PHARMACEUTICAL COMPOSITION FOR ORAL ADMINISTRATION

Abstract

The present disclosure relates to a pharmaceutical composition that delayed-releases tegoprazan and releases clopidogrel immediately. The pharmaceutical composition may exhibit significantly excellent effects on the prevention and treatment of gastrointestinal disorders caused by administration of clopidogrel and thrombosis-related diseases.

Claims

1. A pharmaceutical composition comprising: a first compartment comprising a first active ingredient; and a second compartment comprising a second active ingredient, wherein the first active ingredient is delayed-released, and the second active ingredient is released immediately; wherein the first active ingredient is tegoprazan, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof; and wherein the second active ingredient is clopidogrel, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

2. The pharmaceutical composition of claim 1, wherein the first compartment comprising the first active ingredient and the second compartment comprising the second active ingredient are co-administered.

3. The pharmaceutical composition of claim 2, wherein the first compartment is a unit dosage form comprising the first active ingredient, and the second compartment is a unit dosage form comprising the second active ingredient.

4. The pharmaceutical composition of claim 3, wherein the unit dosage form comprising the first active ingredient comprises a particle comprising: a core comprising the first active ingredient; and an enteric coating layer positioned on the core and surrounding the core.

5. The pharmaceutical composition of claim 4, wherein the particle is a tablet, a granule, a pellet, or a mixture thereof.

6. The pharmaceutical composition of claim 4, wherein the particle in the unit dosage form comprising the first active ingredient further comprises at least one additional coating layer.

7. The pharmaceutical composition of claim 3, wherein the unit dosage forms comprising the first active ingredient and the second active ingredient, respectively, are tablets or capsules which are administered independently of each other.

8. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a complex in a unit dosage form comprising both the first active ingredient and the second active ingredient.

9. The pharmaceutical composition of claim 8, wherein the unit dosage form comprises: a first layer which is the first compartment comprising the first active ingredient; and a second layer which is the second compartment comprising the second active ingredient.

10. The pharmaceutical composition of claim 9, wherein the unit dosage form comprises a particle comprising: a first layer, which is the first compartment comprising the first active ingredient, comprising: a core comprising the first active ingredient; and an enteric coating layer positioned on the core and surrounding the core; and a second layer positioned on the enteric coating layer and surrounding the enteric coating layer and containing the second active ingredient.

11. The pharmaceutical composition of claim 10, wherein the particle is a tablet, a granule, a pellet, or a mixture thereof.

12. The pharmaceutical composition of claim 10, wherein the particle in the unit dosage form further comprises an isolation layer positioned between the first layer and the second layer and preventing contact between the first active ingredient and the second active ingredient.

13. The pharmaceutical composition of claim 8, wherein the unit dosage form comprises: a first compartment which is a particle comprising the first active ingredient; and a second compartment which is a particle containing the second active ingredient, wherein the first compartment which is a particle comprising the first active ingredient is a particle comprising: a core comprising the first active ingredient; and an enteric coating layer positioned on the core and surrounding the core.

14. The pharmaceutical composition of claim 13, wherein the particle comprising the first active ingredient further comprises an isolation layer positioned on the enteric coating layer.

15. The pharmaceutical composition of claim 13, wherein the particle comprising the first active ingredient and the particle comprising the second active ingredient are each independently a tablet, a pellet or a granule.

16. A complex comprising: a first compartment comprising a first active ingredient; a second compartment comprising a second active ingredient; and an isolation layer preventing contact between the first active ingredient and the second active ingredient, wherein the first active ingredient is tegoprazan, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, and the second active ingredient is clopidogrel, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

17. The complex of claim 16, wherein the isolation layer is positioned between the first compartment comprising the first active ingredient and the second compartment comprising the second active ingredient.

18. The complex of claim 16, wherein the complex comprises: a first layer which is the first compartment comprising the first active ingredient; the isolation layer formed on the first layer and preventing contact between the first active ingredient and the second active ingredient; and a second layer which is the second compartment comprising the second active ingredient.

19. The complex of claim 18, wherein the complex is a tablet.

20. The complex of claim 19, wherein the tablet is a multilayered-tablet, wherein the first layer in the multilayered-tablet comprises a granule comprising the first active ingredient, wherein the second layer in the multilayered-tablet comprises a granule comprising the second active ingredient, and wherein the isolation layer in the multilayered-tablet comprises a granule comprising a pharmaceutically acceptable additive.

21. The complex of claim 20, wherein the granule comprising the first active ingredient further comprises an enteric coating layer.

22. The complex of claim 16, wherein the complex is a multilayered-tablet, wherein the multilayered-tablet comprises: a core which is the first compartment comprising the first active ingredient; an isolation layer positioned on the core and comprising a pharmaceutically acceptable additive; and a second compartment positioned on the isolation layer and comprising the second active ingredient.

23. The complex of claim 22, wherein the multilayered-tablet further comprises an enteric coating layer between the core and the isolation layer.

24. The complex of claim 16, wherein the complex is a capsule.

25. The complex of claim 24, wherein the capsule comprises a particle comprising: a core which is the first compartment comprising the first active ingredient; an isolation layer which is positioned on the core and a coating layer comprising a pharmaceutically acceptable additive; and a second compartment positioned on the isolation layer and comprising the second active ingredient.

26. The complex of claim 25, wherein the particle is a tablet, a granule or a pellet, and the capsule is filled with the tablet, granule, pellet, or mixture thereof.

27. The complex of claim 25, wherein the particle further comprises an enteric coating layer for delayed release of the first active ingredient.

28. The complex of claim 16, wherein the complex is a capsule, wherein the capsule comprises: a first compartment which is a particle comprising the first active ingredient; and a second compartment which is a particle comprising the second active ingredient, wherein the first compartment which is a particle comprising the first active ingredient is a particle comprising: a core comprising the first active ingredient; and an isolation layer positioned on the core and surrounding the core.

29. The complex of claim 28, wherein the first compartment which is a particle comprising the first active ingredient further comprises an enteric coating layer.

30. The complex of claim 29, wherein the enteric coating layer is positioned between the core and the isolation layer.

31. The complex of claim 28, wherein the particle comprising the first active ingredient and the particle comprising the second active ingredient are each independently a tablet, a pellet or a granule.

32. A pharmaceutical composition for preventing or treating gastrointestinal disorders caused by administration of clopidogrel, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, comprising tegoprazan, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

33. The pharmaceutical composition of claim 32, wherein the tegoprazan, optical isomer thereof, pharmaceutically acceptable salt thereof, hydrate or solvate thereof, or mixture thereof is delayed-released.

34. A pharmaceutical composition for inhibiting gastric acid secretion, comprising tegoprazan, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, wherein the pharmaceutical composition is co-administered with clopidogrel, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

35. The pharmaceutical composition of claim 34, wherein the tegoprazan, optical isomer thereof, pharmaceutically acceptable salt thereof, hydrate or solvate thereof, or mixture thereof is delayed-released.

36. A pharmaceutical combination comprising: tegoprazan, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof; and clopidogrel, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

37. A method for preventing or treating gastrointestinal disorders caused by administration of clopidogrel, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof, comprising administering to a subject a pharmaceutically effective amount of the pharmaceutical composition according to any one of claims 1 to 15 or the complex according to any one of claims 16 to 31.

38. A method for preventing or treating thrombosis-related diseases, comprising administering to a subject a pharmaceutically effective amount of the pharmaceutical composition according to any one of claims 1 to 15 or the complex according to any one of claims 16 to 31.

39. Use of the pharmaceutical composition according to any one of claims 1 to 15 or the complex according to any one of claims 16 to 31 for preventing or treating gastrointestinal disorders caused by administration of clopidogrel, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

40. Use of the pharmaceutical composition according to any one of claims 1 to 15 or the complex according to any one of claims 16 to 31 in the manufacture of a medicament for preventing or treating gastrointestinal disorders caused by administration of clopidogrel, an optical isomer thereof, a pharmaceutically acceptable salt thereof, a hydrate or solvate thereof, or a mixture thereof.

41. Use of the pharmaceutical composition according to any one of claims 1 to 15 or the complex according to any one of claims 16 to 31 for preventing or treating thrombosis-related diseases.

42. Use of the pharmaceutical composition according to any one of claims 1 to 15 or the complex according to any one of claims 16 to 31 in the manufacture of a medicament for preventing or treating thrombosis-related diseases.

Description

DESCRIPTION OF DRAWINGS

[0207] FIG. 1 illustrates a schematic view of a tablet according to the present disclosure.

[0208] FIG. 2 shows the dissolution rates of clopidogrel from formulations according to the present disclosure.

[0209] FIG. 3 shows the dissolution of tegoprazan from formulations according to the present disclosure.

[0210] FIG. 4 shows the dissolution of clopidogrel from formulations according to the present disclosure.

[0211] FIG. 5 shows the dissolution of tegoprazan from formulations according to the present disclosure.

[0212] FIG. 6 shows the dissolution of tegoprazan from formulations according to the present disclosure.

MODE FOR INVENTION

[0213] 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.

Example 1. Evaluation of Compatibility Between Tegoprazan and Clopidogrel Sulfate

[0214]

TABLE-US-00001 TABLE 1 2 weeks of evaluation of chemical mixture compatibility Initial (Packaging condition: (room Accelerated conditions Stressed conditions HDPE bottle) temperature) (40° C./RH 75 ± 5%) (60° C./RH 75 ± 5%) Tegoprazan alone  99.8% 100.3% 99.1% Clopidogrel sulfate alone 100.2% 101.1% 98.3% Mixture Tegoprazan  99.7%  92.0% 10.5% thereof Clopidogrel 100.3%  78.9% 49.0% sulfate

[0215] According to Table 1 above, in order to examine the effect of each of tegoprazan and clopidogrel hydrogen sulfate, compatibility therebetween was evaluated under storage conditions according to the ICH guideline recommendations and drug safety test regulations.

[0216] It was shown that, when the two components came into direct contact with each other under each storage condition, the contents of the two components decreased. This indicates that the stability of the two components is lowered even by physical contact between the two components.

Example 2: Preparation of Tegoprazan Granules and Tablets

[0217]

TABLE-US-00002 TABLE 2 Pharmaceutical Example 2 ingredients Amount (g)/10,000 tablets (1 batch) Tegoprazan 250.0 Mannitol 250.0 Microcrystalline cellulose 400.0 Croscarmellose sodium 50.0 Hydroxypropyl cellulose 30.0 Colloidal silicon dioxide 10.0 Magnesium stearate 10.0 Total 1,000

[0218] According to Table 2 above, tegoprazan, mannitol, microcrystalline cellulose and croscarmellose sodium were mixed together, sieved through a 750±200 μm mesh, and then placed and mixed in a high-speed mixer. A binding solution was prepared by dissolving hydroxypropyl cellulose in purified water, and the binding solution was introduced into the high-speed mixer, thus preparing wet granules.

[0219] The obtained granules were dried while being fluidized in a fluidized bed dryer at an air supply temperature of 60±10° C.

[0220] The dried granules were milled using the Quadro Comil on a 750±200-μm mesh, and microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide and magnesium stearate were added thereto, mixed, and lubricated to obtain a mixture containing granules of tegoprazan.

[0221] The mixture was tableted using an Erweka tablet press (100±20 rpm) to obtain tablets having a rectangular shape.

Examples 3 and 4: Preparation of Clopidogrel Direct Compression Granules

[0222]

TABLE-US-00003 TABLE 3 Example 3 Example 4 Pharmaceutical ingredients Amount (g)/3,000 tablets (1 batch) Clopidogrel sulfate 293.625 195.73 Copovidone — 24.0 Lactose hydrate — 212.7 Anhydrous lactose 203.0 — Microcrystalline cellulose 120.0 — Pregelatinized starch 63.0 — Low-substituted 36.0 50.0 hydroxypropyl cellulose Colloidal silicon dioxide 0.75 — Light anhydrous silicic acid — 5.0 Povidone 3.6 — Starch sodium glycolate 30.0 — Talc — 12.6 Sodium stearyl furmate 15.0 10.0 Total 764.975 510.03

[0223] According to Table 3 above, clopidogrel sulfate and additives (copovidone, lactose hydrate, anhydrous lactose, microcrystalline cellulose, pregelatinized starch, low-substituted hydroxypropyl cellulose, colloidal silicon dioxide, light anhydrous silicic acid, povidone or sodium starch glycolate) were placed in a mixer (erweka universal) and mixed at 15 rpm for 20 minutes. The mixture was milled using the Quadro Comil on a 750±200 μm mesh to obtain direct compression granules. As a lubricant, sodium stearyl fumurate (Example 3) or talc and sodium stearyl fumurate (Example 4) were added to granules, thus preparing mixtures containing direct compression granules.

Examples 5 to 14: Preparation of Clopidogrel Granules

[0224]

TABLE-US-00004 TABLE 4 Pharmaceutical Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Example 11 Example 12 Example 13 Example 14 ingredients Amount (g)/2,000 tablets (1 batch) Clopidogrel 195.75 195.75 195.75 195.75 195.75 195.75 195.75 195.75 195.75 195.75 sulfate Microcrystalline 258.25 248.25 248.25 278.25 — — 252.25 252.25 252.25 252.25 cellulose Silicified — — — — 248.25 — — — — — microcrystalline cellulose Lactose hydrate 220.0  220.0  220.0  250.0  250.0  448.25 220.0  220.0  220.0  — Mannitol — — — — — — — — — 220.0  Hyroxypropyl 50.0 50.0 50.0 50.0 — — 40.0 40.0 46.0 46.0 cellulose Copovidone — — — — 50.0 50.0 — — — — Low-substituted 56.0 60.0 36.0 36.0 36.0 80.0 36.0 36.0 36.0 36.0 hydroxypropyl cellulose Crospovidone — — — — — — 30.0 — — — Croscarmellose — — 24.0 24.0 — — — 30.0 24.0 24.0 sodium Colloidal silicon — 10.0 10.0 10.0 10.0 10.0 — 10.0 10.0 10.0 dioxide Light — — — — — — 10.0 — — — anhydrous silicic acid Sodium stearyl 20.0 16.0 16.0 16.0 20.0 16.0 16.0 16.0 16.0 16.0 fumarate Total 800.0  800.0  800.0  860.0  810.0  800.0  800.0  800.0  800.0  800.0 

Examples 5 to 8 and Examples 10 to 14

[0225] According to Table 4 above, wet granules containing clopidogrel sulfate were prepared.

[0226] According to Table 4 above, pharmaceutical additives (microcrystalline cellulose or silicified microcrystalline cellulose, lactose hydrate or mannitol) were mixed together, sieved through a 750±200 μm mesh together with clopidogrel sulfate, and then placed and mixed in a high-speed mixer. According to Table 4 above, a binding solution was prepared by dissolving hydroxypropyl cellulose (Examples 5 to 8 and 11 to 14) or copovidone (Example 10) in purified water (Examples 5 and 6) or anhydrous ethanol (Examples 7 and 8 and 10 to 14), and the binding solution was introduced into the high-speed mixer, thus preparing wet granules.

[0227] The obtained granules were dried while being fluidized in a fluidized bed dryer at an air supply temperature of 60±10° C.

[0228] The dried granules were milled using the Quadro Comil on a 750±200 μm mesh, and then low-substituted hydroxypropyl cellulose, crospovidone, croscarmellose sodium, light anhydrous silicic acid and/or sodium stearyl fumarate were/was added thereto, mixed, and lubricated to obtain a mixture containing granules.

Example 9

[0229] In Example 9, direct compression granules were prepared using copovidone as a binding agent.

[0230] According to Table 4 above, clopidogrel sulfate and additives (excluding the lubricant sodium stearyl fumarate) were placed in a mixer (erweka universal) and then mixed at 15 rpm for 20 minutes. The granules were milled using the Quadro Comil on a 750±200 μm mesh to obtain direct compression granules. As a lubricant, sodium stearyl fumurate were added to the granules, thus preparing a mixture containing direct compression granules.

Examples 15 and 16: Preparation for Granules for Isolation Between Clopidogrel and Tegoprazan

[0231]

TABLE-US-00005 TABLE 5 Example 15 Example 16 Pharmaceutical ingredients Amount (g)/10,000 tablets (1 batch) Microcrystalline cellulose 576.0 403.2 Lactose hydrate — 172.8 Hydroxypropyl cellulose 12.0 12.0 Silicon dioxide 6.0 6.0 Sodium stearyl fumarate 6.0 6.0

[0232] According to Table 5 above, granules for forming an isolation layer between the tegoprazan granules and the clopidogrel sulfate were prepared. Specifically, microcrystalline cellulose, lactose hydrate and silicon dioxide were placed and mixed in a high-speed mixer. A binding solution was prepared by dissolving hydroxypropyl cellulose in purified water, and the binding solution was introduced into the high-speed mixer, thus preparing wet granules. The obtained granules were dried while being fluidized in a fluidized bed dryer at an air supply temperature of 60±10° C.

[0233] The dried granules were milled using the Quadro Comil on a 750±200 pin mesh, and sodium stearyl fumarate was added as a lubricant to the granules to obtain a mixture containing granules for forming an isolation layer.

Examples 17 to 19: Preparation of Tegoprazan Wet Granules and Tablets

[0234]

TABLE-US-00006 TABLE 6 Example 17 Example 18 Example 19 Pharmaceutical ingredients Amount (g)/9,408 tablets (1 batch) Tegoprazan 235.21 235.21 235.21 Mannitol 235.21 235.21 235.21 Microcrystalline cellulose 376.33 376.33 376.33 Croscarmellose sodium 47.04 47.04 47.04 Methacrylic acid-ethyl acrylate 77.34 — — copolymer Methacrylic acid-methyl — 77.34 — methacrylate copolymer (1:1) Methacrylic acid-methyl — — 77.34 methacrylate copolymer (1:2) Triethyl citrate 10.07 10.07 10.07 Colloidal silicon dioxide 9.41 9.41 9.41 Magnesium stearate 9.41 9.41 9.41 Total 1,000 1,000 1,000

[0235] According to Table 6 above, tegoprazan, mannitol, microcrystalline cellulose and croscarmellose sodium were mixed together. The mixture was sieved through a 750±200-μm mesh, and then placed in a high-speed mixer and mixed.

[0236] Binding solutions were prepared by each of a methacrylic acid•ethyl acrylate copolymer (Example 17), a methacrylic acid-methyl methacrylate copolymer (1:1) (Example 18), a methacrylic acid-methyl methacrylate copolymer (1:2) (Example 19) and triethyl citrate in 90% ethanol aqueous solution (w/w). Each of the binding solutions was introduced into the high-speed mixer, thus preparing wet granules.

[0237] The obtained wet granules were dried while being fluidized in a fluidized bed dryer at an air supply temperature of 60±20° C.

[0238] The dried granules were mixed with microcrystalline cellulose, croscarmellose sodium, and colloidal silicon dioxide, and then milled using the Quadro Comil on a 750±200 μm mesh. Then, the granules were mixed and lubricated with magnesium stearate to obtain a mixture containing granules.

[0239] The mixture containing granules was tableted using an Erweka tablet press (100±20 rpm) to obtain tablets having a rounded shape.

Examples 20 to 25: Preparation of Core Tablets and Enteric Tablets Containing Tegoprazan

[0240]

TABLE-US-00007 TABLE 7 Example Example Example Example Example Example Pharmaceutical 20 21 22 23 24 25 ingredients Amount (g)/10,000 tablets (1 batch) Core or Tegoprazan 250.0 250.0 250.0 250.0 250.0 250.0 inner Mannitol 250.0 250.0 250.0 250.0 250.0 250.0 tablet Microcrystalline 400.0 400.0 400.0 400.0 400.0 400.0 cellulose Croscarmellose 50.0 50.0 50.0 50.0 50.0 50.0 sodium Hydroxypropyl 30.0 30.0 30.0 30.0 30.0 30.0 cellulose Colloidal silicon 10.0 10.0 10.0 10.0 10.0 10.0 dioxide Magnesium 10.0 10.0 10.0 10.0 10.0 10.0 stearate Total 1,000 1,000 1,000 1,000 1,000 1,000 Weight of tegoprazan core 400 400 400 400 400 400 tablet half-finished product First Hypromellose 12 12 12 12 12 12 coating Polyethylene 1.2 1.2 1.2 1.2 1.2 1.2 (layer-1) glycol Second Methacrylic 45.44 — — 45.44 — — coating acid•ethyl (layer-2) acrylate copolymer Methacrylic — 45.44 — — 45.44 — acid-methyl methacrylate copolymer (1:1) Methacrylic — — 45.44 — — 45.44 acid-methyl methacrylate copolymer (1:2) Triethyl citrate 5.92 5.92 5.92 5.92 5.92 5.92 Polysorbate 80 0.16 0.16 0.16 0.16 0.16 0.16 Third Hypromellose 14.0 14.0 14.0 — — — coating Polyethylene 1.28 1.28 1.28 — — — (layer-3) glycol

Examples 20 to 22

[0241] According to Table 7 above, core tablet containing tegoprazan were prepared.

[0242] The core tablet containing tegoprazan were prepared using the mixture containing the granules prepared according to Example 2.

[0243] The mixture containing the granules prepared according to Example 2 was tableted using a tableting press (erweka universal) equipped with a circular punch having a diameter of 6.5±0.5 mm, thus preparing tablets having a hardness of 12±5 KP.

[0244] The prepared tegoprazan core or inner tablets were placed in a coating machine (Freund Industrial) and coated with a solution of hypromellose and polyethylene glycol in purified water to form a first coating layer (layer-1).

[0245] After formation of the first coating layer, an enteric coating layer (or a second coating layer) was formed. Specifically, a coating solution was prepared by dissolving a methacrylic acid•ethyl acrylate copolymer (Example 20, solvent: purified water or 90% (w/w) ethanol aqueous solution) or a methacrylic acid-methyl methacrylate copolymer (1:1) (Example 21, solvent: 90% (w/w) ethanol aqueous solution) or a methacrylic acid-methyl methacrylate copolymer (1:2) (Example 22, 90% (w/w) ethanol aqueous solution), triethyl citrate and polysorbate 80 in a suitable solvent (purified water, an organic solvent, or a mixture thereof), and the first coating layer of each of the tegoprazan-containing tablets was coated with the coating solution to form a second coating layer, thus preparing enteric tablets containing tegoprazan according to Table 7 above.

[0246] Subsequently, a coating solution was prepared by dissolving hypromellose and polyethylene glycol in purified water, and each of the tegoprazan-containing tablets having the second coating layer formed thereon was coated with the coating solution to form a third coating layer (isolating layer) on the second coating layer.

Examples 23 to 25

[0247] Using the components and contents shown in Table 7 above, tegoprazan-containing enteric tablets, each having a first coating layer and second coating layer formed on a tegoprazan core tablet, were prepared in the same manner as in Examples 20 to 22, except that only the first coating layer and the second coating layer were formed without forming the third coating layer.

[0248] In the preparation of Examples 20 to 25, the processes of forming the first to third coating layers were performed in consideration of the air supply/exhaust temperatures, coating pan rotating speed, coating solution supply speed, product temperature, etc. known in a conventional art and to those skilled in the art. The process conditions are summarized in Table 8 below.

TABLE-US-00008 TABLE 8 Air supply Air exhaust Atom Pattern temperature temperature Pan speed pressure pressure Pump speed First coating 55 ± 10° C. 45 ± 10° C. 5 ± 3 rpm   1 ± 0.5 bar   1 ± 0.5 bar 10 ± 7 rpm Second coating 60 ± 20° C. 50 ± 15° C. 8 ± 5 rpm 1.5 ± 0.7 bar 1.5 ± 0.7 bar 15 ± 9 rpm Third coating 55 ± 10° C. 50 ± 15° C. 7 ± 4 rpm 1.5 ± 0.7 bar 1.5 ± 0.7 bar 15 ± 9 rpm

Examples 26 to 28: Preparation of Tegoprazan Core Tablets and Enteric Tablets

[0249]

TABLE-US-00009 TABLE 9 Pharmaceutical Example 26 Example 27 Example 28 ingredients Amount (g)/10,000 tablets (1 batch) Core or inner Tegoprazan 250.0 250.0 250.0 tablet Mannitol 250.0 250.0 250.0 Microcrystalline 400.0 400.0 400.0 cellulose Croscarmellose 50.0 50.0 50.0 sodium Hydroxypropyl 30.0 30.0 30.0 cellulose Colloidal silicon 10.0 10.0 10.0 dioxide Magnesium 10.0 10.0 10.0 stearate Total 1,000 1,000 1,000 Weight of tegoprazan core tablet 400 400 400 half-finished product First coating Hypromellose 12 12 12 (layer-1) Polyethylene 1.2 1.2 1.2 glycol Second coating Methacrylic 53.7 — — (layer-2) acid-ethyl acrylate copolymer Methacrylic — 53.7 — acid-methyl methacrylate copolymer (1:1) Methacrylic — — 53.7 acid-methyl methacrylate copolymer (1:2) Triethyl citrate 6.99 6.99 6.99 Polysorbate 80 0.19 0.19 0.19 Third coating Hypromellose 16.54 16.54 16.54 (layer-3) Polyethylene 1.51 1.51 1.51 glycol

[0250] Tegoprazan-containing tablets of Examples 26 to 28 were prepared in substantially the same manner as in the method of Examples 20 to 22, except that the components and contents shown in Table 9 above were used. At this time, the tegoprazan-containing core tablets were prepared using the mixture containing the granules prepared according to Example 2.

Examples 29 to 32: Preparation of Multilayered-Tablets Containing Tegoprazan and Clopidogrel

[0251]

TABLE-US-00010 TABLE 10 Tegoprazan Example 29 Example 30 Example 31 Example 32 Weight/tablet granules Granule-containing mixture of Example 2 100 mg Granules forisolation Granule-containing Granule-containing — mixture of Example 15 mixture of Example 16 100 mg 75 mg 100 mg 75 mg — Clopidogrel sulfate granules Granule-containing Granule-containing 255 mg mixture of Example 3 mixture of Example 4

[0252] According to Table 10 above, multilayered-tablets (which is in a form in which the layers are continuously stacked) containing tegoprazan and clopidogrel were prepared.

Examples 29 and 30

[0253] Tri-layer tablets were prepared from the granule-containing mixture of Example 2 (granule-containing mixture before tableting), the granule-containing mixture of Example 15 and the granule-containing mixture of Example 3 by means of the ICHIHASHISEIKI Tablet press.

[0254] At this time, each tri-layer tablet was prepared in such a manner that the layer formed of the granule-containing mixture of Example 15 was positioned between the tegoprazan-containing layer and the clopidogrel sulfate-containing layer. Tegoprazan and clopidogrel sulfate were isolated from each other by the layer formed of the granule-containing mixture of Example 15.

Examples 31 and 32

[0255] Tri-layer tablets were prepared in the same manner as in Examples 29 and 30, except that the granule-containing mixture of Example 16 and the granule-containing mixture of Example 4 were used. At this time, each tri-layer tablet was prepared in such a manner that the layer formed of the granule-containing mixture of Example 15 was positioned between the tegoprazan-containing layer and the clopidogrel sulfate-containing layer. Tegoprazan and clopidogrel sulfate were isolated from each other by the layer formed of the granule-containing mixture of Example 16.

Experimental Example 1. Evaluation of Dissolution Tests for Examples 29 to 32

[0256] Pharmaceutical equivalence of the tablets according to Examples 29 to 32 and control formulations (Plavix® tablet and K-CAB® tablets) were evaluated by measuring dissolution rate according to the United States Pharmacopeia (USP) apparatus 2 (paddle).

[0257] Dissolution conditions were set as follows: pH 2.0 and pH 4.0 (acetate buffer); 37±0.5° C., 900 mL medium; and 50 rpm. The sample solutions obtained after the initiation of dissolution were analyzed using an ultraviolet spectrometer of high-performance liquid chromatography (HPLC; Agilent Technologies) to evaluate the dissolution equivalence of the tablets. The results are shown in Table 11 and 12 below.

TABLE-US-00011 TABLE 11 Dissolution rate (%) at pH 2.0 Sampling time 5 min 10 min 15 min 30 min 45 min 60 min Plavix ® tablet 23.10 50.84 73.17 99.61 101.20 101.68 Example 29 22.79 50.67 76.92 103.14 103.52 103.92 Example 30 20.10 42.20 70.49 102.90 103.40 103.51 Example 31 25.86 48.41 72.37 100.38 100.69 100.83 Example 32 27.70 54.00 73.27 99.12 99.51 99.61

TABLE-US-00012 TABLE 12 Dissolution rate (%) at pH 4.0 Sampling time 5 min 10 min 15 min 30 min 45 min 60 min K-CAB ® tablet 53.84 75.95 85.41 94.98 97.41 98.37 Example 29 43.14 72.77 82.30 92.56 94.78 95.43 Example 30 36.41 58.85 69.39 93.22 98.86 99.56 Example 31 75.87 93.47 99.71 105.08 105.92 106.17 Example 32 68.07 91.31 98.36 103.05 103.09 104.13

[0258] From the dissolution rate measurement result shown in Tables 11 and 12, it could be seen that, even though the tri-layer tablets according to the Examples of the present disclosure were in a single dosage form containing the two active ingredients, each of the ingredients contained in each of the tri-layer tablets showed the same dissolution rate as when each of the ingredients was formulated alone.

[0259] Thus, it can be seen that, even though the tablet formulations of the present disclosure were in a single dosage form containing the two active ingredients, they may exhibit the same therapeutic effects as when formulations containing the two ingredients, respectively, are administered alone, thus significantly improving the patient's medication compliance.

Experimental Example 2. Evaluation of Dissolution Tests for Granule-Containing Tablet Having Enteric Film Formed on Tegoprazan Granules and Tablet Containing Tegoprazan Core Tablet and Having Enteric Coating Layer and Isolation Layer (Evaluation of Dissolution Tests for Examples 2 and 17 to 28)

[0260] Pharmaceutical equivalence of the tablets according to Examples 2 and 17 to 28 were evaluated by measuring dissolution rate according to the United States Pharmacopeia (USP) apparatus 2 (paddle), and the results are shown in Table 13 below.

[0261] Dissolution conditions were set as follows: pH 1.2; 37±0.5° C.; 900 mL medium; and 50 rpm. The sample solutions obtained after the initiation of dissolution were analyzed using an ultraviolet spectrometer of high-performance liquid chromatography (HPLC; Agilent Technologies) to measure the dissolution rates of the tablets, thereby evaluating the acid resistances of the tablets under an acidic condition.

TABLE-US-00013 TABLE 13 Dissolution rate (%) at pH 1.2 Sampling time 5 min 10 min 15 min 30 min 45 min 60 min 90 min 120 min Example 2 96.52 96.81 96.84 95.84 94.47 93.47 93.40 93.11 Example 17 0 0 0 0 0 0 0 0.8 Example 18 0 0 0 0 0 0 0 0.2 Example 19 0 0 0 0 0 0 0 0 Example 20 0 0 0 0 0 0 0 0 Example 21 0 0 0 0 0 0 0 0 Example 22 0 0 0 0 0 0 0 0 Example 23 0 0 0 0 0 0 0 0 Example 24 0 0 0 0 0 0 0 0 Example 25 0 0 0 0 0 0 0 0 Example 26 0 0 0 0 0 0 0 0 Example 27 0 0 0 0 0 0 0 0 Example 28 0 0 0 0 0 0 0 0

[0262] Referring to Table 13 above, it could be confirmed that, in the case of the tablet that does not contain pharmaceutical additives having enteric properties (Example 2), the tablet showed high dissolution rate in the acidic medium, but in the case of the tegoprazan-containing granules or tablets containing the enteric agent (Examples 7 to 28), the granules or tablets had acid resistance in the acidic medium. In addition, it could be confirmed that the tablets (Examples 26 to 28) including the first coating layer, and the second coating layer (enteric coating layer) formed using the pharmaceutical additives having enteric properties, without having the third coating layer (isolation layer), also had acid resistance.

Examples 33 to 35: Preparation of Tablet-In-Tablet Formulation Including Tegoprazan Formulation (Including Tegoprazan Core Tablet Having Enteric Coating Layer Formed Thereon) and Clopidogrel Granule

[0263]

TABLE-US-00014 TABLE 14 Constitution Tablet-in-tablet Example 33 Example 34 Example 35 Weight/tablet Core or inner Enteric-coated Example 20 Example 21 Example 22 122 mg formulation including tegoprazan core tablet Shell Mixture containing Example 5 Example 9 Example 10 255 mg clopidogrel granules

[0264] According to Table 14 above, tablet-in-tablet formulations were prepared with the mixture of each of Examples 5, 9 and 10 by means of a universal tablet press (ICHIHASHISEIKI tablet press) so that the tegoprazan tablet (Examples 20 to 22) having formed thereon the coating layers including the enteric coating layer was located at the core and so that the clopidogrel-containing granules were located at the shell.

[0265] Specifically, the mixture containing the clopidogrel sulfate granules of Example 5, 9 or 10 was placed in the tablet press punch die, and then the coated tegoprazan-containing core tablet of Example 20, 21 or 22 was placed in the punch die. Next, pressure was applied thereto so that the core tablet was not damaged, and tableting was performed, thus preparing tablet-in-tablet formulations.

[0266] During the tableting process for preparation of the tablet-in-tablet formulations, the tableting pressure (850 to 1500 kgf) applied to the clopidogrel shell layer did not result in cracking of the tegoprazan core tablet and the enteric coating layer and leaking of the contents therefrom.

Experimental Example 3. Evaluation of Dissolution Tests for Tablet-In-Tablet Formulations Containing Clopidogrel Sulfate and Tegoprazan (Evaluation of Dissolution Tests for Examples 33 to 35)

[0267] Pharmaceutical equivalence of control tablets (Plavix® tablet and K-CAB® tablet) and the tablets according to Examples 33 to 35 was evaluated by measuring dissolution rate according to the United States Pharmacopeia (USP) apparatus 2.

[0268] Dissolution conditions were set as follows: 0.01N HCl; 37±0.5° C.; 900 mL medium; and 50 rpm. The sample solutions obtained after the initiation of dissolution were analyzed using an ultraviolet spectrometer of high-performance liquid chromatography (HPLC; Agilent Technologies) to evaluate the dissolution rates of tegoprazan and clopidogrel, and the results are shown in FIGS. 2 and 3.

[0269] According to the examination criteria for Pharmaceutical equivalence described in the Korean Pharmacopoeia, where the average dissolution rate of the control tablet (Plavix®) reaches 85% between 15 and 30 minutes, a test tablet can be determined to be equivalent to the control tablet when the value of the similarity factor(f2) is 50 or more or when the average dissolution rate of the test formulation is within ±15% of the average dissolution rate of the control tablet at the time point where the average dissolution rate of the control preparation is around 60% or 85%.

[0270] Referring to FIG. 2, it was confirmed that the dissolution rates of the control tablet Plavix® at 15 min and 30 min were 65.4% and 94.7%, respectively, and at this time, the dissolution rates of clopidogrel sulfate from the tablet of Example 33 at 15 min and 30 min were 58.9% and 91.6%, respectively, the dissolution rates of clopidogrel sulfate from the tablet of Example 34 at 15 min and 30 min were 70.4% and 96.8%, respectively, and the dissolution rates of clopidogrel sulfate from the tablet of Example 35 at 15 min and 30 min were 73.7% and 97.0%, respectively.

[0271] On the other hand, as shown in FIG. 3, as a result of conducting 2-hour dissolution tests for the tablet-in-tablet formulations of Examples 33 to 35 having the tegoprazan core tablets including the enteric coating layer under a 0.01N HCl medium condition (apparatus 2, 50 rpm), it could be confirmed that tegoprazan in the formulations was hardly dissolved, unlike that in K-CAB® tablet, suggesting that the formulations had acid resistance.

[0272] Thus, from the results in FIG. 3, it can be seen that tegoprazan in the tablet-in-tablet formulations of Examples 33 to 35 is not dissolved in the stomach, unlike that the commercially available control tablet K-CAB® tablet, suggesting that tegoprazan is delayed-released from the tablet-in-tablet formulations.

[0273] In the case of the tablets according to Examples 33 to 35 of the present disclosure, tegoprazan is not dissolved in the gastric juice condition due to the enteric coating layer, and only clopidogrel is selectively dissolved in the gastric juice condition, and thus the dissolution rate of clopidogrel from the complex including tegoprazan and clopidogrel is maintained at a high level, and as a result, clopidogrel may exhibit significantly excellent efficacy.

Examples 36 to 42: Preparation of Core Tablets and Enteric Tablets Containing Tegoprazan

[0274]

TABLE-US-00015 TABLE 15 Example Example Example Example Example Example Example Pharmaceutical 36 37 38 39 40 41 42 ingredients Amount (g)/10,000 tablets (1 batch) Core or Tegoprazan 250.0 250.0 250.0 250.0 250.0 250.0 500.0 inner Mannitol 250.0 250.0 250.0 250.0 250.0 250.0 200.0 tablet Microcrystalline 400.0 400.0 400.0 400.0 400.0 400.0 190.0 cellulose Croscarmellose 50.0 50.0 50.0 50.0 50.0 50.0 50.0 sodium Hydroxypropyl 30.0 30.0 30.0 30.0 30.0 30.0 30.0 cellulose Colloidal silicon 10.0 10.0 10.0 10.0 10.0 10.0 20.0 dioxide Magnesium 10.0 10.0 10.0 10.0 10.0 10.0 10.0 stearate Total 1000.0 1000.0 1000.0 1000.0 1000.0 1000.0 1000.0 Weight of tegoprazan core 400.0 400.0 400.0 400.0 400.0 400.0 400.0 tablet half-finished product First Hypromellose 8.0 8.0 8.0 8.0 8.0 8.0 8.0 coating Polyethylene 0.8 0.8 0.8 0.8 0.8 0.8 0.8 (Layer-1) glycol Second Hypromellose 61.32 — — — — — — coating phthalate (Layer-2) Methacrylic — 40.87 — — — — — acid•ethyl acrylate copolymer Methacrylic — — 49.06 40.88 30.66 20.44 20.44 acid•methyl methacrylate copolymer (1:1) Methacrylic — — 12.26 20.44 30.66 40.88 30.66 acid•methyl methacrylate copolymer (1:2) Triethyl citrate 4.91 6.40 7.96 7.96 7.96 7.96 7.96 Polysorbate 80 — 0.16 0.20 0.20 0.20 0.20 0.20 Talc 6.13 — 6.12 6.12 6.12 6.12 6.12 Third Hypromellose 14.32 14.32 14.32 14.32 14.32 14.32 14.32 coating Polyethylene 1.36 1.36 1.36 1.36 1.36 1.36 1.36 (Layer-3) glycol

[0275] The tegoprazan-containing tablets of Examples 36 to 42 were prepared in substantially the same manner as in Examples 20 to 22, except that the components and contents shown in Table 15 above were used.

[0276] For preparation of the tegoprazan-containing core tablets, the core tablets of Examples 36 to 41 were prepared with the granule-containing mixture prepared according to Example 2, and the tegoprazan core tablet of Example 42 was prepared with a mixture prepared in the same manner as in Example 2 using the components and contents shown in Table 15 above.

Examples 43 to 48: Preparation of Tablet-Tablet Formulation Containing Tegoprazan Enteric Tablet and Clopidogrel Granule

[0277]

TABLE-US-00016 TABLE 16 Constitution Tablet-in-tablet Example Example Example Example Example Example 43 44 45 46 47 48 Core or Tegoprazan Example Example Example Example Example Example inner enteric tablet 36 37 38 39 40 41 Shell Clopidogrel Example 7 granule- containing mixture

[0278] According to the combinations shown in Table 16 above, tablet-in-tablet formulations, each containing a tegoprazan enteric tablet and a clopidogrel granule, were prepared in substantially the same manner as the preparation of the tablet-in-tablet formulations according to the method of Examples 33 to 35.

[0279] During preparation of the tablet-in-tablet formulations of Examples 43 to 48, various tableting pressures (850 to 1500 kgf) did not result in cracking of the tegoprazan core tablet and the enteric coating layer.

Experimental Example 4. Evaluation of Tablet-in-Tablet Formulation Containing Clopidogrel Sulfate and Tegoprazan

Experimental Example 4-1. Evaluation of Stability of Tegoprazan Enteric Tablet and Tablet-in-Tablet Formulation

[0280]

TABLE-US-00017 TABLE 17 Example 41 Example 42 1 month under 1 month under stressed stressed (Packaging conditions conditions condition: (60° C./ 60 °C./ HDPE bottle) Initial RH75 ± 5%) Initial RH75 ± 5%) Purity Individual 0.06% 0.05% 0.04% 0.04% maximum Total 0.14% 0.13% 0.08% 0.08%

TABLE-US-00018 TABLE 18 Example Example Example Example (Packaging condition: HDPE bottle) 43 44 46 48 Initial Tegoprazan Individual 0.05% 0.05% 0.04% 0.06% maximum Total 0.10% 0.19% 0.09% 0.14% Clopidogrel Impurity 1 0.07% 0.07% 0.05% 0.06% Impurity 2 0.02% 0.02% 0.02% 0.03% Total 0.19% 0.20% 0.17% 0.21% 1 month under Tegoprazan Individual 0.09% 0.08% 0.07% N/D accelerated maximum conditions Total 0.13% 0.21% 0.11% N/D (40° C./RH75 ± 5%) Clopidogrel Impurity 1 0.18% 0.17% 0.18% 0.17% Impurity 2 0.07% 0.07% 0.08% 0.07% Total 0.39% 0.39% 0.40% 0.36% (N/D means that no impurities were detected.)

[0281] For stability tests for the tegoprazan enteric tablets of Examples 41 and 42 and the tablet-in-tablet formulations of Examples 43, 44, 46 and 48, evaluation was performed under storage conditions (stressed conditions: 40° C./RH 75±5%) in accordance with the ICH guideline recommendations and drug stability test regulations.

[0282] From the results in Table 17 above comparing Examples 41 and 42, it can be confirmed that there is no difference in stability depending on the content of tegoprazan in the prepared tegoprazan enteric tablet.

[0283] In addition, as shown in Table 18 above, as a result of comparing the stability of each of tegoprazan and clopidogrel hydrogen sulfate, it can be confirmed that the stability of the tablet-in-tablet formulation was maintained by preventing physical contact between the two components through the enteric coating layer, etc. positioned between the core and the shell of the tablet-in-tablet formulation.

Experimental Example 4-2. Evaluation of Dissolution Tests for Tablet-in-Tablet Formulations

[0284] For the Examples 43, 44, 46 and 47 prepared according to Table 16 above, dissolution tests were performed under the following conditions: 0.01N HCl and pH6.8 phosphate buffer; USP) apparatus 2; 50 rpm; 900 mL medium; HPLC analysis.

[0285] Specifically, the acid resistances of the tablet-in-tablet formulations of Examples 43, 44, 46 and 47 in 0.01N HCl were evaluated, and then the tablet-in-tablet formulations of Examples 43, 44, 46 and 47 subjected to the acid resistance evaluation were dosed to pH6.8 (alkaline condition) phosphate buffer and were additionally subjected to dissolution tests. The results are shown in FIG. 4 (a dissolution graph of clopidogrel in 0.01N HCl), FIG. 5 (a dissolution graph of tegoprazan in 0.01N HCl) and FIG. 6 (a dissolution graph of tegoprazan at pH 6.8).

[0286] From the results in FIGS. 4 to 6, it could be confirmed that the tablet-in-tablet formulations of Examples 43, 44, 46 and 47 of the present disclosure allowed only clopidogrel to be selectively dissolved in the gastric juice condition. In addition, it can be confirmed that, in the case of the tablet-in-tablet formulations of Examples 43, 44, 46 and 47, the tegoprazan enteric tablet which is the core tablet maintained its shape without breaking of the coating layer thereof after the acid resistance evaluation in 0.01N HCl, and tegoprazan was dissolved as a result of evaluating dissolution thereof in the pH6.8 (alkaline condition) phosphate buffer (FIG. 6).

[0287] Therefore, it can be seen that the tablet-in-tablet formulations of the present disclosure allow only clopidogrel to be selectively dissolved in the gastric juice condition, and delayed-release tegoprazan, suggesting that the excellent efficacy of clopidogrel of the present disclosure is maintained.