ENTERIC-COATED PELLET, METHOD FOR PREPARING SAME AND FORMULATION COMPRISING SAME

Abstract

An enteric-coated pellet, a method for preparing the same and a formulation comprising the same are provided. The enteric-coated pellet can be an ilaprazole enteric-coated pellet.

Claims

1. An enteric-coated pellet, comprising a pellet core, a first isolating layer, a second isolating layer and an enteric coating layer in sequence from inside to outside, wherein the pellet core comprises ilaprazole and/or a pharmaceutically acceptable salt of ilaprazole and a first excipient.

2. The enteric-coated pellet of claim 1, wherein the first isolating layer comprises a first water-insoluble alkaline compound, and the first excipient is a second water-insoluble alkaline compound, wherein the first water-insoluble alkaline compound and the second water-insoluble alkaline compound are the same or different.

3. The enteric-coated pellet of claim 1, wherein the ilaprazole and/or the pharmaceutically acceptable salt of ilaprazole has a particle size D90 of less than or equal to 100 m, and the second isolating layer does not comprise an alkaline substance.

4. The enteric-coated pellet according to claim 1, wherein a protective layer is further provided outside the enteric coating layer.

5. The enteric-coated pellet according to claim 1, wherein no other layer is present between the pellet core and the first isolating layer, and/or no other layer is present between the first isolating layer and the second isolating layer, and/or no other layer is present between the second isolating layer and the enteric coating layer.

6. The enteric-coated pellet according to claim 1, wherein the first excipient is an alkaline compound, preferably a water-insoluble alkaline compound, and more preferably selected from magnesium hydroxide, aluminum hydroxide, magnesium oxide, magnesium carbonate, calcium carbonate and calcium hydroxide.

7. The enteric-coated pellet according to claim 1, wherein the pharmaceutically acceptable salt of ilaprazole can be selected from ilaprazole sodium, ilaprazole magnesium, ilaprazole zinc, ilaprazole potassium, ilaprazole lithium and ilaprazole calcium.

8. The enteric-coated pellet according to claim 1, wherein the pellet core further comprises a surfactant; preferably, the surfactant is tween-80 or sodium dodecyl sulfate.

9. The enteric-coated pellet according to claim 1, wherein the weight ratio of the water-insoluble alkaline compound of the first isolating layer to ilaprazole and/or the pharmaceutically acceptable salt thereof is 0.2:1-5:1, preferably 0.25:1-4:1, more preferably 0.3:1-3:1, particularly preferably 0.5:1-2:1, and most preferably 0.8:1-1.2:1, for example, 1:1.

10. The enteric-coated pellet according to claim 1, wherein the second isolating layer comprises a water-insoluble inert substance capable of preventing the pellet from adhesion, and the weight ratio of the water-insoluble inert substance to a binder is in a range of 1-8:1.5-10, 1-10:1-20, or 4-26:7-44.

11. The enteric-coated pellet according to claim 2, wherein the particle size D90 of ilaprazole and/or the pharmaceutically acceptable salt of ilaprazole is in a range selected from the ranges consisting of any two of the following endpoints: >0 m, 10 m, 20 m, 30 m, 40 m, 50 m, 60 m, 70 m, 80 m, 90 m, and 100 m.

12. A method for preparing the enteric-coated pellet according to claim 1, comprising the following steps: 1) preparing the pellet core comprising ilaprazole and/or the pharmaceutically acceptable salt of ilaprazole and the first excipient; 2) coating the first isolating layer and then coating the second isolating layer; 3) coating the enteric coating layer; and 4) optionally coating the protective layer.

13. The method according to claim 12, wherein step 2) comprises: preparing a first suspension comprising a water-insoluble alkaline compound and not comprising a water-soluble alkaline compound and a water-insoluble inert substance capable of preventing the pellet from adhesion, and coating the pellet core obtained in step 1) with the first suspension; and preparing a second suspension not comprising an alkaline compound, and coating with the second suspension as the second isolating layer, preferably as the second isolating layer closely adjacent to the enteric coating layer.

14. A pharmaceutical composition, selected from the enteric-coated pellet tablet comprising the enteric-coated pellet according to claim 1 and a second excipient and optionally a film coating, a capsule comprising the enteric-coated pellet having the protective layer, and a dry suspension comprising the enteric-coated pellet and dry suspension particles.

15. A method for treating and/or preventing gastrointestinal diseases, comprising a step of administering to a patient in need of such treatment and/or prevention a therapeutically and/or prophylactically effective amount of the enteric-coated pellet according to claim 1.

16. Use of the enteric-coated pellet according to claim 1 for preparing a medicament for treating and/or preventing gastrointestinal diseases, wherein the gastrointestinal diseases are selected from heartburn, inflammatory bowel disease, Crohn's disease, irritable bowel syndrome, ulcerative colitis, peptic ulcer, stress ulcer, bleeding peptic ulcer, duodenal ulcer and duodenal ulcer recurrence, NSAID-associated gastric ulcer, adult active benign gastric ulcer, infectious enteritis, colitis, hyperacidity, dyspepsia, gastroparesis, zollinger-ellison syndrome, gastroesophageal reflux disease (GERD), Helicobacter pylori-associated disease or eradication of Helicobacter pylori, all grades of erosive esophagitis, short bowel syndrome, gastric ulcer, peptic ulcer diseases caused by non-steroidal anti-inflammatory drugs, gastrointestinal bleeding and associated ulcers caused by anti-platelet aggregation drugs and the like, and any combination of the above diseases.

17. The enteric-coated pellet, wherein the first isolating layer comprises a water-insoluble alkaline compound, and the weight ratio of the first excipient to ilaprazole and/or the pharmaceutically acceptable salt of ilaprazole is 0.2:1-5:1.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0076] FIG. 1 is a graph of cumulative dissolution rates in an accelerated stability test of the pellet tablet according to the present invention versus comparative pellet tablets 7 and 8 (referred to as pellet tablets 7 and 8 in the figure) having different isolating layer formulas.

[0077] FIG. 2 is a graph of cumulative dissolution rates in an accelerated stability test of the pellet tablet according to the present invention versus comparative pellet tablets 11 and 16 (referred to as pellet tablets 11 and 16 in the figure) having different pellet core.

[0078] FIG. 3 is a graph of cumulative dissolution rates in an accelerated stability test of the pellet tablet according to the present invention versus comparative pellet tablets 3 and 4 (referred to as pellet tablets 3 and 4 in the figure) having different particle sizes of ilaprazole in pellet core formulas.

[0079] FIG. 4 is a graph of cumulative dissolution rates in an accelerated stability test of the pellet tablet according to the present invention versus a comparative pellet tablet 12 (referred to as a pellet tablet 12 in the figure) without a protective layer.

[0080] FIG. 5 is a graph of real-time human intragastric pH average recordings of the pellet tablet according to the present invention and the comparative pellet tablets 1 and 2 (referred to as pellet tablets 1 and 2 in the figure) prepared according to the method in the prior art.

[0081] FIG. 6 is a graph of plasma concentration change curves in beagle dogs of the pellet tablet according to the present invention versus comparative pellet tablets 1 and 2 (referred to as pellet tablets 1 and 2 in the figure) prepared according to the method of the prior art.

DETAILED DESCRIPTION

[0082] In this section, the enteric-coated pellet formulation according to the present invention and the method for preparing the same will be exemplified, mainly taking the ilaprazole enteric-coated pellet tablet and dry suspension according to the present invention as preferred examples.

[0083] The ilaprazole enteric-coated pellet tablet comprises pellets (which comprise a pellet core, a first isolating layer, a second isolating layer, an enteric coating layer and a protective layer in sequence from inside to outside), a tableting excipient and a film coating, wherein the pellet core comprises a blank pellet core and a drug-loading layer comprising ilaprazole and/or a pharmaceutically acceptable salt of ilaprazole (with a particle size D90 of preferably 50 m), an alkaline compound, a surfactant and a binder; the first isolating layer comprises a water-insoluble alkaline compound and a binder, and does not comprise a water-soluble alkaline compound and a water-insoluble inert substance capable of preventing the pellets from adhesion; and the second isolating layer mainly comprises a binder and a water-insoluble inert substance (such as talc, silica, titanium dioxide and magnesium stearate, which can be used as an anti-adherent) capable of preventing the pellets from adhesion, but does not comprise an alkaline compound.

[0084] Preferably, the alkaline compound comprised in the pellet core is a water-insoluble alkaline compound; and more preferably, the water-insoluble alkaline compound comprised in the pellet core is the same as the water-insoluble alkaline compound comprised in the first isolating layer.

[0085] Specifically, the ilaprazole enteric-coated pellet tablet can comprise, but is not limited to, the following components and proportions: (in parts by weight) Ilaprazole enteric-coated pellet:

1) Pellet Core:

[0086]

TABLE-US-00001 Blank pellet core 5-15; Drug-loading layer, comprising: Ilaprazole (or a pharmaceutically 5-15; acceptable salt thereof) Alkaline compound 5-15; Surfactant 0.2-0.6; Binder 8-24;

2) First Isolating Layer:

[0087]

TABLE-US-00002 Binder 5-36; Water-insoluble 5-36; alkaline compound

3) Second Isolating Layer:

[0088]

TABLE-US-00003 Binder 4-26; Anti-adherent 7-44;

4) Enteric Coating Layer:

[0089]

TABLE-US-00004 Enteric coating material 30-100 (solid content); Anti-adherent 1-5; Plasticizer 9-30;

5) Protective Layer:

[0090]

TABLE-US-00005 Binder 0.5-4; Anti-adherent 0.5-5; Tableting

6) Tableting Excipient:

[0091]

TABLE-US-00006 Filler 100-600; Diluent 50-200; Disintegrant 5-20; Lubricant 1-20;

7) Film Coating:

[0092]

TABLE-US-00007 Coating powder 10-40.

[0093] The enteric-coated pellet tablet has high stability and acid resistance, and is suitable for ilaprazole with rather low stability. In addition, the ilaprazole enteric-coated pellet tablet also has good drug-loading rate and high dissolution rate/bioavailability.

[0094] The present invention will be further described below with reference to specific examples and drawings, which, however, are not intended to limit the present invention. The methods used in the following examples are conventional methods unless otherwise stated. The conclusions that can be shown by the test results in the following examples can be reasonably inferred based on the common knowledge in the art by those skilled in the art, and are not limited to the following text.

Example 1. Preparation of Enteric-Coated Pellets

[0095] In this example, taking ilaprazole and/or a pharmaceutically acceptable salt thereof as an example, the enteric-coated pellets A-G according to the present invention were prepared, and comparative pellets 3-18 were prepared for comparing the effects of different formulas of the component layers of the enteric-coated pellets on the properties of the enteric-coated pellets and their formulations. Compared to the enteric-coated pellets A-G according to the present invention, the comparative pellets 3 and 4 had different particle sizes of ilaprazole in the drug-loading layer; the comparative pellets 5-10 and 14-15 had different isolating layers; the comparative pellets 11, 16 and 17 had drug-loading layers with altered formulas; the comparative pellets 12-13 had different protective layers; and the comparative pellet 18 had an altered ratio of ilaprazole and/or a pharmaceutically acceptable salt thereof to the first excipient.

(I) Formula for Preparing the Component Layers of the Enteric-Coated Pellet

1.1 Formula and Method for Preparing Drug-Containing Pellet (W) and the Drug-Applying Rate of the Drug-Containing Pellet.

[0096] In this example, the drug-containing pellet (i.e., pellet core) comprising a blank pellet core and a drug-loading layer was prepared.

1) Formula W1 of the Drug-Containing Pellet (Unit: g)

[0097]

TABLE-US-00008 Ilaprazole (particle size D90: 46.8 m) 100 Sucrose pellet core (particle size: 100 250-350 m) Magnesium hydroxide 100 Polysorbate-80 4 Hydroxypropylcellulose-SSL 150 Purified water 3000

Preparation Process:

[0098] 150 g of hydroxypropylcellulose-SSL and 4 g of polysorbate-80 were weighed and dissolved in 3000 g of purified water to obtain a hydroxypropylcellulose binder solution, and 100 g of magnesium hydroxide was added to the binder solution and dispersed for 5 min at a high shear rate of 10,000 rpm; and 100 g of ilaprazole starting material with a particle size D90 of 46.8 m was dispersed into the magnesium hydroxide-containing binder and uniformly dispersed at a high shear rate of 10,000 rpm, and then the ilaprazole suspension was sprayed onto the sucrose pellet core through a GLATT GPCG-1 fluidized bed.

[0099] The specific process parameters were as follows:

TABLE-US-00009 Parameters Preheating Drug applying Drying Inlet air volume (m.sup.3/min) 45 50-80 60 Inlet air temperature ( C.) 40-50 40-50 40-50 Material temperature ( C.) 38-40 35-40 35-40 Atomizing pressure (bar) 0.1 0.1-0.2 0.1 Spraying rate (g/min) 0.5-4

The drug-applying rate W.sub.1 of the drug-containing pellet=(actual content of drug-containing pellet)/(theoretical content of drug-containing pellet)100%=95.6%

2) Formula W2 of the Drug-Containing Pellet (Unit: g)

[0100]

TABLE-US-00010 Ilaprazole magnesium (particle size D90: 50 m) 50 Microcrystalline cellulose pellet core 50 Hydroxypropylcellulose-SSL 100 Sodium dodecyl sulfate 2 Magnesium carbonate 150 Purified water 2000

Preparation Process:

[0101] 100 g of hydroxypropylcellulose-SSL and 2 g of sodium dodecyl sulfate according to the formula were weighed and dissolved in 2000 g of purified water, and 150 g of magnesium carbonate was added and dispersed for 5 min at a high shear rate of 10,000 rpm; and 50 g of ilaprazole magnesium was dispersed into the magnesium carbonate-containing binder and uniformly dispersed at a high shear rate of 10,000 rpm, and then the ilaprazole magnesium suspension was sprayed onto the microcrystalline cellulose pellet core through a GLATT GPCG-1 fluidized bed.

The specific process parameters were as follows:

TABLE-US-00011 Parameters Preheating Drug applying Drying Inlet air volume (m.sup.3/min) 35 40-60 50 Inlet air temperature ( C.) 40-50 40-50 40-50 Material temperature ( C.) 38-40 35-40 35-40 Atomizing pressure (bar) 0.1 0.1-0.2 0.1 Spraying rate (g/min) 0.5-3

The drug-applying rate W.sub.2 of the drug-containing pellet=(actual content of drug-containing pellet)/(theoretical content of drug-containing pellet)100%=91.4%

3) Formula W3 of the Drug-Containing Pellet (Unit: g)

[0102]

TABLE-US-00012 Ilaprazole zinc (particle size D90 50 m) 150 Sucrose pellet core 150 Polyvinylpyrrolidone K30 240 Sodium dodecyl sulfate 6 Calcium carbonate 150 Purified water 4800

Preparation Process:

[0103] 240 g of polyvinylpyrrolidone K30 and 6 g of sodium dodecyl sulfate according to the formula were weighed and dissolved in 4800 g of purified water, and 150 g of calcium carbonate was added and uniformly dispersed at a high shear rate of 10,000 rpm; and 150 g of ilaprazole zinc was dispersed into the calcium carbonate-containing binder and uniformly dispersed at a high shear rate of 10,000 rpm, and then the ilaprazole zinc suspension was sprayed onto the sucrose pellet core through a GLATT GPCG-1 fluidized bed.

[0104] The specific process parameters were as follows:

TABLE-US-00013 Parameters Preheating Drug applying Drying Inlet air volume (m.sup.3/min) 45 60-80 60 Inlet air temperature ( C.) 40-50 45-55 45-55 Material temperature ( C.) 38-40 35-40 35-40 Atomizing pressure (bar) 0.1 0.1-0.2 0.1 Spraying rate (g/min) 0.5-3

The drug-applying rate W.sub.3 of the drug-containing pellet=(actual content of drug-containing pellet)/(theoretical content of drug-containing pellet)100%=92.4%

4) Formula W4 of the Drug-Containing Pellet (Unit: g)

[0105]

TABLE-US-00014 Ilaprazole (particle size D90 50 m) 150 Mannitol pellet core 100 Polyvinylpyrrolidone K30 180 Polysorbate-80 6 Magnesium oxide 50 Purified water 3000

Preparation Process:

[0106] 180 g of polyvinylpyrrolidone K30 and 6 g of polysorbate-80 according to the formula were weighed and dissolved in 3000 g of purified water, and 50 g of magnesium oxide was added and uniformly dispersed at a high shear rate at 10,000 rpm; and 150 g of ilaprazole was dispersed into the magnesium oxide-containing binder and uniformly dispersed at a high shear rate of 10,000 rpm, and then the ilaprazole suspension was sprayed onto the mannitol pellet core through a GLATT GPCG-1 fluidized bed.

[0107] The specific process parameters were as follows:

TABLE-US-00015 Parameters Preheating Drug applying Drying Inlet air volume (m.sup.3/min) 50 50-70 60 Inlet air temperature ( C.) 40-50 45-55 45-55 Material temperature ( C.) 38-40 35-40 35-40 Atomizing pressure (bar) 0.1 0.1-0.2 0.1 Spraying rate (g/min) 0.5-4

The drug-applying rate W.sub.4 of the drug-containing pellet=(actual content of drug-containing pellet)/(theoretical content of drug-containing pellet)100%=93.300

TABLE-US-00016 5) Formula W5 of the drug-containing pellet (unit: g) 150 Ilaprazole (particle size D90 50 m) Sucrose pellet core 150 Hydroxypropyl methylcellulose-E5 80 Polysorbate-80 6 Magnesium hydroxide 50 Purified water 1600

Preparation Process:

[0108] 80 g of hydroxypropyl methylcellulose-E5 and 6 g of polysorbate-80 according to the formula were weighed and dissolved in 1600 g of purified water, and 50 g of magnesium hydroxide was added and uniformly dispersed at a high shear rate at 10,000 rpm; and 150 g of ilaprazole was dispersed into the magnesium hydroxide-containing binder and uniformly dispersed at a high shear rate of 10,000 rpm, and then the ilaprazole suspension was sprayed onto the sucrose pellet core through a GLATT GPCG-1 fluidized bed.

[0109] The specific process parameters were as follows:

TABLE-US-00017 Parameters Preheating Drug applying Drying Inlet air volume (m.sup.3/min) 50 50-70 60 Inlet air temperature ( C.) 40-50 45-55 45-55 Material temperature ( C.) 38-40 35-40 35-40 Atomizing pressure (bar) 0.1 0.1-0.2 0.1 Spraying rate (g/min) 0.5-4

The drug-applying rate W.sub.5 of the drug-containing pellet=(actual content of drug-containing pellet)/(theoretical content of drug-containing pellet)100%=94.1%

6) Formula W6 of the Drug-Containing Pellet (Unit: g)

[0110]

TABLE-US-00018 Ilaprazole (particle size D90 50 m) 100 Sucrose pellet core (250-350 m) 100 Hydroxypropylcellulose-SSL 100 Purified water 3000

Preparation Process:

[0111] 100 g of hydroxypropylcellulose-SSL according to the formula was weighed and dissolved in 3000 g of purified water to obtain a hydroxypropylcellulose binder solution, and 100 g of ilaprazole starting material was dispersed into the binder solution and uniformly dispersed at a high shear rate 10,000 rpm, and then the ilaprazole suspension was sprayed onto the sucrose pellet core through a GLATT GPCG-1 fluidized bed.

[0112] The specific process parameters were as follows:

TABLE-US-00019 Parameters Preheating Drug applying Drying Inlet air volume (m.sup.3/min) 45 50-80 60 Inlet air temperature ( C.) 40-50 40-50 40-50 Material temperature ( C.) 38-40 35-40 35-40 Atomizing pressure (bar) 0.1 0.1-0.2 0.1 Spraying rate (g/min) 0.5-4

The drug-applying rate W.sub.6 of the drug-containing pellet=(actual content of drug-containing pellet)/(theoretical content of drug-containing pellet)100%=93.4%

7) Formula W7 of the Drug-Containing Pellet (Unit: g)

[0113]

TABLE-US-00020 Ilaprazole (particle size D90 50 m) 100 Sucrose pellet core (250-350 m) 100 Magnesium hydroxide 100 Hydroxypropylcellulose-SSL 100 Purified water 3000

Preparation Process:

[0114] 100 g of hydroxypropylcellulose-SSL according to the formula was weighed and dissolved in 3000 g of purified water to obtain a hydroxypropylcellulose binder solution, and 100 g of ilaprazole starting material and 100 g of magnesium hydroxide were dispersed into the binder solution and uniformly dispersed at a high shear rate 10,000 rpm, and then the ilaprazole suspension was sprayed onto the sucrose pellet core through a GLATT GPCG-1 fluidized bed.

[0115] The specific process parameters were as follows:

TABLE-US-00021 Parameters Preheating Drug applying Drying Inlet air volume (m.sup.3/min) 45 50-80 60 Inlet air temperature ( C.) 40-50 40-50 40-50 Material temperature ( C.) 38-40 35-40 35-40 Atomizing pressure (bar) 0.1 0.1-0.2 0.1 Spraying rate (g/min) 0.5-4

The drug-applying rate W.sub.7 of the drug-containing pellet=(actual content of drug-containing pellet)/(theoretical content of drug-containing pellet)100%=95.4%

8) Formula W8 of the Drug-Containing Pellet

[0116] This formula was the same as the formula W1 of the drug-containing pellet, except that the particle size D90 of ilaprazole was greater than or equal to 80 m and less than or equal to 100 m. The drug-applying rate W.sub.8 of the drug-containing pellet=(actual content of drug-containing pellet)/(theoretical content of drug-containing pellet)100%=87.2%

9) Formula W9 of the Drug-Containing Pellet

[0117] This formula was the same as the formula W1 of drug-containing pellet, except that the particle size D90 of ilaprazole was >100 m. The drug-applying rate W9 of the drug-containing pellet=(actual content of drug-containing pellet)/(theoretical content of drug-containing pellet)100%=79.3%

10) Formula W10 of the Drug-Containing Pellet (Unit: g)

[0118]

TABLE-US-00022 Ilaprazole (particle size D90: 46.8 m) 100 Sucrose pellet core (particle size: 250-350 m) 100 Polysorbate-80 4 Hydroxypropylcellulose-SSL 150 Purified water 3000

Preparation Process:

[0119] 150 g of hydroxypropylcellulose-SSL and 4 g of polysorbate-80 were weighed and dissolved in 3000 g of purified water to obtain a hydroxypropylcellulose binder solution, and 100 g of ilaprazole starting material with a particle size D90 of 46.8 m was dispersed into the polysorbate-80-containing binder and uniformly dispersed at a high shear rate of 10,000 rpm, and then the ilaprazole suspension was sprayed onto the sucrose pellet core through a GLATT GPCG-1 fluidized bed.

[0120] The specific process parameters were as follows:

TABLE-US-00023 Parameters Preheating Drug applying Drying Inlet air volume (m.sup.3/min) 45 50-80 60 Inlet air temperature ( C.) 40-50 40-50 40-50 Material temperature ( C.) 38-40 35-40 35-40 Atomizing pressure (bar) 0.1 0.1-0.2 0.1 Spraying rate (g/min) 0.5-4

The drug-applying rate W.sub.10 of the drug-containing pellet=(actual content of drug-containing pellet)/(theoretical content of drug-containing pellet)100%=97.6%

11) Formula W11 of the drug-containing pellet (unit: g)

TABLE-US-00024 Ilaprazole magnesium (particle size D90 50 m) 50 Microcrystalline cellulose pellet core 50 Hydroxypropylcellulose-SSL 100 Sodium dodecyl sulfate 2 Magnesium carbonate 200 Purified water 2000

Preparation Process:

[0121] 100 g of hydroxypropylcellulose-SSL and 2 g of sodium dodecyl sulfate according to the formula were weighed and dissolved in 2000 g of purified water, and 200 g of magnesium carbonate was added and dispersed for 5 min at a high shear rate of 10,000 rpm; and 50 g of ilaprazole magnesium was dispersed into the magnesium carbonate-containing binder and uniformly dispersed at a high shear rate of 10,000 rpm, and then the magnesium ilaprazole suspension was sprayed onto the microcrystalline cellulose pellet core through a GLATT GPCG-1 fluidized bed.

[0122] The specific process parameters were as follows:

TABLE-US-00025 Parameters Preheating Drug applying Drying Inlet air volume (m.sup.3/min) 35 40-60 50 Inlet air temperature ( C.) 40-50 40-50 40-50 Material temperature ( C.) 38-40 35-40 35-40 Atomizing pressure (bar) 0.1 0.1-0.2 0.1 Spraying rate (g/min) 0.5-3

The drug-applying rate W.sub.11 of the drug-containing pellet=(actual content of drug-containing pellet)/(theoretical content of drug-containing pellet)100%=92.5%

12) Formula W12 of the Drug-Containing Pellet (Unit: g)

[0123]

TABLE-US-00026 Ilaprazole (particle size D90 50 m) 200 Sucrose pellet core 150 Hydroxypropyl methylcellulose-E5 100 Polysorbate-80 6 Magnesium hydroxide 50 Purified water 2000

Preparation Process:

[0124] 100 g of hydroxypropyl methylcellulose-E5 and 6 g of polysorbate-80 according to the formula were weighed and dissolved in 2000 g of purified water, and 50 g of magnesium hydroxide was added and uniformly dispersed at a high shear rate at 10,000 rpm; and 200 g of ilaprazole was dispersed into the magnesium hydroxide-containing binder and uniformly dispersed at a high shear rate of 10,000 rpm, and then the ilaprazole suspension was sprayed onto the sucrose pellet core through a GLATT GPCG-1 fluidized bed.

[0125] The specific process parameters were as follows:

TABLE-US-00027 Parameters Preheating Drug applying Drying Inlet air volume (m.sup.3/min) 50 50-70 60 Inlet air temperature ( C.) 40-50 45-55 45-55 Material temperature ( C.) 38-40 35-40 35-40 Atomizing pressure (bar) 0.1 0.1-0.2 0.1 Spraying rate (g/min) 0.5-4

The drug-applying rate W.sub.12 of the drug-containing pellet=(actual content of drug-containing pellet)/(theoretical content of drug-containing pellet)100%=93.8%

13) Formula W13 of the Drug-Containing Pellet (Unit: g)

[0126]

TABLE-US-00028 Ilaprazole (particle size D90 50 m) 180 Microcrystalline cellulose pellet core 50 Hydroxypropylcellulose-SSL 100 Sodium dodecyl sulfate 2 Magnesium carbonate 30 Purified water 2000

Preparation Process:

[0127] 100 g of hydroxypropylcellulose-SSL and 2 g of sodium dodecyl sulfate according to the formula were weighed and dissolved in 2000 g of purified water, and 30 g of magnesium carbonate was added and dispersed for 5 min at a high shear rate of 10,000 rpm; and 180 g of ilaprazole was dispersed into the magnesium carbonate-containing binder and uniformly dispersed at a high shear rate of 10,000 rpm, and then the ilaprazole suspension was sprayed onto the microcrystalline cellulose pellet core through a GLATT GPCG-1 fluidized bed.

[0128] The specific process parameters were as follows:

TABLE-US-00029 Parameters Preheating Drug applying Drying Inlet air volume (m.sup.3/min) 35 40-60 50 Inlet air temperature ( C.) 40-50 40-50 40-50 Material temperature ( C.) 38-40 35-40 35-40 Atomizing pressure (bar) 0.1 0.1-0.2 0.1 Spraying rate (g/min) 0.5-3

The drug-applying rate W.sub.13 of the drug-containing pellet=(actual content of drug-containing pellet)/(theoretical content of drug-containing pellet)100%=94.5%

1.2 Formula for Preparing the Isolating Layer (G)

1) Formula G1 of the Isolating Layer (Unit: g)

[0129]

TABLE-US-00030 Ilaprazole-containing pellet 90 Formula of the first isolating layer Hydroxypropylcellulose-SSL 10 Magnesium carbonate 10 Purified water 200 Formula of the second isolating layer Hydroxypropylcellulose-SSL 8 Talc 14 Purified water 160

Preparation Process:

[0130] 10 g of hydroxypropylcellulose-SSL according to the formula was weighed and dissolved in 200 g of purified water, and then 10 g of magnesium carbonate was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating suspension of the first isolating layer. 8 g of hydroxypropylcellulose-SSL was weighed and dissolved in 160 g of purified water, and 14 g of talc was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating suspension of the second isolating layer. The coating suspensions of the two isolating layers were sprayed onto the drug-containing pellet core sequentially through a GLATT GPCG-1 fluidized bed.

[0131] The specific process parameters were as follows:

TABLE-US-00031 Parameters Preheating Isolating coating Drying Inlet air volume (m.sup.3/min) 50 50-60 60 Inlet air temperature ( C.) 40-50 45-55 45-55 Material temperature ( C.) 38-40 35-40 35-40 Atomizing pressure (bar) 0.1 0.1-0.2 0.1 Spraying rate (g/min) 0.5-3.5

2) Formula G2 of the Isolating Layer (Unit: g)

[0132]

TABLE-US-00032 Ilaprazole-containing pellet 90 Formula of the first isolating layer Hydroxypropylcellulose-SSL 23 Magnesium carbonate 23 Purified water 460 Formula of the second isolating layer Hydroxypropylcellulose-SSL 17.2 Talc 28.8 Purified water 344

Preparation Process:

[0133] 23 g of hydroxypropylcellulose-SSL according to the formula was weighed and dissolved in 460 g of purified water, and then 23 g of magnesium carbonate was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating suspension of the first isolating layer. 17.2 g of hydroxypropylcellulose-SSL was weighed and dissolved in 344 g of purified water, and 28.8 g of talc was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating suspension of the second isolating layer. The coating suspensions of the two isolating layers were sprayed onto the drug-containing pellet core sequentially through a GLATT GPCG-1 fluidized bed.

[0134] The formula G1 of the isolating layer was referred to for specific process parameters.

3) Formula G3 of the Isolating Layer (for Comparative Pellet 7) (Unit: g)

[0135]

TABLE-US-00033 Ilaprazole-containing pellet 90 Formula of the first isolating layer Hydroxypropylcellulose-SSL 88 Magnesium carbonate 88 Purified water 1140 Formula of the second isolating layer Hydroxypropylcellulose-SSL 17.2 Talc 28.8 Purified water 520

Preparation Process:

[0136] 88 g of hydroxypropylcellulose-SSL according to the formula was weighed and dissolved in 1140 g of purified water, and then 88 g of magnesium carbonate was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating suspension of the first isolating layer. 17.2 g of hydroxypropylcellulose-SSL was weighed and dissolved in 520 g of purified water, and 28.8 g of talc was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating suspension of the second isolating layer. The coating suspensions of the two isolating layers were sprayed onto the drug-containing pellet core sequentially through a GLATT GPCG-1 fluidized bed.

[0137] The formula G1 of the isolating layer was referred to for specific process parameters.

4) Formula G4 of the Isolating Layer (for Comparative Pellet 9) (Unit: g)

[0138]

TABLE-US-00034 Ilaprazole-containing pellet 90 Formula of the first isolating layer Hydroxypropylcellulose-SSL 23 Magnesium carbonate 23 Talc 11.5 Purified water 460 Formula of the second isolating layer Hydroxypropylcellulose-SSL 17.2 Talc 28.8 Purified water 344

Preparation Process:

[0139] 23 g of hydroxypropylcellulose-SSL according to the formula was weighed and dissolved in 460 g of purified water, and then 23 g of magnesium carbonate and 11.5 g of talc were added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating suspension of the first isolating layer. 17.2 g of hydroxypropylcellulose-SSL was weighed and dissolved in 344 g of purified water, and 28.8 g of talc was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating suspension of the second isolating layer. The coating suspensions of the two isolating layers were sprayed onto the drug-containing pellet core sequentially through a GLATT GPCG-1 fluidized bed.

[0140] The formula G1 of the isolating layer was referred to for specific process parameters.

5) Formula G5 of the Isolating Layer (for Comparative Pellet 10) (Unit: g)

[0141]

TABLE-US-00035 Ilaprazole-containing pellet 90 Formula of the first isolating layer Hydroxypropylcellulose-SSL 23 Sodium carbonate 23 Purified water 460 Formula of the second isolating layer Hydroxypropylcellulose-SSL 17.2 Talc 28.8 Purified water 344

Preparation Process:

[0142] 23 g of hydroxypropylcellulose-SSL according to the formula was weighed and dissolved in 460 g of purified water, and then 23 g of sodium carbonate was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating suspension of the first isolating layer. 17.2 g of hydroxypropylcellulose-SSL was weighed and dissolved in 344 g of purified water, and 28.8 g of talc was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating suspension of the second isolating layer. The coating suspensions of the two isolating layers were sprayed onto the drug-containing pellet core sequentially through a GLATT GPCG-1 fluidized bed.

[0143] The formula G1 of the isolating layer was referred to for specific process parameters.

6) Formula G6 of the Isolating Layer (for Comparative Pellet 5) (Unit: g)

[0144]

TABLE-US-00036 Ilaprazole-containing pellet 90 Hydroxypropylcellulose-SSL 33 Talc 57 Purified water 890

Preparation Process:

[0145] 33 g of hydroxypropylcellulose-SSL according to the formula was weighed and dissolved in 890 g of purified water, and then 57 g of talc was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating suspension of the isolating layer. The coating suspension of the isolating layer was sprayed onto the drug-containing pellet core through a GLATT GPCG-1 fluidized bed.

[0146] The formula G1 of the isolating layer was referred to for specific process parameters.

7) Formula G7 of the Isolating Layer (for Comparative Pellet 6) (Unit: g)

[0147]

TABLE-US-00037 Ilaprazole-containing pellet 90 Formula of the first isolating layer Povidone K30 23 Titanium dioxide 23 Purified water 460 Formula of the second isolating layer Povidone K30 26 Silica 44 Purified water 520

Preparation Process:

[0148] 23 g of povidone K30 according to the formula was weighed and dissolved in 460 g of purified water, and then 23 g of titanium dioxide was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating suspension of the first isolating layer. 26 g of povidone K30 was weighed and dissolved in 520 g of purified water, and then 44 g of silica was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating suspension of the second isolating layer; the coating suspensions of the two isolating layers were sprayed onto the drug-containing pellet core sequentially through a GLATT GPCG-1 fluidized bed.

[0149] The formula G1 of the isolating layer was referred to for specific process parameters.

8) Formula G8 of the Isolating Layer (for Comparative Pellet 8) (Unit: g)

[0150]

TABLE-US-00038 Ilaprazole-containing pellet 90 Formula of the first isolating layer Hydroxypropylcellulose-SSL 23 Magnesium carbonate 23 Purified water 720 Formula of the second isolating layer Hydroxypropylcellulose-SSL 52 Talc 100 Purified water 1040

Preparation Process:

[0151] 23 g of hydroxypropylcellulose-SSL according to the formula was weighed and dissolved in 720 g of purified water, and then 23 g of magnesium carbonate was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating suspension of the first isolating layer. 52 g of hydroxypropylcellulose-SSL was weighed and dissolved in 1040 g of purified water, and 100 g of talc was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating suspension of the second isolating layer. The coating suspensions of the two isolating layers were sprayed onto the drug-containing pellet core sequentially through a GLATT GPCG-1 fluidized bed.

[0152] The formula G1 of the isolating layer was referred to for specific process parameters.

9) Formula G9 of the Isolating Layer (for Comparative Pellet 14) (Unit: g)

[0153]

TABLE-US-00039 Ilaprazole-containing pellet 90 Formula of the first isolating layer Hydroxypropylcellulose-SSL 10 Sodium carbonate 5 Talc 5 Purified water 200 Formula of the second isolating layer Hydroxypropylcellulose-SSL 8 Talc 14 Purified water 160

Preparation Process:

[0154] 10 g of hydroxypropylcellulose-SSL, 5 g of sodium carbonate and 5 g of talc according to the formula were weighed and dissolved in 200 g of purified water to obtain a coating suspension of the first isolating layer. 8 g of hydroxypropylcellulose-SSL was weighed and dissolved in 160 g of purified water, and 14 g of talc was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating suspension of the second isolating layer. The coating suspensions of the two isolating layers were sprayed onto the drug-containing pellet core sequentially through a GLATT GPCG-1 fluidized bed.

[0155] The formula G1 of the isolating layer was referred to for specific process parameters.

10) Formula G10 of the Isolating Layer (Unit: g)

[0156]

TABLE-US-00040 Ilaprazole-containing pellet 90 Formula of the first isolating layer Hydroxypropyl methylcellulose-E5 15 Magnesium oxide 15 Purified water 300 Formula of the second isolating layer Hydroxypropyl methylcellulose-E5 12 Titanium dioxide 21 Purified water 240

Preparation Process:

[0157] 15 g of hydroxypropyl methylcellulose-E5 according to the formula was weighed and dissolved in 300 g of purified water, and then 15 g of magnesium oxide was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating suspension of the first isolating layer. 12 g of hydroxypropyl methylcellulose-E5 was weighed and dissolved in 240 g of purified water, and 21 g of titanium dioxide was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating suspension of the second isolating layer. The coating suspensions of the two isolating layers were sprayed onto the drug-containing pellet core sequentially through a GLATT GPCG-1 fluidized bed.

[0158] The formula G1 of the isolating layer was referred to for specific process parameters.

11) Formula G11 of the Isolating Layer (Unit: g)

[0159]

TABLE-US-00041 Ilaprazole-containing pellet 90 Formula of the first isolating layer Hydroxypropylcellulose-SSL 20 Magnesium hydroxide 20 Purified water 400 Formula of the second isolating layer Hydroxypropylcellulose-SSL 8 Talc 14 Purified water 160

Preparation Process:

[0160] 20 g of hydroxypropylcellulose-SSL according to the formula was weighed and dissolved in 400 g of purified water, and then 20 g of magnesium hydroxide was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating suspension of the first isolating layer. 8 g of hydroxypropylcellulose-SSL was weighed and dissolved in 160 g of purified water, and 14 g of talc was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating suspension of the second isolating layer. The coating suspensions of the two isolating layers were sprayed onto the drug-containing pellet core sequentially through a GLATT GPCG-1 fluidized bed.

[0161] The formula G1 of the isolating layer was referred to for specific process parameters.

12) Formula G12 of the Isolating Layer (Unit: g)

[0162]

TABLE-US-00042 Ilaprazole-containing pellet 90 Formula of the first isolating layer Hydroxypropylcellulose-SSL 23 Magnesium hydroxide 23 Purified water 460 Formula of the second isolating layer Hydroxypropylcellulose-SSL 46 Purified water 920

Preparation Process:

[0163] 23 g of hydroxypropylcellulose-SSL according to the formula was weighed and dissolved in 460 g of purified water, and then 23 g of magnesium hydroxide was added and uniformly dispersed at a high shear rate of 10,000 rpm to obtain a coating suspension of the first isolating layer. 46 g of hydroxypropylcellulose-SSL was weighed and dissolved in 920 g of purified water to obtain a coating suspension of the second isolating layer. The coating suspensions of the two isolating layers were sprayed onto the drug-containing pellet core sequentially through a GLATT GPCG-1 fluidized bed.

[0164] The formula G1 of the isolating layer was referred to for specific process parameters.

1.3 Formula for Preparing the Enteric Coating Layer (C)

Formula C1 of the Enteric Coating Layer (Unit: g)

[0165]

TABLE-US-00043 Ilaprazole isolated pellet 92 Eudragit L30D-55 223.8 Talc 3.4 Triethyl citrate 20.1 Purified water 447.6

Preparation Process:

[0166] 20.1 g of triethyl citrate according to the formula was weighed and dissolved in 447.6 g of purified water, and 3.4 g of talc was uniformly dispersed at a high shear rate of 10,000 rpm; 223.8 g of Eudragit L30D-55 was added and the mixture was stirred for 45 min to obtain an enteric coating solution for later use; and the enteric coating solution was sprayed onto the isolated pellet through a GLATT GPCG-1 fluidized bed.

[0167] The specific process parameters were as follows:

TABLE-US-00044 Parameters Preheating Enteric coating Drying Inlet air volume (m3/min) 50 50-80 60 Inlet air temperature ( C.) 35-30 33-42 35-45 Material temperature ( C.) 25-30 25-30 30-35 Atomizing pressure (bar) 0.1 0.15-0.25 0.1 Spraying rate (g/min) 0.5-3

1.4 Preparation of the Protective Layer (B)

1) Formula B1 of the Protective Layer (Unit: g)

[0168]

TABLE-US-00045 Ilaprazole enteric-coated pellet 100 Hydroxypropyl 2.5 methylcellulose-E5 Magnesium stearate 1.2 Purified water 50

Preparation Process:

[0169] 2.5 g of hydroxypropyl methylcellulose-E5 according to the formula was weighed and dissolved in 50 g of purified water, and then 1.2 g of magnesium stearate was added and uniformly dispersed at a high shear rate of 5000 rpm to obtain a coating solution of the protective layer. The coating solution of the protective layer was sprayed onto the enteric-coated pellet through a GLATT GPCG-1 fluidized bed.

[0170] The specific process parameters were as follows:

TABLE-US-00046 Isolating Parameters Preheating coating Drying Inlet air volume (m.sup.3/min) 50 50-60 60 Inlet air temperature ( C.) 40-50 45-55 45-55 Material temperature ( C.) 38-40 35-40 35-40 Atomizing pressure (bar) 0.1 0.1-0.2 0.1 Spraying rate (g/min) 0.5-3.5

2) Formula B2 of the Protective Layer (Unit: g)

[0171]

TABLE-US-00047 Ilaprazole enteric-coated pellet 100 Hydroxypropylcellulose-SSL 0.5 Magnesium stearate 0.5 Purified water 10

Preparation Process:

[0172] 0.5 g of hydroxypropylcellulose-SSL according to the formula was weighed and dissolved in 10 g of purified water, and then 0.5 g of magnesium stearate was added and uniformly dispersed at a high shear rate of 3000 rpm to obtain a coating solution of the protective layer. The coating solution of the protective layer was sprayed onto the enteric-coated pellet through a GLATT GPCG-1 fluidized bed.

[0173] The formula B1 of the protective layer was referred to for specific process parameters.

3) Formula B3 of the Protective Layer (Unit: g)

[0174]

TABLE-US-00048 Ilaprazole enteric-coated pellet 100 Hydroxypropylcellulose-SSL 4 Magnesium stearate 5 Purified water 80

Preparation Process:

[0175] 4 g of hydroxypropylcellulose-SSL according to the formula was weighed and dissolved in 80 g of purified water, and then 5 g of magnesium stearate was added and uniformly dispersed at a high shear rate of 5000 rpm to obtain a coating solution of the protective layer. The coating solution of the protective layer was sprayed onto the enteric-coated pellet through a GLATT GPCG-1 fluidized bed.

[0176] The formula B1 of the protective layer was referred to for specific process parameters.

4) Formula B4 of the Protective Layer (Unit: g)

[0177]

TABLE-US-00049 Ilaprazole enteric-coated pellet 100 Hydroxypropylcellulose-SSL 2.5 Talc 1.2 Purified water 50

Preparation Process:

[0178] 2.5 g of hydroxypropylcellulose-SSL according to the formula was weighed and dissolved in 50 g of purified water, and then 1.2 g of talc was added and uniformly dispersed at a high shear rate of 5000 rpm to obtain a coating solution of the protective layer. The coating solution of the protective layer was sprayed onto the enteric-coated pellet through a GLATT GPCG-1 fluidized bed.

[0179] The formula B1 of the protective layer was referred to for specific process parameters.

5) Formula B5 of the Protective Layer (Unit: g)

[0180]

TABLE-US-00050 Ilaprazole enteric-coated pellet 100 Hydroxypropylcellulose-SSL 2.5 Titanium dioxide 1.2 Purified water 50

Preparation Process:

[0181] 2.5 g of hydroxypropylcellulose-SSL according to the formula was weighed and dissolved in 50 g of purified water, and 1.2 g of titanium dioxide was added and dispersed at a high shear rate of 5000 rpm to obtain a coating solution of the protective layer. The coating solution of the protective layer was sprayed onto the enteric-coated pellet through a GLATT GPCG-1 fluidized bed.

[0182] The formula B1 of the protective layer was referred to for specific process parameters.

6) Formula B6 of the Protective Layer (for Comparative Pellet 13) (Unit: g)

[0183]

TABLE-US-00051 Ilaprazole enteric-coated pellet 100 Hydroxypropyl methylcellulose-E5 2.5 Magnesium stearate 0.2 Purified water 50

Preparation Process:

[0184] 2.5 g of hydroxypropyl methylcellulose-E according to the formula was weighed and dissolved in 50 g of purified water, and then 0.2 g of magnesium stearate was added and uniformly dispersed at a high shear rate of 5000 rpm to obtain a coating solution of the protective layer. The coating solution of the protective layer was sprayed onto the enteric-coated pellet through a GLATT GPCG-1 fluidized bed.

[0185] The formula B1 of the protective layer was referred to for specific process parameters.

(II) Preparation of the Enteric-Coated Pellets

1) Preparation of the Enteric-Coated Pellets According to the Present Invention

[0186] The enteric-coated pellets A-G according to the present invention as shown in Table 1 below were prepared according to the formulas of the component layers of the enteric-coated pellets as listed in the above section (I).

TABLE-US-00052 TABLE 1 Formulas of the enteric-coated pellets (tablets) A-G according to the present invention Pellet A Pellet B Pellet C Pellet D Pellet E Pellet F Pellet G Drug-containing pellet W1 W2 W3 W4 W5 W11 W12 Isolating layer G2 G1 G2 G2 G2 G2 G2 Enteric coating layer C1 C1 C1 C1 C1 C1 C1 Protective layer B1 B2 B3 B4 B5 B2 B1 Tableting and coating Pellet Pellet Pellet Pellet Pellet Pellet Pellet Pellet tablet tablet A tablet B tablet C tablet D tablet E tablet F tablet G Drug-loading rate (%) 95.6 91.4 92.4 93.3 94.1 92.5 93.8 of the drug-containing pellet

where the drug-applying rate W.sub.x of the drug-containing pellet=(actual content of drug-containing pellet)/(theoretical content of drug-containing pellet)100%

2) Preparation of the Comparative Pellets 3-16

[0187] The comparative pellets 3-15 as shown in Tables 2-1 and 2-2 below were prepared according to the formulas of the component layers of the enteric-coated pellets as listed in the above section (I).

TABLE-US-00053 TABLE 2-1 Formulas of the comparative pellets (tablets) 5-10 and 14-15 mainly used for the study on the isolating layer Comparative pellet 5 6 7 8 9 10 14 15 Drug- W1 W1 W1 W1 W1 W1 W1 W1 containing pellet Isolating G6 G7 G3 G8 G4 G5 G9 G12 layer Enteric C1 C1 C1 C1 C1 C1 C1 C1 coating layer Protective B1 B1 B1 B1 B1 B1 B1 B1 layer Particle size 46.8 m* D90 of ilaprazole Tableting and coating Comparative Comparative Comparative Comparative Comparative Comparative Comparative Comparative pellet pellet pellet pellet pellet pellet pellet pellet tablet 5 tablet 6 tablet 7 tablet 8 tablet 9 tablet 10 tablet 14 tablet 15 *In order to facilitate the comparison between the data, ilaprazole with a uniform particle size D90 was used here. According to the present invention, those skilled in the art will understand that the particle size D90 is not limited thereto.

TABLE-US-00054 TABLE 2-2 Formulas of the comparative pellets (tablets) 3-4, 11-13 and 16-18 mainly used for the study on the component layers of the enteric-coated pellets Comparative pellet 3 4 11 12 13 16 17 18 Drug- W8 W9 W6 W1 W1 W7 W10 W13 containing pellet Isolating G2 G2 G2 G2 G2 G2 G2 G2 layer Enteric C1 C1 C1 C1 C1 C1 C1 C1 coating layer Protective B1 B1 B1 None B6 B1 B1 B2 layer Particle size 82.5 m* 105.6 m* 46.8 m* 50 m* D90 of Ilaprazole Comparative Comparative Comparative Comparative Comparative Comparative Comparative Comparative pellet pellet pellet pellet pellet pellet pellet pellet tablet 3 tablet 4 tablet 11 tablet 12 tablet 13 tablet 16 tablet 17 tablet 18 *In order to facilitate the comparison between the data, ilaprazole with a uniform particle (or specific) size D90 was used here. According to the present invention, those skilled in the art will understand that the particle size D90 is not limited thereto.

Example 2. Preparation of Enteric-Coated Pellet Tablets

[0188] In this example, the enteric-coated pellets A-G according to the present invention and the comparative pellets 3-18 prepared in Example 1 were prepared into the enteric-coated pellet tablets A-G according to the present invention and the comparative pellet tablets 3-18. In addition, the comparative pellet tablet 1 (according to CN 1134666 A) and the comparative pellet tablet 2 (according to CN 102525990 A) were also prepared according to the method for preparing the enteric-coated pellet tablets in the prior art, with ilaprazole (particle size D90 of 46.8 m, to facilitate the comparison between the data) serving as the pharmaceutically active substance.

2.1 Preparation of the Enteric-Coated Pellet Tablets A-G According to the Present Invention and Comparative Pellet Tablets 3-18

[0189] The enteric-coated pellets shown in Table 1 above as well as Tables 2-1 and 2-2 above were prepared into the enteric-coated pellet tablets by the following tableting and coating steps respectively.

1) Preparation of the Pellet Tablet (Unit: g)

[0190]

TABLE-US-00055 Ilaprazole outer coated pellet 200 Microcrystalline cellulose PH102 339.2 Crospovidone-XL 113.1 Sodium stearyl fumarate 12.8

Preparation Process of the Tablets:

[0191] The ilaprazole enteric outer coated pellets, microcrystalline cellulose PH102, crospovidone-XL, and sodium stearyl fumarate according to the above formula were added in a 3 L hopper mixer, and the mixture was mixed for 15 min at 10 rpm. Then the mixture was placed in a tablet press for tableting to obtain the tablets with the hardness of 8-12 kg, and the weight equivalent to 5 mg of ilaprazole contained in each tablet.

2) Pellet Tablet Coating (Unit: g)

[0192]

TABLE-US-00056 Pellet tablet 400 Opadry coating powder 20 Purified water 166.5

Preparation Process of the Coating:

[0193] 20 g of Opadry coating solution was weighed and dissolved in 166.5 g of purified water, and the ilaprazole pellet tablets were coated using an efficient coating pan.

2.2 Preparation of Comparative Pellet Tablet 1:

[0194] Comparative pellet tablet 1 was prepared according to the method and process for preparing enteric-coated pellet tablets described in Example 16 of CN 1134666 A, using the outer coating described in Example 15 thereof, with ilaprazole serving as the pharmaceutically active substance and a surfactant added to the drug-loading layer. The method is specified as follows:

1) Preparation of the Drug-Containing Pellet

Formula of the Drug-Containing Pellet (Unit: g)

[0195]

TABLE-US-00057 Sucrose pellet core 100 Ilaprazole 148 Hydroxypropyl methylcellulose-E5 22 Polysorbate-80 3 Purified water 700

Preparation Process:

[0196] 150 g of hydroxypropyl methylcellulose-E5 and 3 g of tween-80 were weighed and dissolved in purified water to obtain a hydroxypropyl methylcellulose binder solution, and the ilaprazole starting material with a particle size D90 less than 50 m was dispersed into the binder and dispersed for 5 min at 10,000 rpm, and then the ilaprazole suspension was sprayed onto the sucrose pellet core through a GLATT GPCG-1 fluidized bed.

[0197] The specific process parameters were as follows:

TABLE-US-00058 Drug Parameters Preheating applying Drying Inlet air volume (m.sup.3/min) 45 50-80 60 Inlet air temperature ( C.) 40-50 40-50 40-50 Material temperature ( C.) 38-40 35-40 35-40 Atomizing pressure (bar) 0.1 0.1-0.2 0.1 Spraying rate (g/min) 0.5-4

2) Preparation of the Isolated Pellet

Formula of the Isolated Pellet (Unit: g)

[0198]

TABLE-US-00059 Ilaprazole-containing pellet 103 Hydroxypropylcellulose-SSL 11 Talc 42.5 Magnesium stearate 2.75 Purified water 387.5

Preparation Process:

[0199] 103 g of hydroxypropylcellulose-SSL was weighed and dissolved in 387.5 g of purified water to obtain a hydroxypropylcellulose binder solution, and 42.5 g of talc and 2.75 g of magnesium stearate were added to the binder solution and dispersed for 5 min at a high shear rate of 10,000 rpm, and then the coating solution of an isolating layer was sprayed onto the ilaprazole-containing pellet through a GLATT GPCG-1 fluidized bed. The specific process parameters were as follows:

TABLE-US-00060 Drug Parameters Preheating applying Drying Inlet air volume (m.sup.3/min) 45 50-80 60 Inlet air temperature ( C.) 40-50 40-50 40-50 Material temperature ( C.) 38-40 35-40 35-40 Atomizing pressure (bar) 0.1 0.1-0.2 0.1 Spraying rate (g/min) 0.5-4

3) Preparation of the Enteric-Coated Pellet

Formula of the Enteric-Coated Pellet (Unit: g)

[0200]

TABLE-US-00061 Ilaprazole magnesium isolated pellet 127.3 Eudragit L30D-55 127 Glyceryl monostearate 1.9 Triethyl citrate 3.8 Polysorbate-80 1.8 Purified water 50

Preparation Process:

[0201] 1.8 g of polysorbate-80, 3.8 g of triethyl citrate and 1.9 g of glyceryl monostearate were weighed and dissolved in 50 g of purified water at 70 C., dispersed for 5 min at a high shear rate of 5000 rpm, and left to stand to room temperature; 127 g of Eudragit L30D-55 was added and the mixture was stirred for 45 min for later use; and the enteric coating solution was sprayed onto the isolated pellet through a GLATT GPCG-1 fluidized bed.

[0202] The specific process parameters were as follows:

TABLE-US-00062 Enteric Parameters Preheating coating Drying Inlet air volume (m.sup.3/min) 50 50-80 60 Inlet air temperature ( C.) 35-30 33-42 35-45 Material temperature ( C.) 25-30 25-30 30-35 Atomizing pressure (bar) 0.1 0.15-0.25 0.1 Spraying rate (g/min) 0.5-3

4) Preparation of the Protective Layer Pellet

Formula of the Protective Layer (Unit: g)

[0203]

TABLE-US-00063 Ilaprazole enteric-coated pellet 171.3 Hydroxypropyl methylcellulose-E5 2.5 Magnesium stearate 0.08 Purified water 51.3

Preparation Process:

[0204] 2.5 g of hydroxypropyl methylcellulose-E5 was weighed and dissolved in 51.3 g of purified water, and then 0.08 g of magnesium stearate was added and uniformly dispersed at a high shear rate of 5000 rpm to obtain a coating solution of the protective layer. The coating solution of the protective layer was sprayed onto the enteric-coated pellet through a GLATT GPCG-1 fluidized bed.

[0205] The specific process parameters were as follows:

TABLE-US-00064 Isolating Parameters Preheating coating Drying Inlet air volume (m.sup.3/min) 60 60-90 80 Inlet air temperature ( C.) 40-50 45-55 45-55 Material temperature ( C.) 38-40 35-40 35-40 Atomizing pressure (bar) 0.1 0.1-0.2 0.1 Spraying rate (g/min) 0.6-4.5

5) Preparation of the Pellet Tablet (Unit: g)

[0206]

TABLE-US-00065 Ilaprazole enteric-coated pellet 173.9 Microcrystalline cellulose PH102 869.5 Crospovidone 17.39 Sodium stearyl fumarate 17.39

Preparation Process of the Tablets:

[0207] The ilaprazole enteric-coated pellets, microcrystalline cellulose, crospovidone and sodium stearyl fumarate according to the above formula were added into a 3 L hopper mixer, and the mixture was mixed for 15 min at 10 rpm. Then the mixture was placed in a tablet press for tableting to obtain the tablets with the hardness of 8-12 kg, and the weight equivalent to 5 mg of ilaprazole contained in each tablet.

6) Preparation of the Pellet Tablet Coating (Unit: g)

[0208]

TABLE-US-00066 Pellet tablet 1000 Opadry coating powder 40 Purified water 333

[0209] 40 g of Opadry coating solution was weighed and dissolved in 333 g of purified water, and the ilaprazole pellet tablets were coated using an efficient coating pan. The comparative pellet tablet 1 was prepared.

2.3 Preparation of Comparative Pellet Tablet 2:

[0210] Comparative pellet 2 was prepared according to the method for preparing enteric-coated pellet tablets described in CN 102525990 A, with ilaprazole serving as the pharmaceutically active substance.

1) Preparation of the Drug-Containing Pellet Core

Formula of the Drug-Containing Pellet Core (Unit: g)

[0211]

TABLE-US-00067 Sucrose pellet core 300 Ilaprazole 30 Magnesium oxide 3 Hydroxypropyl methylcellulose 10 80% (v/v) aqueous ethanol solution 850

Preparation Process:

[0212] Blank sucrose pellet cores (0.25-0.3 mm) were sieved through a 50 mesh sieve and a 60 mesh sieve respectively, and the pellets between 50 mesh and 60 mesh were applied with drug. The method for preparing a drug-applying solution: hydroxypropyl methylcellulose and magnesium oxide according to the formula were dissolved in 80% (v/v) aqueous ethanol solution, and the resulting solution was adjusted to about pH 12 with 4% (m/v) sodium hydroxide solution; and then ilaprazole according to the formula was added, and the mixture was uniformly stirred. The viscosity of the drug-applying solution was 13.22 cp.

[0213] The specific process parameters were as follows:

TABLE-US-00068 Drug Parameters Preheating applying Drying Time (min) 5 160-200 20 Inlet air volume (m.sup.3/min) 60-80 70-90 60-80 Inlet air temperature ( C.) 40-50 40-50 40-50 Outlet air temperature ( C.) 25-40 23-38 38-45 Material temperature ( C.) 28-35 28-35 35-45 Filter bag shaking time (s) 2-5 5-10 5-10 Atomizing pressure (bar) 0.1-0.3 0.2-1.2 0.2-0.5 Spraying rate (g/mL) 1-15 Pump rotation speed (L/min) 5-9 Spraying process Continuous operation

[0214] 310 g of light yellow ilaprazole pellets were prepared, with a yield of 90.3%.

2) Preparation of the Isolated Pellet

Formula of the Isolated Pellet (Unit: g)

[0215]

TABLE-US-00069 Ilaprazole-containing pellet 300 HPMC 5CP 15 Talc 50 80% v/v aqueous ethanol solution 535

Preparation Process:

[0216] 300 g of drug-containing pellets were coated with the isolating layer solution after the pH of the isolating solution was adjusted to be more than 10.5, wherein the viscosity of the isolating solution was 15.24 cp. The operation parameters were shown in the following table:

TABLE-US-00070 Drug Parameters Preheating applying Drying Time (min) 5 40-60 30 Inlet air volume (m.sup.3/min) 50-70 60-100 50-60 Inlet air temperature ( C.) 40-50 40-55 50-55 Outlet air temperature ( C.) 25-40 23-38 38-45 Material temperature ( C.) 30-40 35-45 40 Filter bag shaking time (s) 1-10 5-30 5-30 Atomizing pressure (bar) 0.3 0.3-1.3 0.5 Spraying rate (g/mL) 5-15 Pump rotation speed (L/min) 3-7 Spraying process Continuous operation

[0217] 345 g of pellets were prepared, with a yield of 94.5%.

3) Preparation of the Enteric-Coated Pellet

Formula of the Enteric-Coated Pellet (Unit: g)

[0218]

TABLE-US-00071 Ilaprazole isolated pellet 150 Eudragit L30D-55 180 Polyethylene glycol 6000 10 Tween-80 0.3 Water 200

Preparation Process:

[0219] 6.5 mL of 4% (m/v) aqueous sodium hydroxide solution was added to Eudragit L30D-55, polyethylene glycol 6000 was added with stirring, and the mixture was sieved through an 80 mesh sieve. The isolated pellets were coated with the enteric coating. The main parameters were as follows: the material temperature was 25-30 C., the inlet air temperature was 28-35 C., the spraying speed was 10-30 rpm, and the fan frequency was 30-40. 214.1 g of pellets were prepared, with a yield of 99.9%.

4) Preparation of the Pellet Tablet

Formula of the Pellet Tablet (Unit: g)

[0220]

TABLE-US-00072 Ilaprazole enteric-coated pellet 150 Pregelatinized starch 50 Starch 50 Mannitol 50 Microcrystalline cellulose PH101 240 4% starch slurry 10

[0221] The materials were mixed according to formula in the table, and subjected to tableting to obtain the tablets, with each weighing 314.9 mg. The comparative pellet tablet 2 was prepared.

Example 3. Preparation of Enteric-Coated Pellet Capsules

[0222] 600 g of ilaprazole protective layer-coated pellets A (W.sub.1+G.sub.2+C.sub.1+B.sub.1) were loaded into NO. 3 capsule shells by a capsule filler, with each capsule containing 5 mg of ilaprazole.

Example 4. Performance Test of Enteric-Coated Pellet Tablets and Capsules

[0223] In the example 4, the enteric-coated pellet tablets and capsules prepared in the above examples were tested for content, dissolution rate, related substances, etc., and comparative pellets 3-16 were compared in terms of the test results, with the pellet tablet A according to the present invention serving as a reference. The test method is specified as follows:

1. Determination of Content

[0224] 1) Operation method: General Chapter 0512, Chinese Pharmacopoeia, Volume IV, 2015 Edition was referred to for general methods.

[0225] Specifically, the method comprises the following steps: [0226] Preparation of the sample solution: 5 mL of the sample solution according to the section of related substance test was precisely measured, placed in a 50 mL measuring flask, diluted to volume with mobile phase, shaken and filtered, and the subsequent filtrate was used as the sample solution. [0227] Preparation of the control solution: a proper amount of ilaprazole control was precisely weighed and dissolved with a diluent, and the resulting solution was diluted with the diluent to a solution containing about 20 g of the ilaprazole control per 1 mL. The diluted solution was used as the control solution. [0228] System suitability solution: an appropriate amount of impurity I (ilaprazole sulfone, chemical name: 2-[[(4-methoxy-3-methyl)-2-pyridyl]methyl]-sulfonyl-5-(1H-pyrrol-1-yl)-1H-benzimidazole) control and ilaprazole control were weighed and dissolved with a diluent, and the resulting solution was diluted with the diluent to a solution containing 20 g of the impurity I and ilaprazole per 1 mL. [0229] Chromatographic conditions: octadecylsilane chemically bonded silica was used as a filler, 400 mL of acetonitrile was diluted with a phosphate buffer (2.28 g of dipotassium hydrogen phosphate was dissolved in water, and the resulting solution was diluted with water to 1000 mL and adjusted to pH 7.5 with phosphoric acid) to 1000 mL for use as a mobile phase, the flow rate was 1.0 mL/min, the detection wavelength was 237 nm, and the column temperature was 25 C. [0230] System suitability requirement: in the chromatogram of the system suitability solution, the theoretical number of plates should be not less than 2500 calculated according to the ilaprazole peak, and the resolution between the impurity I peak and the ilaprazole peak should be in accordance with the standard. [0231] Determination method: 20 L of each of the control solution and the sample solution was measured precisely and injected into the liquid chromatograph, and the chromatogram was recorded. [0232] 2) Calculation method: the average content of 10 tablets was calculated according to peak area by external standard method. [0233] 3) Standard: the content of ilaprazole (C19H18N4O2S) should be 90.0%-110.0% of the labeled amount.

2. Determination of Dissolution Rate

[0234] 1) Operation method: the dissolution rate was determined according to the content homogeneity inspection method (Method 1 of the second method of General Chapter 0931, Chinese Pharmacopoeia, Volume IV, 2015 Edition was referred to for general methods). Specifically, the method comprises the following steps:

[0235] According to the content homogeneity inspection method, the product was dissolved in 300 mL of 0.1 mol/L hydrochloric acid solution (dissolution medium, 9.0 mL of hydrochloric acid was diluted with water to 1000 mL), and the rotation speed was 100 rpm; after 120 min, 700 mL of 0.086 mol/L disodium hydrogen phosphate solution (30.8 g of disodium hydrogen phosphate and 7 g of tween-80 was diluted with water to 1000 mL) preheated to 370.5 C. was immediately added to the dissolution cup, and uniformly mixed at a constant rotation speed according to the method; and after 45 min, the mixture was sampled. [0236] Sample solution: a proper amount of dissolution solution was filtered, and 5 mL of subsequent filtrate was precisely measured; and 1 mL of 0.15 mol/L sodium hydroxide solution was added immediately and precisely, shaken uniformly and filtered, and the subsequent filtrate was used as the sample solution. [0237] Control solution: about 10 mg of ilaprazole control was precisely weighed, added to a 20 mL measuring flask, dissolved with a proper amount of acetonitrile, diluted to volume with acetonitrile, and shaken uniformly; 1 mL of the diluted solution was precisely measured, placed in a 100 mL measuring flask, diluted to volume with a phosphate buffer solution (pH 6.8) (700 mL of 0.086 mol/L disodium hydrogen phosphate solution was uniformly mixed with 300 mL of 0.1 mol/L hydrochloric acid solution) and shaken uniformly; 5 mL of the diluted solution was precisely weighed, 1 mL of 0.05 mol/L sodium hydroxide solution was immediately and precisely added, the resulting mixture was shaken uniformly and filtered, and the subsequent filtrate was taken as the control solution.

[0238] The dissolution amount of each tablet was calculated according to the method described in the section of determination of content.

3. Related Substance Test

[0239] 1) Operation method: the related substances were measured according to the high performance liquid chromatography (General Chapter 0512, Chinese Pharmacopoeia, Volume IV, 2015 Edition was referred to general methods). Specifically, the method comprises the following steps: [0240] Diluent: 0.05 mol/L sodium hydroxide-methanol-water=50:20:30 [0241] Sample solution: 10 tablets of the product were added to a 250 mL measuring flask, 125 mL of 0.05 mol/L sodium hydroxide solution was added, and the resulting mixture was shaken in an oscillator (250 rpm) for 20 min; and 50 mL of methanol was added and the resulting mixture was sonicated for 10 min, diluted to volume with water, shaken uniformly, and centrifuged to obtain the supernatant. [0242] Control solution: a proper amount of the sample solution was precisely measured and diluted with a diluent to obtain a solution containing about 1 g of ilaprazole per 1 mL. [0243] Sensitivity solution: 1 mL of the control solution was precisely measured, added to a 10 mL measuring flask, diluted to volume with a diluent, and shaken uniformly. [0244] Impurity I control stock solution: about 6 mg of impurity I was added to a 100 mL measuring flask and diluted to volume with a diluent. [0245] System suitability solution: about 3 mg of ilaprazole control was added to a 10 mL measuring flask, and dissolved in a proper amount of diluent; and 1 mL of impurity I control stock solution was precisely added, and the resulting mixture was diluted to volume with a diluent, and shaken uniformly. [0246] Chromatographic conditions: octadecylsilane chemically bonded silica was used as a filler (Gemini-NX C18 1504.6 mm, 5 m or an equivalent chromatographic column), 0.01 mol/L dipotassium hydrogen phosphate solution (adjusted to pH 7.5 with 10% phosphoric acid) was used as mobile phase A, acetonitrile was used as mobile phase B, and linear gradient elution was performed according to the following table; the flow rate was 1.0 mL/min; the detection wavelength was 237 nm; and the column temperature was 25 C.

TABLE-US-00073 Time Mobile phase A Mobile phase B (min) (%) (%) 0 77 23 5 66 34 15 50 50 40 50 50 40.5 77 23 50 77 23 [0247] System suitability solution requirement: in the chromatogram of the system suitability solution, the resolution between the impurity I peak and the ilaprazole peak should be more than 2.0. In the chromatogram of the sensitivity solution, the signal-to-noise ratio of the peak height of the ilaprazole peak should be greater than 10. [0248] Determination method: 20 L of each of the sample solution and the control solution was measured and injected into the liquid chromatograph, and the chromatogram was recorded.

4.1 Stability Test and Acid Resistance Test of the Enteric-Coated Pellet Tablets and Capsules According to the Present Invention

[0249] 1) In this example, then enteric-coated pellet tablets A-G according to the present invention and the capsule of Example 3 were subjected to the accelerated stability test. The method is specified as follows: [0250] Test protocol: the enteric-coated pellet tablets A-G and the capsule of Example 3 were packaged in HDPE bottles of 14 tablets (capsules) respectively, and the packaged pellet tablets or capsules were placed in an accelerated stability test chamber at 40 C./RH75%, and sampled after 1/3/6 months for detecting related substances of the enteric-coated pellet tablets or capsules with different formulas.

[0251] The stability data of the enteric-coated pellet tablets A-G and the capsule of Example 3 obtained by the test are shown in Table 3-1 below:

TABLE-US-00074 TABLE 3-1 Stability data of the enteric-coated pellet tablets A-G according to the present invention and the capsule of Example 3 Pellet Pellet Pellet Pellet Pellet Pellet Pellet Time tablet A tablet B tablet C tablet D tablet E tablet F tablet G Capsule Day 0 0.12% 0.16% 0.19% 0.15% 0.13% 0.18% 0.26% 0.20% Month 1 0.15% 0.22% 0.26% 0.24% 0.20% 0.36% 0.54% 0.34% Month 3 0.36% 0.25% 0.89% 0.77% 0.97% 0.47% 0.87% 0.58% Month 6 0.87% 1.07% 1.28% 0.82% 0.99% 0.68% 1.02% 0.98%

[0252] As can be seen from Table 3-1, the pellet tablets A-G and the capsule prepared from the enteric-coated pellets according to the present invention had good stability with total impurity content not exceeding 1.5%. [0253] 2) In this example, the enteric-coated pellet tablets A-G according to the present invention and the capsule of Example 3 were subjected to the acid resistance test. The method is specified as follows: according to the method, 6 tablets of each of the enteric-coated pellet tablets A-G and the capsule were dissolved in 300 mL of 0.1 mol/L hydrochloric acid solution (dissolution medium, 9.0 mL of hydrochloric acid was diluted with water to 1000 mL), and the rotation speed was 100 rpm; after 120 min, the dissolution cups were taken out, the hydrochloric acid was filtered off using a suction filtration device, and the remaining pellets were collected in a 50 mL volumetric flask; 20 mL of 0.05 mol/L sodium hydroxide solution was added, and the resulting mixture was shaken in an oscillator (250 rpm) for 20 min; and 30 mL of methanol was added, and the resulting mixture was sonicated for 10 min, diluted to volume with water, shaken uniformly, and centrifuged to obtain the supernatant. The remaining drug content in the pellets, i.e. the acid resistance of the samples, was determined.

TABLE-US-00075 TABLE 3-2 Acid resistance data of the enteric-coated pellet tablets A-G according to the present invention and the capsule of Example 3 Pellet Pellet Pellet Pellet Pellet Pellet Pellet Time tablet A tablet B tablet C tablet D tablet E tablet F tablet G Capsule Day 0 99.6% 99.1% 97.9% 96.5% 97.4% 98.4% 98.7% 96.8% Month 1 98.8% 98.6% 98.2% 96.8% 97.8% 98.2% 98.5% 96.3% Month 3 98.3% 97.9% 98.1% 95.9% 98.2% 98.1% 97.8% 97.2% Month 6 98.2% 98.0% 97.6% 95.6% 97.5% 97.6% 97.9% 96.6%

[0254] As can be seen from Table 3-2, the pellet tablets A-G and the capsule prepared from the enteric-coated pellets according to the present invention both had good acid resistance of above 90%.

4.2 Stability Test and Acid Resistance Test of the Enteric-Coated Pellet Tablets

[0255] In this example, taking an enteric-coated pellet tablet as an example, the effects of the components and the proportions thereof of the enteric-coated pellet tablets on their stability and acid resistance were compared.

4.2.1 Effect of the Ingredients of the Isolating Layer Comprised in the Enteric-Coated Pellets

[0256] 1) Comparison between the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablets 5, 6, 9, 10 and 14 in terms of the stability

[0257] In this example, the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablets 5, 6, 9, 10 and 14 were subjected to the accelerated stability test. In this test, compared to the enteric-coated pellet tablet A according to the present invention, the comparative pellet tablet 5 had only one inert substance isolating layer comprising no alkaline compound; the comparative pellet tablets 6, 9, 10 and 14 all had a first isolating layer closely adjacent to the pellet core and a second isolating layer closely adjacent to the enteric coating layer; however, in the comparative pellet tablet 6, the first isolating layer comprised a binder and an anti-adherent, but did not comprise an alkaline compound; in the comparative pellet tablet 9, the first isolating layer was a mixed layer (which refers to a layer comprising, in addition to the binder, an alkaline compound and a water-insoluble inert substance capable of preventing the pellets from adhesion), and comprised a water-insoluble alkaline compound as an alkaline compound; in the comparative pellet tablet 10, the first isolating layer was an alkaline layer mainly comprising a binder and a water-soluble alkaline compound; and in the comparative pellet 14, the first isolating layer was a mixed layer, and comprised a water-soluble alkaline compound as an alkaline compound.

[0258] Test protocol: the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablets 5, 6, 9, 10 and 14 were packaged in HDPE bottles of 14 tablets respectively, and the packaged pellet tablets were placed in an accelerated stability test chamber at 40 C./RH75%, and sampled after 1/3/6 months for detecting related substances of the pellet tablets with different formulas. The stability data of the pellet tablets obtained by the test are shown in Table 4-1 below:

TABLE-US-00076 TABLE 4-1 Stability data of the pellet tablet A according to the present invention and the comparative pellet tablets 5, 6, 9, 10 and 14 Comparative Comparative Comparative Comparative Comparative Pellet pellet pellet pellet pellet pellet Time tablet A tablet 5 tablet 6 tablet 9 tablet 10 tablet 14 Day 0 0.12% 0.35% 0.89% 0.24% 0.20% 0.49% Month 1 0.15% 0.72% 1.26% 0.63% 0.43% 0.61% Month 3 0.36% 1.25% 1.89% 0.96% 0.66% 1.05% Month 6 0.87% 1.87% 2.68% 1.79% 0.89% 1.68%

[0259] As can be seen from Table 4-1, the stability requirement (i.e., the total impurity content should not exceed 1.5%) cannot be met for ilaprazole with low stability when its enteric-coated pellet tablet comprises only one isolating layer (i.e., the comparative pellet tablet 5). When the enteric-coated pellet tablet comprises at least a first isolating layer and a second isolating layer, its stability can also be affected by the components of these isolating layers, for example: when the first isolating layer is a mixed layer comprising an alkaline compound and a water-insoluble inert substance capable of preventing the pellets from adhesion (i.e., the comparative pellet tablets 9 and 14), the related substances still significantly increase (the total impurity content is 1.79% and 1.68%, respectively) even under the protection of the alkaline compound, and the stability requirement cannot be met; in contrast, when the first isolating layer is an alkaline layer comprising an alkaline compound and not comprising a water-insoluble inert substance capable of preventing the pellets from adhesion (e.g., the pellet tablet A and the comparative pellet tablet 10), the enteric-coated pellet tablet has good stability; in addition, the stability requirement (i.e., the total impurity content should not exceed 1.5%) cannot be met for ilaprazole with low stability when its enteric-coated pellet tablet comprises the alkaline compound only in the pellet core (i.e., the comparative pellet tablet 6). [0260] 2) Comparison between the enteric pellet tablet A according to the present invention and the comparative pellet tablets 10, 14 and 15 in terms of the acid resistance. In this example, the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablets 10, 14 and 15 were subjected to the acid resistance test. In this test, the comparative pellet tablet 15 differed from the enteric-coated pellet tablet A according to the present invention in that: the second isolating layer of the comparative pellet tablet 15 did not comprise a water-insoluble inert substance capable of preventing the pellets from adhesion. The method is specified as follows: [0261] the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablets 10, 14 and 15 were packaged in HDPE bottles of 14 tablets, respectively; and the packaged pellet tablets were placed in an accelerated stability test chamber at 40 C./RH75%, and sampled after 1/3/6 months; then according to the method, the tablets were dissolved in 300 mL of 0.1 mol/L hydrochloric acid solution (dissolution medium, 9.0 mL of hydrochloric acid was diluted with water to 1000 mL), and the rotation speed was 100 rpm; after 120 min, the dissolution cups were taken out, the hydrochloric acid was filtered off using a suction filtration device, and the remaining pellets were collected in a 50 mL volumetric flask; 20 mL of 0.05 mol/L sodium hydroxide solution was added, and the resulting mixture was shaken in an oscillator (250 rpm) for 20 min; and 30 mL of methanol was added, and the resulting mixture was sonicated for 10 min, diluted to volume with water, shaken uniformly, and centrifuged to obtain the supernatant. The remaining drug content in the pellets, i.e. the acid resistance of the samples, was determined. The acid resistance data of the pellet tablets obtained by the test are shown in Table 4-2 below:

TABLE-US-00077 TABLE 4-2 Acid resistance data of the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablets 10, 14 and 15 Comparative Comparative Pellet pellet pellet Comparative Time tablet A tablet 10 tablet 14 pellet 15 Day 0 96.7% 96.2% 95.3% 97.9% Month 1 95.9% 95.6% 92.1% 97.6% Month 3 95.5% 92.1% 87.5% 95.5% Month 6 95.3% 85.6% 82.5% 96.3%

[0262] As can be seen from the results shown in Table 4-2, the comparative pellet tablet (e.g., the comparative pellet tablet 14) which already had lower stability in the stability test also had lower acid resistance under accelerated conditions; the comparative pellet tablet 10 having the first isolating layer comprising a different type of the alkaline compound (i.e., a water-soluble alkaline compound) became less acid resistant (the content of the remaining ilaprazole in the comparative pellet tablet 10 at month 6 was 85.6%) as compared to the enteric-coated pellet tablet A according to the present invention, and the acid resistance was lower than the required standard (i.e., the acid resistance average of 6 tablets should be not less than 90%). That is, although the alkaline compound can provide the enteric-coated pellet tablet with good stability when used as the first isolating layer, the type of the alkaline compound will affect the acid resistance of the enteric-coated pellet tablet. Compared to the first isolating layer comprising a water-soluble alkaline compound, the isolating layer comprising a water-insoluble alkaline compound can improve and enhance the acid resistance of the enteric-coated pellet tablet when used as the first isolating layer of the enteric-coated pellet tablet. In addition, it can also be seen from Table 4-2 that the acid resistance of the comparative pellet tablet 15 in which the second isolating layer does not comprise a water-insoluble inert substance capable of preventing the pellets from adhesion is not affected.

[0263] In summary, with respect to the components of the various isolating layers comprised in the enteric-coated pellet, at least two isolating layers are provided, and for the first isolating layer closely adjacent to the pellet core, when the first isolating layer comprises a water-insoluble alkaline compound, and does not comprise a water-soluble alkaline compound and a water-insoluble inert substance capable of preventing the pellets from adhesion, the ilaprazole enteric-coated pellet tablet prepared from the enteric-coated pellets can have both good stability and acid resistance.

4.2.2 Effect of the Proportions of the Components of the Isolating Layer Comprised in the Enteric-Coated Pellets According to the Present Invention

[0264] 1) Comparison between the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablets 7 and 8 in terms of the stability

[0265] In this example, the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablets 7 and 8 were subjected to the accelerated stability test. In this test, compared to the enteric-coated pellet tablet A according to the present invention, the comparative pellet tablet 7 has a larger amount of the water-insoluble alkaline compound comprised in the first isolating layer; for example, when the amount of ilaprazole is 10 parts, the amount of the water-insoluble alkaline compound comprised in the first isolating layer is more than 36 parts; the comparative pellet tablet 8 has a larger amount of the anti-adherent (equivalent to the water-insoluble inert substance capable of preventing the pellets from adhesion according to the present invention) comprised in the second isolating layer; and for example, when the amount of ilaprazole is 10 parts, the amount of the anti-adherent in the second isolating layer is more than 44 parts.

[0266] The method is specified as follows: [0267] the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablets 7 and 8 were packaged in HDPE bottles of 14 tablets respectively, and the packaged pellet tablets were placed in an accelerated stability test chamber at 40 C./RH75%, and sampled after 1/3/6 months for detecting related substances of the enteric-coated pellet tablets with different formulas. The stability data of the enteric-coated pellet tablets obtained by the test are shown in Table 5-1 below:

TABLE-US-00078 TABLE 5-1 Stability data of the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablets 7 and 8 Pellet tablet Comparative pellet Comparative pellet Time A tablet 7 tablet 8 Day 0 0.12% 0.25% 0.23% Month 1 0.15% 0.34% 0.50% Month 3 0.36% 0.67% 0.87% Month 6 0.87% 0.92% 0.95%

[0268] As can be seen from the results shown in Table 5-1, the stability of the comparative pellet tablets 7 (with different proportions of components in the first isolating layer) and 8 (with different proportions of components in the second isolating layer) with different proportions of components in the isolating layers was still within the standard range (the total impurity content should not exceed 1.5%) compared to that of the enteric-coated pellet tablet A according to the present invention. That is, the change in the proportions of components in the isolating layer does not affect the stability of the enteric-coated pellet tablet. [0269] 2) Comparison between the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablets 7 and 8 in terms of the acid resistance

[0270] In this example, the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablets 7 and 8 were subjected to the acid resistance test. The acid resistance test described in section 4.2.1 was referred to for the specific method.

[0271] The results are shown in Table 5-2 below:

TABLE-US-00079 TABLE 5-2 Acid resistance data of the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablets 7 and 8 Pellet tablet Comparative pellet Comparative pellet Time A tablet 7 tablet 8 Day 0 96.7% 95.6% 96.4% Month 1 95.9% 95.8% 95.8% Month 3 95.5% 96.1% 96.2% Month 6 95.3% 95.4% 94.6%

[0272] As can be seen from the results shown in Table 5-2, the acid resistance of the comparative pellet tablets 7 (with different proportions of components in the first isolating layer) and 8 (with different proportions of components in the second isolating layer) with different proportions of components in the isolating layers was still within the standard range (i.e., the acid resistance average of 6 tablets should be not less than 90%) compared to that of the enteric-coated pellet tablet A according to the present invention. That is, the change in the proportions of components in the isolating layer does not affect the acid resistance of the enteric-coated pellet tablet.

[0273] In summary, the change in the proportions of components in the isolating layers of the enteric-coated pellet will not affect the stability and the acid resistance of the enteric-coated pellet tablet prepared from the enteric-coated pellets.

4.2.3 Comparison Between the Enteric-Coated Pellet Tablets a, F and G According to the Present Invention and the Pellet Tablets 17 and 18 in Terms of the Acid Resistance

[0274] In this example, the enteric-coated pellet tablets A, F and G according to the present invention and the pellet tablets 17 and 18 were subjected to the acid resistance test. The acid resistance test described in section 4.2.1 was referred to for the specific method.

[0275] The results are shown in Table 5-3 below:

TABLE-US-00080 TABLE 5-3 Acid resistance data of the enteric-coated pellet tablets A, F and G according to the present invention and the pellet tablets 17 and 18 Pellet Pellet Pellet Comparative Comparative Time tablet A tablet G tablet H pellet tablet 17 pellet tablet 18 Day 0 96.7% 98.4% 98.7% 96.1% 97.1% Month 1 95.9% 98.2% 98.5% 92.4% 96.5% Month 3 95.5% 98.1% 97.8% 90.5% 95.6% Month 6 95.3% 97.6% 97.9% 88.1% 94.8%

[0276] As can be seen from the results shown in Table 5-3, the acid resistance of the comparative pellet tablet 17 was reduced due to the degradation under accelerated stability conditions, which results in a reduction in the measured acid resistance value. The acid resistance value of pellet tablet 18 was also reduced due to the partial degradation of ilaprazole in the acceleration process. The pellet tablets A, G and H adopting the formula of the pellet core of the present invention can all demonstrate good acid resistance.

4.3 Effect of the Components of the Pellet Core Comprised in the Enteric-Coated Pellets on the Stability of the Enteric-Coated Pellet Tablets:

[0277] In the example 4.3, taking an ilaprazole enteric-coated pellet tablet as an example, the effects of the components of the pellet core comprised in the enteric pellets and the particle size of ilaprazole on their stability were compared.

Effect of the Components of the Pellet Core Comprised in the Enteric-Coated Pellets

[0278] Comparison between the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablets 11, 16 and 17 in terms of the stability

[0279] In this example, the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablets 11, 16 and 17 were subjected to the accelerated stability test. In this test, the pellet core of the comparative pellet tablet 11 does not comprise an alkaline compound and a surfactant, the pellet core of the comparative pellet tablet 16 does not comprise a surfactant but comprises an alkaline compound, and the pellet core of the comparative pellet tablet 17 does not comprise an alkaline compound but comprises a surfactant.

[0280] Test protocol: the enteric-coated pellet tablet A and the comparative pellet tablets 11 and 16 were packaged in HDPE bottles of 14 tablets respectively, and the packaged enteric-coated pellet tablets were placed in an accelerated stability test chamber at 40 C./RH75%, and sampled after 1/3/6 months for detecting related substances of the enteric-coated pellet tablets with different formulas. The stability data of the enteric-coated pellet tablets obtained by the test are shown in Table 6 below:

TABLE-US-00081 TABLE 6 Stability data of the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablets 11, 16 and 17 Comparative Comparative Comparative Pellet pellet tablet pellet tablet pellet tablet Time tablet A 11 16 17 Day 0 0.12% 0.23% 0.26% 1.54% Month 1 0.15% 0.89% 0.57% 3.25% Month 3 0.36% 1.69% 0.86% 6.26% Month 6 0.87% 2.76% 1.05% 8.12%

[0281] As can be seen from the results shown in Table 6, when the pellet core in the ilaprazole enteric-coated pellet did not comprise an alkaline compound and a surfactant (i.e., the comparative pellet tablet 11), the enteric-coated pellet tablet cannot meet the stability requirement (the total impurity content should not exceed 1.5%); and when the pellet core of the ilaprazole enteric-coated pellet did not comprise an alkaline compound (i.e., the comparative pellet tablet 17), the content of the related substances was very high, more than 1.5%, in the freshly prepared pellet tablets. In contrast, the comparative pellet tablet 16 in which the pellet core comprised only an alkaline compound and did not comprise surfactants had good stability results for the accelerated test.

[0282] In summary, the stability requirement (i.e., the total impurity content should not exceed 1.5%) cannot be met for ilaprazole with low stability when its enteric-coated pellet tablet comprises only a water-insoluble alkaline compound in the first isolating layer (i.e., comparative pellet tablet 11); in addition, for the pellet tablet obtained when the pellet core does not comprise an alkaline compound but only a surfactant, the stability requirement cannot be met either.

4.3.2 Effect of the Particle Size of Ilaprazole in the Pellet Core Comprised in the Enteric-Coated Pellets on the Stability of the Enteric-Coated Pellet Tablets

Comparison Between the Enteric-Coated Pellet Tablet A According to the Present Invention and the Comparative Pellet Tablets 3 and 4 in Terms of the Stability

[0283] In this example, the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablets 3 and 4 were subjected to the accelerated stability test. In this test, the particle size D90 of ilaprazole in the pellet core of the enteric-coated pellets in the comparative pellet tablet 3 were greater than or equal to 80 m and less than or equal to 100 m, and the particle size D90 of ilaprazole in the pellet core of the enteric-coated pellets in the comparative pellet tablet 4 is greater than 100 m, compared to that in the enteric-coated pellet tablet A according to the present invention. The method is specified as follows: [0284] Test protocol: the pellet tablet A and the pellet tablets 3 and 4 were packaged in HDPE bottles of 14 tablets respectively, and the packaged pellet tablets were placed in an accelerated stability test chamber at 40 C./RH75%, and sampled after 1/3/6 months for detecting related substances of the pellet tablets with different formulas. The stability data of the pellet tablets obtained by the test are shown in Table 7 below:

TABLE-US-00082 TABLE 7 Stability data of the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablets 3 and 4 Pellet tablet Comparative pellet Comparative pellet Time A tablet 3 tablet 4 Day 0 0.12% 0.25% 0.22% Month 1 0.15% 0.46% 0.22% Month 3 0.36% 0.78% 0.64% Month 6 0.87% 0.99% 0.85%

[0285] As can be seen from the results shown in Table 7, the stability of the comparative pellet tablets 3 (with the particle size D90 of ilaprazole greater than or equal to 80 m and less than or equal to 100 m) and 4 (with the particle size D90 of ilaprazole greater than 100 m) comprising pellet cores with different particle sizes D90 of ilaprazole was still within the standard range (the total impurity content should not exceed 1.5%) compared to that of the enteric-coated pellet tablet A according to the present invention. That is, the change in the particle size D90 of ilaprazole comprised in the pellet core of the enteric-coated pellet does not affect the stability of the enteric-coated pellet tablet.

[0286] In summary, the particle size of ilaprazole comprised in the pellet core of the enteric-coated pellet does not affect the stability and the acid resistance of the enteric-coated pellet tablet prepared from the enteric-coated pellets.

4.4 Effect of the Protective Layer in the Enteric-Coated Pellets on the Stability and the Acid Resistance of the Enteric-Coated Pellet Tablets

[0287] In this example, taking an ilaprazole enteric-coated pellet tablet as an example, the effects of the arrangement of the protective layer and the amount of its components in the enteric-coated pellets on the stability or acid resistance were compared.

4.4.1 Effect of the Arrangement of the Protective Layer in the Enteric-Coated Pellets

[0288] 1) Comparison between the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablet 12 in terms of the stability

[0289] In this example, the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablet 12 were subjected to the accelerated stability test. In this test, the enteric-coated pellets prepared into the comparative pellet tablet 12 did not comprise a protective layer.

[0290] Test protocol: the pellet tablet A and the pellet tablet 12 were packaged in HDPE bottles of 14 tablets respectively, and the packaged pellet tablets were placed in an accelerated stability test chamber at 40 C./RH75%, and sampled after 1/3/6 months for detecting related substances of the pellet tablets with different formulas. The stability data of the pellet tablets obtained by the test are shown in Table 8-1 below:

TABLE-US-00083 TABLE 8-1 Stability data of the pellet tablet A according to the present invention and the comparative pellet tablet 12 Pellet tablet Comparative pellet Time A tablet 12 Day 0 0.12% 0.22% Month 1 0.15% 0.3% Month 3 0.36% 0.46% Month 6 0.87% 0.79%

[0291] As can be seen from the results shown in Table 8-1, the stability of the comparative pellet tablet 12, in which the enteric-coated pellet does not comprise a protective layer, was still within the standard range (the total impurity content should not exceed 1.5%) compared to that of the enteric-coated pellet tablet A according to the present invention. That is, whether the enteric-coated pellet comprises a protective layer does not affect the stability of the enteric pellet tablet. [0292] 2) Comparison between the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablet 12 in terms of the acid resistance

[0293] In this example, the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablet 12 were subjected to the acid resistance test. The acid resistance test described in section 4.2.1 was referred to for the specific method.

[0294] The results are shown in Table 8-2 below:

TABLE-US-00084 TABLE 8-2 Acid resistance data of the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablet 12 Pellet tablet Comparative pellet Time A tablet 12 Day 0 96.7% 88.4% Month 1 95.9% 87.5% Month 3 95.5% 87.3% Month 6 95.3% 86.4%

[0295] As can be seen from Table 8-2, the acid resistance of the comparative pellet tablet 12 without a protective layer on the outside of the enteric coating layer was slightly lower than the standard range (i.e., the acid resistance average of 6 tablets should be not less than 90%). However, the inventors found in the experimental process that the lower acid resistance data of the determination was caused by the fact that the enteric-coated pellets without a protective layer were easy to adhere to each other, and part of the drug was degraded in the treatment process. Therefore, here, those skilled in the art will understand that if in the preparation of the enteric-coated pellet formulation, means other than providing a protective layer, such as timely mixing the formulation with a formulation excipient, can be provided to prevent the enteric-coated pellets from adhesion, whether to provide a protective layer will not affect the acid resistance of the formulation.

4.4.2 Effect of the Amount of the Components of the Protective Layer in the Enteric-Coated Pellets

[0296] In this example, the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablet 13 were tested and compared in terms of the acid resistance.

[0297] In this example, the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablet 13 were subjected to the accelerated stability test. In this test, the content of the anti-adherent (such as magnesium stearate) in the protective layer of the enteric-coated pellets prepared into the comparative pellet tablet 13 was lower; for example, when the amount of ilaprazole was 5-15 parts, the amount of the anti-adherent was less than 0.5 parts.

[0298] Test protocol: the pellet tablet A and the pellet tablet 13 were packaged in HDPE bottles of 14 tablets respectively, and the packaged pellet tablets were placed in an accelerated stability test chamber at 40 C./RH75%, and sampled after 1/3/6 months for detecting the acid resistance of the pellet tablets, that is: the pellet tablet was dissolved in 0.1 M hydrochloric acid solution, and the pellets were collected after 2 h and detected for the content of the remaining ilaprazole. The acid resistance data of the pellet tablets obtained by the test are shown in Table 9 below:

TABLE-US-00085 TABLE 9 Acid resistance data of the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablet 13 Pellet tablet Comparative pellet Time A tablet 13 Day 0 96.7% 96.9% Month 1 95.9% 96.6% Month 3 95.5% 94.1% Month 6 95.3% 91.6%

[0299] As can be seen from the results shown in Table 9, the acid resistance of the enteric-coated pellet tablet 13 also had a tendency to decrease after 6 months of the acceleration (i.e., from 96.9% at the beginning to 91.6% after 6 months) in the long-term test. The inventors found that, after 6 months of the acceleration, in the acid resistance test, part of the enteric-coated pellets of the comparative pellet tablet 13 adhered to the bottom of the dissolution cup, resulting in a decrease in the acid resistance. This indicates that when the amount of the water-insoluble inert material (such as talc, magnesium stearate and titanium dioxide) in the protective layer that is capable of preventing the pellets from adhesion is too low, the protective effect will be poor, and the enteric-coated pellets cannot be effectively prevented from adhesion, thereby affecting the acid resistance.

4.5 Dissolution Test of the Enteric-Coated Pellet Tablets

4.5.1 Comparison Between the Enteric-Coated Pellet Tablet A According to the Present Invention and the Comparative Pellet Tablet 15 in Terms of the Dissolution Rate

[0300] In this example, the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablet 15 were compared in terms of the dissolution rate according to the method described in section 4.1 above. The dissolution rate data of the pellet tablets obtained by the test are shown in Table 10 below:

TABLE-US-00086 TABLE 10 Dissolution rate data of the pellet tablet A according to the present invention and the comparative pellet tablet 15 Comparative pellet T/min Pellet A tablet 15 0 0% 0% 10 35.80% 34.5% 15 68.50% 66.3% 20 82.90% 80.1% 30 95.20% 94.2% 45 94.30% 93.8% 60 92.20% 91.5%

[0301] As can be seen from the dissolution rate results shown in Table 10, both the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablet 15 had good dissolution rate (the dissolution rate should be not less than 80%). This indicates that when the second isolating layer comprises only a binder, and does not comprise water-insoluble inert substance (e.g., an anti-adherent) that is capable of preventing the pellets from adhesion, the dissolution rate of the enteric-coated pellet formulation, and thus the in vivo bioavailability, will not be affected.

4.5.2 Comparison Between the Enteric-Coated Pellet Tablet A According to the Present Invention and the Comparative Pellet Tablets 7 and 8 in Terms of the Dissolution Rate

[0302] In this example, the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablets 7 and 8 were compared in terms of the dissolution rate according to the method described in section 4.1 above. The dissolution rate data of the pellet tablets obtained by the test are shown in Table 11 below and FIG. 1:

TABLE-US-00087 TABLE 11 Dissolution rate data of the pellet tablet A according to the present invention and the comparative pellet tablets 7 and 8 Comparative pellet Comparative pellet T/min Pellet A tablet 7 tablet 8 0 0% 0% 0% 10 35.80% 26.40% 16.80% 15 68.50% 35.70% 25.60% 20 82.90% 49.80% 38.50% 30 95.20% 57.20% 49.50% 45 94.30% 68.90% 57.60% 60 92.20% 72.60% 66.60%

[0303] As can be seen from the dissolution rate results shown in FIG. 1 and Table 11, the enteric-coated pellet tablet A according to the present invention had good dissolution rate (the dissolution rate should be not less than 80%). The dissolution rates of the comparative pellets 7 and 8 were significantly lower than the required standard range (the dissolution rate should be not less than 80%) compared to that of the enteric-coated pellet tablet A according to the present invention, indicating that the release of these enteric-coated pellet tablets was significantly slowed down, which will delay the in vivo action, and thus affect the in vivo bioavailability.

[0304] As described above, the change in the proportions of components in the isolating layers of the enteric-coated pellet will not affect the stability and the acid resistance of the enteric-coated pellet tablet prepared from the enteric-coated pellets. However, the change in the proportions of the components in the isolating layer of the enteric-coated pellet will affect the dissolution rate of the corresponding enteric-coated pellet tablet, and thus affect the in vivo bioavailability of the formulation. Therefore, in order to further improve the in vivo bioavailability, according to the present invention, preferably, the proportions of the components in the isolating layer of the enteric-coated pellet can be: when the amount of ilaprazole is 5-15 parts, the first isolating layer comprises 5-36 parts of a binder and 5-36 parts of a water-insoluble alkaline compound, and the second isolating layer comprises 4-26 parts of a binder and 7-44 parts of a water-insoluble inert substance capable of preventing the pellets from adhesion.

4.5.3 Comparison Between the Enteric-Coated Pellet Tablet A According to the Present Invention and the Comparative Pellet Tablets 11 and 16 in Terms of the Dissolution Rate

[0305] In this example, the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablets 11 and 16 were compared in terms of the dissolution rate according to the method described in section 4.1 above. The dissolution rate data of the pellet tablets obtained by the test are shown in Table 12 below and FIG. 2:

TABLE-US-00088 TABLE 12 Dissolution rate data of the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablets 11 and 16 Comparative Comparative T/min Pellet A pellet 11 pellet 16 0 0% 0% 0% 10 35.8% 22.5% 29.5% 15 68.5% 27.6% 46.3% 20 82.9% 37.2% 66.6% 30 95.2% 45.4% 78.3% 45 94.3% 51.6% 81.8% 60 92.2% 60.5% 83.9%

[0306] As can be seen from the results shown FIG. 2 and Table 12, the dissolution rate of the comparative pellet tablet 11 was significantly lower than the required standard (the dissolution rate should be not less than 80%) compared to that of the enteric-coated pellet tablet A according to the present invention.

[0307] In the comparative pellet tablet 16, the pellet core did not comprise a surfactant, and the drug dissolution rate of the formulation was within the standard range, but was lower than that of the enteric-coated pellet tablet A, and the dissolution rate was less than 85%.

[0308] As described above, the surfactant comprised in the pellet core of the enteric-coated pellet tablet will not affect the stability of the enteric-coated pellet tablet, but will affect the dissolution rate of the formulation. That is, the addition of the surfactant to the pellet core of the enteric-coated pellet tablet can effectively improve the dissolution rate of the formulation and thus the bioavailability.

4.5.4 Comparison Between the Enteric-Coated Pellet Tablet A According to the Present Invention and the Comparative Pellet Tablets 3 and 4 in Terms of the Dissolution Rate

[0309] In this example, the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablets 3 and 4 were compared in terms of the dissolution rate according to the method described in section 4.1 above. The dissolution rate data of the pellet tablets obtained by the test are shown in Table 13 below and FIG. 3:

TABLE-US-00089 TABLE 13 Dissolution rate data of the pellet tablet A according to the present invention and the comparative pellet tablets 3 and 4 Pellet tablet Comparative pellet Comparative pellet T/min A tablet 3 tablet 4 0 0% 0% 0% 10 35.8% 20.5% 13.5% 15 68.5% 36.7% 26.4% 20 82.9% 56.8% 45.6% 30 95.2% 68.4% 56.5% 45 94.3% 75.8% 60.5% 60 92.2% 82.9% 72.5%

[0310] As can be seen from the dissolution rate results shown in FIG. 3 and Table 13, the dissolution rates of the comparative pellet tablets 3 and 4 were significantly reduced compared to that of the enteric-coated pellet tablet A according to the present invention, wherein when the particle size D90 of ilaprazole in the pellet core of the enteric-coated pellet was greater than 100 m (i.e., comparative pellet tablet 4), the dissolution rate was lower than the standard range (i.e., the dissolution rate should be not less than 80%).

4.5.5 Comparison Between the Enteric-Coated Pellet Tablet A According to the Present Invention and the Comparative Pellet Tablet 12 in Terms of the Dissolution Rate

[0311] In this example, the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablet 12 were compared in terms of the dissolution rate according to the method described in section 4.1 above. The dissolution rate data of the pellet tablets obtained by the test are shown in Table 14 below and FIG. 4:

TABLE-US-00090 TABLE 14 Dissolution rate data of the enteric-coated pellet tablet A according to the present invention and the comparative pellet tablet 12 Pellet tablet Comparative pellet T/min A tablet 12 0 0% 0% 10 35.8% 32.5% 15 68.5% 46.8% 20 82.9% 62.5% 30 95.2% 75.6% 45 94.3% 78.2% 60 92.2% 79.2%

[0312] As can be seen from the results shown in FIG. 4 and Table 14, the dissolution rate of the comparative pellet tablet 12 without a protective layer was significantly reduced to about the standard value (the dissolution rate should be not less than 80%) compared to that of the enteric-coated pellet tablet A according to the present invention. The inventors found in the experiment that the significant decrease in the dissolution rate is caused by the fact that the enteric-coated pellets according to the present invention without a protective layer were easy to adhere to each other, thereby affecting the release rate in the dissolution medium. Therefore, the enteric-coated pellet tablet A having a protective layer will not generate the adhesion in the dissolution medium and thus has a higher release rate; while the comparative pellet tablet 12 having no protective layer will generate the adhesion in the medium and thus has a lower release rate. Therefore, here, those skilled in the art will understand that if in the preparation of the enteric-coated pellet formulation, means other than providing a protective layer, such as timely mixing the formulation with a formulation excipient, can be provided to prevent the enteric-coated pellets from adhesion, or if another isolation layer is added between the first isolating layer and the second isolating layer to prevent the enteric-coated pellets from easy adhesion, whether to provide a protective layer will not affect the dissolution rate of the formulation.

4.6 Effect of the Particle Size of Ilaprazole in the Pellet Core Comprised in the Enteric-Coated Pellets on the Drug-Loading Rate of the Enteric-Coated Pellet Tablets

[0313] As can be seen from the comparison of the drug-containing pellet applying rates W (i.e., drug-loading rate) shown in the section 1.1 formula and method for preparing drug-containing pellet (W) and the drug-applying rate of the drug-containing pellet in Example 1, the drug-loading rates W.sub.8 and W.sub.9 of the pellet cores W8 and W9 comprised in comparative pellet tablets 3 and 4 were 87.2% and 79.3%, respectively. In contrast, when the particle size D90 of ilaprazole comprised in the pellet core of the enteric-coated pellet tablet is 50 m, the drug-loading rate of the pellet core (such as W1-W5) is more than 90%.

[0314] As described above, the particle size of ilaprazole comprised in the pellet core of the enteric-coated pellet does not affect the stability and the acid resistance of the enteric-coated pellet tablet prepared from the enteric-coated pellets; the particle size of ilaprazole comprised in the pellet core of the enteric-coated pellet will affect the dissolution rate of the enteric-coated pellet tablet, and thus affect the in vivo bioavailability. In addition, the particle size of ilaprazole comprised in the pellet core of the enteric-coated pellet will also affect the drug-loading rate of the pellet core of the enteric-coated pellet. Therefore, in order to further improve the in vivo bioavailability, preferably, the particle size D90 of ilaprazole in the pellet core of the enteric-coated pellet according to the present invention can be 100 m; more preferably, the particle size D90 of ilaprazole in the pellet core of the enteric-coated pellet according to the present invention can be 50 m, and at this time, not only the drug release rate of the enteric-coated pellet tablet is relatively fast, i.e., the drug release rate reaches over 90% within 30 min, but also the pellet core has a higher drug-loading rate (greater than 90%).

Example 5. Acid-Inhibiting Effect of the Enteric-Coated Pellet Tablet According to the Present Invention

[0315] Objective: To compare the acid-inhibiting effects of the enteric-coated pellet tablet A of the present invention and the comparative pellet tablets 1 and 2 on the first day of oral administration in healthy subjects.

[0316] Test protocol: the study was a randomized, open and cross-designed single-center study, with 18 healthy subjects enrolled. In one cycle of the test, 18 subjects were randomly divided into three groups of 6 persons, and the three groups were administered with the pellet tablet A, the comparative pellet tablet 1 and the comparative pellet tablet 2, respectively. Each person was administered with the drug once under fasting condition, and the intragastric pH was measured for 24 h.

[0317] Intragastric pH recording: intragastric pH was recorded with a pH testing system from Medtronic (Denmark). The catheter was placed in the stomach via the nasal cavity, with one end connected to a Digitrapper MKIII recording device. Intragastric pH of the subjects can be recorded continuously through a microprocessor in the recording device. The catheter was placed 8-10 cm away from the lower esophageal sphincter, with the scale on the surface of the catheter indicating its position. The probe was in the same position in each pH recording and had to be subjected to two-point calibration using pH 7.01 and pH 1.07 buffers before each pH monitoring. The data in the Digitrapper MKIII were downloaded to the computer for further analysis after each recording.

[0318] Test results: the intragastric pH records of the subjects in each group were processed and the analyzed pH averages of a plurality of patients at each time point were plotted as a curve, as shown in FIG. 5.

[0319] As can be seen from FIG. 5, the enteric-coated pellet tablet A according to the present invention acted fast, inhibiting gastric acid to pH 4 or higher only within 1 h after the administration, thus achieving the clinical effect. Compared with the enteric-coated pellet tablet A according to the present invention, the comparative pellet tablet 1 achieved the clinical effect only about 3 h after the administration, and the comparative pellet tablet 2 achieved the clinical effect about 2.5 h after the administration. Therefore, the enteric-coated pellet tablet according to the present invention can achieve the effect quickly, thereby more quickly relieving patients' suffering.

[0320] In addition, in this example, the stability and acid resistance of the comparative pellet tablet 1 and the comparative pellet tablet 2 were also tested according to the methods in the above examples. The results are shown in Tables 15 and 16 below.

TABLE-US-00091 TABLE 15 Stability data of the comparative pellet tablet 1 and the comparative pellet tablet 2 Comparative pellet Comparative pellet Time tablet 1 tablet 2 Day 0 2.12% 0.55% Month 1 4.15% 1.82% Month 3 5.36% 2.42% Month 6 9.87% 5.79%

TABLE-US-00092 TABLE 16 Acid resistance data of the comparative pellet tablet 1 and the comparative pellet tablet 2 Comparative pellet Comparative pellet Time tablet 1 tablet 2 Day 0 92.6% 90.1% Month 1 88.3% 85.5% Month 3 83.5% 81.3% Month 6 80.6% 78.9%

[0321] As can be seen from Tables 15 and 16, the ilaprazole enteric-coated pellet tablets prepared according to the prior art (i.e., comparative pellet tablet 1 and comparative pellet tablet 2) had stability and acid resistance significantly lower than the required standards (stability standard: the total impurity should be not exceed 1.5%; acid resistance standard: the resistance should be no less than 90%) during the accelerated stability test.

Example 6. Pharmacokinetic Test of Ilaprazole Enteric-Coated Pellet Tablets According to the Present Invention in Beagle Dogs

[0322] 1) Experimental design [0323] Test animals: beagle dogs. [0324] Quantity: A total of 12 dogs, half male and half female, were divided into 3 groups (pellet tablet A, comparative pellet tablet 1 and comparative pellet tablet 2). [0325] Administration mode and frequency: oral intragastric administration once (half an hour before the administration, 0.25 mg/mL pentagastrin was administered by intramuscular injection at a dose of 0.024 mL/kg). [0326] Blood sampling points: 0 h before the administration, 1 h, 1.5 h, 1.75 h, 2 h, 2.5 h, 3 h, 3.5 h, 4 h, 5 h, 6 h and 8 h after the administration, for a total of 12 blood sampling points. [0327] Dosage: single tablet. [0328] 2) Experimental period: single-tablet, three-cycle and three-crossover, and a washing period of 7 days, for a total of 15 days.

[0329] Administration regimens for beagle dogs were as follows:

TABLE-US-00093 Beagle dog number 1 2 3 4 5 6 7 8 9 10 11 12 Cycle 1 Pellet Pellet Pellet Pellet Pellet Pellet Pellet Pellet Pellet Pellet Pellet Pellet tablet A tablet A tablet A tablet A tablet 1 tablet 1 tablet 1 tablet 1 tablet 2 tablet 2 tablet 2 tablet 2 Cycle 2 Pellet Pellet Pellet Pellet Pellet Pellet Pellet Pellet Pellet Pellet Pellet Pellet tablet 2 tablet 2 tablet 2 tablet 2 tablet A tablet A tablet A tablet A tablet 1 tablet 1 tablet 1 tablet 1 Cycle 3 Pellet Pellet Pellet Pellet Pellet Pellet Pellet Pellet Pellet Pellet Pellet Pellet tablet 1 tablet 1 tablet 1 tablet 1 tablet 2 tablet 2 tablet 2 tablet 2 tablet A tablet A tablet A tablet A [0330] 3) Sample analysis: ilaprazole concentration in plasma was determined (plasma samples were treated with 1 mol/L NaOH solution to basify the plasma). Analysis method: HPLC-MS/MS. [0331] 4) Results: see FIG. 6.

[0332] As can be seen from the in vivo pharmacokinetic data plot of beagle dogs shown in FIG. 6, the enteric-coated pellet tablet A according to the present invention had higher bioavailability in beagle dogs and achieved the effect of inhibiting gastric acid secretion faster. In contrast, the comparative pellet tablet 1 and the comparative pellet tablet 2 had low cumulative plasma concentration in beagle dogs, indicating that the comparative pellet tablet 1 and the comparative pellet tablet 2 had low bioavailability.

Example 7. Comparison Between Prazoles in Terms of the Stability

[0333] Objective: To investigate the stability of different prazole starting materials in media at pH 6.8 and 8.0

[0334] Phosphate buffer media at pH 6.8 and 8.0 containing 0.5% w/w of sodium dodecyl sulfate were prepared, added into dissolution cups, with 1000 mL per cup. 0.5 mg of each of ilaprazole, omeprazole magnesium, esomeprazole magnesium, rabeprazole sodium, pantoprazole and lansoprazole was weighed and added into the dissolution cups, stirred at 150 rpm by a paddle method to ensure that the prazole starting materials sank into the media and dissolved therein. 5 mL of each of the samples was collected at 15 min, 30 min, 45 min and 60 min respectively, and added to 20 mL of sodium hydroxide stabilization medium, and then the volume was made up to 50 mL with the mobile phase.

[0335] The collected sample content in the media was determined according to the determination method of omeprazole magnesium, esomeprazole magnesium, rabeprazole sodium, pantoprazole sodium and lansoprazole in the Chinese Pharmacopoeia (Volume II, 2015 Edition) so as to determine the stability of the prazoles in the media at pH 6.8 and 8.0. The determination results are shown in Tables 17 and 18 below.

TABLE-US-00094 TABLE 17 The remaining amount of different prazoles after the degradation at different time points in medium at pH 6.8 Time Omeprazole Esomeprazole Rabeprazole Pantoprazole point Ilaprazole magnesium magnesium sodium sodium Lansoprazole 0 min 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 15 min 59.7% 81.2% 89.6% 70.3% 83.6% 85.7% 30 min 42.7% 66.7% 70.9% 51.5% 65.9% 70.2% 45 min 29.4% 47.4% 56.0% 38.6% 50.2% 53.6% 60 min 20.7% 29.2% 41.4% 24.6% 35.4% 38.6%

TABLE-US-00095 TABLE 18 The remaining amount of different prazoles after the degradation at different time points in medium at pH 8.0 Time Omeprazole Esomeprazole Rabeprazole Pantoprazole point Ilaprazole magnesium magnesium sodium sodium Lansoprazole 0 min 100.0% 100.0% 100.0% 100.0% 100.0% 100.0% 15 min 94.3% 98.2% 99.2% 97.3% 98.6% 98.7% 30 min 91.5% 95.4% 98.6% 93.5% 95.9% 96.2% 45 min 88.6% 96.3% 97.6% 90.6% 92.2% 95.3% 60 min 84.6% 91.2% 96.4% 88.5% 91.4% 93.5%

[0336] As can be seen from Tables 17 and 18, the stability of different prazoles in medium at pH 6.8 was relatively poor, wherein the stability of ilaprazole was the worst, and the stability of esomeprazole magnesium was the best.

Example 8. Preparation of Ilaprazole Pellet Dry Suspension

[0337] In this example, by taking the ilaprazole enteric-coated pellet according to the present invention as an example, the ilaprazole pellet dry suspension was prepared. [0338] 1) Formula of dry suspension granules V (unit: g)

TABLE-US-00096 Components Weight (g) Xanthan gum 20 Chitosan 1400 CCNA 75 Aspartame 15 [0339] Preparation method: xanthan gum, chitosan, CCNA and aspartame were mixed uniformly, and added to a dry granulator for granulation. Process parameters: pinch roller spacing: 0.2 mm, feeding speed: 30 rpm, pinch roller rotation speed: 5 rpm, and sizing rotation speed: 10 rpm. After granulation, the granules were sieved for sizing and the particle size was controlled to be 0.5-0.7 mm to obtain dry suspension granules V. [0340] 2) Preparation of dry suspensions E-V [0341] 60.5 mg of the ilaprazole enteric-coated pellets E and 2.0 g of the above dry suspension granules V were mixed and packaged in bottles to obtain the ilaprazole enteric-coated dry suspensions E-V with the specification of 5 mg.

[0342] The above examples only illustrate several embodiments of the present invention for the purpose of specific and detailed description, but should not be construed as limiting the scope of the present invention. It should be noted that various changes and modifications can be made by those skilled in the art without departing from the spirit of the present disclosure, and these changes and modifications are all within the scope of the present disclosure. Therefore, the protection scope of the present disclosure should be determined with reference to the appended claims.