Pharmaceutical composition of anaplastic lymphoma kinase inhibitor and preparation method therefor

Abstract

A pharmaceutical composition of a polycyclic anaplastic lymphoma kinase inhibitor, a preparation method therefor, and use thereof. In particular, the present disclosure relates to a pharmaceutical preparation of 5-chloro-N4-(2-(isopropylsulfonyl)phenyl)-N2-(7-methyl-8-(piperidin-4-yl)-2,3-dihydrobenzo[b][1,4]dioxin-5-yl)pyrimidine-2,4-diamine, a preparation method therefor, and use thereof.

Description

Pharmaceutical composition of anaplastic lymphoma kinase inhibitor and preparation method thereof Technical Field

[0001] The present invention belongs to the field of medicine, and specifically relates to a 5-chloro-N 4 -(2-(isopropylsulfonyl)phenyl)-N 2 The present invention also relates to a pharmaceutical composition of the compound of formula (I) and a method for preparing the pharmaceutical composition of the compound of formula (I) and its use in preparing a drug for treating tumor patients. Background Art

[0002] Anaplastic lymphoma kinase (ALK) is a member of the receptor tyrosine kinase family. It recruits downstream proteins through autophosphorylation, leading to the expression of specific genes and regulating cell metabolism and growth. ALK was first discovered in anaplastic large cell lymphoma (ALCL) and was later found to be highly expressed in non-small cell lung cancer (NSCLC).

[0003] Aberrant expression of ALK in certain ALCL / NSCLC cases results from various chromosomal translocations. These translocations all generate corresponding fusion proteins. Genetic analysis of these fusion proteins reveals that they all contain sequences encoding the intracellular kinase domain at the 3' end of the ALK gene. The ALK fusion gene fragments all contain promoter elements and sequences encoding self-dimerization, leading to high expression and overactivation of the fusion protein with ALK kinase activity, thus causing malignant transformation. Therefore, the activity of the ALK intracellular kinase domain and the corresponding signaling pathways are important molecular mechanisms underlying ALCL development. ROS1, a member of the receptor tyrosine kinase family, is currently a highly targeted gene in lung adenocarcinoma, following ALK. ROS1 is a member of the receptor tyrosine kinase family and has an incidence of approximately 1.7% in NSCLC. ROS1 shares 49% homology with anaplastic lymphoma kinase (ALK) within the amino acid kinase domain and 77% identity within the ATP binding site, making it possible to treat ROS1-rearrangement-positive NSCLC with ALK kinase inhibitors.

[0004] Patent application PCT / CN2015 / 090712 discloses a compound of formula (I) and its preparation method. Studies have shown that the compound of formula (I) has excellent ALK / ROS1 inhibitory activity and exhibits good anti-tumor effects, providing a potential treatment for cancer patients and having a good safety profile.

[0005] In order to meet the requirements of formulation, production, transportation, etc., the applicant conducted in-depth research on the compound of formula (1) and found that the compound has problems such as high viscosity, which need to be further solved in the formulation research and development.

[0006] The applicant has conducted targeted research on the inherent characteristics of the compound of formula (I) in order to discover a pharmaceutical preparation with good stability and dissolution properties to meet the needs of clinical medication. Summary of the Invention

[0007] The inventors of this application discovered during research that the compound of formula (I) involved in this application is difficult to prepare due to its large proportion and high viscosity. The inventors unexpectedly discovered that anhydrous calcium hydrogen phosphate can disperse the viscosity of the compound of formula (I), and that the inclusion of anhydrous calcium hydrogen phosphate in the filler can resolve the problem of the compound of formula (I) being relatively sticky and difficult to prepare.

[0008] The present invention provides a pharmaceutical composition of a compound represented by formula (I), comprising the compound represented by formula (I):

[0009] The pharmaceutical composition further comprises one or more pharmaceutical excipients, wherein the compound of formula (I) is present in an amount of 25% to 70% by weight of the pharmaceutical composition, 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%.

[0010] In some embodiments, the pharmaceutical excipients of the present invention include a filler, a binder, a disintegrant, a lubricant, and a glidant.

[0011] In some embodiments, the pharmaceutical excipients of the present invention include a filler, a binder, a disintegrant, a lubricant, a glidant, and a wetting agent.

[0012] In some embodiments, the filler comprises at least anhydrous calcium hydrogen phosphate.

[0013] In some embodiments, the filler comprises at least 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 comprise lactose.

[0014] In some embodiments, the filler comprises at least 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 comprise lactose.

[0015] In some embodiments, the filler is present in an amount of 30% to 65% by weight of the pharmaceutical composition, preferably 30% to 60%, 35% to 65%, more preferably 30% to 50%, further preferably 35% to 45%, and even more preferably 40% ± 2%.

[0016] In some embodiments, the pregelatinized starch is present in an amount of 2% to 15% by weight of the pharmaceutical composition, preferably 3% to 15%, more preferably 3% to 12%, further preferably 3.5% to 10%, and even more preferably 4% to 9.5%.

[0017] In some embodiments, the anhydrous dibasic calcium phosphate is present in an amount of 5% to 15% by weight of the pharmaceutical composition, preferably 8% to 13%, more preferably 10% to 12%, and further preferably 11% ± 0.5%.

[0018] In some embodiments, the microcrystalline cellulose is present in an amount of 10% to 35% by weight of the pharmaceutical composition, preferably 10% to 30%, more preferably 14% to 26%, further preferably 18% to 22%, and even more preferably 20% ± 1%.

[0019] In some embodiments, the filler comprises at least 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.

[0020] 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 1:1 to 10:1, preferably 1:1 to 8:1, and more preferably 2:1 to 8:1.

[0021] In some embodiments, the pharmaceutical excipient comprises a binder. Preferably, the binder is selected from one or more of povidone, copovidone, alginate, 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.

[0022] In some embodiments, the binder is present in an amount of 1% to 5% by weight of the pharmaceutical composition, preferably 1% to 4%, more preferably 1.5% to 3.5%, further preferably 2% to 3%, and even more preferably 2.5% ± 0.2%.

[0023] In some embodiments, the pharmaceutical excipient comprises at least one disintegrant. In some embodiments, the disintegrant is selected from one or more of croscarmellose sodium, sodium starch glycolate, hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, and starch. In some embodiments, the disintegrant is selected from one or more of croscarmellose sodium and cross-linked polyvinylpyrrolidone.

[0024] In some embodiments, the disintegrant is present in an amount of 1% to 10% by weight of the pharmaceutical composition, preferably 1% to 8%, more preferably 2% to 6%, further preferably 3% to 5%, further preferably 3.5% to 4.5%, and even more preferably 4.0% ± 0.2%.

[0025] In some embodiments, the disintegrant is added internally and externally in a ratio of 1:3 to 3:2, preferably 1:3 to 3:1, and more preferably 1:1.

[0026] In some embodiments, the pharmaceutical excipients of the composition of the present invention include at least one glidant. In some embodiments, the glidant is selected from one or more of silicon dioxide, colloidal silicon dioxide, colloidal silica, corn starch, and talc. In some embodiments, the glidant is selected from silicon dioxide or colloidal silicon dioxide. In some embodiments, the glidant is selected from colloidal silicon dioxide. In some embodiments, the glidant is present in an amount of 0.2% to 2% by weight of the pharmaceutical composition, preferably 0.5% to 1.5%, and more preferably 1% ± 0.2%.

[0027] 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, silicon dioxide, and stearic acid. In some embodiments, the lubricant is selected from magnesium stearate. In some embodiments, the lubricant is present in an amount of 0.5% to 5% by weight of the pharmaceutical composition, 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%.

[0028] In some embodiments, the wetting agent is selected from water, 75% ethanol, 90% ethanol, 95% ethanol, or anhydrous ethanol. In some embodiments, the wetting agent is selected from purified water.

[0029] In some embodiments, the total content of the components of the pharmaceutical composition of the present invention is less than or equal to 100%.

[0030] 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 comprises at least anhydrous calcium hydrogen phosphate.

[0031] 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 comprises at least anhydrous calcium hydrogen phosphate, and the filler does not contain lactose.

[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 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.

[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 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.

[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 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.

[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 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.

[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 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.

[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 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; wherein the pregelatinized starch is present in an amount of 3% to 12% by weight of the pharmaceutical composition, preferably 3.5% to 10%, and further preferably 4% to 9.5%.

[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; the filler comprises at least 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; the filler comprises at least pregelatinized starch and anhydrous calcium hydrogen phosphate, and does not contain lactose.

[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 comprises microcrystalline cellulose, 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 is composed 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, preferably 3.5% to 10%, and more preferably 4% to 9.5%.

[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 compound of formula (I) is present in an amount of 25% to 60% by weight of the pharmaceutical composition; the filler is composed 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; and the disintegrant is cross-linked sodium carboxymethyl cellulose or cross-linked povidone.

[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 compound of formula (I) is present in an amount of 40% to 60% by weight of the pharmaceutical composition; the filler is composed 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 cross-linked sodium carboxymethyl cellulose or cross-linked polyvinylpyrrolidone; the glidant is colloidal silicon dioxide; and the lubricant is magnesium stearate.

[0044] In some embodiments, the pharmaceutical composition of the present invention is an oral preparation. Preferably, the oral preparation is a tablet. More preferably, the tablet is film-coated.

[0045] In some embodiments, the pharmaceutical composition comprises 40% to 60% by weight of a compound of formula (I), 30% to 50% by weight of a filler, 1% to 4% by weight of a binder, 3% to 5% by weight of a disintegrant, 0.5% to 1.5% by weight of a glidant, and 1.5% to 2.5% by weight of a lubricant.

[0046] In some embodiments, the pharmaceutical composition comprises 45% to 55% by weight of a compound of formula (I), 35% to 45% by weight of a filler, 1.5% to 3.5% by weight of a binder, 3.5% to 4.5% by weight of a disintegrant, 0.5% to 1.5% by weight of a glidant, and 1.5% to 2.5% by weight of a lubricant.

[0047] In some embodiments, the pharmaceutical composition comprises 50%±2% by weight of a compound of formula (I), 40%±2% by weight of a filler, 2.5%±0.2% by weight of a binder, 4.0%±0.2% by weight of a disintegrant, 1%±0.2% by weight of a glidant, and 2%±0.2% by weight of a lubricant.

[0048] In some embodiments, the pharmaceutical excipients comprise a filler, a binder, a disintegrant, a lubricant, and a glidant, wherein the filler is selected from a combination of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and pregelatinized starch, the binder is selected from povidone, the disintegrant is selected from cross-linked sodium carboxymethyl cellulose or cross-linked povidone, the lubricant is magnesium stearate, and the glidant is colloidal silicon dioxide.

[0049] In some embodiments, a pharmaceutical composition comprising:

[0050] (1) 40% to 60% by weight of a compound of formula (I);

[0051] (2) 30% to 50% by weight of a filler, wherein the filler comprises at least anhydrous calcium hydrogen phosphate and pregelatinized starch; preferably, the filler consists of microcrystalline cellulose, anhydrous calcium hydrogen phosphate and pregelatinized starch;

[0052] (3) 1% to 4% by weight of a binder, wherein the binder is povidone;

[0053] (4) 3% to 5% by weight of a disintegrant, wherein the disintegrant is croscarmellose sodium or crospovidone;

[0054] (5) 0.5% to 1.5% by weight of a glidant, wherein the glidant is colloidal silicon dioxide;

[0055] (6) 1% to 3% by weight of a lubricant, wherein the lubricant is magnesium stearate.

[0056] In some embodiments, the present invention provides another pharmaceutical composition comprising a compound of formula (I) or a compound of formula (I), wherein the compound of formula (I) is present in an amount of 10 mg to 500 mg. Preferably, the compound of formula (I) is present in an amount of 20 mg to 300 mg; more preferably, the compound of formula (I) is present in an amount of 50 mg to 250 mg, and further preferably, the compound of formula (I) is present in an amount of 50 mg, 100 mg, 150 mg, 200 mg, or 250 mg.

[0057] In some embodiments, in the pharmaceutical composition provided herein, the compound of formula (I) is sieved or crushed before granulation. In some embodiments, in the pharmaceutical composition provided herein, the compound of formula (I) has a particle size distribution D90 of 5-150 μm, preferably 10-100 μm, more preferably 10-85 μm.

[0058] 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 is composed of microcrystalline cellulose, pregelatinized starch, and anhydrous calcium hydrogen phosphate; and the particle size distribution D90 of the compound of formula (I) is 10-100 μm.

[0059] 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 is composed 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; and the compound of formula (I) has a particle size distribution D90 of 10-100 μm.

[0060] In some embodiments, the dissolution of the pharmaceutical composition of the compound of formula (I) is such that at least 75%, preferably 80%, and more preferably 85% of the compound of formula (I) is dissolved after 45 minutes.

[0061] In some embodiments, the present invention also provides a method for preparing a pharmaceutical composition of a compound of formula (I), comprising the step of pre-mixing the compound of formula (I) with a filler and a disintegrant.

[0062] In some embodiments, the preparation method includes a step of wet granulation.

[0063] In some embodiments, the preparation method includes the steps of internal and external addition of a disintegrant.

[0064] In some embodiments, the preparation method comprises the following steps:

[0065] (1) mixing the compound of formula (I), a filler, and a disintegrant, adding a binder, and granulating;

[0066] (2) adding a flow aid and performing dry granulation;

[0067] (3) Add disintegrant and lubricant and mix well;

[0068] (4) Compressing the mixture to obtain the tablet.

[0069] In some embodiments, the preparation method comprises the following steps:

[0070] (1) mixing the compound of formula (I), a filler, and a disintegrant in a granulator to obtain a premix;

[0071] (2) dissolving the adhesive in purified water to prepare an adhesive solution;

[0072] (3) adding the binder solution to the premix in step (1) and granulating;

[0073] (4) Granulation using a wet granulator;

[0074] (5) placing the wet granules into a fluidized bed granulator for drying;

[0075] (6) placing the glidant into the dry granules and performing dry granulation;

[0076] (7) Add disintegrant and lubricant and mix well using a mixer;

[0077] (8) Tablet pressing.

[0078] In some embodiments, the present invention provides a use of a pharmaceutical composition in the preparation of a medicament for treating cancer, optionally further comprising one or more second therapeutic agents.

[0079] In some embodiments, the second therapeutic agent is selected from antimetabolites, growth factor inhibitors, antibodies, mitotic inhibitors, antitumor hormones, alkylating agents, metal platinums, immunosuppressants, purine analogs, antibiotics, adrenocortical inhibitors, or enzyme inhibitors.

[0080] Any one or any combination of two or more of the above embodiments described in the present invention is included in the protection scope of the present invention.

[0081] In some embodiments, the cancer described herein 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 tumor, head and neck squamous cell tumor, Wilms tumor, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, central nervous system tumors, female reproductive tract cancer, carcinoma in situ, lymphoma, neuroblastoma, neurofibromatosis, thyroid cancer, bone cancer, skin cancer, brain cancer, testicular cancer, gastrointestinal stromal tumor, prostate tumor, multiple myeloma, melanoma, neuroblastoma, sarcoma, or glioma.

[0082] In some embodiments, the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.

[0083] In some embodiments, the cancer is selected from a brain tumor, non-Hodgkin's lymphoma, non-small cell lung cancer, small cell lung cancer, colon cancer, mast cell tumor, or melanoma.

[0084] In some embodiments, the cancer is selected from glioma.

[0085] In some embodiments, the cancer is selected from astrocytoma.

[0086] The "pharmaceutical composition" described herein refers to any pharmaceutically acceptable dosage form, which is administered to a patient in need thereof by oral, parenteral, rectal, or transpulmonary administration. For oral administration, the composition can be formulated into conventional solid preparations such as tablets, capsules, pills, and granules; or into oral liquid preparations such as oral solutions, oral suspensions, and syrups. Suitable fillers, binders, disintegrants, and lubricants may be added to the formulation. For transpulmonary administration, the composition can be formulated into an inhaler or spray.

[0087] 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, and coating dispersants.

[0088] 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, and dextrin.

[0089] The adhesives 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, and hypromellose.

[0090] The wetting agent of the present invention is known to those skilled in the art, including but not limited to water, 75% ethanol, 90% ethanol, 95% ethanol, and anhydrous ethanol.

[0091] The disintegrants described in the present invention are known to those skilled in the art, and include but are not limited to cross-linked sodium carboxymethyl cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, cross-linked polyvinyl pyrrolidone hydroxymethyl cellulose calcium, low-substituted hydroxypropyl methyl cellulose, cross-linked polyvinyl pyrrolidone, starch, sodium hydroxymethyl starch, and hydroxypropyl starch.

[0092] The lubricant described in the present invention is known to those skilled in the art, and includes but is not limited to magnesium stearate, calcium stearate, talc, micro-powdered silica gel, silicon dioxide, stearic acid, hydrogenated oil, polyethylene glycol, and magnesium lauryl sulfate.

[0093] The glidant described in the present invention is known to those skilled in the art, including but not limited to silicon dioxide, colloidal silicon dioxide, hydrated silicon dioxide, talc, magnesium silicate, and magnesium trisilicate.

[0094] 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 a PVC aluminum-plastic blister package, and the outer packaging can be a composite film bag.

[0095] The present invention provides the use of a composition of a compound of formula (I) in preparing a drug for treating cancer patients. The present invention also provides the use of a pharmaceutical composition of a compound of formula (I) in preparing a drug for delaying the progression of cancer patients.

[0096] The present invention also provides a method for treating cancer using a composition of a compound of formula (I), which comprises administering a therapeutically effective amount of a composition of a compound of formula (I) to a patient in need of such treatment. Administration can be performed by any conventional and acceptable means known in the art, and the therapeutically effective amount is adjusted based on the patient's race, sex, age, weight, medical condition, type of disease, severity of the disease, route of administration, and relevant health conditions, as well as other factors known to those skilled in the art.

[0097] As used herein, a "therapeutically effective amount" refers to an amount sufficient to cure or at least partially arrest the disease and its complications in a patient already suffering from the disease. Determination of such an effective amount is well within the capabilities of those skilled in the art. For example, an amount effective for therapeutic use will depend on the severity of the disease to be treated, the overall state of the patient's own immune system, the patient's general condition such as age, weight, and sex, the mode of administration of the drug, and other concurrently administered treatments.

[0098] The present invention also provides a pharmaceutical composition of the compound of formula (1) and a composition of one or more other therapeutic agents. These other therapeutic agents can be administered simultaneously or sequentially with the composition of the compound of formula (1) to treat tumor patients.

[0099] The "D90" mentioned in the present invention refers to the particle size corresponding to when the cumulative particle size distribution percentage of a sample reaches 90%.

[0100] The pharmaceutical composition of the present invention comprising the compound of formula (I) has the following advantages:

[0101] (1) It has good stability and can provide a long shelf life;

[0102] (2) Good dissolution performance;

[0103] (3) It has good anti-tumor effect. BRIEF DESCRIPTION OF THE DRAWINGS

[0104] FIG1 is a dissolution curve for filler ratio screening in Example 3.

[0105] FIG2 is a screening curve of adhesive ratio of Example 4.

[0106] FIG3 is a dissolution curve of the prescription verification test of Example 7. DETAILED DESCRIPTION

[0107] The above content of the present invention will be further described in detail below with reference to specific examples and experimental examples. It should be understood that the following examples and experimental examples are only used to illustrate the present disclosure and are not intended to limit the scope of protection of the present disclosure. In the following examples, if no specific conditions are specified, the conventional conditions or the manufacturer's recommendations were followed. The drugs or reagents used, if the manufacturer is not specified, are all conventional products that can be obtained commercially.

[0108] The compounds of formula (I) used in the following examples or experimental examples were prepared according to the preparation method of Example 4 in the specification of patent application PCT / CN2015 / 090712.

[0109] Example 1: Compatibility test of raw materials and auxiliary materials

[0110] The compound of formula (1) was mixed with various auxiliary materials and placed at a high temperature of 60° C. for 10 days. The results are shown in Table 1.

[0111] Table 1 Excipient compatibility test

[0112] From the above results, it can be seen that when the compound of formula (1) and lactose monohydrate are placed at a ratio of 1:5 at 60°C for 10 days, the related substances increase significantly. When the compound of formula (1) and other excipients are placed at the above ratio at 60°C for 10 days, there is no obvious change, indicating that the compound of formula (1) has good compatibility with various excipients.

[0113] Example 2: Tablet Preparation Process

[0114] The compound of formula (1), filler, and disintegrant are placed in a wet granulator according to the dosage of each prescription in the following table, stirred to obtain a premix; the binder is dissolved in purified water to prepare a binder solution; the binder solution is added to the premix, granulated, and granulated using a wet granulator; the wet granules are placed in a fluidized bed granulator for drying; the glidant is placed in the dry granules and dry granulated; the disintegrant and lubricant are added, mixed uniformly using a mixer, and tableted or coated as required.

[0115] Example 3: Investigation of filler types and proportions

[0116] 1. Filler type screening

[0117] In order to select the appropriate filler to ensure a smooth preparation process and rapid disintegration in the dissolution medium, the filler was examined based on the tableting process phenomena and disintegration time limit:

[0118] Table 2 Screening of fillers

[0119] Using microcrystalline cellulose and anhydrous calcium hydrogen phosphate as fillers, the hardness and disintegration time were investigated. The results are shown below:

[0120] Table 3 Results of hardness and disintegration time

[0121] The above results indicate that when microcrystalline cellulose and anhydrous calcium hydrogen phosphate are used as fillers, sticking does not occur and the disintegration rate is appropriate. Therefore, microcrystalline cellulose and anhydrous calcium hydrogen phosphate are suitable as fillers. This formulation is relatively stable at low strengths. However, when the formulation is increased in strength, problems such as high tablet weight and poor compressibility arise. Therefore, further filler screening is required.

[0122] Table 4 Screening of fillers

[0123] As can be seen from the above table, Prescription 1 has poor compressibility and a relatively heavy tablet weight, making it difficult for patients to swallow; Prescription 2 adds pregelatinized starch as a filler, which has good compressibility and reduces tablet weight, thereby increasing patient compliance.

[0124] 2. Screening of filler ratio

[0125] Table 5 Filler ratio investigation

[0126] Different proportions of pregelatinized starch and microcrystalline cellulose have no obvious effect on the granulation properties of the granules, but a high proportion of pregelatinized starch will affect the compressibility of the granules. The compressibility of the granules of formulation 5, in which the mass ratio of microcrystalline cellulose to pregelatinized starch is less than 1 and the weight proportion of pregelatinized starch is 15%, is significantly poor.

[0127] Table 6 Dissolution test results

[0128] From the dissolution curves shown in FIG1 , the dissolution curves of the tablets with the above-mentioned different proportions of pregelatinized starch almost completely overlap, indicating that the amount of pregelatinized starch has no effect on the dissolution behavior of the tablets.

[0129] Example 4: Investigation of adhesive types and proportions

[0130] Based on the results of the compatibility of excipients, the effects of different binders, hydroxypropyl cellulose and povidone, on the formulation were investigated. Through the observation of the formulation, it was found that hydroxypropyl cellulose was difficult to dissolve and needed to be added as a dry powder. It was flocculent and easy to clump, so it needed to be sieved to ensure that the powder was mixed evenly. Therefore, povidone was selected as the binder, and the proportion of povidone was screened. The proportions of povidone were selected as 1.5%, 2.5%, and 3.5%, respectively. The formulation design is shown in the following table.

[0131] Table 7 Screening of adhesive ratio

[0132] The dissolution data of the three formulations above are shown below:

[0133] Table 8 Dissolution test results

[0134] As shown in Figure 2 and Table 8, the dissolution curves of the three formulations are almost identical, demonstrating that different ratios of binders have no effect on the dissolution of the tablets.

[0135] Example 5: Investigation of disintegrant types and proportions

[0136] Select disintegrants cross-linked polyvinylpyrrolidone and cross-linked sodium carboxymethyl cellulose with good compatibility with raw materials and excipients to screen the types of disintegrants. The ratio of internal and external disintegrants was 2% respectively. The other excipients and ratios were referenced to Example 3, Prescription 2. The disintegrants were cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone, and the granule Karl coefficients were 15.1% and 10.5% respectively. The granules were compressed and dissolved for 60 minutes, and the solubility reached more than 90%. This shows that the selection of cross-linked polyvinylpyrrolidone or cross-linked sodium carboxymethyl cellulose as a disintegrant has good granule fluidity and the dissolution meets the quality standard requirements. Further screening was performed on the ratio of internal and external disintegrants. The ratios of internal and external disintegrants were selected as 1:3, 2:2, and 3:1 respectively. The other excipients and ratios were referenced to Example 3, Prescription 2. The granules were compressed and dissolved for 60 minutes, and the solubility reached more than 90%. This shows that adding the above-mentioned internal and external disintegrants in different ratios has no significant effect on the dissolution rate.

[0137] Example 6: Particle size investigation

[0138] The compound of formula (1) was treated in different ways to obtain compounds of formula (1) with different particle size distributions. The same formulation (components and proportions of formulation 2 in reference example 3) and process were used for granulation, tableting, and dissolution testing. The experimental results are shown in Table 9 below.

[0139] Table 9 Particle size investigation

[0140] It can be seen that for the compounds of formula (1) with different particle sizes, when the D90 of the particle size distribution of the raw material drug is less than 5 μm (formulation 9), the process cannot proceed normally. When the D90 of the particle size distribution of the raw material drug is greater than 200 μm (formulation 10), the dissolution rate is slow. When the D90 of the particle size distribution is about 10-100 μm, the formability during the granulation process is good, and when the tablets are made, the dissolution rate reaches more than 90% in 45 minutes.

[0141] Example 7: Prescription Verification Test

[0142] With reference to the components and proportions of Prescription 2 in Example 3, 50 mg and 250 mg prescriptions were prepared, respectively, and the content, related substances and solubility were investigated.

[0143] Table 10 Content, related substances and dissolution test results

[0144] It can be seen from the above table that the tablet content, related substances and dissolution rate all meet the quality standard requirements.

Claims

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

4. The pharmaceutical composition according to any one of claims 1-3, wherein 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, preferably one or more of povidone and copovidone; optionally, the content of the binder is 1% to 4% based on the total weight of the pharmaceutical composition.

5. The pharmaceutical composition according to any one of claims 1-4, wherein the disintegrant is selected from one or more of sodium croscarmellose, sodium carboxymethyl starch, hydroxypropyl cellulose, crospovidone, 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 1-5, wherein the lubricant is selected from one or more of magnesium stearate, calcium stearate, talc, silicon dioxide, and stearic acid; optionally, the content of the lubricant is 1% to 3% based on the total weight of the pharmaceutical composition.

7. The pharmaceutical composition according to any one of claims 1-6, wherein the glidant is selected from one or more of silicon dioxide, colloidal silicon dioxide, colloidal silica, corn starch, and talc; optionally, the content of the glidant 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 1-7, wherein the filler is a combination of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and pregelatinized starch, the binder is povidone, the disintegrant is selected from sodium croscarmellose or crospovidone, the lubricant is magnesium stearate, and the glidant is selected from silicon dioxide or colloidal silicon dioxide.

9. The pharmaceutical composition according to any one of claims 1-8, which contains: (1) 40% to 60% by weight of the compound of formula (I); (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; (3) 1% to 4% by weight of a binder, the binder being povidone; (4) 3% to 5% by weight of a disintegrant, the disintegrant being sodium croscarmellose or crospovidone; (5) 0.5% to 1.5% by weight of a glidant, the glidant being colloidal silicon dioxide; (6) 1% to 3% by weight of a lubricant, the lubricant being magnesium stearate.

10. The pharmaceutical composition according to any one of claims 1-9, wherein the D90 of the particle size distribution of the compound of formula (I) is 10-100 μm.

11. The method for preparing the pharmaceutical composition according to any one of claims 1-10, the method comprising the following steps: (1) Mix the compound of formula (I), a filler, and a disintegrant, and granulate by adding a binder; (2) Add a glidant and perform dry sizing; (3) Add a disintegrant and a lubricant and mix evenly; (4) Press the mixture to obtain the tablets.

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

13. The use according to claim 12, wherein the second therapeutic agent is selected from antimetabolites, growth factor inhibitors, antibodies, mitotic inhibitors, anti-tumor hormones, alkylating agents, metal platinum agents, immunosuppressive agents, purine analogs, antibiotics, adrenocortical inhibitors or enzyme inhibitors.

14. The use according to claim 12, wherein the cancer 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.

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