SOLID PHARMACEUTICAL PREPARATION, PREPARATION METHOD THEREFOR AND USE THEREOF

Abstract

The present invention relates to a solid pharmaceutical preparation and a preparation method therefor. Specifically, disclosed are a solid pharmaceutical preparation that comprises an orexin receptor antagonist compound and a preparation method therefor, the solid pharmaceutical preparation comprising an active ingredient of a compound represented by formula I, a filler, a binder, a disintegrant, and a lubricant. The solid pharmaceutical preparation has good dissolution, stability and in vivo bioavailability.

##STR00001##

Claims

1. A solid pharmaceutical formulation, wherein the solid pharmaceutical formulation comprises an active ingredient, and the active ingredient is a compound represented by formula (I) or a pharmaceutically acceptable salt thereof, or a mixture of both; ##STR00004## wherein R.sup.a is hydrogen, fluorine, chlorine, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy or isopropoxy; Z is N or CR.sub.0; R.sub.0 is hydrogen, halogen or C.sub.1-3 alkyl; n is 0, 1 or 2; and the particle size of the active ingredient is D90≤50 μm.

2. The solid pharmaceutical formulation according to claim 1, wherein the compound represented by formula (I) is a compound of formula (II): ##STR00005##

3. The solid pharmaceutical formulation according to claim 1, wherein the content of the active ingredient is 1%-15% based on the total dry weight of the solid pharmaceutical formulation.

4. The solid pharmaceutical formulation according to claim 1, wherein the solid pharmaceutical formulation further comprises a binder selected from the group consisting of hypromellose, hydroxypropyl cellulose, povidone, sodium alginate, carbopol, polyvinyl alcohol and a combination thereof, wherein the content of the binder is 0.5%-10% based on the total dry weight of the solid pharmaceutical formulation; and/or wherein the solid pharmaceutical formulation further comprises a filler selected from the group consisting of microcrystalline cellulose, lactose, cellulose-lactose complex, pre-gelatinized starch, calcium hydrogen phosphate, calcium carbonate and a combination thereof, wherein the content of the filler is 60%-90% based on the total dry weight of the solid pharmaceutical formulation.

5. (canceled)

6. The solid pharmaceutical formulation according to claim 1, wherein the solid pharmaceutical formulation further comprises a disintegrant selected from the group consisting of croscarmellose sodium, hypromellose-K4M, crospovidone, sodium carboxymethyl starch and a combination thereof, wherein the content of the disintegrant is 5%-15% based on the total dry weight of the solid pharmaceutical formulation; and/or wherein the solid pharmaceutical formulation further comprises a lubricant selected from the group consisting of magnesium stearate, talcum powder, glycerol monostearate, sodium stearyl fumarate and a combination thereof, wherein the content of the lubricant is 0.1%-1% based on the total dry weight of the solid pharmaceutical formulation.

7. (canceled)

8. The solid pharmaceutical formulation according to claim 1, wherein the solid pharmaceutical formulation is a tablet, a capsule, a powder, a granule, a drop pill or a film.

9. The solid pharmaceutical formulation according to claim 1, wherein the solid pharmaceutical formulation comprises the following components based on the total dry weight of the solid pharmaceutical formulation: a) the active ingredient: ((1S,2R,5S)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-8-azabicyclo[3.2.1]octan-8-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone, or a pharmaceutically acceptable salt thereof, or a mixture of both, wherein the content of the active ingredient is 1%-15%; b) a filler selected from the group consisting of microcrystalline cellulose, lactose, cellulose-lactose complex, pre-gelatinized starch, calcium hydrogen phosphate, calcium carbonate and a combination thereof, wherein the content of the filler is 60%-90%; c) a binder selected from the group consisting of hypromellose, hydroxypropyl cellulose, povidone, sodium alginate, carbopol, polyvinyl alcohol and a combination thereof, wherein the content of the binder is 0.5%-10%. d) a disintegrant selected from the group consisting of croscarmellose sodium, hypromellose-K4M, crospovidone, sodium carboxymethyl starch and a combination thereof, wherein the content of the disintegrant is 5%-15%; and e) a lubricant selected from the group consisting of magnesium stearate, talcum powder, glycerol monostearate, sodium stearyl fumarate and a combination thereof, wherein the content of the lubricant is 0.1%-1%; wherein the particle size of the active ingredient is D90≤35 or D90≤30 or D90≤20 μm, or D90≤10 μm, or D90=1 μm to 30 μm, or D90=1 μm to 20 μm, or D90=1 μm to 10 μm, or D90=10 μm to 20 μm.

10. The solid pharmaceutical formulation according to claim 1, wherein the solid pharmaceutical formulation comprises the following components based on the total dry weight of the solid pharmaceutical formulation: a) the active ingredient: ((1S,2R,5S)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-8-azabicyclo[3.2.1]octan-8-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone, or a pharmaceutically acceptable salt thereof, or a mixture of both, wherein the content of the active ingredient is 4%-10%; b) microcrystalline cellulose with a content of 24%-27.5%; c) lactose with a content of 48.5%-56.5%; d) hypromellose-E5 with a content of 1.5%-3%; e) croscarmellose sodium or hypromellose-K4M with a content of 5%-15%; and f) magnesium stearate with a content of 0.4%-0.5%; wherein the particle size of the active ingredient is D90≤35 μm, or D90≤30 μm, or D90≤20 μm, or D90≤10 μm, or D90=1 μm to 30 μm, or D90=1 μm to 20 μm, or D90=1 μm to 10 μm, or D90=10 μm to 20 μm.

11. The solid pharmaceutical formulation according to claim 1, wherein the solid pharmaceutical formulation comprises the following components based on the total dry weight of the solid pharmaceutical formulation: a) the active ingredient: ((1S,2R,5S)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-8-azabicyclo[3.2.1]octan-8-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone, or a pharmaceutically acceptable salt thereof, or a mixture of both, wherein the content of the active ingredient is 9.5%-10%; b) microcrystalline cellulose with a content of 24%-27.5%; c) lactose with a content of 48.5%-56.5%; d) hypromellose-E5 with a content of 1.5%-3%; e) croscarmellose sodium or hypromellose-K4M with a content of 5%-15%; and f) magnesium stearate with a content of 0.48%-0.5%; wherein the particle size of the active ingredient is D90=1 μm to 30 μm, or D90=1 μm to μm, or D90=1 μm to 10 μm, or D90=10 μm to 20 μm, and the solid pharmaceutical formulation is a tablet.

12. A method for preparing a tablet, wherein the method comprises the following steps: (a) performing wet granulation after mixing an active ingredient particle, a filler, a binder and a first disintegrant; (b) drying a resulting product obtained in step (a); (c) dry-blending a resulting product obtained in step (b), a second disintegrant and a lubricant; and (d) compressing a resulting product obtained in step (c) into the tablet; wherein the active ingredient is ((1S,2R,5S)-2-(((5-fluoropyridin-2-yl)oxy)methyl)-8-azabicyclo[3.2.1]octan-8-yl)(5-methyl-2-(pyrimidin-2-yl)phenyl)methanone, or a pharmaceutically acceptable salt thereof, or a mixture of both; and the particle size of the active ingredient particle is D90≤50 μm.

13. The method according to claim 12, wherein the content of the active ingredient is 4%40% based on the total dry weight of the mixture obtained in step (c).

14. The method according to claim 12, wherein the content of the filler is 73%-82.5% based on the total dry weight of the mixture obtained in step (c); and/or wherein the content of the binder is 1.5%-3% based on the total dry weight of the mixture obtained in step (c).

15. (canceled)

16. The method according to claim 12, wherein the content of the first disintegrant is 2%-10% based on the total dry weight of all components in step (a), and wherein the content of the second disintegrant is 5%-10%, based on the total dry weight of all components in step (c).

17. The method according to claim 12, wherein the content of the lubricant is 0.1%-1% based on the total dry weight of all components in step (c).

18. The method according to claim 12, wherein the method further comprises: (e) coating a resulting product obtained in step (d).

19. A unit dosage form, wherein based on a total weight of the unit dosage form, the unit dosage form comprises: about 10 mg, about 20 mg, or about 40 mg of an active ingredient, wherein the active ingredient is a compound of formula (II); ##STR00006## about 25 mg to about 150 mg of microcrystalline cellulose; about 50 mg to about 300 mg of lactose; about 1 mg to about 15 mg of hypromellose; about 10 mg to about 50 mg of croscarmellose sodium; and about 0.5 mg to about 3 mg of magnesium stearate, wherein the particle size of the active ingredient is D90=1 μm to 20 μm; or wherein based on a total weight of the unit dosage form, the unit dosage form comprises: 8 mg to 12 mg of an active ingredient, wherein the active ingredient is a compound of formula (II); ##STR00007## 20 mg to 30 mg of microcrystalline cellulose; 46 mg to 56 mg of lactose; 2 mg to 4 mg of hypromellose; 5 mg to 15 mg of croscarmellose sodium; and 0.3 mg to 0.7 mg of magnesium stearate, wherein the particle size of the active ingredient is D90=1 μm to 20 μm; or wherein based on a total weight of the unit dosage form, the unit dosage form comprises: 18 mg to 22 mg of an active ingredient, wherein the active ingredient is a compound of formula (II); ##STR00008## 46 mg to 56 mg of microcrystalline cellulose; 97 mg to 107 mg of lactose; 5 mg to 7 mg of hypromellose; 15 mg to 25 mg of croscarmellose sodium; and 0.8 mg to 1.2 mg of magnesium stearate, wherein the particle size of the active ingredient is D90=1 μm to 20 μm; or wherein based on a total weight of the unit dosage form, the unit dosage form comprises: 38 mg to 42 mg of an active ingredient, wherein the active ingredient is a compound of formula (II); ##STR00009## 97 mg to 107 mg of microcrystalline cellulose; 199 mg to 209 mg of lactose; 11 mg to 13 mg of hypromellose; 35 mg to 45 mg of croscarmellose sodium; and 1.8 mg to 2.2 mg of magnesium stearate, wherein the particle size of the active ingredient is D90=1 μm to 20 μm.

20. (canceled)

21. (canceled)

22. (canceled)

23. The solid pharmaceutical formulation according to claim 2, wherein the compound of formula (II) as the active ingredient exists in crystalline form A or crystalline form B.

24. The unit dosage form according to claim 19, wherein the unit dosage form is a tablet or a capsule.

25. A method for treating an orexin-associated disease, comprising administering the solid pharmaceutical formulation according to claim 1.

26. The methoduse according to claim 25, wherein the orexin-associated disease include insomnia, chronic obstructive pulmonary disease, obstructive sleep apnea, somnolence, anxiety, obsessive-compulsive disorder, panic, nicotine dependence or eating disorder.

Description

DESCRIPTION OF THE DRAWINGS

[0101] FIG. 1 is a graph showing the dissolution curves of the formulations of Preparation Examples 1-1, 1-2, 1-3 and 1-4.

[0102] FIG. 2 is a graph showing the dissolution curves of the formulations of Preparation Examples 2-1, 2-2, 2-6 and 2-7.

[0103] FIG. 3 is a graph showing the dissolution curves of the formulations of Preparation Examples 2-1, 2-2, 2-3, 2-4 and 2-5.

[0104] FIG. 4 is a graph showing the dissolution curves of the formulations of Preparation Examples 3, 2-1 and 2-4.

[0105] FIG. 5 is a graph showing the dissolution curves of the formulations of Preparation Examples 4-1, 4-2 and 4-3.

[0106] FIG. 6 is an XRPD spectrum using Cu-Kα radiation of the compound of formula (II) in crystalline form A.

[0107] FIG. 7 is an XRPD spectrum using Cu-Kα radiation of the compound of formula (II) in crystalline form B.

[0108] FIG. 8 is a graph showing the in vitro dissolution curves of the formulations of Preparation Examples 2-8 and Preparation Example 6, using phosphate buffer at pH 6.8 as the dissolution medium.

[0109] FIG. 9 is a graph showing the in vitro dissolution curves of the formulations of Preparation Examples 2-8 and Preparation Example 6, using 0.1 N HCl as the dissolution medium.

[0110] FIG. 10 is a three-dimensional ellipsoid structure of the single crystal of the compound of formula (II).

PREPARATION METHOD

[0111] The solid pharmaceutical formulation of the present invention can be prepared by methods well known in the art. For example, in the case of granule, the compound represented by formula (I) or formula (II) or a pharmaceutically acceptable salt thereof and an excipient, a binder, a disintegrant, a wetting agent and the like can be mixed, and subjected to stirring granulation, extrusion granulation, rotary granulation, one-step spray granulation and the like, or direct dry granulation as required to prepare the granule. In addition, the granule can also be prepared by applying medicine to pellets. In addition, granulation and grinding can also be carried out as required. Furthermore, excipients, disintegrants, binders, antioxidants, colorants and the like can be further added to the above granule for tableting.

[0112] For further illustration, the uncoated tablet (plain tablet) or the coated tablet of the present invention can be prepared by the following preparation process by changing the added amount or the corresponding component according to different prescriptions. The preparation process includes: grinding the active pharmaceutical ingredient, sieving the auxiliary material, weighing, mixing and granulating, wet granule sizing, drying, dry granule sizing, final mixing, tableting, and coating (required when preparing a coated tablet).

[0113] Grinding the active pharmaceutical ingredient: the particle size of qualified active pharmaceutical ingredient (the compound of formula (I) or formula (II), the pharmaceutically acceptable salt thereof, or the mixture thereof) should be 120-150 μm, which can be achieved by adjusting different parameters of grinding equipment. (1) Particle size control D90≤10 μm, D90≤20 μm or D90≤30 μm: pass the qualified active pharmaceutical ingredient (the compound of formula (I) or formula (II), the pharmaceutically acceptable salt thereof, or the mixture thereof) through a sieve, then add into a jet mill for grinding, control the particle size of the ground active pharmaceutical ingredient by controlling the rotary speed of the feeder at 100 to 500 rpm, adjusting the feed pressure to 3 to 7 bar and the grinding pressure to 2 to 7 bar, and then measure the particle size distribution by a laser particle size distribution analyzer, in which the particle size distribution should meet the particle size D90≤10 μm, D90≤20 μm, or D90≤30 μm; or (2) particle size control D90≤50 μm: taking the qualified active pharmaceutical ingredient (of formula (I) or formula (II)), grinding by a laboratory shear pulverizer, grinding 3 minutes with an interval of 5 minutes, after grinding for a certain period of time, measuring the particle size of the active pharmaceutical ingredient, in which the particle size distribution measured by a laser particle size distribution analyzer should meet D90≤50 μm.

[0114] Sieving the auxiliary material: obtain a qualified auxiliary material, lactose (Granulac 200 mesh).

[0115] Weighing: weigh the active pharmaceutical ingredient (ground), microcrystalline cellulose (PH1 0 1), lactose (Granulac 200 mesh) (sieved), hypromellose-E5, croscarmellose sodium or hypromellose-K4M (with a disintegrant added).

[0116] Mixing and granulating: pulping, i.e., binder preparation: weigh 300g of purified water, add 30 g of hypromellose-E5 while stirring, keep stirring until dissolved to obtain a 10% hypromellose-E5 aqueous solution, pass through a 60-mesh sieve and reserve. Mixing, i.e.: add the active pharmaceutical ingredient (ground) and lactose (sieved) into a wet mixing granulator successively to start stirring and mixing with a stirring speed of 300-500 rpm (for example, 300 rpm or 400 rpm), a chopping speed of 350-400 rpm or 400-500 rpm (for example, 400 rpm), and a stirring time of 300 seconds; open the pot cover, add croscarmellose sodium or hypromellose-K4M (with a disintegrant added), microcrystalline cellulose (PH101) into the pot successively to start stirring and mixing with a stirring speed of 300-500 rpm (for example, 350 rpm or 400 rpm), a chopping speed of 400-500 rpm (preferably 400 rpm), and a stirring time of 600 seconds. Preparing damp mass, the whole process of which is divided into two stages, a first stage: open the wet mixing granulator with pre-set parameters, set the stirring speed to 350-500 rpm (for example, 350 rpm), and the cutting speed to 1000-1500 rpm (for example, 1000 rpm), run for 10 seconds, then slowly add all of 10% (w/w) hypromellose-E5 aqueous binder into the wet mixing granulator, after adding the binder solution, homogenize the obtained wet granules with stirring paddle and chopper until no obvious agglomerates exist, in which the granulation time (slurry adding time) is ≤300 seconds (for example, 60s); and a second stage: set the stirring speed to 500 rpm or 350 rpm, and the cutting speed to 1500 rpm or 1000 rpm, start stirring and cutting at the same time, and continue stirring and cutting for 60s to prepare suitable wet granules.

[0117] Wet granule sizing: subject the resulting wet granules to granule sizing by passing through a 18-mesh stainless steel sieve in a swing granule sizing machine or to manually wet granule sizing by passing through a 20-mesh sieve.

[0118] Drying: spread the wet granules after granule sizing evenly in a baking tray, in which the thickness of spread wet granules in the tray should be 1.5 cm ±0.5 cm, put the baking tray with the spread wet granules into an oven to start drying with a drying temperature of 65.0° C. ±5.0° C. Turn the spread wet granules in the tray over and measure the moisture content of the granules for every 30 minutes of drying until the drying end point when the moisture content of the granules after drying 2.0%.

[0119] Dry granule sizing: subject the dried granules to granule sizing by passing through a 20-mesh stainless steel sieve in a swing granule sizing machine.

[0120] Final mixing: add croscarmellose sodium or hypromellose-K4M (with a disintegrant added), the granules after dry granule sizing and magnesium stearate into a mixer at the same time and mix for 300 seconds with a mixing speed of 16 rpm. After final mixing, the total moisture content of the granules should be 3.0%.

[0121] Tableting: obtain the final mixed granules of the active pharmaceutical ingredient, and subject to tableting by a rotary tableting machine.

[0122] Coating: coat the plain tablets obtained by tableting to obtain a desired coating weight gain of 2% to 3%. The stomach-soluble film coating premix is selected as the coating material, and the concentration of the coating solution is 15%. The specific preparation method comprises: taking 30 g of coating powder, adding into 200 g of purified water, and stirring to disperse evenly to obtain the coating solution (formulated according to 200% of the weight gain at 3%), and then coating the tablets by a high-efficiency coater. Coating can be carried out by using the following process parameters.

TABLE-US-00003 Inlet air temperature (° C.) 55.0-65.0 Outlet air temperature (° C.) 45.0-50.0 Heating (° C.) 70.0-75.0 Air volume (m.sup.3/h) 80.0-85.0 Flow rate (g/min)   85-90 Main engine rotary speed  3.0-5.5 (rpm) Spray gun pressure (bar) 0.11 or 0.9

DETAILED DESCRIPTION OF THE INVENTION

[0123] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions, or in accordance with the conditions suggested by the manufacturer. Percentages and parts are weight percentages and weight parts unless otherwise specified. The experimental materials and reagents used in the following examples can be obtained from commercial sources unless otherwise specified.

[0124] The single crystal structure is tested using a D8 Venture X-ray single crystal diffractometer, light source: Cu target, X-ray: Cu-Kα (=1.54178 Å), detector: CMOS surface detector, resolution: 0.8 Å, current and voltage: 50kV, 1.2mA, exposure time: 10s, distance from the surface detector to the sample: 40mm, test temperature: 150(2)K.

[0125] Unless otherwise stated, the weight percentages set forth for the active ingredient, the filler component, the binder component, the disintegrant component, and the lubricant component of the solid pharmaceutical formulation disclosed herein are the percentage of each component in the final solid pharmaceutical formulation without any surface coverings, such as a tablet coating (e.g., any clear coating or colored coating) or a capsule. The calculation of the weight percentages of the active ingredient, the filler component, the binder component, the disintegrant component and the lubricant component may slightly change, since the coated tablet in the following specific examples include the weight of the coating. However, the following examples are only used to illustrate the present invention and are not intended to limit the scope of the present invention. Unless otherwise stated, the active ingredient of the compound of formula (II) exists in crystalline form A, the microcrystalline cellulose is microcrystalline cellulose PH101, the lactose is lactose Granulac 200 mesh, and the croscarmellose sodium is croscarmellose sodium SD711 in the specific formulations in the following preparation examples.

PREPARATION EXAMPLE 1-1

Uncoated Plain Tablet Formulation

[0126] Tablet formulation comprising the compound of formula (II) (mass percent):

TABLE-US-00004 compound of formula (II)    4% microcrystalline cellulose 26.16% lactose 56.32% hypromellose-E5  3.04% croscarmellose sodium   10% magnesium stearate  0.48%

[0127] The compound of formula (II) was passed through a 20-mesh sieve, and then the sieved active pharmaceutical ingredient was added into a jet mill and ground under the grinding pressure of 6 to 7 bar, the inlet pressure of 7 to 8 bar, the feed pressure of 6 to 7 bar, and the feed rotary speed of 100 to 150 rpm. After the grinding was completed, samples were taken and tested, and the particle size distribution was measured by a laser particle size distribution analyzer, showing the particle size D90≤10 μm (D90=7.461 μm). The compound of formula (II) with the particle size of D90≤10 μm (D90=7.461 μm) and lactose were added into a wet mixing granulator, stirred and mixed, and then microcrystalline cellulose and croscarmellose sodium were added, stirred and mixed. Then 10% (mass percent) hypromellose-E5 aqueous solution was slowly added into the wet mixing granulator for performing wet granulation. The resultant was subjected to wet granule sizing and dried in an oven. The moisture content of the dried granules was ≤2.0%. Then dry granule sizing was performed. The resulting granules after dry granule sizing, croscarmellose sodium and magnesium stearate were finally mixed in a mixer. The total moisture content of the granules after final mixing was ≤3.0%. The granules were tableted to prepare uncoated plain tablets having a specification of 500 mg.

PREPARATION EXAMPLE 1-2

Uncoated Plain Tablet Formulation

[0128] Tablet formulation comprising the compound of formula (II) (mass percent):

TABLE-US-00005 compound of formula (II)    4% microcrystalline cellulose 26.16% lactose 56.32% hypromellose-E5  3.04% croscarmellose sodium   10% magnesium stearate  0.48%

[0129] The compound of formula (II) was passed through a 20-mesh sieve, and then the sieved active pharmaceutical ingredient was added into a jet mill and ground under the grinding pressure of 4 to 6 bar, the inlet pressure of 6 to 7 bar, the feed pressure of 5 to 6 bar, and the feed rotary speed of 200 to 300 rpm. Samples were taken and tested, and the particle size distribution was measured by a laser particle size distribution analyzer, showing the particle size D90≤20 μm (D90=17.89 μm).The compound of formula (II) with D90≤20 μm (D90=17.89 μm) and lactose were added into a wet mixing granulator, stirred and mixed, and then microcrystalline cellulose and croscarmellose sodium were added, stirred and mixed. Then 10% (mass percent) hypromellose-E5 aqueous solution was slowly added into the wet mixing granulator for performing wet granulation. The resultant was subjected to wet granule sizing and dried in an oven. The moisture content of the dried granules was ≤2.0%. Then dry granule sizing was performed. The resulting granules after dry granule sizing, croscarmellose sodium and magnesium stearate were finally mixed in a mixer. The total moisture content of the granules after final mixing was 3.0%. The granules were tableted to prepare uncoated plain tablets having a specification of 500 mg.

PREPARATION EXAMPLE 1-3

Uncoated Plain Tablet Formulation

[0130] Tablet formulation comprising the compound of formula (II) (mass percent):

TABLE-US-00006 compound of formula (II)    4% microcrystalline cellulose 26.16% lactose 56.32% hypromellose-E5  3.04% croscarmellose sodium   10% magnesium stearate  0.48%

[0131] The compound of formula (II) was passed through a 20-mesh sieve, and then the sieved active pharmaceutical ingredient was added into a jet mill and ground under the grinding pressure of 2 to 4 bar, the inlet pressure of 4 to 5 bar, the feed pressure of 3 to 4 bar, and the feed rotary speed of 300 to 400 rpm. After the grinding was completed, samples were taken and tested, and the particle size distribution was measured by a laser particle size distribution analyzer, showing the particle size D90≤35 μm (D90=30.7 μm). The compound of formula (II) with D90≤35 μm (D90=30.7 μm) and lactose were added into a wet mixing granulator, stirred and mixed, and then microcrystalline cellulose and croscarmellose sodium were added, stirred and mixed. Then 10% (mass percent) hypromellose-E5 aqueous solution was slowly added into the wet mixing granulator for performing wet granulation. The resultant was subjected to wet granule sizing and dried in an oven. The moisture content of the dried granules was ≤2.0%. Then dry granule sizing was performed. The resulting granules after dry granule sizing, croscarmellose sodium and magnesium stearate were finally mixed in a mixer. The total moisture content of the granules after final mixing was ≤3.0%. The granules were tableted to prepare uncoated plain tablets having a specification of 500 mg.

PREPARATION EXAMPLE 1-4

Uncoated Plain Tablet Formulation

[0132] Tablet formulation comprising the compound of formula (II) (mass percent):

TABLE-US-00007 compound of formula (II)    4% microcrystalline cellulose 26.16% lactose 56.32% hypromellose-E5  3.04% croscarmellose sodium   10% magnesium stearate  0.48%

[0133] After the compound of formula (II) was passed through a 20-mesh sieve, the particle size distribution was measured by a laser particle size distribution analyzer, showing the particle size D90≤150 μm (D90=144.5 μm). The compound of formula (II) with the particle size of D90≤150 μm (D90=144.5 μm) and lactose were added into a wet mixing granulator, stirred and mixed, and then microcrystalline cellulose and croscarmellose sodium were added, stirred and mixed. Then 10% (mass percent) hypromellose-E5 aqueous solution was slowly added into the wet mixing granulator for performing wet granulation. The resultant was subjected to wet granule sizing and dried in an oven. The moisture content of the dried granules was 2.0%. Then dry granule sizing was performed. The resulting granules after dry granule sizing, croscarmellose sodium and magnesium stearate were finally mixed in a mixer. The total moisture content of the granules after final mixing was 3.0%. The granules were tableted to prepare uncoated plain tablets having a specification of 500 mg.

PREPARATION EXAMPLE 2-1

Coated Tablet Formulation

[0134] Tablet formulation comprising the compound of formula (II) (mass percent):

TABLE-US-00008 compound of formula (II)  9.76% microcrystalline cellulose 24.88% lactose 49.76% hypromellose-E5  2.93% croscarmellose sodium  9.76% magnesium stearate  0.49% film coating premix  2.44%

[0135] The compound of formula (II) was passed through a 20-mesh sieve, and then the sieved active pharmaceutical ingredient was added into a jet mill and ground under the grinding pressure of 4 to 6 bar, the inlet pressure of 6 to 7 bar, the feed pressure of 5 to 6 bar, and the feed rotary speed of 200 to 300 rpm. Samples were taken and tested, and the particle size distribution was measured by a laser particle size distribution analyzer, showing the particle size D90≤20 μm (D90=17.89 μm). The compound of formula (II) with the particle size of D90≤20 μm (D90=17.89 μm) and lactose were added into a wet mixing granulator, stirred and mixed, and then microcrystalline cellulose and croscarmellose sodium were added, stirred and mixed. Then 10% (mass percent) hypromellose-E5 aqueous solution was slowly added into the wet mixing granulator for performing wet granulation. The resultant was subjected to wet granule sizing and dried in an oven. The moisture content of the dried granules was ≤2.0%. Then dry granule sizing was performed. The resulting granules after dry granule sizing, croscarmellose sodium and magnesium stearate were finally mixed in a mixer. The total moisture content of the granules after final mixing was ≤3.0%. The granules were tableted and coated with a stomach-soluble film coating premix to prepare tablets having a specification of 205 mg.

PREPARATION EXAMPLE 2-2

Coated Tablet Formulation

[0136] Tablet formulation comprising the compound of formula (II) (mass percent):

TABLE-US-00009 compound of formula (II)  9.76% microcrystalline cellulose 24.88% lactose 49.76% hypromellose-E5  2.93% croscarmellose sodium  9.76% magnesium stearate  0.49% film coating premix  2.44%

[0137] The compound of formula (II) was passed through a 20-mesh sieve, and then the sieved active pharmaceutical ingredient was added into a jet mill and ground under the grinding pressure of 4 to 6 bar, the inlet pressure of 6 to 7 bar, the feed pressure of 5 to 6 bar, and the feed rotary speed of 200 to 300 rpm. Samples were taken and tested, and the particle size distribution was measured by a laser particle size distribution analyzer, showing the particle size D90≤20 μm (D90=17.89 μm).The compound of formula (II) with D90≤20 μm (D90=17.89 μm) and lactose were added into a wet mixing granulator, stirred and mixed, and then microcrystalline cellulose and croscarmellose sodium were added, stirred and mixed. Then 10% (mass percent) hypromellose-E5 aqueous solution was slowly added into the wet mixing granulator for performing wet granulation. The resultant was subjected to wet granule sizing and dried in an oven. The moisture content of the dried granules was ≤2.0%. Then dry granule sizing was performed. The resulting granules after dry granule sizing, croscarmellose sodium and magnesium stearate were finally mixed in a mixer. The total moisture content of the granules after final mixing was ≤3.0%. The granules were tableted and coated with a stomach-soluble film coating premix to prepare tablets having a specification of 410 mg.

PREPARATION EXAMPLE 2-3

Coated Tablet Formulation

[0138] Tablet formulation comprising the compound of formula (II) (mass percent):

TABLE-US-00010 compound of formula (II)  9.76% microcrystalline cellulose 24.88% lactose 49.76% hypromellose-E5  2.93% croscarmellose sodium  9.76% magnesium stearate  0.49% film coating premix  2.44%

[0139] The compound of formula (II) was passed through a 20-mesh sieve, and then the sieved active pharmaceutical ingredient was added into a jet mill and ground under the grinding pressure of 6 to 7 bar, the inlet pressure of 7 to 8 bar, the feed pressure of 6 to 7 bar, and the feed rotary speed of 100 to 150 rpm. After the grinding was completed, samples were taken and tested, and the particle size distribution was measured by a laser particle size distribution analyzer, showing the particle size D90≤10 μm (D90=7.461 82 m).The compound of formula (II) with the particle size of D90≤10 μm (D90=7.461 μm) and lactose were added into a wet mixing granulator, stirred and mixed, and then microcrystalline cellulose and croscarmellose sodium were added, stirred and mixed. Then 10% (mass percent) hypromellose-E5 aqueous solution was slowly added into the wet mixing granulator for performing wet granulation. The resultant was subjected to wet granule sizing and dried in an oven. The moisture content of the dried granules was ≤2.0%. Then dry granule sizing was performed. The resulting granules after dry granule sizing, croscarmellose sodium and magnesium stearate were finally mixed in a mixer. The total moisture content of the granules after final mixing was ≤3.0%. The granules were tableted and coated with a stomach-soluble film coating premix to prepare tablets having a specification of 205 mg.

PREPARATION EXAMPLE 2-4

Coated Tablet Formulation

[0140] Tablet formulation comprising the compound of formula (II) (mass percent):

TABLE-US-00011 compound of formula (II)  9.76% microcrystalline cellulose 24.88% lactose 49.76% hypromellose-E5  2.93% croscarmellose sodium  9.76% magnesium stearate  0.49% film coating premix  2.44%

[0141] The compound of formula (II) was passed through a 20-mesh sieve, and ground by a laboratory shear pulverizer, grinding 3 minutes with an interval of 5 minutes. After grinding for 10 minutes, the particle size distribution was measured by a laser particle size distribution analyzer, showing the particle size D90≤50 μm (D90=45.71 μm). The compound of formula (II) with the particle size of D90≤50 μm (D90=45.71 μm) and lactose were added into a wet mixing granulator, stirred and mixed, and then microcrystalline cellulose and croscarmellose sodium were added, stirred and mixed. Then 10% (mass percent) hypromellose-E5 aqueous solution was slowly added into the wet mixing granulator for performing wet granulation. The resultant was subjected to wet granule sizing and dried in an oven. The moisture content of the dried granules was ≤2.0%. Then dry granule sizing was performed. The resulting granules after dry granule sizing, croscarmellose sodium and magnesium stearate were finally mixed in a mixer. The total moisture content of the granules after final mixing was ≤3.0%. The granules were tableted and coated with a stomach-soluble film coating premix to prepare tablets having a specification of 205 mg.

PREPARATION EXAMPLE 2-5

Coated Tablet Formulation

[0142] Tablet formulation comprising the compound of formula (II) (mass percent):

TABLE-US-00012 compound of formula (II)  9.76% microcrystalline cellulose 24.88% lactose 49.76% hypromellose-E5  2.93% croscarmellose sodium  9.76% magnesium stearate  0.49% film coating premix  2.44%

[0143] After the compound of formula (II) was passed through a 20-mesh sieve, the particle size distribution was measured by a laser particle size distribution analyzer, showing the particle size D90≤150 μm (D90=144.5 μm). The compound of formula (II) with the particle size of D90≤150 μm (D90=144.5 μm) and lactose were added into a wet mixing granulator, stirred and mixed, and then microcrystalline cellulose and croscarmellose sodium were added, stirred and mixed. Then 10% (mass percent) hypromellose-E5 aqueous solution was slowly added into the wet mixing granulator for performing wet granulation. The resultant was subjected to wet granule sizing and dried in an oven. The moisture content of the dried granules was ≤2.0%. Then dry granule sizing was performed. The resulting granules after dry granule sizing, croscarmellose sodium and magnesium stearate were finally mixed in a mixer. The total moisture content of the granules after final mixing was ≤3.0%. The granules were tableted and coated with a stomach-soluble film coating premix to prepare tablets having a specification of 205 mg.

PREPARATION EXAMPLE 2-6

Uncoated Plain Tablet Formulation

[0144] Tablet formulation comprising the compound of formula (II) (mass percent):

TABLE-US-00013 compound of formula (II)   10% microcrystalline cellulose 25.5% lactose   51% hypromellose-E5   3% croscarmellose sodium   10% magnesium stearate  0.5%

[0145] The compound of formula (II) was passed through a 20-mesh sieve, and then the sieved active pharmaceutical ingredient was added into a jet mill and ground under the grinding pressure of 4 to 6 bar, the inlet pressure of 6 to 7 bar, the feed pressure of 5 to 6 bar, and the feed rotary speed of 200 to 300 rpm. Samples were taken and tested, and the particle size distribution was measured by a laser particle size distribution analyzer, showing the particle size D90≤20 μm (D90=17.89 μm). The compound of formula (II) with the particle size of D90≤20 μm (D90=17.89 μm) and lactose were added into a wet mixing granulator, stirred and mixed, and then microcrystalline cellulose and croscarmellose sodium were added, stirred and mixed. Then 10% (mass percent) hypromellose-E5 aqueous solution was slowly added into the wet mixing granulator for performing wet granulation. The resultant was subjected to wet granule sizing and dried in an oven. The moisture content of the dried granules was ≤2.0%. Then dry granule sizing was performed. The resulting granules after dry granule sizing, croscarmellose sodium and magnesium stearate were finally mixed in a mixer. The total moisture content of the granules after final mixing was ≤3.0%. The granules were tableted to prepare uncoated tablets having a specification of 200 mg.

PREPARATION EXAMPLE 2-7

Uncoated Plain Tablet Formulation

[0146] Tablet formulation comprising the compound of formula (II) (mass percent):

TABLE-US-00014 compound of formula (II)   10% microcrystalline cellulose 25.5% lactose   51% hypromellose-E5   3% croscarmellose sodium   10% magnesium stearate  0.5%

[0147] The compound of formula (II) was passed through a 20-mesh sieve, and then the sieved active pharmaceutical ingredient was added into a jet mill and ground under the grinding pressure of 4 to 6 bar, the inlet pressure of 6 to 7 bar, the feed pressure of 5 to 6 bar, and the feed rotary speed of 200 to 300 rpm. Samples were taken and tested, and the particle size distribution was measured by a laser particle size distribution analyzer, showing the particle size D90≤20 μm (D90=17.89 μm). The compound of formula (II) with the particle size of D90≤20 μm (D90=17.89 μm) and lactose were added, stirred and mixed, and then microcrystalline cellulose and croscarmellose sodium were added, stirred and mixed. Then 10% (mass percent) hypromellose-E5 aqueous solution was slowly added into the wet mixing granulator for performing wet granulation. The resultant was subjected to wet granule sizing and dried in an oven. The moisture content of the dried granules was ≤2.0%. Then dry granule sizing was performed. The resulting granules after dry granule sizing, croscarmellose sodium and magnesium stearate were finally mixed in a mixer. The total moisture content of the granules after final mixing was 3.0%. The granules were tableted to prepare uncoated plain tablets having a specification of 400 mg.

PREPARATION EXAMPLE 2-8

Coated Tablet Formulation

[0148] Tablet formulation comprising the compound of formula (II) (mass percent):

TABLE-US-00015 compound of formula (II)  9.76% microcrystalline cellulose 24.88% lactose 49.76% hypromellose-E5  2.93% croscarmellose sodium  9.76% magnesium stearate  0.49% film coating premix  2.44%

[0149] The compound of formula (II) was passed through a 20-mesh sieve, and then the sieved active pharmaceutical ingredient was added into a jet mill and ground under the grinding pressure of 6 to 7 bar, the inlet pressure of 7 to 8 bar, the feed pressure of 6 to 7 bar, and the feed rotary speed of 100 to 150 rpm. After the grinding was completed, samples were taken and tested, and the particle size distribution was measured by a laser particle size distribution analyzer, showing the particle size D90≤10 μm (D90=8.93 μm). The compound of formula (II) with the particle size of D90≤10 μm (D90=8.93 μm) and lactose were added into a wet mixing granulator, stirred and mixed, and then microcrystalline cellulose and croscarmellose sodium were added, stirred and mixed. Then 10% (mass percent) hypromellose-E5 aqueous solution was slowly added into the wet mixing granulator for performing wet granulation. The resultant was subjected to wet granule sizing and dried in an oven. The moisture content of the dried granules was ≤2.0%. Then dry granule sizing was performed. The resulting granules after dry granule sizing, croscarmellose sodium and magnesium stearate were finally mixed in a mixer. The total moisture content of the granules after final mixing was ≤3.0%. The granules were tableted and coated with a stomach-soluble film coating premix to prepare tablets having a specification of 205 mg.

PREPARATION EXAMPLE 3

Uncoated Plain Tablet Formulation

[0150] Tablet formulation comprising the compound of formula (II) (mass percent):

TABLE-US-00016 compound of formula (II)   4% microcrystalline cellulose 26.2% lactose 56.3% hypromellose-E5   3% croscarmellose sodium   10% magnesium stearate 0.48%

[0151] The compound of formula (II) was passed through a 20-mesh sieve, and then the sieved active pharmaceutical ingredient was added into a jet mill and ground under the grinding pressure of 6 to 7 bar, the inlet pressure of 7 to 8 bar, the feed pressure of 6 to 7 bar, and the feed rotary speed of 100 to 150 rpm. After the grinding was completed, samples were taken and tested, and the particle size distribution was measured by a laser particle size distribution analyzer, showing the particle size D90≤10 μm (D90=7.461 μm).The compound of formula (II) with the particle size of D90≤10 μm (D90=7.461 μm), lactose, and microcrystalline cellulose were added into a wet mixing granulator, stirred and mixed. Then 10% (mass percent) hypromellose-E5 aqueous solution was slowly added for performing wet granulation. The resultant was subjected to wet granule sizing and dried in an oven. The moisture content of the dried granules was ≤2.0%. Then dry granule sizing was performed. The resulting granules after dry granule sizing, croscarmellose sodium and magnesium stearate were finally mixed in a mixer. The total moisture content of the granules after final mixing was ≤3.0%. The granules were tableted to prepare tablets having a specification of 500 mg.

PREPARATION EXAMPLE 4-1

Uncoated Plain Tablet Formulation

[0152] Tablet formulation comprising the compound of formula (II) (mass percent):

TABLE-US-00017 compound of formula (II)   10% microcrystalline cellulose 24.3% lactose 48.7% hypromellose-E5  1.5% hypromellose-K4M   15% magnesium stearate  0.5%

[0153] The compound of formula (II) was passed through a 20-mesh sieve, and then the sieved active pharmaceutical ingredient was added into a jet mill and ground under the grinding pressure of 4 to 6 bar, the inlet pressure of 6 to 7 bar, the feed pressure of 5 to 6 bar, and the feed rotary speed of 200 to 300 rpm. Samples were taken and tested, and the particle size distribution was measured by a laser particle size distribution analyzer, showing the particle size D90≤20 μm (D90=17.89 μm).The compound of formula (II) with D90≤20 μm (D90=17.89 μm), lactose, microcrystalline cellulose and hypromellose-K4M were added into a wet mixing granulator, stirred and mixed. Then 10% (mass percent) hypromellose-E5 aqueous solution was slowly added for performing wet granulation. The resultant was subjected to wet granule sizing and dried in an oven. The moisture content of the dried granules was ≤2.0%. Then dry granule sizing was performed. The resulting granules after dry granule sizing, hypromellose-K4M and magnesium stearate were finally mixed in a mixer. The total moisture content of the granules after final mixing was ≤3.0%. The granules were tableted to prepare tablets having a specification of 200 mg.

PREPARATION EXAMPLE 4-2

Uncoated Plain Tablet Formulation

[0154] Tablet formulation comprising the compound of formula (II) (mass percent):

TABLE-US-00018 compound of formula (II)   10% microcrystalline cellulose 27.5% lactose   55% hypromellose-E5   2% hypromellose-K4M   5% magnesium stearate  0.5%

[0155] The compound of formula (II) was passed through a 20-mesh sieve, and then the sieved active pharmaceutical ingredient was added into a jet mill and ground under the grinding pressure of 4 to 6 bar, the inlet pressure of 6 to 7 bar, the feed pressure of 5 to 6 bar, and the feed rotary speed of 200 to 300 rpm. Samples were taken and tested, and the particle size distribution was measured by a laser particle size distribution analyzer, showing the particle size D90≤20 μm (D90=17.89 μm).The compound of formula (II) with D90≤20 μm (D90=17.89 μm), lactose, microcrystalline cellulose and hypromellose-K4M were added into a wet mixing granulator, stirred and mixed. Then 10% (mass percent) hypromellose-E5 aqueous solution was slowly added for performing wet granulation. The resultant was subjected to wet granule sizing and dried in an oven. The moisture content of the dried granules was ≤2.0%. Then dry granule sizing was performed, and the resulting granules after dry granule sizing, hypromellose-K4M and magnesium stearate were finally mixed in a mixer. The total moisture content of the granules after final mixing was ≤3.0%. The granules were tableted to prepare tablets having a specification of 200 mg.

PREPARATION EXAMPLE 4-3

Uncoated Plain Tablet Formulation

[0156] Tablet formulation comprising the compound of formula (II) (mass percent):

TABLE-US-00019 compound of formula (II)   10% microcrystalline cellulose 25.8% lactose 51.7% hypromellose-E5   2% hypromellose-K4M   10% magnesium stearate  0.5%

[0157] The compound of formula (II) was passed through a 20-mesh sieve, and then the sieved active pharmaceutical ingredient was added into a jet mill and ground under the grinding pressure of 4 to 6 bar, the inlet pressure of 6 to 7 bar, the feed pressure of 5 to 6 bar, and the feed rotary speed of 200 to 300 rpm. Samples were taken and tested, and the particle size distribution was measured by a laser particle size distribution analyzer, showing the particle size D90≤20 μm (D90=17.89 μm).The compound of formula (II) with D90≤20 μm (D90=17.89 μm), lactose, microcrystalline cellulose and hypromellose-K4M were added into a wet mixing granulator, stirred and mixed. Then 10% (mass percent) hypromellose-E5 aqueous solution was slowly added for performing wet granulation. The resultant was subjected to wet granule sizing and dried in an oven. The moisture content of the dried granules was ≤2.0%. Then dry granule sizing was performed, and the resulting granules after dry granule sizing, hypromellose-K4M and magnesium stearate were finally mixed in a mixer. The total moisture content of the granules after final mixing was ≤3.0%. The granules were tableted to prepare tablets having a specification of 200 mg.

PREPARATION EXAMPLE 5

Coated Tablet Formulation

[0158] Tablet formulation comprising the compound of formula (II) (mass percent):

TABLE-US-00020 compound of formula (II)  9.8% microcrystalline cellulose   25% lactose   50% hypromellose-E5 2.94% croscarmellose sodium  9.8% magnesium stearate 0.49% film coating premix 1.96%

[0159] The compound of formula (II) was passed through a 20-mesh sieve, and then the sieved active pharmaceutical ingredient was added into a jet mill and ground under the grinding pressure of 4 to 6 bar, the inlet pressure of 6 to 7 bar, the feed pressure of 5 to 6 bar, and the feed rotary speed of 200 to 300 rpm. Samples were taken and tested, and the particle size distribution was measured by a laser particle size distribution analyzer, showing the particle size D90≤20 μm (D90=17.89 μm).The compound of formula (II) with D90≤20 μm (D90=17.89 μm) and lactose were added into a wet mixing granulator, stirred and mixed, and then microcrystalline cellulose and croscarmellose sodium were added, stirred and mixed. Then 10% (mass percent) hypromellose-E5 aqueous solution was slowly added into the wet mixing granulator for performing wet granulation. The resultant was subjected to wet granule sizing and dried in an oven. The moisture content of the dried granules was ≤2.0%. Then dry granule sizing was performed. The resulting dry granules, croscarmellose sodium and magnesium stearate were finally mixed in a mixer. The total moisture content of the granules after final mixing was ≤3.0%. The granules were tableted and coated with a stomach-soluble film coating premix to prepare tablets having a specification of 102 mg.

PREPARATION EXAMPLE 6

Coated Tablet Formulation

[0160] Tablet formulation comprising the compound of formula (II) (mass percent):

TABLE-US-00021 compound of formula (II)  9.76% microcrystalline cellulose 24.88% lactose 49.76% hypromellose-E5  2.93% croscarmellose sodium  9.76% magnesium stearate  0.49% film coating premix  2.44%

[0161] The compound of formula (II) (in crystalline form B) was passed through a 20-mesh sieve, and then the sieved active pharmaceutical ingredient was added into a jet mill and ground under the grinding pressure of 6 to 7 bar, the inlet pressure of 7 to 8 bar, the feed pressure of 6 to 7 bar, and the feed rotary speed of 100 to 150 rpm. Samples was taken and tested, and the particle size distribution was measured by a laser particle size distribution analyzer, showing the particle size D90≤20prn (D90=10.09 μm).The compound of formula (II) with the particle size of D90≤20 μm (D90=10.09 μm) and lactose were added into a wet mixing granulator, stirred and mixed, and then microcrystalline cellulose and croscarmellose sodium were added, stirred and mixed. Then 10% (mass percent) hypromellose-E5 aqueous solution was slowly added into the wet mixing granulator for performing wet granulation. The resultant was subjected to wet granule sizing and dried in an oven. The moisture content of the dried granules was ≤2.0%. Then dry granule sizing was performed. The resulting granules after dry granule sizing, croscarmellose sodium and magnesium stearate were finally mixed in a mixer, the total moisture content of the granules after final mixing was ≤3.0%. The granules were tableted and coated with a stomach-soluble film coating premix to prepare tablets having a specification of 205 mg.

TEST EXAMPLE 1

In Vitro Dissolution Test

[0162] According to the second method of Chinese Pharmacopoeia 2015 4.sup.th Edition General Principles 0931, the tablet formulations prepared in the above preparation examples were subjected to an in vitro dissolution test to detect their dissolution levels in a phosphate buffer under pH 6.8, in which the dissolution device used paddle method, the dissolution medium was a pH 6.8 buffer, the water bath temperature was 37.0±0.5° C., the dissolution volume was 900 ml, the rotation speed was 50 rpm, the sampling time was 5min, 10min, 15min, 20min, 30min, 45min, 60min, the sampling volume was 5 ml, and the filter membrane was polyethersulfone filter. The test results were shown in the following Tables 1-1 to 1-5 and FIGS. 1 to 5.

TABLE-US-00022 TABLE 1-1 In vitro dissolution results of Preparation Examples 1-1 to 1-4 Preparation Preparation Preparation Preparation Example 1-4 Example 1-3 Example 1-2 Example 1-1 T, Dissolution Dissolution Dissolution Dissolution min Level, % RSD Level, % RSD Level, % RSD Level, % RSD 0 0 0 0 0 0.0 0 0 0 5 11 10.1 35.6 2.6 29.6 2.1 38.8 6.5 10 30.3 48.3 47.5 4.1 48.0 1.9 52.5 2.1 15 27.9 1.2 54.6 4.5 58.6 1.0 61.5 1.8 20 33.3 3.1 59.3 0.1 65.9 0.4 68.2 0.7 30 41.4 1.3 66.8 1.0 75.4 1.2 75.4 0.6 45 47.1 0.9 75.7 0.9 82.0 0.4 82.4 0.6 60 51.3 3.9 79.5 0.7 86.5 1.0 86.9 0.8

TABLE-US-00023 TABLE 1-2 In vitro dissolution results of Preparation Examples 2-1, 2-2, 2-6 and 2-7 Preparation Preparation Preparation Preparation Example 2-6 Example 2-1 Example 2-7 Example 2-2 T, Dissolution Dissolution Dissolution Dissolution min Level, % RSD Level, % RSD Level, % RSD Level, % RSD 0 0 0 0 0 0.0 0 0 0 5 33.5 2.8 26.8 11.0 25.8 6.4 28.6 8.5 10 50.1 4.6 45.8 6.4 40.4 3.1 42.4 4.7 15 61.3 1.6 57.8 5.7 50.0 1.9 51.1 2.9 20 67.3 1.9 64.9 3.9 55.9 1.3 56.0 2.0 30 75.3 1.3 73.3 2.0 62.6 0.8 62.6 0.9 45 81.5 0.5 79.5 1.5 68.3 0.3 68.1 1.1 60 84.8 0.7 83.0 1.4 71.0 0.5 70.3 1.0

TABLE-US-00024 TABLE 1-3 In vitro dissolution results of Preparation Examples 2-1 to 2-5 Preparation Preparation Preparation Preparation Preparation Example 2-1 Example 2-2 Example 2-3 Example 2-5 Example 2-4 T, Dissolution Dissolution Dissolution Dissolution Dissolution min Level, % RSD Level, % RSD Level, % RSD level, % RSD Level, % RSD 0 0 0 0 0 0.0 0 0 0 0 0 5 33.5 2.8 25.8 6.4 29.8 13.3 13.1 12.2 17.9 9.3 10 50.1 4.6 40.4 3.1 51.8 4.5 24.3 6.8 31.9 3.1 15 61.3 1.6 50.0 1.9 63.7 3.3 32.0 3.3 40.8 1.5 20 67.3 1.9 55.9 1.3 71.5 2.6 36.7 2.8 46.7 0.9 30 75.3 1.3 62.6 0.8 80.7 1.7 44.2 1.2 55.1 1.2 45 81.5 0.5 68.3 0.3 86.8 1.4 51.4 1.5 62.5 0.7 60 84.8 0.7 71.0 0.5 90.6 1.5 56.3 0.8 67.6 1.8

TABLE-US-00025 TABLE 1-4 In vitro dissolution results of Preparation Examples 3, 2-1 and 2-4 Preparation Preparation Preparation Example 3 Example 2-1 Example 2-4 T, Dissolution Dissolution Dissolution min Level, % RSD Level, % RSD Level, % RSD 0 0 0 0 0 0 0 5 38.8 6.5 33.5 2.8 17.9 9.3 10 52.5 2.1 50.1 4.6 31.9 3.1 15 61.5 1.8 61.3 1.6 40.8 1.5 20 68.2 0.7 67.3 1.9 46.7 0.9 30 75.4 0.6 75.3 1.3 55.1 1.2 45 82.4 0.6 81.5 0.5 62.5 0.7 60 86.9 0.8 84.8 0.7 67.6 1.8

TABLE-US-00026 TABLE 1-5 In vitro dissolution results of Preparation Examples 4-1 to 4-3 Preparation Preparation Preparation Example 4-1 Example 4-2 Example 4-3 Dissolution Dissolution Dissolution T, h Level, % RSD Level, % RSD Level, % RSD 0 0.0 0 0.0 0 0.0 0 0.25 3.7 46.2 25.3 15.6 10.3 27.5 0.5 7.5 29.2 45.6 11.6 18.0 30.7 1 12.4 23.9 67.4 6.9 27.9 23.4 2 20.5 18.2 84.2 3.7 42.8 17.2 4 32.0 14.2 96.0 2.5 70.9 6.5 6 41.4 9.8 97.9 2.6 88.1 2.1 8 49.8 8.8 98.9 2.6 96.5 1.6 24 93.8 3.2 101.9 2.4 102.1 1.9

TABLE-US-00027 TABLE 1-6 In vitro dissolution results of Preparation Examples 2-8 and 6 pH 6.8 0.1N HCL Preparation Preparation Preparation Preparation Example 2-8 Example 6 Example 2-8 Example 6 ,T, Dissolution RSD, Dissolution RSD, Dissolution RSD, Dissolution RSD, min Level, % % Level, % % Level, % % Level, % % 00 0 0 0.0 0 0 0 0.0 0 55 41.9 7.3 59.3 6.6 59.8 12.6 65.9 14.2 110 62.3 10.8 74.6 3.0 73.6 6.3 82.1 8.2 115 67.7 2.0 81.3 2.6 79.8 7.5 89.5 5.6 220 71.1 1.9 85.0 2.0 82.6 5.1 94.1 2.1 330 75.6 1.2 91.1 2.2 87.8 4.2 99.5 1.5 445 80.1 1.3 96.4 2.0 92.7 2.5 102.7 1.2 660 83.0 2.2 99.3 1.6 94.4 0.6 103.8 1.2

TEST EXAMPLE 2

Stability Test

[0163] After placing the prepared samples under high temperature of 60° C. and accelerated conditions (40° C/75%RH) for a certain period of time, the samples were tested for content, related substances and dissolution level according to the Second method of Chinese Pharmacopoeia 2015 4t.sup.h Edition General Principles 0512 and 0931, to assess the stability thereof. The test results were shown in Table 2-1.

TABLE-US-00028 TABLE 2-1 Stability results of Preparation Examples 2-1, 2-2 and 2-4 Single Impurity, % Unknown Other Total Impurity Impurities Impurity, Preparation RRT1.08 RRT1.25 % Content, Dissolution Example Conditions ≤0.30% ≤0.25% ≤1.5% % Level, % Preparation 0 d 0.07 0.14 0.21 97.7 84.3 Example 1-1 60° C., 1M 0.07 0.14 0.21 98.9 / 40° C./75% RH, 1M 0.07 0.14 0.21 98.3 / 60° C., 2M 0.04 0.12 0.16 98.3 / 40° C./75% RH, 2M 0.04 0.13 0.17 98.9 / Preparation 0 d 0.05 0.12 0.17 100.9 / Example 2-4 60° C., 1M 0.06 0.12 0.18 98.7 / 40° C./75% RH, 1M 0.06 0.12 0.18 97.4 / Preparation 0 d 0.05 0.16 0.21 95.6 / Example 2-2 60° C., 1M 0.05 0.15 0.20 96.1 / 40° C./75% RH, 1M 0.05 0.16 0.21 97.2 / 60° C., 2M 0.04 0.13 0.17 104.1 / 40° C./75% RH, 2M 0.04 0.13 0.17 104.3 / 40° C./75% RH, 2M 0.06 0.13 0.19 97.7 87.5

TEST EXAMPLE 3

Dog Oral Bioavailability Test

[0164] A dog oral bioavailability research was performed on the prepared samples. The research was designed according to the technical guidelines for non-clinical pharmacokinetic research of the former China Food and Drug Administration (CFDA) and ICH M3(R2). The tablet has a specification of 20 mg, 1 tablet/1 dog. The samples were collected according to the designed time point. The concentrations of the active ingredients in the samples were detected by HPLC-MS/MS method, and the pharmacokinetic parameters were calculated. The specific test contents were as follows:

[0165] Animals and administration: common grade 7-14 month old Beagle dogs weight of 9.51 kg-11.14 kg were used. Oral administration was performed with single administration on each administration day with administration time 8:00-12:00. All animals were fasted overnight before each administration, and continued to fast for 2-3 hours after administration, but the total fasting time did not exceed 24 hours.

[0166] Blood collection: forelimb venous blood collection was used. Blood collection time was each administration day (i.e., Day 1, Day 5, Day 8, Day 12 and Day 15). Blood collection time points were before administration (0h), 5min, 15min, 30min, 1h, 2h, 4h, 6h, 8h and 24h after administration. About 1 mL of blood was collected in EDTA dipotassium anticoagulant vacuum blood collection tube. After blood collection, the blood collection tube was shaken gently to mix blood and anticoagulant thoroughly. Blood was placed in crushed ice after collection, and centrifuged (4° C., 2000 g, 10 min) within 1 hour after collection. After centrifugation, about 400 pL of plasma was collected in a brown plastic tube, and immediately stored in a container of dry ice, then transferred to an ultra-low temperature refrigerator (≤−65° C.) and stored in the dark.

[0167] Sample analysis: HPLC-MS/MS method was used to detect the concentration of the active ingredients in the sample, and Microsoft Excel 2013 was used for data processing and calculation. After analyzing and measuring the concentration of samples in plasma, the concentration-time curve was plotted by WinNonlin6.3 software, and the pharmacokinetic parameters were calculated according to the non-compartmental model. The results of the pharmacokinetic parameters of the corresponding formulations are shown in the following Table 3-1, Table 3-2 and Table 3-3, respectively. The results in the same table are obtained by testing in the same batch, and the results in different tables are obtained by testing in different batches.

TABLE-US-00029 TABLE 3-1 Oral bioavailability of Preparation Examples 1-4, 1-3 and 1-2 Preparation Example Preparation Preparation Preparation Example 1-3 Example 1-2 Example 1-4 2 mpk AUC.sub.0-t 888 1537 2096 (hr*ng/mL) AUC.sub.0-∞ 1069 1804 2169 (hr*ng/mL) T.sub.max (h) 1.17 0.667 1.33 C.sub.max (ng/mL) 288 708 827 F (%) 53.1 89.7 108

TABLE-US-00030 TABLE 3-2 Oral bioavailability of Preparation Examples 2-1, 2-3 and 2-5 Preparation Example Preparation Preparation Preparation Example 2-3 Example 2-1 Example 2-5 T.sub.max (h)  1.13 ± 0.737  1.08 ± 0.492 2.25 ± 2.86 C.sub.max (ng/mL) 383 ± 372 533 ± 520 143 ± 103 AUC.sub.0-t 1205 ± 1032 1252 ± 990  722 ± 812 (hr*ng/mL) AUC.sub.0-∞ 1297 ± 1121 1272 ± 976   883 ± 1022 (hr*ng/mL)

TABLE-US-00031 TABLE 3-3 Oral bioavailability of Preparation Examples 3, 2-1, 2-3 and 2-4 T.sub.1/2 T.sub.max C.sub.max AUC.sub.0-t Preparation Example (h) (h) (ng/mL) (ng*h/mL) Preparation Example 3 1.38 0.875 436 1000 Preparation Example 2-1 1.88 1.25 708 1060 Preparation Example 2-4 6.17 0.875 393 901 Preparation Example 2-3 0.79 1.25 613 927

[0168] It can be seen from the table above that different particle sizes of the active ingredient in the formulation have different effects on pharmacokinetic parameters, such as prolonged half-life or decreased exposure in Beagle dogs.

[0169] All documents mentioned in the present invention are incorporated herein by reference as if each of documents is individually incorporated by reference. In addition, it should be understood that after reading the above disclosures of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.