PHARMACEUTICAL COMPOSITION COMPRISING BENZIMIDAZOLE DERIVATIVE COMPOUND

Abstract

The present disclosure relates to a pharmaceutical composition containing a benzimidazole derivative compound. Specifically, the present disclosure relates to a formulation capable of maintaining a sustained blood concentration of the benzimidazole derivative compound.

Claims

1. A modified-release pharmaceutical composition comprising: tegoprazan, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof; and a release modifying agent.

2. The modified-release pharmaceutical composition of claim 1, wherein the release modifying agent comprises at least one selected from the group consisting of a sustained-release agent and an enteric agent.

3. The modified-release pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises a particle comprising, tegoprazan, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof as an active ingredient.

4. The modified-release pharmaceutical composition of claim 3, wherein the release modifying agent is contained in the particle.

5. The modified-release pharmaceutical composition of claim 4, wherein the release modifying agent comprises at least one selected from the group consisting of a sustained-release agent and an enteric agent.

6. The modified-release pharmaceutical composition of claim 3, wherein the particle comprises a layer comprising the release modifying agent.

7. The modified-release pharmaceutical composition of claim 6, wherein the release modifying agent comprises at least one selected from the group consisting of a sustained-release agent and an enteric agent.

8. A modified-release pharmaceutical composition comprising: a core comprising tegoprazan, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof as an active ingredient; and a release modifying agent-containing layer formed on the core.

9. The modified-release pharmaceutical composition of claim 8, wherein the core comprises: an inert particle; and an active ingredient layer, which comprises the active ingredient, positioned on the inert particle.

10. The modified-release pharmaceutical composition of claim 9, wherein the inert particle comprises at least one selected from the group consisting of white sugar, lactose, starch, mannitol, sucrose, dextrin, and microcrystalline cellulose.

11. The modified-release pharmaceutical composition of claim 8, wherein the pharmaceutical composition comprises an organic acid.

12. The modified-release pharmaceutical composition of claim 11, wherein the organic acid is at least one selected from the group consisting of tartaric acid, fumaric acid, succinic acid, citric acid, malic acid, glutamic acid and aspartic acid.

13. The modified-release pharmaceutical composition of claim 9, wherein the inert particle and the active ingredient are comprised in the core at a weight ratio within a range of 5:1 to 1:5.

14. The modified-release pharmaceutical composition of claim 8, wherein the core is a core tablet prepared by tableting a mixture of a granule comprising the active ingredient and a pharmaceutically acceptable additive.

15. The modified-release pharmaceutical composition of claim 8, wherein the core is a granule comprising a mixture comprising the active ingredient and a pharmaceutically acceptable additive.

16. The modified-release pharmaceutical composition of claim 8, wherein the release modifying agent comprises at least one selected from the group consisting of a sustained-release agent and an enteric agent.

17. The modified-release pharmaceutical composition of claim 16, wherein the enteric agent is any one or more selected from the group consisting of ethyl cellulose, cellulose acetate, polyvinyl acetate, cellulose butyrate phthalate, cellulose hydrogen phthalate, cellulose propionate phthalate, polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methyl cellulose phthalate, polyvinyl acetate, hydroxypropyl methyl acetate, dioxypropyl methyl cellulose succinate, carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose acetate succinate, and polymers thereof; Shellac; and acrylic acid, methacrylic acid or esters thereof or copolymer formed from thereof.

18. The modified-release pharmaceutical composition of claim 17, wherein the enteric agent is any one or more selected from the group consisting of methacrylic acid-ethyl acrylate copolymer, methacrylic acid copolymer L, and methacrylic acid copolymer S.

19. The modified-release pharmaceutical composition of claim 18, wherein the enteric agent comprises methacrylic acid copolymer L and methacrylic acid copolymer S at a weight ratio within a range of 1:3 to 1:0.2.

20. The modified-release pharmaceutical composition of claim 18, wherein the enteric agent comprises methacrylic acid-ethyl acrylate copolymer and methacrylic acid copolymer S at a weight ratio within a range of 0.3:1 to 3:1.

21. The modified-release pharmaceutical composition of claim 16, wherein the sustained-release agent comprises one or more selected from the group consisting of polyvinyl alcohol, polyethylene oxide, methacrylic acid copolymer, hydroxypropyl methyl cellulose, ethyl cellulose, povidone, and talc.

22. The modified-release pharmaceutical composition of claim 8, wherein the release modifying agent-containing layer is pH-dependent soluble at pH 5.5 or higher.

23. The modified-release pharmaceutical composition of claim 8, wherein the release modifying agent-containing layer is comprised in an amount of 10 to 70 wt % based on the weight of the pharmaceutical composition.

24. (canceled)

25. The modified-release pharmaceutical composition of claim 8, wherein the core comprises the release modifying agent.

26. The modified-release pharmaceutical composition of claim 25, wherein the pharmaceutical composition comprises: a core comprising, tegoprazan, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof as an active ingredient, and a first release modifying agent; and a release modifying agent-containing layer, which comprises a second release modifying agent, formed on the core, and wherein the first release modifying agent and the second release modifying agent each independently comprises at least one selected from the group consisting of a sustained-release agent and an enteric agent.

27. The modified-release pharmaceutical composition of claim 26, wherein the pharmaceutical composition further comprises an additional coating layer comprising a third release modifying agent, between the core and the release modifying agent-containing layer comprising the second release modifying agent.

28. The modified-release pharmaceutical composition of claim 27, wherein the first release modifying agent and the third release modifying agent comprise a sustained-release agent, and the second release modifying agent comprises an enteric agent.

29.-52. (canceled)

Description

DESCRIPTION OF DRAWINGS

[0165] FIG. 1 illustrates a schematic view of a tablet according to the present disclosure.

[0166] FIG. 2 shows changes in plasma concentrations of tegoprazan in beagles after oral administration of the modified-released formulation of the present disclosure and a commercially available K-CAB® tablet and an immediate-release formulation.

[0167] FIG. 3 shows changes in plasma concentrations of tegoprazan in mini-pigs after oral administration of a formulation containing a sugar-based sucrose as an inert particle and a formulation containing an organic acid according to the present disclosure.

[0168] FIG. 4 shows changes in blood concentrations of tegoprazan in monkeys after oral administration of a formulation containing a sugar-based sucrose as an inert particle and a formulation containing an organic acid according to the present disclosure.

MODE FOR INVENTION

[0169] Hereinafter, the present disclosure will be described in more detail with reference to examples. However, these examples serve to illustrate the present disclosure, and the scope of the present disclosure is not limited by these examples.

Preparation Example

[0170] To determine a suitable coating solution composition enabling tegoprazan coating, coating solutions were prepared using an active ingredient and various types of pharmaceutical additives (binding agent, surfactant, anti-adhesion agent, plasticizer, etc.) and solvents.

TABLE-US-00001 TABLE 1 Coating Coating Coating Coating Coating Coating Coating solution 1 solution 2 solution 3 solution 4 solution 5 solution 6 solution 7 Pharmaceutical ingredients Batch weight (g) Tegoprazan 4.81 4.81 4.81 4.81 4.81 4.81 4.81 Hydroxypropyl cellulose 0.96 0.96 0.96 — — — — Povidone — — — 0.96 0.96 0.96 — Hypromellose — — — — — — 0.96 Polyethylene glycol 0.23 0.23 0.23 0.23 0.23 0.23 0.23 Talc 0.17 0.17 0.17 0.17 0.17 0.17 0.17 Polysorbate 80 0.48 0.48 0.48 0.48 0.48 0.48 0.48 Purified water q.s. — — q.s. — — — Isopropyl alcohol — q.s. — — q.s. — — Anhydrous ethanol — — q.s. — — q.s. — Coating solution Suspended Partially Dissolved Suspended Partially Dissolved Suspended appearance dissolved dissolved and and suspended suspended

[0171] It was confirmed that the above-prepared coating solutions were suspended, or partially dissolved and suspended, or dissolved depending on the pharmaceutically usable solvent used. Each of the prepared coating solutions was applied thinly to a 150-mm Petri dish and dried, and then the solvent was evaporated. In this state, each of the coating layers was observed, and as a result, it was confirmed that, in the case of the coating solution in a suspended form, a layer was formed in a state in which the active ingredient particles were contained in the matrix structure of the binding, and in the case of the coating solution in a dissolved form, a translucent or transparent layer was formed.

Examples 1 to 3

[0172] Before coating with a active ingredient layer containing tegoprazan, a separate inert coating (coating layer) was performed with each of the compositions (hypromellose, polyethylene glycol, and talc) shown in Table 2 below in order to increase the stability of the active ingredient layer, ensure the efficient formation of the coating layer and increase abrasion resistance.

TABLE-US-00002 TABLE 2 Example 1 Example 2 Example 3 Pharmaceutical ingredients Batch weight (g) Suglet 2,000.0 2,000.0 2,000.0 Hypromellose 40.0 40.0 40.0 Polyethylene glycol 8.0 8.0 — Talc 32.0 32.0 40.0 Solvent Purified water 920.0 as mixture 920 920 Anhydrous — — ethanol

[0173] Specifically, spherical pellets (product name: Suglet, Colorcon) based on sucrose were used as inert particles, and a fluidized-bed pellet coater (GPCG-1, Bottom spray, Glatt, Germany) was used for coating. The operating conditions of the fluidized bed pellet coater were an air supply temperature of 60±10° C., an exhaust air flap pressure of 0.6±0.2 bar, and a coating solution spray pressure of 1.5±0.6 bar. During the coating solution spraying process, the height of the partition and the feed rate of the coating solution were appropriately adjusted while observing fluidization according to the amount of pellets charged.

[0174] After completion of the coating solution spraying, drying was performed in the fluidized bed pellet coater for about 30 to 120 minutes while the pellets were fluidized by supplying air at 75±10° C. The drying process could be operated within the allowable residual solvent range depending on the binding agent used, and could be performed by a vacuum drying method or an oven drying method.

Examples 4 to 6

[0175] For coating of an active ingredient layer containing tegoprazan, a coating solution having the composition shown in Table 3 below was prepared using pharmaceutically acceptable additives and solvents. Then, the outer surface of a certain amount or the entire amount of the process product containing Examples 1 or 3 was coated with an active ingredient layer using a fluidized-bed pellet coater (GPCG-1, Bottom spray, Glatt, GERMANY). At this time, coating was performed so that a single particle included 25 to 200 mg.

TABLE-US-00003 TABLE 3 Example 4 Example 5 Example 6 Pharmaceutical ingredients Batch weight (g) Example 1 Example 2 Example 3 Tegoprazan 250 528.85 480.77 Povidone 50 105.77 96.15 Polyethylene glycol 12 — — Talc 9 21.15 72.12 Polysorbate 80 25 21.15 19.23 Solvent Purified water — 1992 2527 Anhydrous 3114 408 517 ethanol

[0176] The operating conditions of the fluidized bed pellet coater used for the coating were an air supply temperature of 65±10° C., an exhaust air flap pressure of 0.7±0.3 bar, and a coating solution spray pressure of 1.5±0.7 bar. During the coating solution spraying process, the height of the partition and the feed rate of the coating solution were appropriately adjusted while observing fluidization according to the amount of pellets charged.

[0177] After completion of the coating solution spraying, drying was performed in the fluidized bed pellet coater for about 30 to 120 minutes while the pellets were fluidized by supplying air at 75±10° C. The drying process could be operated within the allowable residual solvent range depending on the pharmaceutical binding agent used, and could be performed by a vacuum drying method or an oven drying method.

Examples 7 to 9

[0178] To increase the stability of the active ingredient layer containing tegoprazan, ensure the efficient formation of the coating layer and increase abrasion resistance, coating solutions having the composition shown in Table 4 below were prepared, and then inert coating (coating layer) was performed on the outer surface of a certain amount or the entire amount of the process product containing each of Examples 4 to 6 using a fluidized-bed pellet coater (GPCG-1, Bottom spray, Glatt, Germany).

TABLE-US-00004 TABLE 4 Example 7 Example 8 Example 9 Pharmaceutical ingredients Batch weight (g) Example 4 Example 5 Example 6 Hypromellose 3 cps 31.96 61.35 — Hypromellose 6 cps — — 53.79 Polyethylene glycol  7.39 Talc 10.16 25.54 21.5 Solvent Purified water 569.0 as mixture 988.0  1180 Anhydrous — — ethanol

[0179] The operating conditions of the fluidized bed pellet coater used for the coating were an air supply temperature of 60±10° C., an exhaust air flap pressure of 0.6±0.2 bar, and a coating solution spray pressure of 1.5±0.6 bar. During the coating solution spraying process, the height of the partition and the feed rate of the coating solution were appropriately adjusted while observing fluidization according to the amount of pellets charged.

[0180] After completion of the coating solution spraying, drying was performed in the fluidized bed pellet coater for about 30 to 120 minutes while the pellets were fluidized by supplying air at 75±10° C. The drying process could be operated within the allowable residual solvent range depending on the pharmaceutical binding agent used, and could be performed by a vacuum drying method or an oven drying method.

Examples 10 to 21

[0181] In order for a certain amount or the entire amount of the process product containing Example 7 or 8 to have a delayed modified-release (modified-release) form, coating solutions having the compositions shown in Tables 5 and 6 below were prepared using pharmaceutically acceptable additives and solvents, and then delayed modified-release pellets were prepared using a fluidized-bed pellet coater (GPCG-1, Bottom spray, Glatt, Germany).

TABLE-US-00005 TABLE 5 Example 10 Example 11 Example 12 Example 13 Example 14 Example 15 Pharmaceutical ingredients Batch weight (g) Example 7 Example 7 Example 8 Example 8 Example 8 Example 8 Triethyl citrate 11.25 11.29 11.7 11.7 10.24 10.41 Talc 9.3 12.85 25.19 25.19 22.04 22.4 Polysorbate 80 2.15  2.87 0.48 0.48 0.42 0.39 Methacrylic acid-ethyl acrylate copolymer 45.02 72.03 90.01 — — 79.99 Methacrylic acid-methylmethacrylate 36.02 18.01 — 90.01 — — copolymer (1:1) Methacrylic acid-methylmethacrylate 9 — — — 78.76 — copolymer (1:2) Solvent Purified water 779 as 518 as 852 115 100 757 Anhydrous ethyl mixture mixture — 1032 903 — Isopropyl alcohol — — — — — — Acetone — — — — — —

TABLE-US-00006 TABLE 6 Example 16 Example 17 Example 18 Example 19 Example 20 Example 21 Pharmaceutical ingredients Batch weight (g) Example 8 Example 8 Example 8 Example 8 Example 8 Example 8 Triethyl citrate 10.41 10.41 10.41 10.41 13.01 13.01 Talc 22.4 22.4 22.4 22.4 28 28 Polysorbate 80 0.39 0.39 0.39 0.39 0.48 0.48 Methacrylic acid-ethyl acrylate copolymer — — 79.99 15.98 62.5 33.3 Methacrylic acid-methylmethacrylate 79.99 — — 64 — — copolymer (1:1) Methacrylic acid-methylmethacrylate — 79.99 — — 37.53 66.7 copolymer (1:2) Solvent Purified water 102 102 102 102 127 127 Anhydrous ethyl 917 917 — — 1146 1146 Isopropyl alcohol — — 611 611 — — Acetone — — 306 306 — —

[0182] When the solvent was purified water, the operating conditions of the fluidized bed pellet coater used for the coating were an air supply temperature of 60±10° C., an exhaust air flap pressure of 40±10 bar, and a coating solution spray pressure of 1.5±0.6 bar, and when the solvent was a mixture of purified water, alcohol and acetone, the operating conditions of the fluidized bed pellet coater used for the coating were an air supply temperature of 35±10° C., an exhaust air flap pressure of 0.6±0.2 bar, and a coating solution spray pressure of 1.5±0.6 bar. During the coating solution spraying process, the height of the partition and the feed rate of the coating solution were appropriately adjusted while observing fluidization according to the amount of pellets charged.

[0183] After completion of the coating solution spraying, drying was performed in the fluidized bed pellet coater for about 30 to 120 minutes while the pellets were fluidized by supplying air at 75±1° C. The drying process could be operated within the allowable residual solvent range depending on the pharmaceutical binding agent used, and could be performed by a vacuum drying method or an oven drying method.

Experimental Example 1. Dissolution Evaluation Under Acidic Conditions

[0184] For dissolution evaluation, in order to exclude the effect of the disintegration or disruption time of the hard capsule, the pellets not filled in the capsule were weighed, and dissolution evaluation of Examples 8 to 10 was performed according to the United States Pharmacopeia (USP) apparatus 1 (basket).

[0185] Dissolution conditions were set as follows: pH 1.2 (hydrochloric acid buffer); 37±0.5° C.; 900 ml medium; 100 rpm. The sample solution obtained after the initiation of dissolution was analyzed using an ultraviolet spectrometer of high-performance liquid chromatography (HPLC; manufactured by Agilent Technologies).

TABLE-US-00007 TABLE 7 5 10 15 30 45 60 min min min min min min Example 7 101.8 101.7 101.7 100.9 99.79 99.24 Example 8 86.8 94.2 94.5 94.3 93.4 92.4 Example 9 98.1 98.4 98.5 98.6 98.6 98.4

[0186] As can be seen in Table 7 above, it could be confirmed that, in the case of Examples 7 to 9 to which the delayed modified-release layer was not applied, tegoprazan was dissolved under the acidic medium condition within a short time, suggesting that the pellet of the present disclosure could be used as a pellet for immediate release of tegoprazan.

Experimental Example 2. Evaluation of Acid Resistance

[0187] For dissolution evaluation, in order to exclude the effect of the disintegration time of the hard capsule, the pellets not filled in the capsule were weighed, and dissolution evaluation of Examples 10 to 21 was performed according to the United States Pharmacopeia (USP) apparatus 1 (basket) to evaluate the acid resistances thereof.

[0188] Dissolution conditions were set as follows: pH 1.2 (hydrochloric acid buffer); 37±0.5° C.; 900 ml medium; 100 rpm. The sample solution obtained after the initiation of dissolution was analyzed using an ultraviolet spectrometer of high-performance liquid chromatography (HPLC; manufactured by Agilent Technologies).

TABLE-US-00008 TABLE 8 5 10 15 30 45 60 90 120 min min min min min min min min Example 10 0 0 0 0 0 0 0 0 Example 11 0 0 0 0 0 0 0 0 Example 12 0 0 0 0 0 0 0 0 Example 13 0 0 0 0 0 0 2.1 4.7 Example 14 0 0 0 0 0 0 0 0 Example 15 0 0 0 0 0 0 0 0 Example 16 0 0 0 0 0 0 0 1.2 Example 17 0 0 0 0 0 0 0 0 Example 18 0 0 0 0 0 0 0 0.4 Example 19 0 0 0 0 0 0 0.3 1.3 Example 20 0 0 0 0 0 0 0 0 Example 21 0 0 0 0 0 0 0 0

[0189] As can be seen in Table 8 above, it could be confirmed that, unlike Examples 7 to 9 which showed high dissolution rate under the acidic medium condition because the delayed modified-release layer was not included, in the case of Examples 10 to 21 including the delayed modified-release layer, tegoprazan was not dissolved within 2 hours (120 minutes) under the acidic medium condition, or only a low dissolution rate appeared after 90 minutes, suggesting that sufficient acid resistance was ensured.

Experimental Example 3. Evaluation of Dissolution Under Weak Alkaline Condition

[0190] After completion of acid resistance evaluation in Experimental Example 2, dissolution evaluation for the pellets including the modified-release layer was performed in a weak alkaline medium.

[0191] The continuous dissolution test in this Experimental Example is a method by which a conventional technician or a person skilled in the art and related persons can evaluate a delayed modified-release formulation in laboratory or in-vitro. In this method, the dissolution in an acidic medium for a specified period of time is evaluated, and then the sample is transferred to a weak alkaline medium, or the pH in the medium is increased using an alkalizing agent. This method is used for the purpose of quality control and to evaluate in vitro behavior of drugs (Guidance for Industry, SUPAC-MR: Modified Release Solid Oral Dosage Form).

[0192] Specifically, after completion of acid resistance evaluation, the basket (apparatus 1) containing the pellets was set to the following dissolution conditions: preheated pH 6.8 (phosphate buffer); 37±0.5° C.; 900 ml medium; 100 rpm. The sample solution obtained after the initiation of dissolution was analyzed using an ultraviolet spectrometer of high-performance liquid chromatography (HPLC; manufactured by Agilent Technologies), and the results are shown in Table 9 below.

TABLE-US-00009 TABLE 9 5 10 15 30 45 60 90 120 180 240 300 360 min min min min min min min min min min min min Example 10 0 0 3.3 11.4 18.0 23.8 33.0 41.0 51.7 60.9 69.0 75.5 Example 12 1.9 27.6 45.5 64.0 72.8 76.8 79.9 82.7 85.2 86.5 86.8 89.1 Example 13 0 3.7 22.9 55.9 70.3 76.1 81.0 83.0 85.0 86.8 86.5 87.6 Example 15 1.3 27.4 48.9 64.6 74.3 78.2 80.5 81.8 82.8 83.7 83.7 83.7 Example 19 2.3 7.4 21.4 47.7 59.3 65.4 72.6 75.8 79.0 80.2 81.6 82.1 Example 20 0 0 6.1 33.3 54.8 67.0 81.0 83.5 85.7 86.7 87.5 88.5 Example 21 0 0 0 1.9 30.0 42.1 61.0 73.3 82.2 84.9 86.5 87.7

Examples 22 and 23

[0193] In order to increase the stability of the active ingredient layer, ensure the efficient formation of a coating layer and increase abrasion resistance, coating solutions having the compositions (hypromellose 3 cps, hypromellose 6 cps, talc, and solvent) shown in Table 10 below were prepared with additives and solvents, and then inert particles containing an organic acid were coated with each of the coating solution using a fluidized-bed pellet coater (GPCG-1, Bottom spray, Glatt, Germany) to form a separate isolation layer.

TABLE-US-00010 TABLE 10 Example 22 Example 23 Pharmaceutical ingredients Batch weight (g) Tartaric add pellets 2000  2000 Hypromellose 3 cps 40 — Hypromellose 6 cps — 40 Talc 40 40 Solvent Purified water 920  46 Anhydrous — 874 ethanol

[0194] The operating conditions of the fluidized bed pellet coater used for the coating were an air supply temperature of 60±10° C., an exhaust air flap pressure of 0.6±0.2 bar, and a coating solution spray pressure of 1.5±0.6 bar. During the coating solution spraying process, the height of the partition and the feed rate of the coating solution were appropriately adjusted while observing fluidization according to the amount of pellets charged.

[0195] After completion of the coating solution spraying, drying was performed in the fluidized bed pellet coater for about 30 to 120 minutes while the pellets were fluidized by supplying air at 75±10° C. The drying process could be operated within the allowable residual solvent range depending on the pharmaceutical binding agent used, and could be performed by a vacuum drying method or an oven drying method.

Examples 24 to 28

[0196] For coating with an active ingredient layer containing tegoprazan, coating solutions having the compositions shown in Table 11 below were prepared with pharmaceutical additives and solvents, and then the outer surface of a certain amount or the entire amount of the process product including Example 22 or 23 was coated with each of the coating solution using a fluidized bed pellet coater (GPCG-1, Bottom spray, Glatt, Germany).

TABLE-US-00011 TABLE 11 Example 24 Example 25 Example 26 Example 27 Example 28 Pharmaceutical ingredients Batch weight (g) Example 22 Example 23 Example 23 Example 23 Example 23 Tegoprazan 576.92 480.77 480.77 480.77 480.77 Povidone 115.38 96.15 96.15 96.15 96.15 Talc 23.08 19.23 48.08 72.12 96.15 Polysorbate 80 23.08 19.23 19.23 19.23 19.23 Solvent Purified water 2173 2494 2436 2527 2628 Anhydrous ethanol 445 511 499 518 536

[0197] The operating conditions of the fluidized bed pellet coater used for the coating were an air supply temperature of 60±10° C., an exhaust air flap pressure of 0.7±0.3 bar, and a coating solution spray pressure of 1.5±0.7 bar. During the coating solution spraying process, the height of the partition and the feed rate of the coating solution were appropriately adjusted while observing fluidization according to the amount of pellets charged.

[0198] After completion of the coating solution spraying, drying was performed in the fluidized bed pellet coater for about 30 to 120 minutes while the pellets were fluidized by supplying air at 75±10° C. The drying process could be operated within the allowable residual solvent range depending on the pharmaceutical binding agent used, and could be performed by a vacuum drying method or an oven drying method.

Examples 29 and 30

[0199] To increase the stability of the active ingredient layer containing tegoprazan, ensure the efficient formation of the coating layer and increase abrasion resistance, coating solutions having the composition shown in Table 12 below were prepared, and then inert coating (coating layer) was performed on the outer surface of a certain amount or the entire amount of the process product containing Example 24 to 25 using a fluidized-bed pellet coater (GPCG-1, Bottom spray, Glatt, Germany).

TABLE-US-00012 TABLE 12 Example 29 Example 30 Pharmaceutical ingredients Batch weight (g) Example 24 Example 25 Hypromellose 66.92 66.92 Talc 26.77 26.77 Solvent Purified water 54 1467 Anhydrous 1024 — ethanol

[0200] The operating conditions of the fluidized bed pellet coater used for the coating were an air supply temperature of 60±10° C., an exhaust air flap pressure of 0.6±0.2 bar, and a coating solution spray pressure of 1.5±0.6 bar. During the coating solution spraying process, the height of the partition and the feed rate of the coating solution were appropriately adjusted while observing fluidization according to the amount of pellets charged.

[0201] After completion of the coating solution spraying, drying was performed in the fluidized bed pellet coater for about 30 to 120 minutes while the pellets were fluidized by supplying air at 75±10° C. The drying process could be operated within the allowable residual solvent range depending on the pharmaceutical binding agent used, and could be performed by a vacuum drying method or an oven drying method.

Examples 31 to 38

[0202] In order for a certain amount or the entire amount of the process product containing Example 29 or 30 to have a delayed modified-release form, coating solutions having the compositions shown in Table 13 below were prepared with additives and solvents, and then delayed modified-release pellets were prepared using a fluidized-bed pellet coater (GPCG-1, Bottom spray, Glatt, Germany).

TABLE-US-00013 TABLE 13 Example 31 Example 32 Example 33 Example 34 Example 35 Example 36 Example 37 Example 38 Pharmaceutical ingredients Batch weight (g) Example 29 Example 29 Example 29 Example 29 Example 29 Example 29 Example 30 Example 30 Triethyl citrate 7.8 10.41 10.41 10.41 10.41 10.41 13.0 13.0 Talc 16.79 22.4 22.4 22.4 22.4 22.4 28 28 Polysorbate 80 0.32 0.39 0.39 0.39 0.39 0.39 0.5 0.5 Methacrylic acid-ethyl 60.01 79.99 — — 79.99 15.98 62.5 33.3 acrylate copolymer Methacrylic acid- — — 79.99 — — 64.0 — — methylmethacrylate copolymer (1:1) Methacrylic acid- — — — 79.99 — — 37.53 66.7 methylmethacrylate copolymer (1:2) Solvent Purified water 568 757 102 102 102 102 127 127 Anhydrous ethyl — — 917 917 — — 1146 1146 Isopropyl alcohol — — — — 611 611 — — Acetone — — — — 306 306 — —

[0203] When the solvent was purified water, the operating conditions of the fluidized bed pellet coater used for the coating were an air supply temperature of 60±10° C., an exhaust air flap pressure of 40±10 bar, and a coating solution spray pressure of 1.5±0.6 bar, and when the solvent was a mixture of purified water, alcohol and acetone, the operating conditions of the fluidized bed pellet coater used for the coating were an air supply temperature of 35±10° C., an exhaust air flap pressure of 0.6±0.2 bar, and a coating solution spray pressure of 1.5±0.6 bar. During the coating solution spraying process, the height of the partition and the feed rate of the coating solution were appropriately adjusted while observing fluidization according to the amount of pellets charged.

[0204] After completion of the coating solution spraying, drying was performed in the fluidized bed pellet coater for about 30 to 120 minutes while the pellets were fluidized by supplying air at 75±10° C. The drying process could be operated within the allowable residual solvent range depending on the pharmaceutical binding agent used, and could be performed by a vacuum drying method or an oven drying method.

Experimental Example 4. Evaluation of Acid Resistance

[0205] For dissolution evaluation, in order to exclude the effect of the disintegration time of the hard capsule, the pellets not filled in the capsule were weighed, and dissolution evaluation of Examples 31, 32, 34, 37 and 38 was performed according to the United States Pharmacopeia (USP) apparatus 1 (basket) to evaluate the acid resistances thereof under an acidic condition.

[0206] Dissolution conditions were set as follows: pH 1.2 (hydrochloric acid buffer); 37±0.5° C.; 900 ml medium; 100 rpm. The sample solution obtained after the initiation of dissolution was analyzed using an ultraviolet spectrometer of high-performance liquid chromatography (HPLC; manufactured by Agilent Technologies).

TABLE-US-00014 TABLE 14 5 10 15 30 45 60 90 120 min min min min min min min min Example 31 0 0 0 0 0 0 3.4 5.2 Example 32 0 0 0 0 0 0.6 4.3 7.4 Example 34 0 0 0 0 0 0 0.3 0.7 Example 37 0 0 0 0 0 0 0 0 Example 38 0 0 0 0 0 0 0 0

[0207] As can be seen in Table 14 above, it could be confirmed that, in the case of Examples 31, 32, 34, 37 and 38 including the delayed modified-release layer, tegoprazan was not dissolved within 2 hours (120 minutes) under the acidic medium condition, or only a low dissolution rate appeared after 90 minutes, suggesting that sufficient acid resistance was ensured.

Experimental Example 5. Evaluation of Dissolution Under Weak Alkaline Condition

[0208] After completion of acid resistance evaluation in Experimental Example 4, dissolution evaluation for the delayed modified-release pellets was performed in a weak alkaline medium.

[0209] Specifically, after completion of acid resistance evaluation, the basket (apparatus 1) containing the pellets was set to the following dissolution conditions: preheated pH 6.8 (phosphate buffer); 37±0.5° C.; 900 ml medium; 100 rpm. The sample solution obtained after the initiation of dissolution was analyzed using an ultraviolet spectrometer of high-performance liquid chromatography (HPLC; manufactured by Agilent Technologies), and the results are shown in Table 15 below.

TABLE-US-00015 TABLE 15 5 10 15 30 45 60 90 120 180 240 300 360 min min min min min min min min min min min min Example 32 1.6 23.8 41.7 60.3 73.3 80.3 85.6 86.9 88.4 89.1 90.6 92.4 Example 34 0 0 1.3 3.3 5.6 8.1 13.3 18.3 26.8 33.9 40.0 44.0 Example 37 0 0 0 31.9 47.1 52.5 58.4 61.6 66.2 68.6 70.3 71.5 Example 38 0 0 0 0 13.5 42.3 53.2 58.0 62.8 64.7 65.9 66.7

Experimental Example 6. Evaluation of Pharmacokinetic Absorption Affect in Beagles

[0210] In the present disclosure, all experimental procedures regarding the evaluation of pharmacokinetic characteristics in non-clinical models were performed following the regulations of the Animal Experimental Ethics Committee (IACUC, Institutional Animal Care and Use Committee), and performed in consideration of human equivalent doses (HEDs).

[0211] For evaluation of the in vivo pharmacokinetic characteristics of the pellets (test group) of Examples 12 to 14, commercially available K-CAB® tablet (control group 1) and Example 8 including no modified-release layer (control group 2) were set as control groups. Hard capsules were filled with the pellets of each of the test group and control group 2 so that they contained tegoprazan at the same dose as the K-CAB® tablet, and then a non-clinical test was conducted.

[0212] The non-clinical model animals used in the test were a total of 15 beagles (20±2 months old males with an average weight of 13±2 kg) divided into each group, consisting of three animals. Each test drug was administered orally to the animals by single-dose parallel design in a fasting condition after fasting for at least 12 hours the day before administration. Before administration (0 hours) and at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12 and 24 hours after administration, blood was collected from the cephalic vein using a disposable 3 ml syringe. As a blood sample container, a 4 ml sodium heparin tube (BD Biosciences, USA) containing an anticoagulant was used. The collected blood was centrifuged at 3,000 rpm for 15 minutes to isolate plasma, and the plasma was stored in a cryogenic (−70° C.) freezer until analysis.

[0213] As an analysis instrument, a liquid chromatography mass spectrometer (LC-MS) was used, and analysis was performed in in-house method validation and electrospray ionization modes. The results are shown in Table 16 and FIG. 2.

TABLE-US-00016 TABLE 16 PK Control 1 Control 2 Example 12 Example 13 Example 14 T.sub.max(h).sup.1) 1.3 ± 0.6 0.7 ± 0.3 3.0 ± 0.0 2.7 ± 0.6 4.0 ± 0.0 T.sub.1/2(h).sup.2) 3.5 ± 0.2 3.1 ± 0.5 3.5 ± 0.5 7.6 ± 5.7 4.0 ± 0.9 C.sub.max(ng/mL).sup.3) 1840 ± 199  2400 ± 495  1720 ± 440  1130 ± 336  428 ± 141 AUG.sub.t(ng .Math. h/mL).sup.4) 9850 ± 1200 9750 ± 3300 10300 ± 4290  7620 ± 2540 3630 ± 1910 .sup.1)T.sub.max: the time taken to reach C.sub.max; .sup.2)T.sub.1/2: the time taken for drug concentration to decrease to half the original concentration; .sup.3)C.sub.max: the maximum concentration of the drug after drug administration; .sup.4)AUC.sub.t: Area under the plasma concentration-time curve from administration time to the last sampling time t

[0214] As shown in Table 16 above and FIG. 2, it could be confirmed that control group 2 showed a faster T.sub.max and a higher C.sub.max value than control group 1 due to an increase in surface area after disintegration or dissolvation of the hard capsule film in the body, suggesting that it showed high in vivo exposure within a short time after administration. In addition, it could be confirmed that Examples 12 to 14 showed different in vivo absorption rates due to the pH-dependent physical properties of the enteric agent used for modified-release, and Examples 12 to 14 including the delayed modified-release layer showed a delay in the T.sub.max value of the plasma concentration of tegoprazan compared to the control groups.

Experimental Example 7. Evaluation of Pharmacokinetic Absorption Affect in Mini-Pigs According to Type of Inert Particles

[0215] For evaluation of in vivo pharmacokinetic absorption affect according to the type of inert particles, hard capsules were filled with the pellets of each of Examples 15, 17, 32 and 34 so that they could contain same dose of tegoprazan, and then a non-clinical test was conducted.

[0216] Mini-pigs having a relatively long gastrointestinal (GI) tract compared to beagles were selected as a non-clinical model, and comparative evaluation was performed using single-dose parallel design method.

[0217] mini-pigs (8 to 11 months old males with an average weight of 25.9±1.4 kg) divided into each group, consisting of three animals, were used in the test. Each test drug was administered orally to the animals by single-dose parallel design method in a fasting condition after fasting for at least 12 hours the day before administration.

[0218] At 0.5, 1, 1.5, 2, 3, 4, 5, 6, 7, 8, 12 and 24 hours after administration, about 3 ml of blood was collected from the jugular vein using a disposable syringe. As a blood sample container, a heparinized tube (5 IU/mL) was used. The collected blood was centrifuged at 3,000 rpm for 5 minutes to isolate plasma, and the plasma was stored in a cryogenic (−70° C.) freezer until analysis.

[0219] The plasma concentration of the drug was analyzed using LC-MS/MS in in-house method validation and electrospray ionization modes, and the results are shown in Table 17 below and FIG. 3.

TABLE-US-00017 TABLE 17 Inert pellet Sugar-based sucrose inert particle Organic add-containing inert particle PK Example 15 Example 17 Example 32 Example 34 T.sub.max 3.7 ± 1.2 4.3 ± 1.5 4.7 ± 1.5 4.7 ± 1.5 C.sub.max(ng/mL)  158 ± 75.6 108 ± 105  160 ± 43.5  115 ± 34.4 AUG.sub.t(ng .Math. h/mL) 632 ± 137 671 ± 546 843 ± 240 836 ± 103

[0220] As shown in Table 17 and FIG. 3, the in vivo exposure of the modified-release formulation containing tegoprazan was higher in Examples 32 and 34, in which the inert particles containing organic acids were used, among the two types of inert particles used in the experiment.

[0221] There is a slight difference in intestinal length and intestinal pH between animal species, but mini-pigs are close to human-like environments. Thus, the above results suggest that, when inert particles containing an organic acid are used in the pharmaceutical composition of the present disclosure, the in vivo absorption rate of tegoprazan can be increased.

Experimental Example 8. Evaluation of Pharmacokinetic Absorption Affect in Monkeys According to Type of Inert Particles

[0222] Monkeys which are the animal model most similar to humans in terms of anatomy, physiology and endocrinology were used as an animal model. Using this animal model, pharmacokinetic absorption affect according to the types of inert particles were comparatively evaluated by single dose parallel design method.

[0223] For evaluation of in vivo pharmacokinetic absorption affect, hard capsules were filled with the pellets of each of Examples 15 and 32 so that they could contain uniform amounts of tegoprazan, and then a non-clinical test was conducted.

[0224] The non-clinical model animals used in the test were a total of 6 cynomolgus monkeys (30 to 50 months old males with an average weight of 3.19±0.37 kg) divided into each group, consisting of three animals. Each test drug was administered orally to the animals by single-dose parallel design method in a fasting condition after fasting for at least 16 hours the day before administration.

[0225] At 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours after oral administration, about 1 ml of blood was collected from the femoral vein using a disposable syringe. As a blood sample container, BD Microtainer® (Sodium Heparin tube, BD Biosciences, USA) was used. The collected blood was centrifuged at 3,000 rpm at 4° C. for 15 minutes to isolate plasma, and the plasma was stored in a cryogenic (−70° C.) freezer until analysis.

[0226] The plasma concentration of the drug was analyzed using LC-MS/MS in in-house method validation and electrospray ionization modes, and the results are shown in Table 18 below and FIG. 4.

TABLE-US-00018 TABLE 18 PK Example 15 Example 32 T.sub.max(h) 4.5 ± 0.7 4.3 ± 0.6 T.sub.1/2(h) 6.3 ± 3.1 5.8 ± 4.8 C.sub.max(ng/mL) 145 ± 25  362 ± 143 AUG.sub.t(ng .Math. h/mL) 1520 ± 280  1700 ± 990 

[0227] As shown in Table 18 and FIG. 4, the in vivo exposure of the modified-release formulation containing tegoprazan was higher in Examples 32, in which the inert particles containing organic acids were used, among the two types of inert particles used in the experiment.

[0228] The above results suggest that, when inert particles containing an organic acid are used, the in vivo absorption rate of tegoprazan can be increased.

[0229] Experimental Example 9. Evaluation of Pharmacokinetic Absorption Affect in Monkeys by Single Dose Parallel Design

[0230] A series of studies and analysis related experimental items for evaluating the pharmacokinetic absorption affect of immediate-release and modified-release pellets in monkeys by single dose parallel design method were conducted under conditions similar to those of Experimental Example 7. Monkeys (average weight: 4.48±0.56 kg; 4±2 years old) were divided into each group, consisting of 6 animals, and each drug was administered to each animal group. The results are shown in Table 19 below.

TABLE-US-00019 TABLE 19 PK Example 8 Example 20 Example 21 T.sub.max(h) 1.7 ± 0.9 3.2 ± 0.8 3.4 ± 1.4 C.sub.max(ng/mL) 274 ± 108  170 ± 35.8  123 ± 22.1 AUG.sub.t(ng .Math. h/mL) 1260 ± 251  1420 ± 286  1200 ± 286 

[0231] As shown in Table 19, it was confirmed that T.sub.max was delayed in Examples 20 and 21 including the delayed modified-release layer, compared to Example 8 not including the delayed modified-release layer, suggesting that the formulation including the delayed modified-release layer showed a modified-release pattern. In addition, it was confirmed that Example 20 and 21 which are delayed modified-release formulations were similar to Example 8 which is an immediate-release formulation in the result of in vivo exposure of the drug, and among the pharmacokinetics (PK) of tegoprazan according to the release pattern of the formulation, the area under the concentration-time curve (AUC) was similar between the Examples.

Examples 39 to 46

[0232] For coating with the active ingredient layer containing tegoprazan, coating solutions having the pharmaceutical additive compositions shown in Table 20 below were prepared (solvent: q.s.) with various binding agents, and then sucrose-based inert pellets (product name: Suglet, Colorcon) were coated with each of the coating solution using a fluidized bed pellet coater (GPCG-1, Bottom spray, Glatt, Germany).

TABLE-US-00020 TABLE 20 Example Example Example Example Example Example Example Example 39 40 41 42 43 44 45 46 Suglet 25/30 52.00 100.00 100.00 100.00 100.00 100.00 100.00 100.00 Tegoprazan Tegoprazan 50.00 50.00 50.00 50.00 50.00 50.00 50.00 50.00 layer Povidone K90 10.00 10.00 — — — — — — Polyvinyl alcohol — — 10.00 — 5.00 — — — (EG-40) Hydroxypropyl — — — 10.00 — — — — cellulose (EXF) Polyethylene — — — — — 10.00 — — glycol•polyvinyl alcohol copolymer Hydroxypropyl — — — — — — 10.00 — methylcellulose (15 cps) Hydroxypropyl — — — — — — — 10.00 cellulose (GXF) Polysorbate 80 2.00 — — — — — — — Talc 7.50 7.50 7.50 7.50 7.50 7.50 7.50 7.50 Total 121.50 167.50 167.50 167.50 162.50 167.50 167.50 167.50 (unit: mg/capsule)

[0233] The content in Table 20 is expressed in terms of the amount (mg) of pellets filled per capsule.

[0234] The operating conditions of the fluidized bed pellet coater were an air supply temperature of 75±10° C., an exhaust air flap pressure of 0.7±0.3 bar, and a coating solution spray pressure of 1.5±0.7 bar. During the coating solution spraying process, the height of the partition and the feed rate of the coating solution were appropriately adjusted while observing fluidization according to the amount of pellets charged.

[0235] After completion of the coating solution spraying, drying was performed in the fluidized bed pellet coater for about 30 to 120 minutes while the pellets were fluidized by supplying air at 75±10° C. The drying process could be operated within the allowable residual solvent range depending on the binding agent used, and could be performed by a vacuum drying method or an oven drying method.

Experimental Example 10. Dissolution Evaluation

[0236] For dissolution evaluation, in order to exclude the effect of the disintegration time of the hard capsule, the pellets not filled in the capsule were weighed, and dissolution evaluation of Examples 39 to 44 was performed according to the United States Pharmacopeia (USP) apparatus 1 (basket).

[0237] Dissolution conditions were set as follows: pH 4.0 (acetate buffer); 37±0.5° C.; 900 mL medium; 50 rpm. The sample solution obtained after the initiation of dissolution was analyzed using an ultraviolet spectrometer of high-performance liquid chromatography (HPLC; manufactured by Agilent Technologies). The results are shown in Table 21 below.

TABLE-US-00021 TABLE 21 5 10 15 30 45 60 90 120 min min min min min min min min Example 39 28.6 66.6 80.4 93.8 96.4 97.4 98.2 98.6 Example 40 12.2 28.6 39.0 58.1 69.1 76.1 83.6 87.9 Example 41 16.9 55.7 73.0 83.9 86.4 87.8 89.5 90.5 Example 42 40.3 64.7 71.7 79.4 82.9 85.0 87.4 88.7 Example 43 2.3 10.0 20.9 43.3 58.7 69.0 83.2 90.6 Example 44 63.6 81.2 89.2 98.0 99.5 99.5 99.7 99.5

[0238] As shown in Table 21 above, it can be seen that the release rate of tegoprazan can be modified depending on the type of a polymer. Specifically, it can be seen that the release rate of the active ingredient decreased as the viscosity of the polymer used increased, and that Example 43 (using 5.0 mg PVA) had the lowest release rate, and Example 44 (using 10.0 mg polyethylene glycol) had the highest release rate.

Examples 47 to 55

[0239] For coating with an active ingredient layer containing tegoprazan, coating solutions having the compositions shown in Table 22 below were prepared with pharmaceutical additives and solvents, and then inert pellets were coated with each of the coating solutions. Coating was performed under substantially the same conditions and using the same method as in Examples 39 to 47.

TABLE-US-00022 TABLE 22 Example Example Example Example Example Example Example Example Example 47 48 49 50 51 52 53 54 55 mg/capsule Suglet 25/30 50.00 50.00 50.00 50.00 50.00 50.00 50.00 50.00 50.00 Tegoprazan Tegoprazan 50.00 50.00 50.00 50.00 50.00 50.00 50.00 50.00 50.00 layer Polyvinyl 5.00 2.50 5.00 5.00 5.00 2.50 2.50 3.75 2.50 alcohol (EG-40) Talc 22.50 7.50 7.50 7.50 22.50 22.50 7.50 15.00 22.50 Purified 310.00 240.00 250.00 145.83 180.83 175.00 140.00 206.25 300.00 water Total 127.50 110.00 112.50 112.50 127.50 125.00 110.00 118.75 125.00

Experimental Example 11. Dissolution Evaluation

[0240] Dissolution evaluation of Examples 47 to 55 was performed under substantially the same conditions and using the same method as in Experimental Example 9. The results are shown in Table 23.

TABLE-US-00023 TABLE 23 5 10 15 30 45 60 90 120 min min min min min min min in Example 47 0.4 2.5 3.9 8.7 15.0 21.5 31.9 40.1 Example 48 1.7 4.1 6.6 13.1 19.3 24.6 33.2 40.9 Example 49 1.2 4.7 9.6 29.3 45.3 57.5 74.5 84.3 Example 50 2.6 10.0 22.8 49.5 65.6 74.0 82.3 87.0 Example 51 1.3 3.0 4.6 13.6 22.9 31.2 44.1 54.5 Example 52 1.7 3.3 4.9 9.7 15.5 20.6 29.1 36.3 Example 53 3.8 9.3 15.0 29.6 42.1 52.3 67.4 79.0 Example 54 1.3 2.9 4.3 9.0 14.4 20.3 31.8 42.7 Example 55 1.4 2.7 3.9 7.2 10.1 12.9 17.2 20.7

[0241] As shown in Table 23 above, it can be seen that the release rate of tegoprazan can be modified depending on the amount of talc. In particular, it can be seen that the batch of Example 55 (using an excessive amount (22.5 mg) of talc) had the lowest release rate, and the batch of Example 50 (using a small amount (7.5 mg) of talc) had the highest release rate.

Examples 56 and 61

[0242] To increase the stability of the active ingredient layer containing tegoprazan and the pellets including the same, ensure the efficient formation of the coating layer and increase abrasion resistance, coating solutions having the compositions shown in Table 24 below were prepared, and then the outer surface of a certain amount or the entire amount of the process product containing Example 39, 50 or 51 was coated with each of the coating solutions using a fluidized-bed pellet coater (GPCG-1, Bottom spray, Glatt, Germany).

TABLE-US-00024 TABLE 24 Example Example Example Example Example Example 56 57 58 59 60 61 mg/capsule Active ingredient Example 39 Example 39 Example 39 Example 39 Example 51 Example 50 coating pellet 121.50 121.50 121.50 121.50 127.50 112.50 Hydroxypropyl methyl — — — — 2.55 2.25 cellulose (3 cps) Ethyl cellulose 16.63 12.15 18.23 24.30 — — Polyethylene 2.91 2.13 3.20 4.26 — — glycol•polyvinyl alcohol copolymer Triethyl citrate 4.15 3.04 4.56 6.08 — — Talc 4.74 1.73 2.60 3.46 2.55 2.25 Purified water 55.42 40.50 60.75 81.00 58.65 51.75 Total 149.93 140.55 150.09 159.60 132.60 117.00

[0243] The operating conditions of the fluidized bed pellet coater were an air supply temperature of 50±10° C., an exhaust air flap pressure of 0.6±0.2 bar, and a coating solution spray pressure of 1.5±0.6 bar. During the coating solution spraying process, the height of the partition and the feed rate of the coating solution were appropriately adjusted while observing fluidization according to the amount of pellets charged.

[0244] After completion of the coating solution spraying, curing was performed in the fluidized bed pellet coater for about 30 to 120 minutes while the pellets were fluidized by supplying air at 75±10° C. The drying process could also be performed by an oven drying method.

Experimental Example 12. Dissolution Evaluation

[0245] For dissolution evaluation, in order to exclude the effect of the disintegration time of the hard capsule, the pellets not filled in the capsule were weighed, and dissolution evaluation of Examples 39 and 56 to 59 was performed according to the United States Pharmacopeia (USP) apparatus 1 (basket).

[0246] Dissolution conditions were set as follows: pH 6.8 (phosphate buffer); 37±0.5° C.; 900 mL medium; and 100 rpm. The sample solution obtained after the initiation of dissolution was analyzed using an ultraviolet spectrometer of high-performance liquid chromatography (HPLC; manufactured by Agilent Technologies), and the results are shown in Table 25 below.

TABLE-US-00025 TABLE 25 15 30 45 60 90 120 240 360 480 720 min min min min min min min min min min Example 39 62.4 81.8 90.6 95.0 98.3 99.1 99.3 99.5 99.0 98.9 Example 56 17.2 45.0 60.1 68.5 77.7 82.9 93.0 98.0 100.7 102.8 Example 26.8 52.3 67.3 76.8 86.4 91.5 98.8 102.5 104.0 105.6 57(10%) Example 14.2 34.5 46.4 54.5 64.4 70.3 81.1 87.1 90.0 94.1 58(15%) Example 9.2 28.2 39.8 48.1 58.8 65.2 76.0 81.6 84.4 88.2 59(20%)

[0247] As shown in Table 25 above, it can be seen that the release rate can be modified according to the presence or absence of the coating layer and the composition of the coating layer. Specifically, it can be seen that, as the amount of the coating layer increases, the release rate of the active ingredient decreases.

[0248] Therefore, it can be confirmed that the pharmaceutical composition of the present disclosure can release tegoprazan in a sustained manner by modifying the release rate of tegoprazan, and in particular, it can be confirmed that the pharmaceutical composition may release tegoprazan in a sustained manner even in the intestinal environment.

[0249] Therefore, it can be seen that the pharmaceutical composition of the present disclosure may have a modified-release pattern in which tegoprazan is released in a sustained manner in a region ranging from the gastric juice environment to the intestinal environment.

Examples 62 to 69

[0250] Enteric coating solutions having the compositions shown in Table 26 below were prepared with pharmaceutically acceptable additives and solvents, and then a certain amount or the entire amount of the process product including Example 56, 67 or 61 was coated with each of the enteric coating solutions using a fluidized bed pellet coater (GPCG-1, Bottom spray, Glatt, Germany).

TABLE-US-00026 TABLE 26 Example Example Example Example Example Example Example Example 62 63 64 65 66 67 68 69 mg/capsule Active ingredient Example 56 Example 60 Example 61 Example 61 Example 61 Example 60 Example 60 Example 60 coating pellet 149.93 132.60 117.00 117.00 117.00 132.60 132.60 132.60 Methacrylic acid 10.00 13.26 17.55 23.40 35.10 19.89 26.52 39.78 copolymer S Methacrylic acid 5.00 6.63 — — — — — — copolymer L Potassium hydroxide — — 0.39 0.52 0.79 0.45 0.59 0.89 (KOH) Triethyl citrate 3.00 1.99 10.53 14.04 21.06 11.93 15.91 23.87 Talc 7.50 9.95 8.78 11.70 17.55 9.95 13.26 19.89 Purified water 12.62 11.67 148.99 198.66 297.98 168.86 225.14 337.72 Anhydrous ethanol 216.79 221.71 — — — — — — Total 175.43 164.43 154.25 166.66 191.50 174.82 188.88 217.03

[0251] The operating conditions of the fluidized bed pellet coater used for the coating were an air supply temperature of 35±10° C., an exhaust air flap pressure of 0.7±0.3 bar, and a coating solution spray pressure of 1.5±0.7 bar. During the coating solution spraying process, the height of the partition and the feed rate of the coating solution were appropriately adjusted while observing fluidization according to the amount of pellets charged.

[0252] After completion of the coating solution spraying, drying was performed in the fluidized bed pellet coater for about 30 to 120 minutes while the pellets were fluidized by supplying air at 40±10° C. The drying process could also be performed by a vacuum drying method or an oven drying method.

Experimental Example 13. Dissolution Evaluation

[0253] Dissolution evaluation of Examples 62 to 69 was performed under substantially the same conditions and using the same method as in Experimental Example 12. The results are shown in Table 27.

TABLE-US-00027 TABLE 27 15 30 45 60 90 120 240 360 480 720 min min min min min min min min min mim Example 62 0.0 3.5 10.2 16.0 25.2 32.0 50.0 57.7 61.7 66.6 Example 63 0.0 0.0 0.0 1.0 7.2 20.2 39.9 45.4 49.1 54.3 Example 0.0 2.2 4.1 6.4 10.4 17.2 41.2 53.6 59.1 64.4 64(15%) Example 0.0 1.7 2.8 4.6 9.0 13.2 40.1 52.6 58.2 64.8 65(20%) Example 0.0 0.0 0.9 2.1 3.5 5.1 12.4 27.7 37.8 53.1 66(30%) Example 0.4 3.3 6.8 10.7 17.0 21.8 37.5 44.0 48.0 53.0 67(15%) Example 0.0 0.8 2.9 4.8 8.9 13.4 36.4 47.9 52.7 56.6 68(20%) Example 0.0 0.0 0.0 0.4 1.3 3.2 11.6 22.2 31.3 49.1 69(30%)

[0254] As shown in Table 27, it can be seen that, in the case of Examples 62 to 69, to which sustained-release and delayed modified-release were applied, tegoprazan was released for 720 minutes or more in a weak alkaline medium condition. That is, it can be seen that the pellets of the present disclosure can be used as delayed and modified-release pellets that release tegoprazan in the intestinal environment and release tegoprazan in a sustained manner.

[0255] In addition, as shown in Table 27, it can be seen that both the batch using the organic solvent and the batch using only purified water achieve similar sustained-release properties, and both the solution compositions can be used.

[0256] Furthermore, when comparing Examples 64 to 66 and Examples 67 to 69, it can be seen that, as the enteric coating rate in the pellet increases, the total dissolution rate tends to decrease, and even in the case the pellets having similar enteric coating rates, if there is a difference in the release rate of the active ingredient, the total dissolution rate is different. Accordingly, it can be seen that the final dissolution rate can be adjusted as desired by modifying the release rate of the active ingredient and the composition of the enteric coating layer.

[0257] Therefore, it can be seen that the pharmaceutical composition of the present disclosure can be used as a modified-release formulation that modifies the release of tegoprazan so as to have a desired release (dissolution) rate.

Examples 70 to 74

[0258] To provide a sustained and modified-release form, granules having the compositions shown in Table 28 below were prepared with pharmaceutical additives, and then tableted to produce sustained-release tablets.

TABLE-US-00028 TABLE 28 Example Example Example Example Example Sustained-release 70 71 72 73 74 Process formulation mg/Tablet Inside of Tegoprazan 25.00 25.00 25.00 25.00 25.00 granule Mannitol 160C 25.00 25.00 25.00 25.00 25.00 Microcrystalline cellulose 21.00 21.00 21.00 21.00 21.00 Croscarmellose sodium 3.00 3.00 3.00 3.00 3.00 Binding Hydroxypropyl cellulose 3.00 3.00 3.00 3.00 3.00 solution Purified water 33.00 33.00 33.00 33.00 33.00 Outside of Polyethylene oxide 22.00 — — — — granule Hydroxypropyl methyl — 22.00 — — — cellulose (15,000 cps) Hydroxypropyl methyl — — 22.00 44.00 66.00 cellulose (100,000 cps) lubricant Magnesium stearate 1.00 1.00 1.00 1.00 1.00 Total 100.00 100.00 100.00 122.00 144.00

[0259] Specifically, according to the amounts shown in Table 28 above, tegoprazan was mixed with mannitol, microcrystalline cellulose and croscarmellose sodium, and then sieving was performed. After the sieved material was added to a high shear mixer (DIOSNA), the granulation process was performed while the prepared binding solution was added.

[0260] The prepared granules were dried, and then subjected to a milling process using a screen having an appropriate size. Extragranular excipients shown in Table 28 above were added to and mixed with the milled granules in the amounts shown in Table 28. After completion of the mixing process, a lubrication process was performed by adding sieved magnesium stearate to the mixture. The lubricated materials were tableted using an appropriate punch, thus preparing sustained-release tablets.

Experimental Example 14. Dissolution Evaluation of Sustained-Release Tablets

[0261] Dissolution evaluation was performed the United States Pharmacopeia (USP) apparatus 2 (paddle) under the following conditions: pH 6.8 (phosphate buffer); 37±0.5° C.; 900 mL medium; and 50 rpm. The sample solution obtained after the initiation of dissolution was analyzed using an ultraviolet spectrometer of high-performance liquid chromatography (HPLC; Agilent Technologies), and the results are shown in Table 29 below.

TABLE-US-00029 TABLE 29 15 30 45 60 90 120 240 360 480 720 min min min min min min min min min min K-CAB ® 31.1 46.4 53.9 59.5 66.5 71.1 79.8 83.2 85.1 88.0 25 mg Example 72 4.6 6.6 7.6 8.8 11.1 13.1 21.5 30.6 40.2 58.6 Example 73 5.4 8.0 9.6 11.2 14.0 16.6 26.6 37.1 48.2 69.0 Example 74 3.0 3.3 3.4 3.9 4.5 4.9 7.9 11.6 16.8 29.0

[0262] As shown in Table 29, it can be confirmed that the sustained-release tablets of Examples 72 to 74 released tegoprazan slowly and sustainedly in a weak alkaline environment. In addition, when comparing Examples 72 to 74, it can be seen that the release rate of tegoprazan could be modified according to the proportion of the sustained-release agent.

Examples 75 and 76

[0263] Granules having the compositions shown in Table 30 below were prepared with pharmaceutical additives, and then tableted to prepare immediate-release tablets. Granules and tablets were prepared under substantially the same conditions and using the same method as in Examples 70 to 74, except that the components and contents shown in Table 30 below were used.

TABLE-US-00030 TABLE 30 Example 75 Example 76 Process Components mg/Dosage unit Inside of Tegoprazan 50.00 50.00 granule Mannitol 50.00 50.00 Microcrystalline cellulose 42.00 42.00 Croscarmellose sodium 6.00 6.00 Binding Hydroxypropyl cellulose 6.00 6.00 solution Purified water 66.00 66.00 Outside of Vivapur112 — 34.00 granule Croscarmellose sodium — 8.00 Colloidal silicon dioxide — 2.00 Lubricant Magnesium stearate 2.00 2.00 Total 156.00 200.00

Example 77

[0264] A mixture having the composition shown in Table 31 below was prepared with pharmaceutical additives.

TABLE-US-00031 TABLE 31 Example 77 Components mg/Dosage unit Tegoprazan 50.00 Mannitol 50.00 Microcrystalline cellulose 86.00 Croscarmellose sodium 10.00 Colloidal silicon dioxide 2.00 Magnesium stearate 2.00 Total 200.00

[0265] Specifically, tegoprazan was sieved together with mannitol, microcrystalline cellulose, croscarmellose sodium, and colloidal silicon dioxide in the amounts shown in Table 31 above, and then mixed. Sieved magnesium stearate was added to the mixture, and a lubrication process was performed to prepare a powdery mixture.

Example 78

[0266] The immediate-release tablet shown in Table 32 below was prepared.

TABLE-US-00032 TABLE 32 Example 78 Components mg/Tablet Uncoated tablet Tegoprazan 12.5 Mannitol 67.5 Microcrystalline cellulose 100.0 Croscarmellose sodium 10.0 Hydroxypropyl cellulose 6.0 Colloidal silicon dioxide 2.0 Magnesium stearate 2.0 Coating Opadry white 6.0 Total 206.00

[0267] A granule and an uncoated tablet were prepared under substantially the same conditions and using the same method as in Examples 70 to 74, except that the components and contents shown in Table 32 above were used. Then, the prepared tablet was coated with Opadry white, thus preparing a final coated tablet.

Example 79

[0268] The enteric-coated tablet shown in Table 33 below was prepared with pharmaceutical additives.

TABLE-US-00033 TABLE 33 Example 79 Components mg/Tablet Uncoated tablet Tegoprazan 25.00 Mannitol 25.00 Microcrystalline cellulose 40.00 Croscarmellose sodium 5.00 Hydroxypropyl cellulose 3.00 Colloidal silicon dioxide 1.00 Magnesium stearate 1.00 First coating Hydroxypropyl methyl cellulose (3 cps) 2.00 Polyethylene glycol 400 0.20 Second coating Methacrylic acid-ethyl acrylate copolymer 7.67 Methacrylic acid copolymer S 7.67 Triethyl citrate 1.99 Polysorbate 80 0.05 Talc 1.53 Third coating Hydroxypropyl methyl cellulose (3 cps) 3.58 Polyethylene glycol 400 0.34 Total 125.03

[0269] An uncoated tablet was prepared under substantially the same conditions and using the same method as in Examples 70 to 74, except that the components and contents shown in Table 33 above were used. Then, using a tablet coater (Labcoat, O'hara), the prepared uncoated tablet was subjected sequentially to first coating, second coating and third coating using the components and contents shown in Table 33 above.

Examples 80 to 83

[0270] In order to achieve various release patterns through combinations of the Examples, formulations, each including a tegoprazan immediate-release portion and a tegoprazan modified-release portion, were prepared using the combinations shown in Table 34 below.

TABLE-US-00034 TABLE 34 Example 82 Example 83 Example 80 Example 81 (immediate- (immediate- (immediate-release (immediate- release/enteric release/sustained- tablet + enteric release/enteric sustained-release release bilayer tablet) pellet capsule) pellet capsule) tablet) Weight weight weight weight Example (mg) Example (mg) Example (mg) Example (mg) Immediate-release Example 78 206 Example 76 50 Example 76 50 Example 76 50 portion (12.5 mg tegoprazan) Modified-release Example 79 125.03 Example 21 93.5 Example 62 89 Example 72 100 portion (25 mg tegoprazan) — — — Hand q.s. Hand q.s. Opadry 85F 4.5 capsule No. capsule No. 3 3 Total — — — 193.5 — 189  — 154.5

[0271] In order to confirm the immediate release and delayed release in the tablet form, Example 80 was prepared by combining an immediate-release tablet (Example 78) with an enteric tablet (Example 79). The immediate release/enteric pellet of Example 81 was a single formulation obtained by filling a hard capsule with the granule of Example 76 (an immediate release portion) and the enteric pellet of Example 21 (modified-release portion). The immediate-release/enteric sustained-release pellet of Example 82 was a single formulation obtained by filling a hard capsule with the granule of Example 76 (immediate-release portion) and the enteric sustained-release pellet of Example 62 (modified-release portion). The immediate-release/sustained-release tablet of Example 83 was a coated tablet prepared by tableting the granule of Example 76 and the granule of Example 72 into a bilayer tablet and then coating the bilayer tablet with Opadry 85F.

Experimental Example 15. Dissolution Evaluation of Formulations

[0272] Dissolution of the formulations of Examples 80 to 83 was evaluated.

[0273] Dissolution evaluation was performed using a buffer transition dissolution test that can provide an environment similar to an in vivo environment.

[0274] Specifically, after the release pattern of the drug was examined using a 0.1N HCl solution (pH of about 1.1) for 2 hours, the acidity was increased to pH 7.4 by adding a buffer. Then, 0.5% polysorbate 80 was added, and the release rate of tegoprazan was comparatively evaluated.

[0275] Dissolution conditions were set to USP dissolution apparatus 2 (Paddle) and 50 rpm, and the sample solution obtained after the initiation of dissolution was analyzed using an ultraviolet spectrometer of high-performance liquid chromatography (HPLC; Agilent Technologies).

TABLE-US-00035 TABLE 35 (min) 5 10 15 30 45 60 90 120 135 150 165 180 210 240 360 480 600 840 Example 80 30.4 32.3 32.9 32.8 32.4 31.7 30.5 31.5 31.9 41.5 63.0 74.9 79.6 81.5 84.4 85.1 85.8 86.5 Example 81 27.8 30.4 31.4 32.1 32.5 32.6 31.2 31.7 39.9 55.1 64.5 71.1 76.4 78.7 80.6 80.9 81.0 80.9 Example 82 26.2 28.6 29.1 29.6 29.7 29.7 28.8 30.2 33.0 36.9 39.9 42.2 46.2 50.1 57.6 63.5 66.7 70.0 Example 83 24.3 30.1 34.0 41.4 47.4 48.7 57.1 63.8 73.7 74.6 75.7 76.8 77.5 78.3 80.8 81.6 82.8 85.1

[0276] Referring to the buffer transition dissolution test results in Table 35 above, it can be seen that, since all the Examples include an immediate-release portion and a modified-release portion, the active ingredient was rapidly released in the acidic solution and completely released in the weakly alkaline solution.

[0277] Specifically, when comparing Examples 80 to 83, it could be confirmed that the immediate-release/sustained-release bilayer tablet of Example 83, which is not an enteric concept, achieved sustained release together with immediate release under the acidic solution condition (within 2 hours). In addition, it could be confirmed, in case of Examples 80, 81 and 82 including the enteric concept, only the immediate-release portion was released under the acidic solution condition, and when the pH was changed to 6.8 by adding an additional buffer, the release of the remaining modified-release portion proceeded. In particular, it could be confirmed that, in the case of Example 82, the release did not increase rapidly even if the pH was changed, because the modified-release layer coating was added between the active ingredient layer and the enteric coating layer.

[0278] Therefore, it can be confirmed that the formulation of the present disclosure can release tegoprazan for a certain period in accordance with a desired release rate in a region ranging from gastric juice environment to the intestinal environment.

Experimental Example 16. Evaluation of Pharmacokinetic Absorption Affect in Monkeys by Single Dose Parallel Design

[0279] For in vivo evaluation, non-clinical evaluation of the formulation combinations of Examples 80 to 83 was performed on 5 monkeys per group using a single dose parallel design method.

[0280] The non-clinical model animals used in the test were 6 cynomolgus monkeys (30 to 53 months old males with an average weight of 3.19±0.37 kg). Each test drug was administered orally to the animals by single-dose parallel design method in a fasting condition after fasting for at least 16 hours the day before administration (in the case of Example 80, the immediate-release tablet and the enteric tablet were administered simultaneously). At 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12 and 24 hours, blood was collected from the femoral vein using a disposable syringe.

[0281] As a blood sample container, BD Microtainer® (Sodium Heparin tube, BD Biosciences, USA) was used. The collected blood was centrifuged at 3,000 rpm at 4° C. for 15 minutes to isolate plasma, and the plasma was stored in a cryogenic (−70° C.) freezer until analysis. The plasma concentration of the drug was analyzed LC-MS/MS in in-house method validation and electrospray ionization modes.

TABLE-US-00036 TABLE 36 Example 81 Example 82 Example 83 Example 80 K-CAB ®tablet (IR/DR (IR/DRSR (IR/SR (IR tablet/ PK 25 mg capsule) capsule) bilayer) DR tablet) T.sub.max(h) 2.6 ± 1.1 4.2 ± 2.6 5.6 ± 0.5 3.0 ± 1.8 2.3 ± 1.5 C.sub.max(ng/mL) 436 ± 138 523 ± 195  487 ± 92.7 592 ± 177 492 ± 103 AUC.sub.t(ng .Math. h/mL) 2360 ± 588  3580 ± 314  3860 ± 750  3640 ± 1090 2820 ± 481 

[0282] In the test results in Table 36 above, it was confirmed that the IR/DR, IR/DRSR and IR/SR formulations according to Examples 80 to 83 of the present disclosure had a T.sub.max delay effect without affecting the total absorption, compared to the K-CAB® tablet or the IR capsule.

[0283] Therefore, it can be seen that the formulation of the present invention may achieve various release rate modifies not only the immediate-release portion but also by the delayed-release portion even in an actual in vivo environment. In addition, it can be seen that, since the formulation of the present disclosure can release tegoprazan sustainedly not only in the gastric juice environment but also in the intestinal environment, it is able to maintain a high blood concentration of the active ingredient for a long period of time after taking the formulation.

Examples 84 to 87

[0284] As shown in Table 37 below, capsule formulations, each including a tegoprazan immediate-release portion and a tegoprazan modified-release portion, were prepared, which are combinations capable of double modified-release among the above-described embodiments.

TABLE-US-00037 TABLE 37 Example 84 Example 85 Example 86 Example 87 weight weight weight weight Example (mg) Example (mg) Example (mg) Example (mg) Immediate-release Example 77 100.00 Example 77 100.00 Example 77 100.00 Example 77 100.00 portion (25 mg tegoprazan) Modified-release Example 62 89.00 Example 63 82.21 Example 66 95.75 Example 68 94.445 portion (25 mg tegoprazan)

[0285] Examples 84 to 87 were single dosage forms prepared by double-filling a single capsule with the immediate-release portion (powder (mixture) of Example 77) and the modified-release portion (pellets of Examples 62, 63, 66 and 68, respectively).

Experimental Example 17. Dissolution Evaluation of Combined Capsule Formulations

[0286] Dissolution tests for the capsule formulations were performed using a buffer transition dissolution test.

[0287] Specifically, after the release pattern of the drug was examined using a 0.1N HCl solution (pH of about 1.1) for 2 hours, the acidity was increased to pH 6.8 by adding a buffer. Then, 0.5% polysorbate 80 was added, and the release rate of tegoprazan was comparatively evaluated.

[0288] Dissolution conditions were set to USP dissolution apparatus 2 (Paddle) and 50 rpm, and the sample solution obtained after the initiation of dissolution was analyzed using an ultraviolet spectrometer of high-performance liquid chromatography (HPLC; Agilent Technologies). The results are shown in Table 38 below.

TABLE-US-00038 TABLE 38 60 120 125 130 135 150 165 180 210 240 300 360 420 480 min min min min min min min min min min min min min min Example 84 48.6 48.2 48.9 52.8 58.5 68.2 72.7 75.7 79.1 81.3 85.5 88.2 93.8 96.1 Example 85 48.3 47.8 47.0 47.7 47.8 52.9 69.6 79.1 88.6 92.8 96.2 96.9 101.4 101.1 Example 86 47.3 47.2 47.3 47.3 47.2 47.1 47.4 48.2 49.1 52.1 82.5 100.3 100.8 100.6 Example 87 47.9 48.2 48.4 48.1 47.9 47.8 48.3 53.8 86.0 95.4 98.5 98.8 98.5 98.4

[0289] Referring to the buffer transition dissolution test results in Table 38 above, it can be seen that the immediate-release portions of all the Examples were all dissolved within 1 hour in the acidic solution. When comparing the dissolution rate and the composition between the Examples, it could be confirmed that dissolution from the modified-release portion in the acidic solution did not occur in the case of Examples 84 to 87, and the dissolution occurred depending on the composition of each Example after pH adjustment (after 2 hours).

[0290] Therefore, since the formulation of the present disclosure includes an immediate-release portion and a modified-release portion, it may achieve not only rapid release of tegoprazan, but also delayed release and/or sustained release of tegoprazan, and thus may release tegoprazan in a sustained manner in a region ranging from the gastric juice environment to the intestinal environment.

[0291] As described above, the pharmaceutical composition of the present disclosure can prolong the therapeutic effect for a long time by modifying the release of the active ingredient, thus improving the patient's medication compliance. Thus, the composition may be effectively used for a disease for which a drug needs to be taken for a long period of time or the blood concentration of the drug at a time when the patient cannot take the drug needs to be maintained at a certain level or higher.