WO2024187321A1 - 含有egfr抑制剂的药物组合物及其制备方法和应用 - Google Patents

含有egfr抑制剂的药物组合物及其制备方法和应用 Download PDF

Info

Publication number
WO2024187321A1
WO2024187321A1 PCT/CN2023/080921 CN2023080921W WO2024187321A1 WO 2024187321 A1 WO2024187321 A1 WO 2024187321A1 CN 2023080921 W CN2023080921 W CN 2023080921W WO 2024187321 A1 WO2024187321 A1 WO 2024187321A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
granules
group
anhydrous
cellulose
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.)
Ceased
Application number
PCT/CN2023/080921
Other languages
English (en)
French (fr)
Inventor
沈孝坤
黄金文
明从梅
宋赠
栗增
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.)
Convalife Shanghai Co Ltd
Zhejiang Convalife Pharmaceutical Co Ltd
Original Assignee
Convalife Shanghai Co Ltd
Zhejiang Convalife Pharmaceutical Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Convalife Shanghai Co Ltd, Zhejiang Convalife Pharmaceutical Co Ltd filed Critical Convalife Shanghai Co Ltd
Priority to PCT/CN2023/080921 priority Critical patent/WO2024187321A1/zh
Priority to EP23926680.2A priority patent/EP4682143A1/en
Publication of WO2024187321A1 publication Critical patent/WO2024187321A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to a pharmaceutical composition containing an EGFR inhibitor, and a preparation method and application thereof.
  • (E)-N-(4-(3-chloro-4-(pyridin-2-ylmethoxy)phenylamino-3-cyano-7-ethoxyquinolin-6-yl)-4-(dimethylamino)but-2-enamide monomaleate also known as neratinib maleate, has the following specific structure and is a specific protein kinase inhibitor.
  • EGFR epidermal growth factor receptor
  • EGFR epidermal growth factor receptor
  • Overexpression of EGFR plays an important role in the progression of malignant tumors.
  • EGFR is overexpressed in glial cells, renal cancer, lung cancer, prostate cancer, pancreatic cancer, breast cancer and other tissues. Elevated concentrations of EGFR and HER2 can be found in more than 30% of breast cancer patients, among which HER2 is one of the most important genes in the EGFR family.
  • neratinib maleate The active ingredient of neratinib maleate is neratinib, which is an irreversible HER2/EGFR inhibitor that can effectively inhibit the activity of HER1 and HER2 tyrosine kinases. This inhibits the growth of tumor cells.
  • Neratinib maleate was originally developed by Wyeth. After being acquired by Pfizer, it was licensed to PUMA Biotech in the United States for development, marketing, production and sales. It was approved for marketing by the U.S. Food and Drug Administration (FDA) on July 17, 2017, and the trade name is Neratinib maleate tablets are made from anhydrous neratinib maleate as the raw material, which is mixed with excipients and obtained through fluidized bed granulation, tableting and coating. Finally, the crystal form of the active ingredient neratinib maleate is converted into a crystalline form.
  • Neratinib has a good effect of inhibiting the growth of tumor cells, but it is easy to degrade and has poor stability. Especially after being prepared into a pharmaceutical composition, due to the presence of various excipients and water, there are mainly the following two problems:
  • Neratinib maleate is easily transformed from anhydrous crystalline form to monocrystalline form when in contact with water.
  • the change of crystalline form will affect the control of drug quality.
  • dissolution and release of the drug which in turn affects the therapeutic effect and side effects of the drug, this requires avoiding the use of water as much as possible during the preparation process. Based on the above two points, it is a challenge for those skilled in the art to provide a stable neratinib preparation.
  • Patent CN102724970 discloses a method for preparing neratinib maleate tablets, but the method is only aimed at improving the cohesiveness of neratinib during the granulation process.
  • a fluidized bed wet granulation process is used, which has a high temperature and water environment. It does not target the chemical properties of neratinib itself, which is unstable and easy to be converted into a crystalline form and easy to degrade, and cannot guarantee that the final preparation has good stability and dissolution properties.
  • neratinib maleate is converted from an anhydrous crystalline form to a crystalline form during the granulation process, and it is impossible to control whether the crystalline form is completely converted, which brings challenges to the quality control of the drug.
  • Patent CN106913529 discloses a method for preparing neratinib maleate tablets, which adopts a fluidized bed granulation process, controls the maximum water content of the particles in the granulation preparation process to be less than 10%, and removes moisture through the high temperature (70-90 degrees) of the granulation process, and controls the moisture content of the final particles to be less than 2%. After the coating is completed, the moisture can be reduced to less than 2% by drying with a rotary vacuum dryer alone. This procedure is generally not used in large-scale production. Combined with the preparation process of the patent, it can be seen that neratinib maleate will inevitably undergo crystal transformation. This easily causes inconsistent crystal transformation between batches of drugs.
  • the dissolution rate of neratinib capsules is relatively fast, and more than 80% can be dissolved in 15 minutes, which is significantly faster than the original maleic acid neratinib drug on the market; compared with the original research, the risk of bioequivalence of the tablets produced in the patent is high in vivo.
  • the technical problem solved by the present invention is to overcome the defect of limited types of pharmaceutical compositions containing EGFR inhibitors in the prior art, and to this end, a pharmaceutical composition containing EGFR inhibitors and a preparation method and application thereof are provided.
  • the pharmaceutical composition containing EGFR inhibitors of the present invention has good stability and a dissolution curve consistent with that of a reference preparation, and has in vivo biological activity with the same effect as that of the reference preparation.
  • the present invention solves the above technical problems through the following technical solutions.
  • the present invention provides a compound as shown in the following formula I:
  • R 1 , R 2 and R 3 are each independently H or a C 1-6 alkyl group substituted by one or more R 1-1 ;
  • Each R 1-1 is independently "a 4-6 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S", "a 4-6 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S" substituted by one or more R 1 -a , or -SO 2 -C 1-6 alkyl;
  • Each R 1-a is independently halogen or -N(C 1-6 alkyl) 2 .
  • R 1 and R 2 are H, and R 3 is C 1-6 alkyl substituted with one or more R 1-1 .
  • R 2 and R 3 are H, and R 1 is C 1-6 alkyl substituted with one or more R 1-1 .
  • each R 1-1 is independently "a 4-6 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" or -SO 2 -C 1-6 alkyl group substituted by one or more R 1-a .
  • the C 1-6 alkyl in the “C 1-6 alkyl substituted by one or more R 1-1 ”, the “—SO 2 -C 1-6 alkyl” and the “—N(C 1-6 alkyl) 2 ” are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.
  • the "4-6 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from N, O and S" substituted by one or more R 1-a is
  • the “4-6 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms and a heteroatom selected from 1, 2 or 3 of N, O and S” and the “4-6 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms and a heteroatom selected from 1, 2 or 3 of N, O and S and a heteroatom selected from 1, 2 or 3 of N , O and S” are independently 4-6 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms and a heteroatom selected from 1, 2 or 3 of N, O and S, ...
  • the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.
  • R1 and R2 are H
  • R3 is
  • R2 and R3 are H, and R1 is
  • the compound as shown in Formula I is any of the following compounds:
  • the present invention also provides a pharmaceutical composition 1, which comprises a compound as shown in Formula I or a pharmaceutically acceptable salt thereof; and pharmaceutical excipients.
  • the present invention also provides a use of a compound as shown in Formula I or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing or treating EGFR-related diseases.
  • the EGFR-related disease is preferably breast cancer, ovarian cancer, epithelial tumor, colon cancer, prostate cancer, kidney cancer, bladder cancer, laryngeal cancer, esophageal cancer, gastric cancer or lung cancer.
  • the present invention also provides a pharmaceutical composition 2, comprising granules, wherein the granules comprise the following components by mass fraction: 30-45% of a compound as represented by Formula II or a pharmaceutically acceptable salt thereof, 7-28% of copovidone, 25-48% of a filler, 1.0-8.0% of a disintegrant, 0.5-4.0% of a glidant and 0.5-4.0% of a lubricant;
  • the sum of the mass fractions of all components in the particulate matter is 100%; the mass fraction is the mass percentage of the mass of each component in the particulate matter to the total mass of each component;
  • R 4 , R 5 and R 6 are each independently H or C 1-6 alkyl substituted by one or more R 4-1 ;
  • Each R 4-1 is independently -N(C 1-6 alkyl) 2 , "a 4-6 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S", "a 4-6 membered heterocycloalkyl group having 1, 2 or 3 heteroatoms selected from the group consisting of N, O and S" substituted with one or more R 4-a , or -SO 2 -C 1-6 alkyl;
  • Each R 4-a is independently halogen or -N(C 1-6 alkyl) 2 .
  • R 4 and R 6 are H, and R 5 is C 1-6 alkyl substituted with one or more R 4-1 .
  • R 5 and R 6 are H, and R 4 is C 1-6 alkyl substituted with one or more R 4-1 .
  • each R 4-1 is independently -N(C 1-6 alkyl) 2 , "a 4-6 membered heterocycloalkyl having 1, 2 or 3 heteroatoms selected from N, O and S" substituted by one or more R 4-a , or -SO 2 -C 1-6 alkyl. base.
  • the C 1-6 alkyl in the “C 1-6 alkyl substituted by one or more R 4-1 ”, the “—SO 2 -C 1-6 alkyl” and the “—N(C 1-6 alkyl) 2 ” are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, preferably methyl.
  • the “4-6-membered heterocycloalkyl group having 1, 2 or 3 heteroatoms and a heteroatom selected from 1, 2 or 3 of N, O and S” and the “ 4-6- membered heterocycloalkyl group having 1, 2 or 3 heteroatoms and a heteroatom selected from 1, 2 or 3 of N, O and S and a heteroatom selected from 1, 2 or 3 of N, O and S” are independently 4-6-membered heterocycloalkyl group having 1, 2 or 3 heteroatoms and a heteroatom selected from 1, 2 or 3 of N, O and S, ...
  • said halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.
  • R4 and R6 are H, and R5 is
  • R 5 and R 6 are H, and R 4 is
  • the compound represented by Formula II is any of the following compounds:
  • the pharmaceutically acceptable salt thereof is the maleate salt of the compound represented by Formula II.
  • the pharmaceutically acceptable salt thereof exists in an anhydrous crystalline form or an amorphous form, preferably in an anhydrous crystalline form.
  • the mass fraction of the compound of Formula II or a pharmaceutically acceptable salt thereof may be 35-42%, for example 36%.
  • the mass fraction of the copovidone may be 8-22%, for example 21%.
  • the filler may be a conventional filler in the pharmaceutical field, preferably a sugar alcohol and/or a water-swellable additive, and more preferably mannitol and microcrystalline cellulose.
  • the sugar alcohol is preferably one or more of mannitol, erythritol and xylitol, such as mannitol.
  • the water-swellable filler is preferably pregelatinized starch, gelatinized starch, microcrystalline cellulose (crystalline cellulose), corn starch, hydroxypropyl methylcellulose (HPMC-K100LV), calcium sulfate, sodium carboxymethyl starch, carboxymethyl cellulose (carboxymethyl cellulose), carboxymethyl cellulose calcium, cross-linked carboxymethyl cellulose sodium (cross-linked sodium carboxymethyl cellulose), soy lecithin, low-substituted hydroxypropyl cellulose, tragacanth gum powder and bentonite or more, such as microcrystalline cellulose.
  • the mass fraction of the filler may be 34-45%, for example 37%.
  • the disintegrant can be a conventional disintegrant in the pharmaceutical field, preferably one or more of adipic acid, alginic acid, gelatinized starch, sodium carboxymethyl starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, hydrated silicon dioxide, calcium citrate, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, light anhydrous silicic acid, crystalline cellulose (microcrystalline cellulose), synthetic aluminum silicate, wheat starch, rice starch, cellulose acetate phthalate, calcium stearate, low-substituted hydroxypropyl cellulose, corn starch, tragacanth powder, potato starch, hydroxyethyl methylcellulose, hydroxypropyl starch, pregelatinized starch, monosodium fumarate, polyvinylpyrrolidone, anhydrous citric acid, methylcellulose and dicalcium phosphate, more preferably cross-linked polyvinylpyrrol
  • the mass fraction of the disintegrant may be 1.7-4.9%, for example 2.0%.
  • the glidant can be a conventional glidant in the pharmaceutical field, preferably one or more of hydrated silicon dioxide (colloidal silicon dioxide), gel silicon dioxide, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, titanium oxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, corn starch and magnesium aluminum metasilicate, preferably colloidal silicon dioxide or gel silicon dioxide.
  • the amount of the glidant may be a conventional amount in the pharmaceutical field.
  • the mass fraction of the glidant may be 1.0-4.0%, for example 2.0%.
  • the lubricant can be a conventional lubricant in the pharmaceutical field, preferably one or more of cocoa fat, carnauba wax, hydrated silicon dioxide (colloidal silicon dioxide), aluminum hydroxide xerogel, glycerol fatty acid ester, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, hardened oil, synthetic aluminum silicate, white beeswax, magnesium oxide, sodium potassium tartrate, sucrose fatty acid ester, stearic acid, calcium stearate, magnesium stearate, sodium stearyl fumarate, stearyl alcohol and polyethylene glycol 40 stearate, preferably sodium stearyl fumarate. Or magnesium stearate.
  • the mass fraction of the lubricant may be 1.0-4.0%, for example 2%.
  • the pharmaceutical composition 2 further comprises a coating agent.
  • the coating agent may be a conventional coating agent for such drugs in the art, preferably one or more of hydroxypropyl methylcellulose, methyl cellulose, ethyl cellulose, methyl cellulose or hydroxypropyl cellulose, polyvinyl alcohol, povidone, polyvinyl acetate resin, polyvinyl acetal diethylamino acetate, methacrylate aminoalkyl copolymer RS and ethyl acrylate-methyl methacrylate copolymer dispersion, sucrose, mannitol and Opadry (trade name, OPADRY), preferably Opadry.
  • hydroxypropyl methylcellulose preferably one or more of hydroxypropyl methylcellulose, methyl cellulose, ethyl cellulose, methyl cellulose or hydroxypropyl cellulose
  • polyvinyl alcohol povidone
  • polyvinyl acetate resin polyvinyl acetal diethylamino acetate
  • the pharmaceutical composition 2 comprises granules, wherein the granules comprise the following components by mass fraction: 30-45% anhydrous neratinib maleate, 7-28% copovidone, 25-48% filler, 1.0-8.0% disintegrant, 0.5-4.0% glidant and 0.5-4.0% lubricant;
  • the sum of the mass fractions of all components in the particulate matter is 100%; the mass fraction is the mass percentage of the mass of each component in the particulate matter to the total mass of each component.
  • the anhydrous neratinib maleate may be a crystalline form of anhydrous neratinib maleate, and its X-ray powder diffraction pattern represented by a diffraction angle of 2 ⁇ has characteristic peaks at 6.0 ⁇ 0.2°, 7.3 ⁇ 0.2°, 10.1 ⁇ 0.2°, 12.1 ⁇ 0.2°, 15.6 ⁇ 0.2°, 17.3 ⁇ 0.2° and 19.9 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form of neratinib maleate may be substantially as shown in Figures 1, 2 or 3.
  • the mass fraction of the anhydrous neratinib maleate may be 35-42%, for example 36%.
  • the mass fraction of the copovidone may be 8-22%, for example, 21%.
  • the filler can be a conventional filler in the pharmaceutical field, preferably a sugar alcohol and/or a water-swellable additive, and more preferably mannitol and microcrystalline cellulose.
  • the sugar alcohol is preferably one or more of mannitol, erythritol and xylitol, such as mannitol.
  • the water-swellable filler is preferably pregelatinized starch, gelatinized starch, microcrystalline cellulose (crystalline cellulose), corn starch, hydroxypropyl methylcellulose (HPMC-K100LV), calcium sulfate, sodium carboxymethyl starch, carboxymethyl cellulose (carboxymethyl cellulose), carboxymethyl cellulose calcium, cross-linked carboxymethyl cellulose sodium (cross-linked sodium carboxymethyl cellulose), soy lecithin, low-substituted hydroxypropyl cellulose, tragacanth gum powder and bentonite or more, such as microcrystalline cellulose.
  • the mass fraction of the filler may be 34-45%, for example 37%.
  • the disintegrant can be a conventional disintegrant in the pharmaceutical field, preferably one or more of adipic acid, alginic acid, gelatinized starch, sodium carboxymethyl starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose, hydrated silicon dioxide, calcium citrate, cross-linked sodium carboxymethyl cellulose, cross-linked polyvinylpyrrolidone, light anhydrous silicic acid, crystalline cellulose (microcrystalline cellulose), synthetic aluminum silicate, wheat starch, rice starch, cellulose acetate phthalate, calcium stearate, low-substituted hydroxypropyl cellulose, corn starch, tragacanth powder, potato starch, hydroxyethyl methylcellulose, hydroxypropyl starch, pregelatinized starch, monosodium fumarate, povidone, anhydrous citric acid, methyl cellulose and dicalcium phosphate, more preferably cross-linked polyvinylpyrrolidone, such
  • the mass fraction of the disintegrant may be 1.7-4.9%, for example 2.0%.
  • the glidant can be a conventional glidant in the pharmaceutical field, preferably one or more of hydrated silicon dioxide (colloidal silicon dioxide), gel silicon dioxide, light anhydrous silicic acid, crystalline cellulose, synthetic aluminum silicate, titanium oxide, stearic acid, calcium stearate, magnesium stearate, tricalcium phosphate, talc, corn starch and magnesium aluminum metasilicate, preferably colloidal silicon dioxide or Gel silica.
  • the amount of the glidant can be the conventional amount in the pharmaceutical field.
  • the mass fraction of the glidant can be 1.0-4.0%, for example, 2.0%.
  • the lubricant can be a conventional lubricant in the pharmaceutical field, preferably one or more of cocoa fat, carnauba wax, hydrated silicon dioxide (colloidal silicon dioxide), aluminum hydroxide xerogel, glycerol fatty acid ester, magnesium silicate, light anhydrous silicic acid, crystalline cellulose, hardened oil, synthetic aluminum silicate, white beeswax, magnesium oxide, sodium potassium tartrate, sucrose fatty acid ester, stearic acid, calcium stearate, magnesium stearate, sodium stearyl fumarate, stearyl alcohol and polyethylene glycol 40 stearate, preferably sodium stearyl fumarate or magnesium stearate.
  • the mass fraction of the lubricant may be 1.0-4.0%, for example, 2%.
  • the components of the particles preferably include an inner component of the particles and an outer component of the particles;
  • the inner components of the granules 30-45% anhydrous neratinib maleate (e.g. 35%, 36% or 42%), 7-28% copovidone (e.g. 8%, 21% or 22%), 25-48% filler (e.g. 34%, 37% or 45%), 1.0-8.0% disintegrant (e.g. 2.4%), 1.0-4.0% glidant (e.g. 1%, 2% or 4%) and 0.5-4.0% lubricant (e.g. 1%);
  • the outer components of the granules include: 0-2.5% disintegrant and/or 0-1% lubricant, and the disintegrant and the lubricant are not 0 at the same time.
  • the granules are composed of the following components in mass fractions: the anhydrous neratinib maleate mentioned above (including the type and mass fraction of neratinib maleate), the copovidone mentioned above, the filler mentioned above (including the type and mass fraction of the filler), the disintegrant mentioned above (including the type and mass fraction of the disintegrant), the glidant mentioned above (including the type and mass fraction of the glidant), the lubricant mentioned above (including the type and mass fraction of the lubricant) and the coating agent mentioned above (including the type and mass fraction of the coating agent).
  • the particulate matter consists of components from the following group (1), group (2) or group (3):
  • Group (1) the inner components of the granules: 34.9% anhydrous neratinib maleate, 26.2% dry alcohol, 8.3% microcrystalline cellulose, 21.7% copovidone, 2.5% crospovidone XL-10, 2.0% colloidal silicon dioxide and 1.0% magnesium stearate;
  • the outer components of the granules 2.5% cross-linked polyvinylpyrrolidone XL-10 and 1.0% magnesium stearate;
  • Group (2) the inner components of the granules: 42.3% anhydrous neratinib maleate, 31.7% dry alcohol, 13.1% microcrystalline cellulose, 8.0% copovidone, 2.0% crospovidone XL-10, 2.0% colloidal silicon dioxide and 1.0% magnesium stearate;
  • the outer component of the granules 1.0% magnesium stearate;
  • Group (3) the inner components of the granules: 36.1% anhydrous neratinib maleate, 27.1% dry alcohol, 8.6% microcrystalline cellulose, 22.4% copovidone, 1.7% crospovidone XL-10, 2.0% colloidal silicon dioxide and 1.0% magnesium stearate;
  • the outer component of the granules 1.0% magnesium stearate.
  • the pharmaceutical composition 2 may further include a coating agent.
  • the coating agent may be a conventional coating agent for such drugs in the art, preferably one or more of hydroxypropyl methylcellulose, methylcellulose, ethylcellulose, methylcellulose or hydroxypropyl cellulose, polyvinyl alcohol, povidone, polyvinyl acetate resin, polyvinyl acetal diethylaminoacetate, methacrylate aminoalkyl copolymer RS and ethyl acrylate-methyl methacrylate copolymer dispersion, sucrose, mannitol and Opadry (trade name, OPADRY), preferably Opadry.
  • OPADRY trade name, OPADRY
  • the amount of the coating agent used can be the conventional amount used in this type of medicine in the art.
  • the ratio may be 0.01:1-0.05:1, such as 0.03:1, 0.034:1 or 0.036:1.
  • the drug particle component is composed of the following components in mass fraction: the above-mentioned anhydrous neratinib maleate (including the type and mass fraction of neratinib maleate), the above-mentioned copovidone, the above-mentioned filler (including the type and mass fraction of the filler), the above-mentioned disintegrant (including the type and mass fraction of the disintegrant), the above-mentioned glidant (including the type and mass fraction of the glidant), the above-mentioned lubricant (including the type and mass fraction of the lubricant) and the above-mentioned coating agent (including the type and mass fraction of the coating agent).
  • the pharmaceutical composition 2 is composed of the following components in group (a), group (b) or group (c):
  • the internal components of the granules are: 34.9% anhydrous neratinib maleate, 26.2% dry dew alcohol, 8.3% microcrystalline cellulose, 21.7% copovidone, 2.5% cross-linked polyvinylpyrrolidone XL-10, 2.0% colloidal silicon dioxide and 1.0% magnesium stearate;
  • the outer components of the granules 2.5% cross-linked polyvinylpyrrolidone XL-10 and 1.0% magnesium stearate;
  • the internal components of the granules are: 42.3% anhydrous neratinib maleate, 31.7% dry dew alcohol, 13.1% microcrystalline cellulose, 8.0% copovidone, 2.0% cross-linked polyvinylpyrrolidone XL-10, 2.0% colloidal silicon dioxide and 1.0% magnesium stearate;
  • the outer component of the granules 1.0% magnesium stearate;
  • the internal components of the granules are: 36.1% anhydrous neratinib maleate, 27.1% dry dew alcohol, 8.6% microcrystalline cellulose, 22.4% copovidone, 1.7% cross-linked polyvinylpyrrolidone XL-10, 2.0% colloidal silicon dioxide and 1.0% magnesium stearate;
  • the outer component of the granules 1.0% magnesium stearate.
  • the present invention also provides a method for preparing the above-mentioned pharmaceutical composition 2, which comprises the following steps: granulating the following raw materials by mass fraction to obtain granules;
  • the raw materials contain 30-45% anhydrous neratinib maleate, 7-28% copovidone, 25-48% filler, 1.0-8.0% disintegrant, 0.5-4.0% glidant and 0.5-4.0% lubricant; the sum of the mass fractions of all components in the granules is 100%; the mass fraction is the mass percentage of the mass of each component in the granules to the total mass of each component.
  • the copolyvidone, the filler (including type and content), the disintegrant (including type and content), the glidant (including type and content) and the lubricant (including type and content) are the same as described above.
  • the dry granulation adopts a dry granulator, and the preferred parameters of the dry granulator are as follows:
  • the roller pressure of the dry granulator is preferably 65-100 bar, such as 80 bar.
  • the feeding speed of the dry granulator is preferably 40-50 rpm.
  • the roller speed of the dry granulator is preferably 5-15 rpm, such as 6 rpm.
  • the granulation speed of the dry granulator is preferably 50-500 rpm, such as 100 rpm.
  • the mesh size of the dry granulator is preferably 0.6-1.2 mm, such as 0.8 mm.
  • the preparation method of the pharmaceutical composition may further comprise a coating step.
  • the water content of the pharmaceutical composition is ⁇ 3%.
  • the type and dosage of the coating agent are the same as described above.
  • a coating machine is used for coating, and the coating machine preferably has the following parameters:
  • the air inlet temperature of the coating machine is preferably 55-60°C.
  • the atomization pressure of the coating machine is preferably 0.10-0.30 MPa.
  • the peristaltic pump speed of the coating machine is preferably 2.0-12.0 rpm.
  • the air outlet temperature of the coating machine is preferably 35-42°C.
  • the preparation method of the pharmaceutical composition 2 preferably comprises the following steps:
  • Step 1 dry granulating the internal raw materials of the granules to obtain granules 1;
  • the internal raw materials of the granules are: 30-45% anhydrous neratinib maleate, 7-28% copovidone, 25-48% filler, 1-8% disintegrant, 1-4% glidant and 0.5-4% lubricant;
  • Step 2 Compress the granules 1 and the external raw materials of the granules (for example, mix the granules 1 and the external raw materials of the granules 1, and press the mixture into tablets using a tablet press (10.5 mm*5.5 mm special-shaped die)) to obtain the granules:
  • the extra-granular raw materials include: 0-2.5% disintegrant and/or 0-1% lubricant, and the disintegrant and the lubricant are not 0 at the same time.
  • the present invention also provides a pharmaceutical composition 2 prepared by the preparation method of the above-mentioned pharmaceutical composition 2.
  • the present invention also provides a pharmaceutical solid preparation, which comprises the above-mentioned pharmaceutical composition 2 and pharmaceutically acceptable excipients.
  • the solid preparation may be a tablet, granules, powder (including fine granules), or capsule, such as a tablet.
  • the solid preparation is a tablet
  • the pharmaceutical composition 2 of the present invention when the pharmaceutical composition 2 of the present invention is in the form of a tablet, the tablet can be obtained by compressing the granules obtained as described above.
  • the compression pressure may be 10-20 kN.
  • the shape of the tablet is not particularly limited, such as lentil-shaped, disc-shaped, round, oval (such as caplet), teardrop-shaped or polygonal (such as triangle or rhombus).
  • the prepared tablets can be coated by spraying a suspension/solution of the coating agent using a pan coater. After coating, the moisture content of the final tablets can be controlled within 3% by a drying process.
  • the drying temperature can be selected to be 40-80°C, for example 40-50°C.
  • the humidity of the pressing environment is controlled to ensure that the moisture content of the final plain tablet is less than 3% (below 3%), and the moisture content of the final composition is ensured to be less than 3% by vacuum drying the final composition.
  • the present invention also provides an application of a substance A in the preparation of an EGFR inhibitor, wherein the substance A is the above-mentioned pharmaceutical composition 2 or the above-mentioned pharmaceutical solid preparation.
  • the substance A may also be the compound represented by formula I or a pharmaceutically acceptable salt thereof.
  • the present invention also provides an application of a substance A in the preparation of a drug for preventing or treating EGFR-related diseases, wherein the substance A is the above-mentioned pharmaceutical composition 2 or the above-mentioned pharmaceutical solid preparation.
  • the substance A may also be the compound represented by formula I or a pharmaceutically acceptable salt thereof.
  • the EGFR-related disease is preferably breast cancer, ovarian cancer, epithelial tumor, colon cancer, prostate cancer, kidney cancer, bladder cancer, laryngeal cancer, esophageal cancer, gastric cancer or lung cancer.
  • the present invention also provides a pharmaceutical composition 3, which comprises a substance X and a substance Y;
  • the substance X is neratinib maleate
  • the substance Y is compound CVL218 or a pharmaceutically acceptable salt thereof.
  • the structure of the compound CVL218 is shown below:
  • the present invention also provides a pharmaceutical composition 4, which comprises a substance M and a substance N;
  • the substance M is neratinib maleate
  • the substance N is compound CVL237 or a pharmaceutically acceptable salt thereof.
  • the structure of the compound CVL237 is shown below:
  • the present invention also provides the use of the pharmaceutical composition 3 in preparing a drug for preventing or treating bile duct cancer.
  • the present invention also provides the use of the pharmaceutical composition 4 in preparing a drug for preventing or treating bile duct cancer.
  • the term "pharmaceutically acceptable salt” refers to a salt prepared from the compound of the present invention and a relatively non-toxic, pharmaceutically acceptable acid.
  • the term "granular matter” refers to granular matter with a particle size between 30 mesh and 200 mesh.
  • the term "pharmaceutical excipients” may be those excipients widely used in the field of drug production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide methods to dissolve the active ingredient at a desired rate after the subject receives the administration, or promote the active ingredient to be effectively absorbed after the subject receives the composition administration.
  • the pharmaceutical excipients may be inert fillers, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition.
  • the pharmaceutical excipients may include one or more of the following excipients: adhesives, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.
  • excipients adhesives, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adhesive agents, glidants, wetting agents, gelling agents, absorption delay agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents and sweeteners.
  • the reagents and raw materials used in the present invention are commercially available.
  • the neratinib or its pharmaceutically acceptable salt or solvate described in the present invention can be obtained according to the methods described in US6002008, US6288082, US6297258, US6384051 and US7399865, or purchased through commercial channels.
  • the reference preparation of neratinib maleate described in the present invention is the original drug of neratinib maleate (coated tablets) produced by Puma Biotechnology.
  • the pharmaceutical composition of the present invention has good stability and achieves the same in vitro dissolution effect as the original reference preparation; and the preparation method of the present invention obtains a product with uniform and stable particle size distribution, small tablet weight difference and easy-to-control tablet hardness.
  • FIG1 is the XRPD pattern of Example 1 (anhydrous crystalline form).
  • FIG. 2 is the XRPD pattern of Example 2 (no crystalline form).
  • FIG3 is the XRPD pattern of Example 3 (no crystalline form).
  • FIG. 4 is an XRPD pattern of the reference preparation (with crystalline form).
  • FIG. 5 is a dissolution curve diagram of Example 1, Example 2 and the reference preparation.
  • FIG6 is the XRPD pattern of Example 4 (no crystalline form).
  • FIG. 7 is an XRPD pattern of the enlarged batch 1 in Example 5 (no crystalline form).
  • FIG8 is an XRPD pattern of the enlarged batch 2 in Example 5 (no crystalline form).
  • FIG. 9 is an XRPD pattern of the enlarged batch 3 in Example 5 (no crystalline form).
  • FIG. 10 is the XRPD pattern of the enlarged batch 1 after 6 months of accelerated experiment in Example 5 (no crystalline form).
  • FIG. 11 is the XRPD pattern of the enlarged batch 2 after 6-month accelerated experiment in Example 5 (no crystalline form).
  • FIG. 12 is the XRPD pattern of the enlarged batch 3 after 6-month accelerated experiment in Example 5 (no crystalline form).
  • FIG. 13 is an XRPD pattern of the enlarged batch 1 after a long-term 12-month experiment in Example 5 (no crystalline form).
  • FIG. 14 is an XRPD pattern of the enlarged batch 2 after a 12-month long-term experiment in Example 5 (no crystalline form).
  • FIG. 15 is an XRPD pattern of the enlarged batch 3 in Example 5 after a long-term 12-month experiment (no crystalline form).
  • FIG. 16 is a dissolution curve diagram of the scaled-up batch and the reference preparation in Example 5.
  • Example 17 is a dissolution curve of the scaled-up batch in Example 5 after accelerated 6-month experiment and the reference preparation.
  • FIG. 18 is a dissolution curve of the scaled-up batch in Example 5 after a long-term 12-month experiment.
  • FIG. 19 is a curve showing changes in mouse body weight in the biological example.
  • FIG. 20 is a curve showing changes in tumor volume in a biological example.
  • Step 1 (E)-4-Bromo-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)but-2-enamide
  • Step 2 (E)-N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-4-(3-(dimethylamino)azetidin-1-yl)but-2-enamide
  • N,N-dimethylazetidine-3-amine (0.33 g, 2.00 mmol) and 2-(bromomethyl)propylene (0.35 g, 2.00 mmol) were dissolved in N,N-dimethylacetamide (20 mL), and then DIEA (1 ml, 6.00 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated and directly purified by reverse phase (0-20% acetonitrile) to obtain the target product (white solid 0.20 g, yield 55.4%).
  • Step 2 Preparation of N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-2-((3-(dimethylamino)azetidin-1-yl)methyl)acrylamide
  • Step 2 Preparation of N-(4-((3-chloro-4-(pyridin-2-ylmethoxy)phenyl)amino)-3-cyano-7-ethoxyquinolin-6-yl)-2-((4-(dimethylamino)piperidin-1-yl)methyl)acrylamide
  • This experiment uses the CellTiter-Glo (CTG) kit, which is a homogenized cell viability assay that measures the cell viability of cultured cells by quantifying ATP. It has become the mainstream cell viability assay kit because of its high sensitivity and simple operation process.
  • CTG CellTiter-Glo
  • the purpose of this experiment is to use the CTG method to evaluate the effects of 6 test compounds on the cell proliferation of an EGFR cell line, using afatinib as the control compound.
  • the cells in the 96-well plate were cultured at 37°C and 5% CO 2 .
  • Cell survival rate (%) (Lum test drug -Lum culture medium control )/(Lum solvent control -Lum culture medium control ) ⁇ 100%.
  • the method for determining the moisture content of the granules or compositions involved in the present invention is to use an infrared rapid moisture meter (measurement temperature 105° C.), which is a common method for determining moisture content known to those skilled in the art and is widely used in the determination of moisture content in granules, tablets, powders, etc.
  • the following neratinib maleate is neratinib combined with one maleate salt.
  • neratinib maleate tablets 40 mg (calculated as C 30 H 29 ClN 6 O 3 ), and the prescription is shown in Table 1:
  • the obtained granules were then mixed with the extragranular components of cross-linked polyvinylpolypyrrolidone XL-10 and magnesium stearate, and the mixture was pressed into tablets using a tablet press (10.5 mm*5.5 mm special-shaped die) with a hardness controlled at 70-140 N. Subsequently, the tablets were film-coated with a 15 w/v% coating agent suspension (OPADRY) mainly composed of polyvinyl alcohol using a high-efficiency coating machine, so that the amount of coating in the tablets was 4.15 mg.
  • OADRY 15 w/v% coating agent suspension
  • the X-ray powder diffraction pattern of the tablets is shown in Figure 1.
  • the coating process was controlled according to the parameters in Table 3, so that the maximum moisture content of the tablets during the coating process was controlled below 3%.
  • the obtained granules were then mixed with the extragranular component magnesium stearate, and the mixture was pressed into tablets using a tablet press (10.5 mm*5.5 mm special-shaped die) with a hardness controlled at 70-140 N. Subsequently, the tablets were film-coated with a 15 w/v% coating agent suspension (OPADRY) mainly composed of polyvinyl alcohol using a high-efficiency coating machine, so that the amount of coating in the tablets was 4.15 mg.
  • OPADRY 15 w/v% coating agent suspension
  • the X-ray powder diffraction pattern of the tablets is shown in Figure 2.
  • the coating process was controlled according to the parameters in Table 3, so that the maximum moisture content of the tablets during the coating process was controlled below 3%.
  • neratinib maleate tablets 40 mg (calculated as C 30 H 29 ClN 6 O 3 ), as shown in Table 6.
  • the obtained granules were then mixed with the extragranular component magnesium stearate, and the mixture was pressed into tablets using a tablet press (10.5 mm*5.5 mm special-shaped die) with a hardness controlled at 70-140 N. Subsequently, the tablets were film-coated with a 15 w/v% coating agent suspension (OPADRY) mainly composed of polyvinyl alcohol using a high-efficiency coating machine, so that the amount of coating in the tablets was 4.15 mg.
  • OPADRY 15 w/v% coating agent suspension
  • the X-ray powder diffraction pattern of the tablets is shown in Figure 3.
  • the coating process was controlled according to the parameters in Table 3, so that the maximum moisture content of the tablets during the coating process was controlled below 3%.
  • neratinib maleate tablets 40 mg (calculated as C 30 H 29 ClN 6 O 3 ), as shown in Table 8 below.
  • the obtained granules were then mixed with the extragranular component magnesium stearate, and the mixture was pressed into tablets using a tablet press (10.5 mm*5.5 mm special-shaped die) with a hardness controlled at 70-140 N. Subsequently, the tablets were film-coated with a 15 w/v% coating agent suspension (OPADRY) mainly composed of polyvinyl alcohol using a high-efficiency coating machine, so that the amount of coating in the tablets was 4.15 mg.
  • OPADRY 15 w/v% coating agent suspension
  • the X-ray powder diffraction pattern of the tablets is shown in Figure 6.
  • the coating process was controlled according to the parameters in Table 3 so that the maximum moisture content of the tablets during the coating process was controlled below 3%.
  • Embodiment 5 is a diagrammatic representation of Embodiment 5:
  • Example 4 The prescription process described in Example 4 was scaled up to the production workshop, and the batch size was scaled up from a few hundred tablets in the laboratory to 100,000 tablets, and three batches were produced continuously, with the batch numbers being scaled up batch 1, scaled up batch 2, and scaled up batch 3.
  • the prescription is shown in Table 10 below.
  • the obtained granules were then mixed with the extragranular component magnesium stearate, and the mixture was pressed into tablets using a tablet press (10.5 mm*5.5 mm special-shaped die) with a hardness controlled at 70-140 N. Subsequently, the tablets were film-coated with a 15 w/v% coating agent suspension (OPADRY) mainly composed of polyvinyl alcohol using a high-efficiency coating machine, so that the amount of coating in the tablets was 4.15 mg.
  • OPADRY 15 w/v% coating agent suspension
  • the X-ray powder diffraction patterns of the tablets are shown in Figures 7-9.
  • the coating process was controlled according to the parameters in Table 3 so that the maximum moisture content of the tablets during the coating process was controlled below 3%.
  • the pilot scale-up was performed on the neratinib maleate tablets of Examples 1, 2, and 3 according to each prescription.
  • the pilot scale-up was performed according to Examples 1, 2, and 3.
  • the three batches of neratinib maleate tablets were compared with the reference preparation.
  • the reference preparation selected was Puma Biotechnology neratinib maleate original drug (coated tablets).
  • the dissolution curve was carried out based on the dissolution and release determination method (Method 0931, Part 4, General Rules, 2020 Edition of the Chinese Pharmacopoeia).
  • the conditions of the dissolution curve are paddle method pH 1.2, 500mL, 50rpm and paddle method pH 3.0, 75rpm, 900mL. Samples are taken at various time points of 5-60 minutes, and an appropriate amount of the dissolution solution is taken, filtered, at least 2ml of the initial filtrate is discarded, and the subsequent filtrate is taken. An appropriate amount of the maleic acid neratinib reference substance is taken, accurately weighed, and the dissolution medium is added to ultrasonically dissolve and dilute to prepare a solution containing about 44 ⁇ g of neratinib (calculated as C 30 H 29 ClN 6 O 3 ) per 1ml, which is used as the reference substance solution.
  • octadecylsilane bonded silica gel was used as the filler (Waters Xbridge C18, 4.6mm ⁇ 150mm, 5 ⁇ m or equivalent chromatographic column is recommended); 0.1% trifluoroacetic acid solution-methanol (67:33) was used as the mobile phase; the detection wavelength was 266nm; the column temperature was 40°C, the flow rate was 1.5ml/min, the running time was 10 minutes, and the injection volume was 10 ⁇ l.
  • the peak area of neratinib was calculated to calculate the dissolution amount of each tablet at each time point, and the similarity factor comparison method was used to compare the f2 value with the first batch of the reference preparation.
  • n is the time point
  • Rt is the average percentage of drug release of the reference preparation
  • Tt is the average percentage of drug release of the test preparation. If the f2 value is greater than or equal to 50, the dissolution of the test preparation and the reference preparation is considered to be similar. Specific dissolution data are shown in Tables 15-16.
  • each embodiment of the present invention all showed similar dissolution behavior to the reference preparation in a dissolution curve test with discriminating power (similarity factor f2 value greater than or equal to 50), and had equivalent in vivo biological activity.
  • A+2.2S test method Take 10 pieces of the test product, the absolute value of the difference between the labeled amount represented by 100 and the measured mean is A, the standard deviation is S, and A+2.2S ⁇ 15.0 indicates that the product content uniformity meets the requirements.
  • Example 5 Three batches of the scaled-up production of Example 5 were investigated. The production process was monitored, and the particle size results are shown in Table 21, the mixing uniformity results are shown in Table 22, and the tablet weight difference and hardness results are shown in Table 23.
  • the stability of three batches of preparations produced by the scaled-up production of Example 5 was investigated.
  • the investigation conditions were accelerated (temperature 40°C ⁇ 2°C, relative humidity 75% RH ⁇ 5% RH) and long-term (temperature 25°C ⁇ 2°C, relative humidity 60% RH ⁇ 5% RH).
  • the sampling time points for the accelerated test were 1, 2, 3, and 6 months, and the time points for the long-term sampling were 3, 6, 9, and 12 months.
  • the investigation indicators were related substances, content, moisture, crystal form, and dissolution curve.
  • the reference preparation selected Puma Biotechnology original research drug of neratinib maleate (coated tablets).
  • the dissolution test was conducted on three scale-up batches that were directly prepared without accelerated experiments and long-term experiments.
  • the dissolution curve results are shown in Figure 16.
  • the dissolution curve results of the three batches were similar, which was similar to the reference, indicating that the products produced according to this specification have similar quality to the reference.
  • the dissolution curves of the three scaled-up batches accelerated for 6 months are shown in Figure 17, and the long-term dissolution curves for 12 months are shown in Figure 18. They are also compared with the dissolution curve of the second batch of the reference preparation. The dissolution characteristics of the three batches of products have not changed and are similar to those of the reference preparation.
  • the type or content of the adhesive in Table 33 below replaces the copolyvidone or its content in Example 1, and the rest is the same as Example 1.
  • the obtained product is tested for dissolution according to the method of Effect Example 4, and the test results are shown in Tables 34 and 35.
  • the reference preparation is the third batch of Puma Biotechnology neratinib maleate original drug (coated tablets).
  • CVL218 is the compound in patent CN103242273B
  • CVL237 is a compound
  • Tumor tissue was surgically removed from tumor-bearing mice and immersed in HBSS buffer. Non-tumor tissue and necrotic tissue were removed in a biosafety cabinet, and the tissue was cut into 1-3 cubic millimeter pieces. The tumor pieces were digested with collagenase at 37 degrees Celsius for 1-2 hours. Single cell suspension was collected through a sieve. The supernatant was removed by centrifugation at 1200 rpm for 3 minutes. The cells were resuspended in serum-free medium and counted, and the cell concentration was adjusted to 1.11 ⁇ 10 5 /mL. Use BIO-MPM-1 medium to dilute 1000 ⁇ high concentration drug stock solution to 20 ⁇ intermediate concentration.
  • Inhibition rate (%) ((VControl-VBlank)-(Vdrug treatment group-VBlank))/(VControl-VBlank) ⁇ 100%
  • the concentration setting range is shown in Table 36 below:
  • This experiment uses the CellTiter-Glo (CTG) kit, which is a homogenized cell viability assay that measures the cell viability of cultured cells by quantifying ATP. It has become the mainstream cell viability assay kit because of its high sensitivity and simple operation process.
  • CTG CellTiter-Glo
  • the purpose of this experiment is to use the CTG method to evaluate the effect of a test compound on the cell proliferation of 5 EGFR cell lines, using afatinib as the control compound.
  • Ba/F3-EGFR-G719S cells were revived and cultured in vitro to obtain 8 ⁇ 10 7 cells.
  • the hair of the mice at the inoculation site was removed, the inoculation site was disinfected with iodine cotton balls, and 0.1 mL of cell suspension was inoculated subcutaneously on the right shoulder of the mice with a 1 mL syringe, 2 ⁇ 10 6 cells/point.
  • the average tumor volume reached about 100 mm 3 they were randomly divided into 5 groups according to tumor volume and body weight, with 8 mice in each group: solvent control group, 20, 40, 80 mg/kg A009 group, and 40 mg/kg afatinib group.
  • T is the tumor volume of the drug-treated group
  • T0 is the initial tumor volume of the drug-treated group
  • C is the tumor volume of the control group
  • C0 is the initial tumor volume of the control group.
  • the weight and tumor volume data were expressed as mean + standard error (Mean+SEM). All data were statistically analyzed using Graphpad prism6. For pairwise comparisons, T-Test analysis was used; for comparisons between more than three groups, two-way analysis of variance (Two-Way ANOVA) and Bonferroni's test were used. P ⁇ 0.05 was considered to be significantly different.
  • mice in each group and the changes in tumor volume are shown in Figures 19 and 20.
  • A009 can inhibit the proliferation of Ba/F3-EGFR-G719S cells in a dose-dependent manner, and can cause tumor regression at medium and high doses, suggesting that it has the potential to treat non-small cell lung cancer (NSCLC) with rare G719X mutations; the anti-tumor effect is similar to that of Yangshen Afatinib at the same dose, but the overall safety is better than that of Afatinib.
  • NSCLC non-small cell lung cancer
  • QD means administration once a day
  • Q2D means administration once every two days.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Molecular Biology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biophysics (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开了一种含有EGFR抑制剂的药物组合物及其制备方法和应用。该药物组合物包含颗粒物，所述的颗粒物包含以如下的质量分数计的组分：30-45％无水奈拉替尼马来酸盐、7-28％共聚维酮、25-48％填充剂、1.0-8.0％崩解剂、0.5-4.0％助流剂和0.5-4.0％润滑剂。本发明的药物组合物具有良好的稳定性以及与参比制剂等效果的体内生物活性，具有良好的应用前景。

Description

含有EGFR抑制剂的药物组合物及其制备方法和应用 技术领域
本发明涉及一种含有EGFR抑制剂的药物组合物及其制备方法和应用。
背景技术
(E)-N-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基-3-氰基-7-乙氧基喹啉-6-基)-4-(二甲基氨基)丁-2-烯酰胺一马来酸盐，也称为奈拉替尼马来酸盐，具体结构如下，是一种特定的蛋白激酶抑制剂。
研究表明在许多实体肿瘤中存在EGFR(表皮细胞生长因子受体)的高表达或异常表达。EGFR与肿瘤细胞的增殖、血管生成、肿瘤侵袭、转移及细胞凋亡的抑制有关。EGFR的过表达在恶性肿瘤的演进中起重要作用，胶质细胞、肾癌、肺癌、前列腺癌、胰腺癌、乳腺癌等组织中都有EGFR的过表达。在30％以上乳腺癌患者中可发现EGFR和HER2浓度升高，其中，HER2为EGFR家族中最为重要的基因之一。
奈拉替尼马来酸盐的有效成分为奈拉替尼，是不可逆HER2/EGFR抑制剂，能有效抑制HER1和HER2酪氨酸激酶活性。从而抑制肿瘤细胞的生长。马来酸奈拉替尼最初由惠氏公司研制,被辉瑞制药公司并购后,授权给美国PUMA生物科技公司负责开发、上市、生产和销售。2017年7月17日被美国食品药品管理局(FDA)批准上市,商品名为马来酸奈拉替尼片以无水晶型的马来酸奈拉替尼为原料，与辅料混合，经流化床制粒工艺、压片、包衣而得，最终活性成分马来酸奈拉替尼的晶型转变为有水晶型。
奈拉替尼具有良好的抑制肿瘤细胞生长的作用，但是奈拉替尼易于降解，稳定性差，尤其是在制成药物组合物后，由于多种辅料和水的存在，主要有以下两个方面的问题：
1.会加速奈拉替尼马来酸盐降解，其降解杂质的具体结构式如下，此降解杂质在高温和高湿情况下加速增长，这要求在制剂制备过程中尽可能的避免高温和遇水。而在临床上应用，由于奈拉替尼杂质副作用大，通常来说，需要控制奈拉替尼制剂的降解杂质含量小于1.5％，因此，需要提供稳定的奈拉替尼制剂对于本领域技术人员是一种挑战。
2.奈拉替尼马来酸盐遇水容易从无水晶型转变为一水晶型，晶型的转变会影响药物质量的控制， 以及药物的溶出、释放，进而影响药物的治疗效果和副作用，这要求在制剂制备过程中尽可能的避免使用水。基于以上两点，需要提供稳定的奈拉替尼制剂对于本领域技术人员是一种挑战。
专利CN102724970公开了一种奈拉替尼马来酸盐片的制备方法，但该方法仅仅是针对改善奈拉替尼在制粒过程中表现出的粘结性。在过程中采用了流化床湿法制粒工艺，存在高温和遇水的环境，没有针对于奈拉替尼自身不稳定易于转化为有水晶型和易于降解的化学特性，并不能保证最终制剂具有良好的稳定性和溶出性质。同时，奈拉替尼马来酸盐在制粒过程由无水晶型转化为有水晶型，无法控制晶型是否转化完全，给药品的质量控制带来挑战。
专利CN106913529公开了一种奈拉替尼马来酸盐片的制备方法，采用流化床制粒工艺，同时控制造粒制备过程的颗粒最大含水量10％以下，并通过造粒过程的高温(70-90度)去除水分，控制最终颗粒的水分小于2％。在包衣结束后，单独采用旋转真空干燥机进行干燥才能将水分降低至2％以下。这种程序一般在大生产中时不采用的。结合该专利的制备工艺，可以看出，来奈拉替尼马来酸盐不可避免会发生晶型转化。这样容易造成批间药品转晶程度不一致。而且，该专利中，奈拉替尼胶囊的溶出速度较快，15min即可溶出80％以上，明显快于市面上的马来酸奈拉替尼原研药；与原研先比，该专利的产片在体内生物等效的风险大。
综上，为了药物的在临床应用，需要开发一种稳定、避免用水和高温的片剂制备工艺以制得稳定性好以及杂质含量低的药物。
发明内容
本发明所用解决的技术问题是为了克服现有技术中含有EGFR抑制剂的药物组合物的种类有限的缺陷，为此，而提供了一种含有EGFR抑制剂的药物组合物及其制备方法和应用。本发明的含有EGFR抑制剂的药物组合物具有良好的稳定性且溶出曲线与参比制剂一致，具有与参比制剂等效果的体内生物活性。
本发明是通过以下技术方案解决上述技术问题的。
本发明提供了如下式I所示化合物，
其中，R1、R2和R3分别独立地为H或被一个或多个R1-1取代的C1-6烷基；
各R1-1分别独立地为“杂原子选自N、O和S中的1种、2种或3种，杂原子个数为1个、2个或3个”的4-6元杂环烷基、被一个或多个R1-a取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子个数为1个、2个或3个的4-6元杂环烷基”或-SO2-C1-6烷基；
各R1-a分别独立地为卤素或-N(C1-6烷基)2。
在一些实施方式中，R1和R2为H，R3为被一个或多个R1-1取代的C1-6烷基。
在一些实施方式中，R2和R3为H，R1为被一个或多个R1-1取代的C1-6烷基。
在一些实施方式中，各R1-1分别独立地为被一个或多个R1-a取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子个数为1个、2个或3个的4-6元杂环烷基”或-SO2-C1-6烷基。
在一些实施方式中，所述R1、R2、R3、R1-1和R1-a中，所述“被一个或多个R1-1取代的C1-6烷基”、所述“-SO2-C1-6烷基”和所述“-N(C1-6烷基)2”中的C1-6烷基分别独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，优选甲基。
在一些实施方式中，所述被一个或多个R1-a取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子个数为1个、2个或3个的4-6元杂环烷基”为
在一些实施方式中，所述R1-1中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子个数为1个、2个或3个的4-6元杂环烷基”和所述“被一个或多个R1-a取代的杂原子选自N、O和S中的1种、2种或3种，杂原子个数为1个、2个或3个的4-6元杂环烷基”中的“杂原子选自N、O和S中的1种、2种或3种，杂原子个数为1个、2个或3个的4-6元杂环烷基”分别独立地为杂原子为N，杂原子个数为1个的4-6元杂环烷基，优选
在一些实施方式中，所述R1-a中，所述卤素为氟、氯、溴或碘，优选氟。
在一些实施方式中，R1和R2为H，R3为
在一些实施方式中，R2和R3为H，R1为
在一些实施方式中，所述如式I所示化合物为如下任一化合物：

本发明还提供了一种药物组合物1，其包含如式I所示的化合物或其药学上可接受的盐；以及药用辅料。
本发明还提供了一种如式I所示化合物或其药学上可接受的盐在制备预防或治疗与EGFR相关疾病的药物中的应用。
所述的与EGFR相关疾病优选为乳腺癌、卵巢癌、上皮样瘤、结肠癌，前列腺癌、肾癌、膀胱癌、喉癌、食道癌、胃癌或肺癌。
本发明还提供了一种药物组合物2，其包含颗粒物，所述的颗粒物包含以如下的质量分数计的组分：30-45％如式II所示化合物或其药学上可接受的盐、7-28％共聚维酮、25-48％填充剂、1.0-8.0％崩解剂、0.5-4.0％助流剂和0.5-4.0％润滑剂；
所述的颗粒物中的所有组分的质量分数之和为100％；所述的质量分数为颗粒物中各组分的质量占各组分的总质量的质量百分比；
R4、R5和R6分别独立地为H或被一个或多个R4-1取代的C1-6烷基；
各R4-1分别独立地为-N(C1-6烷基)2、“杂原子选自N、O和S中的1种、2种或3种，杂原子个数为1个、2个或3个”的4-6元杂环烷基、被一个或多个R4-a取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子个数为1个、2个或3个的4-6元杂环烷基”或-SO2-C1-6烷基；
各R4-a分别独立地为卤素或-N(C1-6烷基)2。
在一些实施方式中，R4和R6为H，R5为被一个或多个R4-1取代的C1-6烷基。
在一些实施方式中，R5和R6为H，R4为被一个或多个R4-1取代的C1-6烷基。
在一些实施方式中，各R4-1分别独立地为-N(C1-6烷基)2、被一个或多个R4-a取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子个数为1个、2个或3个的4-6元杂环烷基”或-SO2-C1-6烷 基。
在一些实施方式中，所述R4、R5、R6、R4-1和R4-a中，所述“被一个或多个R4-1取代的C1-6烷基”、所述“-SO2-C1-6烷基”和所述“-N(C1-6烷基)2”中的C1-6烷基分别独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基，优选甲基。
在一些实施方式中，所述R4-1中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子个数为1个、2个或3个的4-6元杂环烷基”和所述“被一个或多个R4-a取代的杂原子选自N、O和S中的1种、2种或3种，杂原子个数为1个、2个或3个的4-6元杂环烷基”中的“杂原子选自N、O和S中的1种、2种或3种，杂原子个数为1个、2个或3个的4-6元杂环烷基”分别独立地为杂原子为N，杂原子个数为1个的4-6元杂环烷基，优选
在一些实施方式中，所述R4-a中，所述卤素为氟、氯、溴或碘，优选氟。
在一些实施方式中，R4和R6为H，R5为
在一些实施方式中，R5和R6为H，R4为
在一些实施方式中，所述如式II所示化合物为如下任一化合物：

在一些实施方式中，所述其药学上可接受的盐为如式II所示化合物的马来酸盐。
在一些实施方式中，所述其药学上可接受的盐以无水晶型或无定形形式存在，优选以无水晶型形式存在。
在一些实施方式中，所述的如式II所示化合物或其药学上可接受的盐的质量分数可以为35-42％，例如36％。
在一些实施方式中，所述的共聚维酮的质量分数可以为8-22％，例如21％。
在一些实施方式中，所述的填充剂可以为药剂领域中常规的填充剂，优选为糖醇和/或水溶胀性添加剂，进一步优选为甘露醇和微晶纤维素。
所述的糖醇优选为甘露醇、赤藓糖醇和木糖醇中的一种或多种，例如甘露醇。
所述的水溶胀性填充剂优选为预胶凝淀粉、胶凝淀粉、微晶纤维素(结晶纤维素)、玉米淀粉、羟丙基甲基纤维素(HPMC-K100LV)、硫酸钙、羧甲基淀粉钠、羧甲纤维素(羧甲基纤维素)、羧甲纤维素钙、交联羧甲纤维素钠(交联羧甲基纤维素钠)、大豆卵磷脂、低取代的羟丙基纤维素、黄蓍胶粉和膨润土中的或多种，例如微晶纤维素。
在一些实施方式中，所述的填充剂的质量分数可以为34-45％，例如37％。
在一些实施方式中，所述的崩解剂可以为药剂领域中常规的崩解剂，优选为己二酸、海藻酸、胶凝淀粉、羧甲基淀粉钠、羧甲纤维素、羧甲纤维素钙、羧甲纤维素钠、水合二氧化硅、柠檬酸钙、交联羧甲纤维素钠、交联聚维酮、轻质无水硅酸、结晶纤维素(微晶纤维素)、合成硅酸铝、小麦淀粉、米淀粉、乙酸邻苯二甲酸纤维素、硬脂酸钙、低取代的羟丙基纤维素、玉米淀粉、黄蓍胶粉、马铃薯淀粉、羟乙基甲基纤维素、羟丙基淀粉、预胶凝淀粉、富马酸单钠、聚维酮、无水柠檬酸、甲基纤维素和磷酸二氢钙中的一种或多种，更优选交联聚维酮，例如交联聚维酮XL-10。
在一些实施方式中，所述的崩解剂的质量分数可以为1.7-4.9％，例如2.0％。
在一些实施方式中，所述的助流剂可以为药剂领域中常规的助流剂，优选为水合二氧化硅(胶态二氧化硅)、凝胶二氧化硅、轻质无水硅酸、结晶纤维素、合成硅酸铝、氧化钛、硬脂酸、硬脂酸钙、硬脂酸镁、磷酸三钙、滑石粉、玉米淀粉和偏硅酸铝镁中的一种或多种，优选胶态二氧化硅或凝胶二氧化硅。
在一些实施方式中，所述的助流剂的用量可以为药剂领域中常规的用量。所述的助流剂的质量分数可以为1.0-4.0％，例如2.0％。
在一些实施方式中，所述的润滑剂可以为药剂领域中常规的润滑剂，优选为可可脂肪、巴西棕榈蜡、水合二氧化硅(胶态二氧化硅)、氢氧化铝干凝胶、甘油脂肪酸酯、硅酸镁、轻质无水硅酸、结晶纤维素、硬化油、合成硅酸铝、白蜂蜡、氧化镁、酒石酸钠钾、蔗糖脂肪酸酯、硬脂酸、硬脂酸钙、硬脂酸镁、硬脂酸富马酸钠、硬脂醇和聚乙二醇40硬脂酸酯中的一种或多种，优选硬脂酸富马酸钠 或硬脂酸镁。
在一些实施方式中，所述的润滑剂的质量分数可以为1.0-4.0％，例如2％。
在一些实施方式中，所述的药物组合物2还进一步包括包衣剂。
在一些实施方式中，所述的包衣剂可为本领域此类药物中常规的包衣剂，优选为羟丙甲纤维素、甲基纤维素、乙基纤维素、甲基纤维素或羟丙基纤维素、聚乙烯醇、聚维酮、聚乙酸乙烯酯树脂、聚乙烯醇缩醛二乙氨基乙酸酯、甲基丙烯酸氨基烷基酯共聚物RS和丙烯酸乙酯-甲基丙烯酸甲酯共聚物分散体、蔗糖、甘露醇和欧巴代(商品名，OPADRY)中的一种或多种，优选为欧巴代。
在一些实施方式中，所述药物组合物2，其包含颗粒物，所述的颗粒物包含以如下的质量分数计的组分：30-45％无水奈拉替尼马来酸盐、7-28％共聚维酮、25-48％填充剂、1.0-8.0％崩解剂、0.5-4.0％助流剂和0.5-4.0％润滑剂；
所述的颗粒物中的所有组分的质量分数之和为100％；所述的质量分数为颗粒物中各组分的质量占各组分的总质量的质量百分比。
所述的药物组合物2中，所述的无水奈拉替尼马来酸盐可以无水奈拉替尼马来酸盐的晶型，其以衍射角为2θ表示的X-射线粉末衍射图在6.0±0.2°、7.3±0.2°、10.1±0.2°、12.1±0.2°、15.6±0.2°、17.3±0.2°和19.9±0.2°处有特征峰。所述的奈拉替尼马来酸盐的晶型的X-射线粉末衍射图可以基本如图1、2或3所示。
所述的药物组合物2中，所述的无水奈拉替尼马来酸盐的质量分数可以为35-42％，例如36％。
所述的药物组合物2中，所述的共聚维酮的质量分数可以为8-22％，例如21％。
所述的药物组合物2中，所述的填充剂可以为药剂领域中常规的填充剂，优选为糖醇和/或水溶胀性添加剂，进一步优选为甘露醇和微晶纤维素。
所述的糖醇优选为甘露醇、赤藓糖醇和木糖醇中的一种或多种，例如甘露醇。
所述的水溶胀性填充剂优选为预胶凝淀粉、胶凝淀粉、微晶纤维素(结晶纤维素)、玉米淀粉、羟丙基甲基纤维素(HPMC-K100LV)、硫酸钙、羧甲基淀粉钠、羧甲纤维素(羧甲基纤维素)、羧甲纤维素钙、交联羧甲纤维素钠(交联羧甲基纤维素钠)、大豆卵磷脂、低取代的羟丙基纤维素、黄蓍胶粉和膨润土中的或多种，例如微晶纤维素。
所述的药物组合物2中，所述的填充剂的质量分数可以为34-45％，例如37％。
所述的药物组合物2中，所述的崩解剂可以为药剂领域中常规的崩解剂，优选为己二酸、海藻酸、胶凝淀粉、羧甲基淀粉钠、羧甲纤维素、羧甲纤维素钙、羧甲纤维素钠、水合二氧化硅、柠檬酸钙、交联羧甲纤维素钠、交联聚维酮、轻质无水硅酸、结晶纤维素(微晶纤维素)、合成硅酸铝、小麦淀粉、米淀粉、乙酸邻苯二甲酸纤维素、硬脂酸钙、低取代的羟丙基纤维素、玉米淀粉、黄蓍胶粉、马铃薯淀粉、羟乙基甲基纤维素、羟丙基淀粉、预胶凝淀粉、富马酸单钠、聚维酮、无水柠檬酸、甲基纤维素和磷酸二氢钙中的一种或多种，更优选交联聚维酮，例如交联聚维酮XL-10。
所述的药物组合物2中，所述的崩解剂的质量分数可以为1.7-4.9％，例如2.0％。
所述的药物组合物2中，所述的助流剂可以为药剂领域中常规的助流剂，优选为水合二氧化硅(胶态二氧化硅)、凝胶二氧化硅、轻质无水硅酸、结晶纤维素、合成硅酸铝、氧化钛、硬脂酸、硬脂酸钙、硬脂酸镁、磷酸三钙、滑石粉、玉米淀粉和偏硅酸铝镁中的一种或多种，优选胶态二氧化硅或 凝胶二氧化硅。
所述的药物组合物2中，所述的助流剂的用量可以为药剂领域中常规的用量。所述的助流剂的质量分数可以为1.0-4.0％，例如2.0％。
所述的药物组合物2中，所述的润滑剂可以为药剂领域中常规的润滑剂，优选为可可脂肪、巴西棕榈蜡、水合二氧化硅(胶态二氧化硅)、氢氧化铝干凝胶、甘油脂肪酸酯、硅酸镁、轻质无水硅酸、结晶纤维素、硬化油、合成硅酸铝、白蜂蜡、氧化镁、酒石酸钠钾、蔗糖脂肪酸酯、硬脂酸、硬脂酸钙、硬脂酸镁、硬脂酸富马酸钠、硬脂醇和聚乙二醇40硬脂酸酯中的一种或多种，优选硬脂酸富马酸钠或硬脂酸镁。
所述的药物组合物2中，所述的润滑剂的质量分数可以为1.0-4.0％，例如2％。
所述的药物组合物2中，所述的颗粒物的组分优选包含颗粒物的内组分和颗粒物的外组分；
所述的颗粒物的内组分：30-45％无水奈拉替尼马来酸盐(例如35％、36％或42％)、7-28％共聚维酮(例如8％、21％或22％)、25-48％填充剂(例如34％、37％或45％)、1.0-8.0％崩解剂(例如2.4％)、1.0-4.0％助流剂(例如1％、2％或4％)和0.5-4.0％润滑剂(例如1％)；
所述的颗粒物的外组分：0-2.5％崩解剂和/或0-1％润滑剂，且所述的崩解剂和所述的润滑剂不同时为0。
在一实施方案中，所述的颗粒物由如下的质量分数的组分组成：上述的无水奈拉替尼马来酸盐(包括奈拉替尼马来酸盐的种类和质量分数)、上述的共聚维酮、上述的填充剂(包括填充剂的种类和质量分数)、上述的崩解剂(包括崩解剂的种类和质量分数)、上述的助流剂(包括助流剂的种类和质量分数)、上述的润滑剂(包括润滑剂种类和质量分数)和上述的包衣剂(包括包衣剂种类和质量分数)。
优选，所述的颗粒物由如下组(1)、组(2)或组(3)中的组分组成：
组(1)：所述的颗粒物的内组分：34.9％无水奈拉替尼马来酸盐、26.2％干露醇、8.3％微晶纤维素、21.7％共聚维酮、2.5％交联聚维酮XL-10、2.0％胶态二氧化硅和1.0％硬脂酸镁；
所述的颗粒物的外组分：2.5％交联聚维酮XL-10和1.0％硬脂酸镁；
组(2)：所述的颗粒物的内组分：42.3％无水奈拉替尼马来酸盐、31.7％干露醇、13.1％微晶纤维素、8.0％共聚维酮、2.0％交联聚维酮XL-10、2.0％胶态二氧化硅和1.0％硬脂酸镁；
所述的颗粒物的外组分：1.0％硬脂酸镁；
组(3)：所述的颗粒物的内组分：36.1％无水奈拉替尼马来酸盐、27.1％干露醇、8.6％微晶纤维素、22.4％共聚维酮、1.7％交联聚维酮XL-10、2.0％胶态二氧化硅和1.0％硬脂酸镁；
所述的颗粒物的外组分：1.0％硬脂酸镁。
所述的药物组合物2还可以进一步包括包衣剂。
所述的包衣剂可为本领域此类药物中常规的包衣剂，优选为羟丙甲纤维素、甲基纤维素、乙基纤维素、甲基纤维素或羟丙基纤维素、聚乙烯醇、聚维酮、聚乙酸乙烯酯树脂、聚乙烯醇缩醛二乙氨基乙酸酯、甲基丙烯酸氨基烷基酯共聚物RS和丙烯酸乙酯-甲基丙烯酸甲酯共聚物分散体、蔗糖、甘露醇和欧巴代(商品名，OPADRY)中的一种或多种，优选为欧巴代。
所述的包衣剂的用量可为本领域此类药物中常规的用量。所述的包衣剂与所述的药物颗粒的质量 比可为0.01:1-0.05:1，例如0.03:1、0.034:1或0.036:1。
所述的药物组合物2中，所述的药物颗粒组分由如下的质量分数的组分组成：上述的无水奈拉替尼马来酸盐(包括奈拉替尼马来酸盐的种类和质量分数)、上述的共聚维酮、上述的填充剂(包括填充剂的种类和质量分数)、上述的崩解剂(包括崩解剂的种类和质量分数)、上述的助流剂(包括助流剂的种类和质量分数)、上述的润滑剂(包括润滑剂种类和质量分数)和上述的包衣剂(包括包衣剂种类和质量分数)。
所述的药物组合物2由如下组(a)、组(b)或组(c)中的组分组成：
组(a)：颗粒物和欧巴代，所述的欧巴代与所述的颗粒物的质量比为0.03：1；
所述的颗粒物的内组分：34.9％无水奈拉替尼马来酸盐、26.2％干露醇、8.3％微晶纤维素、21.7％共聚维酮、2.5％交联聚维酮XL-10、2.0％胶态二氧化硅和1.0％硬脂酸镁；
所述的颗粒物的外组分：2.5％交联聚维酮XL-10和1.0％硬脂酸镁；
组(b)：颗粒物和欧巴代，所述的欧巴代与所述的颗粒物的质量比为0.034：1；
所述的颗粒物的内组分：42.3％无水奈拉替尼马来酸盐、31.7％干露醇、13.1％微晶纤维素、8.0％共聚维酮、2.0％交联聚维酮XL-10、2.0％胶态二氧化硅和1.0％硬脂酸镁；
所述的颗粒物的外组分：1.0％硬脂酸镁；
组(c)：颗粒物和欧巴代，所述的欧巴代与所述的颗粒物的质量比为0.036：1；
所述的颗粒物的内组分：36.1％无水奈拉替尼马来酸盐、27.1％干露醇、8.6％微晶纤维素、22.4％共聚维酮、1.7％交联聚维酮XL-10、2.0％胶态二氧化硅和1.0％硬脂酸镁；
所述的颗粒物的外组分：1.0％硬脂酸镁。
本发明还提供了一种上述的药物组合物2的制备方法，其包括如下步骤：将如下以质量分数计的原料进行造粒得到颗粒物；
所述的原料包含30-45％无水奈拉替尼马来酸盐、7-28％共聚维酮、25-48％填充剂、1.0-8.0％崩解剂、0.5-4.0％助流剂和0.5-4.0％润滑剂；所述的颗粒物中的所有组分的质量分数之和为100％；所述的质量分数为颗粒物中各组分的质量占各组分的总质量的质量百分比。
本发明中，所述的奈拉替尼马来酸盐优选为无水奈拉替尼马来酸盐，所述的无水奈拉替尼马来酸盐均同前所述(包含种类和含量)。
本发明中，所述的共聚维酮、所述的填充剂(包含种类和含量)、所述的崩解剂(包含种类和含量)、所述的助流剂(包含种类和含量)和所述的润滑剂(包含种类和含量)均同前所述。
本发明中，所述的造粒的方法可以为本领域常规的方法，优选为干法造粒。所述的干法造粒的条件和操作均为制剂领域常规的条件，本发明特别优选如下的条件和操作：
所述的干法造粒中，所述的干法造粒采用干法制粒机，所述的干法制粒机的优选如下参数：
所述的干法制粒机的压辊压力优选为65-100bar，例如80bar。
所述的干法制粒机的送料速度优选为40-50rpm。
所述的干法制粒机的压辊速度优选为5-15rpm，例如6rpm。
所述的干法制粒机的整粒速度优选为50-500rpm，例如100rpm。
所述的干法制粒机的筛网孔径优选为0.6-1.2mm，例如0.8mm。
所述的药物组合物的制备方法还可进一步包含包衣步骤。
所述的包衣步骤中，所述的药物组合物的含水量≤3％。
所述的包衣剂的种类和用量均同前所述。
所述的包衣步骤中，采用包衣机进行包衣，所述的包衣机优选如下的参数：
所述的包衣机的进风温度优选为55-60℃。
所述的包衣机的雾化压力优选为0.10-0.30MPa。
所述的包衣机的蠕动泵转速优选为2.0-12.0rpm。
所述的包衣机的出风温度优选为35-42℃。
在本发明一实施方案中，所述的药物组合物2的制备方法优选包括如下步骤：
步骤1：将颗粒物的内原料通过干法制粒得到颗粒物1；
颗粒物的内原料：30-45％无水奈拉替尼马来酸盐、7-28％共聚维酮、25-48％填充剂、1-8％崩解剂、1-4％助流剂和0.5-4％润滑剂；
步骤2：将颗粒物1与颗粒物的外原料进行压片(例如将颗粒物1与颗粒物1的外原料混合，混合物用压片机(10.5mm*5.5mm异形冲模)压成片剂)，得到颗粒物：
所述的颗粒物外原料：0-2.5％崩解剂和/或0-1％润滑剂，且所述的崩解剂和所述的润滑剂不同时为0。
本发明还提供了一种通过上述药物组合物2的制备方法制得到药物组合物2。
本发明还提供了一种药物固体制剂，其包含上述药物组合物2和药学上可接受的辅料。
所述的固体制剂可以为片剂、粒剂、粉剂(包括精细的粒剂)，或胶囊剂，例如片剂。
当所述的固体制剂为片剂时，当本发明所述的药用组合物2采用片剂时，可通过压制如上所述获得的颗粒得到片剂。
其中，所述的压制的压力可为10-20kN。所述的片剂的形状无特殊限制，例如扁豆形、圆盘形、圆形、椭圆形(如囊片)、泪滴形或多角形(如三角形或菱形)。
可通过盘式包衣机(pan coater)喷洒包衣剂的混悬液/溶液的方式将制备的片剂进行包衣。在包衣完成后，可通过干燥过程将最终片剂的水分含量控制在3％以内。干燥温度可选择40-80℃，例如40-50℃。
在压制过程中控制压制的环境湿度保证最终素片的含水量小于3％(3％以下)，并通过对最终的组合物采用真空干燥法处理保证最终组合物的含水量小于3％。
本发明还提供了一种物质A在制备EGFR抑制剂中的应用，所述的物质A为上述的药物组合物2或上述的药物固体制剂。
在一些实施方式中，所述物质A还可为上述如式I所示化合物或其药学上可接受的盐。
本发明还提供了一种物质A在制备预防或治疗与EGFR相关疾病的药物中的应用，所述的物质A为上述的药物组合物2或上述的药物固体制剂。
在一些实施方式中，所述物质A还可为上述如式I所示化合物或其药学上可接受的盐。
所述的与EGFR相关疾病优选为乳腺癌、卵巢癌、上皮样瘤、结肠癌，前列腺癌、肾癌、膀胱癌、喉癌、食道癌、胃癌或肺癌。
本发明还提供了一种药物组合物3，其包括物质X和物质Y；
所述物质X为马来酸奈拉替尼，所述物质Y为化合物CVL218或其药学上可接受的盐，所述化合物CVL218的结构如下所示：
本发明还提供了一种药物组合物4，其包括物质M和物质N；
所述物质M为马来酸奈拉替尼，所述物质N为化合物CVL237或其药学上接受的盐，所述化合物CVL237的结构如下所示：
本发明还提供了药物组合物3在制备预防或治疗胆管癌药物中的应用。
本发明还提供了药物组合物4在制备预防或治疗胆管癌药物中的应用。
本发明中，术语“药学上可接受的盐”是指本发明化合物与相对无毒的、药学上可接受的酸制备得到的盐。
本发明中，术语“颗粒物”是指粒径在30目至200目之间的颗粒物。
本发明中，术语“药用辅料”可为药物生产领域中广泛采用的那些辅料。辅料主要用于提供一个安全、稳定和功能性的药物组合物，还可以提供方法，使受试者接受给药后活性成分以所期望速率溶出，或促进受试者接受组合物给药后活性成分得到有效吸收。所述的药用辅料可以是惰性填充剂，或者提供某种功能，例如稳定该组合物的整体pH值或防止组合物活性成分的降解。所述的药用辅料可以包括下列辅料中的一种或多种：粘合剂、助悬剂、乳化剂、稀释剂、填充剂、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂和甜味剂。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明所述的奈拉替尼或其可药用盐或溶剂合物等可按照US6002008、US6288082、US6297258、US6384051和US7399865中所述方法获得，或通过商业途径购得。
本发明所述的马来酸奈拉替尼参比制剂为Puma Biotechnology公司生产的马来酸奈拉替尼原研药(包衣片)。
本发明的积极进步效果在于：本发明的药物组合物的稳定性好以及达到与原研参比制剂相同的体外溶出效果；而且本发明的制备方法得到的具有产品粒径分布均一稳定、片重差异小以及片硬度易于控制的优选。
附图说明
图1为实施例1的XRPD图谱(无水晶型)。
图2为实施例2的XRPD图谱(无水晶型)。
图3为实施例3的XRPD图谱(无水晶型)。
图4为参比制剂的XRPD图谱(有水晶型)。
图5为实施例1、实施例2和参比制剂的溶出曲线图。
图6为实施例4的XRPD图谱(无水晶型)。
图7为实施例5中放大批次1的XRPD图谱(无水晶型)。
图8为实施例5中放大批次2的XRPD图谱(无水晶型)。
图9为实施例5中放大批次3的XRPD图谱(无水晶型)。
图10为实施例5中放大批次1加速6个月实验后的XRPD图谱(无水晶型)。
图11为实施例5中放大批次2加速6个月实验后的XRPD图谱(无水晶型)。
图12为实施例5中放大批次3加速6个月实验后的XRPD图谱(无水晶型)。
图13为实施例5中放大批次1长期12个月实验后的XRPD图谱(无水晶型)。
图14为实施例5中放大批次2长期12个月实验后的XRPD图谱(无水晶型)。
图15为实施例5中放大批次3进行长期12个月实验后的XRPD图谱(无水晶型)。
图16为实施例5中放大批次和参比制剂的溶出曲线图。
图17为实施例5中放大批次加速6个月实验后和参比制剂的溶出曲线图。
图18为实施例5中放大批次进行长期12个月实验后的溶出曲线图。
图19为生物学实施例中小鼠体重变化曲线。
图20为生物学实施例中肿瘤体积变化曲线。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
制备例1
(E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-3-氰基-7-乙氧基喹啉-6-基)-4-(3-(二甲基氨基)氮杂环丁烷-1-基)丁-2-烯酰胺的合成(化合物A0901)
步骤1：(E)-4-溴-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-3-氰基-7-乙氧基喹啉-6-基)丁-2-烯酰胺
将(E)-4-溴丁-2-烯酸(1.1g，6.70mmol)溶解于二氯甲烷(10mL)中，冰浴冷却，加入草酰氯(850mg， 6.70mmol),控温10℃下搅拌4小时，再加入6-氨基-4-{[3-氯-4-(吡啶-2-基甲氧基)苯基]氨基}-7-乙氧基喹啉-3-腈(2.5g，5.60mmol)和碳酸二钾(2.32g，16.8mmol)的乙腈(50mL)溶液中，然后将反应在10℃下搅拌1小时。将反应混合物倒入水(100mL)中，用乙酸乙酯(150mL×2)萃取。用盐水(100mL)洗涤合并的有机层，用无水硫酸钠干燥，过滤，浓缩，得到所需化合物中间体2(2.30g)，为黄色固体。LC-MS(ESI,m/z)592.1[M+H]+.1HNMR(400MHz,DMSO-d6)δ9.94-9.70(m,2H),9.00-8.89(m,1H),8.61-8.53(m,2H),7.90-7.86(m,1H),7.59(d,J＝7.6Hz,1H),7.44-7.34(m,3H),7.29-7.22(m,2H),6.96-6.70(m,1H),5.34(s,2H),4.35-4.27(m,2H),3.36(br s,2H),1.47(t,J＝6.8Hz,3H).
步骤2：(E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-3-氰基-7-乙氧基喹啉-6-基)-4-(3-(二甲基氨基)氮杂环丁烷-1-基)丁-2-烯酰胺
向(2E)-4-溴-N-(4-{[3-氯-4-(吡啶-2-基甲氧基)苯基]氨基}-3-氰基-7-乙氧基喹啉-6-基)丁-2-烯酰胺(100mg，0.169mmol)在DMF(3mL)中的溶液中加入N，N-二甲基氮杂环丁烷-3-胺盐酸盐(58.4mg，0.337mmol)和乙基二异丙胺(65.4mg，0.16mmol)将反应混合物倒入水(10mL)中，用乙酸乙酯(10mL×2)萃取。用盐水(10mL)洗涤合并的有机层，用无水硫酸钠干燥并过滤。浓缩，柱层析纯化得100mg，为黄色固体。LC-MS(ESI，m/z)612.1[M+H]+.1HNMR(400MHz,DMSO-d6)δ9.64(s,1H),9.57(s,1H),8.95(s,1H),8.60(d,J＝4.4Hz,1H),8.48(s,1H),7.90-7.86(m,1H),7.59(d,J＝7.2Hz,1H),7.40(s,2H),7.38-7.36(m,1H),7.26(d,J＝8.8Hz,1H),7.21-7.19(m,1H),6.71-6.66(m,1H),6.61-6.57(m,1H),5.29(m,2H),4.32(q,J＝6.8Hz,2H),3.69-3.61(m,2H),3.52-3.42(m,2H),3.27-3.09(m,3H),2.26(br s,6H),1.47(t,J＝6.8Hz,3H).
制备例2
(E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-3-氰基-7-乙氧基喹啉-6-基)-4-(3，3-二氟氮杂环丁烷-1-基)丁-2-烯酰胺(化合物A0902)
向(2E)-4-溴-N-(4-{[3-氯-4-(吡啶-2-基甲氧基)苯基]氨基}-3-氰基-7-乙氧基喹啉-6-基)丁-2-烯酰胺(100毫克，83％纯度，0.169mmol)的DMF(3mL)溶液中加入碳酸二钾(70.0毫克，0.506mmol)和3-氟氮杂环丁烷盐酸盐(25.5毫克，0.337mmol将反应混合物倒入水(10mL)中，用乙酸乙酯(10mL×2)萃取。用盐水(10mL)洗涤合并的有机层，用无水硫酸钠干燥并过滤。浓缩滤液，柱层析纯化得到110mg，黄色固体。LC-MS(ESI，m/z)587.2[M+H]+.
制备例3
(E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-3-氰基-7-乙氧基喹啉-6-基)-4-(3，3-二氟氮杂环丁烷-1-基)丁-2-烯酰胺(化合物A0903)
向(2E)-4-溴-N-(4-{[3-氯-4-(吡啶-2-基甲氧基)苯基]氨基}-3-氰基-7-乙氧基喹啉-6-基)丁-2-烯酰胺(100毫克，83％纯度，0.169mmol)的DMF(3mL)溶液中加入碳酸二钾(70.0毫克，0.506mmol)和3，3-二氟氮杂环丁烷盐酸盐(43.7毫克，0.337mmol将反应混合物倒入水(10mL)中，用乙酸乙酯(10mL×2)萃取。用盐水(10mL)洗涤合并的有机层，用无水硫酸钠干燥并过滤。浓缩滤液，柱层析纯化得到120mg，黄色固体。LC-MS(ESI，m/z)605.0[M+H]+.1HNMR(400MHz,DMSO-d6)δ9.61(s,1H),9.52(s,1H),8.95(s,1H),8.60(d,J＝4.0Hz,1H),8.47(s,1H),7.90-7.85(m,1H),7.58(d,J＝7.6Hz,1H),7.39-7.36(m,3H),7.25(d,J＝8.8Hz,1H),7.20-7.18(m,1H),6.76-6.70(m,1H),6.60-6.56(m,1H),5.28(s,2H),4.32(q,J＝6.8Hz,2H),3.70-3.63(m,4H),3.41(d,J＝4.0Hz,2H),1.47(t,J＝7.2Hz,3H).19F NMR(376MHz,DMSO-d6)-97.41(s,2F)
制备例4
(E)-N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-3-氰基-7-乙氧基喹啉-6-基)-4-(甲磺酰基)-丁-2-烯酰胺(化合物A0904)
在25℃下，向(2E)-4-溴-N-(4-{[3-氯-4-(吡啶-2-基甲氧基)苯基]氨基}-3-氰基-7-乙氧基喹啉-6-基)丁-2-烯酰胺(180mg，0.304mmol)在二恶烷(4mL)和水(2mL)中的溶液中加入亚甲酸钠(46.5毫克，0.455mmol)，然后将混合物在100℃下搅拌将反应混合物冷却至25℃，倒入水(10mL)中，用EtOAc(10mL×2)萃取。用盐水(10mL)洗涤合并的有机层，用无水硫酸钠干燥，过滤，浓缩，柱层析纯化得220mg，为黄色固体。LC-MS(ESI，m/z)592.0[M+H]+.1H NMR(400MHz,DMSO-d6)δ9.73(s,1H),9.63(s,1H),8.93(s,1H),8.60(d,J＝5.2Hz,1H),8.48(s,1H),7.90-7.85(m,1H),7.58(d,J＝8.0Hz,1H),7.40(d,J＝2.0Hz,2H),7.39-7.36(m,1H),7.27-7.25(m,1H),7.22-7.19(m,1H),6.76-6.74(m,2H),5.29(s,2H),4.32(q,J＝7.2Hz,2H),4.20(d,J＝5.2Hz,2H),3.02(s,3H),1.47(t,J＝7.2Hz,3H).
制备例5
N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-3-氰基-7-乙氧基喹啉-6-基)-2-((3-(二甲基氨基)氮杂环丁烷-1-基)甲基)丙烯酰胺的制备(化合物A0905)
步骤1：2-((3-(二甲基氨基)氮杂环丁烷-1-基)甲基)丙烯酸
将N,N-二甲基氮杂环丁烷-3-胺(0.33g,2.00mmol)和2-(溴甲基)丙烯(0.35g,2.00mmol)溶于N，N-二甲基乙酰胺(20mL)中，然后加入DIEA(1ml,6.00mmol)。反应混合物在室温条件下搅拌反应2小时。将反应液浓缩后直接反相纯化(0-20％乙腈)得到目标产物(白色固体0.20g,收率55.4％.)。LC-MS(ESI,m/z)185.2[M+H]+；1H NMR(400MHz,DMSO-d6)δ12.06(s,1H),6.30(s,1H),5.97(s,1H),3.99-3.84(m,7H),2.54(s,6H).
步骤2：N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-3-氰基-7-乙氧基喹啉-6-基)-2-((3-(二甲基氨基)氮杂环丁烷-1-基)甲基)丙烯酰胺的制备
将6-氨基-4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-7-乙氧基喹啉-3-腈(0.11g,0,25mmol)和2-((3-(二甲基氨基)氮杂环丁烷-1-基)甲基)丙烯酸(0.10g，0.5mmol)溶于1.5mL DMSO,然后加入DIEA(0.13ml,0.75mmol)。将HOPO(0.03g,0.28mmol)和EDCI(0.05g,0.28mmol)溶于1.5ml的DCM。将反应加热到50℃,搅拌反应4小时。将反应液浓缩后，水(5ml)淬灭,乙酸乙酯(5ml*3)萃取，食盐水(10ml*3)水洗，无水硫酸钠干燥。有机相旋干送制备高效液相色谱(0.1％FA)得到目标化合物(白色固体，121.00mg,收率79.08％)。LC-MS(ESI,m/z)612.2[M+H]+；1H NMR(400MHz,MeOD-d4)δ8.67(d,J＝4.8Hz,1H),8.62(s,1H),8.12-8.08(m,1H)7.84(d,J＝8.0Hz,1H),7.59-7.56(m,2H),7.40-7.25(m,4H),5.55(d,J＝8.0Hz,2H),5.42(s,2H),4.73(s,1H),4.62(S,1H),4.43-4.09(m,9H),2.83(s,6H)1.61(t,J＝7.2Hz,3H).
制备例6
N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-3-氰基-7-乙氧基喹啉-6-基)-2-((4-(二甲基氨基)哌啶-1-基)甲基)丙烯酰胺(化合物A0906)的制备
步骤1：2-((4-(二甲氨基)哌啶-1-基)甲基)丙烯酸的制备
将N,N-二甲基哌啶-4-胺(0.40g,2.00mmol)和2-(溴甲基)丙烯(0.33g,2.00mmol)溶于N，N-二甲基乙酰胺(20mL)中，然后加入DIEA(1ml,6.0mmol)。反应混合物在室温条件下搅拌反应2小时。将反应液浓缩后直接反相纯化(0-20％乙腈)得到目标产物(白色油状物，0.30g,收率56.6％.)。LC-MS(ESI,m/z)213.4[M+H]+；1H NMR(400MHz,MeOD-d1)δ8.38(s,1H),6.27(s,1H),5.76(s,1H),3.69(s,2H),3.58-3.52(m,1H),3.45-3.30(m,4H),2.83-2.81(m,6H),2.30-2.20(m,4H).
步骤2：N-(4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-3-氰基-7-乙氧基喹啉-6-基)-2-((4-(二甲基氨基)哌啶-1-基)甲基)丙烯酰胺的制备
将6-氨基-4-((3-氯-4-(吡啶-2-基甲氧基)苯基)氨基)-7-乙氧基喹啉-3-腈(0.09g,0.20mmol)和2-((4-(二甲氨基)哌啶-1-基)甲基)丙烯酸(0.06g，0.30mmol)溶于1.0mL DMSO,然后加入DIEA(0.1ml,0.6mmol)。将2-羟基吡啶-N-氧化物(0.02g,0.22mmol)和1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.04g,0.22mmol)溶于1.0ml的DCM。将反应加热到50℃,搅拌反应4小时。将反应液浓缩后，水(5ml)淬灭,乙酸乙酯(5ml*3)萃取，食盐水(10ml*3)水洗，无水硫酸钠干燥。有机相旋干送制备高效液相色谱(0.1％FA)得到目标化合物(白色固体，35.00mg,收率79.08％)。LC-MS(ESI,m/z)640.2[M+H]+；1H NMR(400MHz,MeOD-d4)δ8.54(d,J＝4.8Hz,1H),8.51(s,1H),7.99-7.94(m,1H),7.72(d,J＝8.0Hz,1H),7.49(d,J＝2.4Hz,1H),7.46-7.43(m,1H),7.32-7.29(m,1H),7.20-7.14(m,4H),5.30(s,2H),5.27(s,1H),5.19(s,1H),4.64(s,1H),4.32-4.27(m,2H),4.20(s,1H),4.11(s,2H),3.41-3.34(m,1H),3.20(s,1H),2.77(s,6H),2.80(s,1H),2.02(s,2H),1.51-1.48(m,5H).
效果例A抑制剂体外药效学实验
本实验采用CellTiter-Glo(CTG)试剂盒，它是一种均质法细胞活力检测方法，通过对ATP的定量来测定培养细胞的细胞活力。因为灵敏度高、操作流程简便而成为目前主流的细胞活力检测试剂盒。本实验的目的是利用CTG方法评估6个受试化合物对1株EGFR细胞株的细胞增殖的影响，以afatinib为对照化合物。
1)实验操作
a)所有细胞株于37℃,5％CO2条件下培养于完全培养基。
b)收获处于对数生长期的细胞并采用血小板计数器进行细胞计数。用台盼蓝排斥法检测细胞活力，确保细胞活力在90％以上。
c)使用完全培养基调整细胞密度，随后接种于96孔细胞培养板，每孔接种90μL，共3000个细胞。
d)将96孔板中的细胞置于37℃、5％CO2条件下培养。
e)配制10倍药物溶液，检测最高浓度为1μM，9个浓度，4倍稀释，然后转移连续稀释化合物各10μL至96孔细胞板的相应实验孔中，每个药物浓度设置三个复孔。
f)将已加药的96孔板中的细胞置于37℃、5％CO2条件下继续培养72小时，之后进行CTG分析。
g)融化CTG试剂并平衡细胞板至室温30分钟。
h)每孔加入等体积的CTG溶液。
i)在定轨摇床上振动5分钟使细胞裂解。
j)将细胞板放置于室温20分钟以稳定冷光信号。
k)读取冷光值，收集数据。
2)数据分析：
使用GraphPad Prism 7.0软件分析数据，利用非线性S曲线回归来拟合数据得出剂量-效应曲线，并由此计算IC50值。
细胞存活率(％)＝(Lum待测药-Lum培养液对照)/(Lum溶剂对照-Lum培养液对照)×100％.
3)受试化合物抗细胞增殖效果
本发明涉及的颗粒物或组合物水分测定的方法，为红外快速水分测定仪测定(测定温度105℃)，该方法属于本领域技术人员所熟知的测定水分的常用方法，广泛应用于颗粒剂、片剂、粉剂等中水分含量测定。以下马来酸奈拉替尼为结合1个马来酸盐的奈拉替尼。
实施例1
马来酸奈拉替尼片规格40mg(按C30H29ClN6O3计)，处方如表1所示：
表1马来酸奈拉替尼片实施例1处方

按以上处方，使用干法制粒机依照表2中的参数设定进行制粒。
表2干法制粒机参数
继续将制得的颗粒，与颗粒外组分交联聚维酮XL-10和硬脂酸镁混合，将混合物用压片机(10.5mm*5.5mm异形冲模)压成片剂，硬度控制在70～140N。随后，用高效包衣机将这些片剂用主要由聚乙烯醇组成的15w/v％包衣剂混悬液(OPADRY)薄膜包衣，使在片剂中包衣的量为4.15mg。片剂的X-射线粉末衍射图谱为图1。
包衣过程中，依照表3参数控制包衣过程。使得包衣过程中片剂的最大含水量控制在3％以下。
表3包衣过程参数设定
实施例2
马来酸奈拉替尼片处方：规格40mg(按C30H29ClN6O3计)，如表4所示。
表4马来酸奈拉替尼片实施例2处方
按以上处方，使用干法制粒机依照表5中的参数设定进行制粒。
表5干法制粒机参数

继续将制得的颗粒，与颗粒外组分硬脂酸镁混合，将混合物用压片机(10.5mm*5.5mm异形冲模)压成片剂，硬度控制在70～140N。随后，用高效包衣机将这些片剂用主要由聚乙烯醇组成的15w/v％包衣剂混悬液(OPADRY)薄膜包衣，使在片剂中包衣的量为4.15mg。片剂的X-射线粉末衍射图谱为图2。
包衣过程中，依照表3参数控制包衣过程。使得包衣过程中片剂的最大含水量控制在3％以下。
实施例3
马来酸奈拉替尼片规格40mg(按C30H29ClN6O3计)，如表6所示。
表6马来酸奈拉替尼片处方三
按以上处方，使用干法制粒机依照表7中的参数设定进行制粒。
表7干法制粒机参数
继续将制得的颗粒，与颗粒外组分硬脂酸镁混合，将混合物用压片机(10.5mm*5.5mm异形冲模)压成片剂，硬度控制在70～140N。随后，用高效包衣机将这些片剂用主要由聚乙烯醇组成的15w/v％包衣剂混悬液(OPADRY)薄膜包衣，使在片剂中包衣的量为4.15mg。片剂的X-射线粉末衍射图谱为图3。
包衣过程中，依照表3参数控制包衣过程。使得包衣过程中片剂的最大含水量控制在3％以下。
实施例4
马来酸奈拉替尼片规格40mg(按C30H29ClN6O3计)，如下表8所示。
表8马来酸奈拉替尼片处方四：

按以上处方，使用干法制粒机依照下表9中的参数设定进行制粒。
表9干法制粒机参数：
继续将制得的颗粒，与颗粒外组分硬脂酸镁混合，将混合物用压片机(10.5mm*5.5mm异形冲模)压成片剂，硬度控制在70～140N。随后，用高效包衣机将这些片剂用主要由聚乙烯醇组成的15w/v％包衣剂混悬液(OPADRY)薄膜包衣，使在片剂中包衣的量为4.15mg。片剂的X-射线粉末衍射图谱为图6。
包衣过程中，依照表3参数控制包衣过程。使得包衣过程中片剂的最大含水量控制在3％以下。
实施例5：
将实施例4所述的处方工艺，到生产车间进行放大生产，批量由实验室规模的几百片放大至10万片，且连续生产3批，批号分别为放大批次1、放大批次2、放大批次3。其处方见下表10。
表10马来酸奈拉替尼片处方五：
按以上处方，使用干法制粒机依照下表11中的参数设定进行制粒。
表11干法制粒机参数：
继续将制得的颗粒，与颗粒外组分硬脂酸镁混合，将混合物用压片机(10.5mm*5.5mm异形冲模)压成片剂，硬度控制在70～140N。随后，用高效包衣机将这些片剂用主要由聚乙烯醇组成的15w/v％包衣剂混悬液(OPADRY)薄膜包衣，使在片剂中包衣的量为4.15mg。片剂的X-射线粉末衍射图谱为图7-9。
包衣过程中，依照表3参数控制包衣过程。使得包衣过程中片剂的最大含水量控制在3％以下。
效果实施例：
对实施例1、2、3的马来酸奈拉替尼片按各处方进行中试放大。按实施例1、2、3进行中试放大。将这三个批次的马来酸奈拉替尼片与参比制剂进行对比试验。参比制剂选择Puma Biotechnology马来酸奈拉替尼原研药(包衣片)。
效果实施例1：有关物质试验
对实施例1、2、3、参比制剂第一批次的有关物质进行检测，检测结果见表12。实施例3得到的两批马来酸奈拉替尼片的降解杂质(杂质1)、总杂都比参比制剂中的小。
表12有关物质检测结果
效果实施例2：水分和晶型检测结果
对实施例1、2、3、参比制剂第一批次的水分和晶型进行检测，检测结果见表13。
表13水分和晶型检测结果
效果实施例3：稳定性考察
对实施例1、2、3、参比制剂第一批次进行稳定性放样，考察降解杂质的增加情况。结果见表14。
表14马来酸奈拉替尼的稳定性考察中降解杂质的增加情况

由上表看，在加速6个月后，实施例1、2、3的降解杂质含量小于参比制剂，且符合质量标准≤1.5％，而参比制剂已经超标。可见，本发明的片剂稳定性良好。
效果实施例4：溶出曲线考察
溶出曲线依照溶出度与释放度测定法(中国药典2020年版四部通则0931第二法)为基础开展。
溶出曲线的条件为桨法pH1.2、500mL、50rpm及桨法pH3.0、75rpm、900mL。经5-60分钟的各个时间点取样，取溶出液适量，滤过，至少弃去2ml初滤液，取续滤液。取马来酸奈拉替尼对照品适量，精密称定，加溶出介质超声溶解并稀释制成每1ml中约含奈拉替尼(按C30H29ClN6O3计)44μg的溶液，作为对照品溶液。照高效液相色谱法(中国药典2020年版四部通则0512)，用十八烷基硅烷键合硅胶为填充剂(推荐Waters Xbridge C18，4.6mm×150mm，5μm或效能相当的色谱柱)；以0.1％三氟乙酸溶液-甲醇(67:33)为流动相；检测波长为266nm；柱温为40℃，流速为1.5ml/min，运行时间为10分钟，进样体积10μl。精密量取供试品溶液和对照品溶液注入液相色谱仪，记录色谱图。按外标法以奈拉替尼峰面积计算，计算每片每个时间点的溶出量，采用相似因子比较法与参比制剂第一批次进行f2值的比较。
上述公式中n为时间点，Rt是参比制剂药物释放平均百分数，Tt是受试制剂药物释放平均百分数。f2值大于等于50的，视为受试制剂与参比制剂的溶出相似。具体溶出数据见表15-16。
表15各个实施例在pH1.2(50rpm-500mL)介质的溶出数据
表16各个实施例在pH3.0(75rpm-900mL)介质溶出数据
本发明中的各个实施例产品均在具有区分力的溶出曲线测试中，显示了与参比制剂相似的溶出行为(相似因子f2值大于等于50)，具有等效的体内生物活性。
效果实施例5：
对实施例1、2、3的马来酸奈拉替尼片制备过程中的总混颗粒进行了考察，见表17、表18、表19。实施例1、2和参比制剂第一批次的溶出曲线图如图5所示。
A+2.2S测试方法：取供试品10片，以100表示的标示量与测定均值之差的绝对值为A，标准差为S，A+2.2S≤15.0表示产品含量均匀度符合要求。
表17总混颗粒混合均匀度考察结果
表18素片重差异和硬度检测结果
表19包衣片各项指标检验结果
由以上结果说明，本发明经干法制粒工艺后得到的总混颗粒含量均匀，流动相良好，不影响压片工序的物料的可压性和流动相。
效果实施例6：
对实施例4制备的片剂进行考察，结果见表20。
表20实施例4检验结果
由以上结果说明，实施例4制备的片剂各指标与实施例1-3相当。
效果实施例7：
对实施例5放大生产的3批进行考察。对生产过程中进行监控，颗粒粒径结果见表21，混合均匀度结果见表22，片重差异和硬度结果见表23。
表21颗粒粒径结果
表22混合均匀度结果
表23片重差异和硬度结果
由以上结果说明，按照本发明生产的3批放大批次，生产过程中，颗粒粒径分布均匀，3批之间无显著差异，颗粒的混合均匀度符合要求，说明物料均匀，可用于后续压片。压片过程中，片重差异、硬度符合要求，说明物料可压性很好。
效果实施例8
检测实施例5放大生产的3批产品的含量、有关物质、水分，结果见表24。
表24含量、有关物质、水分检测结果
由以上结果说明，按照本发明生产的3批产品的有关物质、水分、含量等均符合要求，3批之间无显著差异，说明按照本发明放大生产的产品质量均匀、合格。
效果实施例9
对实施例5放大生产的3批制剂进行稳定性考察，考察条件分别为加速(温度40℃±2℃，相对湿度75％RH±5％RH)、长期(温度25℃±2℃，相对湿度60％RH±5％RH)，加速试验的取样时间点为1、2、3、6月，长期取样的时间点为3、6、9、12月。考察指标为有关物质、含量、水分、晶型和溶出曲线。参比制剂选择Puma Biotechnology马来酸奈拉替尼原研药(包衣片)。
3批放大批次加速6个月的X-射线粉末衍射图谱为图10-12，长期12月的X-射线粉末衍射图谱为图13-15，晶型未发生变化。
对尚未进行加速实验和长期实验，直接制备得到的三批放大批次进行溶出考察，其溶出曲线结果见图16，同时对比参比制剂第二批次，三批溶出曲线结果相似，其与参比相似，说明按照本说明生产的产品与参比质量具有相似性。
3批放大批次加速6个月的溶出曲线见图17，长期12月的溶出曲线见图18，并同步与参比制剂第二批次的溶出曲线进行对比，3批产品溶出特征未发生变化，与参比制剂相似。
3批放大批次的加速稳定性实验和长期稳定性实验中的有关物质、含量、水分的稳定性结果见表25-30，并同步与参比制剂第二批次的稳定性结果进行对比(表31-32)。
表25放大批次1加速稳定性结果
表26放大批次2加速稳定性结果

表27放大批次3加速稳定性结果
表28放大批次1长期稳定性结果
表29放大批次2长期稳定性结果
表30放大批次3长期稳定性结果
表31参比制剂加速稳定性结果
表32参比制剂长期稳定性结果
由以上结果说明，按照本发明放大批量生产的3批制剂稳定性好，批间差异较小、质量均一。与参比制剂相比，杂质比参比制剂更小。
对比例1-5及效果对比例1-5：
将下表33中的粘合剂的种类或含量替换实施例1中的共聚维酮或其含量，其他均同实施例1。将得到的产品按照效果实施例4的方法测试产品的溶出情况，测试结果如表34和35所示。参比制剂为第三批次Puma Biotechnology马来酸奈拉替尼原研药(包衣片)。
表33粘合剂筛选种类和用量信息
表34 pH1.2(50rpm-500mL)介质溶出曲线结果
表35 pH3.0(70rpm-900mL)介质溶出曲线结果
由筛选结果可知，使用共聚维酮S630用量为3.0％、6.5％、羟丙基纤维素HPC-L(用量15％)、聚维酮K25(用量为8％)、羟丙纤维素(用量为8％)制备的样品的溶出曲线与参比制剂均不相似，与原研体内生物等效的风险大。
生物学实施例
(A009即为马来酸奈拉替尼，CVL218为专利CN103242273B中化合物CVL237为化合物)
1.胆管癌PDX模型LD1-0060-200791体外抗增殖实验。
从荷瘤鼠皮下手术摘取肿瘤组织，浸没于HBSS缓冲液中。生物安全柜中去除非肿瘤组织和坏死组织，将组织切成1-3立方毫米小块，使用胶原酶37摄氏度消化肿瘤块1-2小时。通过筛网收集单细胞悬液。1200rpm离心3分钟去除上清。使用无血清培养基重悬细胞并计数，调整细胞浓度为 1.11×105/mL。分别使用BIO-MPM-1培养基稀释1000×高浓度药物储液至20×中间浓度。每个96孔板孔中分别加入7.5μL不同浓度的20×药物或含2％DMSO的BIO-MPM-1(具体浓度设置范围如下表所示)，使每孔的DMSO的最终浓度为0.2％。每孔加入135μL细胞悬液检测培养前细胞的ATP含量37摄氏度细胞培养箱中连续培养6天，每孔加入50μL CTG试剂，混匀反应后，取80μL于多功能酶标仪中检测ATP含量。通过读板仪对每孔信号做记录，用于绘制抑制曲线和计算相关参数如IC50。每个药物浓度对应的抗肿瘤增殖抑制率使用Excel软件计算，公式是：
抑制率(％)＝((VControl-VBlank)-(V药物处理组-VBlank))/(VControl-VBlank)×100％
抑制曲线图使用Xlfit(IDBS)绘制，并计算对应的参数(最高抑制率、最低抑制率、绝对IC50、相对IC50和斜率)
增殖率(增殖倍数)＝(Vday6Control-Vday6Blank)/(Vday0Control-Vday0Blank)
浓度设置范围如下表36：
表36
体外抗增殖实验数据如表37所示：
表37
2.Ba/F3工程细胞EGFR-G719X/E709X突变的体外抗增殖实验。
本实验采用CellTiter-Glo(CTG)试剂盒，它是一种均质法细胞活力检测方法，通过对ATP的定量来测定培养细胞的细胞活力。因为灵敏度高、操作流程简便而成为目前主流的细胞活力检测试剂盒。本实验的目的是利用CTG方法评估1个受试化合物对5株EGFR细胞株的细胞增殖的影响，以afatinib为对照化合物。
试验步骤：
a)所有细胞株于37℃,5％CO2条件下培养于完全培养基。
b)收获处于对数生长期的细胞并采用血小板计数器进行细胞计数。用台盼蓝排斥法检测细胞活力，确保细胞活力在90％以上。
c)使用完全培养基调整细胞密度，随后接种于96孔细胞培养板，每孔接种90μL，共3000个细胞。
d)将96孔板中的细胞置于37℃、5％CO2条件下培养。
e)配制10倍药物溶液，检测最高浓度为10μM，9个浓度，3.16倍稀释，然后转移连续稀释化合物各10μL至96孔细胞板的相应实验孔中，每个药物浓度设置三个复孔。
f)将已加药的96孔板中的细胞置于37℃、5％CO2条件下继续培养72小时，之后进行CTG分析。
g)融化CTG试剂并平衡细胞板至室温30分钟。
h)每孔加入等体积的CTG溶液。
i)在定轨摇床上振动5分钟使细胞裂解。
j)将细胞板放置于室温20分钟以稳定冷光信号。
k)读取冷光值，收集数据。
数据分析：
使用GraphPad Prism 7.0软件分析数据，利用非线性S曲线回归来拟合数据得出剂量-效应曲线，并由此计算IC50值。
细胞存活率(％)＝(Lum待测药-Lum培养液对照)/(Lum溶剂对照-Lum培养液对照)×100％。
受试化合物抗细胞增殖活性如下表：
(下述表格38中细胞株均为针对非小细胞肺癌的罕见突变类型)
表38
3.Ba/F3工程细胞EGFR-G719S异体模型中的体内抗肿瘤实验。
复苏Ba/F3-EGFR-G719S细胞，体外培养，获得8×107细胞。小鼠剔除接种部位体毛，碘伏棉球消毒接种部位，用1mL注射器在小鼠右侧肩部皮下接种0.1mL细胞悬液，2×106细胞/点。当平均肿瘤体积达到约100mm3，依据肿瘤体积和体重随机分为5组，每组8只：溶媒对照组、20、40、80mg/kg A009组、40mg/kg阿法替尼组。接种后至分组前，每周一次测量实验动物体重和肿瘤体积。接种分组后，每周3次测量动物体重和肿瘤体积。利用游标卡尺测量肿瘤长短径，使用公式TV＝1/2×a×b2计算肿瘤体积。其中a是肿瘤的长径，b是肿瘤的短径。抗肿瘤活性指标包括：
相对肿瘤增值率％ΔT/C＝(mean(T)-mean(T0))/(mean(C)-mean(C0))*100％；
肿瘤抑制率TGI％＝((mean(C)-mean(C0))-(mean(T)-mean(T0)))/(mean(C)-mean(C0))*100％
其中T-给药组肿瘤体积，T0-给药组初始肿瘤体积，C-对照组肿瘤体积，C0-对照组初始肿瘤体积。
体重和肿瘤体积数据表示为均值+标准误(Mean+SEM)。所有的数据使用Graphpad prism6进行统计分析。对于两两比较，采用T-Test分析方法；对于三个以上的组间比较，采用双因素方差分析(Two-Way ANOVA)，及Bonferroni's test。P＜0.05视为有显著差异。
各组小鼠体重变化曲线，及肿瘤体积变化如附图19和20所示。A009可剂量依赖性抑制Ba/F3-EGFR-G719S细胞增殖，中高剂量下可导致肿瘤消退，提示具有治疗G719X罕见突变非小细胞肺癌(NSCLC)的潜力；同剂量下抗肿瘤效果与阳参阿法替尼类似，但总体安全性优于阿法替尼。
附图19和20中，QD表示每天给药一次；Q2D表示每两天给药一次。
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (24)

  1. 一种如式I所示化合物，
    其中，R1、R2和R3分别独立地为H或被一个或多个R1-1取代的C1-6烷基；
    各R1-1分别独立地为“杂原子选自N、O和S中的1种、2种或3种，杂原子个数为1个、2个或3个”的4-6元杂环烷基、被一个或多个R1-a取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子个数为1个、2个或3个的4-6元杂环烷基”或-SO2-C1-6烷基；
    各R1-a分别独立地为卤素或-N(C1-6烷基)2。
  2. 如权利要求1所述的如式I所示化合物，其特征在于，其满足以下条件的一个或多个：
    (1)各R1-1分别独立地为被一个或多个R1-a取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子个数为1个、2个或3个的4-6元杂环烷基”或-SO2-C1-6烷基；
    (2)所述R1、R2、R3、R1-1和R1-a中，所述“被一个或多个R1-1取代的C1-6烷基”、所述“-SO2-C1- 6烷基”和所述“-N(C1-6烷基)2”中的C1-6烷基分别独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；优选甲基；
    (3)所述R1-1中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子个数为1个、2个或3个的4-6元杂环烷基”和所述“被一个或多个R1-a取代的杂原子选自N、O和S中的1种、2种或3种，杂原子个数为1个、2个或3个的4-6元杂环烷基”中的“杂原子选自N、O和S中的1种、2种或3种，杂原子个数为1个、2个或3个的4-6元杂环烷基”分别独立地为杂原子为N，杂原子个数为1个的4-6元杂环烷基；优选
    (4)所述R1-a中，所述卤素为氟、氯、溴或碘；优选氟。
  3. 如权利要求1所述的如式I所示化合物，其特征在于，其满足以下条件的任一条件：
    (1)R2和R3为H，R1为被一个或多个R1-1取代的C1-6烷基；优选R2和R3为H，R1为
    (2)R1和R2为H，R3为被一个或多个R1-1取代的C1-6烷基；优选R1和R2为H，R3为
  4. 如权利要求1所述的如式I所示化合物，其特征在于，所述如式I所示化合物为如下任一化合物：
  5. 一种药物组合物1，其包含如权利要求1所述如式I所示的化合物或其药学上可接受的盐；以及药用辅料。
  6. 一种药物组合物2，其包含颗粒物，所述的颗粒物包含以如下的质量分数计的组分：30-45％如式II所示化合物或其药学上可接受的盐、7-28％共聚维酮、25-48％填充剂、1.0-8.0％崩解剂、0.5-4.0％助流剂和0.5-4.0％润滑剂；
    所述的颗粒物中的所有组分的质量分数之和为100％；所述的质量分数为颗粒物中各组分的质量占各组分的总质量的质量百分比；
    R4、R5和R6分别独立地为H或被一个或多个R4-1取代的C1-6烷基；
    各R4-1分别独立地为-N(C1-6烷基)2、“杂原子选自N、O和S中的1种、2种或3种，杂原子个数为1个、2个或3个”的4-6元杂环烷基、被一个或多个R4-a取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子个数为1个、2个或3个的4-6元杂环烷基”或-SO2-C1-6烷基；
    各R4-a分别独立地为卤素或-N(C1-6烷基)2。
  7. 如权利要求6所述的药物组合物2，其特征在于，其满足以下条件的一个或多个：
    (1)各R4-1分别独立地为-N(C1-6烷基)2、被一个或多个R4-a取代的“杂原子选自N、O和S中的1种、2种或3种，杂原子个数为1个、2个或3个的4-6元杂环烷基”或-SO2-C1-6烷基；
    (2)所述R4、R5、R6、R4-1和R4-a中，所述“被一个或多个R4-1取代的C1-6烷基”、所述“-SO2-C1- 6烷基”和所述“-N(C1-6烷基)2”中的C1-6烷基分别独立地为甲基、乙基、正丙基、异丙基、正丁基、异丁基或叔丁基；优选甲基；
    (3)所述R4-1中，所述“杂原子选自N、O和S中的1种、2种或3种，杂原子个数为1个、2个或3个的4-6元杂环烷基”和所述“被一个或多个R4-a取代的杂原子选自N、O和S中的1种、2种或3种，杂原子个数为1个、2个或3个的4-6元杂环烷基”中的“杂原子选自N、O和S中的1种、2种或3种，杂原子个数为1个、2个或3个的4-6元杂环烷基”分别独立地为杂原子为N，杂原子个数为1个的4-6元杂环烷基；优选
    (4)所述R4-a中，所述卤素为氟、氯、溴或碘；优选为氟。
  8. 如权利要求6所述的药物组合物2，其特征在于，其满足以下条件的一个或多个：
    (1)R5和R6为H，R4为被一个或多个R4-1取代的C1-6烷基；优选R5和R6为H，R4为
    (2)R4和R6为H，R5为被一个或多个R4-1取代的C1-6烷基；优选R4和R6为H，R5为
  9. 如权利要求6所述的药物组合物2，其特征在于，所述如式II所示化合物为如下任一化合物：

  10. 如权利要求6所述的药物组合物2，其特征在于，其满足以下条件的一个或多个：
    (1)所述的药物组合物中，所述其药学上可接受的盐为如式II所示化合物的马来酸盐；
    (2)所述的药物组合物中，所述的如式II所示化合物或其药学上可接受的盐的质量分数为35-42％；优选为36％；
    (3)所述的药物组合物中，所述的共聚维酮的质量分数为8-22％；优选为21％；
    (4)所述的药物组合物中，所述的填充剂为糖醇和/或水溶胀性添加剂；优选为甘露醇和微晶纤维素；
    (5)所述的药物组合物中，所述的填充剂的质量分数为34-45％；优选为37％；
    (6)所述的药物组合物中，所述的崩解剂为己二酸、海藻酸、胶凝淀粉、羧甲基淀粉钠、羧甲纤维素、羧甲纤维素钙、羧甲纤维素钠、水合二氧化硅、柠檬酸钙、交联羧甲纤维素钠、交聚维酮、轻质无水硅酸、结晶纤维素、合成硅酸铝、小麦淀粉、米淀粉、乙酸邻苯二甲酸纤维素、硬脂酸钙、低取代的羟丙基纤维素、玉米淀粉、黄蓍胶粉、马铃薯淀粉、羟乙基甲基纤维素、羟丙基淀粉、预胶凝淀粉、富马酸单钠、聚维酮、无水柠檬酸、甲基纤维素和磷酸二氢钙中的一种或多种；优选为交聚聚维酮，更优选交联聚维酮XL-10；
    (7)所述的药物组合物中，所述的崩解剂的质量分数为1.7-4.9％；优选为2.0％；
    (8)所述的药物组合物中，所述的助流剂为胶态二氧化硅、凝胶二氧化硅、轻质无水硅酸、结晶纤维素、合成硅酸铝、氧化钛、硬脂酸、硬脂酸钙、硬脂酸镁、磷酸三钙、滑石粉、玉米淀粉和偏硅酸铝镁中的一种或多种；优选为胶态二氧化硅或凝胶二氧化硅；
    (9)所述的助流剂的质量分数为1.0-4.0％；优选为2.0％；
    (10)所述的药物组合物中，所述的润滑剂为可可脂肪、巴西棕榈蜡、水合二氧化硅(胶态二氧化硅)、氢氧化铝干凝胶、甘油脂肪酸酯、硅酸镁、轻质无水硅酸、结晶纤维素、硬化油、合成硅酸铝、白蜂蜡、氧化镁、酒石酸钠钾、蔗糖脂肪酸酯、硬脂酸、硬脂酸钙、硬脂酸镁、硬脂酸富马酸钠、硬脂醇和聚乙二醇40硬脂酸酯中的一种或多种；优选为为硬脂酸富马酸钠或硬脂酸镁；
    (11)所述的药物组合物中，所述的润滑剂的质量分数可以为1.0-4.0％；优选为2％；
    (12)所述的药物组合物中，所述其药学上可接受的盐以无水晶型或无定形形式存在；优选以无水晶型形式存在。
  11. 如权利要求6所述的药物组合物2，其特征在于，其包含颗粒物，所述的颗粒物包含以如下的质量分数计的组分：30-45％无水奈拉替尼马来酸盐、7-28％共聚维酮、25-48％填充剂、1.0-8.0％崩解剂、0.5-4.0％助流剂和0.5-4.0％润滑剂；所述的颗粒物中的所有组分的质量分数之和为100％。
  12. 如权利要求11所述的药物组合物2，其特征在于，其满足如下1个或多个条件：
    (1)所述的药物组合物2中，所述的无水奈拉替尼马来酸盐为无水奈拉替尼马来酸盐的晶型，其以衍射角为2θ表示的X-射线粉末衍射图在6.0±0.2°、7.3±0.2°、10.1±0.2°、12.1±0.2°、15.6±0.2°、17.3±0.2°和19.9±0.2°处有特征峰；优选所述的奈拉替尼马来酸盐的晶型的X-射线粉末衍射图基本如图1、2或3所示；
    (2)所述的药物组合物2中，所述的无水奈拉替尼马来酸盐的质量分数为35-42％；优选36％；
    (3)所述的药物组合物2中，所述的共聚维酮的质量分数为8-22％；优选21％；
    (4)所述的药物组合物2中，所述的填充剂为糖醇和/或水溶胀性添加剂；优选为甘露醇和微晶纤维素；
    (5)所述的药物组合物2中，所述的填充剂的质量分数为34-45％；优选为37％；
    (6)所述的药物组合物2中，所述的崩解剂为己二酸、海藻酸、胶凝淀粉、羧甲基淀粉钠、羧甲纤维素、羧甲纤维素钙、羧甲纤维素钠、水合二氧化硅、柠檬酸钙、交联羧甲纤维素钠、交联聚维酮、轻质无水硅酸、结晶纤维素、合成硅酸铝、小麦淀粉、米淀粉、乙酸邻苯二甲酸纤维素、硬脂酸钙、低取代的羟丙基纤维素、玉米淀粉、黄蓍胶粉、马铃薯淀粉、羟乙基甲基纤维素、羟丙基淀粉、预胶凝淀粉、富马酸单钠、聚维酮、无水柠檬酸、甲基纤维素和磷酸二氢钙中的一种或多种；优选为交联聚维酮，更优选交联聚维酮XL-10；
    (7)所述的药物组合物2中，所述的崩解剂的质量分数为1.7-4.9％；优选为2.0％；
    (8)所述的药物组合物2中，所述的助流剂为胶态二氧化硅、凝胶二氧化硅、轻质无水硅酸、结晶纤维素、合成硅酸铝、氧化钛、硬脂酸、硬脂酸钙、硬脂酸镁、磷酸三钙、滑石粉、玉米淀粉和偏硅酸铝镁中的一种或多种；优选为胶态二氧化硅或凝胶二氧化硅；
    (9)所述的助流剂的质量分数为1.0-4.0％；优选为2.0％；
    (10)所述的药物组合物2中，所述的润滑剂为可可脂肪、巴西棕榈蜡、水合二氧化硅(胶态二氧化硅)、氢氧化铝干凝胶、甘油脂肪酸酯、硅酸镁、轻质无水硅酸、结晶纤维素、硬化油、合成硅酸铝、白蜂蜡、氧化镁、酒石酸钠钾、蔗糖脂肪酸酯、硬脂酸、硬脂酸钙、硬脂酸镁、硬脂酸富马酸钠、硬脂醇和聚乙二醇40硬脂酸酯中的一种或多种；优选为硬脂酸富马酸钠或硬脂酸镁；
    (11)所述的药物组合物2中，所述的润滑剂的质量分数可以为1.0-4.0％，优选为2％；
    (12)所述的药物组合物2还进一步包括包衣剂；所述的包衣剂优选为羟丙甲纤维素、甲基纤维素、乙基纤维素、甲基纤维素或羟丙基纤维素、聚乙烯醇、聚维酮、聚乙酸乙烯酯树脂、聚乙烯醇缩醛二乙氨基乙酸酯、甲基丙烯酸氨基烷基酯共聚物RS和丙烯酸乙酯-甲基丙烯酸甲酯共聚物分散体、蔗糖、甘露醇和欧巴代中的一种多种，更优选为欧巴代；所述的包衣剂与药物颗粒的质量比优选为0.01:1-0.05:1，例如0.03:1、0.034:1或0.036:1。
  13. 如权利要求11所述的药物组合物2，其特征在于，所述的药物组合物2满足如下1个或多个条件：所述的药物组合物2中，所述的颗粒物的组分包含颗粒物的内组分和颗粒物的外组分；
    所述的颗粒物的内组分：30-45％无水奈拉替尼马来酸盐、7-28％共聚维酮、25-48％填充剂、1.0-8.0％崩解剂、1.0-4.0％助流剂和0.5-4.0％润滑剂；
    所述的颗粒物的外组分：0-2.5％崩解剂和/或0-1％润滑剂，且所述的崩解剂和所述的润滑剂不同时为0；
    优选，所述的颗粒物由如下组(1)、组(2)或组(3)中的组分组成：
    组(1)：所述的颗粒物的内组分：34.9％无水奈拉替尼马来酸盐、26.2％甘露醇、8.3％微晶纤维素、21.7％共聚维酮、2.5％交联聚维酮XL-10、2.0％胶态二氧化硅和1.0％硬脂酸镁；
    所述的颗粒物的外组分：2.5％交联聚维酮XL-10和1.0％硬脂酸镁；
    组(2)：所述的颗粒物的内组分：42.3％无水奈拉替尼马来酸盐、31.7％干露醇、13.1％微晶纤维素、8.0％共聚维酮、2.0％交联聚维酮XL-10、2.0％胶态二氧化硅和1.0％硬脂酸镁；
    所述的颗粒物的外组分：1.0％硬脂酸镁；
    组(3)：所述的颗粒物的内组分：36.1％无水奈拉替尼马来酸盐、27.1％干露醇、8.6％微晶纤维素、22.4％共聚维酮、1.7％交联聚维酮XL-10、2.0％胶态二氧化硅和1.0％硬脂酸镁；
    所述的颗粒物的外组分：1.0％硬脂酸镁。
  14. 如权利要求13所述的药物组合物2，其特征在于，所述的药物组合物2由如下组(a)、组(b)或组(c)中的组分组成：
    组(a)：颗粒物和欧巴代，所述的欧巴代与所述的颗粒物的质量比为0.03：1；
    所述的颗粒物的内组分：34.9％无水奈拉替尼马来酸盐、26.2％干露醇、8.3％微晶纤维素、21.7％共聚维酮、2.5％交联聚维酮XL-10、2.0％胶态二氧化硅和1.0％硬脂酸镁；
    所述的颗粒物的外组分：2.5％交联聚维酮XL-10和1.0％硬脂酸镁；
    组(b)：颗粒物和欧巴代，所述的欧巴代与所述的颗粒物的质量比为0.034：1；
    所述的颗粒物的内组分：42.3％无水奈拉替尼马来酸盐、31.7％干露醇、13.1％微晶纤维素、8.0％共聚维酮、2.0％交联聚维酮XL-10、2.0％胶态二氧化硅和1.0％硬脂酸镁；
    所述的颗粒物的外组分：1.0％硬脂酸镁；
    组(c)：颗粒物和欧巴代，所述的欧巴代与所述的颗粒物的质量比为0.036：1；
    所述的颗粒物的内组分：36.1％无水奈拉替尼马来酸盐、27.1％干露醇、8.6％微晶纤维素、22.4％共聚维酮、1.7％交联聚维酮XL-10、2.0％胶态二氧化硅和1.0％硬脂酸镁；
    所述的颗粒物的外组分：1.0％硬脂酸镁。
  15. 一种如权利要求11-14中任一项所述的药物组合物2的制备方法，其特征在于，其包括如下步骤：将如下以质量分数计的原料进行造粒得到颗粒物；
    所述的原料包含30-45％无水奈拉替尼马来酸盐、7-28％共聚维酮、25-48％填充剂、1.0-8.0％崩解剂、0.5-4.0％助流剂和0.5-4.0％润滑剂；所述的颗粒物中的所有组分的质量分数之和为100％；所述的质量分数为颗粒物中各组分的质量占各组分的总质量的质量百分比。
  16. 如权利要求15所述的药物组合物2的制备方法，其特征在于，所述的药物组合物2的制备方法满足如下1个或多个条件：
    (1)所述的奈拉替尼马来酸盐为无水奈拉替尼马来酸盐，所述的无水奈拉替尼马来酸盐的种类 和含量均如权利要求11-14中任一项所述；
    (2)所述的共聚维酮、所述的填充剂、所述的崩解剂、所述的助流剂和、所述的润滑剂均如权利要求11-14中任一项所述；
    (3)所述的造粒的方法为干法造粒，所述的干法造粒采用干法制粒机。
  17. 如权利要求16所述的药物组合物2的制备方法，其特征在于，所述的药物组合物2的制备方法满足如下1个或多个条件：
    (1)所述的干法制粒机的压辊压力为65-100bar，例如80bar；
    (2)所述的干法制粒机的送料速度优选为40-50rpm；
    (3)所述的干法制粒机的压辊速度优选为5-15rpm，例如6rpm；
    (4)所述的干法制粒机的整粒速度优选为50-500rpm，例如100rpm；
    (5)所述的药物组合物2的制备方法还进一步包含包衣步骤；所述的包衣步骤中，采用包衣机进行包衣，所述的包衣机的参数如下：所述的包衣机的进风温度优选为55-60℃；所述的包衣机的雾化压力优选为0.10-0.30MPa；所述的包衣机的蠕动泵转速优选为2.0-12.0rpm；所述的包衣机的出风温度优选为35-42℃。
  18. 如权利要求15所述的药物组合物2的制备方法，其特征在于，所述的药物组合物2的制备方法包括如下步骤：
    步骤1：将颗粒物的内原料通过干法制粒得到颗粒物1；
    颗粒物的内原料：30-45％无水奈拉替尼马来酸盐、7-28％共聚维酮、25-48％填充剂、1-8％崩解剂、1-4％助流剂和0.5-4％润滑剂；
    步骤2：将颗粒物1与颗粒物的外原料进行压片，得到颗粒物：
    所述的颗粒物外原料：0-2.5％崩解剂和/或0-1％润滑剂，且所述的崩解剂和所述的润滑剂不同时为0。
  19. 一种通过如权利要求11-14中任一项所述的药物组合物2的制备方法制得到药物组合物2。
  20. 一种药物固体制剂，其包含如权利要求11-14和19中任一项所述的药物组合物2和药学上可接受的辅料。
  21. 一种物质A在制备EGFR抑制剂或预防或治疗与EGFR相关疾病的药物中的应用，所述的物质A为如权利要求1所述如式I所示化合物或其药学上可接受的盐，如权利要求11-14和19中任一项所述的药物组合物2或如权利要求20所述的药物固体制剂。
  22. 一种药物组合物3，其包括物质X和物质Y；
    所述物质X为马来酸奈拉替尼，所述物质Y为化合物CVL218或其药学上可接受的盐，所述化合物CVL218的结构如下所示：
  23. 一种药物组合物4，其包括物质M和物质N；
    所述物质M为马来酸奈拉替尼，所述物质N为化合物CVL237或其药学上接受的盐，所述化合物CVL237的结构如下所示：
  24. 如权利要求22所述的药物组合物3或如权利要求23所述的药物组合物4在制备预防或治疗胆管癌药物中的应用。
PCT/CN2023/080921 2023-03-10 2023-03-10 含有egfr抑制剂的药物组合物及其制备方法和应用 Ceased WO2024187321A1 (zh)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/CN2023/080921 WO2024187321A1 (zh) 2023-03-10 2023-03-10 含有egfr抑制剂的药物组合物及其制备方法和应用
EP23926680.2A EP4682143A1 (en) 2023-03-10 2023-03-10 Pharmaceutical composition containing egfr inhibitor, and preparation method therefor and use thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/CN2023/080921 WO2024187321A1 (zh) 2023-03-10 2023-03-10 含有egfr抑制剂的药物组合物及其制备方法和应用

Publications (1)

Publication Number Publication Date
WO2024187321A1 true WO2024187321A1 (zh) 2024-09-19

Family

ID=92754186

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/080921 Ceased WO2024187321A1 (zh) 2023-03-10 2023-03-10 含有egfr抑制剂的药物组合物及其制备方法和应用

Country Status (2)

Country Link
EP (1) EP4682143A1 (zh)
WO (1) WO2024187321A1 (zh)

Citations (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6002008A (en) 1997-04-03 1999-12-14 American Cyanamid Company Substituted 3-cyano quinolines
US6288082B1 (en) 1998-09-29 2001-09-11 American Cyanamid Company Substituted 3-cyanoquinolines
US6297258B1 (en) 1998-09-29 2001-10-02 American Cyanamid Company Substituted 3-cyanoquinolines
US6384051B1 (en) 2000-03-13 2002-05-07 American Cyanamid Company Method of treating or inhibiting colonic polyps
CN1659145A (zh) * 2001-11-27 2005-08-24 惠氏控股公司 作为egf－r和her2激酶抑制剂的3－氰基喹啉
US7399865B2 (en) 2003-09-15 2008-07-15 Wyeth Protein tyrosine kinase enzyme inhibitors
CN101880273A (zh) * 2009-05-06 2010-11-10 上海恒瑞医药有限公司 苯并六元n杂环类衍生物、其制备方法及其在医药上的应用
WO2011029265A1 (zh) * 2009-09-14 2011-03-17 江苏恒瑞医药股份有限公司 6-氨基喹唑啉或3-氰基喹啉类衍生物、其制备方法及其在医药上的应用
CN102209714A (zh) * 2008-11-10 2011-10-05 巴塞尔大学 三嗪、嘧啶和吡啶类似物和它们作为治疗剂和诊断探针的应用
CN102724970A (zh) 2009-11-09 2012-10-10 惠氏有限责任公司 来那替尼马来酸盐的片剂制剂
CN102838539A (zh) * 2011-06-21 2012-12-26 苏州迈泰生物技术有限公司 喹啉烯酰胺衍生物及其在制备抗恶性肿瘤药物中的用途
CN103242273A (zh) * 2012-02-09 2013-08-14 中国科学院上海药物研究所 2-芳基苯并呋喃-7-甲酰胺类化合物、其制备方法及用途
WO2013131424A1 (zh) * 2012-03-09 2013-09-12 上海恒瑞医药有限公司 4-喹唑啉胺类衍生物及其用途
CN103965120A (zh) * 2013-01-25 2014-08-06 上海医药集团股份有限公司 喹啉及喹唑啉衍生物、制备方法、中间体、组合物及应用
CN106913529A (zh) 2015-12-24 2017-07-04 江苏恒瑞医药股份有限公司 一种来那替尼或其可药用盐药物组合物的制备方法
WO2017186140A1 (zh) * 2016-04-28 2017-11-02 江苏恒瑞医药股份有限公司 一种制备酪氨酸激酶抑制剂及其衍生物的方法
CN115806548A (zh) * 2021-09-15 2023-03-17 甫康（上海）健康科技有限责任公司 含有egfr抑制剂的药物组合物及其制备方法和应用

Patent Citations (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6002008A (en) 1997-04-03 1999-12-14 American Cyanamid Company Substituted 3-cyano quinolines
US6288082B1 (en) 1998-09-29 2001-09-11 American Cyanamid Company Substituted 3-cyanoquinolines
US6297258B1 (en) 1998-09-29 2001-10-02 American Cyanamid Company Substituted 3-cyanoquinolines
US6384051B1 (en) 2000-03-13 2002-05-07 American Cyanamid Company Method of treating or inhibiting colonic polyps
CN1659145A (zh) * 2001-11-27 2005-08-24 惠氏控股公司 作为egf－r和her2激酶抑制剂的3－氰基喹啉
US7399865B2 (en) 2003-09-15 2008-07-15 Wyeth Protein tyrosine kinase enzyme inhibitors
CN102209714A (zh) * 2008-11-10 2011-10-05 巴塞尔大学 三嗪、嘧啶和吡啶类似物和它们作为治疗剂和诊断探针的应用
CN101880273A (zh) * 2009-05-06 2010-11-10 上海恒瑞医药有限公司 苯并六元n杂环类衍生物、其制备方法及其在医药上的应用
WO2011029265A1 (zh) * 2009-09-14 2011-03-17 江苏恒瑞医药股份有限公司 6-氨基喹唑啉或3-氰基喹啉类衍生物、其制备方法及其在医药上的应用
CN102724970A (zh) 2009-11-09 2012-10-10 惠氏有限责任公司 来那替尼马来酸盐的片剂制剂
CN102838539A (zh) * 2011-06-21 2012-12-26 苏州迈泰生物技术有限公司 喹啉烯酰胺衍生物及其在制备抗恶性肿瘤药物中的用途
CN103242273A (zh) * 2012-02-09 2013-08-14 中国科学院上海药物研究所 2-芳基苯并呋喃-7-甲酰胺类化合物、其制备方法及用途
CN103242273B (zh) 2012-02-09 2015-06-03 中国科学院上海药物研究所 2-芳基苯并呋喃-7-甲酰胺类化合物、其制备方法及用途
WO2013131424A1 (zh) * 2012-03-09 2013-09-12 上海恒瑞医药有限公司 4-喹唑啉胺类衍生物及其用途
CN103965120A (zh) * 2013-01-25 2014-08-06 上海医药集团股份有限公司 喹啉及喹唑啉衍生物、制备方法、中间体、组合物及应用
CN106913529A (zh) 2015-12-24 2017-07-04 江苏恒瑞医药股份有限公司 一种来那替尼或其可药用盐药物组合物的制备方法
WO2017186140A1 (zh) * 2016-04-28 2017-11-02 江苏恒瑞医药股份有限公司 一种制备酪氨酸激酶抑制剂及其衍生物的方法
CN115806548A (zh) * 2021-09-15 2023-03-17 甫康（上海）健康科技有限责任公司 含有egfr抑制剂的药物组合物及其制备方法和应用

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CATERINA CARMI, ELENA GALVANI, FEDERICA VACONDIO, SILVIA RIVARA, ALESSIO LODOLA, SIMONETTA RUSSO, STEFANIA AIELLO, FABRIZIO BORDI,: "Irreversible Inhibition of Epidermal Growth Factor Receptor Activity by 3-Aminopropanamides", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 55, no. 5, 8 March 2012 (2012-03-08), US , pages 2251 - 2264, XP055623654, ISSN: 0022-2623, DOI: 10.1021/jm201507x *
See also references of EP4682143A1

Also Published As

Publication number Publication date
EP4682143A1 (en) 2026-01-21

Similar Documents

Publication Publication Date Title
JP5934204B2 (ja) Ｃ−ｍｅｔ調節剤の薬学的組成物
AU2014210103B2 (en) Pharmaceutical composition with improved bioavailability
JP7277534B2 (ja) ｓＧＣ刺激薬を含んでなる固体分散剤
ES2535478T3 (es) Composición farmacéutica
CN101316590A (zh) 血管生成抑制剂和c-kit激酶抑制剂的组合使用
WO2001095912A1 (fr) Compositions permettant de reguler la plage et/ou la vitesse de liberation du ph
CN115806548B (zh) 含有egfr抑制剂的药物组合物及其制备方法和应用
WO2024187321A1 (zh) 含有egfr抑制剂的药物组合物及其制备方法和应用
TW202342040A (zh) 藥物配製物
JPWO2007007656A1 (ja) チアゾリジンジオン化合物を含有する医薬組成物
JP2022020459A (ja) ニロチニブ錠剤
JP7648238B2 (ja) トリアゾロピラジン誘導体化合物を有効成分とする薬学的組成物のタブレット錠の製造方法
KR20160068975A (ko) 약학 조성물
CN106880608A (zh) 一种特立氟胺分散片及其制备方法
JP2019026583A (ja) エルロチニブを有効成分とする医薬錠剤及びその製造方法
HK40045939A (zh) 具有改善的生物利用度的药物组合物
HK40047361A (zh) 具有改善的生物利用度的药物组合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23926680

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2501005940

Country of ref document: TH

WWE Wipo information: entry into national phase

Ref document number: 2023926680

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2023926680

Country of ref document: EP

Effective date: 20251010

ENP Entry into the national phase

Ref document number: 2023926680

Country of ref document: EP

Effective date: 20251010

ENP Entry into the national phase

Ref document number: 2023926680

Country of ref document: EP

Effective date: 20251010

ENP Entry into the national phase

Ref document number: 2023926680

Country of ref document: EP

Effective date: 20251010

ENP Entry into the national phase

Ref document number: 2023926680

Country of ref document: EP

Effective date: 20251010