ORALLY DISINTEGRATING TABLET COMPRISING BENZIMIDAZOLE DERIVATIVE COMPOUND AND PREPARATION METHOD THEREOF

Abstract

The present invention relates to an orally disintegrating tablet including a benzimidazole derivative compound and a preparation method thereof.

Claims

1. An orally disintegrating tablet comprising wet granules including a compound represented by formula 1 below, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof; and a sweetening agent: ##STR00003##

2. The orally disintegrating tablet of claim 1, wherein the wet granules comprise the compound represented by formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and the sweetening agent at a weight ratio of 1:0.001 to 1:0.4.

3. The orally disintegrating tablet of claim 2, wherein the wet granules comprise the compound represented by formula 1, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and the sweetening agent at a weight ratio of 1:0.05 to 1:0.2.

4. The orally disintegrating tablet of claim 1, wherein the sweetening agent is one selected from the group consisting of sucralose, aspartame, saccharin, acesulfame potassium, stevioside, enzymatically modified stevia, sucrose, isomalt, maltitol, mannitol, sorbitol, steviol glycoside, erythritol, xylose, xylitol, lactitol, neotame, ribose, tomatine, polyglycitol, advantam, tagatose, trehalose, glucose, maltose, dextrose, white sugar, fructose, honey, glycyrrhizin, monellin, rubusoside, curculin, corn syrup, lactose, oligosaccharides, and mixtures thereof.

5. The orally disintegrating tablet of claim 1, wherein the sweetening agent is comprised in an amount of 0.01 to 10 wt % based on the total weight of the tablet.

6. The orally disintegrating tablet of claim 1, wherein the orally disintegrating tablet further comprises a disintegrant.

7. The orally disintegrating tablet of claim 6, wherein the disintegrant is one selected from the group consisting of crospovidone, croscarmellose sodium, sodium starch glycolate, alginic acid, sodium alginate, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, corn starch, pregelatinized starch, microcrystalline cellulose, hydroxypropyl cellulose, sodium bicarbonate, and mixtures thereof.

8. The orally disintegrating tablet of claim 6, wherein the disintegrant is comprised in an amount of 1 to 50 wt % based on the total weight of the tablet.

9. The orally disintegrating tablet of claim 1, wherein the orally disintegrating tablet further comprises diluents, flavoring agents, sweetening agents, lubricants, or mixtures thereof.

10. The orally disintegrating tablet of claim 9, wherein the diluent is one selected from the group consisting of mannitol, lactose, starch, micro-crystalline cellulose, ludipress, pearlitol flash, calcium dihydrogen phosphate, dextrose, maltose, erythritol, sucrose, maltitol, trihalose, glucose, xylitol, F-melt, sorbitol, pregelatinized starch, anhydrous calcium hydrogen phosphate, dicalcium phosphate, and mixtures thereof.

11. The orally disintegrating tablet of claim 9, wherein the diluent is comprised in an amount of 1 to 99 wt % based on the total weight of the tablet.

12. The orally disintegrating tablet of claim 9, wherein the flavoring agent is one selected from the group consisting of peppermint flavor, yogurt flavor, fruit flavor, and mixtures thereof.

13. The orally disintegrating tablet of claim 9, wherein the flavoring agent is comprised in an amount of 0.01 to 10 wt % based on the total weight of the tablet.

14. The orally disintegrating tablet of claim 9, wherein the lubricant is one selected from the group consisting of stearic acid, stearic acid metal salts, talc, colloidal silica, sucrose fatty acid ester, hydrogenated vegetable oil, wax, glycerin fatty acid ester, glycerol dibehenate, and mixtures thereof.

15. The orally disintegrating tablet of claim 9, wherein the lubricant is comprised in an amount of 0.1 to 10 wt % based on the total weight of the tablet.

16. The orally disintegrating tablet of claim 1, wherein the wet granules are prepared with a binder solution including one selected from the group consisting of alcohol, water, and a mixture thereof and a sweetening agent.

17. The orally disintegrating tablet of claim 16, wherein the binder solution further comprises a binder or an additive capable of giving binding force.

18. The orally disintegrating tablet of claim 17, wherein the binder or the additive capable of giving binding force is one selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), gelatin, pregelatinized starch, polyvinylpyrrolidone, polyvinyl alcohol, pullulan, polyethylene glycol, natural gum, synthetic gum, copovidone, ethyl cellulose, methacrylate copolymer, and mixtures thereof.

19. The orally disintegrating tablet of claim 1, wherein the wet granules are prepared by high-speed shear granulation or fluidized bed granulation.

20. The orally disintegrating tablet of claim 1, wherein the orally disintegrating tablet disintegrates within 30 seconds.

21. The orally disintegrating tablet of claim 1, wherein the orally disintegrating tablet has a masked bitter taste.

22. The orally disintegrating tablet of claim 1, wherein the orally disintegrating tablet is used for preventing or treating diseases mediated by an acid pump antagonistic activity.

23. The orally disintegrating tablet according to claim 22, wherein the diseases mediated by an acid pump antagonistic activity are at least one selected from the group consisting of gastrointestinal disease, gastroesophageal disease, gastroesophageal reflux disease (GERD), peptic ulcer, gastric ulcer, duodenal ulcer, NSAID-induced ulcer, gastritis, Helicobacter pylori infection, dyspepsia, functional dyspepsia, Zollinger-Ellison syndrome, nonerosive reflux disease (NERD), visceral referred pain, purosis, nausea, esophagitis, dysphagia, salivation, airway lesion and asthma.

24. A method for preparing an orally disintegrating tablet, comprising: (1) preparing wet granules including a compound represented by formula 1 below, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and a sweetening agent; (2) preparing a mixture by adding one or more pharmaceutically acceptable additives to the wet granules; and (3) compressing the mixture into tablets: ##STR00004##

25. The method of claim 24, wherein the sweetening agent is one selected from the group consisting of sucralose, aspartame, saccharin, acesulfame potassium, stevioside, enzymatically modified stevia, sucrose, isomalt, maltitol, mannitol, sorbitol, steviol glycoside, erythritol, xylose, xylitol, lactitol, neotame, ribose, tomatine, polyglycitol, advantam, tagatose, trehalose, glucose, maltose, dextrose, white sugar, fructose, honey, glycyrrhizin, monellin, rubusoside, curculin, corn syrup, lactose, oligosaccharides, and mixtures thereof.

26. The method of claim 24, wherein the preparing of wet granules is performed by a wet granulation with a binder solution including one selected from the group consisting of alcohol, water, and a mixture thereof and a sweetening agent.

27. The method of claim 26, wherein the binder solution further comprises a binder or an additive capable of giving binding force.

28. The method of claim 27, wherein the binder or the additive capable of giving binding force is one selected from the group consisting of hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), gelatin, pregelatinized starch, polyvinylpyrrolidone, polyvinyl alcohol, pullulan, polyethylene glycol, natural gum, synthetic gum, copovidone, ethyl cellulose, methacrylate copolymer, and mixtures thereof.

29. The method of claim 26, wherein the wet granulation is a high-speed shear granulation or a fluidized bed granulation.

30. The method of claim 24, wherein the pharmaceutically acceptable additives are disintegrants, diluents, flavoring agents, sweetening agents, lubricants, or mixtures thereof.

31. An orally disintegrating tablet prepared by the preparation method according to any one of claims 24 to 30.

32. A method for preventing or treating diseases mediated by an acid pump antagonistic activity, which comprises administering the orally disintegrating tablet according to any one of claims 1 to 23.

33. A use of the orally disintegrating tablet according to any one of claims 1 to 23 for preventing or treating diseases mediated by an acid pump antagonistic activity.

34. A use of the orally disintegrating tablet according to any one of claims 1 to 23 in preparation of a drug for preventing or treating diseases mediated by an acid pump antagonistic activity.

Description

BRIEF DESCRIPTION OF DRAWINGS

[0097] FIG. 1 is a view showing a drug dissolution rate at pH 1.2 with respect to the tablet prepared according to Example 1 and the K-CAP tablet.

[0098] FIG. 2 is a view showing a drug dissolution rate at pH 4.0 with respect to the tablet prepared according to Example 1 and the K-CAP tablet.

[0099] FIG. 3 is a view showing a change in properties of the tablets prepared according to Example 1 and Comparative Example 1 under stress and accelerated conditions.

MODE FOR THE INVENTION

[0100] Hereinafter, the present invention will be described in more detail through exemplary embodiments. However, these exemplary embodiments are provided only for the purpose of illustrating the present invention, and thus the scope of the present invention is not limited thereto.

Example 1: Preparation of Tegoprazan Orally Disintegrating Tablet 1

[0101] An orally disintegrating tablet was prepared according to the materials and contents described in Example 1 of table 1 below. Specifically, a binder solution was prepared by adding sucralose, a sweetening agent, to an aqueous solution of 58% (w/w) ethanol, followed by stirring for two hours or longer until completely dissolved. Tegoprazan, a main component, and mannitol 200SD, an excipient, were sieved through a 25-mesh sieve, mixed in a high-speed shear mixer, kneaded and granulated with the addition of the binder solution. The granulated product was dried in a fluidized bed dryer and subjected to a size regulation. Pearlitol flash, crospovidone CL-SF, maltitol, enzymatically modified stevia, peppermint flavor, and colloidal silicon dioxide were added to the size-regulated product as an excipient, disintegrant, sweetening agent, and flavoring agent, and then mixed and lubricated with the addition of magnesium stearate. After that, a tablet compression was performed by a conventional tableting method using a tableting machine. Each tablet was prepared to have a weight of 350 mg and hardness in the range of 5-8 kP.

Example 2: Preparation of Tegoprazan Orally Disintegrating Tablet 2

[0102] An orally disintegrating tablet was prepared according to the materials and contents described in Example 2 of table 1 below. Specifically, a binder solution was prepared by adding hydroxypropyl methylcellulose (Pharmacoat 603), a binder, to an aqueous solution of 50% (w/w) ethanol to be completely dissolved, and then adding sucralose, a sweetening agent, followed by stirring for two hours or longer until completely dissolved. Tegoprazan, a main component, and mannitol 200SD, an excipient, were sieved through a 25-mesh sieve, added to a fluidized bed granulator (GPCG 1, manufactured by Glatt), prepared as granules by spraying the binder solution, and then subjected to size-regulation. Pearlitol flash, crospovidone CL-SF, maltitol, enzymatically modified stevia, peppermint flavor, and colloidal silicon dioxide were added to the size-regulated product as an excipient, disintegrant, sweetening agent, and flavoring agent, and then mixed and lubricated with the addition of magnesium stearate. After that, a tablet compression was performed by a conventional tableting method using a tableting machine. Each tablet was prepared to have a weight of 350.5 mg and hardness in the range of 5-8 kP.

Example 3: Preparation of Tegoprazan Orally Disintegrating Tablet 3

[0103] An orally disintegrating tablet was prepared according to the materials and contents described in Example 3 of table 1 below. Specifically, a binder solution was prepared by adding maltitol, a sweetening agent, to an aqueous solution of 50% (w/w) ethanol, followed by stirring for two hours or longer until completely dissolved. Tegoprazan, a main component, and mannitol 2005D, an excipient, were sieved through a 25-mesh sieve, mixed in a high-speed shear mixer, kneaded and granulated with the addition of the binder solution. The granulated product was dried in a fluidized bed dryer and subjected to a size regulation. Pearlitol flash, crospovidone CL-SF, maltitol, enzymatically modified stevia, peppermint flavor, and colloidal silicon dioxide were added to the size-regulated product as an excipient, disintegrant, sweetening agent, and flavoring agent, and then mixed and lubricated with the addition of magnesium stearate. After that, a tablet compression was performed by a conventional tableting method using a tableting machine. Each tablet was prepared to have a weight of 350 mg and hardness in the range of 5-8 kP.

Example 4: Preparation of Tegoprazan Orally Disintegrating Tablet 4

[0104] An orally disintegrating tablet was prepared according to the materials and contents described in Example 4 of table 1 below. Specifically, a binder solution was prepared by adding aspartame, a sweetening agent, to an aqueous solution of 50% (w/w) ethanol, followed by stirring for two hours or longer until completely dissolved. Tegoprazan, a main component, and mannitol 2005D, an excipient, were sieved through a 25-mesh sieve, mixed in a high-speed shear mixer, kneaded and granulated with the addition of the binder solution. The granulated product was dried in a fluidized bed dryer and subjected to a size regulation. Pearlitol flash, crospovidone CL-SF, maltitol, enzymatically modified stevia, peppermint flavor, and colloidal silicon dioxide were added to the size-regulated product as an excipient, disintegrant, sweetening agent, and flavoring agent, and then mixed and lubricated with the addition of magnesium stearate. After that, a tablet compression was performed by a conventional tableting method using a tableting machine. Each tablet was prepared to have a weight of 350 mg and hardness in the range of 5-8 kP.

Example 5: Preparation of Tegoprazan Orally Disintegrating Tablet 5

[0105] An orally disintegrating tablet was prepared according to the materials and contents described in Example 5 of table 1 below. Specifically, a binder solution was prepared by adding sucralose, a sweetening agent, to a 50% (w/w) aqueous solution of ethanol, followed by stirring for two hours or longer until completely dissolved. Tegoprazan, a main component, and xylitol, an excipient, were sieved through a 25-mesh sieve, mixed in a high-speed shear mixer, kneaded and granulated with the addition of the binder solution. The granulated product was dried in a fluidized bed dryer and subjected to a size regulation. Pearlitol flash, crospovidone CL-SF, maltitol, enzymatically modified stevia, peppermint flavor, and colloidal silicon dioxide were added to the size-regulated product as an excipient, disintegrant, sweetening agent, and flavoring agent, and then mixed and lubricated with the addition of magnesium stearate. After that, a tablet compression was performed by a conventional tableting method using a tableting machine. Each tablet was prepared to have a weight of 350 mg and hardness in the range of 5-8 kP.

Comparative Example 1. Preparation of Tegoprazan Orally Disintegrating Tablet 6

[0106] An orally disintegrating tablet was prepared according to the materials and contents described in Comparative Example 1 of table 1 below. Specifically, all the materials described in Comparative Example 1 of table 1 were sieved through a 25-mesh sieve, mixed and subjected to a tablet compression by a conventional tableting method using a tableting machine. Each tablet was prepared to have a weight of 350 mg and hardness in the range of 5-8 kP.

TABLE-US-00001 TABLE 1 Example 1 Example 3 Example 4 Example 5 Comparative High- Example 2 High- High- High- Example 1 speed Fluidized speed speed speed Direct shear bed shear shear shear tableting Classification granulation granulation granulation granulation granulation method Composition Usage Usage Usage Usage Usage Usage (mg/T) (mg/T) (mg/T) (mg/T) (mg/T) (mg/T) Pre-mix Tegoprazan 50.0 50.0 50.0 50.0 50.0 50.0 portion Mannitol 50.0 50.0 50.0 50.0 — 50.0 (200SD) Xylitol — — — — 50.0 — Binder Sucralose 3.5 3.5 — — 3.5 — solution Maltitol — — 3.5 — — — Aspartame — — — 3.5 — — HPMC — 0.5 — — — — Purified water 3.6 75.0 7.5 7.5 7.5 — Ethanol 5.0 75.0 7.5 7.5 7.5 — Post-mix Pearlitol flash 192.3 195.0 195.0 195.0 195.0 195.0 portion Crospovidone 17.5 17.0 17.0 17.0 17.0 17.0 Maltitol 17.5 17.0 17.0 17.0 17.0 17.0 Sucralose — — — — — 3.5 Enzymatically 1.8 1.5 1.5 1.5 1.5 1.5 modified stevia Peppermint 3.5 3.0 3.0 3.0 3.0 3.0 flavor Colloidal 3.5 3.0 3.0 3.0 3.0 3.0 silicon dioxide Magnesium 10.5 10.0 10.0 10.0 10.0 10.0 stearate Total weight 350.0 350.5 350.0 350.0 350.0 350.0

Experimental Example 1: Evaluation of Disintegration Time

[0107] An orally disintegrating tablet needs to be administered while disintegrating in the oral cavity, and thus rapid disintegration is required. Thus, a disintegration time of the tablets prepared according to Examples 1 to 5 and Comparative Example 1 was measured.

[0108] For an in vitro disintegration experiment, a filter paper having a diameter of 90 mm

[0109] (see WH1442090) was placed on a petri dish (100×10 mm), and then 10 mL of an aqueous solution of 10% (w/w) cobalt(II) chloride hexahydrate was completely soaked into the filter paper of the dish, after which a tablet was placed thereon so as to measure a time taken until water reached to an end surface of the tablet due to a capillary action by visually checking a change in colors with naked eyes (measured three times).

[0110] For an in vivo disintegration experiment, ten subjects were asked to take the tablet without water, so as to measure a time taken until the tablet is completely disintegrated by saliva in the oral cavity.

[0111] For a disintegration experiment in a disintegration tester, a measurement was made according to a disintegration test method of the Korean Pharmacopoeia general test method (n=6).

[0112] An average value of each test is shown in table 2 below.

TABLE-US-00002 TABLE 2 Hardness Disintegration No. (kP) in vitro in vivo tester Example 1 6 17 sec 22 sec 19 sec Example 2 6 16 sec 22 sec 23 sec Example 3 6 17 sec 21 sec 22 sec Example 4 6 18 sec 22 sec 20 sec Example 5 6 19 sec 22 sec 22 sec Comparative 6 18 sec 20 sec 23 sec Example 1

[0113] As a result, it was confirmed that the tablets prepared according to Examples 1 to 5 and Comparative Example 1 disintegrate rapidly within 30 seconds in the in vitro disintegration experiment, the in vivo disintegration experiment, and the disintegration experiment in the disintegration tester all.

Experimental Example 2: Sensory Evaluation

[0114] Ten subjects were asked to take the tablets prepared according to above Examples 1 to 5 and Comparative Example 1 without water, after which a sensory evaluation (for a feeling of irritation and a bitter taste) was performed. Each subject recorded a score (0-5 points) for the feeling of irritation and the bitter taste, and the resulting scores were averaged and shown in table 3 below.

TABLE-US-00003 TABLE 3 Feeling of No. irritation.sup.1) Bitter taste.sup.2) Feeling in the mouth Example 1 1.1 1.0 Gently disintegrates Example 2 1.3 1.3 Gently disintegrates Example 3 1.8 1.8 Gently disintegrates Example 4 1.7 1.9 Gently disintegrates Example 5 1.8 1.5 Gently disintegrates Comparative 1.3 4.6 Unpleasant feeling Example 1 in the mouth and a strong bitter taste .sup.1)Feeling of irritation: Very much-5 points; slightly much-4 points; Average-3 points; slightly less-2 points; very little-1 point; None-0 points .sup.2)Bitter taste: Very much-5 points; slightly much-4 points; Average-3 points; slightly less-2 points; very little-1 point; None-0 points

[0115] As a result, it was confirmed that Comparative Example 1 prepared with the direct

[0116] tableting method of adding the sweetening agent in a powder form has a very strong bitter taste and an unpleasant feeling in the mouth, while Examples 1 and 3 to 5 prepared with the high-speed shear granulation and Example 2 prepared with the fluidized bed granulation have a very little bitter taste and a feeling of smooth disintegration in the oral cavity as the binder solution including the sweetening agent attaches and coats the particles of tegoprazan and excipients, thereby showing an effect on alleviating the bitter taste as well as excellent sensory properties.

Experimental Example 3: Dissolution Rate Evaluation

[0117] A dissolution rate of the drug was compared between the tablet prepared according to above Example 1 and the 50 mg K-CAP tablet of HK Innoen Co., Ltd., on the basis of Chapter 3 Comparative Dissolution Test of Pharmaceutical Equivalence Test Standards. Upon starting the test, samples of the dissolution test solution at pH 1.2 were collected at 0, 5, 10, 15 and 30 minutes and those at pH 4.0 were collected at 0, 5, 10, 15, 30, 45, 60, 90 and 120 minutes and subjected to a liquid chromatography under the following conditions, after which the dissolution rates of tegoprazan were calculated and shown in Table 4 and FIGS. 1 and 2 below.

[0118] <Dissolution Conditions> [0119] Number of rotations: 50 rotations/min [0120] Amount of test solution: 900 mL [0121] Temperature of test solution: 37±0.5° C. [0122] Test solution: Solutions at pH 1.2 and pH 4.0 of Korean Pharmacopoeia

[0123] <Liquid Chromatography Conditions> [0124] Column: A column filled with octadecylsilylated silica gel for liquid chromatography with a particle diameter of 5 μm in a stainless tube with an inner diameter of about 4.6 mm and a length of 15 cm [0125] Column temperature: Constant temperature around 30° C. [0126] Amount of sample injection: 10 μL [0127] Mobile phase: 0.01 mol/L ammonium acetate buffer: ACN=11:9 [0128] Flow rate: 1.0 mL/min [0129] Detector: Ultraviolet absorbance photometer (measurement wavelength of 262 nm)

TABLE-US-00004 TABLE 4 pH 1.2 dissolution rate (%) pH 4.0 dissolution rate (%) Time K-CAP tablet K-CAP tablet (minute) Example 1 50 mg Example 1 50 mg 0 0 0 0 0 5 95.7 96.2 49.5 38.2 10 99.8 97.6 61.3 56.0 15 99.5 97-3 69.5 65.9 30 98.8 96.8 80.5 80.3 45 85.3 86.8 60 87.9 90.3 90 90.9 93-5 120 92.3 94.6

[0130] As a result, it was confirmed that the tablet prepared according to Example 1 exhibits an excellent dissolution rate of tegoprazan at a level similar to that of the control drug K-CAP tablet without any delay in release.

Experimental Example 4: Stability Evaluation

[0131] In order to evaluate the stability under stress and accelerated conditions of Example 1 and Comparative Example 1, a stability test was performed in the HDPE bottles and PTP (aluminum) packaging materials under stress conditions (60° C., 80% RH) and accelerated conditions (40° C., 75% RH), and the total amount of related substances and the change in appearance thereof are shown in Table 6 and FIG. 3 below, respectively.

[0132] <Liquid Chromatography Conditions> [0133] Column: A column filled with octadecylsilylated silica gel for liquid chromatography with a particle diameter of 2.7 μcm in a stainless tube with an inner diameter of about 4.6 mm and a length of 15 cm [0134] Column temperature: Constant temperature around 30° C. [0135] Amount of sample injection: 10 μL [0136] Mobile phase A: 0.01 mol/L ammonium acetate buffer: ACN=19:1 [0137] Mobile phase B: ACN [0138] Flow rate: 0.8 mL/min [0139] Detector: Ultraviolet absorbance photometer (measurement wavelength of 220 nm)

TABLE-US-00005 TABLE 5 Mobile phase gradient conditions Mobile phase Time (minute) A (%) B (%) 0~2 88 12 2~3 88 .fwdarw. 70 12 .fwdarw. 30  3~15 70 30 15~16 70 .fwdarw. 20 30 .fwdarw. 80 16~17 20 .fwdarw. 10 80 .fwdarw. 90 17~20 10 90   20~20.01 10 .fwdarw. 88 90 .fwdarw. 12 20.01~25   88 12

TABLE-US-00006 TABLE 6 No. Total related Example 1 Comparative Example 1 substance HDPE Bottle Al/Al PTP HDPE Bottle Al/Al PTP Initial 0.12 0.12 0.15 0.15 Stress week 2 0.12 0.12 0.27 0.18 Stress week 4 0.13 0.13 0.39 0.22 Accelerated 1 0.12 0.12 0.15 0.15 month

[0140] As a result, it was confirmed that the tablet prepared according to Example 1 produces a less total amount of related substances under stress and accelerated conditions compared to the tablet prepared according to Comparative Example 1 (Table 6), and the tablet of Comparative Example 1 produces a black-brown spot on a tablet surface under stress and accelerated conditions, while the tablet prepared according to Example 1 shows no change in appearance under stress and accelerated conditions (FIG. 3), thereby exhibiting excellent stability.

Experimental Example 5: Stability Evaluation According to Sweetening Agent Type and Weight Ratio

[0141] In order to evaluate stability under stress conditions according to the type of sweetening agent included in the granules and the weight ratio of tegoprazan and sweetening agent in the granules, an orally disintegrating tablet was prepared according to the materials and contents described in table 7 below (Examples 6 to 10 and Comparative Example 2 were prepared by the same method as in Example 1), and thus a stability test was performed under stress conditions (60° C., 80% RH).

[0142] The total amount of related substances is shown in table 8 below.

TABLE-US-00007 TABLE 7 Comparative Classification Example 6 Example 7 Example 8 Example 2 Example 9 Example 10 Tegoprazan:sweetening 1:0.05 1:0.1 1:0.2 1:0.5 1:0.2 1:0.2 agent Composition Usage Usage Usage Usage Usage Usage (mg/T) (mg/T) (mg/T) (mg/T) (mg/T) (mg/T) Pre-mix Tegoprazan 50.0 50.0 50.0 50.0 50.0 50.0 portion Mannitol 50.0 50.0 50.0 50.0 50.0 50.0 (200SD) Binder Sucralose 2.5 5.0 10.0 25.0 — — solution Aspartame 1 1 — — 10.0 — Maltitol — — — — — 10.0 Purified water 7.5 7.5 7.5 7.5 7.5 7.5 Ethanol 7.5 7.5 7.5 7.5 7.5 7.5 Post-mix Pearlitol flash 192.3 192.3 192,3 192.3 192.3 192.3 portion Crospovidone 17.5 17.5 17.5 17.5 17.5 17.5 Maltitol 17.5 17.5 17.5 17.5 17.5 17.5 Enzymatically 1.8 1.8 1.8 1.8 1.8 1.8 modified stevia Peppermint 3.5 3.5 3.5 3.5 3.5 3.5 flavor Colloidal silicon 3.5 3.5 3.5 3.5 3.5 3.5 dioxide Magnesium 10.5 10.5 10.5 10.5 10.5 10.5 stearate Total weight 349.0 351.5 356.5 371.5 356.5 356.5

TABLE-US-00008 TABLE 8 Comparative Classification Example 6 Example 7 Example 8 Example 2 Example 9 Example 10 Tegoprazan:sucralos 1:0.05 1:0.1 1:0.2 1:0.5 — — Tegoprazan:aspartame — — — — 1:0.2 — Tegoprazan:maltitol — — — — — 1:0.2 Initial 0.08 0.08 0.08 0.08 0.10 0.10 Stress week 2 0.08 0.08 0.08 0.99 0.11 0.10 Stress week 4 0.08 0.08 0.08 1.91 0.11 0.10

[0143] As a result, it was confirmed that a less total amount of related substances are

[0144] produced from the tablets of Examples 6 to 10 in which the weight ratio of tegoprazan and the sweetening agent is 1:0.05 to 1:0.2 compared to the tablet of Comparative Example 2 in which the weight ratio of tegoprazan and the sweetening agent is 1:0.5, thereby exhibiting excellent stability.

[0145] Meanwhile, according to the type of the sweetening agent, it was confirmed that the tablet of Example 8 having sucralose, the tablet of Example 9 having aspartame, and the tablet of Example 10 having maltitol all produce a less total amount of related substances, thereby exhibiting excellent stability regardless of the type of sweetening agent.

[0146] While specific portions of the present invention have been described in detail above,

[0147] it is apparent to those skilled in the art that such detailed descriptions are set forth to illustrate exemplary embodiments only, but are not construed to limit the scope of the present invention. Thus, it should be understood that the substantial scope of the present invention is defined by the accompanying claims and equivalents thereto.