Solid dispersion, its manufacturing method and solid preparation containing the same

Abstract

A solid dispersion, its preparation method and a solid preparation containing the same. The solid dispersion comprises compound A and a pharma- ceutically acceptable matrix polymer, the pharma-ceutically acceptable matrix polymer comprises an enteric polymer and a non-enteric polymer, and the compound A is 1-{(6-[(1-methyl)-4-pyrazolyl]-imidazole[1,2-a]pyridine)-3-sulfonyl}-6-[(1-methyl)-4-pyrazolyl]-1-hydro-pyrazolyl[4,3-b]pyridine. The solid dispersion can significantly improve the solubility and dissolution stability of compound A, and can extend the supersaturation maintenance time of the drug to improve the bioavailability of the drug. The solid preparation prepared using the solid dispersion has a bioavailability in the body that meets the requirements for oral administration of compound A.

Description

[Technical Field]

[0001] This application claims priority from Chinese Patent Application No. 2021113088364, filed on November 5, 2021. This application incorporates the full text of the above Chinese patent application.

[0002] The present invention belongs to the field of drug formulations, and specifically relates to a solid dispersion, a method for preparing the same, a solid drug formulation containing the same, and the use of the solid dispersion in the preparation of a drug for preventing and / or treating diseases and tumors associated with protein tyrosine kinase disorders. [Background technology]

[0003] Patent CN104230922A discloses compound A (1-{(6-[(1-methyl)-4-pyrazolyl]-imidazole[1,2-a]pyridine)-3-sulfonyl}-6-[(1-methyl)-4-pyrazolyl]-1-hydro-pyrazolyl[4,3-b]pyridine), and the use of compound A and its pharmaceutically acceptable salts in the manufacture of drugs for preventing or treating diseases associated with abnormal cell proliferation, morphological changes, and hypermotility associated with protein tyrosine kinase disorders in vivo, and diseases associated with angiogenesis or cancer metastasis, in particular the use of drugs as C-Met inhibitors.

[0004] Overexpression of C-Met is observed in human liver cancer, cholangiocarcinoma, pancreatic cancer, lung cancer, thyroid cancer, and pleural stromal tumors, particularly in tumors that metastasize. Its actions may include affecting tumor cell adhesion, promoting extracellular matrix degradation, inducing angiogenesis, and promoting cell proliferation. These findings indicate that C-Met is an important target for tumor therapy. Compound A is a highly selective C-Met inhibitor, and its C-Met inhibitory activity and antitumor activity in vivo and in vivo are superior to those of the clinically used analogue INCB28060 (CAS number: 1029712-80-8). Compound A exhibits potent activity, minimal toxicity, and minimal side effects, demonstrating promising future prospects.

[0005] Further research on Compound A revealed that its equilibrium solubility in buffered saline solutions of pH 1.2-7.4 was less than 1.0 μg / mL, making it a poorly water-soluble drug. Animal studies showed that after direct administration of conventional formulations of Compound A, the bioavailability in the body was less than 1%, resulting in low absorption in the body and ineffective therapeutic effects, and that it needed to be solubilized to improve oral absorption before use.

[0006] The inventors have tried the currently commonly used conventional solubilization and absorption enhancement methods and found that compound A has problems (1) to (4): (1) they tried to make compound A into a salt, but found that there was no significant improvement in its solubility; (2) they tried to make compound A into various crystalline forms, but found that there was no significant difference in the solubility of the various crystalline forms; (3) they tried to micronize compound A and then solubilize it to enhance its absorption, but found that the bioavailability was only 3.3%, which was not suitable for oral administration; (4) they tried to make compound A into a solubilized solution with a solubilizer, but compound A has a melting point above 250°C, has a strong tendency to crystallize, and crystallizes after standing, resulting in low long-term stability and inability to redissolve after crystallization, which fails to solve the problems of low drug absorption. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a solid dispersion, a method for producing the same, and a solid formulation containing the same, in order to overcome the deficiencies of the prior art in that Compound A has low solubility in water and low bioavailability in the body.

[0008] Compound A in the solid dispersion of the present invention has high solubility in simulated intestinal fluid, and furthermore, the solid dispersion of the present invention significantly improves the solubility and dissolution stability of Compound A, prevents drug precipitation, and extends the supersaturation maintenance time of the drug, thereby improving the bioavailability of the drug. The solid formulation of the present invention has high bioavailability.

[0009] The present invention improves the manufacturing process of solid dispersions to effectively control the degradation of components in the dispersion, especially the degradation of matrix polymer materials, thereby reducing the impurity content of the dispersion. Furthermore, the present invention optimizes the grinding process of the solid dispersion and the mixing process of the solid dispersion powder, thereby greatly improving the tabletability of solid dispersion tablets, thereby avoiding situations such as low tablet hardness, low brittle grindability, and serious powder shedding during transportation.

[0010] In one aspect, the present invention provides a solid dispersion, comprising Compound A and a pharmaceutically acceptable matrix polymer, wherein the pharmaceutically acceptable matrix polymer comprises an enteric polymer and a non-enteric polymer, Compound A is 1-{(6-[(1-methyl)-4-pyrazolyl]-imidazole[1,2-a]pyridine)-3-sulfonyl}-6-[(1-methyl)-4-pyrazolyl]-1-hydro-pyrazolyl[4,3-b]pyridine, and the weight ratio of Compound A to the pharmaceutically acceptable matrix polymer is 1:3 to 1:35.

[0011] Additionally, the solid dispersion optionally further comprises one, two or three of a fluidizing agent, a plasticizer and a surfactant.

[0012] In a specific embodiment of the present invention, the enteric polymer is preferably one or more selected from hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), polymethyl acrylate, polyvinyl acetate phthalate (PVAP), cellulose acetate phthalate, and cellulose acetate succinate, and more preferably the enteric polymer is hydroxypropyl methylcellulose phthalate and / or hydroxypropyl methylcellulose acetate succinate.

[0013] In a specific embodiment of the present invention, the non-enteric polymer is preferably one or more selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), copovidone (i.e., N-vinylpyrrolidone / vinyl acetate copolymer, PVP / VA), povidone (i.e., polyvinylpyrrolidone, PVP), polyvinyl alcohol, 2-hydroxy-β-cyclodextrin (HPBCD), hydroxypropyl methylcellulose (HPMC), and hydroxypropyl cellulose (HPC), and more preferably, the non-enteric polymer is one or more selected from copovidone, polyvinyl alcohol, povidone, and hydroxypropyl methylcellulose.

[0014] In certain embodiments of the invention, the pharmaceutically acceptable matrix polymer comprises any combination of hydroxypropyl methylcellulose phthalate and povidone, hydroxypropyl methylcellulose phthalate and copovidone, hydroxypropyl methylcellulose acetate succinate and povidone, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose, hydroxypropyl methylcellulose acetate succinate and polyvinyl alcohol, hydroxypropyl methylcellulose acetate succinate and copovidone, hydroxypropyl methylcellulose phthalate and polyvinyl alcohol, cellulose acetate phthalate and povidone, or cellulose acetate succinate and copovidone.

[0015] In one specific embodiment of the present invention, the weight ratio of the enteric high molecular weight polymer to the non-enteric high molecular weight polymer may be 2:1 to 10:1, preferably 2:1 to 6:1, for example, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, 5:1 or 6:1.

[0016] In one specific embodiment of the present invention, the weight ratio of compound A to the pharmaceutically acceptable matrix polymer may be 1:4 to 1:25, preferably 1:5 to 1:15, for example, 1:4, 1:5, 1:5.5, 1:6, 1:7.5, 1:8, 1:9, 1:10, 1:12, 1:15, or 1:21. In vivo pK testing has shown that when the weight ratio of compound A to the pharmaceutically acceptable matrix polymer is 1:4 to 1:25, the solubility of the prepared solid dispersion can be improved and the exposure of compound A in the body can be significantly improved.

[0017] In a specific embodiment of the present invention, the weight ratio of the compound A to the enteric polymer may be 1:2 to 1:15, more preferably 1:3 to 1:10, for example, 1:3, 1:4, 1:4.5, 1:5, 1:6, 1:8 or 1:10.

[0018] In a specific embodiment of the present invention, the weight ratio of compound A to the non-enteric polymer may be 2:1 to 1:10, preferably 2:1 to 1:5, more preferably 1:1 to 1:5, or 1:2 to 1:5, for example, 2:1, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:5, 1:8, or 1:10.

[0019] In a specific embodiment of the present invention, the fluidizing agent may be a conventional fluidizing agent in the art, preferably, the fluidizing agent is one or more selected from colloidal silica, animal fat, vegetable fat, and wax, for example, colloidal silica. The amount of the fluidizing agent used can be selected according to the conventional amount of fluidizing agents used in the art, and preferably, the weight ratio of the fluidizing agent to compound A is 1:1 to 1:100, preferably 1:4 to 1:50, for example, 1:6, 1:10, 1:15, 1:20, 1:30, 1:50, 1:80, or 1:100.

[0020] In a specific embodiment of the present invention, the presence of a plasticizer can improve the processability of the solid dispersion. The plasticizer may be a conventional plasticizer used in the art. Preferably, the plasticizer is one or more selected from the group consisting of tributyl O-acetylcitrate, triethyl O-acetylcitrate, benzyl benzoate, acetone chloroform, dextrin, dibutyl phthalate, diethyl phthalate, dimethyl phthalate, glycerin, glyceryl monostearate, polyoxyl 40 stearate, mannitol, mineral oil, lanolin alcohol, palmitic acid, polyethylene glycol, polyethylene glycol monostearate, polyvinyl acetate, propylene glycol, 2-pyrrolidone, sorbitol, stearic acid, triacetin, tributyl citrate, triethanolamine, and triethyl citrate. More preferably, the plasticizer is a plasticizer with a low glass transition temperature, such as glyceryl monostearate and / or polyoxyl 40 stearate.

[0021] The amount of the plasticizer used can be selected according to the usual amount of plasticizers used in this field, and preferably the weight ratio of the plasticizer to the compound A is 1:1 to 1:20, preferably 1:1 to 1:5, for example, 1:1.5, 1:2, 1:2.5, 1:5, 1:10, 1:15 or 1:20.

[0022] In a specific embodiment of the present invention, the surfactant can further enhance the therapeutic potential of the solid dispersion of the present invention. The surfactant may be a conventional surfactant in the art, and preferably, the surfactant is one or more selected from anionic surfactants, cationic surfactants, and nonionic surfactants.

[0023] The anionic surfactant is preferably sodium dodecyl sulfate (sodium lauryl sulfate) and / or sodium polyester. The cationic surfactant is preferably one or more of cetrimide, benzethonium chloride, cetylpyridinium chloride, and lauric acid. The nonionic surfactant is preferably one or more of polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester (e.g., Tween 80, 60, 40, and 20), polyoxyethylene castor oil derivative (e.g., polyoxyethylene hydrogenated castor oil (Cremophor RH40)), polyoxyethylene stearic acid ester, and polyoxyethylene polyoxypropylene ether block copolymer (e.g., poloxamer). More preferably, the surfactant is one or more of sodium dodecyl sulfate, sodium polyester, lauric acid, polyoxyethylene alkyl ether, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene castor oil derivative, poloxamer, and polyoxyethylene stearic acid ester. Most preferably, the surfactant is sodium dodecyl sulfate and / or polyoxyethylene stearate.

[0024] The amount of the surfactant used can be selected according to the usual amount of surfactants used in this field, and preferably the weight ratio of the surfactant to the compound A is 1:1 to 1:10, preferably 1:1 to 1:5, for example, 1:2.5, 1:3, 1:4, 1:5, 1:8 or 1:10.

[0025] In a specific embodiment of the present invention, the solid dispersion comprises Compound A, a pharmaceutically acceptable matrix polymer, a fluidizing agent, and a plasticizer, wherein the pharmaceutically acceptable matrix polymer comprises an enteric high molecular weight polymer and a non-enteric high molecular weight polymer.

[0026] In a specific embodiment of the present invention, the solid dispersion comprises Compound A, a pharmaceutically acceptable matrix polymer, a fluidizing agent, and a plasticizer, wherein the pharmaceutically acceptable matrix polymer includes an enteric high molecular weight polymer and a non-enteric high molecular weight polymer.

[0027] In a specific embodiment of the present invention, the solid dispersion comprises Compound A, a pharmaceutically acceptable matrix polymer, a fluidizing agent, a plasticizer, and a surfactant, wherein the pharmaceutically acceptable matrix polymer comprises an enteric high molecular weight polymer and a non-enteric high molecular weight polymer.

[0028] In a specific embodiment of the present invention, the solid dispersion comprises Compound A, a pharmaceutically acceptable matrix polymer, a fluidizing agent, a plasticizer, and a surfactant, wherein the pharmaceutically acceptable matrix polymer includes an enteric high molecular weight polymer and a non-enteric high molecular weight polymer.

[0029] In the present invention, when the pharmaceutically acceptable matrix polymer comprises an enteric high molecular weight polymer and a non-enteric high molecular weight polymer, it is advantageous not only in improving the solubility of the solid dispersion but also in improving the processability of the solid dispersion. The inventors have attempted to solubilize and enhance the absorption of Compound A using conventional solid dispersion technology based on the prior art. However, research results have shown that solid dispersions of Compound A prepared using a single matrix polymer according to conventional methods all have certain problems. For example, a solid dispersion of Compound A prepared using only copovidone, a conventional non-enteric matrix polymer, showed a dissolution rate of less than 90% in simulated intestinal fluid after 90 minutes, low supersaturation stability, and only 6.3% bioavailability (Comparative Example 3, Experimental Examples 2, 3, and 4). A solid dispersion of Compound A prepared using only hydroxypropyl methylcellulose phthalate, an enteric matrix polymer, could slightly improve the solubility of Compound A, but its solubility decreased over time, which resulted in drug precipitation and low supersaturation stability (Comparative Example 4), which was unfavorable for improving drug absorption. In vivo research results showed that its bioavailability was only 12.4% (Experimental Example 4).

[0030] The present inventors further unexpectedly discovered that the solid dispersion of the present invention can form stable mixed micelles with an average particle size of 100-200 nm in simulated intestinal fluid, and further improve the solubility of the drug by utilizing the principle of micellar solubilization, further prevent drug precipitation, extend the drug supersaturation maintenance time, and improve the drug bioavailability. The solid dispersion of the present invention overcomes the drawback of conventional solid dispersion drugs being prone to precipitation.

[0031] In another aspect, the present invention provides a method for producing a pharmaceutical composition comprising: (1) uniformly mixing the components of the solid dispersion by melting or dissolving to obtain a uniform dispersion; (2) solidifying the uniform dispersion to obtain a solid dispersion.

[0032] In a specific embodiment of the present invention, the solidification may be performed by a solvent evaporation method or a melt extrusion method, and is preferably performed by a melt extrusion method.

[0033] The melt extrusion method (hot melt extrusion method) produces a homogeneous dispersion by applying heat and / or mechanical stress. Specifically, in melt extrusion, a drug, such as Compound A, a pharmaceutically acceptable matrix polymer, and auxiliary materials, such as a plasticizer, are mixed in a molten state and extruded to form a solid dispersion. This method heats and melts the drug (e.g., crystalline drug), and then disperses it in an amorphous or molecular state in a carrier material (a pharmaceutically acceptable matrix polymer), ultimately improving the solubility, dissolution rate, and oral bioavailability of poorly soluble drugs. The homogeneous dispersion obtained by the melt extrusion method is also called a melt. A "melt" refers to a liquid or rubber-like state in which one component may be uniformly embedded in another. Generally, one component melts and the other component dissolves in the melt to form the melt. The formation of the melt usually depends on the softening point of the medicinal matrix polymer, and melt production can be carried out by various methods. The components can be mixed before, during, or after melt formation. For example, the components may be mixed first and then heated, or mixed and heated simultaneously. Typically, the active substance should be uniformly dispersed in the melt, resulting in a paste-like or viscous melt. The operating temperature in the present invention is typically determined by the type of extruder or the structure of the extruder used. Part of the energy required for melting, mixing, and dissolving the components in the extruder can be provided by a heating element. Friction and shear of the materials in the extruder can also provide a large amount of energy to the mixture, contributing to the formation of a uniform melt of the components. The extrudate can be formed using a molding module in the extruder, and the extrudate can be cut into blocks before or after solidification. The extrusion temperature for the melt extrusion method is 70 to 250°C, preferably 80 to 230°C, and most preferably 120 to 210°C.

[0034] In the melt extrusion method, the formation and extrusion of the melt can be carried out by a conventional device, preferably an extruder and a kneader. The extruder may be a rod-type extruder including a single-screw extruder, a twin-screw extruder or other multi-screw extruder, preferably a twin-screw extruder, which can rotate in a forward or reverse direction and is optionally equipped with a kneading disk.

[0035] In one preferred embodiment of the present invention, the melt extrusion method comprises: (1a) uniformly mixing the components of the solid dispersion to obtain a powdery mixture; (2a) feeding the powdery mixture into a hot melt extruder feeder, extruding, pulverizing, and sieving to obtain a solid dispersion containing Compound A.

[0036] In the melt extrusion method, the sleeve temperature of the melt extruder is 150 to 220° C., preferably 150 to 200° C., 150 to 180° C., or 180 to 200° C., and more preferably 160 to 180° C. When the temperature is 150 to 200° C., an increase in impurities due to an increase in temperature or a decrease in the screw rotation speed (an increase in residence time) can be avoided.

[0037] In the melt extrusion method, the screw extrusion rotation speed of the melt extruder is 50 to 300 rpm, preferably 50 to 240 rpm, 50 to 180 rpm, 100 to 210 rpm, or 180 to 240 rpm.

[0038] In the melt extrusion method, the feeding speed is 10 to 100 rpm, preferably 50 to 100 rpm or 50 to 70 rpm.

[0039] In the melt extrusion method, for example, when the pharmaceutically acceptable matrix polymer contains hydroxypropylmethylcellulose phthalate or polyvinyl acetate phthalate, which are enteric polymers, an increase in the content of phthalic acid, which is an impurity, can be avoided by controlling the extrusion sleeve temperature, screw rotation speed, and feed rate.

[0040] Preferably, the content of phthalic acid in the solid dispersion is 6 wt % or less (based on the total components of the solid dispersion), and more preferably, the content of phthalic acid is 4.8 wt % or less.

[0041] In another preferred embodiment, the solvent evaporation method comprises: (1b) dissolving each component of the solid dispersion in a solvent to obtain a uniform dispersion; (2b) removing the solvent in the uniform dispersion to obtain the solid dispersion.

[0042] In step (1b), the solvent may be a common solvent in the art, and preferably is one or more selected from ketone solvents, halogenated alkane solvents, alcohol solvents, and water. The ketone solvent is preferably acetone. The alcohol solvent is preferably isopropanol, methanol, and / or ethanol. The halogenated alkane solvent is preferably a chlorinated alkane, more preferably dichloromethane or trichloromethane. The solvent is selected from acetone, acetone / dichloromethane, methanol / dichloromethane, acetone / water, acetone / methanol, acetone / ethanol, dichloromethane / ethanol, ethanol / water, etc., where " / " represents a mixed solvent of the two.

[0043] The solvent removal method in step (2b) may be a conventional solvent removal method in the art, preferably rotary evaporation, vacuum drying, spray drying, freeze drying and thin film evaporation, or may be achieved by low-temperature freezing and freeze drying, or other techniques such as solvent-controlled precipitation, pH-controlled precipitation and low-temperature co-polishing may be used.

[0044] In another aspect, the present invention further provides a solid formulation comprising the solid dispersion and a pharmaceutically acceptable excipient.

[0045] In the solid formulation, the pharmaceutically acceptable additives may be any conventional pharmaceutically acceptable additives in the art, and preferably include one or more of the following: a fluidizing agent, a binder, a disintegrant, a filler, a coloring agent, a pH adjusting agent, a surfactant, a lubricant, a stabilizer (e.g., an antioxidant, a light stabilizer, a radical scavenger, a stabilizer against microbial attack, etc.), etc. The specific selection range and amount of the additives are within the ordinary skill in the art.

[0046] In the solid formulation, the binder may be a conventional binder in this field, and preferably, the binder is one or more selected from copovidone, povidone, methylcellulose, ethylcellulose, and hydroxypropylcellulose.

[0047] In the solid preparation, the colorant may be a colorant commonly used in this field, and the amount of the colorant used may be an amount commonly used in this field.

[0048] In the solid dosage form, the disintegrant promotes rapid disintegration of the solid dosage form in the stomach and keeps the released granules separate. Preferably, the disintegrant comprises a cross-linked polymer such as cross-linked sodium carboxymethylcellulose and / or cross-linked polyvinylpyrrolidone (i.e., cross-linked povidone PVPP).

[0049] In the solid preparation, the filler is preferably one or more selected from lactose, sucrose, mannitol, calcium hydrogen phosphate, microcrystalline cellulose, starch, and isomaltose.

[0050] In the solid preparation, the binder is preferably one or more selected from povidone, copovidone, methylcellulose, ethylcellulose, hydroxypropylcellulose, etc. Among them, povidone and copovidone as pharmaceutically acceptable matrix polymers may also function as binders.

[0051] In the solid preparation, the lubricant is preferably one or more selected from polyethylene glycol (for example, having a molecular weight of 1000 to 6000), magnesium stearate, calcium stearate, sodium stearyl fumarate, and the like.

[0052] In the solid preparation, the pH adjuster is preferably a conventional pH adjuster in the art, and is preferably citric acid.

[0053] The solid dosage form further comprises a film coating, which can improve taste and provide a refined appearance. For example, the film coating of a tablet can contribute to swallowing comfort. The film coating may be a conventional film coating used in the art, or may be a moisture-proof coating. The film coating typically comprises a polymeric film material such as hydroxypropylmethylcellulose, hydroxypropylcellulose, and an acrylic acid ester or methyl propiolate copolymer. In addition to the polymeric film material, the film coating may also comprise a plasticizer such as polyethylene glycol, a surfactant such as Tween, an anti-adhesive agent such as talc, and an optional pigment such as titanium dioxide or iron oxide. These additives may account for about 0 to about 20% of the total weight of the solid dosage form.

[0054] In a specific embodiment of the present invention, the solid dispersion may preferably account for 60 to 90% by mass of the solid preparation.

[0055] In a specific embodiment of the present invention, the pharmaceutical additive may preferably account for 15 to 40% by mass of the solid preparation.

[0056] In another aspect, the present invention further provides a method for producing the aforementioned solid dosage form, comprising the step of mixing powder or particles of the aforementioned solid dispersion with a pharmaceutical excipient to produce a solid dosage form.

[0057] Preferably, the powder or particles of said solid dispersion are obtained by grinding, milling or polishing said solid dispersion.

[0058] During the production of solid dosage forms, the present invention further optimizes the milling and blending processes of the solid dispersion to significantly improve the tablet compressibility of solid dosage forms produced from the resulting solid dispersion, thereby avoiding situations such as low tablet hardness and low brittleness, which can lead to serious powder shedding during transportation. For example, when producing solid dispersions using hot-melt extrusion, if the milling speed is 5000-5400 rpm and / or the sieving mesh number is 60-120 mesh, the resulting solid dispersions have a good particle size distribution, thereby effectively improving the tablet compressibility during the production of solid dosage forms. When producing solid dosage forms, if the mixing time of the solid dispersion and pharmaceutical excipients is 20-40 minutes, the resulting mixture has good mixing uniformity and high tablet compressibility, with the resulting tablet hardness being approximately 80-135 N. Therefore, by optimizing and controlling the milling process parameters and blending process, the tablet compressibility of tablets produced from solid dispersions can be effectively improved, thereby improving the pharmaceutical potential of the solid dosage forms.

[0059] The solid formulation of the present invention may contain 2 mg to 1500 mg of Compound A. Patients may generally be adults or children, and other mammals may also be treated.

[0060] The solid formulations provided by the present invention are suitable for administration to patients via mucous membranes, i.e., they can be administered to the mucous membrane and absorbed through the membrane. Therefore, suitable administration routes include inhalation, oral administration, intranasal administration, and rectal administration. Oral administration is particularly preferred. Those skilled in the art can select tablets, capsules, or other formulation forms depending on the administration route. However, other administration routes, such as parenteral administration, are not excluded. For example, the solid formulations of the present invention may be tablets, capsules, granules, powders, etc.

[0061] The solid formulation of the present invention has higher bioavailability than solid formulations obtained in other embodiments. In one specific embodiment of the present invention, the relative bioavailability of the solid formulation of Compound A is 1000% or more of that of a micronized formulation, the relative bioavailability of the solid formulation of Compound A is 600% or more of that of a conventional solid dispersion formulation, and the absolute bioavailability of the solid formulation of Compound A is greater than 40% (see Experimental Example 4). Improved bioavailability contributes to reducing the required dosage of a comparable exposure observed with conventional formulations (e.g., conventional micronized formulation IR tablets), thereby reducing the effective therapeutic dose of the drug, improving the therapeutic effect of the drug, reducing drug costs, and reducing drug toxicity and side effects.

[0062] In another aspect, the present invention further provides the use of said solid dispersion or solid formulation in the manufacture of a medicament for preventing and / or treating a disease and / or tumor associated with a protein tyrosine kinase disorder.

[0063] In a preferred embodiment of the present invention, the disease and / or tumor associated with a protein tyrosine kinase disorder comprises a solid cancer, such as, but not limited to, lung cancer, gastric cancer, esophageal cancer, colon cancer, colorectal cancer, liver cancer, renal cell carcinoma, head and neck cancer, thyroid cancer, ovarian cancer, breast cancer, pancreatic cancer, prostate cancer, oral cancer, malignant glial carcinoma, rhabdomyosarcoma, or bone cancer.

[0064] Preferably, the disease and / or tumor is lung cancer, gastric cancer, liver cancer, renal cell carcinoma, ovarian cancer, breast cancer, pancreatic cancer, prostate cancer or thyroid cancer.

[0065] More preferably, the disease and / or tumor described herein is lung cancer, in particular non-small cell lung cancer (NSCLC).

[0066] In another aspect, the present invention further provides a use of the solid dispersion or solid formulation in the manufacture of a C-Met inhibitor.

[0067] The C-Met inhibitor is used for the prevention or treatment of diseases associated with abnormal cell proliferation, morphological changes, and hypermotility associated with protein tyrosine kinase disorders in vivo, and diseases associated with angiogenesis or cancer metastasis, for example, as a drug used for the treatment or prevention of tumor growth and metastasis.

[0068] In another aspect, the present invention further provides a method for preventing and / or treating diseases and tumors associated with protein tyrosine kinase disorders, comprising administering an effective amount of said solid dispersion or solid formulation to an individual in need thereof.

[0069] In another aspect, the present invention provides a kit comprising the solid dispersion or solid formulation.

[0070] As used herein, "treatment" includes administering the combination of the present invention to an individual in need thereof to achieve, including but not limited to, the palliative, cure, symptom relief, reduction of symptoms, prolongation of survival, and delay of progression of a disease or condition or its symptoms (e.g., cancer), and in the case of cancer, such treatment includes inhibiting the growth of solid tumors, reducing tumor volume, preventing the growth or development of tumor metastases and micrometastases, etc. "Delayed progression" refers to the administration of the combination to a patient who is in a pre-stage or early stage of cancer awaiting treatment, a patient who has been diagnosed with a pre-form of the corresponding cancer, and / or a patient who has been diagnosed with a condition that may lead to the progression of the corresponding cancer.

[0071] As used herein, "prevention" includes inhibiting or delaying the onset or frequency of a disease or disease symptom or symptom thereof (e.g., cancer), and typically refers to administration of a drug prior to the onset of the disease symptom or symptom, particularly in an at-risk individual. "Prevention" further includes preventing the onset or recurrence of cancer.

[0072] As used herein, an "effective amount" refers to the amount (e.g., a therapeutically effective amount, particularly a combined therapeutically effective amount) of an active agent of the present disclosure used for (i) to (iii): (i) treating a particular disease; (ii) reducing, ameliorating, or eliminating one or more symptoms of a particular disease; or (iii) preventing or delaying the onset of one or more symptoms of a particular disease described herein. In the case of cancer, a therapeutically effective amount of an active agent can reduce the number of cancer cells, reduce tumor size, inhibit (i.e., reduce to some extent, and preferably stop) cancer cell invasion into surrounding organs, inhibit (i.e., reduce to some extent, and preferably stop) tumor metastasis, inhibit tumor growth to some extent, and / or alleviate to some extent one or more symptoms associated with cancer.

[0073] As used herein, "individual" or "patient" refers to mammals and non-mammals. Mammal refers to any member of the mammalian genus, including, but not limited to, humans, non-human primates, cattle, horses, sheep, pigs, rabbits, dogs, and cats. The term "individual" does not limit a particular age or sex. Preferably, the individual or patient is human.

[0074] As used herein, "pharmaceutically acceptable" refers to something that is non-toxic, biologically tolerable, and suitable for administration to an individual.

[0075] The term "pharmaceutically acceptable salt" as used in the present invention refers to a non-toxic, biologically tolerable acid addition salt or base addition salt of compound A that is suitable for administration to an individual, and includes acid addition salts formed between compound A and an inorganic acid, such as hydrochloride, hydrobromide, carbonate, bicarbonate, phosphate, sulfate, sulfite, nitrate, etc.; acid addition salts formed between compound A and an organic acid, such as formate, acetate, malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethanesulfonate, benzoate, salicylate, stearate; and acid addition salts formed between compound A and a compound of the formula HOOC-(CH2). nThe "pharmaceutically acceptable salt" includes, but is not limited to, salts formed with alkanedicarboxylic acids of -COOH (wherein n is 0 to 4). The "pharmaceutically acceptable salt" also includes base addition salts formed with Compound A and pharmaceutically acceptable cations such as sodium, potassium, calcium, aluminum, lithium, and ammonium.

[0076] As used herein, "polymer" refers to a macromolecule composed of repeating structural units linked by covalent bonds. The term includes linear and branched polymers, cyclic polymers (e.g., cyclic oligosaccharides (including cyclodextrins), homopolymers, and copolymers).

[0077] As used herein, "matrix polymer" refers to a material that exhibits low moisture absorption and a high softening temperature, and includes a polymer or a blend of two or more polymers.

[0078] As used herein, "high softening temperature" refers to a material having a glass transition temperature (Tg) or melting point (Tm) >100°C as measured by differential scanning calorimetry (DSC), where Tg is a quantity appropriate for amorphous or morphological polymers and Tm is a metric appropriate for crystalline or morphological polymers.

[0079] As used herein, "surfactant" refers to a pharmaceutically acceptable surfactant.

[0080] As used herein, the term "solid dispersion" refers to a system in which a compound is dispersed in an excipient carrier. In terms of the state of a drug in such a system, a solid dispersion can include a composition in which a drug is dispersed in an excipient carrier as discrete domains or individual molecules of crystalline or amorphous drug. In contrast to the entire drug-excipient complex, a solid dispersion can be a relatively large solid substance such as a pill, tablet, film, or micelle, or it can exist as a free-flowing powder composed of micron- or nano-scale primary particles or their aggregates. In the present invention, the definition of a solid dispersion does not include physical mixtures obtained by dry blending, wet blending, or dry blending operations, or a simple mixture of compound crystals and other auxiliary materials.

[0081] As used herein, the term "AUC" refers to the area under the drug blood concentration-time curve and is used in its conventional sense, i.e., the area under the plasma concentration-time curve from, for example, 0 to 24 hours. AUC has units of concentration multiplied by time. Once the test concentration-time point is determined, AUC can be easily calculated, for example, by a computer program or the ladder method.

[0082] As long as it does not violate common knowledge in the art, any combination of the above-mentioned preferable conditions can be used to obtain each of the preferable embodiments of the present invention.

[0083] All of the reagents and raw materials used in the present invention are commercially available.

[0084] The positive advancement effects of the present invention are as follows: The solid dispersion of the present invention significantly improves the solubility and dissolution stability of Compound A, prolongs the supersaturation maintenance time of the drug, and improves the bioavailability of the solid formulation of Compound A. The solid formulation of the present invention has high bioavailability. Due to its high bioavailability, a lower dose is required for the equivalent exposure observed in conventional formulations, thereby reducing the effective therapeutic dose of the drug, improving the therapeutic effect of the drug, reducing drug costs, and reducing the toxicity and side effects of the drug.

[0085] The present invention further improves the process for producing solid dispersions, particularly the extrusion process, to effectively control the degradation of components in the dispersion, thereby reducing the impurity content of the dispersion.The present invention also optimizes the solid dispersion grinding process and the solid dispersion powder mixing process, greatly improving the tableting properties of tablets made from solid dispersions, thereby avoiding situations such as low tablet hardness, low brittle grindability, and serious powder shedding during transportation. [Brief explanation of the drawings]

[0086] [Figure 1] FIG. 1 is a particle size diagram of the solid dispersion prepared in Preparation Example 1 of the present invention after dilution with 5% SDS-simulated intestinal fluid. [Figure 2] FIG. 2 is a comparative diagram of in vitro dissolution of various solid preparations prepared in Preparation Examples 5, 6, and 7 of the present invention and Comparative Examples 1 and 3 (n=6). [Figure 3] FIG. 3 is a graph comparing the in vitro dissolution rate of the solid preparation prepared in Preparation Example 5 of the present invention after standing under accelerated conditions for 6 months with the in vitro dissolution rate at 0 month (n=6). [Figure 4] FIG. 4 is a graph comparing the in vitro dissolution rate of the solid preparation prepared in Preparation Example 6 of the present invention after standing under accelerated conditions for 6 months with the in vitro dissolution rate at 0 month (n=6). [Figure 5] FIG. 5 is a graph comparing the in vitro dissolution rate of the solid preparation prepared in Preparation Example 7 of the present invention after standing under accelerated conditions for 6 months with the in vitro dissolution rate at 0 month (n=6). [Figure 6] FIG. 1 is a diagram for examining the dissolution stability of various solid preparations prepared in Preparation Examples 5, 6, and 7 of the present invention and Comparative Examples 1 and 3. DETAILED DESCRIPTION OF THE INVENTION

[0087] The present invention will be further described below with reference to examples, but the present invention is not limited to the scope of the examples. In the following examples, experimental methods for which specific conditions are not clearly described are selected according to conventional methods and conditions or product instructions.

[0088] In the present invention, the origin and trade name of the reagents, equipment used are all specified when they first appear, and the same reagents used subsequently are all the same as those specified for the first time unless otherwise specified, and reagents not annotated are generally purchased from China National Pharmaceutical Group Chemical Reagents Co., Ltd. Here, compound A was synthesized by Shanghai Institute of Materia Medica according to the method disclosed in CN104230922A.

[0089] Experimental animals: male beagle dogs weighing 8-10 kg. They were sourced from the Experimental Animal Center of the Shanghai Institute of Materia Medica. The animals were reared and adapted to the experimental conditions at the experimental site for 3-7 days before the test. Example 1 [ka]

[0090] Preparation method: Hydroxypropyl methylcellulose phthalate (50.0 parts by weight) (Shin-Etsu Chemical Co., Ltd., HP-55), copovidone (25.0 parts by weight) (PVP / VA64, BASF), polyoxyl 40 stearate (5.0 parts by weight) (Hunan Erkang Pharmaceutical Co., Ltd., S40), sodium dodecyl sulfate (4.0 parts by weight) (BASF) were mixed with compound A (10.0 parts by weight) and colloidal silica (1.0 part by weight) (EVONIK, Aerosil). The powdery mixture was then placed in a twin-screw extruder (screw diameter 11 mm, Thermo Scientific) at an extrusion speed of 100 rpm and a temperature of 190°C. The mixture was extruded into strands by the screws. The hot-melt extruded strands were pulverized and sieved through a 60-mesh sieve to obtain solid dispersion 1 containing compound A.

[0091] The powder of Solid Dispersion 1 was dissolved in 5% sodium dodecyl sulfate (SDS) and simulated intestinal fluid at pH 6.8 (containing 6.8 g of potassium dihydrogen phosphate and 0.944 g of sodium hydroxide per liter of water), and the particle size of the formed polymer micelles was measured (Zetasizer Nano ZS laser particle sizer, Malvern Instruments Ltd., UK). The average particle size of this product was measured to be 182.3 nm (Figure 1).

[0092] Solid Dispersion 1 and Compound A drug substance powder were each placed in simulated intestinal fluid of pH 6.8 containing different concentrations of SDS surfactant (1%, 3%, 5%) to measure the solubility of Compound A (37°C, 100 rpm shaking for 6 hours), and the solid dispersion group was sampled at 3 and 6 hours, with the measurement results shown in Table 1. The measurement results demonstrated that Solid Dispersion 1 produced by the present invention can significantly improve the solubility of drug substance Compound A, and that Solid Dispersion 1 can maintain good solubility even after 6 hours, without crystallization. [Table 1]

[0093] Note: 1 Each liter of water contains 10g of sodium dodecyl sulfate, 6.8g of potassium dihydrogen phosphate, and 0.944g of sodium hydroxide. 2 Each liter of water contains 30g of sodium dodecyl sulfate, 6.8g of potassium dihydrogen phosphate, and 0.944g of sodium hydroxide. 3 Each liter of water contains 50g of sodium dodecyl sulfate, 6.8g of potassium dihydrogen phosphate, and 0.944g of sodium hydroxide.

[0094] The powder of Solid Dispersion 1 was left under accelerated conditions (40°C ± 2°C, 75% ± 5% RH) for 6 months, and then its solubility was measured (37°C, shaking at 100 rpm for 6 hours). The solubilities in the above simulated intestinal fluids of 1%, 3%, and 5% SDS-pH 6.8 were 153.4 μg / mL, 449.6 μg / mL, and 875.3 μg / mL, respectively. This indicates that Solid Dispersion 1 of the present invention still has good solubilizing effect on Compound A after being left under accelerated conditions for 6 months.

[0095] As is clear from the above solubility measurement results, the solid dispersion 1 prepared in this example does not crystallize the drug, can effectively prevent drug precipitation, and has good supersaturation stability and long-term storage stability, which can extend the supersaturation maintenance time of the drug and ensure effective absorption of the drug in the body. Example 2 [ka]

[0096] Preparation method: Hydroxypropyl methylcellulose phthalate (55.0 parts by weight) (Shin-Etsu Chemical Co., Ltd., HP-50), copovidone (20.0 parts by weight) (PVP / VA64, BASF), glyceryl monostearate (6.0 parts by weight) (Hunan Erkang Pharmaceutical Co., Ltd.), sodium dodecyl sulfate (6.0 parts by weight) were mixed with compound A (15.0 parts by weight) and colloidal silica (1.0 part by weight). The powdery mixture was then placed in a twin-screw extruder (screw diameter 11 mm) at an extrusion speed of 150 rpm and a temperature of 200°C, and the mixture was extruded into strands by the screws. The hot-melt-extruded strands were pulverized and sieved through a 100-mesh sieve to obtain solid dispersion 2 containing compound A.

[0097] The solubility of Compound A was measured by adding Solid Dispersion 2 to simulated intestinal fluid at pH 6.8 containing different concentrations of SDS surfactant (1%, 3%, 5%) (37°C, 100 rpm shaking for 6 hours). The solubility of Compound A-containing Solid Dispersion 2 was 115.70 μg / mL in the simulated intestinal fluid of 1% SDS-pH 6.8, 424.5 μg / mL in the simulated intestinal fluid of 3% SDS-pH 6.8, and 723.1 μg / mL in the simulated intestinal fluid of 5% SDS-pH 6.8. These test results demonstrate that the solubility of Compound A can be significantly improved by Solid Dispersion 2 containing Compound A. Example 3 [ka]

[0098] Preparation method: Hydroxypropyl methylcellulose acetate succinate (50.0 parts by weight) (Shin-Etsu Chemical Co., Ltd., model number: HF), povidone (15.0 parts by weight) (PVP K12, BASF), sodium dodecyl sulfate (4.0 parts by weight) (BASF), glyceryl monostearate (12.0 parts by weight) (Hunan Erkang Pharmaceutical Co., Ltd.) were mixed with compound A (12.0 parts by weight) and colloidal silica (2.0 parts by weight). The powder mixture was then placed in a twin-screw extruder (screw diameter 11 mm) at an extrusion speed of 100 rpm and a temperature of 180°C. The mixture was extruded into strips by the screws. The hot-melt extruded strips were pulverized and sieved through a 90-mesh sieve to obtain solid dispersion 3 containing compound A.

[0099] The solubility of Compound A in Solid Dispersion 3 was measured by adding it to simulated intestinal fluid (5% SDS-pH 6.8) (37°C, shaking at 100 rpm for 6 hours). The measurement showed that the solubility of Solid Dispersion 3 containing Compound A in simulated intestinal fluid (5% SDS-pH 6.8) was 815.5 μg / mL. The test results showed that Solid Dispersion 3 containing Compound A significantly improved the solubility of Compound A and was stable. Example 4 [ka]

[0100] Preparation method: Hydroxypropyl methylcellulose phthalate (60.0 parts by weight) (product number: HP-50), hydroxypropyl methylcellulose (15.0 parts by weight) (HPMC HME 15 LV, DuPont, USA), sodium dodecyl sulfate (2.0 parts by weight), polyoxyl 40 stearate (8.0 parts by weight), colloidal silica (2.0 parts by weight), and Compound A (8.0 parts by weight) were dissolved in a mixed solvent of acetone and dichloromethane (volume ratio 2:1). The solvent was then dried using a rotary evaporator at 30°C. The resulting material was dried in a vacuum drying box at 40°C for more than 12 hours to remove residual organic solvent. The resulting solid material was pulverized and sieved through a 60-mesh sieve to obtain Solid Dispersion 4 containing Compound A.

[0101] The solubility of Compound A in solid dispersion 4 was measured by adding it to 5% SDS-pH 6.8 simulated intestinal fluid (37°C, 100 rpm shaking for 3 and 6 hours). The solubility of solid dispersion 4 containing Compound A in 5% SDS-pH 6.8 simulated intestinal fluid was 765.5 and 715.6 μg / mL after 3 and 6 hours, respectively. The measurement results showed that solid dispersion 4 containing Compound A can significantly improve the solubility of Compound A and has a long supersaturation maintenance time, which is advantageous for drug absorption. Example 5

[0102] Solid Dispersion 1 (95.0 parts by weight) prepared in Example 1 was uniformly mixed with copovidone (17.4 parts by weight) (PVP / VA64, BASF), cross-linked povidone (3.6 parts by weight) (International Specialties Corporation, USA), and sodium stearyl fumarate (1.0 part by weight) (JRS Group Pharmaceutical Supplements, Germany), and pressed into 585.0 mg tablets using a single punch tablet press. The tablets were then placed in a coating pan and thin-film coated at 60°C using an aqueous thin-film coating dispersion (Opadry, Shanghai Colorcon Coating Technology Co., Ltd.) to obtain Solid Formulation 1 containing Compound A. This solid formulation was a tablet. Example 6

[0103] The solid dispersion 2 (103.0 parts by weight) prepared in Example 2 was uniformly mixed with microcrystalline cellulose (13.2 parts by weight) (Taiwan Mingtai Chemical Co., Ltd.), pregelatinized starch (8.0 parts by weight) (Shanghai Kabocon Coating Technology Co., Ltd.), low-substituted hydroxypropyl cellulose (4.8 parts by weight) (Japan Shin-Etsu Chemical Co., Ltd.), and magnesium stearate (1.0 part by weight) (Anhui Shanhe Pharmaceutical Co., Ltd.), and filled into capsules at 260 mg / shot using a 0# capsule filling machine to obtain solid formulation 2 containing compound A. This solid formulation was a capsule. Example 7

[0104] Solid Dispersion 3 (95.0 parts by weight) prepared in Example 3 was uniformly mixed with lactose (12.0 parts by weight) (DFE Pharma, Netherlands), cross-linked sodium carboxymethylcellulose (4.0 parts by weight), and sodium stearyl fumarate (1.0 part by weight), and pressed into 467 mg tablets using a single punch tablet press. The tablets were then placed in a coating pan and thin-film coated at 60°C using an aqueous thin-film coating dispersion (Opadry, Shanghai Colorcon Coating Technology Co., Ltd.) to obtain Solid Formulation 3 containing Compound A. This solid formulation was a tablet. Example 8 [ka]

[0105] Preparation method: Hydroxypropyl methylcellulose phthalate (45.0 parts by weight) (Shin-Etsu Chemical Co., Ltd.), copovidone (10.0 parts by weight) (PVP / VA64, BASF), polyoxyl 40 stearate (5.0 parts by weight) (Croda Singapore Pte Ltd), Compound A (10.0 parts by weight), and colloidal silica (0.5 parts by weight) (JRS) were pretreated and uniformly mixed to obtain a powdery mixture. The powdery mixture was then placed in a twin-screw extruder (screw diameter 18 mm, LEISTRITZ) at an extrusion speed of 100-240 rpm and a temperature of 160-200°C. The mixture was extruded into strips by the screws at a feed rate of 50-70 rpm. The extrudates were cooled by rapid cold rolling, and the hot-melt extruded strips were placed in a hammer mill and pulverized to obtain a solid dispersion 5 containing Compound A.

[0106] In this example, the obtained powder mixture was passed through a melt extruder with different process parameters to obtain solid dispersions containing different compounds A. DSC and XRPD measurements showed that all of these dispersions were amorphous. Phthalic acid, a decomposition product of the solid dispersions during the production process, was measured, and the results are shown in Table 2 below. [Table 2]

[0107] As can be seen from the results, the decomposition level of phthalic acid increased with increasing hot melt extrusion temperature, and the decomposition level of phthalic acid increased with decreasing screw rotation speed and feed rate.By optimizing the process parameters, the increase in the impurity phthalic acid due to increasing temperature and extending residence time could be effectively avoided.

[0108] In this example, the grinding process of the solid dispersion was also studied, and it was found that when the grinding rotation speed was 5000-5400 rpm and / or the mesh number of the sieve after grinding was 60-120 mesh, the prepared solid dispersion had a relatively good particle size distribution (e.g., D90<200 μm), thereby effectively improving the tabletability during the production of solid dosage forms. Example 9

[0109] Solid Dispersion 5 (75.0 parts by weight) prepared in Example 8 was mixed with copovidone (16.0 parts by weight) (PVP / VA64, BASF), cross-linked povidone (20.5 parts by weight, ASHLAND), and citric acid (2.0 parts by weight, Merck) in a mixing bucket at 10 rpm for 20-40 min. Sodium dodecyl sulfate (3.0 parts by weight, BASF) and sodium stearyl fumarate (0.6 parts by weight, JRS) were then added and lubricated at 10 rpm for 3-10 min to obtain a homogeneously mixed powder. The mixture was then compressed into 600 mg tablets using a Fate tablet press to obtain the corresponding Formulation 4.

[0110] In this example, different mixing processes were investigated for mixing and tableting solid dispersion 5 to examine the tablet compressibility of the resulting tablets. The results show that when the mixing time of the solid dispersion and pharmaceutical excipients was 20 to 40 minutes, the resulting mixed powder had good mixing uniformity and good tablet compressibility, with tablet hardness of approximately 80 to 135 N. Furthermore, when pharmaceutical excipients were added and mixed, particularly when surfactants and lubricants (if present) were added, the resulting mixed powder had good tablet compressibility when the lubricating mixing time was controlled within 10 minutes. Too long a lubricating mixing time can adversely affect the tablet compressibility of the powder, resulting in a tablet hardness of 50 to 70 N, which adversely affects brittleness. Example 10 [ka]

[0111] Preparation method: Hydroxypropyl methylcellulose phthalate (35.0 parts by weight) (HP-55, Shin-Etsu Chemical Co., Ltd.), copovidone (5.0 parts by weight) (PVP / VA64, BASF), polyoxyl 40 stearate (5.0 parts by weight) (Croda Singapore Pte Ltd), compound A (10.0 parts by weight) and colloidal silica (0.5 parts by weight, EVONIK) were mixed to obtain a powdery mixture, which was then processed using different preparation methods to obtain the corresponding solid formulations.

[0112] Preparation method 1): The powdery mixture was dissolved in a mixed solvent of dichloromethane / methanol (volume ratio 10:1). After dissolution, the solvent was dried at 40°C using a rotary evaporator. The sample was then transferred to a vacuum drying oven (40°C, vacuum degree 0.9 bar) and left overnight (12 hours or more) to remove residual organic solvent. The resulting dried product was ground and pulverized, and then sieved through an 80-mesh sieve to obtain solid dispersion 6 powder containing compound A.

[0113] Production method 2): The powdery mixture was placed in a twin-screw extruder at a screw rotation speed of 120 rpm and a temperature of 175°C, and the mixture was extruded into strands by the screws. The hot-melt extruded strands were pulverized and then sieved through an 80-mesh sieve to obtain a powder of solid dispersion 7 containing compound A.

[0114] By examining the dissolution behavior of the dispersion powder and X-ray diffraction of the solid dispersions produced by the two processes, it was found that there was no significant difference in the solubility of the two, and that their drug solubilization abilities were the same.

[0115] Solid Dispersion 6 (55.5 parts by weight) and Solid Dispersion 7 (55.5 parts by weight) were each placed in a mixing bucket with copovidone (18.5 parts by weight) (PVP / VA64, BASF), cross-linked povidone (20.5 parts by weight, ASHLAND), and citric acid (2.0 parts by weight, Merck). The mixing speed was 15 rpm and the mixing time was 20 min. Sodium dodecyl sulfate (3.0 parts by weight, BASF) and sodium stearyl fumarate (0.5 parts by weight, JRS) were added and lubricated. The mixing speed was 15 rpm and the mixing time was 5 min. A homogeneously mixed total mixed powder was obtained. After being compressed into 500 mg tablets using a tablet press, solid formulations T1 and T2 containing Compound A were obtained, respectively. [Table 3]

[0116] As can be seen from Table 3, the dissolution rate of solid formulation T1 produced by the solvent evaporation method was faster than that of solid formulation T2 produced by the hot-melt extrusion method. However, after 30 minutes, both formulations were completely released, and the dissolution profiles of both formulations were almost identical with no significant difference. This indicates that the quality of the formulations produced by the two processes, solvent evaporation method and hot-melt extrusion method, is almost identical, and therefore it is inferred that there is no significant difference in the solubility of solid dispersions 6 and 7.

[0117] The bioavailability of solid formulations T1 and T2 was measured in beagle dogs (Beijing Mas Biotechnology Co., Ltd., n=6). The pharmacokinetic measurement method was the same as in Example 5 of Experimental Example 4. The concentration of compound A in the sample was measured by LC-MS / MS, and the pharmacokinetic parameters of compound A after administration to beagle dogs were calculated according to a non-compartmental model using WinNonLin (version 8.3, Pharsight). [Table 4]

[0118] The results showed that the relative bioavailability of solid formulation T1 prepared by solvent evaporation method (rotary evaporation) was 57.67% of that of solid formulation T2 prepared by melt extrusion method. Example 11 [ka]

[0119] Production method: Hydroxypropyl methylcellulose phthalate (58.0 parts by weight) (Shin-Etsu Chemical Co., Ltd., Japan), polyvinyl alcohol (15.0 parts by weight) (Merck), and polyoxyl 40 stearate (10.0 parts by weight) (Nanjing Weir Chemical Co., Ltd.) were mixed with compound A (12.0 parts by weight) and colloidal silica (2.0 parts by weight). The powdery mixture was then placed in a twin-screw extruder (screw diameter: 16 mm) at an extrusion speed of 200 rpm and a temperature of 200°C, and the mixture was extruded into strands by the screws. The hot-melt-extruded strands were pulverized and then sieved through a 60-mesh sieve to obtain solid dispersion 8 containing compound A.

[0120] The solubility of Compound A in solid dispersion 8 was measured by adding it to simulated intestinal fluid (5% SDS-pH 6.8) (37°C, 100 rpm shaking for 6 hours). The measurement showed that the solubility of Compound A in solid dispersion 8 in simulated intestinal fluid (5% SDS-pH 6.8) was 657.8 μg / mL after 6 hours. The test results showed that solid dispersion 8 containing Compound A can significantly improve the solubility of Compound A. Comparative Example Comparative Example 1

[0121] Compound A was pulverized using a jet mill (MC JETMILL-50, JETPHARMA SOLUTIONS SA) to an average particle size of approximately 20 μm (12.5 parts by weight), and the mixture was uniformly mixed with hydroxypropyl methylcellulose phthalate (57.7 parts by weight), polyoxyl 40 stearate (4.7 parts by weight), sodium dodecyl sulfate (2.3 parts by weight), colloidal silica (0.9 parts by weight), copovidone (17.3 parts by weight) (PVP / VA64, BASF), cross-linked povidone (3.6 parts by weight), and sodium stearyl fumarate (1.0 part by weight), and pressed into 400.0 mg micronized IR tablets using a single punch tablet press. Next, the tablets were placed in a coating pan and thin-film coated using an aqueous dispersion for thin-film coating (Opadry, Shanghai Colorcon Coating Technology Co., Ltd.) at a temperature of 60°C to obtain a conventional solid formulation I containing Compound A, which was a conventional micronized formulation. Comparative Example 2

[0122] Compound A (0.3 parts by weight), propylene glycol (40.7 parts by weight) (Dow Chemical Company, USA), and polyoxyethylene castor oil (59.0 parts by weight) (BASF) were placed in an appropriate container and stirred at 300 rpm at 70-110 °C until Compound A was completely dissolved, yielding a liquid formulation containing Compound A at a concentration of 3 mg / mL (1 wt%). This gave Liquid Formulation II containing Compound A. Comparative Example 3 [ka]

[0123] Preparation method: Copovidone (75.0 parts by weight) (PVP VA64, BASF), polyoxyl 40 stearate (5.0 parts by weight) (Hunan Erkang Pharmaceutical Co., Ltd., S40), sodium dodecyl sulfate (4.0 parts by weight) (BASF) were mixed with compound A (10.0 parts by weight) and colloidal silica (1.0 part by weight) (EVONIK, Aerosil). The powdery mixture was then loaded into a twin-screw extruder (screw diameter 11 mm, Thermo Scientific) at an extrusion speed of 100 rpm and a temperature of 170°C. The mixture was extruded into strips by the screws. The hot-melt extruded strips were pulverized and sieved through a 60-mesh sieve to obtain solid dispersion 10 containing compound A.

[0124] Solid Dispersion 10 (95.0 parts by weight) was homogeneously mixed with copovidone (17.4 parts by weight) (PVP VA64, BASF), cross-linked povidone (3.6 parts by weight) (International Specialties Corporation, USA), and sodium stearyl fumarate (1.0 part by weight) (JRS Group Pharmaceutical Supplements, Germany), and pressed into 585.0 mg tablets using a single-punch tablet press. The tablets were then placed in a coating pan and thin-film coated at 60°C using an aqueous thin-film coating dispersion (Opadry, Shanghai Colorcon Coating Technology Co., Ltd.) to obtain a conventional solid dispersion formulation III containing Compound A. This solid formulation was a solid formulation made from a solid dispersion containing no enteric polymer. Comparative Example 4 [ka]

[0125] Preparation method: Hydroxypropyl methylcellulose phthalate (40.0 parts by weight) (model number: HP-50), polyoxyl 40 stearate (5.0 parts by weight) (Hunan Erkang Pharmaceutical Co., Ltd., S40), sodium dodecyl sulfate (4.0 parts by weight) (BASF) were mixed with compound A (10.0 parts by weight) and colloidal silica (1.0 part by weight). The powdery mixture was then placed in a twin-screw extruder (screw diameter 11 mm) at an extrusion speed of 150 rpm and a temperature of 180°C, and the mixture was extruded into strands by the screws to obtain solid dispersion 11 containing compound A.

[0126] The solubility of Compound A was measured by adding Solid Dispersion 11 to simulated intestinal fluid of pH 6.8 containing SDS surfactant (1%) (37°C, 100 rpm shaking for 3 hours and 6 hours). The solubility of Compound A-containing Solid Dispersion 6 in 1% SDS-pH 6.8 simulated intestinal fluid was 53.7 μg / mL after 3 hours and 43.3 μg / mL after 6 hours. This result indicates that Solid Dispersion 6 containing Compound A can slightly improve the solubility of Compound A, but the solubility decreased over time, resulting in drug precipitation and indicating that the stability of the supersaturated state was low, which is unfavorable for drug absorption.

[0127] Solid Dispersion 11 (300.0 parts by weight) was uniformly mixed with lactose (100.0 parts by weight), cross-linked sodium carboxymethylcellulose (20.00 parts by weight), and sodium stearyl fumarate (2.00 parts by weight), and the mixture was pressed into 422 mg tablets using a single-punch tablet press to obtain Solid Dispersion Formulation IV containing Compound A. Comparative Example 5 [ka]

[0128] Production method: Hydroxypropyl methylcellulose phthalate (80.0 parts by weight) (product number: HP-50), copovidone (50.0 parts by weight) (PVP VA64, BASF), sodium dodecyl sulfate (1.0 part by weight), glyceryl monostearate (25.0 parts by weight), colloidal silica (1.0 part by weight), and compound A (50.0 parts by weight) were mixed together, and the powdery mixture was then placed in a twin-screw extruder (screw diameter: 11 mm) at an extrusion speed of 150 rpm and a temperature of 200°C. The mixture was extruded into a strip shape by the screws, and the resulting solid material was pulverized and sieved through a 60-mesh sieve to obtain solid dispersion 12 containing compound A (a solid dispersion outside the range of parts by weight according to the present invention).

[0129] The solubility of Compound A was measured by adding Solid Dispersion 12 to simulated intestinal fluid of pH 6.8 containing SDS surfactant (1%) (37°C, shaking at 100 rpm for 3 hours and 6 hours). The solubility of Solid Dispersion 6 containing Compound A in 1% SDS-pH 6.8 simulated intestinal fluid was 31.3 μg / mL after 3 hours and 22.4 μg / mL after 6 hours. These measurement results indicated that Solid Dispersion 12 containing Compound A had very little effect on improving the solubility of Compound A and that the solubility decreased over time, resulting in drug precipitation and low stability of the supersaturated state, which is disadvantageous for improving drug absorption.

[0130] Solid Dispersion 12 (207.0 parts by weight) was uniformly mixed with lactose (50.0 parts by weight), cross-linked sodium carboxymethylcellulose (10.00 parts by weight), and sodium stearyl fumarate (2.00 parts by weight), and the mixture was pressed into 269 mg tablets using a single-punch tablet press to obtain Solid Dispersion Formulation V containing Compound A. Experimental Example Experimental Example 1

[0131] Equilibrium solubility and permeability considerations Equilibrium solubility study: The solubility of raw material Compound A in a series of solvents was studied. The main solvents were water, simulated gastric fluid at pH 1.2 (containing 2 g of potassium chloride and 7 mL of hydrochloric acid per liter of water), phosphate buffer at pH 4.5 (containing 12.9 g of citric acid and 0.63 g of disodium hydrogen phosphate per liter of water), and simulated intestinal fluid at pH 6.8. Approximately 0.1 g of Compound A was added to 100 mL of each of the above solvents and shaken at 100 rpm for 24 hours at 37°C. The supernatant was collected and centrifuged at 8000 rpm for 15 minutes, after which the concentration of Compound A was measured by HPLC. The solubility of Compound A in various media is shown in Table 5. [Table 5]

[0132] Permeability study: The permeability of Compound A was evaluated using a Caco-2 cell model. The concentrations of Compound A and the positive control drugs aterol, pranolol, and digoxin were measured using LC / MS / MS, and the apparent permeability coefficient (Papp) and the ratio of the apparent permeability coefficients were calculated as the Papp ratio = Papp (B→A) / Papp (A→B) The permeability of the compound and whether it is a substrate of P-gp were evaluated based on this calculation. The results are shown in Table 6. [Table 6]

[0133] From Table 6, it can be seen that the solubility test results for Compound A showed that the solubility in various pH media was less than 1 μg / mL, making it an almost insoluble or insoluble drug. The permeability analysis results in Table 6 showed that Compound A had high permeability characteristics, and at high concentrations, the permeability coefficient was significantly different from that at low concentrations due to the solubility of the drug. There was no significant exocytosis in Caco-2 cells at concentrations between 2.00 and 50.0 μM. Experimental Example 2

[0134] In vitro dissolution test considerations Dissolution tests were performed on solid formulations 1, 2, and 3 prepared in Examples 5, 6, and 7, as well as solid formulations I and III prepared in Comparative Examples 1 and 3, using the paddle method (method 2) of the Chinese Pharmacopoeia, 2015, Part 4, General Provisions (0931). Each single-dose formulation was placed in 1000 mL of 5% SDS-pH 6.8 simulated intestinal fluid at 37°C and agitated at 50 rpm. After 5, 10, 15, 30, 45, 60, and 90 minutes, 8 mL samples were taken and replenished with the same volume of liquid. The samples were diluted 3-fold and their absorbance was measured at a wavelength of 316 nm using UV-visible spectrophotometry (Chinese Pharmacopoeia, 2015, Part 4, General Provisions (0401)). The dissolution amounts of the corresponding formulations were calculated, and dissolution curves were plotted (see Figure 2).

[0135] Solid formulations 1, 2, and 3 prepared in Examples 5, 6, and 7 were left to stand for 6 months under accelerated conditions of 40±2°C and 75%±5% RH, and then the drug dissolution behavior was measured under the same conditions as above, and dissolution curves were plotted (see Figures 3, 4, and 5).

[0136] As can be seen from Figures 2 to 5, solid formulations 1, 2 and 3 prepared in Examples 5, 6 and 7 were able to significantly improve the dissolution rate and solubility of Compound A compared with IR conventional formulation I (conventional micronized formulation, Comparative Example 1) and conventional solid dispersion formulation III (solid formulation prepared only from a solid dispersion containing a non-enteric high molecular weight polymer, Comparative Example 3). Furthermore, the solid formulations of the present invention after standing under accelerated conditions did not show significant changes in dissolution behavior, had good solubilizing effects on the drug and were stable. Experimental Example 3

[0137] Dissolution stability considerations The preparations prepared in Examples 5, 6, 7, Comparative Examples 1 and 3 were taken and finely ground. Each single-dose preparation was weighed and placed in 250 mL of 3% SDS-pH 6.8 simulated intestinal fluid at 37°C and a stirring speed of 100 rpm. After 1 hour, 2 hours, 4 hours, 6 hours and 8 hours, samples were taken out and centrifuged at 8000 rpm for 15 minutes. The concentration of Compound A was measured by HPLC, and a time-concentration curve was plotted (see Figure 6).

[0138] As can be seen from FIG. 6, the solid formulations prepared in Examples 5, 6, and 7 of the present invention had good dissolution stability within 8 hours and stable supersaturated states, which were favorable for drug absorption. However, the conventional IR formulation (conventional micronized formulation, Comparative Example 1) and the conventional solid dispersion formulation (solid formulation prepared using a solid dispersion containing no enteric polymer, Comparative Example 3) showed a decrease in solubility within 2 hours and a continuous decrease in drug concentration over time, indicating the occurrence of drug precipitation and poor stability of the supersaturated state, which was unfavorable for drug absorption. Experimental Example 4

[0139] Bioavailability study in dogs The formulations prepared in Examples 5, 7, Comparative Examples 1, 3, 4, and 5 were orally administered to fully fed beagle dogs (n=3, Experimental Animal Center, Shanghai Institute of Materia Medica). The dosage of the formulations prepared in Examples 5, 7, Comparative Examples 1, 3, 4, and 5 was 50 mg / dog. Food was provided uniformly before the test, and the drug was administered 30 minutes later. Water was available throughout the test, with a washout period of 7 days. 0.5 mL of blood was collected from a limb vein before administration (0 h) and 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12, 24, 48, and 72 h after administration. The blood was placed in an EDTA-K2 anticoagulant tube and centrifuged at 3500 rpm for 10 minutes to separate the plasma, which was then frozen and stored in a -70°C refrigerator for analysis.

[0140] The liquid formulation of Comparative Example 2 was diluted 6-fold with saline and then administered intravenously to sated beagle dogs (n=3) at a dose of 1 mg / kg of Compound A (2 mL / kg). Food was provided uniformly before the test, and the drug was administered 30 minutes later. Water was available throughout the test. Blood samples (0.5 mL) were taken before administration (0 h) and at 5 min, 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12, 24, 48, and 72 h after administration. These samples were placed in EDTA-K2 anticoagulant tubes and centrifuged at 3500 rpm for 10 min to separate the plasma, which was then frozen and stored in a -70°C refrigerator for analysis.

[0141] The concentration of Compound A in the samples was measured by LC-MS. The pharmacokinetic parameters of Compound A after administration to beagle dogs were calculated using a non-compartmental model in Phoenix 6.4 software (Pharsight, USA), and the data summary is shown in Table 7. [Table 7]

[0142] As can be seen from the results, compared to the conventional formulation of IR prepared in Comparative Example 1 (a conventional micronized formulation), the conventional solid dispersion formulation prepared in Comparative Example 3 (a solid formulation prepared only with a solid dispersion containing a non-enteric high molecular weight polymer), the solid dispersion formulation prepared in Comparative Example 4 (a solid formulation prepared only with a solid dispersion containing an enteric high molecular weight polymer), and the solid dispersion formulation prepared in Comparative Example 5 (a solid dispersion formulation outside the range of parts by weight of the present invention), Solid Formulation 1 prepared in Example 5 of the present invention and Solid Formulation 3 prepared in Example 7 all significantly improved the bioavailability of Compound A and had good in vivo absorption. Comparative Examples 1, 3, 4, and 5 had poor in vivo absorption. (Addendum) The invention of the present disclosure includes the following aspects. <Item 1> 1. A solid dispersion comprising: Compound A; and a pharmaceutically acceptable matrix polymer, wherein the pharmaceutically acceptable matrix polymer comprises an enteric polymer and a non-enteric polymer; Compound A is 1-{(6-[(1-methyl)-4-pyrazolyl]-imidazole[1,2-a]pyridine)-3-sulfonyl}-6-[(1-methyl)-4-pyrazolyl]-1-hydro-pyrazolyl[4,3-b]pyridine; and the weight ratio of Compound A to the pharmaceutically acceptable matrix polymer is 1:3 to 1:35. <Item 2> The enteric polymer is one or more selected from the group consisting of hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polymethyl acrylate, polyvinyl acetate phthalate, cellulose acetate phthalate, and cellulose acetate succinate; and / or the non-enteric polymer is one or more selected from polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, copovidone, povidone, polyvinyl alcohol, 2-hydroxy-β-cyclodextrin, hydroxypropyl methylcellulose, and hydroxypropyl cellulose; And / or the weight ratio of the enteric high molecular weight polymer to the non-enteric high molecular weight polymer is 2:1 to 10:1. <Item 3> (1) The enteric polymer is hydroxypropyl methylcellulose phthalate and / or hydroxypropyl methylcellulose acetate succinate, (2) The non-enteric polymer is one or more selected from copovidone, polyvinyl alcohol, povidone, and hydroxypropyl methylcellulose; (3) the solid dispersion optionally further comprises one or more of a fluidizing agent, a plasticizer, and a surfactant; (4) The weight ratio of the enteric polymer to the non-enteric polymer is 2:1 to 6:1; and (5) The solid dispersion according to <Item 1>, wherein the weight ratio of compound A to the pharmaceutically acceptable matrix polymer is 1:4 to 1:25, and preferably 1:5 to 1:15. <Item 4> (1) the weight ratio of the compound A to the enteric polymer is 1:2 to 1:15, preferably 1:3 to 1:10; (2) the weight ratio of the compound A to the non-enteric polymer is 2:1 to 1:10, preferably 2:1 to 1:5; (3) The fluidizing agent is one or more selected from colloidal silica, animal fat, vegetable fat, and wax; (4) the weight ratio of the fluidizing agent to the compound A is 1:1 to 1:100; (5) The plasticizer is one or more selected from the group consisting of tributyl O-acetylcitrate, triethyl O-acetylcitrate, benzyl benzoate, acetone chloroform, dextrin, dibutyl phthalate, diethyl phthalate, dimethyl phthalate, glycerin, glyceryl monostearate, polyoxyl 40 stearate, mannitol, mineral oil, lanolin alcohol, palmitic acid, polyethylene glycol, polyethylene glycol monostearate, polyvinyl acetate, propylene glycol, 2-pyrrolidone, sorbitol, stearic acid, triacetin, tributyl citrate, triethanolamine, and triethyl citrate; (6) the weight ratio of the plasticizer to the compound A is 1:1 to 1:20; (7) The surfactant is one or more selected from anionic surfactants, cationic surfactants, and nonionic surfactants, the anionic surfactant is preferably sodium dodecyl sulfate and / or sodium polyester, the cationic surfactant is preferably one or more selected from cetrimide, benzethonium chloride, cetylpyridinium chloride, and lauric acid, and the nonionic surfactant is preferably one or more selected from polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, polyoxyethylene stearic acid esters, and polyoxyethylene polyoxypropylene ether block copolymers, and (8) The solid dispersion according to <Item 3>, characterized in that it satisfies one or more of the following conditions: the weight ratio of the surfactant to the compound A is 1:1 to 1:10. <Item 5> A method for producing the solid dispersion according to any one of <Item 1> to <Item 4>, (1) uniformly mixing the components of the solid dispersion by melting or dissolving to obtain a uniform dispersion; (2) solidifying the uniform dispersion to obtain a solid dispersion. <Item 6> The solidification is a melt extrusion method, and the method for producing the solid dispersion includes the steps of: (1) In the melt extrusion method, the sleeve temperature of the melt extruder is 150 to 220°C, (2) In the melt extrusion method, the screw extrusion rotation speed of the melt extruder is 50 to 300 rpm, (3) In the melt extrusion method, the feed rate is 10 to 100 rpm, and (4) The melt extrusion method (1a) uniformly mixing the components of the solid dispersion to obtain a powdery mixture; (2a) feeding the powdery mixture into a hot melt extruder feeder, extruding, pulverizing, and sieving the mixture to obtain a solid dispersion containing compound A. <Item 7> A solid formulation comprising the solid dispersion according to any one of <Item 1> to <Item 4> and a pharmaceutically acceptable additive, wherein the pharmaceutically acceptable additive preferably comprises one or more of a fluidizing agent, a binder, a disintegrant, a filler, a lubricant, a colorant, a pH adjuster, a surfactant, a lubricant, and a stabilizer. <Item 8> The solid dispersion according to any one of <Item 1> to <Item 4> or the solid formulation according to <Item 7>, wherein the content of phthalic acid in the total components of the solid dispersion is ≦6.0 wt% and preferably ≦4.8 wt%. <Item 9> Use of the solid dispersion according to any one of <Item 1> to <Item 4> or the solid formulation according to <Item 7> in the manufacture of a drug for preventing and / or treating a disease and / or tumor associated with a protein tyrosine kinase disorder. <Item 10> the disease and / or tumor comprises a solid cancer, for example, lung cancer, gastric cancer, esophageal cancer, colon cancer, colorectal cancer, liver cancer, renal cell carcinoma, head and neck cancer, thyroid cancer, ovarian cancer, breast cancer, pancreatic cancer, prostate cancer, oral cancer, malignant glial cancer, rhabdomyosarcoma, or bone cancer; Preferably, the disease and / or tumor is lung cancer, gastric cancer, liver cancer, renal cell carcinoma, ovarian cancer, breast cancer, pancreatic cancer, prostate cancer or thyroid cancer; More preferably, the disease and / or tumor is lung cancer, for example, non-small cell lung cancer. <Item 11> A method for preventing and / or treating a disease and / or tumor associated with a protein tyrosine kinase disorder, comprising administering an effective amount of the solid dispersion according to any one of <Item 1> to <Item 4> or the solid formulation according to <Item 7> to an individual in need thereof.

Claims

1. 1. A solid dispersion comprising: Compound A; and a pharmaceutically acceptable matrix polymer, wherein the pharmaceutically acceptable matrix polymer comprises an enteric polymer and a non-enteric polymer; Compound A is 1-{(6-[(1-methyl)-4-pyrazolyl]-imidazole[1,2-a]pyridine)-3-sulfonyl}-6-[(1-methyl)-4-pyrazolyl]-1-hydro-pyrazolyl[4,3-b]pyridine; the weight ratio of Compound A to the pharmaceutically acceptable matrix polymer is 1:3 to 1:35; and the weight ratio of the enteric polymer to the non-enteric polymer is 2:1 to 10:

1.

2. the enteric polymer is one or more selected from the group consisting of hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polymethyl acrylate, polyvinyl acetate phthalate, cellulose acetate phthalate, and cellulose acetate succinate; and / or the non-enteric polymer is one or more selected from the group consisting of polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, copovidone, povidone, polyvinyl alcohol, 2-hydroxy-β-cyclodextrin, hydroxypropyl methylcellulose, and hydroxypropyl cellulose.

3. (1) The enteric polymer is hydroxypropyl methylcellulose phthalate and / or hydroxypropyl methylcellulose acetate succinate, (2) The non-enteric polymer is one or more selected from the group consisting of copovidone, polyvinyl alcohol, povidone, and hydroxypropyl methylcellulose; (3) The solid dispersion optionally further comprises one or more of a fluidizing agent, a plasticizer, and a surfactant; (4) The weight ratio of the enteric polymer to the non-enteric polymer is 2:1 to 6:1; and (5) The solid dispersion according to claim 1, wherein the weight ratio of compound A to the pharmaceutically acceptable matrix polymer is 1:4 to 1:

25.

4. The solid dispersion described in claim 3, characterized in that the weight ratio of compound A to the pharmaceutically acceptable matrix polymer is 1:5 to 1:

15.

5. (1) the weight ratio of the compound A to the enteric polymer is 1:2 to 1:15; (2) the weight ratio of the compound A to the non-enteric polymer is 2:1 to 1:10; (3) The fluidizing agent is one or more selected from colloidal silica, animal fat, vegetable fat, and wax; (4) the weight ratio of the fluidizing agent to the compound A is 1:1 to 1:100; (5) The plasticizer is one or more selected from the group consisting of tributyl O-acetylcitrate, triethyl O-acetylcitrate, benzyl benzoate, acetone chloroform, dextrin, dibutyl phthalate, diethyl phthalate, dimethyl phthalate, glycerin, glyceryl monostearate, polyoxyl 40 stearate, mannitol, mineral oil, lanolin alcohol, palmitic acid, polyethylene glycol, polyethylene glycol monostearate, polyvinyl acetate, propylene glycol, 2-pyrrolidone, sorbitol, stearic acid, triacetin, tributyl citrate, triethanolamine, and triethyl citrate; (6) The weight ratio of the plasticizer to the compound A is 1:1 to 1:20; (7) The surfactant is one or more selected from anionic surfactants, cationic surfactants, and nonionic surfactants, and (8) The solid dispersion according to claim 3, wherein the weight ratio of the surfactant to the compound A is 1:1 to 1:

10.

6. (1) The weight ratio of the compound A to the enteric polymer is 1:3 to 1:10, (2) the weight ratio of the compound A to the non-enteric high molecular weight polymer is 2:1 to 1:5; (3) The anionic surfactant is sodium dodecyl sulfate and / or sodium polyester; (4) The cationic surfactant is one or more selected from the group consisting of cetrimide, benzethonium chloride, cetylpyridinium chloride, and lauric acid; (5) The solid dispersion according to claim 5, characterized in that the nonionic surfactant is one or more selected from the group consisting of polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, polyoxyethylene stearic acid esters, and polyoxyethylene polyoxypropylene ether block copolymers.

7. A method for producing the solid dispersion according to any one of claims 1 to 6, comprising: (1) uniformly mixing the components of the solid dispersion by melting or dissolving to obtain a uniform dispersion; (2) solidifying the uniform dispersion to obtain a solid dispersion.

8. The solidification is a melt extrusion method, and the method for producing the solid dispersion includes the steps of: (1) In the melt extrusion method, the sleeve temperature of the melt extruder is 150 to 220°C; (2) In the melt extrusion method, the screw extrusion rotation speed of the melt extrusion device is 50 to 300 rpm; (3) In the melt extrusion method, the feed rate is 10 to 100 rpm; and (4) The melt extrusion method (1a) uniformly mixing the components of the solid dispersion to obtain a powdery mixture; (2a) feeding the powdery mixture into a hot melt extruder feeder, extruding, pulverizing, and sieving the mixture to obtain a solid dispersion containing Compound A.

9. A solid formulation comprising the solid dispersion according to any one of claims 1 to 6 and a pharmaceutically acceptable additive.

10. 7. The solid dispersion according to claim 1, wherein the content of phthalic acid in the total components of the solid dispersion is ≦6.0 wt %.

11. The solid dispersion of claim 1 for use in treating diseases and / or tumors associated with protein tyrosine kinase disorders.

12. The solid dispersion of claim 11, wherein the disease and / or tumor associated with a protein tyrosine kinase disorder is lung cancer, gastric cancer, esophageal cancer, colon cancer, colorectal cancer, liver cancer, renal cell carcinoma, head and neck cancer, thyroid cancer, ovarian cancer, breast cancer, pancreatic cancer, prostate cancer, oral cancer, malignant glial carcinoma, rhabdomyosarcoma, or bone cancer.

13. The solid dispersion of claim 12, wherein the lung cancer is non-small cell lung cancer.

Images