Pharmaceutical composition of anaplastic lymphoma kinase inhibitor and preparation method thereof

Abstract

The invention relates to a pharmaceutical composition of a polycyclic anaplastic lymphoma kinase inhibitor as well as a preparation method and application of the pharmaceutical composition. In particular to a pharmaceutical preparation of 5-chloro-N4-(2-(isopropyl sulfonyl) phenyl)-N2-(7-methyl-8-(piperidine-4-yl)-2, 3-dihydrobenzo [b] [1, 4] dioxin-5-yl) pyrimidine-2, 4-diamine, a method for preparing the pharmaceutical preparation and application of the pharmaceutical preparation.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and particularly relates to a pharmaceutical composition of 5-chloro-N 4 -(2-(isopropylsulfonyl)phenyl)-N 2 -(7-methyl-8-(piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pyrimidine-2,4-diamine (abbreviated as the compound of formula (I)). The present invention also relates to a preparation method of the pharmaceutical composition of the compound of formula (I), and its use in the preparation of a drug for treating tumor patients. Background Art

[0002] Anaplastic lymphoma kinase (ALK) is a member of the receptor tyrosine kinase family. It can recruit downstream proteins through autophosphorylation, and then express specific genes to regulate cell metabolism and growth. Anaplastic lymphoma kinase was first discovered in anaplastic large cell lymphoma (ALCL), and later it was found that it is also highly expressed in non-small cell lung cancer (NSCLC).

[0003] The abnormal expression of ALK in some ALCL / NSCLC results from different chromosomal translocations. These chromosomal translocations can all produce corresponding fusion proteins. Gene analysis of these fusion proteins shows that they all contain the gene sequence encoding the intracellular kinase region at the 3' end of the ALK gene, while the gene fragments fused with ALK contain promoter elements and sequences encoding mediators of autodimerization, resulting in high expression and overactivation of the fusion proteins with ALK kinase activity in cells, causing malignant transformation of cells. Therefore, the activity of the ALK intracellular kinase region and the corresponding signal transduction pathway are important molecular mechanisms leading to the formation of ALCL. ROS1 is a target gene that has been intensively studied in lung adenocarcinoma after ALK. ROS1 is a member of the receptor tyrosine kinase family, and the incidence of ROS1 in NSCLC is about 1.7%. There is 49% homology between ROS1 and anaplastic lymphoma kinase ALK within the amino acid kinase domain, and 77% identity at the ATP binding site, which makes it possible to use ALK kinase inhibitors to treat ROS1 rearrangement-positive NSCLC.

[0004] Patent application PCT / CN2015 / 090712 discloses the compound of formula (I) and its preparation method. Research shows that the compound of formula (I) has excellent ALK / ROS1 inhibitory activity, shows good anti-tumor effects, provides the possibility for the treatment of cancer patients, and has good safety.

[0005]

[0006] In order to meet the requirements of formulation, production, transportation, etc., the applicant has conducted in-depth research on the compound of formula (1), and found that there are problems such as stickiness in the compound, and these problems need to be further solved in the formulation research.

[0007] The applicant has conducted targeted research on the characteristics of the compound of formula (I) in order to discover a pharmaceutical preparation with good stability and dissolution performance to meet the needs of clinical medication. Summary of the Invention

[0008] The inventors of the present application have found in the research that when preparing the preparation with the compound of formula (I) involved in the present application, due to the relatively large proportion and stickiness of the compound of formula (I), there is a phenomenon that the preparation is relatively difficult. The applicant unexpectedly found in the research that anhydrous calcium hydrogen phosphate can disperse the viscosity of the compound of formula (I); the inclusion of anhydrous calcium hydrogen phosphate in the filler can solve the problems of the relatively sticky compound of formula (I) and the relatively difficult preparation.

[0009] The present invention provides a pharmaceutical composition of a compound represented by formula (I), which comprises the compound represented by formula (I):

[0010]

[0011] The pharmaceutical composition further comprises one or more pharmaceutical excipients, wherein the compound of formula (I) is present in the pharmaceutical composition in an amount of 25% to 70% by weight, preferably 25% to 60%, 30% to 60%, 40% to 60%, more preferably 25% to 55%, 30% to 55%, 40% to 55%, 45% to 55%, and further preferably 50% ± 2%.

[0012] In some embodiments, the pharmaceutical excipients of the present invention comprise a filler, a binder, a disintegrant, a lubricant, and a glidant.

[0013] In some embodiments, the pharmaceutical excipients of the present invention comprise a filler, a binder, a disintegrant, a lubricant, a glidant, and a wetting agent.

[0014] In some embodiments, the filler at least comprises anhydrous calcium hydrogen phosphate.

[0015] In some embodiments, the filler at least comprises pregelatinized starch and anhydrous calcium hydrogen phosphate. In some embodiments, the filler further comprises one or more of microcrystalline cellulose, mannitol, corn starch, glucose, sucrose, and dextrin. In some embodiments, the filler further comprises one or more of microcrystalline cellulose and corn starch. In some embodiments, the filler comprises a combination of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and pregelatinized starch. In some embodiments, the filler does not contain lactose.

[0016] In some embodiments, the filler at least comprises microcrystalline cellulose and anhydrous calcium hydrogen phosphate. In some embodiments, the filler further comprises one or more of pregelatinized starch, mannitol, corn starch, glucose, sucrose, and dextrin. In some embodiments, the filler further comprises one or more of pregelatinized starch and corn starch. In some embodiments, the filler comprises a combination of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and pregelatinized starch. In some embodiments, the filler does not contain lactose.

[0017] In some embodiments, the filler is present in the pharmaceutical composition in an amount of 30% to 65% by weight, preferably 30% to 60%, 35% to 65%, more preferably 30% to 50%, further preferably 35% to 45%, and even more preferably 40% ± 2%.

[0018] In some embodiments, the pregelatinized starch is present in the pharmaceutical composition in an amount of 2% to 15% by weight, preferably 3% to 15%, more preferably 3% to 12%, further preferably 3.5% to 10%, and even more preferably 4% to 9.5%.

[0019] In some embodiments, the anhydrous calcium hydrogen phosphate is present in the pharmaceutical composition in an amount of 5% to 15% by weight, preferably 8% to 13%, more preferably 10% to 12%, and further preferably 11% ± 0.5%.

[0020] In some embodiments, the microcrystalline cellulose is present in the pharmaceutical composition in an amount of 10% to 35% by weight, preferably 10% to 30%, more preferably 14% to 26%, further preferably 18% to 22%, and even more preferably 20% ± 1%.

[0021] In some embodiments, the filler at least comprises a combination of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and pregelatinized starch, wherein the weight ratio of microcrystalline cellulose to pregelatinized starch is 1:1 to 10:1, preferably 1:1 to 8:1, and more preferably 2:1 to 8:1.

[0022] In some embodiments, the filler is a combination of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and pregelatinized starch, wherein the weight ratio of microcrystalline cellulose to pregelatinized starch is from 1:1 to 10:1, preferably from 1:1 to 8:1, more preferably from 2:1 to 8:1.

[0023] In some embodiments, the pharmaceutical excipient contains a binder. Preferably, the binder is selected from one or more of povidone, copovidone, alginic acid, chitosan, dextrin, maltodextrin, maltose, carbomer, gum arabic, hydroxypropyl cellulose, and hydroxypropyl methylcellulose. More preferably, the binder is selected from one or more of povidone and copovidone.

[0024] In some embodiments, the binder is present in the pharmaceutical composition in an amount of 1% to 5% by weight, preferably 1% to 4%, more preferably 1.5% to 3.5%, further preferably 2% to 3%, and even more preferably 2.5% ± 0.2%.

[0025] In some embodiments, the pharmaceutical excipient contains at least one disintegrant. In some embodiments, the disintegrant is selected from one or more of sodium croscarmellose, sodium carboxymethyl starch, hydroxypropyl cellulose, crospovidone, and starch. In some embodiments, the disintegrant is selected from one or more of sodium croscarmellose and crospovidone.

[0026] In some embodiments, the disintegrant is present in the pharmaceutical composition in an amount of 1% to 10% by weight, preferably 1% to 8%, more preferably 2% to 6%, further preferably 3% to 5%, still further preferably 3.5% to 4.5%, and even more preferably 4.0% ± 0.2%.

[0027] In some embodiments, the disintegrant is used in a combination of internal addition and external addition, and the ratio of internal addition to external addition is from 1:3 to 3:2, preferably from 1:3 to 3:1, more preferably 1:1.

[0028] In some embodiments, the pharmaceutical excipient of the composition of the present invention contains at least one glidant. In some embodiments, the glidant is selected from one or more of silica, colloidal silica, colloidal silicate, corn starch, and talc. In some embodiments, the glidant is selected from silica or colloidal silica. In some embodiments, the glidant is selected from colloidal silica. In some embodiments, the glidant is present in the pharmaceutical composition in an amount of 0.2% to 2% by weight, preferably 0.5% to 1.5%, more preferably 1% ± 0.2%.

[0029] In some embodiments, the pharmaceutical excipients of the composition of the present invention include at least one lubricant. In some embodiments, the lubricant is selected from one or a mixture of two or more of magnesium stearate, calcium stearate, talc powder, silicon dioxide, and stearic acid. In some embodiments, the lubricant is selected from magnesium stearate. In some embodiments, the lubricant is present in the pharmaceutical composition in an amount of 0.5% to 5% by weight, preferably 1% to 5%, 0.5% to 3%, more preferably 1% to 3%, further preferably 1.5% to 2.5%, and even more preferably 2% ± 0.2%.

[0030] In some embodiments, the wetting agent is selected from water, 75% ethanol, 90% ethanol, 95% ethanol, or absolute ethanol. In some embodiments, the wetting agent is selected from purified water.

[0031] In some embodiments, the total content of each component of the pharmaceutical composition of the present invention is less than or equal to 100%.

[0032] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant, and a glidant; and based on the total weight of the pharmaceutical composition, the content of the compound of formula (I) is 25% to 70%, the content of the binder is 1% to 5%, the content of the filler is 30% to 65%, the content of the disintegrant is 1% to 10%, the content of the lubricant is 0.5% to 5%, the content of the glidant is 0.2% to 2%, and the filler at least comprises dicalcium hydrogen phosphate anhydrous.

[0033] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant, and a glidant; and based on the total weight of the pharmaceutical composition, the content of the compound of formula (I) is 25% to 55%, the content of the binder is 1% to 5%, the content of the filler is 30% to 65%, the content of the disintegrant is 1% to 10%, the content of the lubricant is 0.5% to 5%, the content of the glidant is 0.2% to 2%, the filler at least comprises dicalcium hydrogen phosphate anhydrous, and the filler does not contain lactose.

[0034] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant, and a glidant; and based on the total weight of the pharmaceutical composition, the content of the compound of formula (I) is 25% to 55%, the content of the binder is 1% to 5%, the content of the filler is 35% to 65%, the content of the disintegrant is 3% to 5%, the content of the lubricant is 0.5% to 3%, the content of the glidant is 0.5% to 1.5%, the filler comprises at least microcrystalline cellulose and anhydrous calcium hydrogen phosphate, and the filler does not contain lactose.

[0035] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant, and a glidant; and based on the total weight of the pharmaceutical composition, the content of the compound of formula (I) is 25% to 70%, the content of the binder is 1% to 5%, the content of the filler is 30% to 60%, the content of the disintegrant is 1% to 10%, the content of the lubricant is 1% to 5%, the content of the glidant is 0.2% to 2%, and the filler comprises at least pregelatinized starch and anhydrous calcium hydrogen phosphate.

[0036] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant, and a glidant; and based on the total weight of the pharmaceutical composition, the content of the compound of formula (I) is 25% to 70%, the content of the binder is 1% to 5%, the content of the filler is 30% to 60%, the content of the disintegrant is 1% to 10%, the content of the lubricant is 1% to 5%, the content of the glidant is 0.2% to 2%, the filler comprises at least pregelatinized starch and anhydrous calcium hydrogen phosphate, and the filler does not contain lactose.

[0037] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant, and a glidant; and based on the total weight of the pharmaceutical composition, the content of the compound of formula (I) is 25% to 55%, the content of the binder is 1% to 5%, the content of the filler is 35% to 65%, the content of the disintegrant is 3% to 5%, the content of the lubricant is 0.5% to 3%, the content of the glidant is 0.5% to 1.5%, and the filler comprises at least pregelatinized starch and anhydrous calcium hydrogen phosphate.

[0038] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant, and a glidant; and based on the total weight of the pharmaceutical composition, the content of the compound of formula (I) is 25% to 55%, the content of the binder is 1% to 4%, the content of the filler is 30% to 50%, the content of the disintegrant is 3% to 5%, the content of the lubricant is 1% to 3%, the content of the glidant is 0.5% to 1.5%, and the filler comprises microcrystalline cellulose, pregelatinized starch, and anhydrous calcium hydrogen phosphate.

[0039] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant, and a glidant; and based on the total weight of the pharmaceutical composition, the content of the compound of formula (I) is 25% to 70%, the content of the binder is 1% to 5%, the content of the filler is 30% to 60%, the content of the disintegrant is 1% to 10%, the content of the lubricant is 1% to 5%, the content of the glidant is 0.2% to 2%, and the filler at least comprises pregelatinized starch and anhydrous calcium hydrogen phosphate; wherein the pregelatinized starch is present in the pharmaceutical composition in an amount of 3% to 12% by weight, preferably 3.5% to 10%, and more preferably 4% to 9.5%.

[0040] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant, and a glidant; the filler at least comprises pregelatinized starch and anhydrous calcium hydrogen phosphate.

[0041] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant, and a glidant; the filler at least comprises pregelatinized starch and anhydrous calcium hydrogen phosphate and does not contain lactose.

[0042] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant, and a glidant; the filler comprises microcrystalline cellulose, pregelatinized starch, and anhydrous calcium hydrogen phosphate.

[0043] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant, and a glidant; the filler consists of microcrystalline cellulose, pregelatinized starch, and anhydrous calcium hydrogen phosphate; wherein the pregelatinized starch is present in the pharmaceutical composition in an amount of 3% to 12% by weight, preferably 3.5% to 10%, and more preferably 4% to 9.5%.

[0044] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant, and a glidant; the compound of formula (I) is present in an amount of 25% to 60% by weight of the pharmaceutical composition; the filler consists of microcrystalline cellulose, pregelatinized starch, and anhydrous calcium hydrogen phosphate; wherein the pregelatinized starch is present in an amount of 3% to 12% by weight of the pharmaceutical composition; the binder is povidone; the disintegrant is croscarmellose sodium or crospovidone.

[0045] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant, and a glidant; the compound of formula (I) is present in an amount of 40% to 60% by weight of the pharmaceutical composition; the filler consists of microcrystalline cellulose, pregelatinized starch, and anhydrous calcium hydrogen phosphate; wherein the pregelatinized starch is present in an amount of 3.5% to 10% by weight of the pharmaceutical composition; the binder is povidone; the disintegrant is croscarmellose sodium or crospovidone; the glidant is colloidal silicon dioxide; the lubricant is magnesium stearate.

[0046] In some embodiments, the pharmaceutical composition of the present invention is an oral preparation, preferably, the oral preparation is a tablet, and more preferably, the tablet is film-coated.

[0047] In some embodiments, the pharmaceutical composition comprises 40% to 60% by weight of the compound of formula (I), 30% to 50% by weight of the filler, 1% to 4% by weight of the binder, 3% to 5% by weight of the disintegrant, 0.5% to 1.5% by weight of the glidant, and 1.5% to 2.5% by weight of the lubricant.

[0048] In some embodiments, the pharmaceutical composition comprises 45% to 55% by weight of the compound of formula (I), 35% to 45% by weight of the filler, 1.5% to 3.5% by weight of the binder, 3.5% to 4.5% by weight of the disintegrant, 0.5% to 1.5% by weight of the glidant, and 1.5% to 2.5% by weight of the lubricant.

[0049] In some embodiments, the pharmaceutical composition comprises 50% ± 2% by weight of the compound of formula (I), 40% ± 2% by weight of the filler, 2.5% ± 0.2% by weight of the binder, 4.0% ± 0.2% by weight of the disintegrant, 1% ± 0.2% by weight of the glidant, and 2% ± 0.2% by weight of the lubricant.

[0050] In some embodiments, the pharmaceutical excipients include a filler, a binder, a disintegrant, a lubricant, and a glidant, wherein the filler is selected from the combination of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and pregelatinized starch, the binder is selected from povidone, the disintegrant is selected from croscarmellose sodium or crospovidone, the lubricant is magnesium stearate, and the glidant is colloidal silicon dioxide.

[0051] In some embodiments, a pharmaceutical composition comprises:

[0052] (1) 40% to 60% by weight of the compound of formula (I);

[0053] (2) 30% to 50% by weight of a filler, the filler comprising at least anhydrous calcium hydrogen phosphate and pregelatinized starch; preferably, the filler consists of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and pregelatinized starch;

[0054] (3) 1% to 4% by weight of a binder, the binder being povidone;

[0055] (4) 3% to 5% by weight of a disintegrant, the disintegrant being croscarmellose sodium or crospovidone;

[0056] (5) 0.5% to 1.5% by weight of a glidant, the glidant being colloidal silicon dioxide;

[0057] (6) 1% to 3% by weight of a lubricant, the lubricant being magnesium stearate.

[0058] In some embodiments, the present invention provides another pharmaceutical composition comprising the compound of formula (I) or the compound of formula (I), wherein the compound of formula (I) is present in an amount of 10 mg - 500 mg. Preferably, the compound of formula (I) is present in an amount of 20 mg - 300 mg; more preferably, the compound of formula (I) is present in an amount of 50 mg - 250 mg, and still more preferably, the compound of formula (I) is present in amounts of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg.

[0059] In some embodiments, in the pharmaceutical composition provided by the present invention, the compound of formula (I) is sieved or pulverized before granulation. In some embodiments, in the pharmaceutical composition provided by the present invention, the compound of formula (I) has a D90 of particle size distribution of 5 - 150 μm, preferably 10 - 100 μm, more preferably 10 - 85 μm.

[0060] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant, and a glidant; the filler consists of microcrystalline cellulose, pregelatinized starch, and anhydrous dibasic calcium phosphate; the compound of formula (I) has a D90 of the particle size distribution of 10 - 100 μm.

[0061] In some embodiments, the present invention provides a pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant, and a glidant; the filler consists of microcrystalline cellulose, pregelatinized starch, and anhydrous dibasic calcium phosphate; wherein the pregelatinized starch is present in the pharmaceutical composition in an amount of 3% to 12% by weight; the compound of formula (I) has a D90 of the particle size distribution of 10 - 100 μm.

[0062] In some embodiments, the dissolution of the pharmaceutical composition of the compound of formula (I) is such that at least 75%, preferably 80%, more preferably 85% of the compound of formula (I) is dissolved after 45 minutes.

[0063] In some embodiments, the present invention further provides a method for preparing a pharmaceutical composition of a compound of formula (I), the preparation method comprising the step of premixing the compound of formula (I) with a filler and a disintegrant.

[0064] In some embodiments, the preparation method comprises the step of wet granulation.

[0065] In some embodiments, the preparation method comprises the steps of internal addition and external addition of the disintegrant.

[0066] In some embodiments, the preparation method comprises the following steps:

[0067] (1) Mix the compound of formula (I), the filler, and the disintegrant, add the binder, and granulate;

[0068] (2) Add the glidant and perform dry sizing;

[0069] (3) Add the disintegrant and the lubricant and mix evenly;

[0070] (4) Compress the mixture to obtain the tablets.

[0071] In some embodiments, the preparation method comprises the following steps:

[0072] (1) Mix the compound of formula (I), the filler, and the disintegrant in a granulator to obtain a premix;

[0073] (2) Dissolve the binder in purified water to prepare a binder solution;

[0074] (3) Add the binder solution to the premix in step (1) and granulate;

[0075] (4) Screen the granules using a wet granulator;

[0076] (5) Feed the wet granules into a fluidized bed granulator for drying;

[0077] (6) Place the glidant in the dry granules and perform dry screening;

[0078] (7) Add the disintegrant and lubricant, and mix well using a mixer;

[0079] (8) Compress tablets.

[0080] In some embodiments, the present invention provides the use of a pharmaceutical composition in the preparation of a medicament for treating cancer, optionally further comprising one or more second therapeutic agents.

[0081] In some embodiments, the second therapeutic agent is selected from antimetabolites, growth factor inhibitors, antibodies, mitotic inhibitors, anti-tumor hormones, alkylating agents, metal platinum agents, immunosuppressants, purine analogs, antibiotics, adrenocortical inhibitors, or enzyme inhibitors.

[0082] Any one or any combination of two or more of the above embodiments of the present invention is included within the scope of protection of the present invention.

[0083] In some embodiments, the cancer of the present invention is selected from lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer, hepatoblastoma, papillary renal cell carcinoma, head and neck squamous cell carcinoma, nephroblastoma, renal cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, central nervous system tumors, female genital tract cancer, carcinoma in situ, lymphoma, neuroblastoma, neurofibromatosis, thyroid cancer, bone cancer, skin cancer, brain cancer, testicular cancer, gastrointestinal stromal tumors, prostate tumors, multiple myeloma, melanoma, neuroblastoma, sarcoma, or glioma.

[0084] In some embodiments, the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

[0085] In some embodiments, the cancer is selected from brain tumors, non-Hodgkin lymphoma, non-small cell lung cancer, small cell lung cancer, colon cancer, mast cell tumors, or melanoma.

[0086] In some embodiments, the cancer is selected from gliomas.

[0087] In some embodiments, the cancer is selected from astrocytomas.

[0088] The "pharmaceutical composition" described in the present invention is any pharmaceutically acceptable dosage form and is administered to a patient in need thereof by oral, parenteral, rectal, or pulmonary administration, etc. When used for oral administration, it can be made into conventional solid preparations, such as tablets, capsules, pills, granules, etc.; it can also be made into oral liquid preparations, such as oral solutions, oral suspensions, syrups, etc. When making oral preparations, suitable fillers, binders, disintegrants, lubricants, etc. can be added. When used for pulmonary administration, it can be made into inhalants or sprays, etc.

[0089] The pharmaceutical excipients described in the present invention are known to those skilled in the art and include but are not limited to: fillers, binders, wetting agents, disintegrants, lubricants, glidants, coating premixes, coating dispersants.

[0090] The fillers described in the present invention are known to those skilled in the art and include but are not limited to one or a combination of two or more selected from microcrystalline cellulose, anhydrous calcium hydrogen phosphate, pregelatinized starch, mannitol, corn starch, glucose, sucrose, dextrin.

[0091] The binders described in the present invention are known to those skilled in the art and include but are not limited to alginic acid, chitosan, povidone, copovidone, dextrin, maltodextrin, maltose, carbomer, gum arabic, hydroxypropyl cellulose, hydroxypropyl methylcellulose.

[0092] The wetting agents described in the present invention are known to those skilled in the art and include but are not limited to water, 75% ethanol, 90% ethanol, 95% ethanol, absolute ethanol.

[0093] The disintegrants described in the present invention are known to those skilled in the art and include but are not limited to sodium carboxymethylcellulose cross-linked, hydroxyethyl cellulose, hydroxypropyl cellulose, polyvinylpyrrolidone cross-linked, calcium carboxymethylcellulose, low-substituted hydroxypropyl methylcellulose, cross-linked polyvinylpyrrolidone, starch, sodium carboxymethyl starch, hydroxypropyl starch.

[0094] The lubricants described in the present invention are known to those skilled in the art and include but are not limited to magnesium stearate, calcium stearate, talc powder, colloidal silica, silica, stearic acid, hydrogenated oil, polyethylene glycol, magnesium lauryl sulfate.

[0095] The glidants described in the present invention are known to those skilled in the art and include but are not limited to silica, colloidal silica, hydrated silica, talc, magnesium silicate, magnesium trisilicate.

[0096] The pharmaceutical composition of the present invention can be packaged in any packaging that does not affect the stability of the pharmaceutical preparation. For example, the inner packaging can be PVC-aluminum plastic blister packaging, and the outer packaging is a composite film bag.

[0097] The present invention provides the use of a composition of a compound of formula (I) in the preparation of a medicament for treating cancer patients. The present invention also provides the use of a pharmaceutical composition of a compound of formula (I) in the preparation of a medicament for delaying the progression of cancer patients.

[0098] The present invention also provides a method for treating cancer with a composition of a compound of formula (I), which comprises administering to a patient in need of such treatment a therapeutically effective amount of the composition of the compound of formula (1), and the administration can be carried out by any conventional and acceptable method known in the art. The therapeutically effective amount is adjusted according to the race, gender, age, weight, medical condition, type of disease, severity of the disease, route of administration and related health status of the patient, as well as other factors known to those skilled in the art.

[0099] As used herein, "therapeutically effective amount" means an amount sufficient to cure or at least partially prevent the disease and its complications in a patient already suffering from the disease. Determining such an effective amount is entirely within the ability of those skilled in the art. For example, the amount effective for therapeutic use will depend on the severity of the disease to be treated, the overall status of the patient's own immune system, the general condition of the patient such as age, weight and gender, the mode of administration of the drug, and other treatments administered simultaneously, etc.

[0100] The present invention also provides a composition of a pharmaceutical composition of a compound of formula (1) and one or more other therapeutic agents, and these other therapeutic agents can be administered simultaneously or sequentially with the composition of the compound of formula (1) for treating tumor patients.

[0101] As used in the present invention, "D90" refers to the particle size corresponding to when the cumulative particle size distribution percentage of a sample reaches 90%.

[0102] The present invention includes a pharmaceutical composition containing a compound of formula (I), which has the following advantages:

[0103] (1) It has good stability and can provide a long shelf life;

[0104] (2) It has good dissolution performance;

[0105] (3) It has good anti-tumor effects. Description of the Drawings

[0106] Figure 1 Dissolution curve for filler ratio screening in Example 3.

[0107] Figure 2 Curve for binder ratio screening in Example 4.

[0108] Figure 3 Dissolution curve for prescription verification test in Example 7. Detailed Description of the Invention

[0109] The above content of the present invention will be further described in detail below in conjunction with specific examples and experimental examples. It should be understood that the following examples and experimental examples are only used to illustrate the present disclosure, but do not limit the protection scope of the present disclosure. For those conditions not specified in the following examples, they are carried out according to conventional conditions or those recommended by the manufacturer. For the drugs or reagents whose manufacturers are not specified, they are all conventional products that can be obtained through commercial purchase.

[0110] The compound of formula (I) used in the following examples or experimental examples was prepared according to the preparation method in Example 4 of the specification in Patent Application PCT / CN2015 / 090712.

[0111] Example 1: Compatibility test of raw materials and excipients

[0112] The compound of formula (1) was mixed with each excipient and placed at 60 °C for 10 days. The inspection results are shown in Table 1.

[0113] Table 1 Compatibility test of excipients

[0114]

[0115]

[0116] From the above results, it can be seen that when the compound of formula (1) and lactose monohydrate are placed at 60 °C for 10 days in a ratio of 1:5, the related substances increase significantly. When the compound of formula (1) and other excipients are placed at 60 °C for 10 days in the above ratio, there is no obvious change, indicating that the compound of formula (1) has good compatibility with a variety of excipients.

[0117] Example 2: Tablet preparation process

[0118] The compound of formula (1), filler, and disintegrant were put into a wet granulator according to the dosages in each prescription in the following table, stirred to obtain a premix; the binder was dissolved in purified water to prepare a binder solution; the binder solution was added to the premix, granulated, and sized with a wet granulator; the wet granules were put into a fluidized bed granulator for drying; the glidant was placed in the dry granules for dry sizing; the disintegrant and lubricant were added and mixed evenly with a mixer, then pressed into tablets, or coated according to requirements.

[0119] Example 3: Investigation of filler types and ratios

[0120] 1. Screening of filler types

[0121] To select a suitable filler to ensure the smooth preparation process of the preparation and its faster disintegration in the dissolution medium, the filler was investigated based on the phenomena during the tableting process and the disintegration time limit:

[0122] Table 2 Screening of fillers

[0123]

[0124] Using microcrystalline cellulose and anhydrous calcium hydrogen phosphate as fillers, their hardness and disintegration time limit were investigated. The results are as follows:

[0125] Table 3 Investigation results of hardness and disintegration time limit

[0126]

[0127] From the above results, it can be seen that when microcrystalline cellulose and anhydrous calcium hydrogen phosphate are selected as fillers, there is no phenomenon of sticking to the punch, and the disintegration speed is appropriate. Therefore, microcrystalline cellulose and anhydrous calcium hydrogen phosphate can be used as fillers. This formulation is relatively stable in low-dose formulations. When the formulation specification is increased, there are problems such as a relatively large tablet weight and poor compressibility. Therefore, further screening of the fillers is carried out.

[0128] Table 4 Screening of fillers

[0129]

[0130]

[0131] As can be seen from the above table, Formulation 1 has poor compressibility and a relatively large tablet weight, making it difficult for patients to swallow; Formulation 2 adds pregelatinized starch as a filler, which has good compressibility and reduces the tablet weight, increasing patient compliance.

[0132] 2. Screening of filler ratio

[0133] Table 5 Investigation of filler ratio

[0134]

[0135] Different ratios of pregelatinized starch and microcrystalline cellulose have no obvious effect on the granulation of granules, but a relatively high proportion of pregelatinized starch will affect the compressibility of granules. For Formulation 5 with a mass ratio of microcrystalline cellulose to pregelatinized starch less than 1 and a weight proportion of pregelatinized starch of 15%, the compressibility of its granules is significantly poor.

[0136] Table 6 Dissolution test results

[0137]

[0138] From Figure 1 the dissolution curves as shown, the dissolution curves of the tablets of the above different ratios of pregelatinized starch almost completely overlap, indicating that the amount of pregelatinized starch used has no effect on the dissolution behavior of the tablets.

[0139] Example 4: Investigation of binder type and ratio

[0140] According to the results of excipient compatibility, the effects of different binders, hydroxypropyl cellulose and povidone, on the preparation were investigated. Through the observation of the preparation, it was found that hydroxypropyl cellulose was relatively difficult to dissolve and needed to be added in dry powder form. It was in a flocculent state and prone to caking, and sieving was required to ensure uniform mixing of the powder materials. Therefore, povidone was selected as the binder, and the proportion of povidone was screened. The povidone proportions were respectively selected as 1.5%, 2.5%, and 3.5%. The prescription design is shown in the following table.

[0141] Table 7 Screening of Binder Proportions

[0142]

[0143] The dissolution rates of the above three prescriptions were determined, and the dissolution data are shown as follows:

[0144] Table 8 Results of Dissolution Rate Determination

[0145]

[0146] From Figure 2 and Table 8, it can be seen that the dissolution curves of the three prescriptions almost coincide, proving that binders with different proportions have no effect on the dissolution of tablets.

[0147] Example 5: Investigation of Disintegrant Types and Proportions

[0148] Crospovidone and croscarmellose sodium, which have good compatibility with the raw and auxiliary materials, were selected as the disintegrants for the screening of disintegrant types. The internal addition and external addition proportions of the disintegrants were both 2%. The other excipients and their proportions referred to Prescription 2 of Example 3. The Carr's coefficients of the granules of croscarmellose sodium and crospovidone were 15.1% and 10.5% respectively. The granules were tabletted, and the dissolution was carried out for 60 min, and the dissolution rates all reached over 90%. This shows that when crospovidone or croscarmellose sodium was selected as the disintegrant, the granule fluidity was relatively good, and the dissolution met the quality standard requirements. Further screening was carried out on the internal addition and external addition proportions of the disintegrant. The internal addition and external addition proportions were respectively selected as 1:3, 2:2, and 3:1. The other excipients and their proportions referred to Prescription 2 of Example 3. The granules were tabletted, and the dissolution was carried out for 60 min, and the dissolution rates all reached over 90%. This shows that adding the internal and external disintegrants with the above different proportions had no significant effect on the dissolution rate.

[0149] Example 6: Investigation of Particle Size

[0150] The compound of formula (1) was treated with different treatment methods to obtain the compound of formula (1) with different particle size distributions. Granulation, tabletting were carried out with the same prescription (referring to the components and proportions of Prescription 2 of Example 3) and process, and the dissolution rate was investigated. The experimental results are shown in Table 9 below.

[0151] Table 9 Investigation of Particle Size

[0152]

[0153]

[0154] It can be seen that for the compounds of formula (1) with different particle sizes above, when the D90 of the particle size distribution of the active pharmaceutical ingredient is less than 5 μm (Prescription 9), the process cannot proceed normally; when the D90 of the particle size distribution of the active pharmaceutical ingredient is greater than 200 μm (Prescription 10), the dissolution rate is slow; while when the D90 of the particle size distribution is about 10 - 100 μm, the formability is good during the granulation process, and when made into tablets, the dissolution degree reaches over 90% at 45 minutes.

[0155] Example 7: Prescription verification test

[0156] Prepare prescriptions of 50 mg and 250 mg specifications respectively with reference to the components and proportions of Prescription 2 in Example 3, and examine the content, related substances and dissolution degree.

[0157] Table 10 Test results of content, related substances and dissolution degree

[0158]

[0159] As can be seen from the above table, the content, related substances and dissolution degree of the tablets all meet the requirements of the quality standard.

Claims

1. A pharmaceutical composition comprising a compound of formula (I), a binder, a filler, a disintegrant, a lubricant and a glidant; and based on the total weight of the pharmaceutical composition, the content of the compound of formula (I) is 25% to 70%, the content of the binder is 1% to 5%, the content of the filler is 30% to 65%, the content of the disintegrant is 1% to 10%, the content of the lubricant is 0.5% to 5%, the content of the glidant is 0.2% to 2%, and the filler comprises at least anhydrous calcium hydrogen phosphate; 2. The pharmaceutical composition according to claim 1, wherein the content of the compound of formula (I) is 40% to 60% based on the total weight of the pharmaceutical composition.

3. The pharmaceutical composition of claim 1 or 2, wherein the filler further comprises one or more of microcrystalline cellulose, mannitol, and corn starch; optionally, based on the total weight of the pharmaceutical composition, the filler content is 30% to 50%.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the binder is selected from the group consisting of: one or more of povidone, copovidone, alginate, chitosan, dextrin, maltodextrin, maltose, carbomer, gum arabic, hydroxypropyl cellulose, and hypromellose, preferably one or more of povidone and copovidone; optionally, based on the total weight of the pharmaceutical composition, the binder content is 1% to 4%.

5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the disintegrant is selected from one or more of cross-linked sodium carboxymethyl cellulose, sodium hydroxymethyl starch, hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, and starch; optionally, the content of the disintegrant is 3% to 5% based on the total weight of the pharmaceutical composition.

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the lubricant is selected from one or more of magnesium stearate, calcium stearate, talc, silicon dioxide, and stearic acid; optionally, the lubricant content is 1% to 3% based on the total weight of the pharmaceutical composition.

7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the glidant is selected from one or more of silicon dioxide, colloidal silicon dioxide, colloidal silica, corn starch, and talc; optionally, the glidant content is 0.5% to 1.5% based on the total weight of the pharmaceutical composition.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the filler is selected from a combination of microcrystalline cellulose, anhydrous calcium hydrogen phosphate and pregelatinized starch, the binder is povidone, the disintegrant is selected from cross-linked sodium carboxymethyl cellulose or cross-linked povidone, the lubricant is magnesium stearate, and the glidant is selected from silicon dioxide or colloidal silicon dioxide.

9. A method for preparing the pharmaceutical composition according to any one of claims 1 to 8, comprising the steps of: (1) mixing the compound of formula (I), a filler, and a disintegrant, and adding a binder to granulate; (2) adding a glidant and performing dry granulation; (3) Add disintegrant and lubricant and mix well; (4) compressing the mixture to obtain the tablet.

10. Use of the pharmaceutical composition according to any one of claims 1 to 8 in the preparation of a medicament for treating cancer, optionally, the pharmaceutical composition further comprises one or more second therapeutic agents.

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