TW201617069A - A pharmaceutical composition including solid dispersion of cyclin inhibitor and preparation method thereof - Google Patents

Abstract

The present invention discloses a pharmaceutical composition including solid dispersion of cyclin inhibitor and preparation method thereof. In particular, the present invention relates to a compound of formula I 6-acetyl-8-cyclopentyl-5-methyl-2-(5-piperazin-1-yl-pyridin-2-yl-amino)-8H-pyrido[2,3-d]pyrimidin-7-one as an active ingredient of pharmaceutical composition, its preparation method and the use thereof. The said pharmaceutical composition comprises solid dispersion prepared by formula I, disintegrant, diluent, blinder, glidant or lubricant. Preparation solid disperision or using inclusion technology improves the dissolution and bioavailability of poorly soluble drugs.

Description

Medicinal composition containing solid dispersion of cyclin inhibitor and preparation method thereof

The invention belongs to the field of pharmaceutical preparations, and in particular relates to a pharmaceutical preparation comprising a cyclin inhibitor and a preparation method thereof.

A total of 13 members of the cyclin-dependent kinase (CDK), belonging to the family of serine/threonine protein kinases, rely on binding to cyclins to promote cell cycle phase transition, initiate DNA synthesis and regulation. Key functions such as cell transcription.

The critical role of CDKs in the proliferation and death of all cells, including healthy and tumor cells, is that it is difficult for a broad spectrum of CDK inhibitors, especially for patients who have not been genetically screened, to exhibit a higher therapeutic window. The dose is too toxic and too small to be effective. Therefore, it is particularly important to selectively suppress part of the CDK. Of course, because most CDK subtypes have relatively similar chemical structures, how to increase the selectivity of CDK inhibitors is another challenge.

The compound of formula I is a targeted CDK4/6 inhibition The agent selectively inhibits cyclin-dependent kinases 4 and 6 (CDK4/6), restores cell cycle control, and blocks tumor cell proliferation. Its effect on MDA-MB-435 breast cancer cells can effectively reduce the phosphorylation of Rb at Ser780 and Ser795, IC50 is 66nM and 63nM, respectively.

The solubility of the compound of formula I in water is about 9 μg/ml, insoluble or almost insoluble, which directly affects the absorption and bioavailability of the compound in vivo. The solubilization method of the insoluble drug mainly includes: 1 micronization technology; 2 salt formation ester; 3 solid dispersion, inclusion compound and other solubilization techniques.

An object of the present invention is to solve the problem of solubilization of an active ingredient of the composition of the present invention as a poorly soluble drug, and to provide a pharmaceutical composition capable of improving bioavailability in vivo.

The technical solution of the present invention is achieved by a pharmaceutical composition comprising a solid dispersion prepared by the compound of the formula I, a disintegrating agent, a diluent, a binder, a lubricant, a glidant, wherein each component The weight is as follows:

Optionally, the pharmaceutical composition may further comprise a flavoring agent, a coloring agent or a coating material. Preferably, the sum of the weight percentages of the above components is 100%.

Preferably, the weight of each component is as follows:

Optionally, the pharmaceutical composition may further comprise a flavoring agent, a coloring agent or a coating material. Preferably, the sum of the weight percentages of the above components is 100%.

Preferably, the solid dispersion comprises a compound of formula I, a carrier material comprising polyethylene glycol, poloxamer, polyvinylpyrrolidone, stearic acid, shellac, glycerin gelatin, glyceryl monostearate. Or several, preferably, the weight ratio of the compound of the formula I to the carrier material is from 1:1 to 1:6, more preferably, the weight ratio of the compound of the formula I to the carrier material is 1:1~1:4.

Preferably, the diluent is selected from at least one of a sugar, a sugar alcohol, a starch and a cellulose. More preferably, the diluent is at least one selected from the group consisting of lactose, microcrystalline cellulose and starch, and the amount thereof is 15~ 50%.

Preferably, the binder is at least one of a cellulose derivative and a povidone. More preferably, the binder is at least one selected from the group consisting of hydroxypropyl cellulose and povidone, and the amount thereof is 2-10. %.

Preferably, the disintegrant is at least one of a cellulose derivative and a starch derivative. More preferably, the disintegrant is selected from the group consisting of crospovidone, sodium carboxymethyl starch, and croscarmellose fiber. At least one of the sodium salts is used in an amount of from 1 to 15%.

Preferably, the lubricant is a stearate. More preferably, the lubricant is magnesium stearate in an amount of from 0.1 to 2.5%.

Preferably, the glidant is at least one of micronized rubber and cerium oxide, and the amount thereof is 1 to 5%.

The solid dispersion is prepared by a hot melt extrusion granulator hot melt granulation, a spray type solid dispersion preparation machine or a boiling granulation dryer, wherein the pharmaceutical dosage form is a tablet or a capsule.

Preferably, the solid dispersion is prepared as follows: (1) uniformly mixing the compound of the formula I and the support material; (2) hot-melt granulation by a hot melt extrusion granulator, a spray-type solid dispersion preparation machine Or the boiling granulation dryer prepares the mixture obtained in the step (1) into a solid dispersion.

Another object of the present invention is to provide a preparation of the A method for medicinating a pharmaceutical composition by wet granulation, the method is as follows: (1) mixing the solid dispersion obtained in the step (2) of claim 13 of the patent application with a diluent and a disintegrating agent, Adding binder granulation, drying at 45 ° C for 1 h; (2) drying sieving step (1) dry granules as needed; (3) mixing step (2) drying granules, glidant and lubrication in a mixer To obtain a final mixture; (4) optionally, by filling a mixture of the above step (3) with a suitable capsule filling machine, to prepare a capsule; (5) as needed, by using a suitable tableting machine The mixture of the above step (3) is pressed, and it is tableted to obtain a core; (6) The core of the step (5) is film-coated with a film coating as needed.

Another object of the present invention is to provide an alternative method of preparing the pharmaceutical composition which is granulated by dry process as follows: (1) Application in a suitable roller press a solid dispersion, a diluent, a disintegrant and a binder obtained in the step (2) of the scope of claim 13; (2) crushing the ribbon obtained during the step (1) by a suitable grinding or sieving step Granules; (3) mixing step (2), lubricant and glidant in a mixer to obtain a final mixture, if necessary; (4) filling the above steps as needed by a suitable capsule filling machine a mixture of (3), preparing a capsule; (5) if necessary, pressing the mixture of the above step (3) on a suitable tableting machine, and compressing the tablet to obtain a core; (6) If desired, the core of step (5) is film coated with a film coating.

Another object of the present invention is to provide an alternative method of preparing the pharmaceutical composition which is prepared by direct mixing, and the steps are as follows: (1) mixing application in a hopper mixer a solid dispersion, a binder, a diluent, a disintegrant, a lubricant and a glidant obtained in the step (2) of the scope of claim 13 of the patent, to obtain a mixture; (2) if necessary, by a suitable capsule filling machine Preparing a capsule by the mixture of the above step (1); (3) if necessary, pressing the mixture of the above step (1) on a suitable tableting machine, and compressing the tablet to obtain a core; 4) Film coating of the core of step (3) is carried out by film coating as needed.

Another object of the present invention is to provide an additional pharmaceutical composition comprising a cyclodextrin inclusion compound prepared from a compound of formula I.

Preferably, the preparation method of the inclusion compound is selected from one of spray drying and freeze drying.

The present invention provides a solid dispersion, inclusion complex technique and a preparation method thereof for a compound of the formula I. A large number of studies have shown that the solid dispersion and the inclusion complex prepared by the present invention can significantly increase the solubility of the compound. Improve bioavailability in the body.

After conducting a large number of experiments, the inventors found that the hot-melt extrusion granulator hot-melt granulation, spray-type solid dispersion preparation machine or boiling granulation dryer made the active ingredient and the carrier material into a solid dispersion containing the active ingredient. After that, it can significantly increase the solubility of the drug, increase the absorption of the drug and improve the bioavailability of the drug in vivo.

Embodiments of the present invention will be described in detail below with reference to specific embodiments. The following examples are merely illustrative of the invention and are not to be considered as limiting the scope of the invention.

Example 1

1.1 Preparation method

200 g of API and 200 g of PEG 4000 were added to a hot melt extruder for hot melt extrusion to obtain a solid dispersion which was pulverized through a 100 mesh sieve and used.

1000 tablets / tablet prescription: weigh 50g of the above solid dispersion, 50g of lactose, 15g of microcrystalline cellulose, 8g of hydroxypropylcellulose, 8g of sodium carboxymethyl starch, put into a wet granulator, stir for 20min, add 50% ethanol water Granulation, 50 ° C fluidized bed drying for 10 min, 1.0 mm sieve mesh, adding 4 g of cerium oxide and 1 g of magnesium stearate, medium controlled content, filling capsules or tableting.

1.2 Solubility

1.3 dissolution results

For the dissolution of the above capsules, refer to the Chinese Pharmacopoeia 2010 edition two appendix XC second method paddle method, the stirring speed is 75 rpm, the dissolution medium is 900 mL pH 4.5 buffer, and the sampling time point is 45 min.

Example 2

2.1 Preparation method

200 g of API and 200 g of PEG 4000 were added to a hot melt extruder for hot melt extrusion to obtain a solid dispersion which was pulverized through a 100 mesh sieve and used.

1000 tablets/grain prescription: Weigh 200 g of the above solid dispersion, 50 g of lactose, 25 g of microcrystalline cellulose, 4 g of hydroxypropylcellulose, and carboxyformate 4g of sodium powder, put into the wet granulator, stir for 20min, add 50% ethanol water to granulate, 50 °C fluidized bed drying for 10min, 1.0mm sieve mesh, add cerium dioxide 2g and magnesium stearate 1g, medium Control the content, fill the capsule or tablet.

2.2 dissolution results

For the dissolution of the above capsules, refer to the Chinese Pharmacopoeia 2010 edition two appendix XC second method paddle method, the stirring speed is 75 rpm, the dissolution medium is 900 mL pH 4.5 buffer, and the sampling time point is 45 min.

Example 3

3.1 Preparation method

200 g of API and 200 g of PEG 4000 were added to a hot melt extruder for hot melt extrusion to obtain a solid dispersion which was pulverized through a 100 mesh sieve and used.

1000 tablets/grain prescription: Weigh 50g of the above solid dispersion, 30g of microcrystalline cellulose, 20g of starch, 12g of povidone, 20g of crospovidone, put into a wet granulator, stir for 20min, add 50% ethanol water Granulation, 50 ° C fluidized bed drying for 10 min, 1.0 mm sieve mesh, adding 3 g of cerium oxide and 1 g of magnesium stearate, medium control content, filling capsules or tableting.

3.2 dissolution results

For the dissolution of the above capsules, refer to the Chinese Pharmacopoeia 2010 edition two appendix XC second method paddle method, the stirring speed is 75 rpm, the dissolution medium is 900 mL pH 4.5 buffer, and the sampling time point is 45 min.

Example 4

4.1 Preparation method

200 g of API and 200 g of PEG 4000 were added to a hot melt extruder for hot melt extrusion to obtain a solid dispersion which was pulverized through a 100 mesh sieve and used.

1000 tablets / tablet prescription: weigh 50g of the above solid dispersion, 20g of lactose, 30g of starch, 12g of povidone, 20g of crospovidone, put into a wet granulator, stir for 20min, add 50% ethanol water to granulate, The mixture was dried in a fluidized bed at 50 ° C for 10 min, and sieved into a 1.0 mm sieve. 3 g of cerium oxide and 1 g of magnesium stearate were added, and the content was controlled, and the capsule was filled or compressed.

4.2 dissolution results

For the dissolution of the above capsules, refer to the Chinese Pharmacopoeia 2010 edition two appendix XC second method paddle method, the stirring speed is 75 rpm, the dissolution medium is 900 mL pH 4.5 buffer, and the sampling time point is 45 min.

Example 5

5.1 Preparation method

100 g of API, 100 g of poloxamer was added to a hot melt extruder for hot melt extrusion to obtain a solid dispersion which was pulverized through a 100 mesh sieve and used.

1000 tablets / tablet prescription: weigh 50g of the above solid dispersion, 30g of lactose, 20g of microcrystalline cellulose, 12g of povidone, 20g of crospovidone, put into a wet granulator, stir for 20min, add 50% ethanol water Granulation, 50 ° C fluidized bed drying for 10 min, 1.0 mm sieve mesh, adding 3 g of cerium oxide and 1 g of magnesium stearate, medium control content, filling capsules or tableting.

5.2 Solubility

5.3 dissolution results

For the dissolution of the above capsules, refer to the Chinese Pharmacopoeia 2010 edition two appendix XC second method paddle method, the stirring speed is 75 rpm, the dissolution medium is 900 mL pH 4.5 buffer, and the sampling time point is 45 min.

Example 6

6.1 Preparation method

50 g of API, 100 g of poloxamer was added to a hot melt extruder for hot melt extrusion to obtain a solid dispersion which was pulverized through a 100 mesh sieve and used.

1000 tablets/grain prescription: Weigh 75g of the above solid dispersion, 30g of lactose, 20g of microcrystalline cellulose, 12g of povidone, 20g of crospovidone, put into a wet granulator, stir for 20min, add 50% ethanol water Granulation, 50 ° C fluidized bed drying for 10 min, 1.0 mm sieve mesh, adding 3 g of cerium oxide and 1 g of magnesium stearate, medium control content, filling capsules or tableting.

6.2 Solubility

6.3 dissolution results

For the dissolution of the above capsules, refer to the Chinese Pharmacopoeia 2010 edition two appendix XC second method paddle method, the stirring speed is 75 rpm, the dissolution medium is 900 mL pH 4.5 buffer, and the sampling time point is 45 min.

Example 7

7.1 Preparation method

50 g of API, 200 g of poloxamer was added to a hot melt extruder for hot melt extrusion to obtain a solid dispersion which was pulverized through a 100 mesh sieve and used.

1000 tablets/grain prescription: Weigh 125g of the above solid dispersion, 30g of lactose, 20g of microcrystalline cellulose, 12g of povidone, 20g of crospovidone, put into a wet granulator, stir for 20min, add 50% ethanol water Granulation, 50 ° C fluidized bed drying for 10 min, 1.0 mm sieve mesh, adding 3 g of cerium oxide and 1 g of magnesium stearate, medium control content, filling capsules or tableting.

7.2 Solubility

7.3 dissolution results

For the dissolution of the above capsules, refer to the Chinese Pharmacopoeia 2010 edition two appendix XC second method paddle method, the stirring speed is 75 rpm, the dissolution medium is 900 mL pH 4.5 buffer, and the sampling time point is 45 min.

Example 8

8.1 Preparation method

50 g of API, 100 g of Kollidon VA 64 was added to a hot melt extruder for hot melt extrusion to obtain a solid dispersion which was pulverized through a 100 mesh sieve and used.

1000 tablets/grain prescription: Weigh 75 g of the above solid dispersion, 30 g of lactose, 20 g of microcrystalline cellulose, 12 g of hydroxypropylcellulose, 20 g of crospovidone, compact the above mixture, crush into granules, and add cerium oxide 2.5. g And 1 g of magnesium stearate, medium controlled content, filled capsules or compressed tablets.

8.2 Solubility

8.3 dissolution results

For the dissolution of the above capsules, refer to the Chinese Pharmacopoeia 2010 edition two appendix XC second method paddle method, the stirring speed is 75 rpm, the dissolution medium is 900 mL pH 4.5 buffer, and the sampling time point is 45 min.

Example 9

9.1 Preparation method

50 g of API and 150 g of povidone were dissolved in a methanol/dichloromethane mixed solvent, and spray-dried to obtain a solid dispersion which was pulverized through a 100 mesh sieve and used.

1000 tablets/grain prescription: 100 g of the above solid dispersion, 30 g of lactose, 30 g of microcrystalline cellulose, and 10 g of croscarmellose sodium were weighed, the above mixture was compacted, granulated, and 1.5 g of magnesium stearate was added. Medium control content, filling capsules or tableting.

9.2 Solubility

9.3 Dissolution results

For the dissolution of the above capsules, refer to the Chinese Pharmacopoeia 2010 edition two appendix XC second method paddle method, the stirring speed is 75 rpm, the dissolution medium is 900 mL pH 4.5 buffer, and the sampling time point is 45 min.

Example 10

10.1 Preparation method

50 g of API and 100 g of povidone were dissolved in a methanol/dichloromethane mixed solvent, and spray-dried to obtain a solid dispersion which was pulverized through a 100 mesh sieve and used.

1000 tablets/grain prescription: Weigh 75g of the above solid dispersion, 30g of lactose, 20g of microcrystalline cellulose, 3g of hydroxypropylcellulose, 6g of croscarmellose sodium, compact the mixture, crush into granules, add hard Magnesium oleate 1.0g, medium controlled content, filled capsules or compressed tablets.

10.2 Solubility

10.3 Dissolution results

For the dissolution of the above capsules, refer to the Chinese Pharmacopoeia 2010 edition two appendix XC second method paddle method, the stirring speed is 75 rpm, the dissolution medium is 900 mL pH 4.5 buffer, and the sampling time point is 45 min.

Example 11

11.1 Preparation method

50 g of API and 50 g of povidone were dissolved in a methanol/dichloromethane mixed solvent, and spray-dried to obtain a solid dispersion which was pulverized through a 100 mesh sieve and used.

1000 tablets/grain prescription: Weigh 50g of the above solid dispersion, 30g of lactose, 20g of microcrystalline cellulose, 6g of hydroxypropylcellulose, 10g of croscarmellose sodium, put into a wet granulator, stir for 20min, add 50% ethanol water granulation, 50 ° C fluidized bed drying for 10 min, 1.0 mm mesh granules, adding 2 g of cerium oxide and 1 g of magnesium stearate, medium controlled content, filling capsules or tableting.

11.2 Solubility

11.3 Dissolution results

For the dissolution of the above capsules, refer to the Chinese Pharmacopoeia 2010 edition two appendix XC second method paddle method, the stirring speed is 75 rpm, the dissolution medium is 900 mL pH 4.5 buffer, and the sampling time point is 45 min.

Example 12

12.1 Preparation method

50 g of API and 50 g of povidone were dissolved in a methanol/dichloromethane mixed solvent, and spray-dried to obtain a solid dispersion which was pulverized through a 100 mesh sieve and used.

1000 tablets/grain prescription: Weigh 50g of the above solid dispersion, 50g of lactose, 50g of microcrystalline cellulose, 10g of hydroxypropylcellulose, 20g of crospovidone, 2g of cerium oxide and 1g of magnesium stearate. Content, filling capsules or tableting.

12.2 Solubility

12.3 Dissolution results

For the dissolution of the above capsules, refer to the Chinese Pharmacopoeia 2010 edition two appendix XC second method paddle method, the stirring speed is 75 rpm, the dissolution medium is 900 mL pH 4.5 buffer, and the sampling time point is 45 min.

Example 13

13.1 Preparation method

100 g of microcrystalline cellulose PH200 was put into a boiling pellet dryer to preheat, 50 g of API and 150 g of povidone were dissolved in a methanol/methylene chloride mixed solvent, and sprayed into a boiling pellet dryer, after the solution was sprayed. Dry to a solid dispersion for use.

1000 tablets/grain prescription: Weigh 100g of the above solid dispersion, 50g of lactose, 30g of microcrystalline cellulose, 10g of hydroxypropylcellulose, 10g of crospovidone, 2g of cerium oxide and 1g of magnesium stearate. Content, filling capsules or tableting.

13.2 Solubility

13.3 Dissolution results

For the dissolution of the above capsules, refer to the Chinese Pharmacopoeia 2010 edition two appendix XC second method paddle method, the stirring speed is 75 rpm, the dissolution medium is 900 mL pH 4.5 buffer, and the sampling time point is 45 min.

Example 14

14.1 Preparation method

100 g of microcrystalline cellulose PH200 was put into a boiling pellet dryer to preheat, 50 g of API and 150 g of povidone were dissolved in a methanol/methylene chloride mixed solvent, and sprayed into a boiling pellet dryer, after the solution was sprayed. Dry to a solid dispersion for use.

1000 tablets / tablet prescription: weigh the above solid dispersion 100g, 20g of lactose, 10g of microcrystalline cellulose, 10g of hydroxypropylcellulose, 5g of sodium carboxymethyl starch, put into a wet granulator, stirred for 20min, granulated with 50% ethanol water, and dried in a fluidized bed at 50 °C for 10 min, 1.0 Mm sieve whole grain, add 2g of cerium oxide and 1g of magnesium stearate, medium-controlled content, filling capsule or tableting.

14.2 Solubility

14.3 Dissolution results

For the dissolution of the above capsules, refer to the Chinese Pharmacopoeia 2010 edition two appendix XC second method paddle method, the stirring speed is 75 rpm, the dissolution medium is 900 mL pH 4.5 buffer, and the sampling time point is 45 min.

Example 15

15.1 Preparation method

100 g of microcrystalline cellulose PH200 was put into a boiling pellet dryer to preheat, 50 g of API and 150 g of povidone were dissolved in a methanol/methylene chloride mixed solvent, and sprayed into a boiling pellet dryer, after the solution was sprayed. Dry to a solid dispersion for use.

1000 tablets/grain prescription: 100 g of the above solid dispersion, 20 g of lactose, 10 g of microcrystalline cellulose, 10 g of hydroxypropylcellulose, and 5 g of sodium carboxymethyl starch were weighed, and the mixture was compacted, granulated, and magnesium stearate 1.0 was added. g, medium control content, filling capsule or tableting.

15.2 Solubility

15.3 dissolution results

For the dissolution of the above capsules, refer to the Chinese Pharmacopoeia 2010 edition two appendix XC second method paddle method, the stirring speed is 75 rpm, the dissolution medium is 900 mL pH 4.5 buffer, and the sampling time point is 45 min.

Example 16

50 g of API and 50 g of β-cyclodextrin were dissolved in a methanol/dichloromethane mixed solvent, and spray-dried to obtain an inclusion compound, which was pulverized through a 100 mesh sieve and used.

1000 tablets/grain prescription: weigh 50g of the above inclusion compound, 50g of lactose, 50g of microcrystalline cellulose, 8g of hydroxypropylcellulose, 15g of crospovidone, 2g of cerium oxide and 1g of magnesium stearate. Content, filling capsules or tableting.

16.2 Solubility

16.3 Dissolution results

For the dissolution of the above capsules, refer to the Chinese Pharmacopoeia 2010 edition two appendix XC second method paddle method, the stirring speed is 75 rpm, the dissolution medium is 900 mL pH 4.5 buffer, and the sampling time point is 45 min.

Example 17

50 g of API, 20 g of β-cyclodextrin, and 30 g of mannitol were dissolved in a methanol/dichloromethane mixed solvent, and freeze-dried to obtain an inclusion compound, which was pulverized through a 100 mesh sieve and used.

1000 tablets / tablet prescription: Weigh 50g of the above inclusion compound, 30g of lactose, 20g of microcrystalline cellulose, 8g of hydroxypropylcellulose, 15g of croscarmellose sodium, put into a wet granulator, stir for 20min, add 50% ethanol water granulation, 50 ° C fluidized bed drying for 10 min, 1.0 mm mesh granules, adding 2 g of cerium oxide and 1 g of magnesium stearate, medium-controlled content, filling capsules or tableting.

17.2 Solubility

17.3 Dissolution results

For the dissolution of the above capsules, refer to the Chinese Pharmacopoeia 2010 edition two appendix XC second method paddle method, the stirring speed is 75 rpm, the dissolution medium is 900 mL pH 4.5 buffer, and the sampling time point is 45 min.

Claims (18)

A pharmaceutical composition comprising a solid dispersion, a disintegrant, a diluent, a binder, a glidant or a lubricant prepared from a compound of formula I: The pharmaceutical composition according to claim 1, which comprises a solid dispersion, a disintegrant, a diluent, a binder, a lubricant or a glidant prepared by the compound of the formula I, and the weight of each component is as follows: The pharmaceutical composition according to claim 1, which comprises a solid dispersion, a disintegrant, a diluent, a binder, a lubricant or a glidant prepared by the compound of the formula I, wherein the weight of each component is as follows : The pharmaceutical composition according to claim 1, wherein the solid dispersion comprises a compound of formula I and a carrier material selected from the group consisting of polyethylene glycol, poloxamer, polyvinylpyrrolidone, and stearic acid. Or one or more of shellac, glycerin gelatin or glyceryl monostearate; the weight ratio of the compound of formula I to the carrier material is from 1:1 to 1:6. The pharmaceutical composition according to claim 4, wherein the weight ratio of the compound of the formula I to the carrier material is from 1:1 to 1:4. The pharmaceutical composition according to claim 1, wherein the diluent is at least one selected from the group consisting of sugars, sugar alcohols, starches, and celluloses. The pharmaceutical composition according to claim 1, wherein the binder is at least one selected from the group consisting of a cellulose derivative and a povidone. The pharmaceutical composition according to claim 1, wherein the disintegrating agent is at least one selected from the group consisting of a cellulose derivative and a starch derivative. The pharmaceutical composition according to claim 1, wherein the lubricant is a stearate. The pharmaceutical composition according to claim 1, wherein the glidant is at least one selected from the group consisting of micronized rubber and cerium oxide. The pharmaceutical composition according to any one of claims 1 to 10, wherein the pharmaceutical composition is tablet or capsule. The pharmaceutical composition according to any one of claims 1 to 10, wherein the solid dispersion is prepared by a hot melt extrusion granulator, a spray type solid dispersion preparation machine or a boiling granulation dryer Made of. The pharmaceutical composition according to claim 12, wherein the solid dispersion is prepared by: 1) uniformly mixing the compound of the formula I and the carrier material; 2) hot melting by a hot melt extrusion granulator The granulated, spray-type solid dispersion preparation machine or boiling granulation dryer prepares the mixture obtained in the step 1) into a solid dispersion. A method of preparing a pharmaceutical composition according to any one of claims 1 to 10, wherein the pharmaceutical composition is granulated by a wet method, and the method is as follows: 1) Step 2 of item 13)) The obtained solid dispersion is uniformly mixed with a diluent and a disintegrating agent, and granulated with a binder, and dried at 45 ° C for 1 hour; 2) as needed, dry sieving step 1) dried granules; 3) Mixing step 2) the dried granules, glidant and lubricant to obtain the final mixture; 4) filling the mixture of the above step 3) by a suitable capsule filling machine as needed to prepare a capsule; 5) If necessary, the mixture of the above step 3) is pressed on a suitable tablet press and tableted to obtain a core; 6) optionally, the core of step 5) is coated with a film. thin Film coating. A method of preparing a pharmaceutical composition according to any one of claims 1 to 10, wherein the pharmaceutical composition is granulated by a dry process, as follows: 1) Pressing at a suitable roller In-machine compaction of the solid dispersion, diluent, disintegrant and binder obtained in step 2) of claim 13; 2) the ribbon obtained during step 1) by a suitable grinding or sieving step The material is broken into granules; 3) if necessary, mixing step 2), lubricant and glidant in the mixer to obtain the final mixture; 4) filling the above step 3) with a suitable capsule filling machine as needed a mixture of the preparation of the capsule; 5) if necessary, by pressing the mixture of the above step 3) on a suitable tableting machine, and compressing the tablet to obtain a core; 6) if necessary, using a film package The core of step 5) is film coated. A method of preparing a pharmaceutical composition according to any one of claims 1 to 10, wherein the pharmaceutical composition is obtained by a direct mixing method, and the steps are as follows: 1) in a hopper Mixing the solid dispersion, binder, diluent, disintegrant, lubricant and glidant obtained in step 2) of the scope of claim 13 in the mixer to obtain a mixture; 2) if necessary, by suitable capsules Filling machine filling the above steps a mixture of the first step 1) to prepare a capsule; 3) if necessary, by compressing the mixture of the above step 1) on a suitable tableting machine, and compressing the tablet to obtain a core; 4) as needed, The core of step 3) was film coated with a film coating. A pharmaceutical composition comprising a cyclodextrin inclusion compound prepared from a compound of formula I. The pharmaceutical composition according to claim 17, wherein the preparation method of the cyclodextrin inclusion compound is one selected from the group consisting of spray drying and freeze drying.