Compositions containing heterocyclic compounds, methods for producing the same, and applications

Abstract

The present disclosure provides a solid dispersion comprising a vector and an active ingredient, the active ingredient being one or more of the compound of formula (I) (APG-115), its pharmaceutically acceptable salts, its crystalline forms, and its hydrates. The solid dispersion can improve the dissolution rate of the active ingredient APG-115. The dissolution rate of APG-115 in some solid dispersions can reach 90% or more and has good stability. It can improve the dissolution rate and dissolution rate of the drug in gastrointestinal fluids, thereby improving oral bioavailability. The solid dispersion exhibits high plasma exposure in animals, i.e., high peak drug concentrations and high areas under the blood concentration curve. JPEG2023549763000026.jpg69135

Description

Technical Field

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[0001] This application claims the priority of Chinese Patent Application CN202011206371.7, filed on November 3, 2020, the content of which is incorporated herein in its entirety.

[0002] The present invention relates to a composition containing a heterocyclic compound, a method for producing the same, and an application thereof.

Background Art

[0003] MDM2 is one of the oncogenes and has a regulatory effect on cell growth. MDM2 can bind to the p53 protein to form an MDM2-p53 negative feedback loop and exert p53-dependent activity. MDM2 is the main inhibitor of p53. It suppresses the function of p53 through various mechanisms mediated by its interaction. Small molecule inhibitors that inhibit the interaction between MDM and p53 may achieve the purpose of treating human cancers by restoring the tumor suppressor function of wild-type p53.

[0004] APG-115 is an effective small molecule inhibitor that highly selectively targets the interaction between MDM2 and p53 proteins by oral administration, and current clinical research is being carried out.

Chemical Formula

Summary of the Invention

[0005] The present invention provides a solid dispersion, which Carrier contains a carrier and an active ingredient, and the active ingredient is one or more of the compound shown in formula (I), its pharmaceutically acceptable salt, its crystal form, and its hydrate

Chemical Formula

[0006] In the embodiments of the present invention, CarrierThis is selected from one or more of the following: homopolymers and copolymers of N-vinyl lactam, cellulose esters, pH-dependent cellulose derivatives, nonionic water-soluble cellulose ethers, cellulose ethers, high molecular weight polyalkylene oxides, N-vinylamide polymers, polyacrylic acid esters, polymethacrylate esters, polyacrylamides, vinyl acetate polymers, polyethylene glycols, polyvinyl caprolactam / polyvinyl acetate graft copolymers, oligosaccharides and polysaccharides, and also includes povidone, copovidone, Hypromellose acetate succinate , which may be one or more of polyethylene glycol / polyvinyl caprolactam / polyvinyl acetate graft copolymer, and Hypromellose acetate succinate It may be one or more of hydroxypropyl cellulose, povidone, and acrylic resin.

[0007] In embodiments of the present invention, Hypromellose acetate succinate This includes, but is not limited to, one or more of the HPMCAS 126G, HPMCAS 716G, and HPMCAS 912G.

[0008] In the embodiments of the present invention, hydroxypropyl cellulose includes, but is not limited to, one or more of HPC EXF, HPC LF, HPC JF, and HPC GF, and may also be HPC EXF.

[0009] In embodiments of the present invention, povidone includes, but is not limited to, one or more of PVP VA 64, PVP K29 / 32, PVP S-630, PVP K25, PVP K-90, PVP C-15, and PVP C-30, or one or more of PVP VA64, PVP K29 / 32, and PVP S-630.

[0010] In the embodiments of the present invention, the acrylic resin includes, but is not limited to, Eudragit L100, Eudragit S100, Eudragit L100-55, Eudragit RLPO, and Eudragit RSPO, and may be one or more of Eudragit L100, Eudragit S100, and Eudragit L100-55.

[0011] In the embodiments of the present invention, pharmaceutically acceptable salts of the compound shown in formula (I) include hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, 2-hydroxyethanesulfonate, phosphate, hydrogen phosphate, acetate, adipine, alginate, lysine salt, arginine salt, histidine salt, aspartate, benzoate, hydrogen sulfate, butyrate, camphorate, camphor sulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, caproate, formate, succinate, fumaric acid, maleate, ascorbate, hydroxyethylsulfonate, salicylate, methanesulfonate, mesityleneate, naphthalenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, bishydroxynaphthaleneate, and pectinate. It may be phosphate, persulfate, 3-phenylpropionate, picrate, pivaphosphate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, ethanedisulfonate, benzenesulfonate, l-tartrate, maleate, sodium salt, potassium salt, choline salt, aminobutanol salt, calcium salt, or p-toluenesulfonate, or phosphate, sulfate, l-tartrate, hydrochloride, maleate, hydrobromide, methanesulfonate, lysine salt, arginine salt, histidine salt, sodium salt, potassium salt, choline salt, aminobutanol salt, or calcium salt.

[0012] In the embodiments of the present invention, the hydrate of the compound shown in formula (I) may be a hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, nunahydrate, decahydrate, elevenhydrate, or dodecahydrate.

[0013] In the present invention Carrier ,for example Hypromellose acetate succinate HPMCAS (HPMCAS) refers to commercially available products such as HPMCAS 126G, HPMCAS 716G, HPMCAS 912G, HPMCAS HG, HPMCAS LG, and HPMCAS MG, or selected from HPMCAS with an acetyl substitution degree (%) of 5.0-9.0 and a succinoyl substitution degree (%) of 14.0-18.0 (e.g., HPMCAS 716G or HPMCAS LG), or selected from HPMCAS with an acetyl substitution degree (%) of 7.0-11.0 and a succinoyl substitution degree (%) of 10.0-14.0 (e.g., HPMCAS 912G or HPMCAS MG), or selected from HPMCAS with an acetyl substitution degree (%) of 10.0-14.0 and a succinoyl substitution degree (%) of 4.0-8.0 (e.g., HPMCAS 126G or HPMCAS HG).

[0014] Other polymers, such as povidone (PVP), hydroxypropyl cellulose (HPC), and acrylic resin (AC), are also commercially available. For example, povidone (PVP) is derived from PVP K12, PVP K15, PVP K17, PVP K30, PVP K60, PVP C-12, PVP C-17, PVP VA64, PVP K29 / 32, PVP S-630, PVP K25, PVP K-90, PVP C-15, PVP C-30, PVP VA64, PVP K29 / 32, and PVP S-630. For example, hydroxypropyl cellulose (HPC) is derived from HPC EXF, HPC LF, HPC JF, HPC GF, HPC EXF, HPC H (including HF and HXF), HPC M (including MF and MXF), HPC G (including GF and GXF), HPC J (including JF and JXF), HPC L (including LF and LXF), HPC E (including EF and EXF), HPC L, HPC M, HPC H, HPC SL, and HPC SSL. For example, acrylic resin (AC) is selected from E100, EPO, L100-55, L100, S100, RL100, RLPO, RL30D, RS100, RSPO, RS30D, NE30D, and RD100.

[0015] In embodiments of the present invention, Carrier This may be one or more of HPMCAS 912G (or HPMCAS MG), HPC Klucel EXF, Eudragit S100, and Eudragit L100-55. The resulting dispersion does not show any obvious endothermic or exothermic peaks on DSC scanning, and the resulting dispersion is an amorphous dispersion.

[0016] In embodiments of the present invention, Carrier This may be one or more of HPMCAS 912G (or HPMCAS MG), HPMCAS 126G (or HPMCAS HG), HPC Klucel EXF, PVP VA64, PVP K29 / 32, and Eudragit L100-55. The stability of the resulting dispersion is good.

[0017] In the examples of the present invention, Carrier may be one or more of HPMCAS 716G (or HPMCAS LG), HPMCAS 912G (or HPMCAS MG), and PVP VA64. The solubility of the obtained dispersion is significantly improved (the equilibrium solubility is greater than 0.1 mg / ml).

[0018] In the examples of the present invention, Carrier may be one or more of HPMCAS 126G (or HPMCAS HG), HPMCAS 716G (or HPMCAS LG), HPMCAS 912G (or HPMCAS MG), Eudragit L100, and Eudragit S100. The drug elution of the obtained dispersion is complete (the drug elution at 10 min is greater than 50%, and the drug elution at 60 min is greater than 97%).

[0019] In the examples of the present invention, Carrier may be HPMCAS912G (or HPMCAS MG).

[0020] In the examples of the present invention, the active ingredient may be the compound shown in formula (I).

[0021] In the examples of the present invention, in the solid dispersion, the mass ratio of the active ingredient to Carrier may be 1:1.2 to 1:8, or 1:2 to 1:4 (for example, 1:2). When the mass ratio of the active ingredient to Carrier is within the range of 1:1.2 to 1:8, at least one of the equilibrium solubility, stability, or drug elution of the solid dispersion has a good effect. For example, the elution can reach 90% or more, and for example, the equilibrium solubility is greater than 0.1 mg / ml. When the mass ratio of the active ingredient to Carrier is within the range of 1:2 to 1:4, the equilibrium solubility, stability, or drug elution of the solid dispersion has a better effect (for example, the elution may be greater than 98%, and the content after 30 days at 75% RH or 60 °C does not significantly change with related substances).

[0022] In the embodiments of the present invention, taking the mass of the active ingredient as 1 part, the solid dispersion may contain 1 part of the active ingredient and Carrier 1.2 to 8 parts.

[0023] In the embodiments of the present invention, taking the mass of the active ingredient as 1 part, the solid dispersion may contain 1 part of the active ingredient and Carrier 2 to 4 parts.

[0024] In the embodiments of the present invention, taking the mass of the active ingredient as 1 part, the solid dispersion may contain 1 part of the active ingredient and Hypromellose acetate succinate 1.2 to 8 parts.

[0025] In the embodiments of the present invention, taking the mass of the active ingredient as 1 part, the solid dispersion may contain 1 part of the active ingredient and Hypromellose acetate succinate 2 to 4 parts.

[0026] In the embodiments of the present invention, taking the mass of the active ingredient as 1 part, the solid dispersion may contain 1 part of the active ingredient and 2 to 4 parts of HPMCAS 912G (or HPMCAS MG).

[0027] In the embodiments of the present invention, taking the mass of the active ingredient as 1 part, the solid dispersion may contain 1 part of the active ingredient and 2 to 4 parts of HPMCAS 126G (or HPMCAS HG).

[0028] In the embodiments of the present invention, taking the mass of the active ingredient as 1 part, the solid dispersion may contain 1 part of the active ingredient and 2 to 4 parts of HPMCAS 716G (or HPMCAS LG).

[0029] In the embodiments of the present invention, taking the mass of the active ingredient as 1 part, the solid dispersion may contain 1 part of the active ingredient and Hypromellose acetate succinate 2 parts.

[0030] In the embodiments of the present invention, taking the mass of the active ingredient as 1 part, the solid dispersion may contain 1 part of the active ingredient and 2 parts of HPMCAS 912G (or HPMCAS MG).

[0031] In the embodiments of the present invention, the mass of the active ingredient is 1 part, and the solid dispersion may contain 1 part of the active ingredient and 2 parts of HPMCAS 126G (or HPMCAS HG).

[0032] In the embodiments of the present invention, the mass of the active ingredient is 1 part, and the solid dispersion may contain 1 part of the active ingredient and 2 parts of HPMCAS 716G (or HPMCAS LG).

[0033] In the embodiments of the present invention, the mass of the active ingredient is 1 part, and the solid dispersion may contain 1 part of the active ingredient and 1.2 to 8 parts of hydroxypropyl cellulose.

[0034] In the embodiments of the present invention, the mass of the active ingredient is 1 part, and the solid dispersion may contain 1 part of the active ingredient and 2 to 4 parts of hydroxypropyl cellulose.

[0035] In the embodiments of the present invention, the mass of the active ingredient is 1 part, and the solid dispersion may contain 1 part of the active ingredient and 2 to 4 parts of HPC EXF.

[0036] In the embodiments of the present invention, the mass of the active ingredient is 1 part, and the solid dispersion contains 1 part of the active ingredient and 2 parts of hydroxypropyl cellulose.

[0037] In the embodiments of the present invention, the mass of the active ingredient may be 1 part, and the solid dispersion may contain 1 part of the active ingredient and 2 parts of HPC EXF.

[0038] In the embodiments of the present invention, the mass of the active ingredient is 1 part, and the solid dispersion may contain 1 part of the active ingredient and 1.2 to 8 parts of povidone.

[0039] In the embodiments of the present invention, the mass of the active ingredient is 1 part, and the solid dispersion may contain 1 part of the active ingredient and 2 to 4 parts of povidone.

[0040] In the embodiments of the present invention, the mass of the active ingredient is 1 part, and the solid dispersion may contain 1 part of the active ingredient and 2 to 4 parts of PVP VA64.

[0041] In the embodiments of the present invention, the mass of the active ingredient may be 1 part, and the solid dispersion may contain 1 part of the active ingredient and 2 to 4 parts of PVP K29 / 32.

[0042] In the embodiments of the present invention, the mass of the active ingredient is 1 part, and the solid dispersion may contain 1 part of the active ingredient and 2 to 4 parts of PVP S-630.

[0043] In the embodiments of the present invention, the mass of the active ingredient is 1 part, and the solid dispersion contains 1 part of the active ingredient and 2 parts of povidone.

[0044] In the embodiments of the present invention, the mass of the active ingredient may be 1 part, and the solid dispersion may contain 1 part of the active ingredient and 2 parts of PVP VA64.

[0045] In the embodiments of the present invention, the mass of the active ingredient may be 1 part, and the solid dispersion may contain 1 part of the active ingredient and 2 parts of PVP K29 / 32.

[0046] In the embodiments of the present invention, the mass of the active ingredient is 1 part, and the solid dispersion may contain 1 part of the active ingredient and 2 parts of PVP S-630.

[0047] In the embodiments of the present invention, the mass of the active ingredient is 1 part, and the solid dispersion may contain 1 part of the active ingredient and 1.2 to 8 parts of acrylic resin.

[0048] In the embodiments of the present invention, the mass of the active ingredient is 1 part, and the solid dispersion may contain 1 part of the active ingredient and 2 to 4 parts of acrylic resin.

[0049] In the embodiments of the present invention, the mass of the active ingredient is 1 part, and the solid dispersion may contain 1 part of the active ingredient and 2 to 4 parts of Eudragit L100.

[0050] In the embodiments of the present invention, the mass of the active ingredient is 1 part, and the solid dispersion may contain 1 part of the active ingredient and 2 to 4 parts of Eudragit S100.

[0051] In the embodiments of the present invention, the mass of the active ingredient is 1 part, and the solid dispersion may contain 1 part of the active ingredient and 2 to 4 parts of Eudragit L100-55.

[0052] In the embodiments of the present invention, the mass of the active ingredient is 1 part, and the solid dispersion contains 1 part of the active ingredient and 2 parts of acrylic resin.

[0053] In the embodiments of the present invention, the mass of the active ingredient is 1 part, and the solid dispersion may contain 1 part of the active ingredient and 2 parts of Eudragit L100.

[0054] In the embodiments of the present invention, the mass of the active ingredient may be 1 part, and the solid dispersion may contain 1 part of the active ingredient and 2 parts of Eudragit S100.

[0055] In the embodiments of the present invention, the mass of the active ingredient is 1 part, and the solid dispersion may contain 1 part of the active ingredient and 2 parts of Eudragit L100-55.

[0056] In embodiments of the present invention, the solid dispersion further comprises an anti-tack agent. The anti-tack agent may contain one or more of colloidal silica, talc, starch, D-leucine, L-leucine, sodium lauryl sulfate, and metal stearate, for example, the anti-tack agent may be colloidal silica. The mass ratio of the anti-tack agent to the active ingredient may be 0.05 : 1 to 0.08 : 1 (for example, 0.064 : 1).

[0057] In the embodiments of the present invention, the mass of the active ingredient is 1 part, and the solid dispersion consists of 1 part of the active ingredient and 1.2 to 8 parts Carrier It may also contain 0.05 to 0.08 parts of an anti-tack agent.

[0058] In the embodiments of the present invention, the mass of the active ingredient is 1 part, and the solid dispersion contains 1 part of the active ingredient, Hypromellose acetate succinate It may also contain 1.2 to 8 parts and 0.05 to 0.08 parts of colloidal silica.

[0059] In the embodiments of the present invention, the mass of the active ingredient is 1 part, and the solid dispersion may contain 1 part of the active ingredient, 1.2 to 8 parts of HPMCAS 912G (or HPMCAS MG), and 0.05 to 0.08 parts of colloidal silica.

[0060] In the embodiments of the present invention, the mass of the active ingredient is 1 part, and the solid dispersion contains 1 part of the active ingredient, Hypromellose acetate succinate It may also contain 2 to 4 parts and 0.06 to 0.07 parts of colloidal silica.

[0061] In the embodiments of the present invention, the mass of the active ingredient is 1 part, and the solid dispersion may contain 1 part of the active ingredient, 2 to 4 parts of HPMCAS 912G (or HPMCAS MG), and 0.06 to 0.07 parts of colloidal silica.

[0062] In the embodiments of the present invention, the mass of the active ingredient is 1 part, and the solid dispersion contains 1 part of the active ingredient, Hypromellose acetate succinate It may also contain 2 parts and 0.064 parts of colloidal silica.

[0063] In the embodiments of the present invention, the mass of the active ingredient is 1 part, and the solid dispersion may contain 1 part of the active ingredient, 2 parts of HPMCAS 912G (or HPMCAS MG), and 0.064 parts of colloidal silica.

[0064] In this embodiment of the present invention, the solid dispersion is Carrier It may consist of an active ingredient.

[0065] In this embodiment of the present invention, the solid dispersion is Carrier It consists of an active ingredient and an anti-tack agent.

[0066] In the embodiments of the present invention, the solid dispersion is an amorphous solid dispersion.

[0067] The present invention further provides a method for producing a solid dispersion, and this method is Carrier The process includes the steps of mixing the active ingredient solvent with the active ingredient solvent to obtain a mixture, and then drying the mixture, and optionally mixing the mixture with an anti-tack agent before drying.

[0068] In the embodiments of the present invention, the mass-volume ratio of the active ingredient to the solvent may be 5:1 to 30:1 mg / ml, or 15:1 to 25:1 mg / ml (for example, 19.5:1 mg / ml). When the mass-volume ratio of the active ingredient to the solvent is within the range of 5:1 to 30:1 mg / ml, the stability of the active ingredient is good, and the amount of solvent residue in the produced solid dispersion is low (for example, it may be below the solvent limit).

[0069] In the embodiments of the present invention, the solvent may be one or more of the following: an alcohol-based solvent, water, an ester-based solvent, a ketone-based solvent, a halogenated hydrocarbon solvent, a nitrile-based solvent, or an ether-based solvent, or an ester-based solvent. The alcohol-based solvent may be ethanol. The ester-based solvent may be methyl acetate. The ether-based solvent may be tetrahydrofuran. The ketone-based solvent may be acetone. The halogenated hydrocarbon solvent may be dichloromethane. The nitrile-based solvent may be acetonitrile.

[0070] In embodiments of the present invention, drying may include a first drying and a second drying, the first drying may be spray drying or fluidized bed boiling drying. The second drying may be vacuum reduced-pressure drying or electric heated air drying, for example, vacuum reduced-pressure drying.

[0071] In the embodiments of the present invention, the drying endpoint is defined as the point at which the amount of residual solvent in the solid dispersion is within the limit range.

[0072] In the embodiments of the present invention, the drying time may be 4 to 16 hours. The drying time for the first stage may be 2 to 8 hours (for example, 5 hours). The drying time for the second stage may be 2 to 8 hours (for example, 2 hours).

[0073] The inventors discovered that an anti-tack agent can improve the electrostatic adhesion of powder during the spray-drying process. The effect of improving the electrostatic adhesion of powder during the drying process is better when the mass ratio of the anti-tack agent to the active ingredient is within the range of 0.05 : 1 to 0.08 : 1.

[0074] The present invention further provides a solid dispersion produced by the method for producing the solid dispersion.

[0075] The present invention further provides a pharmaceutical composition comprising the solid dispersion and an excipient.

[0076] The excipients used to prepare the above-mentioned pharmaceutical composition may include one or more of the following: encapsulating materials or preparation additives, such as absorption enhancers, antioxidants, dry anti-tack agents, buffers, coating materials, colorants, diluents, disintegrants, emulsifiers, flavoring agents, humectants, lubricants, anti-tack agents, fluidity enhancers, preservatives, solubilizers, flavoring agents, and release agents. The excipients may have two or more functions in the drug combination.

[0077] The present invention further provides a pharmaceutical composition comprising a solid dispersion, a diluent, a disintegrant, and a lubricant.

[0078] In the embodiments of the present invention, the diluent is cellulose (e.g., one or more of powdered cellulose, microcrystalline cellulose, silicified microcrystalline cellulose, α-amorphous cellulose, cellulose acetate, etc.), lactose (e.g., anhydrous lactose and / or lactose monohydrate), lactitol, maltitol, mannitol, sorbitol, xylitol, glucose (e.g., anhydrous glucose and / or glucose monohydrate), fructose, sucrose and sucrose-based diluents (e.g., one or more of compressible sugar, powdered sugar, candy shot, etc.), maltose, inosole, It may also contain hydrolyzed cereal solids, starch (one or more of the following: corn starch, wheat starch, rice starch, potato starch, tapioca starch, etc.), starch components (one or more of the following: amylose and glucose binder, and modified or processed starch, such as pregelled starch), dextrin, calcium salts (one or more of the following: calcium carbonate, calcium phosphate, calcium sulfate and calcium lactate, etc.), magnesium salts (e.g., magnesium carbonate and / or magnesium oxide), bentonite, kaolin and sodium chloride, one or more of the following.

[0079] In the embodiments of the present invention, the diluent may be one or more of the following: microcrystalline cellulose, silicified microcrystalline cellulose, calcium phosphate, pregelled starch, lactose, mannitol, and anhydrous calcium hydrogen phosphate; one or more of the following: microcrystalline cellulose, silicified microcrystalline cellulose, pregelled starch, calcium phosphate, and anhydrous calcium phosphate; or one or more of the following: microcrystalline cellulose, pregelled starch, and calcium phosphate; or microcrystalline cellulose and anhydrous calcium hydrogen phosphate. The microcrystalline cellulose may have a pH of 102 and / or a KG of 802. When the diluent is microcrystalline cellulose and anhydrous calcium hydrogen phosphate, the mass ratio of microcrystalline cellulose to anhydrous calcium hydrogen phosphate may be 0.1 : 1 to 10 : 1, or 0.5 : 1 to 2 : 1 (for example, 1 : 1).

[0080] In embodiments of the present invention, the disintegrant may include one or more of the following: starch (e.g., pregelled starch and / or sodium hydroxyacetate starch), clay, magnesium aluminum silicate, cellulosic disintegrants (e.g., powdered cellulose, microcrystalline cellulose, methylcellulose, lower-substituted hydroxypropylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose and cross-linked sodium carboxymethylcellulose), alginates, povidone, cross-linked povidone, potassium polacrin, gums (e.g., one or more of agar, guar gum, locust bean gum, ezocust bean gum, pectin and tragacanth gum, etc.), and colloidal silica.

[0081] In embodiments of the present invention, the disintegrant may be cross-linked carboxymethylcellulose sodium and / or cross-linked povidone.

[0082] The lubricant reduces friction between the solid formulation material and the equipment during formulation molding, for example, between the tablet press mixture and the tablet press device during tablet pressing. In embodiments of the present invention, the lubricant may include behenic acid glyceride, stearic acid and its salts (e.g., one or more of magnesium stearate, calcium stearate, sodium stearate, etc.), hydrogenated vegetable oil, palmitic stearate glyceride, talc, wax, sodium benzoate, sodium acetate, sodium fumarate, sodium stearyl fumarate, PEG (e.g., PEG4000 and / or PEG6000), poloxam, polyvinyl alcohol, sodium oleate, sodium lauryl sulfate, and magnesium lauryl sulfate, one or more of the above.

[0083] In the embodiments of the present invention, the lubricant may be one or more of magnesium stearate, polyethylene glycol, and magnesium laurate sulfate, or magnesium stearate.

[0084] Other excipients, such as dry anti-tacks, buffers, stabilizers, solubilizers, antioxidants, colorants, and flavorings, are known in the pharmaceutical field and can be used in the compositions of the present invention. The tablets do not need to be coated and may include tablets coated with, for example, a non-functional film or a release-modified or enteric coating. The capsules may have a hard or soft shell, which optionally contains one or more plasticizers, such as gelatin (in the form of a hard gelatin capsule or a soft elastic gelatin capsule), starch, carrageenan, and / or hydroxypropyl cellulose.

[0085] In the embodiments of the present invention, the mass ratio of the diluent to the solid dispersion may be 0.2 : 1 to 8 : 1, 0.5 : 1 to 8 : 1, 0.8 : 1 to 2 : 1, or 0.5 : 1 to 1 : 1 (for example, 1.15 : 1, 0.76 : 1, 1.36 : 1). When the mass ratio of the diluent to the solid dispersion is within the range of 0.2 : 1 to 8 : 1, the uncoated tablets produced by the pharmaceutical composition have a white sheet surface and are free of spots.

[0086] In the embodiments of the present invention, the mass ratio of the disintegrant to the solid dispersion may be 0.03 : 1 to 0.3 : 1, 0.1 : 1 to 0.2 : 1, 0.05 : 1 to 0.2 : 1, or 0.05 : 1 to 0.15 : 1 (for example, 0.08 : 1, 0.15 : 1, or 0.13 : 1). When the mass ratio of the disintegrant to the solid dispersion is within the range of 0.03 : 1 to 0.3 : 1, tablets produced by the pharmaceutical composition have good disintegration and dissolution effects (for example, the disintegration time may be 0.5 to 7.5 minutes, and the dissolution rate may be 90% or more).

[0087] In the embodiments of the present invention, the mass ratio of the lubricant to the solid dispersion may be 0.005 : 1 to 0.2 : 1, 0.01 : 1 to 0.2 : 1, 0.02 : 1 to 0.04 : 1, or 0.01 : 1 to 0.02 : 1 (for example, 0.042 : 1, 0.014 : 1, 0.026 : 1). When the mass ratio of the lubricant to the solid dispersion is within the range of 0.005 : 1 to 0.2 : 1, the powder produced by the pharmaceutical composition has good fluidity.

[0088] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.2 to 8 parts of a diluent, 0.03 to 0.3 parts of a disintegrant, and 0.005 to 0.2 parts of a lubricant.

[0089] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.5 to 1 part of silicified microcrystalline cellulose, 0.1 to 0.2 parts of cross-linked povidone, and 0.01 to 0.02 parts of magnesium stearate.

[0090] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.65 to 0.85 parts of silicified microcrystalline cellulose, 0.13 to 0.17 parts of cross-linked povidone, and 0.012 to 0.016 parts of magnesium stearate.

[0091] In the embodiments of the present invention, the mass of the solid dispersion may be 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.76 parts of silicified microcrystalline cellulose, 0.15 parts of cross-linked povidone, and 0.014 parts of magnesium stearate.

[0092] In this embodiment of the present invention, the pharmaceutical composition comprises a solid dispersion, a diluent, a disintegrant, and a lubricant.

[0093] In the embodiments of the present invention, the pharmaceutical composition may further include an anti-tack agent and a fluidity enhancer.

[0094] Anti-sticking agents can reduce adhesion to equipment surfaces during pharmaceutical manufacturing. In embodiments of the present invention, the anti-sticking agent may include one or more of the following: talc, colloidal silica, starch, D-leucine, L-leucine, sodium lauryl sulfate, and metal stearate.

[0095] In the embodiments of the present invention, the anti-tack agent may be one or more of colloidal silica, talc, and calcium chloride, or colloidal silica.

[0096] The fluidity enhancer improves the flow properties and reduces static electricity in the tablet mixture. In embodiments of the present invention, the fluidity enhancer may include one or more of the following: colloidal silica, starch, powdered cellulose, sodium lauryl sulfate, magnesium trisilicate, and metal stearate.

[0097] In the embodiments of the present invention, the fluidity enhancer may be colloidal silica and / or talc, or colloidal silica.

[0098] In the embodiments of the present invention, the mass ratio of the total mass of the anti-tack agent and the fluidity aid to the solid dispersion in the pharmaceutical composition may be 0.02 : 1 to 0.3 : 1, 0.05 : 1 to 0.1 : 1, or 0.1 : 1 to 0.2 : 1 (for example, 0.08 : 1, 0.13 : 1). When the mass ratio of the anti-tack agent and the fluidity aid to the solid dispersion is within the range of 0.02 : 1 to 0.3 : 1, it is more effective in preventing filming of the punch surface during the tablet pressing period and reducing stick punching of the tablets.

[0099] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.2 to 8 parts of a diluent, 0.02 to 0.3 parts of (anti-tack agent and fluidity enhancer), 0.03 to 0.3 parts of a disintegrant, and 0.005 to 0.2 parts of a lubricant.

[0100] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.8 to 2 parts of microcrystalline cellulose PH 102, 0.05 to 0.2 parts of cross-linked carboxymethylcellulose sodium, 0.05 to 0.1 parts of colloidal silica, and 0.02 to 0.04 parts of magnesium stearate.

[0101] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 1.26 to 1.46 parts of microcrystalline cellulose PH 102, 0.11 to 0.15 parts of cross-linked carboxymethylcellulose sodium, 0.06 to 0.1 parts of colloidal silica, and 0.02 to 0.04 parts of magnesium stearate.

[0102] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.53 to 1.32 parts of microcrystalline cellulose PH 102, 0.27 to 0.68 parts of pregelled starch, 0.05 to 0.2 parts of cross-linked carboxymethylcellulose sodium, 0.05 to 0.1 parts of colloidal silica, and 0.02 to 0.04 parts of magnesium stearate.

[0103] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.81 to 1.01 parts of microcrystalline cellulose PH 102, 0.35 to 0.55 parts of pregelled starch, 0.11 to 0.15 parts of cross-linked carboxymethylcellulose sodium, 0.06 to 0.1 parts of colloidal silica, and 0.02 to 0.04 parts of magnesium stearate.

[0104] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.4 to 1 part of microcrystalline cellulose PH 102, 0.4 to 1 part of calcium phosphate, 0.05 to 0.2 parts of cross-linked carboxymethylcellulose sodium, 0.05 to 0.1 parts of colloidal silica, and 0.02 to 0.04 parts of magnesium stearate.

[0105] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.58 to 0.78 parts of microcrystalline cellulose PH 102, 0.58 to 0.78 parts of calcium phosphate, 0.11 to 0.15 parts of cross-linked carboxymethylcellulose sodium, 0.07 to 0.09 parts of colloidal silica, and 0.02 to 0.04 parts of magnesium stearate.

[0106] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.4 to 1 part of microcrystalline cellulose KG 802, 0.4 to 1 part of anhydrous calcium phosphate, 0.05 to 0.2 parts of cross-linked carboxymethylcellulose sodium, 0.05 to 0.1 parts of colloidal silica, and 0.02 to 0.04 parts of magnesium stearate.

[0107] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.61 to 0.81 parts of microcrystalline cellulose KG 802, 0.61 to 0.81 parts of anhydrous calcium phosphate, 0.068 to 0.088 parts of cross-linked carboxymethylcellulose sodium, 0.05 to 0.054 parts of colloidal silica, and 0.03 to 0.04 parts of magnesium stearate.

[0108] In the embodiments of the present invention, the mass of the solid dispersion may be 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 1.36 parts of microcrystalline cellulose PH 102, 0.13 parts of cross-linked carboxymethylcellulose sodium, 0.08 parts of colloidal silica, and 0.03 parts of magnesium stearate.

[0109] In the embodiments of the present invention, the mass of the solid dispersion may be 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.91 parts of microcrystalline cellulose PH 102, 0.45 parts of pregelled starch, 0.13 parts of cross-linked carboxymethylcellulose sodium, 0.08 parts of colloidal silica, and 0.03 parts of magnesium stearate.

[0110] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.68 parts of microcrystalline cellulose PH 102, 0.68 parts of calcium phosphate, 0.13 parts of cross-linked carboxymethylcellulose sodium, 0.08 parts of colloidal silica, and 0.03 parts of magnesium stearate.

[0111] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.71 parts of microcrystalline cellulose KG 802, 0.71 parts of anhydrous calcium phosphate, 0.078 parts of cross-linked carboxymethylcellulose sodium, 0.052 parts of colloidal silica, and 0.04 parts of magnesium stearate.

[0112] In this embodiment of the present invention, the pharmaceutical composition comprises a solid dispersion, a diluent, a disintegrant, an anti-tack agent, a fluidity enhancer, and a lubricant.

[0113] In the embodiments of the present invention, the pharmaceutical composition may further contain a dry anti-sticking agent.

[0114] In embodiments of the present invention, the dry anti-tack agent may include one or more of the following: gum arabic, tragacanth gum, glucose, polyglucose, starch (e.g., pregelled starch), gelatin, modified cellulose (e.g., one or more of methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, and ethylcellulose), dextrin (e.g., maltodextrin), zein, alginic acid and alginate (e.g., sodium alginate), magnesium aluminum silicate, bentonite, polyethylene glycol, polyethylene oxide, guar gum, polysaccharide acid, polyvinylpyrrolidone, polyacrylic acid (e.g., capom), polymethacrylate ester, etc.

[0115] In the embodiments of the present invention, the dry anti-tack agent in the pharmaceutical composition may be hydroxypropylcellulose and / or hydroxypropylmethylcellulose, or hydroxypropylcellulose.

[0116] In the embodiments of the present invention, the mass ratio of the dry anti-tack agent to the solid dispersion in the pharmaceutical composition may be 0.02 : 1 to 0.5 : 1, or 0.1 : 1 to 0.3 : 1 (for example, 0.13 : 1). When the mass ratio of the dry anti-tack agent to the solid dispersion is within the range of 0.02 : 1 to 0.5 : 1, the hardness and brittleness of the tablets produced by the pharmaceutical composition are high, and when the mass ratio is within the range of 0.1 : 1 to 0.3 : 1, the hardness and brittleness of the tablets produced by the pharmaceutical composition are even higher (for example, the hardness may be between 60 and 170 N, and the brittleness may be between 0.07% and 0.55% (200 rpm)).

[0117] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.2 to 8 parts of a diluent, 0.02 to 0.5 parts of a dry anti-tack agent, 0.02 to 0.3 parts of (anti-tack agent and fluidity enhancer), 0.03 to 0.3 parts of a disintegrant, and 0.005 to 0.2 parts of a lubricant.

[0118] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.25 to 4 parts of microcrystalline cellulose KG 802, 0.25 to 4 parts of calcium phosphate, 0.03 to 0.3 parts of cross-linked carboxymethylcellulose sodium, 0.02 to 0.5 parts of hydroxypropyl cellulose, 0.02 to 0.3 parts of colloidal silica, and 0.02 to 0.3 parts of magnesium stearate.

[0119] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.5 to 0.7 parts of microcrystalline cellulose KG 802, 0.5 to 0.7 parts of calcium phosphate, 0.11 to 0.15 parts of cross-linked carboxymethylcellulose sodium, 0.14 to 0.18 parts of hydroxypropyl cellulose, 0.04 to 0.08 parts of colloidal silica, and 0.02 to 0.04 parts of magnesium stearate.

[0120] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.25 to 4 parts of microcrystalline cellulose KG 802, 0.25 to 4 parts of anhydrous calcium phosphate, 0.03 to 0.3 parts of cross-linked carboxymethylcellulose sodium, 0.02 to 0.5 parts of hydroxypropyl cellulose, 0.02 to 0.3 parts of colloidal silica, and 0.02 to 0.3 parts of magnesium stearate.

[0121] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.55 to 0.75 parts of microcrystalline cellulose KG 802, 0.55 to 0.75 parts of anhydrous calcium phosphate, 0.07 to 0.15 parts of cross-linked carboxymethylcellulose sodium, 0.07 to 0.18 parts of hydroxypropyl cellulose, 0.04 to 0.15 parts of colloidal silica, and 0.02 to 0.06 parts of magnesium stearate.

[0122] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.61 parts of microcrystalline cellulose KG 802, 0.61 parts of calcium phosphate, 0.13 parts of cross-linked carboxymethylcellulose sodium, 0.16 parts of hydroxypropyl cellulose, 0.06 parts of colloidal silica, and 0.03 parts of magnesium stearate.

[0123] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.65 parts of microcrystalline cellulose KG 802, 0.65 parts of anhydrous calcium phosphate, 0.078 parts of cross-linked carboxymethylcellulose sodium, 0.14 parts of hydroxypropyl cellulose, 0.05 parts of colloidal silica, and 0.03 parts of magnesium stearate.

[0124] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.66 parts of microcrystalline cellulose KG 802, 0.66 parts of anhydrous calcium phosphate, 0.078 parts of cross-linked carboxymethylcellulose sodium, 0.1 parts of hydroxypropyl cellulose, 0.052 parts of colloidal silica, and 0.04 parts of magnesium stearate.

[0125] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.65 parts of microcrystalline cellulose KG 802, 0.65 parts of anhydrous calcium phosphate, 0.084 parts of cross-linked carboxymethylcellulose sodium, 0.13 parts of hydroxypropyl cellulose, 0.052 parts of colloidal silica, and 0.03 parts of magnesium stearate.

[0126] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.61 parts of microcrystalline cellulose KG 802, 0.61 parts of calcium phosphate, 0.13 parts of cross-linked carboxymethylcellulose sodium, 0.16 parts of hydroxypropyl cellulose, 0.065 parts of colloidal silica, and 0.026 parts of magnesium stearate.

[0127] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.65 parts of microcrystalline cellulose KG 802, 0.65 parts of anhydrous calcium phosphate, 0.078 parts of cross-linked carboxymethylcellulose sodium, 0.13 parts of hydroxypropyl cellulose, 0.052 parts of colloidal silica, and 0.032 parts of magnesium stearate.

[0128] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.61 parts of microcrystalline cellulose KG 802, 0.61 parts of anhydrous calcium phosphate, 0.082 parts of cross-linked carboxymethylcellulose sodium, 0.13 parts of hydroxypropyl cellulose, 0.049 parts of colloidal silica, and 0.038 parts of magnesium stearate.

[0129] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.59 parts of microcrystalline cellulose KG 802, 0.59 parts of anhydrous calcium phosphate, 0.082 parts of cross-linked carboxymethylcellulose sodium, 0.13 parts of hydroxypropyl cellulose, 0.075 parts of colloidal silica, and 0.057 parts of magnesium stearate.

[0130] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.57 parts of microcrystalline cellulose KG 802, 0.57 parts of anhydrous calcium phosphate, 0.082 parts of cross-linked carboxymethylcellulose sodium, 0.13 parts of hydroxypropyl cellulose, 0.14 parts of colloidal silica, and 0.057 parts of magnesium stearate.

[0131] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.61 parts of microcrystalline cellulose KG 802, 0.61 parts of anhydrous calcium phosphate, 0.13 parts of cross-linked carboxymethylcellulose sodium, 0.16 parts of hydroxypropyl cellulose, 0.065 parts of colloidal silica, and 0.026 parts of magnesium stearate.

[0132] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.65 parts of microcrystalline cellulose KG 802, 0.65 parts of anhydrous calcium phosphate, 0.078 parts of cross-linked carboxymethylcellulose sodium, 0.14 parts of hydroxypropyl cellulose, 0.052 parts of colloidal silica, and 0.032 parts of magnesium stearate.

[0133] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.57 parts of microcrystalline cellulose KG 802, 0.57 parts of anhydrous calcium phosphate, 0.082 parts of cross-linked carboxymethylcellulose sodium, 0.13 parts of hydroxypropyl cellulose, 0.14 parts of colloidal silica, and 0.057 parts of magnesium stearate.

[0134] In the embodiments of the present invention, the mass of the solid dispersion is 1 part, and the pharmaceutical composition may contain 1 part of the solid dispersion, 0.575 parts of microcrystalline cellulose KG 802, 0.575 parts of anhydrous calcium phosphate, 0.13 parts of hydroxypropyl cellulose, 0.08 parts of cross-linked carboxymethylcellulose sodium, 0.13 parts of colloidal silica, and 0.042 parts of magnesium stearate.

[0135] In this embodiment of the present invention, the pharmaceutical composition may consist of a solid dispersion, a diluent, a dry anti-tack agent, a disintegrant, an anti-tack agent, a fluidity enhancer, and a lubricant.

[0136] The present invention further provides a pharmaceutical formulation comprising a pharmaceutical composition, the pharmaceutical formulation may be a solid formulation or a powder, granules, tablet, capsule, dropper, or film formulation.

[0137] The present invention further provides a method for manufacturing tablets, Step 1 involves mixing a solid dispersion, a diluent, and a disintegrant to obtain a mixture, sieving and granulating to obtain particles, optionally mixing a dry anti-tack agent with the mixture before sieving, optionally mixing an anti-tack agent, a fluidity enhancer, and the mixture before sieving, optionally adding a lubricant before granulation or after sieving. Step 2 includes mixing the particles from Step 1 with a lubricant and pressing the tablets, and optionally mixing the particles from Step 1 with an anti-tack agent and a flow aid.

[0138] The anti-tack agent and fluidity enhancer may all be added in step 1 (without adding them in step 2), or some of the anti-tack agent and fluidity enhancer may be added in step 1 and the remaining anti-tack agent and fluidity enhancer may be added in step 2.

[0139] The lubricant may be added entirely in step 2 (without adding any lubricant in step 1), or some of the lubricant may be added in step 1 and the remaining lubricant in step 2.

[0140] In the embodiments of the present invention, when a portion of the anti-tack agent and fluidity enhancer are added in step 1, and the remaining anti-tack agent and fluidity enhancer are added in step 2, the total amount of the anti-tack agent and fluidity enhancer is 100%, and the mass percentage of the anti-tack agent and fluidity enhancer in step 1 is 0.5% to 20% (for example, 5.8%).

[0141] In the embodiments of the present invention, when a portion of the lubricant is added in step 1 and the remaining lubricant is added in step 2, the total amount of lubricant is 100%, and the mass percentage of the lubricant in step 1 is 0.1% to 10% (for example, 1.9%).

[0142] In embodiments of the present invention, in step 1, mixing may be performed in a mixer, the mixing speed may be 15 to 21 rpm (e.g., 18 rpm), and the mixing time may be 4 to 10 minutes (e.g., 5 minutes).

[0143] In embodiments of the present invention, in step 1, the sieving may be performed using a sieve with a mesh size of 30 to 50 (for example, a sieve with a mesh size of 40).

[0144] In embodiments of the present invention, in step 1, granulation may be dry granulation. The press wheel pressure for dry granulation may be 2.0 to 10.0 MPa (e.g., 4.0 to 7.0 MPa). The press wheel gap for dry granulation may be 0.5 to 8.0 mm (e.g., 1.0 to 5.0 mm). The press wheel speed for dry granulation may be 2.0 to 10.0 rpm (e.g., 3.0 to 7.0 rpm). The granulation member speed for dry granulation may be 20 to 120 rpm (e.g., 30 to 90 rpm). The supply shaft speed for dry granulation may be 10 to 120 rpm (e.g., 18 to 90 rpm). The fine screen for dry granulation may be a screen of 0.6 to 10.0 mm (e.g., a 0.8 mm screen).

[0145] In embodiments of the present invention, in step 2, the tablet press feeding speed may be 3 to 40 rpm (e.g., 5 to 30 rpm). The tablet rotation speed may be 15 to 40 rpm (e.g., 20 to 30 rpm). The tablet thickness scale may be 0.1 to 7 mm (e.g., 0.3 to 5.0 mm). The tablet feeding scale may be 7 to 18 mm (e.g., 10.5 to 15.5 mm). The primary pressure range for the tablets may be 5 to 35 kN (e.g., 10 to 25 kN).

[0146] The present invention further provides tablets manufactured by a method for manufacturing tablets.

[0147] The present invention further provides coated tablets containing a pharmaceutical composition.

[0148] In the embodiments of the present invention, the mass ratio of the pharmaceutical composition to the coating in the coated tablet may be 0.02 : 1 to 0.2 : 1, or 0.05 : 1 to 0.1 : 1 (for example, 0.08 : 1).

[0149] In the embodiments of the present invention, the coating in the coated tablet comprises polyvinyl alcohol, titanium dioxide, talc, triethylglycerin, and hydroxypropyl methylcellulose.

[0150] In the embodiments of the present invention, the coating in the coated tablets is OPADRY® II film coating premix.

[0151] The present invention further provides coated tablets, including tablets manufactured by the method for manufacturing tablets.

[0152] In the embodiments of the present invention, the mass ratio of the tablet to the coating in the coated tablet may be 0.02 : 1 to 0.2 : 1, or 0.05 : 1 to 0.1 : 1 (for example, 0.08 : 1).

[0153] In the embodiments of the present invention, the coating in the coated tablet comprises polyvinyl alcohol, titanium dioxide, talc, triethylglycerin, and hydroxypropyl methylcellulose.

[0154] In the embodiments of the present invention, the coating of the coated tablets is OPADRY® II film coating premix.

[0155] The present invention further provides applications, for example, in the manufacture of drugs for treating related diseases caused by P53 and / or MDM2 abnormalities, of the above-mentioned solid dispersions.

[0156] In the embodiments of the present invention, the associated disease resulting from P53 and / or MDM2 abnormalities is cancer or a hyperproliferative disorder.

[0157] The present invention provides a method for treating cancer, comprising administering a therapeutically effective amount of the solid dispersion, the pharmaceutical composition, the tablet, or the coated tablet to the required individual.

[0158] In the embodiments of the present invention, cancer refers to adrenocortical carcinoma, terminal cancer, anal cancer, anemia with regenerative disorders, cholangiocarcinoma, bladder cancer, bone cancer, bone metastases, adult brain / CNS tumors, pediatric brain / CNS tumors, breast cancer, male breast cancer, pediatric cancer, unknown primary cancer, giant lymph node proliferation (Castleman disease), cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, Ewing family of tumors, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors (GIST), gestational trophoblastic disease, Hodgkin's disease, and Kaposi's sarcoma. sarcoma), renal cancer, laryngeal and hypopharyngeal cancer, adult acute lymphocytic leukemia (ALL), acute skeletal leukemia (AML), chronic lymphocytic leukemia (CLL), chronic skeletal leukemia (CML), chronic skeletal leukemia Coccytic leukemia (CMML), childhood leukemia, liver cancer, non-small cell lung cancer, small cell lung cancer, lung carcinoid tumor, cutaneous lymphoma, malignant mesothelioma, multiple osteodylar tumors, abnormal bone growth syndrome, nasal cavity / sinus cancer, nasopharyngeal cancer These include neuroblastoma, non-Hodgkin lymphoma, pediatric non-Hodgkin lymphoma, oral and oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic adenocarcinoma, penile cancer, pituitary tumor, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma - adult soft tissue cancer, basal skin cancer and squamous cell carcinoma, skin cancer - melanoma, small intestine cancer, gastric cancer, testicular cancer, thymic cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenstrom macroglobulinemia, or Wilms' tumor.

[0159] In this invention, “optional” means that the events or environments described later may occur, but are not required to occur. The description includes both cases in which such events or environments occur and cases in which they do not occur.

[0160] In this invention, "solid dispersion" means any solid composition having at least two components. It includes an active component (a compound shown in formula (I)), and the active component is at least one other component (e.g., Hypromellose acetate succinate It will be distributed among the following:

[0161] As shown in formula (I), a pharmaceutically acceptable salt of the compound may be an acid addition salt formed with a pharmaceutically acceptable acid. Examples of acids that make up a pharmaceutically acceptable salt include inorganic acids such as nitric acid, boric acid, hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid, and citric acid. Non-limiting examples of salts of the compounds of the present invention include hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, 2-hydroxyethanesulfonate, phosphate, hydrogen phosphate, acetate, adipine, alginate, aspartate, benzoate, hydrogen sulfate, butyrate, camphorate, camphor sulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, caproate, formate, succinate, fumarate, maleate, ascorbate, hydroxyethylsulfonate, salicylate, methanesulfonate, mesityleneate, This includes, but is not limited to, naphthalene sulfonate, nicotinate, 2-naphthalene sulfonate, oxalate, bishydroxynaphthaleneate, pectinate, persulfate, 3-phenylpropionate, picrate, pivaphosphate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfonate, undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, ethanedisulfonate, benzenesulfonate, and p-toluenesulfonate.

[0162] Without contradicting the common sense of those skilled in the art, each of the above preferred conditions may be arbitrarily combined to obtain each of the preferred embodiments of the present invention.

[0163] A positive effect of the present invention is that the solid dispersion according to the present invention can improve the elution rate of the active ingredient APG-115, and the elution rate of some of the solid dispersions of the present invention, APG-115, can reach 90% or more (e.g., 93.7%, 95.2%, 99.0%, etc.), and has good stability, improving the solubility and elution rate of the drug in gastrointestinal fluid and improving oral bioavailability. The solid dispersion of the present invention shows high plasma exposure in dogs, i.e., high drug peak concentration and high area under the blood concentration curve. [Brief explanation of the drawing]

[0164] [Figure 1] These are the curves for oral administration of APG-115ASD and APG-115 hydrate in dogs. [Modes for carrying out the invention]

[0165] The present invention will be further described below using the methods of the embodiments, but the present invention is not limited to the scope of the embodiments.

[0166] In the following examples, the method for producing APG-115 hydrate may refer to CN106794171A, and other raw materials are commercially available.

[0167] DSC test method: The test sample was placed on a sealed aluminum plate and heated to 300°C at a rate of 10°C / min using a nitrogen stream, and a differential scanning calorimetry (DSC) curve was obtained.

[0168] Equilibrium solubility test: A suspension sample prepared with water was stirred at 37°C and 50 rpm for 6 hours, then centrifuged to obtain the upper clarified liquid, and the concentration of APG-115 in the upper clarified liquid was measured by HPLC.

[0169] Drug dissolution test: The Chinese Pharmacopoeia dissolution test method II (pulp method) was adopted. 900 ml of pH 6.8 phosphate solution (0.2% sodium dodecyl sulfate) was used as the elution medium, and the rotation speed was 75 revolutions per minute.

[0170] In the following examples, the APG-115 hydrate used is APG-115 monohydrate. Other hydrates of APG-115 (e.g., hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, nunahydrate, decahydrate, elevenhydrate, dodecahydrate, etc.) may be used in the production of APG-115ASD. Of course, ASD may also be produced using salts or crystalline forms of APG-115. Example 1

[0171] APG-115 hydrate and HPMCAS126G (with a mass ratio of 1:3 between APG-115 hydrate and HPMCAS126G, i.e., a drug load of 25%) were weighed. A certain volume of ethyl acetate (which can completely dissolve HPMCAS126G and APG-115 hydrate) was weighed out and placed in a narrow-mouthed glass bottle. HPMCAS126G and APG-115 hydrate were slowly added by magnetic stirring and stirred until completely dissolved. The resulting solution was spray-dried (actual blow-off temperature 40-70°C, 5 hours), filtered through a 40-mesh screen, and APG-115ASD was obtained.

[0172] Amorphous solid dispersion (APG-115ASD) was tested for related substances, equilibrium solubility, and drug dissolution. Results: The related substance was present at 0.47%, the equilibrium solubility was 0.0898 mg / ml, and the drug dissolution rates at 10 min, 30 min, and 60 min were 64.5%, 95.2%, and 99.0%, respectively. Example 2

[0173] In Example 1, HPMCAS126G was replaced with HPMCAS716G, and APG-115ASD was prepared and characterized using the same method as in Example 1. Results: The relevant substance was 0.53%, the equilibrium solubility was 0.1099 mg / ml, and the drug dissolution rates at 10 min, 30 min, and 60 min were 78%, 93.6%, and 97.1%, respectively. Example 3

[0174] In Example 1, HPMCAS126G was replaced with HPMCAS912G, and APG-115ASD was prepared using the same method as in Example 1. DSC scanning, related substance analysis, equilibrium solubility, and drug dissolution tests were then performed. Results: The DSC scan showed no obvious endothermic or exothermic peaks. Related substance: 0.50%. Equilibrium solubility: 0.1028 mg / ml. Drug dissolution at 10 min, 30 min, and 60 min was 80.8%, 97.5%, and 101.4%, respectively. Example 4

[0175] In Example 1, HPMCAS126G was replaced with HPC Klucel EXF, and APG-115ASD was prepared using the same method as in Example 1. DSC scanning and related substance testing were then performed. Results: The DSC scan showed no obvious endothermic or exothermic peaks, and the related substance was 0.33%. Example 5

[0176] APG-115ASD was prepared and characterized by replacing HPMCAS126G with PVP VA64 in Example 1 and using the same method as in Example 1. Results: The relevant substance was 0.41%, the equilibrium solubility was 0.2384 mg / mL, and the drug dissolution rates at 10 min, 30 min, and 60 min were 11.0%, 65.6%, and 91.1%, respectively. Example 6

[0177] APG-115ASD was prepared and characterized by replacing HPMCAS126G with PVP K29 / 32 in Example 1, and using the same method as in Example 1. Results: The relevant substance was present at 0.23%, the equilibrium solubility was 0.0558 mg / mL, and the drug dissolution rates at 10 min, 30 min, and 60 min were 6.0%, 48.4%, and 90.1%, respectively. Example 7

[0178] In Example 1, HPMCAS126G was replaced with PVP S-630, and APG-115ASD was prepared and characterized using the same method as in Example 1. Results: The relevant substance was 0.85%, the equilibrium solubility was 0.0351 mg / mL, and the drug dissolution rates at 10 min, 30 min, and 60 min were 13.0%, 76.9%, and 97.7%, respectively. Example 8

[0179] In Example 1, HPMCAS126G was replaced with Eudragit L100, and APG-115ASD was prepared using the same method as in Example 1. Related substance and drug dissolution tests were then performed. Results: Related substance dissolution was 0.53%, and drug dissolution at 10 min, 30 min, and 60 min was 54.2%, 97.5%, and 98.3%, respectively. Example 9

[0180] In Example 1, HPMCAS126G was replaced with Eudragit S100, and APG-115ASD was prepared using the same method as in Example 1. DSC scanning and drug dissolution testing were then performed to characterize the drug. Results: The DSC scan showed no obvious endothermic or exothermic peaks, and the drug dissolution rates at 10 min, 30 min, and 60 min were 48.7%, 96.3%, and 99.7%, respectively. Example 10

[0181] HPMCAS126G in Example 1 was replaced with Eudragit L100-55. APG-115 ASD was prepared using the same method as in Example 1, and DSC scanning, related substance analysis, and drug dissolution tests were performed. Results: The DSC scan showed no obvious endothermic or exothermic peaks, and the drug dissolution rates at 10 min, 30 min, and 60 min were 83.7%, 92.8%, and 96.6%, respectively. Example 11

[0182] APG-115 hydrate, HPMCAS912G (mass ratio of APG-115 hydrate to HPMCAS912G is 1:4), and colloidal silica (mass ratio of colloidal silica to APG-115 hydrate is 1:9.8) were weighed. A certain volume of ethyl acetate (HPMCAS126G, which can completely dissolve APG-115 hydrate and colloidal silica) was weighed out and placed in a narrow-mouthed glass bottle. HPMCAS912G, APG-115 hydrate, and colloidal silica were slowly added sequentially by magnetic stirring until completely dissolved. The resulting solution was spray-dried (actual blowing temperature 40-65°C, 5 hours), filtered through a 40-mesh screen, and obtained APG-115ASD. DSC and drug dissolution tests were performed on the amorphous solid dispersion (APG-115ASD). Results: DSC scans showed no obvious endothermic or exothermic peaks, and drug dissolution rates at 10 min, 30 min, and 60 min were 85.7%, 101.4%, and 101.8%, respectively. Example 12

[0183] In Example 11, the amounts of APG-115 hydrate, HPMCAS912G, and colloidal silica were changed, with the mass ratio of APG-115 hydrate to HPMCAS912G set to 1:3 and the mass ratio of colloidal silica to HPMCAS912G set to 1:12.25. APG-115ASD was prepared using the same method as in Example 10, and DSC scanning, drug dissolution, and total impurities were tested. Results: The DSC scan showed no obvious endothermic or exothermic peaks. The drug dissolution at 10 min, 30 min, and 60 min was 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

[0184] In Example 11, the amounts of APG-115 hydrate, HPMCAS912G, and colloidal silica were changed, with the mass ratio of APG-115 hydrate to HPMCAS912G set to 1:2 and the mass ratio of colloidal silica to HPMCAS912G set to 1:16.35. APG-115ASD was prepared using the same method as in Example 10, and DSC scanning, drug dissolution, and total impurities were tested. Results: The DSC scan showed no obvious endothermic or exothermic peaks. The drug dissolution at 10 min, 30 min, and 60 min was 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

[0185] In Example 11, the amounts of APG-115 hydrate, HPMCAS912G, and colloidal silica were changed to a mass ratio of 1:1 between APG-115 hydrate and HPMCAS912G, and a mass ratio of 1:24.5 between colloidal silica and HPMCAS912G. APG-115ASD was prepared using the same method as in Example 10, and DSC scanning and drug dissolution tests were performed. Results: The DSC scan showed the presence of a sharp crystalline endothermic peak, and the drug dissolution rates at 10 min, 30 min, and 60 min were 21.1%, 87.6%, and 100.9%, respectively. Example 15

[0186] APG-115 hydrate and Hypromellose acetate succinate The following was weighed out: A certain volume of 90% ethanol was measured out, placed in a glass narrow-necked bottle, and APG-115 hydrate was dissolved by magnetic stirring until completely dissolved. Hypromellose acetate succinate The drug was slowly added to prepare a drug-containing solution, the total impurities in the drug-containing solution were measured, the drug-containing solution was left to stand for more than 20 hours, and the total impurities in the drug-containing solution were measured again. Results: The initial total impurities in the drug-containing solution were 0.20%, and the total impurities in the solution left to stand for more than 20 hours were 0.63%. Example 16

[0187] In Example 14, 90% ethanol was replaced with ethanol and tetrahydrofuran (volume ratio 4:1), and a drug-containing solution was prepared in the same manner as in Example 15, and a total impurity test was performed. Results: The initial total impurity content of the drug-containing solution was 0.23%, and the total impurity content of the solution after standing for 20 hours or more was 0.34%. Example 17

[0188] APG-115 hydrate and Hypromellose acetate succinate (APG-115 hydrate and Hypromellose acetate succinate A certain volume of methyl acetate (the mass ratio of is 1:2) was weighed. Hypromellose acetate succinate (It is sufficient if the APG-115 hydrate can be completely dissolved) Measure out the required amount, place it in a glass narrow-necked bottle, and stir with magnetic force until completely dissolved. Hypromellose acetate succinateThe drug was slowly added to prepare a drug-containing solution, and the total impurities in the drug-containing solution were measured. The drug-containing solution was then left to stand for more than 20 hours, and the total impurities in the drug-containing solution were measured again. The drug solution was spray-dried (actual blowing temperature 40-65°C, 5 hours) and vacuum-dried (50°C, 2 hours). A solvent residue test was performed on the dried APG-115ASD. Results: The total impurities in the initial solution were 0.34%, and the total impurities in the solution left to stand for more than 20 hours were 0.37%, with a residual solvent of 0.02%. Example 18

[0189] In Example 17, methyl acetate was replaced with tetrahydrofuran, and a drug-containing solution was prepared using the same method as in Example 17. A total impurity test was performed to prepare APG-115ASD, and a solvent residue test was performed on the dried APG-115ASD. Results: The total impurity content of the initial solution was 0.25%, the total impurity content of the solution after standing for more than 20 hours was 0.27%, and the residual solvent content was 3.48%. Example 19

[0190] In Example 13, APG-115ASD, microcrystalline cellulose Avicel® PH 102, cross-linked carboxymethylcellulose sodium, colloidal silica, and magnesium stearate (where APG-115ASD, microcrystalline cellulose Avicel® PH 102, cross-linked carboxymethylcellulose sodium, colloidal silica, and magnesium stearate account for 38.5%, 52.5%, 5%, 3%, and 1% of the total substance, respectively) were weighed. After passing the APG-115ASD, microcrystalline cellulose Avicel® PH 102, cross-linked carboxymethylcellulose sodium, and colloidal silica through a 40-mesh screen three times, they were shaken and mixed 200 times in a clean, dry LDPE bag. 0.5% magnesium stearate (mass percentage is the mass fraction of the total substance) sieved through a 60-mesh sieve was added to the mixed powder and shaken 60 times to perform dry granulation (where the roll speed was 5 The pressure of the pressure roll was set to 7-11 MPa, the fine screen was 24 mesh, and the dry particles were collected in a clean, dry LDPE bag. Magnesium stearate, which had been screened on the remaining 60 mesh, was added to the dry particles and shaken 60 times in the LDPE bag to obtain a total mixed powder. The total mixed powder was pressed onto a single punching machine in a shallow arc with a diameter of 10 mm to form 400 mg tablets. Various parameters and drug dissolution tests were performed on the tablets, and the results are shown in Table 1. [Table 1] Example 20

[0191] APG-115ASD, microcrystalline cellulose Avicel® PH 102, pregelled starch, cross-linked carboxymethylcellulose sodium, colloidal silica, and magnesium stearate (here, APG-115ASD, microcrystalline cellulose Avicel® PH 102, pregelled starch, cross-linked carboxymethylcellulose sodium, colloidal silica, and magnesium stearate account for 38.5%, 35%, 17.5%, 5%, 3%, and 1% of the total substances, respectively) were weighed, and APG-115ASD, microcrystalline cellulose Avicel® PH 102. Pregelled starch, cross-linked carboxymethylcellulose sodium, and colloidal silica were passed through a 40-mesh screen three times, then placed in a clean, dry LDPE bag and shaken 200 times. 0.5% magnesium stearate (mass percentage is the mass fraction of the total substance) passed through a 60-mesh screen was added to the above mixed powder and shaken 60 times to perform dry granulation (where the roll speed was 5 rpm, the pressure roll pressure was 7-11 MPa, the fine screen was 24 mesh, and the dry particles were collected in a clean, dry LDPE bag). The remaining magnesium stearate passed through a 60-mesh screen was added to the dry particles and shaken 60 times in the LDPE bag to obtain the total mixed powder. The total mixed powder was pressed on a single punching machine in a shallow arc with a diameter of 10 mm to form 400 mg tablets. The parameters and drug dissolution rate of the tablets were tested, and the results are shown in Table 2. [Table 2] Example 21

[0192] APG-115ASD from Example 13, microcrystalline cellulose Avicel® PH 102, calcium phosphate, cross-linked carboxymethylcellulose sodium, colloidal silica, and magnesium stearate (where APG-115ASD, microcrystalline cellulose Avicel® PH 102, calcium phosphate, cross-linked carboxymethylcellulose sodium, colloidal silica, and magnesium stearate account for 38.5%, 26.25%, 26.25%, 5%, 3%, and 1% of the total substance, respectively) were weighed, and APG-115ASD, microcrystalline cellulose Avicel® PH 102, calcium phosphate, cross-linked carboxymethylcellulose sodium, and colloidal silica were passed through a 40-mesh screen three times, then placed in a clean, dry LDPE bag and shaken 200 times. 0.5% magnesium stearate (mass percentage is the mass fraction of the total substance) passed through a 60-mesh screen was added to the above mixed powder and shaken 60 times to perform dry granulation (where the roll speed was 5 rpm, the pressure roll pressure was 7-11 MPa, the fine screen was 24 mesh, and the dry particles were collected in a clean, dry LDPE bag). The remaining magnesium stearate passed through a 60-mesh screen was added to the dry particles and shaken 60 times in the LDPE bag to obtain the total mixed powder. The total mixed powder was pressed on a single punching machine in a shallow arc with a diameter of 10 mm to form 400 mg tablets. The parameters and drug dissolution tests of the tablets were performed, and the results are shown in Table 3. [Table 3] Example 22

[0193] APG-115ASD, microcrystalline cellulose KG 802, calcium phosphate, cross-linked carboxymethylcellulose sodium, hydroxypropylcellulose, colloidal silica, and magnesium stearate from Example 13 were weighed (here, APG-115ASD, microcrystalline cellulose KG 802, calcium phosphate, cross-linked carboxymethylcellulose sodium, hydroxypropylcellulose, colloidal silica, and magnesium stearate account for 38.5%, 23.5%, 23.5%, 5%, 6%, 2.5%, and 1% of the total substance, respectively), and APG-115ASD, microcrystalline cellulose KG 802, calcium phosphate, cross-linked carboxymethylcellulose sodium, hydroxypropylcellulose, and colloidal silica are passed through a 40-mesh screen three times, then placed in a clean, dry LDPE bag and shaken 200 times. 0.5% magnesium stearate (mass percentage is the mass fraction of the total substance) passed through a 60-mesh screen is added to the above mixed powder and shaken 60 times to perform dry granulation (where the roll rotation speed is 5 rpm, the roll pressure is 7-11 mpa, the fine screen is 24 mesh, and the dry particles are collected in a clean, dry LDPE bag), and the amount of fine powder (<80 mesh) is greater than 20%. The remaining magnesium stearate passed through a 60-mesh screen is added to the above dry particles and shaken 60 times in the LDPE bag to obtain the total mixed powder. The total mixed powder is pressed into 400 mg tablets using a 9.5 mm diameter circular punch on a single punching machine, and OPADRY II 85f620079 (OPADRY II The uncoated tablets were coated with a film coating premix (the mass of 85f620079 is 3% of the uncoated tablet mass). Drug dissolution tests were performed on each parameter of the uncoated tablets and on the coated tablets. The results are shown in Table 4. [Table 4] Example 23

[0194] The following were weighed out: APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, cross-linked sodium carboxymethylcellulose, hydroxypropyl cellulose, colloidal silica, and magnesium stearate (the mass percentages of the total substances in APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, cross-linked sodium carboxymethylcellulose, hydroxypropyl cellulose, colloidal silica, and magnesium stearate were 38.5%, 25%, 25%, 3%, 5.25%, 2%, and 1.25%, respectively) and APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, cross-linked sodium carboxymethylcellulose, hydroxypropylcellulose, and colloidal silica are passed through a 40-mesh screen three times, then placed in a clean, dry LDPE bag and shaken 200 times to mix. 0.75% magnesium stearate (mass percentage is the mass fraction of the total substance) passed through a 60-mesh screen is added to the above mixed powder and shaken 60 times to perform dry granulation (where the roll speed is 5 rpm, the press wheel pressure is 7-11 MPa, the fine screen is 24 mesh, and the dry particles are collected in a clean, dry LDPE bag), and the amount of fine powder (<80 mesh) is 18%. The remaining magnesium stearate passed through a 60-mesh screen is added to the above dry particles and shaken 60 times in the LDPE bag to obtain the total mixed powder. The total mixed powder is pressed into 400 mg tablets on a single punching machine using a circular punching die with a diameter of 9.5 mm, and OPADRY II 85f620079 (OPADRY II Coated tablets were obtained by thinly coating the uncoated tablets with a film coating premix (the mass of 85f620079 is 3% of the uncoated tablet mass). Drug dissolution tests were performed on each parameter of the uncoated tablets and the coated tablets. The results are shown in Table 5. [Table 5] Example 24

[0195] The following were weighed out: APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, cross-linked sodium carboxymethylcellulose, hydroxypropyl cellulose, colloidal silica, and magnesium stearate (the mass percentages of the total substances in APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, hydroxypropyl cellulose, cross-linked sodium carboxymethylcellulose, colloidal silica, and magnesium stearate were 38.5%, 25.5%, 25.5%, 4%, 3%, 2%, and 1.5%, respectively) and APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, cross-linked sodium carboxymethylcellulose, hydroxypropylcellulose, and colloidal silica are passed through a 40-mesh screen three times, then placed in a clean, dry LDPE bag and shaken 200 times to mix. 1% magnesium stearate (mass percentage is the mass fraction of the total substance) passed through a 60-mesh screen is added to the above mixed powder and shaken 60 times to perform dry granulation (where the roll speed is 5 rpm, the press wheel pressure is 7-11 MPa, the fine screen is 24 mesh, and the dry particles are collected in a clean, dry LDPE bag). The remaining magnesium stearate passed through a 60-mesh screen is added to the above dry particles and shaken 60 times in the LDPE bag to obtain the total mixed powder. The total mixed powder is pressed into 400 mg tablets using a 9.5 mm diameter circular die on a single punching machine, and OPADRY II 85f80010 (OPADRY II Coated tablets were obtained by coating the uncoated tablets with a film coating premix (the mass of 85f80010 is 3% of the uncoated tablet mass). Various parameters of the uncoated tablets were tested, and the results are shown in Table 6. [Table 6] Example 25

[0196] In Example 13, APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, cross-linked sodium carboxymethylcellulose, colloidal silica, and magnesium stearate (where the mass percentages of APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, cross-linked sodium carboxymethylcellulose, colloidal silica, and magnesium stearate in total substances are 38.5%, 27.5%, 27.5%, 3%, 2%, and 1.5%, respectively) were weighed, and the APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, cross-linked sodium carboxymethylcellulose, and colloidal silica were passed through a 40-mesh screen three times, then placed in a clean, dry LDPE bag and shaken 200 times. Magnesium stearate (mass percentage is the mass fraction of the total substance) that had been sieved through a 60-mesh sieve at 1% was added to the mixed powder and shaken 60 times to perform dry granulation (where the roll speed was 5 The machine was operated at rpm, with a pressure roll pressure of 7-11 MPa, a fine screen of 24 mesh, and the dry particles were collected in a clean, dry LDPE bag. Magnesium stearate, which had been screened on the remaining 60 mesh, was added to the dry particles and shaken 60 times in the LDPE bag to obtain a total mixed powder. The total mixed powder was pressed into 400 mg tablets using a 9.5 mm diameter circular die on a single punching machine, and the tablets were coated with OPADRY II 85f80010 (the mass of OPADRY II 85f80010 is 3% of the tablet's mass) film coating premix to obtain coated tablets. Each parameter of the tablets was tested, and the results are shown in Table 7. [Table 7] Example 26

[0197] In Example 13, APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, cross-linked sodium carboxymethylcellulose, hydroxypropylcellulose, colloidal silica, and magnesium stearate (the mass percentages of APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, hydroxypropylcellulose, cross-linked sodium carboxymethylcellulose, colloidal silica, and magnesium stearate in total are 38.5%, 25%, 25%, 5%, 3.25%, 2%, and 1.25%, respectively) were weighed, and APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, cross-linked sodium carboxymethylcellulose, hydroxypropylcellulose, and colloidal silica were passed through a 40-mesh screen three times, and then shaken 200 times in a clean, dry LDPE bag. 0.75% magnesium stearate (mass percentage is the mass fraction of the total substance) passed through a 60-mesh screen was added to the above mixed powder and shaken 60 times to perform dry granulation (where the roll speed was 5 rpm, the press wheel pressure was 7-11 MPa, the fine screen was 24 mesh, and the dry particles were collected in a clean, dry LDPE bag). The remaining magnesium stearate passed through a 60-mesh screen was added to the above dry particles and shaken 60 times in the LDPE bag to obtain the total mixed powder. The total mixed powder was pressed into 400 mg uncoated tablets using a 9.5 mm diameter circular die on a single punching machine. The parameters and drug dissolution tests of the uncoated tablets were performed, and the results are shown in Table 8. [Table 8] Example 27

[0198] In Example 13, APG-115ASD, silicified microcrystalline cellulose, cross-linked povidone, and magnesium stearate (where the mass percentages of APG-115ASD, silicified microcrystalline cellulose, cross-linked povidone, and magnesium stearate in the total substances were 51.75%, 39.5%, 8%, and 0.75%, respectively) were weighed. The APG-115ASD, silicified microcrystalline cellulose, and cross-linked povidone were passed through a 40-mesh screen three times, and then mixed 200 times in a clean, dry LDPE bag. Magnesium stearate, which had been passed through a 60-mesh screen, was added to the mixed powder and shaken 60 times. The entire mixed powder was then pressed into 400 mg tablets using a 9.5 mm diameter circular punch on a single punching machine. Disintegration time and drug dissolution tests were performed on the tablets. The results showed that the disintegration time was 7 minutes, and the drug dissolution is shown in Table 9. [Table 9] Example 28

[0199] APG-115ASD, microcrystalline cellulose KG 802, calcium phosphate, cross-linked carboxymethylcellulose sodium, hydroxypropylcellulose, colloidal silica, and magnesium stearate (APG-115ASD, microcrystalline cellulose KG 802, calcium phosphate, cross-linked carboxymethylcellulose sodium, hydroxypropylcellulose, colloidal silica, and magnesium stearate account for 38.5%, 23.5%, 23.5%, 5%, 6%, 2.5%, and 1% of the total substances, respectively) were weighed, and APG-115ASD, microcrystalline cellulose KG 802, calcium phosphate, cross-linked carboxymethylcellulose sodium, hydroxypropylcellulose, and colloidal silica were passed through a 40-mesh screen three times and then shaken 200 times in a clean, dry LDPE bag. 0.5% magnesium stearate (mass fraction of total substances as a mass percentage) passed through a 60-mesh screen was added to the above mixed powder and shaken 60 times to perform dry granulation (where the roll rotation speed was 5 rpm, the pressure of the pressure roll was 7-11 mpa, the fine screen was 24 mesh, and the dry particles were collected in a clean, dry LDPE bag). The remaining magnesium stearate passed through a 60-mesh screen was added to the above dry particles and shaken 60 times in the LDPE bag to obtain the total mixed powder. The total mixed powder was pressed into 400 mg tablets using a 9.5 mm diameter circular punch on a single punching machine. Parameters and drug dissolution tests were performed on the tablets, and the results are shown in Table 10. [Table 10] Example 29

[0200] In Example 13, APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, cross-linked sodium carboxymethylcellulose, hydroxypropylcellulose, colloidal silica, and magnesium stearate (the mass percentages of APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, cross-linked sodium carboxymethylcellulose, hydroxypropylcellulose, colloidal silica, and magnesium stearate in total are 38.5%, 25%, 25%, 3.25%, 5%, 2%, and 1.25%, respectively) were weighed, and APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, cross-linked sodium carboxymethylcellulose, hydroxypropylcellulose, and colloidal silica were passed through a 40-mesh screen three times, and then shaken 200 times in a clean, dry LDPE bag. 0.75% magnesium stearate (mass percentage is the mass fraction of the total substance) passed through a 60-mesh screen was added to the above mixture and shaken 60 times to perform dry granulation (where the roll speed was 5 rpm, the press wheel pressure was 7-11 MPa, the fine screen was 24 mesh, and the dry particles were collected in a clean, dry LDPE bag). The remaining magnesium stearate passed through a 60-mesh screen was added to the above dry particles and shaken 60 times in the LDPE bag to obtain the total mixed powder. The total mixed powder was pressed into 400 mg tablets using a 9.5 mm diameter circular die on a single punching machine. The parameters and drug dissolution tests of the tablets were performed, and the results are shown in Table 11. [Table 11] Example 30

[0201] In Example 13, APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, cross-linked sodium carboxymethylcellulose, hydroxypropylcellulose, colloidal silica, and magnesium stearate (the mass percentages of APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, cross-linked sodium carboxymethylcellulose, hydroxypropylcellulose, colloidal silica, and magnesium stearate in total are 39.65%, 24.31%, 24.31%, 3.26%, 5.01%, 1.96%, and 1.50%, respectively) were weighed, and the APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, hydroxypropylcellulose, cross-linked sodium carboxymethylcellulose, and colloidal silica were placed in a mixer and mixed at a mixing rate of 18 The mixture is mixed at 18 rpm for 5 minutes, the resulting material is sieved through a 40-mesh sieve, and 0.75% magnesium stearate (mass percentage is the mass fraction of the total substance) is added and mixed. The mixing speed is 18 rpm and the mixing time is 5 minutes. The resulting material is placed in a dry granulator and dry granulation is performed (pressure roll pressure is 4.0~7.0 MPa, pressure roll gap is 1.0~5.0 mm, pressure roll speed is 3.0~7.0 rpm, granulation member speed is 30~90 rpm, feed shaft speed is 18~90 rpm, and fine screen is 0.8 mm). The resulting particles are collected, the remaining magnesium stearate is added to the resulting particles, mixed and lubricated, and tablets are pressed using a 10 mm diameter circular punching die (feed speed is 5~30 rpm, tablet pressing speed is 20~30 rpm, tablet thickness scale is 0.3~5.0). The dimensions were mm, the supply scale was 10.5 to 15.5 mm, and the primary pressure range was 10 to 25 kN, and uncoated tablets were obtained. Each parameter of the uncoated tablets and drug dissolution tests were performed, and the results are shown in Table 12. [Table 12] Example 31

[0202] In Example 13, APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, cross-linked sodium carboxymethylcellulose, hydroxypropylcellulose, colloidal silica, and magnesium stearate (the mass percentages of APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, cross-linked sodium carboxymethylcellulose, hydroxypropylcellulose, colloidal silica, and magnesium stearate in total substances are 39.55%, 23.5%, 23.5%, 3.25%, 5%, 2.95%, and 2.25%, respectively) were weighed, and APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, hydroxypropylcellulose, cross-linked sodium carboxymethylcellulose, and 1.45% colloidal silica (the mass percentage is the mass fraction relative to the total substance) were placed in a mixer and mixed at a mixing rate of 18 The mixture is mixed at 18 rpm for 5 minutes, the resulting material is sieved through a 40-mesh sieve, and 0.75% magnesium stearate is added (mass percentage is the mass fraction of the total substance) and mixed. The mixing speed is 18 rpm and the mixing time is 5 minutes. The resulting material is placed in a dry granulator and dry granulation is performed (pressure roll pressure is 4.0~7.0 MPa, pressure roll gap is 1.0~5.0 mm, pressure roll speed is 3.0~7.0 rpm, granulation member speed is 30~90 rpm, feed shaft speed is 18~90 rpm, and fine screen is 0.8 mm). The resulting particles are collected, the remaining colloidal silica and remaining magnesium stearate are added to the resulting particles, mixed and lubricated, and tablets are pressed using a 10 mm diameter circular punching die (feed speed is 5~30 rpm, tablet pressing speed is 20~30 rpm). Coated tablets were obtained using a pressure of rpm, with a tablet thickness scale of 0.3–5.0 mm, a supply scale of 10.5–15.5 mm, and a primary pressure range of 10–25 kN. Each parameter of the coated tablets and drug dissolution tests were performed, and the results are shown in Table 13. [Table 13] Example 32

[0203] In Example 13, APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, cross-linked sodium carboxymethylcellulose, hydroxypropylcellulose, colloidal silica, and magnesium stearate (the mass percentages of APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, cross-linked sodium carboxymethylcellulose, hydroxypropylcellulose, colloidal silica, and magnesium stearate in total substances are 39.35%, 22.39%, 22.39%, 3.23%, 4.98%, 5.42%, and 2.24%, respectively) were weighed, and APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, hydroxypropylcellulose, cross-linked sodium carboxymethylcellulose, and 1.19% colloidal silica (the mass percentage is the mass fraction of the total substance) were placed in a mixer and mixed at a mixing rate of 18 The mixture is mixed at 18 rpm for 5 minutes, the resulting material is sieved through a 40-mesh sieve, and 0.75% magnesium stearate (mass percentage is the mass fraction of the total substance) is added and mixed. The mixing speed is 18 rpm and the mixing time is 5 minutes. The resulting material is then placed in a dry granulator and dry granulation is performed (pressure roll pressure is 4.0~7.0 MPa, pressure roll gap is 1.0~5.0 mm, pressure roll speed is 3.0~7.0 rpm, granulation member speed is 30~90 rpm, feed shaft speed is 18~90 rpm, and fine screen is 0.8 mm). The resulting particles are collected, the remaining colloidal silica and remaining magnesium stearate are added to the resulting particles, mixed and lubricated, and then pressed into tablets using a 10 mm diameter circular punching die (feed speed is 5~30 rpm, tablet pressing speed is 20~30 rpm). Coated tablets were obtained using a pressure of rpm, with a tablet thickness scale of 0.3–5.0 mm, a supply scale of 10.5–15.5 mm, and a primary pressure range of 10–25 kN. Each parameter of the coated tablets and drug dissolution tests were performed, and the results are shown in Table 14. [Table 14] Example 33

[0204] In Example 13, APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, cross-linked sodium carboxymethylcellulose, hydroxypropylcellulose, colloidal silica, and magnesium stearate (APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, cross-linked sodium carboxymethylcellulose, hydroxypropylcellulose, colloidal silica, and magnesium stearate account for 38.5%, 23.5%, 23.5%, 5%, 6%, 2.5%, and 1% of the total substance, respectively) were weighed, and the APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, hydroxypropylcellulose, cross-linked sodium carboxymethylcellulose, and colloidal silica were placed in a mixer and mixed at a mixing speed of 18 rpm for 5 minutes. The resulting material was then sieved through a 40-mesh sieve, and 0.5% magnesium stearate (mass percentage is the mass fraction of the total substance) was added and mixed at a mixing speed of 18 rpm. The mixing time was 5 minutes, and the obtained material was placed in a dry granulator and dry granulation was performed (pressure roll pressure was 4.0~7.0 MPa, pressure roll gap was 1.0~5.0 mm, pressure roll speed was 3.0~7.0 rpm, granulation member speed was 30~90 rpm, feed shaft speed was 18~90 rpm, and fine screen was 0.8 mm). The fluidity was poor and the screen was sticky, so the obtained particles were collected, the remaining magnesium stearate was added to the obtained particles, mixed and lubricated, and tablets were pressed using a circular punching die with a diameter of 10 mm (feed speed was 5~30 rpm, tablet press speed was 20~30 rpm, tablet thickness scale was 0.3~5.0 mm, feed scale was 10.5~15.5 mm, and primary pressure range was 10~25 KN) to obtain uncoated tablets. Each parameter and drug dissolution test was performed on the uncoated tablets, and the results are shown in Table 15. [Table 15] Example 34

[0205] In Example 13, APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, cross-linked sodium carboxymethylcellulose, hydroxypropylcellulose, colloidal silica, and magnesium stearate (the mass percentages of APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, cross-linked sodium carboxymethylcellulose, hydroxypropylcellulose, colloidal silica, and magnesium stearate in total substances are 38.5%, 25%, 25%, 3%, 5.25%, 2%, and 1.25%, respectively) were weighed, and the APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, hydroxypropylcellulose, cross-linked sodium carboxymethylcellulose, and colloidal silica were placed in a mixer and mixed at a mixing speed of 18 rpm for 5 minutes. The resulting material was then sieved through a 40-mesh sieve, and 0.75% magnesium stearate (the mass percentage is the mass fraction of the total substance) was added and mixed at a mixing speed of 18 rpm. The mixture was prepared at a speed of rpm, with a mixing time of 5 minutes. The resulting material was then placed in a dry granulator for dry granulation (pressure roll pressure: 4.0-7.0 MPa, pressure roll gap: 1.0-5.0 mm, pressure roll speed: 3.0-7.0 rpm, granulation member speed: 30-90 rpm, feed shaft speed: 18-90 rpm, and fine screen: 0.8 mm). The resulting particles were collected, the remaining magnesium stearate was added to the particles, mixed and lubricated, and tablets were pressed using a 10 mm diameter circular punching die (feed speed: 5-30 rpm, tablet press speed: 20-30 rpm, tablet thickness scale: 0.3-5.0 mm, feed scale: 10.5-15.5 mm, and primary pressure range: 10-25 KN) to obtain uncoated tablets. The parameters and drug dissolution rates of the uncoated tablets were tested, and the results are shown in Table 16. [Table 16] Example 35

[0206] In Example 13, APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, cross-linked sodium carboxymethylcellulose, hydroxypropylcellulose, colloidal silica, and magnesium stearate (the mass percentages of APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, cross-linked sodium carboxymethylcellulose, hydroxypropylcellulose, colloidal silica, and magnesium stearate in total substances are 39.35%, 22.39%, 22.39%, 3.23%, 4.98%, 5.42%, and 2.24%, respectively) were weighed, and APG-115ASD, microcrystalline cellulose KG 802, anhydrous calcium hydrogen phosphate, hydroxypropylcellulose, cross-linked sodium carboxymethylcellulose, and 1.19% colloidal silica (the mass percentage is the mass fraction of the total substance) were placed in a mixer and mixed at a mixing rate of 18 The mixing speed is 18 rpm and the mixing time is 5 minutes. The obtained material is sieved through a 40-mesh sieve, and the remaining colloidal silica and 0.75% magnesium stearate (mass percentage is the mass fraction of the total substance) are added and mixed. The mixing speed is 18 rpm and the mixing time is 5 minutes. The obtained material is then placed in a dry granulator and dry granulation is performed (pressure roll pressure is 4.0~7.0 Mpa, pressure roll gap is 1.0~5.0 mm, pressure roll speed is 3.0~7.0 rpm, granulation member speed is 30~90 rpm, feed shaft speed is 18~90 rpm, and fine screen is 0.8 mm). The obtained particles are collected, the remaining magnesium stearate is added to the obtained particles, mixed and lubricated, and tablets are pressed using a circular punching die with a diameter of 10 mm (feed speed is 5~30 rpm, tablet press speed is 20~30 Coated tablets were obtained using a pressure of rpm, with a tablet thickness scale of 0.3–5.0 mm, a supply scale of 10.5–15.5 mm, and a primary pressure range of 10–25 kN. Each parameter of the coated tablets and drug dissolution tests were performed, and the results are shown in Table 17. [Table 17] Example 36

[0207] Film coating was performed using OPADRY II 89k680001-CN uncoated tablets, with a coating increase of 3%. Drug dissolution tests were performed on the resulting coated tablets, and the test results are shown in Table 18. [Table 18] Example 37

[0208] 725.2 g Hypromellose acetate succinate(HPMCAS912G) and 359.8 g of APG-115 hydrate were dissolved in 18.457 l of methyl acetate, and 22.4 g of colloidal silica was added and mixed uniformly. A spray dryer was set up and spray-dried for 5 hours, after which the equipment reached a stable state. Methyl acetate was collected to obtain the spray-dried powder. The spray-dried powder was dried twice (vacuum-dried and for 2 hours) until the residual amount of powder solvent was 5000 ppm or less 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 cross-linked carboxymethylcellulose sodium, 33.6 g of colloidal silica, and APG-115ASD powder were placed in a mixer and mixed (mixing speed 18 rpm, mixing time 5 minutes). The mixed material was sieved through a 40-mesh sieve, and 21 g of sieved magnesium stearate was added and mixed (mixing speed: 18 rpm, mixing time: 5 minutes). The resulting material was placed in a dry granulator and dry granulation was performed, and the resulting particles were collected (pressure roll pressure: 4.0~7.0 MPa, roll gap: 1.0~5.0 mm, roll speed: 3.0~7.0 rpm, granulation member speed: 30~90 rpm, feed shaft speed: 18~90 rpm, fine screen: 0.8 mm). 112 g of sieved colloidal silica and 35 g of sieved magnesium stearate were sequentially mixed with the above particles, lubricated, and the material was pressed in a circular die with a diameter of 10 mm (feed rotation speed: 5-30 rpm, tablet press rotation speed: 20-30 rpm, tablet thickness scale: 0.3-5.0 mm, feed scale: 10.5-15.5 mm, and primary pressure range: 10-25 KN) to obtain 7000 uncoated tablets. The uncoated tablets were coated with 84 g of OPADRY (registered trademark) II film coating premix to obtain coated tablets.

[0209] Following the above process, two batches of coated tablets were produced, and their dissolution rate, content, and related substances were measured. (1) Dissolution degree

[0210] The Chinese Pharmacopoeia's Dissolution Method II (Pulp Method) was used, with a 900 ml pH 6.8 phosphate solution (0.2% sodium dodecyl sulfate) as the elution medium, a rotation speed of 75 revolutions per minute, and a cumulative elution amount of 80% or more of the indicated amount after 30 minutes. [Table 19] (2) Content and related substances [Table 20] Effect Example 1

[0211] Sample under test: 1. APG-115 particles: 12.5% ​​APG-115 hydrate, 25.1% Hypromellose acetate succinate APG-115 particles were produced using 21.8% microcrystalline cellulose KG 802, 21.8% anhydrous calcium phosphate, 4.9% hydroxypropyl cellulose, 3.2% cross-linked carboxymethylcellulose sodium, 5.8% colloidal silica, 1.9% magnesium stearate, and a film coating premix (percentages are by mass) as raw materials, according to the manufacturing method of Example 37. 2. APG-115 hydrate.

[0212] Preparation of sample solution: The sample was thoroughly ground and mixed with PEG400 (5% concentration in the sample solution). A small amount (approximately 2 ml) of 0.2% HPMC aqueous solution was then added, and the mixture was ground into a uniform paste until no large particles remained. Under continuous grinding conditions, a sufficient amount of 0.2% HPMC aqueous solution was added, and stirring was maintained for 5 minutes (800 RPM). After sealing the sample solution container with a sealing membrane, it was placed in an ultrasonic device (40 kHz) and ultrasonicated for 20 minutes (the water temperature was controlled to within 40°C to avoid a rise in the temperature of the ultrasonic medium during the ultrasonic process). After stopping the ultrasonic waves, the suspension was uniformly mixed (stirred for approximately 3 minutes) immediately before use, and then sampled (sample concentration 6 mg / ml).

[0213] Test Method: Three male beagle dogs were selected and divided into two groups: Test Product 1 (APG-115 particles) and Test Product 2 (APG-115 hydrate). Each group received one oral capsule. After administration of Test Product 1 was completed and an 8-day washing period had passed, the group name was changed to Test Product 2, and the same procedure was followed for subsequent groups. No reassignment of animal numbers was performed.

[0214] Blood samples were collected before each administration and at 0.5, 1.0, 2.0, 4.0, 6.0, 10, 24, 48, 72, 96, 120, 144, and 168 hours after administration, and plasma was separated. All plasma samples were mailed to the client for detection. The concentration of APG-115 in canine plasma was analyzed by LC-MS / Ms. The lower limit of quantification for this method was 50 ng / ml. Plasma concentration data were analyzed using the non-atrioventricular model (NCA) method of the metabolic dynamics data analysis software winnonlin8.0.0.3176, and pharmacokinetic parameters were calculated. Refer to Table 21 to evaluate the pharmacokinetic characteristics of APG-115 in the animals after administration. [Table 21]

[0215] Conclusion: As shown in Figure 1, the exposure to APG-115 particles was more than 10 times that of APG-115 hydrate, while the exposure to APG-115 hydrate in dogs was extremely low.

[0216] Although specific embodiments of the present invention have been described above, those skilled in the art should understand that these are merely illustrative examples, and the scope of protection of the present invention is limited by the appended claims. Those skilled in the art can make various changes or modifications to these embodiments without departing from the principles and substance of the present invention, and all such changes or modifications are included within the scope of protection of the present invention.

Claims

1. Carrier and formula (I): 【Chemistry 1】 A solid dispersion comprising the active ingredient shown, or a pharmaceutically acceptable salt, crystalline form, or hydrate thereof, The carrier is selected from one or more of povidone, copovidone, and hypromellose acetate succinate, or from one or more of hypromellose acetate succinate, hydroxypropyl cellulose, povidone, and acrylic resin, and A solid dispersion wherein the mass ratio of the active ingredient to the carrier is in the range of 1:1.2 to 1:

8.

2. The povidone is one or more of PVP VA 64, PVP K29 / 32, PVP S-630, PVP K25, PVP K-90, PVP C-15, and PVP C-30, or one or more selected from PVP VA 64, PVP K29 / 32, and PVP S-630. The hypromellose acetate succinate is selected from one or more of HPMCAS 126G, HPMCAS 716G, and HPMCAS 912G. The acrylic resin is selected from one or more of Eudragit L100, Eudragit S100, Eudragit L100-55, Eudragit RLPO, and Eudragit RSPO. The hydroxypropyl cellulose is selected from one or more of HPC EXF, HPC LF, HPC JF, and HPC GF. The pharmaceutically acceptable salts are hydrochloride, hydrobromide, hydroiodide, sulfate, hydrogen sulfate, 2-hydroxyethanesulfonate, phosphate, hydrogen phosphate, acetate, adipine, alginate, lysine, arginine, histidine, aspartate, benzoate, hydrogen sulfate, butyrate, camphorate, camphor sulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, caproate, formate, succinate, fumarate, maleate, ascorbate, hydroxyethylsulfonate, salicylate, methanesulfonate, mesityleneate, naphthalenesulfonate, nicotinic acid, 2-naphthalenesulfonate, oxalate, bishydroxynaphthaleneate, pectinate, and persulfate. Selected from salts, 3-phenylpropionate, picrate, pivaphosphate, propionate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, p-toluenesulfone, undecanoate, lactate, citrate, tartrate, gluconate, methanesulfonate, ethanedisulfonate, benzenesulfonate, L-tartrate, maleate, sodium salt, potassium salt, choline salt, aminobutanol salt, calcium salt or p-toluenesulfonate, or phosphate, sulfate, L-tartrate, hydrochloride, maleate, hydrobromide, methanesulfonate, lysine salt, arginine salt, histidine salt, sodium salt, potassium salt, choline salt, aminobutanol salt and calcium salt, The hydrate is selected from hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, pentahydrate, hexahydrate, heptahydrate, octahydrate, nunahydrate, decahydrate, elevenhydrate and dodecahydrate, and The solid dispersion according to claim 1, further comprising an anti-tack agent selected from one or more of colloidal silica, talc, starch, D-leucine, L-leucine, sodium lauryl sulfate, and metal stearate, wherein the mass ratio of the anti-tack agent to the active ingredient is 0.05:1 to 0.08:

1.

3. The mass ratio of the active ingredient to the carrier is in the range of 1:2 to 1:

4. The mass ratio of the active ingredient to hypromellose acetate succinate is in the range of 1:1.2 to 1:

8. The mass ratio of the active ingredient to hypromellose acetate succinate is in the range of 1:2 to 1:

4. The mass ratio of the active ingredient to hypromellose acetate succinate is 1:

2. The mass ratio of the active ingredient to hydroxypropyl cellulose is in the range of 1:1.2 to 1:

8. The mass ratio of the active ingredient to hydroxypropyl cellulose is in the range of 1:2 to 1:

4. The mass ratio of the active ingredient to hydroxypropyl cellulose is 1:

2. The mass ratio of the active ingredient to povidone is in the range of 1:1.2 to 1:

8. The mass ratio of the active ingredient to povidone is in the range of 1:2 to 1:

4. The mass ratio of the active ingredient to povidone is 1:

2. The mass ratio of the active ingredient to the acrylic resin is in the range of 1:1.2 to 1:

8. The mass ratio of the active ingredient to the acrylic resin is in the range of 1:2 to 1:

4. The mass ratio of the active ingredient to the acrylic resin is 1:

2. The mass ratio of the active ingredient to the carrier is in the range of 1:1.2 to 1:8, and the mass ratio of the active ingredient to the anti-tack agent is in the range of 1:0.05 to 1:0.

08. The mass ratio of the active ingredient to hypromellose acetate succinate is in the range of 1:1.2 to 1:8, and the mass ratio of the active ingredient to colloidal silica is in the range of 1:0.05 to 1:0.

08. The mass ratio of the active ingredient to hypromellose acetate succinate is in the range of 1:1.2 to 1:8, and the mass ratio of the active ingredient to colloidal silica is in the range of 1:0.06 to 1:0.07, or The mass ratio of the active ingredient to hypromellose acetate succinate is 1:2, and the mass ratio of the active ingredient to colloidal silica is 1:0.

064. The solid dispersion according to claim 2.

4. A method for producing a solid dispersion according to claim 2, comprising: 1) mixing one or more carriers, an active ingredient, and a solvent to obtain a mixture; 2) drying the mixture; and 3) optionally mixing the mixture with an anti-tack agent before drying.

5. The mass-volume ratio of the active ingredient to the solvent is 5:1 to 30:1 mg / ml or 15:1 to 25:1 mg / ml. The solvent is one or more of the following: alcohol-based solvents, water, ester-based solvents, ketone-based solvents, halogenated hydrocarbon solvents, nitrile-based solvents, and ether-based solvents. The alcoholic solvent is ethanol, the esteric solvent is methyl acetate, the etheric solvent is tetrahydrofuran, the ketoneic solvent is acetone, the halogenated hydrocarbon solvent is dichloromethane, and the nitrile solvent is acetonitrile. The method for producing a solid dispersion according to claim 4, wherein the drying comprises a first drying and a second drying, the first drying being spray drying or fluidized bed boiling drying, and the second drying being vacuum reduced pressure drying or electric heated air drying.

6. A pharmaceutical composition comprising the solid dispersion and excipient described in claim 2.

7. The excipient includes one or more of the following: an absorption enhancer, an antioxidant, a dry anti-tack agent, a buffer, a coating agent, a colorant, a diluent, a disintegrant, an emulsifier, a flavoring agent, a humectant, a lubricant, an anti-tack agent, a fluidity enhancer, a preservative, a solubilizer, a flavoring agent, and a release agent. The diluent contains one or more of the following: cellulose, lactose, lactitol, maltitol, mannitol, sorbitol, xylitol, glucose, fructose, sucrose and sucrose-based diluents, maltose, inosose, hydrolyzed cereal solids, starch, starch components, dextrin, calcium salts, magnesium salts, bentonite, kaolin, and sodium chloride. The diluent is one or more of the following: microcrystalline cellulose, silicified microcrystalline cellulose, calcium phosphate, pregelled starch, lactose, mannitol, and anhydrous calcium hydrogen phosphate; or one or more of the following: microcrystalline cellulose, silicified microcrystalline cellulose, pregelled starch, calcium phosphate, and anhydrous calcium hydrogen phosphate; or one or more of the following: microcrystalline cellulose, pregelled starch, and calcium phosphate; or a mixture of microcrystalline cellulose and anhydrous calcium hydrogen phosphate. The microcrystalline cellulose has a pH of 102 and / or a KG of 802, and 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 is 0.1:1 to 10:1, or 0.5:1 to 2:

1. The disintegrant is one or more of the following: starch, clay, magnesium aluminum silicate, cellulosic disintegrant, alginate, povidone, cross-linked povidone, potassium polacrin, gum, and colloidal silica, or the disintegrant is cross-linked sodium carboxymethylcellulose and cross-linked povidone. The pharmaceutical composition according to claim 6, wherein the lubricant is one or more of the following: behenic acid glyceride, stearic acid and its salts, hydrogenated vegetable oil, glyceryl palmitostearate, talc, wax, sodium benzoate, sodium acetate, sodium fumarate, sodium stearyl fumarate, PEG, poloxam, polyvinyl alcohol, sodium oleate, sodium lauryl sulfate, and magnesium lauryl sulfate, or the lubricant is magnesium stearate.

8. A pharmaceutical composition according to claim 7, The pharmaceutical composition further comprises an anti-tack agent and a fluidity enhancer, or The pharmaceutical composition further comprises a dry anti-sticking agent, The mass ratio of the diluent to the solid dispersion is 0.2:1 to 8:1, 0.5:1 to 8:1, 0.8:1 to 2:1, or 0.5:1 to 1:

1. The mass ratio of the disintegrant to the solid dispersion is 0.03:1 to 0.3:1, 0.1:1 to 0.2:1, 0.05:1 to 0.2:1, or 0.05:1 to 0.15:

1. The mass ratio of the lubricant to the solid dispersion is 0.005:1 to 0.2:1, 0.01:1 to 0.2:1, 0.02:1 to 0.04:1, or 0.01:1 to 0.02:

1. The anti-tack agent comprises one or more of talc, colloidal silica, starch, D-leucine, L-leucine, sodium lauryl sulfate, and metal stearate. The fluidity enhancer comprises one or more of colloidal silica, starch, powdered cellulose, sodium lauryl sulfate, magnesium trisilicate, and metal stearate. The mass ratio of the total mass of the anti-tack agent and the fluidity aid to the mass of the solid dispersion is 0.02:1 to 0.3:1, 0.05:1 to 0.1:1, or 0.1:1 to 0.2:

1. The dry anti-tack agent contains one or more of the following: gum arabic, tragacanth gum, glucose, polyglucose, starch, gelatin, modified cellulose, dextrin, zeine, alginic acid and alginate, magnesium aluminum silicate, bentonite, polyethylene glycol, polyethylene oxide, guar gum, polysaccharide acid, polyvinylpyrrolidone, polyacrylic acid, and polymethacrylate esters. A pharmaceutical composition in which the mass ratio of the dry anti-tack agent to the solid dispersion is 0.02:1 to 0.5:

1.

9. The mass of the solid dispersion is 1 part by mass, and the pharmaceutical composition comprises 1 part by mass of the solid dispersion, 0.2 to 8 parts by mass of the diluent, 0.03 to 0.3 parts by mass of the disintegrant, and 0.005 to 0.2 parts by mass of the lubricant. The pharmaceutical composition comprises 1 part by mass of a solid dispersion, 0.2 to 8 parts by mass of a diluent, 0.02 to 0.3 parts by mass of the anti-tack agent and a fluidity enhancer, 0.03 to 0.3 parts by mass of a disintegrant, and 0.005 to 0.2 parts by mass of a lubricant, or The pharmaceutical composition according to claim 7, comprising 1 part by mass of the solid dispersion, 0.2 to 8 parts by mass of the diluent, 0.02 to 0.5 parts by mass of the dry anti-tack agent, 0.02 to 0.3 parts by mass of the anti-tack agent and a fluidity aid, 0.03 to 0.3 parts by mass of the disintegrant, and 0.005 to 0.2 parts by mass of the lubricant.

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

11. A pharmaceutical preparation comprising the pharmaceutical composition described in claim 7, wherein the pharmaceutical preparation is a solid preparation, or a powder, granules, tablet, capsule, dropper, or film preparation.

12. A method for manufacturing tablets, Step 1 is a mixture of the solid dispersion described in claim 2, a diluent, and a disintegrant, obtained by mixing the mixture and sieving it to obtain particles. A method for manufacturing a tablet, comprising step 2, wherein the particles from step 1 are mixed with a lubricant and the particles are pressed to obtain a tablet.

13. A method for producing a tablet according to claim 12, further comprising the step of adding an anti-sticking agent, a flow aid, and a lubricant, wherein the granulation in step 1 is dry granulation.

14. A coated tablet comprising the pharmaceutical composition described in claim 7.

15. The mass ratio of the coating to the pharmaceutical composition in the coated tablet is 0.02:1 to 0.2:

1. The coated tablet according to claim 14, wherein the coating in the coated tablet comprises polyvinyl alcohol, titanium dioxide, talc, and hydroxypropyl methylcellulose.

16. A pharmaceutical composition according to claim 7 for treating a disease caused by a P53 and / or MDM2 abnormality, wherein the disease is cancer or a hyperproliferative disease.

17. Cancers include adrenocortical carcinoma, terminal cancer, anal cancer, anemia with regenerative disorders, bile duct cancer, bladder cancer, bone cancer, bone metastases, adult brain / CNS tumors, pediatric brain / CNS tumors, breast cancer, male breast cancer, pediatric cancer, unknown primary cancers, giant lymph node proliferation, cervical cancer, colorectal cancer, endometrial cancer, esophageal cancer, Ewing tumor family, eye cancer, gallbladder cancer, gastrointestinal carcinoid tumors, gastrointestinal stromal tumors, gestational trophoblastic disease, Hodgkin's disease, Kaposi's sarcoma, kidney cancer, laryngeal / hypopharyngeal cancer, adult acute lymphoblastic leukemia, acute osteomyeloblastic leukemia, chronic lymphoblastic leukemia, chronic osteomyeloblastic leukemia, chronic osteomocytic leukemia, pediatric leukemia, liver cancer, and non-small cell lung cancer. The pharmaceutical composition according to claim 16, wherein the patient is small cell lung cancer, pulmonary carcinoid tumor, cutaneous lymphoma, malignant mesothelioma, multiple osteomyeloma, osteomyeloproliferative syndrome, nasal cavity / paranasal sinus cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma, pediatric non-Hodgkin lymphoma, oral / oropharyngeal cancer, osteosarcoma, ovarian cancer, pancreatic adenocarcinoma, penile cancer, pituitary adenocarcinoma, prostate cancer, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma - adult soft tissue cancer, basal skin cancer and squamous cell carcinoma, cutaneous melanoma, small intestine cancer, gastric cancer, testicular cancer, thymic cancer, thyroid cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenström macroglobulinemia, or Wilms' tumor.

18. The diluent is cellulose, lactose, lactitol, maltitol, mannitol, sorbitol, xylitol, glucose, fructose, sucrose, sucrose-based diluents, maltose, inosose, hydrolyzed cereal solids, starch, starch components, dextrin, calcium salts, magnesium salts, bentonite, kaolin, sodium chloride, microcrystalline cellulose, silicified microcrystalline cellulose, calcium phosphate, pregelled starch, anhydrous calcium hydrogen phosphate, or a mixture of microcrystalline cellulose and anhydrous calcium hydrogen phosphate. The method according to claim 12, wherein the disintegrant is starch, clay, magnesium aluminum silicate, cellulosic disintegrant, alginate, povidone, cross-linked povidone, potassium polacrin, gum, or colloidal silica.

19. The anti-tack agent is colloidal silica, talc, starch, D-leucine, L-leucine, sodium lauryl sulfate, or metal stearate, and The method according to claim 13, wherein the fluidity enhancer is colloidal silica, starch, powdered cellulose, sodium lauryl sulfate, magnesium trisilicate, or metal stearate.

20. The method according to claim 18, wherein the microcrystalline cellulose has a pH of 102 or a KG of 802, and the disintegrant is cross-linked carboxymethylcellulose sodium or cross-linked povidone.

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