A Composition Comprising Heterocyclic Compounds, Preparation Method and Application Thereof

Abstract

Provided herein is a solid dispersion, which comprises a carrier and an active ingredient. The active ingredient is one or more of the compound shown in formula (I) (APG-115), its pharmaceutically acceptable salt, its crystal form and its hydrate. The solid dispersion can improve the dissolution of the active ingredient APG-115. The dissolution of APG-115 of some solid dispersions can reach more than 90%, and has good stability. It can improve the dissolution and dissolution of drugs in gastrointestinal fluid, so as to improve the oral bioavailability. The solid dispersion shows high plasma exposure in animals, that is, higher drug peak concentration and higher area under blood concentration curve.

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Claims

1. A solid dispersion comprising a carrier and an active ingredient of formula (I), or a pharmaceutically acceptable salt, crystal form, or hydrate thereof; ##STR00004##

2. The solid dispersion according to claim 1, wherein the carrier is selected from one or more of homopolymer and copolymer cellulose ester of N-vinyl lactam, pH dependent cellulose derivative, non-ionic water-soluble cellulose ether, cellulose ether, high molecular weight polycyclic oxide, N-vinyl amide polymer, polyacrylate, polymethacrylate, polyacrylamide, vinyl acetate polymer, polyethylene glycol, polyvinyl caprolactam/polyvinyl acetate graft copolymer, oligosaccharide and polysaccharide, and can also be one or more of povidone, covidone, hypromellose acetate succinate, polyethylene glycol/polyvinyl caprolactam/polyvinyl acetate graft copolymer, and can also be one or more of hypromellose acetate succinate, hydroxypropyl cellulose, povidone and acrylic resin; wherein the pharmaceutically acceptable salt is selected from hydrochloride, hydrobromate, hydroiodate, sulfate, bisulfate, 2-hydroxyethanesulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, lysine, arginine, histidine, aspartate, benzoate, bisulfate, butyrate, camphorate, camphor sulfonate, diglucosate, glycerophosphate, hemisulfate, heptanate, caproate, formate, succinate, fumarate, maleate, ascorbate, hydroxyethyl sulfonate, salicylate, methanesulfonate, mesitylene sulfonate, naphthalene sulfonate, nicotinic acid, 2-naphthalene sulfonate, oxalate, dihydroxynaphthalate, pectinate, persulfate, 3-phenylpropionate, picrate, tervalerate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, ethyldisulfonate, benzene sulfonate, L-tartrate, maleate, sodium salt, potassium salt, Choline salt, aminobutanol salt, calcium salt or p-toluenesulfonate, or phosphate, sulfate, L-tartrate, hydrochloride, maleate, hydrobromate, methanesulfonate, lysine salt, arginine salt, histidine salt, sodium salt, potassium salt, choline salt, aminobutanol salt and calcium salt; wherein the hydrate is selected from hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, nonahydrate, decahydrate, undecahydrate and dodecahydrate; wherein the solid dispersion further comprises an optional antisticking agent selected from one or more of colloidal silica, talc powder, starch, D-leucine, L-leucine, sodium lauryl sulfate and metal stearate; wherein the mass ratio of the antisticking agent to the active ingredient is 0.05:1˜0.08:1.

3. The solid dispersion according to claim 2, wherein, by mass of 1 part of the active ingredient, the solid dispersion comprises 1 part of the active ingredient and 1.2˜8 parts of the carrier; or, by mass of 1 part of the active ingredient, the solid dispersion comprises 1 part of the active ingredient and 2˜4 parts of the carrier, or, by mass of 1 part of the active ingredient, the solid dispersion comprises 1 part of the active ingredient and 1.2˜8 parts of hypromellose acetate succinate; or, by mass of 1 part of the active ingredient, the solid dispersion comprises 1 part of the active ingredient and 2˜4 parts of hypromellose acetate succinate; or, by mass of 1 part of the active ingredient, the solid dispersion comprises 1 part of the active ingredient and 2 parts of hypromellose acetate succinate; or, by mass of 1 part of the active ingredient, the solid dispersion may include 1 part of the active ingredient and 1.2˜8 parts of hydroxypropyl cellulose; or, by mass of 1 part of the active ingredient, the solid dispersion may include 1 part of the active ingredient and 2˜4 parts of hydroxypropyl cellulose; or, by mass of 1 part of the active ingredient, the solid dispersion comprises 1 part of the active ingredient and 2 parts of hydroxypropyl cellulose; or, by mass of 1 part of the active ingredient, the solid dispersion may include 1 part of the active ingredient and 1.2˜8 parts of povidone; or, by mass of 1 part of the active ingredient, the solid dispersion may include 1 part of the active ingredient and 2˜4 parts of povidone; or, by mass of 1 part of the active ingredient, the solid dispersion comprises 1 part of the active ingredient and 2 parts of povidone; or, by mass of 1 part of the active ingredient, the solid dispersion may include 1 part of the active ingredient and 1.2˜8 parts of acrylic resin; or, by mass of 1 part of the active ingredient, the solid dispersion may include 1 part of the active ingredient and 2˜4 parts of acrylic resin; or, by mass of 1 part of the active ingredient, the solid dispersion comprises 1 part of the active ingredient and 2 parts of acrylic resin; or, by mass of 1 part of the active ingredient, the solid dispersion comprises 1 part of the active ingredient, 1.2˜8 parts of the carrier and 0.05˜0.08 parts of the antisticking agent; or, by mass of 1 part of the active ingredient, the solid dispersion comprises 1 part of the active ingredient, 2˜8 parts of hypromellose acetate succinate and 0.05˜0.08 parts of colloidal silica; or, by mass of 1 part of the active ingredient, the solid dispersion comprises 1 part of the active ingredient, 2˜4 parts of hypromellose acetate succinate and 0.06˜0.07 parts of colloidal silica; or, by mass of 1 part of the active ingredient, the solid dispersion includes 1 part of the active ingredient, 2 parts of hypromellose acetate succinate and 0.064 parts of colloidal silica.

4. A method for preparing solid dispersion of claim 1, which comprises the following steps: 1) mixing one or more carrier and the active ingredient with a solvent to obtain a mixed liquid, 2) drying the mixed liquid; and 3) optionally, mixing the mixture with the antisticking agent before drying.

5. The method for preparing the solid dispersion according to claim 4, wherein, The mass volume ratio of the active ingredient to the solvent is 5:1˜30:1 mg/ml, or 15:1˜25:1 mg/ml; wherein the solvent is one or more of alcohol solvent, water, ester solvent, ketone solvent, halogenated hydrocarbon solvent, nitrile solvent and ether solvent, which can be ester solvent, ether solvent or ester solvent; wherein the alcohol solvent can be ethanol; the ester solvent can be methyl acetate; the ether solvent can be tetrahydrofuran; the ketone solvent can be acetone; the halogenated hydrocarbon solvent can be dichloromethane; the nitrile solvent can be acetonitrile; wherein the drying includes a first drying and a second drying; wherein the first drying can be spray drying or fluidized bed boiling drying; the second drying can be vacuum decompression drying or electric blast drying.

6. A pharmaceutical composition comprising a solid dispersion according to claim 2 and excipients.

7. The pharmaceutical composition according to claim 6, wherein, the excipient comprises one or more of an absorption enhancer, an antioxidant, a dry antisticking agent, a buffer, a coating material, a coating material, a diluent, a disintegrating agent, an emulsifier, a flavor agent, a humectant, a lubricant, an antisticking agent, a glidant, a preservative, a solubilizer, a corrective and a releasing agent; wherein the diluent may include one or more of cellulose, lactose, lactose alcohol, maltitol, mannitol, sorbitol, xylitol, glucose, fructose, sucrose and sucrose based diluent, maltose, inositol, hydrolyzed grain solid, starch, starch component, dextrin, calcium salt, magnesium salt, bentonite, kaolin and sodium chloride; wherein the diluent can be one or more of microcrystalline cellulose, silicified microcrystalline cellulose, calcium phosphate, pregelatinized starch, lactose, mannitol and anhydrous calcium hydrogen phosphate, or one or more of microcrystalline cellulose, silicified microcrystalline cellulose, pregelatinized starch, calcium phosphate and anhydrous calcium hydrogen phosphate, or one or more of microcrystalline cellulose, pregelatinized starch and calcium phosphate, or a mixture of microcrystalline cellulose and anhydrous calcium hydrogen phosphate; wherein the microcrystalline cellulose can be PH 102 and/or KG 802; when the diluent is a mixture of microcrystalline cellulose and anhydrous calcium hydrogen phosphate, the mass ratio of microcrystalline cellulose to anhydrous calcium hydrogen phosphate can be 0.1:1˜10:1, or 0.5:1˜2:1; wherein the disintegrating agent may include one or more of starch, clay, magnesium aluminum silicate, cellulose based disintegrating agent, alginate, povidone, crospovidone, polacrine potassium, gum and colloidal silica; The disintegrating agent can be croscarmellose sodium and/or crospovidone; wherein the lubricant may include one or more of glyceryl behenate, stearic acid and its salts, hydrogenated vegetable oil, glyceryl palmitate, talc powder, wax, sodium benzoate, sodium acetate, sodium fumarate, sodium stearate fumarate, PEG, poloxamer, polyvinyl alcohol, sodium oleate, sodium lauryl sulfate and magnesium lauryl sulfate; wherein lubricant can be magnesium stearate.

8. The pharmaceutical composition of claim 7 wherein the pharmaceutical composition optionally includes an antisticking agent and a glidant; wherein the pharmaceutical composition optionally further comprise a dry antisticking agent; wherein the mass ratio of the diluent to the solid dispersion can be 0.2:1˜8:1, 0.5:1˜8:1, 0.8:1˜2:1 or 0.5:1˜1:1; The wherein the mass ratio of the disintegrating agent to the solid dispersion can be 0.03:1˜0.3:1, 0.1:1˜0.2:1, 0.05:1˜0.2:1 or 0.05:1˜0.15:1; wherein the mass ratio of the lubricant to the solid dispersion can be 0.005:1˜0.2:1, 0.01:1˜0.2:1, 0.02:1˜0.04:1 or 0.01:1˜0.02:1; wherein the antisticking agent may include one or more of talc powder, colloidal silica, starch, D-leucine, L-leucine, sodium lauryl sulfate and metal stearate; wherein the antisticking agent can be colloidal silica; wherein the glidant may include one or more of colloidal silica, starch, powdered cellulose, sodium lauryl sulfate, magnesium trisilicate and metal stearate; wherein the glidant can be colloidal silica; wherein the mass ratio of the total mass of the antisticking agent and the glidant to the mass of the solid dispersion can be 0.02:1˜0.3:1, 0.05:1˜0.1:1 or 0.1:1˜0.2:1; wherein the dry antisticking agent may include one or more of gum Arabic, tragacanth gum, glucose, polyglucose, starch, gelatin, modified cellulose, dextrin, zein, alginic acid and alginate, magnesium aluminum silicate, bentonite, polyethylene glycol, polyethylene oxide, guar gum, polysaccharide acid, polyvinylpyrrolidone, polyacrylic acid, polymethacrylate, etc.; wherein the dry antisticking agent can be hydroxypropyl cellulose; wherein the mass ratio of the dry antisticking agent to the solid dispersion is 0.02:1˜0.5:1, which can be 0.1:1˜0.3:1.

9. The pharmaceutical composition according to claim 7, wherein, by mass of 1 part of the solid dispersion, the pharmaceutical composition comprises 1 part of the solid dispersion, 0.2˜8 parts of the diluent, 0.03˜0.3 parts of the disintegrating agent and 0.005˜0.2 parts of the lubricant; or, by mass of 1 part of the solid dispersion, the pharmaceutical composition comprises 1 part of solid dispersion, 0.2˜8 parts of diluent, 0.02˜0.3 parts of the antisticking agent and glidant, 0.03˜0.3 parts of disintegrating agent and 0.005˜0.2 parts of lubricant; or, by mass of 1 part of the solid dispersion, the pharmaceutical composition comprises 1 part of the solid dispersion, 0.2˜8 parts of the diluent, 0.02˜0.5 parts of the dry antisticking agent, 0.02˜0.3 parts of the antisticking agent and glidant, 0.03˜0.3 parts of the disintegrating agent and 0.005˜0.2 parts of the lubricant.

10. The pharmaceutical composition according to claim 7, wherein, by mass of 1 part of the solid dispersion, the pharmaceutical composition comprises 1 part of the solid dispersion, 0.5˜1 part of silicified microcrystalline cellulose, 0.1˜0.2 part of crospovidone and 0.01˜0.02 part of magnesium stearate; or, by mass of 1 part of the solid dispersion, the pharmaceutical composition comprises 1 part of the solid dispersion, 0.65˜0.85 parts of silicified microcrystalline cellulose, 0.13˜0.17 parts of crospovidone and 0.012˜0.016 parts of magnesium stearate; or, by mass of 1 part of the solid dispersion, the pharmaceutical composition comprises 1 part of the solid dispersion, 0.8˜2 parts of microcrystalline cellulose PH 102, 0.05˜0.2 parts of croscarmellose sodium, 0.05˜0.1 parts of colloidal silica and 0.02˜0.04 parts of magnesium stearate; or, by mass of 1 part of the solid dispersion, the pharmaceutical composition comprises 1 part of the solid dispersion, 1.26˜1.46 parts of microcrystalline cellulose PH 102, 0.11˜0.15 parts of croscarmellose sodium, 0.06˜0.1 parts of colloidal silica and 0.02˜0.04 parts of magnesium stearate; or, by mass of 1 part of the solid dispersion, the pharmaceutical composition comprises 1 part of the solid dispersion, 0.53˜1.32 parts of microcrystalline cellulose PH 102, 0.27˜0.68 parts of pregelatinized starch, 0.05˜0.2 parts of croscarmellose sodium, 0.05˜0.1 parts of colloidal silica and 0.02˜0.04 parts of magnesium stearate; or, by mass of 1 part of the solid dispersion, the pharmaceutical composition comprises 1 part of the solid dispersion, 0.81˜1.01 part of microcrystalline cellulose PH 102, 0.35˜0.55 part of pregelatinized starch, 0.11˜0.15 part of croscarmellose sodium, 0.06˜0.1 part of colloidal silica and 0.02˜0.04 part of magnesium stearate; or, by mass of 1 part of the solid dispersion, the pharmaceutical composition comprises 1 part of the solid dispersion, 0.4˜1 part of microcrystalline cellulose PH 102, 0.4˜1 part of calcium phosphate, 0.05˜0.2 part of croscarmellose sodium, 0.05˜0.1 part of colloidal silica and 0.02˜0.04 part of magnesium stearate; or, by mass of 1 part of the solid dispersion, the pharmaceutical composition comprises 1 part of the solid dispersion, 0.58˜0.78 part of microcrystalline cellulose PH 102, 0.58˜0.78 part of calcium phosphate, 0.11˜0.15 part of croscarmellose sodium, 0.07˜0.09 part of colloidal silica and 0.02˜0.04 part of magnesium stearate; or, by mass of 1 part of the solid dispersion, the pharmaceutical composition comprises 1 part of the solid dispersion, 0.4˜1 part of microcrystalline cellulose KG 802, 0.4˜1 part of anhydrous calcium phosphate, 0.05˜0.2 part of croscarmellose sodium, 0.05˜0.1 part of colloidal silica and 0.02˜0.04 part of magnesium stearate; or, by mass of 1 part of the solid dispersion, the pharmaceutical composition comprises 1 part of the solid dispersion, 0.61˜0.81 parts of microcrystalline cellulose KG 802, 0.61˜0.81 parts of anhydrous calcium phosphate, 0.068˜0.088 parts of croscarmellose sodium, 0.05˜0.054 parts of colloidal silicon dioxide and 0.03˜0.04 parts of magnesium stearate; or, by mass of 1 part of the solid dispersion, the pharmaceutical composition comprises 1 part of the solid dispersion, 0.25˜4 parts of microcrystalline cellulose KG 802, 0.25˜4 parts of calcium phosphate, 0.03˜0.3 parts of croscarmellose sodium, 0.02˜0.5 parts of hydroxypropyl cellulose, 0.02˜0.3 parts of colloidal silica and 0.02˜0.3 parts of magnesium stearate; or, by mass of 1 part of the solid dispersion, the pharmaceutical composition comprises 1 part of the solid dispersion, 0.5˜0.7 parts of microcrystalline cellulose KG 802, 0.5˜0.7 parts of calcium phosphate, 0.11˜0.15 parts of croscarmellose sodium, 0.14˜0.18 parts of hydroxypropyl cellulose, 0.04˜0.08 parts of colloidal silica and 0.02˜0.04 parts of magnesium stearate; or, by mass of 1 part of the solid dispersion, the pharmaceutical composition comprises 1 part of the solid dispersion, 0.25˜4 parts of microcrystalline cellulose KG 802, 0.25˜4 parts of anhydrous calcium phosphate, 0.03˜0.3 parts of croscarmellose sodium, 0.02˜0.5 parts of hydroxypropyl cellulose, 0.02˜0.3 parts of colloidal silica and 0.02˜0.3 parts of magnesium stearate; or, by mass of 1 part of the solid dispersion, the pharmaceutical composition comprises 1 part of the solid dispersion, 0.55˜0.75 parts of microcrystalline cellulose KG 802, 0.55˜0.75 parts of anhydrous calcium phosphate, 0.07˜0.15 parts of croscarmellose sodium, 0.07˜0.18 parts of hydroxypropyl cellulose, 0.04˜0.15 parts of colloidal silica and 0.02˜0.06 pans of magnesium stearate.

11. The pharmaceutical preparation comprising the pharmaceutical composition according to claim 7; wherein the pharmaceutical preparation can be a solid preparation or a powder, granule, tablet, capsule, dropping pill, or film.

12. A method for preparing tablets, comprising the following steps: Step 1: mixing a sold dispersion of claim 2, a diluent, and a disintegrating agent to obtain a mixture: sieving and granulating the mixture to obtain particles, optionally, an antisticking agent or a glidant is added to the mixture before sieving: optionally a lubricant is added after sieving before granulating; Step 2): mixing the particles of step 1 with the lubricant and pressing the particles to obtain a tablet; optionally, the particles of step 1 are mixed with the antisticking agent and glidant.

13. The preparation method of the tablet according to claim 12, wherein, when part of the antisticking agent and glidant is added in step 1, and the remaining part of the antisticking agent and glidant is added in step 2, the total amount of the antisticking agent and glidant is 100%, and the mass percentage of the antisticking agent and glidant in step 1 is 0.5%˜20%; wherein when part of the lubricant is added in step 1 and the remaining part of the lubricant is added in step 2, the total amount of the lubricant is 100%, and the mass percentage of the lubricant in step 1 is 0.1%-10%; where in step 1, the granulation is dry granulation.

14. A coated tablet comprising the pharmaceutical composition according to claim 7.

15. The coated tablet according to claim 14, wherein, the mass ratio of the pharmaceutical composition and the coating in the coated tablet is 0.02:1˜0.2:1, which can be 0.05:1˜0.1:1; wherein the coating in the coated tablet includes polyvinyl alcohol, titanium dioxide, talc powder, triethylglycerol and hydroxypropyl methyl cellulose, which can be a film coating premix.

16. A method for the treatment of diseases caused by P53 and/or MDM2 abnormalities, wherein diseases are cancer or hyperproliferative diseases.

17. The method according to claim 16, wherein cancer is adrenal cortical cancer, advanced cancer, anal cancer, aplastic anemia, cholangiocarcinoma, bladder cancer, bone cancer, bone metastasis, adult brain/CNS tumor, childhood brain/CNS tumor, breast cancer, male breast cancer, childhood cancer, unknown primary cancer, giant lymph node hyperplasia, cervical cancer, colorectal/rectal cancer, endometrial cancer, esophageal cancer, Ewing's tumor family, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor, gestational trophoblastic disease, Hodgkin's disease, Kaposi's sarcoma, renal cancer, laryngeal and hypopharyngeal cancer, adult acute lymphocytic leukemia, acute myeloid leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, chronic myelomonocytic leukemia, childhood leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, lung carcinoid tumor, skin lymphoma, malignant mesothelioma, multiple myeloma, myelodysplastic syndrome, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, non-Hodgkin's lymphoma, childhood non-Hodgkin's lymphoma, oral and oropharyngeal carcinoma, osteosarcoma, ovarian cancer, pancreatic cancer, penile cancer, pituitary adenocarcinoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma—adult soft tissue carcinoma, basal skin cancer and squamous cell carcinoma, skin cancer melanoma, small bowel cancer, gastric cancer, testicular cancer, thymic carcinoma, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom's macroglobulinemia, or Wilms tumor.

18. The method of claim 12, wherein the diluent is cellulose, lactose, lactose alcohol, maltitol, mannitol, sorbitol, xylitol, glucose, fructose, sucrose and sucrose based diluent, maltose, inositol, hydrolyzed grain solid, starch, starch component, dextrin, calcium salt, magnesium salt, bentonite, kaolin and sodium chloride, microcrystalline cellulose, silicified microcrystalline cellulose, calcium phosphate, pregelatinized starch, lactose, mannitol and anhydrous calcium hydrogen phosphate, calcium phosphate, or anhydrous calcium hydrogen phosphate, or a mixture of microcrystalline cellulose and anhydrous calcium hydrogen phosphate; and wherein the disintegrating is starch, clay, magnesium aluminum silicate, cellulose based disintegrating agent, alginate, povidone, crospovidone, polacrine potassium, gum, or colloidal silica.

19. The method of claim 12, wherein the antisticking agent is colloidal silica, talc powder, starch, D-leucine, L-leucine, sodium lauryl sulfate or metal stearate; and wherein the glidant is colloidal silica, starch, powdered cellulose, sodium lauryl sulfate, magnesium trisilicate or metal stearate.

20. The method of claim 19, wherein the microcrystalline cellulose is PH 102 or KG 802; wherein the disintegrating agent is croscarmellose sodium or crospovidone.

Description

DESCRIPTION OF DRAWINGS

[0166] FIG. 1 shows the curve of oral administration of APG-115ASD and APG-115 hydrate in dogs.

SPECIFIC EMBODIMENTS

[0167] The invention will be further described by way of embodiments, but the invention is not limited to the scope of the examples.

[0168] In the following examples, the preparation method of APG-115 hydrate can refer to CN106794171A, and other raw materials are commercially available.

[0169] DSC test method: place the test sample in a closed aluminum plate and raise the temperature to 300° C. at the rate of 10° C./min under nitrogen flow to obtain the differential scanning calorimetry (DSC) curve.

[0170] Equilibrium solubility test: the suspension sample prepared with water was stirred at 37° C. rpm for 6 hours, then centrifuged to take the supernatant, and the concentration of APG-115 in the supernatant was determined by HPLC.

[0171] Drug dissolution test: the dissolution test method II (slurry method) of the Chinese Pharmacopoeia was used. 900 ml of pH 6.8 phosphate solution (0.2% sodium dodecyl sulfate) was used as the dissolution medium, and the rotating speed was 75 revolutions per minute).

[0172] In the following examples, the APG-115 hydrate used is APG-115 monohydrate. Other hydrates of APG-115 (such as hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, nonahydrate, decahydrate, undecahydrate, dodecahydrate, etc.) can also be used to prepare APG-115ASD. Of course, ASD can also be prepared by using the salt or crystal form of APG-115.

EXAMPLE 1

[0173] APG-115 hydrate and HPMCAS126G (the mass ratio of APG-115 hydrate and HIPMCAS126G was 1:3, that was, the drug loading was 25%) was weighed. A certain volume of ethyl acetate (which can completely dissolve HPMCAS126G and APG-115 hydrate) was measured, and placed in a glass bottle with thin mouth, HPMCAS126G and APG-115 hydrate was slowly added under magnetic stirring, and stirred until it was completely dissolved; The solution was spray dried (the actual outlet temperature was 4070° C., 5 hours), filtered through a 40 mesh screen to obtain APG-115ASD.

[0174] The related substances, equilibrium solubility and drug dissolution of amorphous solid dispersion (APG-115ASD) were tested. The results showed that the related substances were 0.47%; The equilibrium solubility was 0.0898 mg/ml; The drug dissolution rates of 10 min, 30 min and 60 min were 64.5%, 95.2% and 99.0%, respectively.

EXAMPLE 2

[0175] HPMCAS126G in example 1 was replaced by HPMCAS716G, and APG-115ASD was prepared and characterized by the same method as in example 1. The results showed that the related substances were 0.53%; The equilibrium solubility was 0.1099 mg/ml; The drug dissolution rates of 10 min, 30 min and 60 min were 78%, 93.6% and 97.1%, respectively.

EXAMPLE 3

[0176] HPMCAS126G in example 1 was replaced by HPMCAS912G, APG-115ASD was prepared by the same method as in example 1, and DSC scanning, related substances, equilibrium solubility and drug dissolution test were performed. The results showed that DSC scanning showed no obvious endothermic and exothermic peaks; Related substances: 0.50%; The equilibrium solubility was 0.1028 mg/ml; The drug dissolution rates of 10 min, 30 min and 60 min were 80.8%, 97.5% and 101.4%, respectively.

EXAMPLE 4

[0177] HPMCAS126G in example 1 was replaced with HPC Klucel EXF, APG-115ASD was prepared by the same method as in example 1, and DSC scanning and related substances were tested. The results showed that DSC scanning showed no obvious endothermic and exothermic peaks; The related substances were 0.33%.

EXAMPLE 5

[0178] The HPMCAS126G in example 1 was replaced with PVP VA64, and APG-115ASD was prepared and characterized by the same method as in example 1. The results showed that: 0.41% related substances; equilibrium solubility, 0.2384 mg/ml; drug dissolution at 10 min, 30 min, and min was 11.0%, 65.6%, and 91.1%, respectively.

EXAMPLE 6

[0179] The HPMCAS126G in example 1 was replaced with PVP K29/32, and APG-115ASD was prepared and characterized by the same method as in example 1. The results showed that: 0.23% of the related substances; equilibrium solubility, 0.0558 mg/ml; drug dissolution at 10 min, 30 min, and 60 min was 6.0%, 48.4%, and 90.1%, respectively.

EXAMPLE 7

[0180] The HPMCAS126G in example 1 was replaced with PVP S-630, and the APG-115ASD was prepared and characterized by the same procedure as in example 1. The results showed that: 0.85% of the involved substances; equilibrium solubility, 0.0351 mg/ml; drug dissolution at 10 min, 30 min, and 60 min was 13.0%, 76.9%, and 97.7%, respectively.

EXAMPLE 8

[0181] HPMCAS126G in example 1 was replaced with Eudragit L100, and APG-115ASD was prepared and tested for the related substances as well as drug dissolution by the same method as in example 1. The results showed that the drug dissolution was 0.53% for the related substances, and 54.2%, 97.5%, and 98.3% for 10 min, 30 min, and 60 min, respectively.

EXAMPLE 9

[0182] HPMCAS126G in example 1 was replaced with Eudragit S100, and APG-115ASD was prepared and characterized by DSC scanning as well as drug dissolution test using the same method as in example 1. The results showed that DSC scanning showed no obvious endothermic, exothermic peaks, and the drug dissolution was 48.7%, 96.3%, and 99.7% at 10 min, 30 min, and 60 min, respectively.

EXAMPLE 10

[0183] HPMCAS126G in example 1 was replaced by Eudragit L100-55. APG-115 ASD was prepared by the same method as in example 1, and DSC scanning, related substances and drug dissolution tests were performed. The results showed that DSC scanning showed no obvious endothermic, exothermic peaks, and the drug dissolution was 83.7%, 92.8%, and 96.6% at 10 min, 30 min, and 60 min, respectively.

EXAMPLE 11

[0184] APG-115 hydrate and HPMCAS912G (the mass ratio of APG-115 hydrate and HPMCAS912G was 1:4), and colloidal silica (the mass ratio of colloidal silica and APG-115 hydrate is 1:9.8) was weighed. A certain volume of ethyl acetate (it enables complete dissolution of HPMCAS126G, APG-115 hydrate, and colloidal silica) was weighed, placed in a glass bottle with thin mouth, HPMCAS912G and APG-115 hydrate and colloidal silica were slowly added in sequence under magnetic stirring until complete dissolution. The resulting solution was spray dried (actual wind out temperature of 40˜65° C., 5 h); filtered through a 40 mesh screen to obtain APG-115ASD. Amorphous solid dispersion (APG-115ASD) was scanned by DSC and drug dissolution test. The results showed that DSC scan showed no obvious endothermic, exothermic peaks; the drug dissolution was 85.7%, 101.4% and 101.8% at 10 min, 30 min as well as 60 min, respectively.

EXAMPLE 12

[0185] The amount of APG-115 hydrate, HPMCAS912G and colloidal silica in example 11 was changed so that the mass ratio of APG-115 hydrate to HPMCAS912G was 1:3 and the mass ratio of colloidal silica to HPMCAS912G was 1:12.25. APG-115ASD was prepared by the same method as in example 10 and tested for DSC scanning, drug dissolution and total impurities. The results showed that DSC scanning showed no obvious endothermic and exothermic peaks; The drug dissolution rates of 10 min, 30 min and 60 min were 62.3%, 101.1% and 102.2%, respectively; The total impurities at initial, 30 days (60° C.) and 30 days (RH 75%) were 0.67%, 0.96% and 1.38%, respectively.

EXAMPLE 13

[0186] The amount of APG-115 hydrate, HPMCAS912G and colloidal silica in example 11 was changed so that the mass ratio of APG-115 hydrate to HPMCAS912G was 1:2 and the mass ratio of colloidal silica to HPMCAS912G was 1:16.35. APG-115ASD was prepared by the same method as in example 10 and tested for DSC scanning, drug dissolution and total impurities. The results showed that DSC scanning showed no obvious endothermic and exothermic peaks; The drug dissolution rates of 10 min, 30 min and 60 min were 36.3%, 101.4% and 102.3%, respectively; The total impurities at initial, 30 days (60° C.) and 30 days (RH75%) were 0.40%, 1.27% and 0.54%, respectively.

EXAMPLE 14

[0187] The amount of APG-115 hydrate, HPMCAS912G and colloidal silica in example 11 was changed so that the mass ratio of APG-115 hydrate to HPMCAS912G was 1:1, and the mass ratio of colloidal silica to HPMCAS912G was 1:24.5. APG-115ASD was prepared by the same method as example 10, and DSC scanning and drug dissolution test were carried out. The results showed that DSC scanning showed that there were sharp crystal endothermic peaks; The drug dissolution rates of 10 min, 30 min and 60 min were 21.1%, 87.6% and 100.9%, respectively.

EXAMPLE 15

[0188] APG-115 hydrate and hypromellose acetate succinate was weighed. A certain volume of 90% ethanol was measured, placed in a glass bottle with thin mouth, APG-115 hydrate and hypromellose acetate succinate was slowly added under magnetic stirring until it was completely dissolved, the drug containing solution was prepared, the total impurities of the drug containing solution was determined, the drug containing solution was placed for more than 20 hours, and the total impurities of the drug containing solution was determined again. The results showed that the initial total impurities of the drug containing solution were 0.20%, and the total impurities of the solution placed for more than 20 hours were 0.63%.

EXAMPLE 16

[0189] The 90% ethanol in example 14 was replaced with ethanol and tetrahydrofuran (volume ratio: 4:1), the drug containing solution was prepared by the same method as in example 15, and its total impurities were tested. The results showed that the initial total impurity of the drug containing solution was 0.23%, and the total impurity of the solution placed for more than 20 hours was 0.34%.

EXAMPLE 17

[0190] APG-115 hydrate and hypromellose acetate succinate (the mass ratio of APG-115 hydrate and hypromellose acetate succinate was 1:2) was weighed. A certain volume of methyl acetate (which can completely dissolve the hypromellose acetate succinate and APG-115 hydrate) was measured, placed in a glass bottle with thin mouth, APG-115 hydrate and hypromellose acetate succinate was slowly added under magnetic stirring, stirred until it was completely dissolved, a drug containing solution was prepared, the total impurities of the drug containing solution were determine, and the drug containing solution was placed for more than 20 hours, the total impurities of the drug containing solution was determined again. Spray drying was carried out with the drug solution (the actual outlet temperature was 4065° C., 5 hours) and vacuum drying (50 h, 2 hours). The residual solvents of dried APG-115ASD were tested. The results showed that the total impurities in the initial solution were 0.34%, and the total impurities in the solution placed for more than 20 hours were 0.37%; The residual solvent was 0.02%.

EXAMPLE 18

[0191] Methyl acetate in example 17 was replaced with tetrahydrofuran, the drug containing solution was prepared and its total impurities were tested in the same way as in example 17, APG-115ASD was prepared and the solvent residue of dried APG-115ASD was tested. The results showed that the total impurities in the initial solution were 0.25%, and the total impurities in the solution placed for more than 20 hours were 0.27%; The residual solvent was 3.48%.

EXAMPLE 19

[0192] APG-115ASD and microcrystalline cellulose Avicel® PH 102, croscarmellose sodium, colloidal silica and magnesium stearate of example 13 were weighed (in which APG-115ASD, microcrystalline cellulose Avicel® PH 102, croscarmellose sodium, colloidal silica and magnesium stearate accounted for 38.5%, 52.5%, 5%, 3% and 1% of the total materials respectively); APG-115ASD, microcrystalline cellulose Avicel® PH 102, croscarmellose sodium and colloidal silica were shaken and mixed 200 times in clean and dry LDPE Bag after passing through 40 mesh screen for 3 times; 0.5% magnesium stearate passing 60 mesh sieve was added (mass percentage was the mass fraction relative to the total material) to the above mixed powder and shaked it for 60 times; Dry granulation (in which the roller speed was 5 pm, the pressure of the pressure roller was 7-11 MPa, the fine screen was 24 mesh, and the dry particles were collected in clean and dry LDPE Bag); The remaining magnesium stearate passing the 60 mesh screen was added into the dry particles and shaked and mixed in the LDPE bag for 60 times to obtain the total mixed powder; The total mixed powder was stamped on a single stamping machine with a shallow arc circle with a diameter of 10 mm to make a plain tablet with a weight of 400 mg. The parameters and drug dissolution of Plain tablet were tested, and the results were shown in Table 1.

TABLE-US-00001 TABLE 1 Parameters of plain tablets Surface condition of Average Average Disintegration Friability the plain tablet hardness thickness time (200 rpm) White with 103.1N 4.82 mm 1 min 03 0.31% occasional spots seconds Drug dissolution rate (%) 5 min 10 min 20 min 30 min 45 min 60 min 90 min 66 86 94 95 94 95 94

EXAMPLE 20

[0193] APG-115ASD and microcrystalline cellulose Avicel® PH 102, pregelatinized starch, croscarmellose sodium, colloidal silica and magnesium stearate of example 13 were weighed (in which APG-115ASD and microcrystalline cellulose Avicel® PH 102, pregelatinized starch, croscarmellose sodium, colloidal silica and magnesium stearate accounted for 38.5%, 35%, 17.5%, 5%, 3% and 1% of the total materials respectively); APG-115ASD, microcrystalline cellulose Avicel® PH 102, pregelatinized starch, croscarmellose sodium and colloidal silica were placed in a clean and dry LDPE bag and shaked for 200 times after passing through a 40 mesh screen for 3 times; 0.5% magnesium stearate passing 60 mesh sieve (mass percentage is the mass fraction relative to the total material) was added to the above mixed powder and shaked it for 60 times; Dry granulation (in which the roller speed was 5 rpm, the pressure of the pressing roller was 7-11 MPa, the fine screen was 24 mesh, and the dry particles were collected in clean and dry LDPE Bag); The remaining magnesium stearate passing the 60 mesh screen was added into the dry particles and shaked and mixed in the LDPE bag for 60 times to obtain the total mixed powder; The total mixed powder was stamped on a single stamping machine with a shallow arc circle with a diameter of 10 mm to make a plain tablet with a weight of 400 mg. The parameters and drug dissolution of Plain tablet were tested, and the results were shown in Table 2.

TABLE-US-00002 TABLE 2 Parameters of plain tablets Surface condition of Average Average Disintegration Friability the plain tablet hardness thickness time (200 rpm) White with 66.1N 4.90 mm 42 seconds 0.50% occasional spots Drug dissolution rate (%) 5 min 10 min 20 min 30 min 45 min 60 min 90 min 76 94 100 101 99 100 100

EXAMPLE 21

[0194] APG-115ASD and microcrystalline cellulose Avicel® PH 102, calcium phosphate, croscarmellose sodium, colloidal silica and magnesium stearate of example 13 were weighed (in which APG-115ASD, microcrystalline cellulose Avicel® PH 102, calcium phosphate, croscarmellose sodium, colloidal silica and magnesium stearate accounted for 38.5%, 26.25%, 26.25%, 5%, 3% and 1% of the total materials respectively); APG-115ASD, microcrystalline cellulose Avicel® PH 102, calcium phosphate, croscarmellose sodium and colloidal silica were placed in a clean and dry LDPE bag and shaked for 200 times after passing through a 40 mesh screen for 3 times; 0.5% magnesium stearate passing 60 mesh sieve (mass percentage is the mass fraction relative to the total material) was added to the above mixed powder and shaked for 60 times; Dry granulation (in which the roller speed was 5 rpm, the pressure of the pressing roller is 7-11 MPa, the fine screen was 24 mesh, and the dry particles were collected in clean and dry LDPE Bag); The remaining magnesium stearate passing the 60 mesh screen was added into the dry particles and shaked and mixed in the LDPE bag for 60 times to obtain the total mixed powder; The total mixed powder was stamped on a single stamping machine with a shallow arc circle with a diameter of 10 mm to make a plain tablet with a weight of 400 mg. The parameters and drug dissolution of Plain tablet were tested, and the results were shown in Table 3.

TABLE-US-00003 TABLE 3 Parameters of plain tablets Surface condition Average Average Disintegration Friability of the plain tablet hardness thickness time (200 rpm) White with 129.7 N 4.60 mm 35 seconds 0.12% occasional spots Drug dissolution rate (%) 5 min 10 min 20 min 30 min 45 min 60 min 90 min 68 84 91 94 95 97 97

EXAMPLE 22

[0195] APG-115ASD, microcrystalline cellulose KG 802, calcium phosphate, croscarmellose sodium, hydroxypropyl cellulose, colloidal silica and magnesium stearate of example 13 were weighed (in which APG-115ASD, microcrystalline cellulose KG 802, calcium phosphate, croscarmellose sodium, hydroxypropyl cellulose, colloidal silica and magnesium stearate accounted for 38.5%, 23.5%, 23.5%, 5%, 6%, 2.5% and 1% of the total materials respectively); APG-115ASD, microcrystalline cellulose KG 802, calcium phosphate, croscarmellose sodium, hydroxypropyl cellulose and colloidal silica were passed through 40 mesh screen for 3 times and then placed in a clean and dry LDPE bag for shaking and mixing for 200 times; 0.5% magnesium stearate passing through 60 mesh screen (mass percentage relative to the total material) was added to the above mixed powder and shaked and mixed for 60 times; Dry granulation (the rotating speed of roller was 5 rpm, the pressure of roller was 7-11 mpa, the fine screen mesh was 24, and the dry particles were collected in clean and dry LDPE Bag), and the amount of fine powder (<80 mesh) was more than 20%; The remaining magnesium stearate passing the 60 mesh screen was added into the above dry particles and shaked and mixed in the LDPE bag for 60 times to obtain the total mixed powder; The total mixed powder was pressed into 400 mg plain tablets with a circular die with a diameter of 9.5 mm on a single stamping machine, and then the OPADRY II 85f620079 (the mass of OPADRY II 85f620079 was 3% of that of plain tablets) film coating premix was used to coat the plain tablets. The parameters of the plain tablets and the drug dissolution of the coated tablets were tested. The results are shown in Table 4.

TABLE-US-00004 TABLE 4 Parameters of plain tablets Surface condition Average Disintegration Friability of the plain tablet hardness time (200 rpm) White with 137 N 55 seconds 0.2% occasional spots Drug dissolution rate (%) 5 min 10 min 20 min 30 min 45 min 60 min 90 min 54 77 90 93 93 93 99

EXAMPLE 23

[0196] APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, croscarmellose sodium, hydroxypropyl cellulose, colloidal silica and magnesium stearate of example 13 were weighed (the mass proportions of APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, croscarmellose sodium, hydroxypropyl cellulose, colloidal silica and magnesium stearate in the total materials were 38.5%, 25%, 25%, 3%, 5.25%, 2% and 1.25% respectively); APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, croscarmellose sodium, hydroxypropyl cellulose and colloidal silica were passed through a 40 mesh screen for 3 times, and then placed in a clean and dry LDPE bag for shaking and mixing for 200 times; 0.75% of magnesium stearate passing a 60 mesh screen (the mass percentage was the mass fraction relative to the total material) was added into the above mixed powder and shaked for 60 times; dry granulation (in which the roller speed was 5 rpm, the pressing wheel pressure was 7-11 MPa, the fine screen mesh was 24, and the dry particles were collected in clean and dry LDPE Bag), and the amount of fine powder (<80 mesh) 18%; The remaining magnesium stearate passing the 60 mesh screen was added into the above dry particles and shaked and mixed in the LDPE bag for 60 times to obtain the total mixed powder; The total mixed powder was pressed into 400 mg plain tablets with a circular die with a diameter of 9.5 mm on a single stamping machine, and then OPADRY II 85f620079 (the mass of OPADRY II 85f620079 was 3% of the plain tablets) film coating premix was used to coat the plain tablets to obtain the coated tablets. The parameters of the plain tablets and the drug dissolution of the coated tablets were tested. The results were shown in Table 5.

TABLE-US-00005 TABLE 5 Parameters of plain tablets Surface condition Average Disintegration Friability of the plain tablet hardness time (200 rpm) White with 135 N 40 seconds 0.2% occasional spots Drug dissolution rate (%) 5 min 10 min 20 min 30 min 45 min 60 min 90 min 47 72 91 95 96 96 101

EXAMPLE 24

[0197] APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, croscarmellose sodium, hydroxypropyl cellulose, colloidal silica and magnesium stearate of example 13 were weighed (the mass proportions of APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, hydroxypropyl cellulose, croscarmellose sodium, colloidal silica and magnesium stearate in the total materials were 38.5%, 25.5%, 25.5%, 4%, 3%, 2% and 1.5% respectively); APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, croscarmellose sodium, hydroxypropyl cellulose and colloidal silica were passed through 40 mesh screen for 3 times, and then placed in clean and dry LDPE bag for shaking and mixing for 200 times; 1% magnesium stearate passing 60 mesh screen (mass percentage was relative to the mass fraction of the total material) was added into the above mixed powder and shaked for 60 times; Dry granulation (in which the roller speed was 5 rpm, the pressing wheel pressure was 7-11 MPa, the fine screen was 24 mesh, and the dry particles were collected in clean and dry LDPE Bag); The remaining magnesium stearate passing the 60 mesh screen was added into the above dry particles and shaked and mixed in the LDPE bag for 60 times to obtain the total mixed powder; The total mixed powder was pressed into 400 mg plain tablets with a circular die with a diameter of 9.5 mm on a single stamping machine, and then OPADRY II 85f80010 (the mass of OPADRY II 85f80010 is 3% of that of plain tablets) film coating premix was used to coat the plain tablets to obtain the coated tablets. The parameters of the plain tablets were tested, and the results were shown in Table 6.

TABLE-US-00006 TABLE 6 Parameters of plain tablets Average hardness Plain Dis- (compression tablet integration Friability pressure 10 kN) thickness time (200 rpm) 120 N 5.21 mm 2 min 29 0.46% seconds

EXAMPLE 25

[0198] APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, croscarmellose sodium, colloidal silica and magnesium stearate of example 13 were weighed (wherein the mass proportions of APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, croscarmellose sodium, colloidal silica and magnesium stearate in the total material were 38.5%, 27.5%, 27.5%, 3%, 2% and 1.5%, respectively); APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, croscarmellose sodium and colloidal silica were passed through a 40 mesh screen for 3 times, and then placed in a clean and dry LDPE bag for shaking and mixing for 200 times; 1% magnesium stearate passing 60 mesh sieve (mass percentage is the mass fraction relative to the total material) was added to the above mixed powder and shake it for 60 times; Dry granulation (in which the roller speed was 5 rpm, the pressure of the pressing roller is 7-11 MPa, the fine screen was 24 mesh, and the dry particles were collected in clean and dry LDPE Bag); The remaining magnesium stearate passing the 60 mesh screen was added into the dry particles and shaked and mixed in the LDPE bag for 60 times to obtain the total mixed powder; The total mixed powder was pressed into 400 mg plain tablets with a circular die with a diameter of 9.5 mm on a single tablet press, and then the plain tablets were coated with OPADRY II 85f80010 (the mass of OPADRY II 85f80010 was 3% of the plain tablets) film coating premix to obtain the coated tablets. The parameters of plain tablets were tested, and the results were shown in Table 7.

TABLE-US-00007 TABLE 7 Parameters of plain tablets Average hardness Plain Dis- (compression tablet integration Friability pressure 10 kN) thickness time (200 rpm) 92.4 N 5.28 mm 45 seconds 0.34%

EXAMPLE 26

[0199] APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, croscarmellose sodium, hydroxypropyl cellulose, colloidal silica and magnesium stearate of example 13 were weighed (the mass proportions of APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, hydroxypropyl cellulose, croscarmellose sodium, colloidal silica and magnesium stearate in the total materials were 38.5%, 25%, 25%, 5%, 3.25%, 2% and 1.25% respectively); APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, croscarmellose sodium, hydroxypropyl cellulose and colloidal silica were passed through a 40 mesh screen for 3 times, and then placed in a clean and dry LDPE bag for shaking and mixing for 200 times; 0.75% of magnesium stearate passing a 60 mesh screen (the mass percentage is the mass fraction relative to the total material) was added into the above mixed powder and shaked for 60 times; Dry granulation (in which the roller speed was 5 rpm, the pressing wheel pressure was 7-11 MPa, the fine screen was 24 mesh, and the dry particles were collected in clean and dry LDPE Bag); The remaining magnesium stearate passing the 60 mesh screen was added into the above dry particles and shaked and mixed in the LDPE bag for 60 times to obtain the total mixed powder; The total mixed powder was pressed into 400 mg plain tablets with a circular die with a diameter of 9.5 mm on a single tablet press. The parameters of plain tablets and drug dissolution were tested, and the results were shown in Table 8.

TABLE-US-00008 TABLE 8 Parameters of plain tablets Average hardness (compression Disintegration Friability pressure 10 kN) time (200 rpm) 136.9 N 1 min 29 seconds 0.09% Drug dissolution rate (%) 5 min 10 min 20 min 30 min 45 min 60 min 90 min 41 65 84 90 91 91 92

EXAMPLE 27

[0200] APG-115ASD, silicified microcrystalline cellulose, crospovidone and magnesium stearate of example 13 were weighed (wherein the mass proportions of APG-115ASD, silicified microcrystalline cellulose, crospovidone and magnesium stearate in the total material were 51.75%, 39.5%, 8% and 0.75% respectively); After APG-115ASD, silicified microcrystalline cellulose and crospovidone was passing through 40 mesh screen for 3 times and placed in a clean and dry LDPE bag for shaking and mixing for 200 times; Magnesium stearate passing a 60 mesh sieve was added into the mixed powder and shaked for 60 times; The total mixed powder was pressed into 400 mg plain tablets by a circular die with a diameter of 9.5 mm on a single tablet press. The disintegration time and drug dissolution of plain tablet were tested. The results showed that the disintegration time was 7 minutes, and the drug dissolution were shown in Table 9.

TABLE-US-00009 TABLE 9 Drug dissolution (%) 5 min 10 min 20 min 30 min 45 min 60 min 90 min 19 41 71 85 93 95 96

EXAMPLE 28

[0201] APG-115ASD, microcrystalline cellulose KG 802, calcium phosphate, croscarmellose sodium, hydroxypropyl cellulose, colloidal silica and magnesium stearate of example 13 were weighed (APG-115ASD, microcrystalline cellulose KG 802, calcium phosphate, croscarmellose sodium, hydroxypropyl cellulose, colloidal silica and magnesium stearate account for 38.5%, 23.5%, 23.5%, 5%, 6%, 2.5% and 1% of the total materials respectively); APG-115ASD, microcrystalline cellulose KG 802, calcium phosphate, croscarmellose sodium, hydroxypropyl cellulose and colloidal silica were passed through a 40 mesh screen for three times and placed in a clean and dry LDPE bag for shaking and mixing for 200 times; 0.5% magnesium stearate passing through a 60 mesh screen (mass percentage is the mass fraction of the total material) was added to the above mixed powder and shaked and mixed for 60 times; Dry granulation (the rotating speed of the roller was 5 rpm, the pressure of the pressure roller was 7-11 mpa, the fine screen was 24 mesh, and the dry particles were collected in clean and dry LDPE Bag); The remaining magnesium stearate passing the 60 mesh screen was added into the above dry particles and shaked and mixed in the LDPE bag for 60 times to obtain the total mixed powder; The total mixed powder was pressed into 400 mg plain tablets with a circular die with a diameter of 9.5 mm on a single tablet press. The parameters of plain tablets and drug dissolution were tested, and the results were shown in Table 10.

TABLE-US-00010 TABLE 10 Parameters of plain tablets Average hardness Disintegration time Friability (200 rpm) 137 N 55 seconds 0.2% Drug dissolution rate (%) 5 min 10 min 20 min 30 min 45 min 60 min 90 min 54 77 90 93 93 93 99

EXAMPLE 29

[0202] APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, croscarmellose sodium, hydroxypropyl cellulose, colloidal silica and magnesium stearate of example 13 were weighed (the mass proportions of APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, croscarmellose sodium, hydroxypropyl cellulose, colloidal silica and magnesium stearate in the total materials were 38.5%, 25%, 25%, 3.25%, 5%, 2% and 1.25% respectively); APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, croscarmellose sodium, hydroxypropyl cellulose and colloidal silica were passed through 40 mesh screen for 3 times, and then placed in clean and dry LDPE bag for shaking and mixing for 200 times; 0.75% magnesium stearate passing 60 mesh screen (mass percentage is relative to the mass fraction of the total material) was added into the above mixed powder and shaked for 60 times; Dry granulation (in which the roller speed was 5 rpm, the pressing wheel pressure was 7-11 MPa, the fine screen was 24 mesh, and the dry particles were collected in clean and dry LDPE Bag); The remaining magnesium stearate passing the 60 mesh screen was added into the above dry particles and shaked and mixed in the LDPE bag for 60 times to obtain the total mixed powder; The total mixed powder was pressed into 400 mg plain tablets with a circular die with a diameter of 9.5 mm on a single tablet press. The parameters of plain tablets and drug dissolution were tested, and the results were shown in Table 11.

TABLE-US-00011 TABLE 11 Parameters of plain tablets Average hardness Disintegration time Friability (200 rpm) 136.9 N 1 min 29 seconds 0.09% Drug dissolution rate (%) 5 min 10 min 20 min 30 min 45 min 60 min 90 min 41 65 84 90 91 91 92

EXAMPLE 30

[0203] APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, croscarmellose sodium, hydroxypropyl cellulose, colloidal silica and magnesium stearate of example 13 were weighed (the mass proportions of APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, croscarmellose sodium, hydroxypropyl cellulose, colloidal silica and magnesium stearate in the total materials were 39.65%, 24.31%, 24.31%, 3.26%, 5.01%, 1.96% and 1.50% respectively); APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, hydroxypropyl cellulose, croscarmellose sodium and colloidal silica were placed in a mixer for mixing at a mixing speed of 18 rpm for 5 minutes; the obtained material was sieved through 40 mesh sieve, and then 0.75% magnesium stearate (mass percentage was the mass fraction relative to the total material) was added to mix, the mixing speed was 18 rpm, the mixing time was 5 minutes, and the obtained materials was placed in the dry granulator for dry granulation (the pressure of the pressure roller was 4.0-7.0 MPa, the clearance of the pressure roller was 1.0-5.0 mm, the speed of the pressure roller was 3.0-7.0 rpm, the speed of the granulating parts was 30-90 rpm, the speed of the feed shaft was 18-90 rpm, and the fine screen was 0.8 mm) to collect the obtained particles; The remaining magnesium stearate was added to the obtained particles and mixed for lubrication; The tablets were pressed with a circular die with a diameter of 10 mm (the feed speed was 5-30 rpm, the tablet pressing speed was 20-30 rpm, the tablet thickness scale was 0.3-5.0 mm, the feed scale was 10.5-15.5 mm, and the main pressure range was 10-25 KN) to get plain tablets. The parameters of plain tablets and drug dissolution were tested, and the results were shown in Table 12.

TABLE-US-00012 TABLE 12 Parameters of plain tablets Average hardness Disintegration time Friability (200 rpm) 143 N 43 seconds 0.14% Drug dissolution rate (%) 5 min 10 min 20 min 30 min 45 min 60 min 90 min 54 79 94 96 97 98 100

EXAMPLE 31

[0204] APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, croscarmellose sodium, hydroxypropyl cellulose, colloidal silica and magnesium stearate of example 13 were weighed (the mass proportions of APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, croscarmellose sodium, hydroxypropyl cellulose, colloidal silica and magnesium stearate in the total materials were 39.55%, 23.5%, 23.5%, 3.25%, 5%, 2.95% and 2.25% respectively); APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, hydroxypropyl cellulose, croscarmellose sodium and 1.45% colloidal silica (mass percentage relative to the total material) were placed in the mixer for mixing at a mixing speed of 18 rpm for 5 minutes; the obtained material was sieved through 40 mesh sieve, and then 0.75% magnesium stearate was added (mass percentage was the mass fraction relative to the total material) mix, the mixing speed was 18 rpm, the mixing time was 5 minutes, and the obtained material was placed in the dry granulator for dry granulation (the pressure of the pressure roller was 4.0-7.0 MPa, the clearance of the pressure roller was 1.0-5.0 mm, the speed of the pressure roller was 3.0-7.0 rpm, the speed of the granulating parts was 30-90 rpm, the speed of the feed shaft was 18-90 rpm, and the fine screen was 0.8 mm) to collect the obtained particles; the remaining colloidal silica and the remaining magnesium stearate was added to the obtained particles for mixed lubrication; the tablets were pressed with a circular die with a diameter of 10 mm (the feed speed was 5-30 rpm, the tablet pressing speed was 20-30 rpm, the tablet thickness scale was 0.3-5.0 mm, the feed scale was 10.5-15.5 mm, and the main pressure range was 10-25 KN) to get plain tablets. The parameters of plain tablets and drug dissolution were tested, and the results were shown in Table 13.

TABLE-US-00013 TABLE 13 Parameters of plain tablets Average hardness Disintegration time Friability (200 rpm) 101 N 31 seconds 0.35% Drug dissolution rate (%) 5 min 10 min 20 min 30 min 45 min 60 min 90 min 46 71 90 94 95 96 100

EXAMPLE 32

[0205] APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, croscarmellose sodium, hydroxypropyl cellulose, colloidal silica and magnesium stearate of example 13 were weighed (the mass proportions of APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, croscarmellose sodium, hydroxypropyl cellulose, colloidal silica and magnesium stearate in the total materials were 39.35%, 22.39%, 22.39%, 3.23%, 4.98%, 5.42% and 2.24% respectively); APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, hydroxypropyl cellulose, croscarmellose sodium and 1.19% colloidal silica (mass percentage relative to the total material) were placed in the mixer for mixing at a mixing speed of 18 rpm for 5 minutes; the obtained material was sieved through 40 mesh sieve, and then 0.75% magnesium stearate was added (mass percentage was the mass fraction relative to the total material) to mix, the mixing speed was 18 rpm, the mixing time was 5 minutes, and the obtained material was placed in the dry granulator for dry granulation (the pressure of the pressure roller was 4.0-7.0 MPa, the clearance of the pressure roller was 1.0-5.0 mm, the speed of the pressure roller was 3.0-7.0 rpm, the speed of the granulating parts was 30-90 rpm, the speed of the feed shaft was 18-90 rpm, and the fine screen was 0.8 mm) to collect the obtained particles; the remaining colloidal silica and the remaining magnesium stearate was added to the obtained particles for mixed lubrication; the tablets were pressed with a circular die with a diameter of 10 mm (the feed speed was 5-30 rpm, the tablet pressing speed was 20-30 rpm, the tablet thickness scale was 0.3-5.0 mm, the feed scale was 10.5-15.5 mm, and the main pressure range was 10-25 KN) to get plain tablets. The parameters of plain tablets and drug dissolution were tested, and the results were shown in Table 14.

TABLE-US-00014 TABLE 14 Parameters of plain tablets Average hardness Disintegration time Friability (200 rpm) 160 N 60 seconds 0.37% Drug dissolution rate (%) 5 min 10 min 20 min 30 min 45 min 60 min 90 min 35 60 84 93 96 97 101

EXAMPLE 33

[0206] APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, croscarmellose sodium, hydroxypropyl cellulose, colloidal silica and magnesium stearate of example 13 were weighed (APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, croscarmellose sodium, hydroxypropyl cellulose, colloidal silica and magnesium stearate account for 38.5%, 23.5%, 23.5%, 5%, 6%, 2.5% and 1% of the total materials respectively); APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, hydroxypropyl cellulose, croscarmellose sodium and colloidal silica were placed in a mixer for mixing at a mixing speed of 18 rpm for 5 minutes; the obtained material was sieved through 40 mesh sieve, and then 0.5% magnesium stearate (mass percentage was the mass fraction relative to the total material) was added to mix, the mixing speed was 18 rpm, the mixing time was 5 minutes, and the obtained materials was placed in the dry granulator for dry granulation (the pressure of the pressure roller was 4.0-7.0 MPa, the clearance of the pressure roller was 1.0-5.0 mm, the speed of the pressure roller was 3.0-7.0 rpm, the speed of the granulating parts was 30-90 rpm, the speed of the feed shaft was 18-90 rpm, and the fine screen was 0.8 mm), the fluidity was poor, the screen was adheres, and the obtained particles were collected; the remaining magnesium stearate was added to the obtained particles and mixed for lubrication; the tablets were pressed with a circular die with a diameter of 10 mm (the feed speed was 5-30 rpm, the tablet pressing speed was 20-30 rpm, the tablet thickness scale was 0.3-5.0 mm, the feed scale was 10.5-15.5 mm, and the main pressure range was 10-25 KN) to get plain tablets. The parameters of plain tablets and drug dissolution were tested, and the results were shown in Table 15.

TABLE-US-00015 TABLE 15 Parameters of plain tablets Average Surface condition Disintegration Friability hardness of the plain tablet time (200 rpm) 137 N White with 55 seconds 0.2% occasional spots Drug dissolution rate (%) 5 min 10 min 20 min 30 min 45 min 60 min 90 min 54 77 90 93 93 93 99

EXAMPLE 34

[0207] APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, croscarmellose sodium, hydroxypropyl cellulose, colloidal silica and magnesium stearate of example 13 were weighed (the mass proportions of APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, croscarmellose sodium, hydroxypropyl cellulose, colloidal silica and magnesium stearate in the total materials were 38.5%, 25%, 25%, 3%, 5.25%, 2% and 1.25% respectively); APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, hydroxypropyl cellulose, croscarmellose sodium and colloidal silica were placed in a mixer for mixing at a mixing speed of 18 rpm for 5 minutes; the obtained material was sieved through 40 mesh sieve, and then 0.75% magnesium stearate (mass percentage was the mass fraction relative to the total material) was added to mix, the mixing speed was 18 rpm, the mixing time was 5 minutes, and the obtained materials was placed in the dry granulator for dry granulation (the pressure of the pressure roller was 4.0-7.0 MPa, the clearance of the pressure roller was 1.0-5.0 mm, the speed of the pressure roller was 3.0-7.0 rpm, the speed of the granulating parts was 30-90 rpm, the speed of the feed shaft was 18-90 rpm, and the fine screen was 0.8 mm) to collected the obtained particles; the remaining magnesium stearate was added to the obtained particles and mixed for lubrication; the tablets were pressed with a circular die with a diameter of 10 mm (the feed speed was 5-30 rpm, the tablet pressing speed was 20-30 rpm, the tablet thickness scale was 0.3-5.0 mm, the feed scale was 10.5-15.5 mm, and the main pressure range was 10-25 KN) to get plain tablets. The parameters of plain tablets and drug dissolution were tested, and the results were shown in Table 16.

TABLE-US-00016 TABLE 16 Parameters of plain tablets Average Surface condition Disintegration Friability hardness of the plain tablet time (200 rpm) 135 N White with 40 seconds 0.2% occasional spots Drug dissolution rate (%) 5 min 10 min 20 min 30 min 45 min 60 min 90 min 47 72 91 95 96 96 101

EXAMPLE 35

[0208] APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, croscarmellose sodium, hydroxypropyl cellulose, colloidal silica and magnesium stearate of example 13 were weighed (the mass proportions of APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, croscarmellose sodium, hydroxypropyl cellulose, colloidal silica and magnesium stearate in the total materials were 39.35%, 22.39%, 22.39%, 3.23%, 4.98%, 5.42% and 2.24% respectively); APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, hydroxypropyl cellulose, croscarmellose sodium and 1.19% colloidal silica (mass percentage relative to the total material) were placed in the mixer for mixing, the mixing speed was 18 rpm, and mixing time was 5 minutes; the obtained material was passed through 40 mesh sieve, the remaining colloidal silica and 0.75% magnesium stearate (mass percentage is the mass fraction relative to the total material) was added for mixing, the mixing speed was 18 rpm, and mixing time was 5 minutes, and the obtained material was placed in the dry granulator for dry granulation (the pressure of the pressure roller was 4.0-7.0 MPa, the clearance of the pressure roller was 1.0-5.0 mm, the speed of the pressure roller was 3.0-7.0 rpm, the speed of the granulating part was 30-90 rpm, the speed of the feed shaft was 18-90 rpm, and the fine screen was 0.8 mm), the obtained particles were collected; the remaining magnesium stearate was added to the obtained particles and mixed for lubrication; the tablets was pressed with a circular die with a diameter of 10 mm (the feed speed was 5-30 rpm, the tablet pressing speed was 20-30 rpm, the tablet thickness scale was 0.3-5.0 mm, the feed scale was 10.5-15.5 mm, and the main pressure range was 10-25 KN); the plain tablets were obtained. The parameters and drug dissolution of the plain tablets were tested, and the results were shown in Table 17.

TABLE-US-00017 TABLE 17 Parameters of plain tablets Average Surface condition Disintegration Friability hardness of the plain tablet time (200 rpm) 160 N White with 60 seconds 0.37% occasional spots Drug dissolution rate (%) 5 min 10 min 20 min 30 min 45 min 60 min 90 min 35 60 84 93 96 97 101

EXAMPLE 36

[0209] OPADRY II 89k680001-CN plain tablets were used for film coating, in which the coating weight gain was 3%. The drug dissolution of the coated tablets was tested, and the test results were shown in Table 18.

TABLE-US-00018 TABLE 18 Drug dissolution rate (%) 5 min 10 min 20 min 30 min 45 min 60 min 90 min 35 60 84 93 96 97 101

EXAMPLE 37

[0210] 725.2 g of hypromellose acetate succinate (HPMCAS912G) and 359.8 g of APG-115 hydrate was dissolved in 18.4571 of methyl acetate, then 22.4 g of colloidal silica was added and stirred evenly. The spray dryer was set up, and the equipment was stable until the spray was dried for 5 hours. The methyl acetate was collected and the spray dried powder was collected. The spray dried powder was dried for two times (vacuum desiccation and drying for 2 hours) until the residual amount of powder solvent did not exceed 5000 ppm to obtain APG-115ASD powder. 630 g of microcrystalline cellulose KG 802, 630 g of anhydrous calcium phosphate, 140 g of hydroxypropyl cellulose, 91 g of croscarmellose sodium, 33.6 g of colloidal silica and APG-115ASD powder were placed in a mixer for mixing (mixing speed was 18 rpm, mixing time was 5 minutes). The mixed material was sieved through 40 meshes, and then 21 g of sieved magnesium stearate was added for mixing (the mixing speed was 18 rpm and the mixing time was 5 minutes). The obtained material was placed in a dry granulator for dry granulation, and the obtained particles were collected (roller pressure: 4.0˜7.0 MPa, roller clearance: 1.0˜5.0 mm, roller speed: 3.0˜7.0 rpm, speed of granulating parts: 30˜90 rpm, feed shaft speed: 18 rpm, fine screen: 0.8 mm). 112 g of colloidal silica after screening and 35 g of magnesium stearate after screening were mixed and lubricated with the above particles in turn, and then the materials were pressed with a circular die with a diameter of 10 mm (the feed rotation speed was 5˜30 rpm, the tablet pressing rotation speed was 20˜30 rpm, the tablet thickness scale was 0.3˜5.0 mm, the feed scale was 10.5˜15.5 mm, and the main pressure range was 10˜25 KN), 7000 plain tablets were obtained. 84 g OPADRY® II film coating premix coated plain tablets to obtain coated tablets.

[0211] Two batches of coated tablets were produced according to the above process, and their dissolution, content and related substances were determined.

[0212] (1) Dissolution

[0213] Adopt the method II (slurry method) of dissolution determination in Chinese Pharmacopoeia, 900 ml pH 6.8 phosphate solution (0.2% sodium dodecyl sulfate) was took as the dissolution medium, the rotating speed was 75 revolutions per minute, and the cumulative dissolution amount after 30 minutes was not less than 80% of the marked amount.

TABLE-US-00019 TABLE 19 Drug dissolution (%) No. (30 min, 75 rpm) 1 95 2 96

[0214] (2) Content and Related Substances

TABLE-US-00020 TABLE 20 Content uniformity Should be Total complied with No. Single impurity impurities Content regulations 1 Maximum 0.4% 96.9% Consistant single impurity with the 0.15% regulations 2 Maximum 0.4% 98.1% Consistant single impurity with the 0.12% regulations

[0215] Effect Example 1

[0216] Sample to be Tested:

[0217] 1. APG-115 particles: 12.5% of APG-115 hydrate, 25.1% of hypromellose acetate succinate, 21.8% of microcrystalline cellulose KG 802, 21.8% of anhydrous calcium phosphate, 4.9% of hydroxypropyl cellulose, 3.2% of croscarmellose sodium, 5.8% of colloidal silica, 1.9% of magnesium stearate and film coating premix (the percentage was mass percentage) were used as raw materials, APG-115 particles were prepared according to the preparation method of example 37;

[0218] 2. APG-115 Hydrate

[0219] Sample Solution Preparation:

[0220] After fully grinding and mixing the samples with PEG400 (the concentration in the sample solution was 5%), a small amount (about 2 ml) of 0.2% HPMC aqueous solution was added to grind into a uniform paste until there were no large particles. Under the condition of continuous grinding, 0.2% HPMC aqueous solution was added to a sufficient amount and maintained stirring (800 RPM) for 5 minutes. After sealing the sample solution container with sealing film, it was placed in the ultrasonic instrument (40 kHz) for ultrasonic for 20 minutes (to avoid the rise of ultrasonic medium water temperature during ultrasonic process, the water temperature was controlled within 40° C.); Stopped the ultrasound, mixed the suspension evenly before use (stirring for about 3 minutes), and then sampled immediately (the concentration of the sample was 6 mg/ml).

[0221] Test method: three male beagle dogs were selected and divided into test article 1 (APG-115 particles) group and test article 2 (APG-115 hydrate) group. Each group received single oral capsule administration: after the administration of test article 1, after an 8-day cleaning period, the group name was changed to test article 2, and so on. Did not reassign animal numbers.

[0222] Blood samples were collected and plasma was separated at 0.5, 1.0, 2.0, 4.0, 6.0, 10, 24, 48, 72, 96, 120, 144 and 168 hours before and after each round of administration. All plasma samples were mailed to the client for testing. The concentration of APG-115 in dog plasma was analyzed by LC-MS/Ms. The lower limit of quantification of the method was 50 ng/ml. The non compartmental model method (NCA) of the metabolic kinetic data analysis software winnonlin 8.0.0.3176 was used to analyze the plasma concentration data and calculate the pharmacokinetic parameters. See table 21 to evaluate the kinetic characteristics of APG-115 in animals after administration.

TABLE-US-00021 TABLE 21 pharmacokinetic parameters of APG-115 sample dogs t .sub.1/2 T .sub.max C .sub.max AUC .sub.last AUC .sub.inf Vd CL MRT Sample (h) (h) (ng/ml) (h .Math. ug/mL) (h .Math. ug/mL) (mL/kg) (mL/h/kg) (h) APG-115 Mean 16.84 2.00 14833.33 372.26 374.07 139.11 5.60 23.70 particles SD 2.44 0.00 3061.59 102.20 101.98 50.60 1.41 3.07 CV% 14.48 0.00 20.64 27.45 27.26 36.37 25.18 12.94 APG-115 Mean 346.43 6.00 135.67 4.58 33.42 29088.77 60.80 31.43 hydrate SD 167.44 3.46 30.24 1.63 5.91 9310.27 10.76 14.62 CV% 48.33 57.74 22.29 35.48 17.69 32.01 17.69 46.52

[0223] Conclusion: as shown in FIG. 1, the exposure of APG-115 particles was more than ten times that of APG-115 hydrate, and the exposure of APG-115 hydrate in dogs was very low.

[0224] Although the specific embodiments of the invention have been described above, those skilled in the art should understand that this is only an example, and the protection scope of the invention is limited by the appended claims. Those skilled in the art can make a variety of changes or modifications to these embodiments without departing from the principle and essence of the invention, but these changes and modifications fall within the protection scope of the invention.