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WO2025140560A1 - Composition pharmaceutique d'inhibiteur de kinase du lymphome anaplasique et son procédé de préparation - Google Patents

Composition pharmaceutique d'inhibiteur de kinase du lymphome anaplasique et son procédé de préparation Download PDF

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Publication number
WO2025140560A1
WO2025140560A1 PCT/CN2024/143207 CN2024143207W WO2025140560A1 WO 2025140560 A1 WO2025140560 A1 WO 2025140560A1 CN 2024143207 W CN2024143207 W CN 2024143207W WO 2025140560 A1 WO2025140560 A1 WO 2025140560A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
cancer
filler
content
disintegrant
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/143207
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English (en)
Chinese (zh)
Inventor
李嘉逵
王云灵
王国骅
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Xuanzhu Biopharmaceutical Co Ltd
Original Assignee
Xuanzhu Biopharmaceutical Co Ltd
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Publication of WO2025140560A1 publication Critical patent/WO2025140560A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention belongs to the field of medicine, and specifically 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 (referred to as the compound of formula (I)).
  • the present invention also relates to a method for preparing the pharmaceutical composition of the compound of formula (I), and its use in preparing a drug for treating tumor patients.
  • Anaplastic lymphoma kinase is a member of the receptor tyrosine kinase family. It can recruit downstream proteins through autophosphorylation, thereby expressing specific genes and regulating cell metabolism and growth. Anaplastic lymphoma kinase was first discovered in anaplastic large cell lymphoma (ALCL), and was later found to be highly expressed in non-small cell lung cancer (NSCLC).
  • ACL anaplastic large cell lymphoma
  • NSCLC non-small cell lung cancer
  • the abnormal expression of ALK in some ALCL/NSCLC is derived from different chromosomal translocations. These chromosomal translocations can all produce corresponding fusion proteins. Genetic analysis of these fusion proteins showed that they all contained the gene sequence encoding the intracellular kinase region at the 3' end of the ALK gene, and the gene fragments fused with ALK all contained promoter elements and sequences encoding self-dimerization, which led to high expression and overactivation of fusion proteins with ALK kinase activity in cells, causing malignant transformation of cells. Therefore, the activity of the intracellular kinase region of ALK and the corresponding signal transduction pathway are important molecular mechanisms leading to the formation of ALCL.
  • ROS1 is currently a hot target gene 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%.
  • Patent application PCT/CN2015/090712 discloses a compound of formula (I) and a method for preparing the same. Studies have shown that the compound of formula (I) has excellent ALK/ROS1 inhibitory activity, exhibits good anti-tumor effects, provides a possibility for the treatment of cancer patients, and has good safety.
  • the applicant has conducted targeted research on the characteristics of the compound of formula (I) in order to find a pharmaceutical preparation with good stability and dissolution properties to meet the needs of clinical medication.
  • 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%.
  • the pharmaceutical excipients of the present invention include fillers, binders, disintegrants, lubricants and glidants.
  • the pharmaceutical excipients of the present invention include fillers, binders, disintegrants, lubricants, glidants, and wetting agents.
  • the filler comprises at least anhydrous calcium hydrogen phosphate.
  • the filler comprises at least pregelatinized starch and anhydrous calcium hydrogen phosphate.
  • the filler further comprises one or more of microcrystalline cellulose, mannitol, corn starch, glucose, sucrose, and dextrin.
  • the filler further comprises one or more of microcrystalline cellulose and corn starch.
  • the filler comprises a combination of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, and pregelatinized starch. In some embodiments, the filler does not comprise lactose.
  • 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.
  • the filler is present in 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%.
  • 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 further preferably 4% to 9.5%.
  • the anhydrous calcium hydrogen 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%.
  • 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%.
  • 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.
  • 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.
  • the pharmaceutical excipient comprises a binder.
  • 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.
  • 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 further preferably 2.5% ⁇ 0.2%.
  • the pharmaceutical excipient comprises at least one disintegrant.
  • the disintegrant is selected from one or more of cross-linked sodium carboxymethyl cellulose, sodium hydroxymethyl starch, hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, and starch.
  • the disintegrant is selected from one or more of cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone.
  • 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 further preferably 4.0% ⁇ 0.2%.
  • 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.
  • the pharmaceutical excipients of the composition of the present invention include at least one glidant.
  • the glidant is selected from one or more of silicon dioxide, colloidal silicon dioxide, colloidal silica, corn starch, and talc.
  • the glidant is selected from silicon dioxide or colloidal silicon dioxide.
  • the glidant is selected from colloidal silicon dioxide.
  • 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%.
  • the pharmaceutical excipients of the composition of the present invention include at least one lubricant.
  • the lubricant is selected from one or more of magnesium stearate, calcium stearate, talc, silicon dioxide, and stearic acid.
  • the lubricant is selected from magnesium stearate.
  • 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 further preferably 2% ⁇ 0.2%.
  • 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.
  • the total content of each component of the pharmaceutical composition of the present invention is less than or equal to 100%.
  • the present invention provides a pharmaceutical composition
  • 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 contains at least anhydrous calcium hydrogen phosphate.
  • the present invention provides a pharmaceutical composition
  • 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 contains at least anhydrous calcium hydrogen phosphate, and the filler does not contain lactose.
  • the present invention provides a pharmaceutical composition
  • 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.
  • the present invention provides a pharmaceutical composition
  • 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.
  • the present invention provides a pharmaceutical composition
  • 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.
  • the present invention provides a pharmaceutical composition
  • 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.
  • the present invention provides a pharmaceutical composition
  • 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.
  • the present invention provides a pharmaceutical composition
  • 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.
  • the present invention provides a pharmaceutical composition
  • 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.
  • the present invention provides a pharmaceutical composition
  • 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 an amount of 3% to 12% by weight of the pharmaceutical composition, preferably 3.5% to 10%, and further preferably 4% to 9.5%.
  • the present invention provides a pharmaceutical composition
  • 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.
  • the present invention provides a pharmaceutical composition
  • 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 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 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 povidone
  • the glidant is colloidal silicon dioxide
  • the lubricant is magnesium stearate.
  • 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.
  • 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.
  • binder 1% to 4% by weight of a binder, wherein the binder is povidone;
  • disintegrant (4) 3% to 5% by weight of a disintegrant, wherein the disintegrant is cross-linked sodium carboxymethylcellulose or cross-linked polyvinylpyrrolidone;
  • glidant 0.5% to 1.5% by weight of a glidant, wherein the glidant is colloidal silicon dioxide;
  • 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-500 mg.
  • 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 further preferably, the compound of formula (I) is present in an amount of 50 mg, 100 mg, 150 mg, 200 mg, 250 mg.
  • the compound of formula (I) in the pharmaceutical composition provided by the present invention, is sieved or crushed before granulation. In some embodiments, in the pharmaceutical composition provided by the present invention, the compound of formula (I) has a particle size distribution D90 of 5-150 ⁇ m, preferably 10-100 ⁇ m, more preferably 10-85 ⁇ m.
  • the present invention provides a pharmaceutical composition
  • 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; the particle size distribution D90 of the compound of formula (I) is 10-100 ⁇ m.
  • the present invention provides a pharmaceutical composition
  • 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 an amount of 3% to 12% by weight of the pharmaceutical composition; and the particle size distribution D90 of the compound of formula (I) is 10-100 ⁇ m.
  • 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.
  • the present invention also provides a method for preparing a pharmaceutical composition of a compound of formula (I), the method comprising the step of premixing the compound of formula (I) with a filler and a disintegrant.
  • the preparation method comprises a step of wet granulation.
  • the preparation method comprises the steps of internal and external addition of a disintegrant.
  • the preparation method comprises the following steps:
  • the preparation method comprises the following steps:
  • step (3) adding the binder solution to the premix in step (1) and granulating;
  • the second therapeutic agent is selected from antimetabolites, growth factor inhibitors, antibodies, mitotic inhibitors, anti-tumor hormones, alkylating agents, metal platinums, immunosuppressants, purine analogs, antibiotics, adrenocortical inhibitors or enzyme inhibitors.
  • 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.
  • the lung cancer is selected from non-small cell lung cancer or small cell lung cancer.
  • 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.
  • the cancer is selected from glioma.
  • the cancer is selected from astrocytoma.
  • the "pharmaceutical composition" of the present invention is any pharmaceutically acceptable dosage form, which is administered to patients in need thereof by oral, parenteral, rectal or transpulmonary administration.
  • 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.
  • suitable fillers, binders, disintegrants, lubricants, etc. can be added.
  • transpulmonary administration it can be made into inhalants or sprays, etc.
  • 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.
  • the filler described in the present invention is known to those skilled in the art, including but 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.
  • the adhesive of the present invention is known to those skilled in the art, including but not limited to alginate, chitosan, povidone, copovidone, dextrin, maltodextrin, maltose, carbomer, gum arabic, hydroxypropyl cellulose, and hydroxypropyl methylcellulose.
  • the wetting agent described in 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.
  • disintegrants described in the present invention are known to those skilled in the art, including but 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.
  • 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.
  • the pharmaceutical composition of the present invention can be packaged in any packaging that does not affect the stability of the pharmaceutical preparation.
  • the inner packaging can be a PVC aluminum-plastic blister packaging
  • the outer packaging can be a composite film bag.
  • 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.
  • the present invention also provides a method for treating cancer with a composition of the compound of formula (I), which comprises administering a therapeutically effective amount of the composition of the compound of formula (I) to a patient in need of such treatment.
  • the administration can be carried out in any conventional and acceptable manner known in the art, and the therapeutically effective amount is adjusted according to the patient's race, sex, age, weight, medical condition, type of disease, severity of the disease, route of administration and related health conditions, as well as other factors known to those skilled in the art.
  • therapeutically effective amount refers to 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 well within the capabilities 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 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 treatments administered simultaneously, etc.
  • 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) for treating tumor patients.
  • 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%.
  • composition of the present invention comprising the compound of formula (I) has the following advantages:
  • the compound of formula (1) was treated in different ways to obtain compounds of formula (1) with different particle size distributions.
  • the same prescription (the components and proportions of prescription 2 in reference example 3) and process were used for granulation and tableting, and the dissolution was investigated.
  • the experimental results are shown in Table 9 below.

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Abstract

L'invention concerne une composition pharmaceutique d'un inhibiteur de kinase du lymphome anaplasique polycyclique, son procédé de préparation et son utilisation. En particulier, la présente invention concerne une préparation pharmaceutique de 5-chloro-N4-(2-(isopropylsulfonyl)phényl)-N 2-(7-méthyl-8-(pipéridine-4-yl)-2,3-dihydrobenzo[b][1,4]dioxine-5-yl)pyrimidine-2,4-diamine, son procédé de préparation et son utilisation.
PCT/CN2024/143207 2023-12-28 2024-12-27 Composition pharmaceutique d'inhibiteur de kinase du lymphome anaplasique et son procédé de préparation Pending WO2025140560A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016050171A1 (fr) * 2014-09-29 2016-04-07 山东轩竹医药科技有限公司 Inhibiteur de la kinase du lymphome anaplasique polycyclique
CN110730678A (zh) * 2017-01-10 2020-01-24 诺华股份有限公司 包含alk抑制剂和shp2抑制剂的药物组合
US20200405727A1 (en) * 2018-01-17 2020-12-31 Fondazione Per L'istituto Oncologico Di Ricerca (Ior) New alk inhibitor senolytic drugs
CN112218626A (zh) * 2019-12-31 2021-01-12 广州帝奇医药技术有限公司 一种持续释放组合物及其制备方法
CN113135905A (zh) * 2020-01-17 2021-07-20 山东轩竹医药科技有限公司 多环类间变性淋巴瘤激酶抑制剂的晶型

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016050171A1 (fr) * 2014-09-29 2016-04-07 山东轩竹医药科技有限公司 Inhibiteur de la kinase du lymphome anaplasique polycyclique
CN110730678A (zh) * 2017-01-10 2020-01-24 诺华股份有限公司 包含alk抑制剂和shp2抑制剂的药物组合
US20200405727A1 (en) * 2018-01-17 2020-12-31 Fondazione Per L'istituto Oncologico Di Ricerca (Ior) New alk inhibitor senolytic drugs
CN112218626A (zh) * 2019-12-31 2021-01-12 广州帝奇医药技术有限公司 一种持续释放组合物及其制备方法
WO2021134647A1 (fr) * 2019-12-31 2021-07-08 广州帝奇医药技术有限公司 Composition à libération prolongée et sa méthode de préparation
CN113135905A (zh) * 2020-01-17 2021-07-20 山东轩竹医药科技有限公司 多环类间变性淋巴瘤激酶抑制剂的晶型

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