X and Y are positive numbers)” means that when the particle size (particle diameter) distribution is represented by a cumulative curve, the particle size is Y at the point where the particle size accumulates to X% (the % is calculated based on number, volume, or weight) from zero. Thus, the particle size D 10 may be defined as the particle size at the 10% point on the cumulative curve of the particle size distribution, the particle size D 50 may be defined as the particle size at the 50% point on the cumulative curve of the particle size distribution, the particle size D 90 may be defined as the particle size at the 90% point on the cumulative curve of the particle size distribution. Further, “particle size D X ” can vary depending on whether it represents the percentage of the total cumulative particles based on number, volume, or weight. The particle size D X determination can be determined by a laser diffraction method, which records the diameter of the particles by considering the particles as volume-equivalent spheres. When the particle size distribution is determined by a laser diffraction method, the particle size D XThe value of X in the above formula indicates a percentage calculated by volume average. Thus, the laser diffraction method is sensitive to volume of particles, and provides a volume average particle size which can be considered as a weight average particle size if the density is constant. Measurement of the volume average particle size distribution can be performed using a commercially available measuring device based on laser diffraction / scattering according to Mie theory. For example, a Mastersizer laser diffraction device of Malvern Instruments can be used for measurement of the particle size.

[0042] In one embodiment, the particle size D 50 may be an average particle size.

[0043] In one embodiment, the microcrystalline cellulose as an excipient in the present application can include a first microcrystalline cellulose having a particle size D 50 of 150 μm to 210 μm and a second microcrystalline cellulose having a particle size D 50 of 230 μm to 270 μm.

[0044] In one embodiment, the particle size D 50 of the first microcrystalline cellulose can be 160 μm to 200 μm, or 170 μm to 190 μm. In this case, the particle size D 50 of the second microcrystalline cellulose can be 240 μm to 260 μm.

[0045] In one embodiment, the first microcrystalline cellulose can be 12、 PH200 or the like; and the second microcrystalline cellulose can be 200 or the like.

[0046] In one embodiment, the weight ratio of the first microcrystalline cellulose to the second microcrystalline cellulose can be 1:1 to 1:1.5.

[0047] By using the first microcrystalline cellulose and the second microcrystalline cellulose together in the present application, the excipient can be very uniformly mixed with the citrate salt of Compound 1 as an active ingredient, while excellent flowability and compressibility of a mixture containing the active ingredient and the excipient are obtained. In comparison with the present application, when the first microcrystalline cellulose or the second microcrystalline cellulose is used alone, or when a microcrystalline cellulose having a particle size D 50 of 130 μm or less is used, it is difficult to achieve a desired tablet formulation containing the citrate salt of Compound 1 as an active ingredient and a mixture containing the active ingredient and the excipient.

[0048] By including microcrystalline cellulose and / or anhydrous lactose satisfying the above conditions as an excipient of the citrate salt of Compound 1 in the present application, it is possible to improve the flowability and compressibility of the composition for preparing a pharmaceutical preparation, uniformly contain the active ingredient included in each pharmaceutical preparation in each unit preparation, improve the compressibility and disintegration of the pharmaceutical preparation, and stabilize the pharmaceutical preparation with respect to temperature and / or humidity.

[0049] In one embodiment, the pharmaceutical preparation can further include a pharmaceutically acceptable additive in addition to the active ingredient and the excipient. Examples of the pharmaceutically acceptable additive include, but are not limited to, a binder, a disintegrant, a lubricant, a diluent, a pH adjuster, a solubilizer, a surfactant, a coating agent, and the like, which can be used in combination of two or more.

[0050] In one embodiment, the pharmaceutical preparation can further include a disintegrant and a lubricant in addition to the active ingredient and the excipient.

[0051] Examples of the disintegrant can include starch or modified starch such as sodium starch glycolate, corn starch, potato starch, or pregelatinized starch; clay such as bentonite, montmorillonite, or magnesium aluminum silicate; cellulose such as hydroxypropyl cellulose or carboxymethyl cellulose; alginate such as sodium alginate or alginic acid; crosslinked cellulose such as crosscarmellose sodium; gum such as guar gum or xanthan gum; crosslinked polymer such as crosslinked polyvinylpyrrolidone; and effervescent agent such as sodium bicarbonate, citric acid, and the like. Each of these can be used alone or in a mixture of two or more.

[0052] Examples of the lubricant can include calcium stearate, glycerol monostearate, glycerol palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, talc, and the like. Each of these can be used alone or in a mixture of two or more.

[0053] In one embodiment, the lubricant of the present application can include sodium stearyl fumarate and magnesium stearate. Due to the inclusion of sodium stearyl fumarate and magnesium stearate, the pharmaceutical preparation of the present application can have improved formulation stability and / or formulation stability. In the pharmaceutical preparation of the present application, the weight ratio of sodium stearyl fumarate to magnesium stearate can be 5:2 to 1:3. For example, in the pharmaceutical preparation according to the present application, when sodium stearyl fumarate is 100 parts by weight, magnesium stearate can be 40 to 300 parts by weight. In the pharmaceutical preparation according to the present application, when sodium stearyl fumarate is 100 parts by weight, magnesium stearate can be 45 to 250 parts by weight.

[0054] Examples of the coating agent can include polyvinyl alcohol, hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, polyvinyl acetate, polyethylene glycol, titanium dioxide, iron oxide, etc.; or trade names such as Opadry White, Opadry Pink, Opadry Green, Opadry Orange, Opadry Blue, Opadry Yellow, Opadry Brown, etc. Each of these can be used alone or in a mixture of two or more. These include Opadry White, Opadry Pink, Opadry Green, Opadry Orange, Opadry Blue, Opadry Yellow, Opadry Brown, etc. Each of these can be used alone or in a mixture of two or more.

[0055] In one embodiment, the pharmaceutical preparation can be an oral preparation.

[0056] In one embodiment, the pharmaceutical preparation is an oral preparation, which can be a tablet.

[0057] In one embodiment, the tablet can be a naked tablet or a coated tablet in which a naked tablet is coated. In this case, the naked tablet can include an active ingredient and an excipient, and the coating layer can include a coating agent. As the coating agent, Opadry Pink can be used.

[0058] In one embodiment, the pharmaceutical preparation can be a naked tablet including an active ingredient and microcrystalline cellulose.

[0059] In one embodiment, the pharmaceutical preparation can be a coated tablet in which a naked tablet including an active ingredient and microcrystalline cellulose is coated by a coating layer.

[0060] The pharmaceutical preparation according to the present application can include a composition for tableting, and the composition for tableting includes a citrate salt of Compound 1 and microcrystalline cellulose. Since the components included in the composition for tableting are substantially the same as those described in the above pharmaceutical preparation, the redundant detailed description is omitted.

[0061] The method of preparing the pharmaceutical preparation according to the present application includes: preparing a composition for tableting by mixing a citrate salt of Compound 1 with microcrystalline cellulose; and

[0062] A tablet is prepared by tableting the composition for tableting.

[0063] In preparing the composition for tableting, the citrate salt of Compound 1 can be mixed with microcrystalline cellulose at a weight ratio of 1:3.5 to 1:12.

[0064] In preparing the composition for tableting, anhydrous lactose can be mixed together.

[0065] The microcrystalline cellulose of the composition for tableting can include a particle size D 50a first microcrystalline cellulose having a particle size D 50 a second microcrystalline cellulose having a particle size D

[0066] The composition for tableting can further include a disintegrant and / or a lubricant.

[0067] The composition for tableting obtained as described above overcomes the dispersibility and stickiness of the citrate salt of Compound 1, enabling the preparation of tablets having stable fluidity and good physical compressibility. The tablets prepared using the composition of the present application are stable in shape, physically stable, have low friability or attrition, and are chemically stable with respect to temperature and / or humidity and long-term storage. In addition, the citrate salt of Compound 1 as the active ingredient in the tablet has excellent dissolution rate and dissolution stability.

[0068] The step of preparing the tablet can include a step of obtaining a naked tablet by tableting the composition for tableting. The step of obtaining the naked tablet can be performed by direct tableting.

[0069] The step of preparing the tablet can include the steps of tableting the composition for tableting to obtain a naked tablet, and coating the naked tablet to obtain a coated tablet.

[0070] (1) The pharmaceutical preparation according to the present application comprises azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt as an active ingredient and microcrystalline cellulose as an excipient.

[0071] (2) In the pharmaceutical preparation according to the above (1), the weight ratio of azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt to microcrystalline cellulose can be 1:3.5 to 1:12.

[0072] (3) In the pharmaceutical preparation according to the above (1) or (2), azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt can be included in an amount of 5 mg to 50 mg per unit preparation.

[0073] (4) The pharmaceutical preparation according to any one of the above (1) to (3) can include anhydrous lactose as an excipient.

[0074] (5) In the pharmaceutical preparation according to any one of the above (1) to (4), the microcrystalline cellulose can include a first microcrystalline cellulose having a particle size D 50 a first microcrystalline cellulose having a particle size D50 a second microcrystalline cellulose of 230 μm to 270 μm.

[0075] (6) In the above (5), the weight ratio of the first microcrystalline cellulose to the second microcrystalline cellulose can be 1:1 to 1:1.5.

[0076] (7) The pharmaceutical preparation according to any one of the above (1) to (6) can contain sodium stearyl fumarate and magnesium stearate as lubricants.

[0077] (8) In the above (7), the weight ratio of the sodium stearyl fumarate to the magnesium stearate can be 5:2 to 1:3.

[0078] (9) The pharmaceutical preparation according to any one of the above (1) to (8) can be a tablet.

[0079] (10) The pharmaceutical preparation according to any one of claims (1) to (9) can be a compressed material prepared by direct compression.

[0080] (11) A method for producing a pharmaceutical preparation according to the present application includes: preparing a composition for tabletting, the composition for tabletting containing azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[l,2-a]pyridin-6-yl}methanone citrate as an active ingredient and microcrystalline cellulose as an excipient; and preparing a tablet by direct compression of the composition for tabletting.

[0081] (12) The pharmaceutical preparation according to any one of the above (1) to (10) can be used for the prophylaxis or treatment of a gastrointestinal inflammatory disease or a gastric acid-related disease.

[0082] (13) The present application provides use of a composition containing azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[l,2-a]pyridin-6-yl}methanone citrate as an active ingredient and microcrystalline cellulose as an excipient for the production of a pharmaceutical preparation according to any one of the above (1) to (10) for the prophylaxis or treatment of a gastrointestinal inflammatory disease or a gastric acid-related disease.

[0083] (14) The present application provides a method for the prophylaxis or treatment of a gastrointestinal inflammatory disease or a gastric acid-related disease, which comprises administering to a subject a pharmaceutical preparation according to any one of the above (1) to (10).

[0084] (15) The present application provides use of a pharmaceutical preparation according to any one of the above (1) to (10) for the prophylaxis or treatment of a gastrointestinal inflammatory disease or a gastric acid-related disease.

[0085] Effects of the Invention

[0086] In the pharmaceutical preparation according to the present application, the preparation method thereof, and the composition for tableting, the pharmaceutical preparation can 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. In addition, the pharmaceutical preparation according to the present application can be prepared in a stable shape, and when prepared on a large scale, the active ingredient contained in each pharmaceutical preparation can be uniformly contained in each unit preparation. In addition, the pharmaceutical preparation is physically stable, has low friability / attrition, and is chemically stable, without changes, in the case of temperature and / or humidity and long-term storage. In addition, the dissolution rate and dissolution stability of azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate are excellent.

[0087] Accordingly, the oral pharmaceutical preparation 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 remarkably excellent bioavailability, can also be highly effective in preventing or treating gastrointestinal inflammatory diseases or gastric acid-related diseases. BRIEF DESCRIPTION OF DRAWINGS

[0088] Figure 1 is a graph showing the dissolution characteristics of a tablet according to Example 1 of the present application over time. DETAILED DESCRIPTION

[0089] Hereinafter, embodiments of the present application will be described in detail. The following embodiments are illustrative of the present application and are not limiting of the present application.

[0090] Preparation Example 1 : Preparation of the citrate salt of Compound 1

[0091] 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 as described in Korean Patent No. 10-1777971. NMR analysis of the above-obtained azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone is shown below.

[0092] 1H NMR (400 MHz, CDC13); 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).

[0093] The azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[l,2- a]pyridin-6-yl}methanone obtained above was then mixed with an alcoholic solvent (isopropanol, IPA), stirred and vacuum dried at about 30°C to 35°C to obtain a dry product. About 10 g of the resulting dry product was taken and stirred with about 167 g of acetone. To this, a solution of citric acid (about 5 g) dissolved in acetone (about 33 g) was slowly added over a period of 60 minutes and stirred for 1 hour at the same temperature. The reaction mixture was cooled to about 20°C to 25°C and stirred for another 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[l,2- a]pyridin-6-yl}methanone citrate. The NMR analysis results of the azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[l,2-a]pyridin-6-yl}methanone citrate obtained above are as follows.

[0094] 1 H NMR (400 MHz, CDC13); 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).

[0095] Examples 1-29: Preparation of tablets

[0096] A mixture was obtained by weighing azetidin-1-yl {8-[(2,6-dimethylbenzyl)amino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl}methanone citrate salt (citrate salt of Compound 1) obtained according to the above Preparation Example 1 and components having amounts according to the following Tables 1 to 6 so that each component has the content of Tables 1 to 6 per unit tablet. Direct compression was performed on the above mixture to obtain tablets. The tabletting pressure in the direct compression was 500 to 600 kgf. Then, the tablets were coated using Opadry.

[0097] In the present application, D 50 about 180 pm and D 50 about 250 pm as a raw material of the tablet. In the case of anhydrous lactose, D 50 .

[0098] [Table 1]

[0099]

[0100]

[0101] [Table 2]

[0102]

[0103] [Table 3]

[0104]

[0105] [Table 4]

[0106]

[0107]

[0108] [Table 5]

[0109]

[0110] [Table 6]

[0111]

[0112]

[0113] Comparative Example: Preparation of tablets

[0114] A comparative tablet composition capable of preparing tablets having the ingredients and contents of Table 7 was prepared, except that 20 mg of Compound 1 was used instead of the citrate salt of Compound 1, which is the same as those of Table 1.

[0115] In addition, comparative tablet compositions capable of preparing tablets were prepared, which had the ingredients and amounts of Table 7, except that 20 mg of the fumarate salt of Compound 1 was used instead of the citrate salt of Compound 1, which were the same as those of Table 1.

[0116] Each of the comparative tablet compositions was directly compressed to obtain tablets of Comparative Example 1 and Comparative Example 2. Then, they were coated using Opadry. In the direct compression process, it was confirmed that the tablets of Comparative Example 1 and Comparative Example 2 could not be stably compressed with substantially the same tabletting pressure as the tablets according to Example 1, and the comparative tablets were prepared by applying a tabletting pressure of at least 1000 kgf, more specifically at least 1100 kgf to 1200 kgf.

[0117] [Table 7]

[0118]

[0119] Evaluation 1 : Dissolution characteristics

[0120] The coated tablets obtained according to Example 1 were subjected to a time-dependent active ingredient dissolution test under pH 1.2 conditions. The dissolution test was performed according to the following method, and the results are shown in Table 8. Figure 1

[0121]

[0122] Referring to Table 8, it can be confirmed that the tablets according to the present application showed about 80% or more of the citrate salt of Compound 1 dissolution within 10 minutes. This is a very good initial dissolution and demonstrates that the tablets according to the present application exhibit a good initial dissolution rate. Figure 1

[0123] Evaluation 2: Accelerated conditions For each of the naked tablets and coated tablets obtained by the same method as described in Example 1, the change in LOD (loss on drying unit %) within 24 hours after they were placed in an accelerated chamber (40°C, 75% RH) was measured. The LOD measurement was performed according to the loss on drying test of the Korean Pharmacopoeia.

[0124] The LOD (%) was measured by packing the naked tablets according to the present application and 1 g of silica gel in a polyethylene container with a lid, and it was found that the measured value after 24 hours was almost the same as the initial value.

[0125]

[0126] Evaluation 3: Pressure conditions

[0127] ​​For each of the naked tablets and the coated tablets obtained by the same method as described in Example 1, the loss on drying (LOD) was measured two weeks after they were put in a severe condition (60°C, 80% RH). In addition, the content change, the impurity change and the dissolution profile under pressure condition were also measured.

[0128] Each experiment was performed according to the following.

[0129]

[0130]

[0131] When the naked tablets according to the present application were packaged in a polyethylene container with a lid (without silica gel) and the LOD (%) was measured, it was confirmed that the difference between the initial value and the measured value after 2 weeks was significantly lower compared to the naked tablets obtained according to Comparative Examples 1 and 2. In other words, the naked tablets according to the present application are very stable tablets with very low hygroscopicity. On the other hand, when the same LOD (%) of tablets containing Compound 1 or the fumarate salt of Compound 1 was measured, it was confirmed that the value significantly increased after 2 weeks.

[0132] The results of the content change of the naked tablets according to Example 1 of the present application under pressure conditions are as follows.

[0133] [Table 8]

[0134]

[0135] Referring to Table 8 above, it can be known that there was no change in the content in each of the first and second weeks compared to the initial value. In other words, it can be confirmed that the naked tablets according to the present application are very stable. In addition, even for the coated tablets according to the present application, when the same content change was measured, it can be confirmed that there was no change in the content at least at the second week pressure condition.

[0136] The purity of the naked tablets according to the present application was measured under pressure conditions to check the occurrence of impurities, and it was found that the purity remained substantially unchanged compared to the initial purity for the first week and the second week. In addition, the purity of the coated tablets according to the present application was measured to check the occurrence of impurities, and it was found that the purity remained substantially unchanged compared to the initial purity for the second week and the fourth week.

[0137] Further, under stress conditions, the change in dissolution rate was examined, and the examination of the dissolution rate was performed at pH 1.2 and pH 4.0. As a result, it was found that the dissolution rate of the naked tablet and the coated tablet according to the present application was substantially maintained and stable compared to the initial dissolution rate at pH 1.2 and pH 4.0, even under the first week and second week stress conditions. For the naked tablet containing the fumarate salt of Compound 1, the change in dissolution rate was equally measured at pH 1.2 and pH 4.0 after storage under stress conditions, and it was confirmed that the change in dissolution rate was significantly higher for the fumarate salt of Compound 1. Accordingly, it can be confirmed that the tablet according to the present application comprising the citrate salt of Compound 1 as an active ingredient exhibits not only excellent dissolution rate but also excellent dissolution stability.

[0138] Evaluation 4: Assessment of content uniformity

[0139] The tablets according to Example 1 (coated tablets) were prepared according to the uniformity test method for coated tablets used in the general test method. The content of the citrate salt of Compound 1 in 10 tablets thereof was measured, and the content uniformity was evaluated by converting it to a percentage of the initial content. The results are shown in Table 9.

[0140] [Table 9]

[0141]

[0142] Referring to Table 9, it can be confirmed that the average value is 99.2% and the deviation is only 1.2%, i.e., the tablets (coated tablets) according to Example 1 have very good content uniformity.

[0143] While the foregoing has been described in some detail for purposes of clarity and the appropriate baseline example, one skilled in the art will soon realize appropriate modifications and changes can be made without departing from the scope and spirit of the application as described in the following claims.

Claims

1. A pharmaceutical preparation comprising azetidin-l-yl {8-[(2,6-dimethylbenzyl)amino]- 2,3-dimethylimidazo[l,2-a]pyridin-6-yl}methanone citrate as an active ingredient and microcrystalline cellulose as an excipient.

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

12.

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

4. The pharmaceutical preparation according to claim 1, which comprises anhydrous lactose as an excipient.

5. The pharmaceutical preparation according to claim 1, wherein the microcrystalline cellulose comprises a particle size D 50 of 150 pm to 210 pm and a particle size D 50 of 230 pm to 270 pm.

6. The pharmaceutical preparation 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. The pharmaceutical preparation according to claim 1, which comprises sodium stearyl fumarate and magnesium stearate as lubricants.

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. The pharmaceutical preparation according to claim 1, which is a tablet.

10. The pharmaceutical preparation according to claim 9, which is a compressed material prepared by direct compression.

11. A method of preparing a pharmaceutical preparation, comprising: preparing a composition for compression, which comprises azetidin-l-yl {8-[(2,6- dimethylbenzyl)amino]-2,3-dimethylimidazo[l,2-a]pyridin-6-yl}methanone citrate as an active ingredient and microcrystalline cellulose as an excipient; and compressing the composition for compression by direct compression to prepare a tablet.

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

13. Use of a composition comprising azetidin-l-yl {8-[(2,6-dimethylbenzyl)amino]-2,3- dimethylimidazo[l,2-a]pyridin-6-yl}methanone citrate as an active ingredient and microcrystalline cellulose as an excipient for the preparation of a pharmaceutical preparation as defined in any one of claims 1 to 10, which is used for the prevention or treatment of a gastrointestinal inflammatory disease or a gastric acid-related disease.

14. A method of preventing or treating a gastrointestinal inflammatory disease or a gastric acid-related disease, which comprises administering a pharmaceutical preparation as defined in any one of claims 1 to 10 to an individual.

15. Use of a pharmaceutical preparation as defined in any one of claims 1 to 10 for the prevention or treatment of a gastrointestinal inflammatory disease or a gastric acid-related disease.

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