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WO2018153379A1 - Composition pharmaceutique de composé 2-amino pyrimidine et son procédé de préparation - Google Patents

Composition pharmaceutique de composé 2-amino pyrimidine et son procédé de préparation Download PDF

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Publication number
WO2018153379A1
WO2018153379A1 PCT/CN2018/077435 CN2018077435W WO2018153379A1 WO 2018153379 A1 WO2018153379 A1 WO 2018153379A1 CN 2018077435 W CN2018077435 W CN 2018077435W WO 2018153379 A1 WO2018153379 A1 WO 2018153379A1
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Prior art keywords
pharmaceutical composition
compound
formula
filler
mannitol
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PCT/CN2018/077435
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English (en)
Chinese (zh)
Inventor
丁健
丁克
耿美玉
谢华
Original Assignee
中国科学院上海药物研究所
中国科学院广州生物医药与健康研究院
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Application filed by 中国科学院上海药物研究所, 中国科学院广州生物医药与健康研究院 filed Critical 中国科学院上海药物研究所
Priority to CN201880014402.3A priority Critical patent/CN110446701B/zh
Publication of WO2018153379A1 publication Critical patent/WO2018153379A1/fr

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    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
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    • A—HUMAN NECESSITIES
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    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
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    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
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    • 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
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
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    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • 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
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present invention belongs to the field of pharmaceutical preparations, in particular, the present invention relates to the compound N-((5-((5-chloro-4-((naphthalen-2-yl)amino))) pyrimidin-2-yl)amino)-2
  • EGFR Epidermal growth factor receptor
  • NSCLC non-small cell lung cancer
  • EGFR-TKI EGFR-tyrosine kinase inhibitor
  • the compound of formula I is an EGFR inhibitor that selectively inhibits the EGFR T790M mutation, and can overcome the resistance induced by the existing drugs gefitinib, erlotinib, etc., and has weak inhibition activity against wild type EGFR.
  • the object of the present invention is to provide an adaptation of N-((5-((5-chloro-4-((naphthalen-2-yl)amino))pyrimidin-2-yl)amino)-2-((N-A) A pharmaceutical composition for administration of keto-N-dimethylaminoethyl)amino)-4-methoxyphenyl)acrylamide.
  • a pharmaceutical composition comprising a compound of formula I,
  • the pharmaceutical composition is prepared by direct compression molding of a powder comprising a compound of formula I, a filler, a glidant, a lubricant, a disintegrant.
  • the filler is selected from the group consisting of starch, sucrose, dextrin, lactose, pregelatinized starch, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, sorbitol, mannitol, or Combination; and/or
  • the glidant is talc or colloidal silica; preferably colloidal silica; and/or
  • the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, sodium stearyl fumarate, polyethylene glycol, and dodecyl sulfate.
  • magnesium stearate calcium stearate, zinc stearate, sodium stearate, stearic acid, sodium stearyl fumarate, polyethylene glycol, and dodecyl sulfate.
  • Sodium, or a combination thereof preferably sodium stearyl fumarate; and/or
  • the disintegrant is selected from the group consisting of dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, and the like; Low-substituted hydroxypropylcellulose and/or croscarmellose sodium; more preferably low-substituted hydroxypropylcellulose or croscarmellose sodium.
  • the compound of formula I has a particle size of from 10 to 150 ⁇ m, preferably from 30 to 100 ⁇ m, in the pharmaceutical composition.
  • the filler is mannitol and microcrystalline cellulose; preferably, the filler has a weight ratio of mannitol to microcrystalline cellulose of (1.5 to 9): 1, preferably (1.8 to 8): 1, more preferably (3 to 7.6): 1.
  • the weight ratio of the filler to the compound of formula I is from 3 to 7):1, preferably from (4 to 6):1, more preferably from (4.5 to 5.5):1; /or
  • the weight ratio of the glidant to the compound of formula I is (0.04 to 0.2): 1, preferably (0.06 to 0.2): 1, more preferably (0.08 to 0.15): 1;
  • the weight ratio of the lubricant to the compound of formula I is (0.08 to 0.44): 1, preferably (0.09 to 0.33): 1, more preferably (0.1 to 0.22): 1;
  • the weight ratio of the disintegrant to the compound of formula I is (0.15 to 0.8): 1, preferably (0.18 to 0.7): 1, more preferably (0.2 to 0.65): 1.
  • the pharmaceutical composition comprises:
  • the pharmaceutical composition comprises:
  • the filler comprises mannitol and microcrystalline cellulose, and the weight ratio of the mannitol to the microcrystalline cellulose is (1.8-8): 1;
  • the disintegrant is selected from the group consisting of low substituted hydroxypropyl cellulose, or croscarmellose sodium.
  • the pharmaceutical composition consists of the following components:
  • the filler comprises mannitol and microcrystalline cellulose, and the weight ratio of the mannitol to the microcrystalline cellulose is (1.8-8): 1;
  • the disintegrant is selected from the group consisting of low substituted hydroxypropyl cellulose, or croscarmellose sodium.
  • the pharmaceutical composition is prepared by direct compression.
  • a method of preparing the pharmaceutical composition of the first aspect of the invention comprising:
  • the compound of formula I is in powder form.
  • the powder of the compound of formula I is obtained by mechanical comminution of a bulk drug of the compound of formula I.
  • the filler is mannitol and microcrystalline cellulose
  • the first partial filler is microcrystalline cellulose
  • the second partial filler is mannitol
  • the pharmaceutical composition is for the preparation of a medicament for treating cancer in a patient, preferably the cancer is an EGFR T790M mutant non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • a pharmaceutical tablet comprising the pharmaceutical composition according to the first aspect of the invention.
  • the medicinal tablet comprises: a tablet core, the tablet core of the pharmaceutical composition of the first aspect of the invention, and a coating coated on the core of the core .
  • the weight ratio of the coating to the core is from 2 to 5:100, preferably from 3-4:100.
  • the pharmaceutical tablet is for the preparation of a medicament for treating cancer in a patient, preferably the cancer is an EGFR T790M mutant non-small cell lung cancer (NSCLC).
  • NSCLC non-small cell lung cancer
  • a kit comprising:
  • a second therapeutic agent for use in combination with the pharmaceutical composition is A second therapeutic agent for use in combination with the pharmaceutical composition.
  • Example 1 is a dissolution profile of three batches of cores prepared in Example 1 in a dissolution medium at pH 1.2;
  • Example 2 is a dissolution curve of the three batches of the core prepared in Example 1 in a dissolution medium at pH 4.5;
  • Example 3 is a dissolution profile of three batches of cores prepared in Example 1 in a FASSIF dissolution medium
  • Figure 4 is a dissolution profile of three batches of 10 mg size tablets prepared in Example 8 in a pH 3.8 dissolution medium;
  • Figure 5 is a dissolution profile of three batches of 80 mg size tablets prepared in Example 8 in a pH 3.8 dissolution medium.
  • the inventors have provided a suitable N-((5-chloro-4-((naphthalen-2-yl)amino)))pyrimidin-2-yl)amino)-2 by long-term and intensive research.
  • the pharmaceutical composition has excellent dissolution and chemical stability. Based on the above findings, the inventors completed the present invention.
  • the term “about” means that the value can vary by no more than 1% from the recited value.
  • the expression “about 100” includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the terms "containing” or “including” may be open, semi-closed, and closed. In other words, the terms also include “consisting essentially of” or “consisting of.”
  • ...size core or “...size tablet” has the meaning that each core or tablet contains a certain amount of a compound of formula I; for example, a 10 mg gauge core represents each One core contains about 10 mg of the compound of formula I.
  • the object of the present invention is to provide a compound N-((5-((5-chloro-4-((naphthalen-2-yl)amino))pyrimidin-2-yl)amino)-2-((N-methyl-)- A suitable industrial production of N-dimethylaminoethyl)amino)-4-methoxyphenyl)acrylamide, a pharmaceutical composition suitable for clinical use.
  • the inventors of the present invention encountered a number of technical problems in the process of studying a pharmaceutical composition suitable for industrial production and meeting clinical use requirements of the compound of Formula I.
  • the compound of formula I has poor fluidity, affecting the uniformity of the content of the pharmaceutical composition, the consistency of dissolution between batches, etc.
  • the compound of formula I is easily oxidized, requiring a quick and easy process. Minimize preparation time; (3) Non-small cell lung cancer patients, especially advanced patients, respiratory disorders make dysphagia difficult, requiring drugs to be administered by nasal feeding.
  • the tableting method can be divided into two major categories, namely, a granulation tableting method and a direct tableting method. Further, the granulation tableting method can be divided into two types: the wet granulation tableting method and the dry granulation tableting method, and the direct compression tableting method is divided into a powder direct compression tablet method and a semi-dry pellet tablet method. Small class.
  • the direct compression method is a method in which a mixture of a drug and an auxiliary material is directly tableted without undergoing a granulation process.
  • the direct compression method has the disadvantages of poor powder flowability, poor content uniformity, and large difference in tablet weight; therefore, the fluidity requirement of the raw material drug is relatively high.
  • the drug substance of the compound of the formula I has poor fluidity, and the inventors' research indicates that the fluidity is poor irrespective of the crystal structure of the drug substance.
  • the powder direct compression method is not suitable for the manufacture of a pharmaceutical composition suitable for industrial production and in accordance with clinical use requirements for the compound of formula I.
  • the inventors have surprisingly found that by the present invention, it is possible to overcome the drawback of poor fluidity, and to obtain a tablet form with uniform content and stable tablet weight by direct compression of the powder.
  • the pharmaceutical composition in the form of a tablet obtained by the direct tableting method of the powder provided by the present invention has a short disintegration time and a fast dissolution rate.
  • a first aspect of the present invention provides a pharmaceutical composition form of a compound of formula I suitable for industrial production, in accordance with clinical use requirements; the pharmaceutical composition of the compound of formula I is preferably in the form of a tablet.
  • the pharmaceutical composition is prepared by direct compression molding of a powder comprising a compound of formula I, a filler, a glidant, a lubricant, and a disintegrant.
  • the compound of the formula I is present as an active ingredient in a pharmaceutical composition, and its content can usually be flexibly set according to the needs of the administration mode.
  • the pharmaceutical composition of the present invention may be selected from one, two, three or more fillers.
  • Fillers also known as diluents, are primarily used to increase the weight and/or volume of the pharmaceutical composition; while reducing the dose bias of the active ingredient and improving compression formability.
  • Pharmaceutical fillers include, but are not limited to, one or more of starch, sucrose, dextrin, lactose, pregelatinized starch, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, sorbitol, mannitol.
  • the weight ratio of the filler to the compound of the formula I is (3 to 7): 1, preferably (4 to 6): 1, more preferably (4.5 to 5.5): 1.
  • mannitol and microcrystalline cellulose are preferably used as a filler.
  • the weight ratio of mannitol and microcrystalline cellulose is (1.5 to 9):1; preferably, the weight ratio is (1.8 to 8):1; more preferably, the weight ratio is (3 to 7.6):1.
  • a material suitable for direct compression is preferably used.
  • Suitable mannitol has an average particle size of from 50 to 200 ⁇ m, preferably from 100 to 200 ⁇ m, which are commercially available, such as from Roquette's Pearlitol 100sd and Pearlitol 200sd.
  • the present invention preferably uses Pearlitol 100sd, which has good fluidity and can meet the requirements of tableting and content uniformity.
  • Suitable microcrystalline cellulose has an average particle size of from 20 to 200 ⁇ m, preferably close to the particle size of mannitol, which is commercially available, such as FMC's Avicel PH-102, Avicel HFE-102, Avicel PH-301, Avicel. PH-302, Avicel PH-200.
  • the invention preferably uses Avicel PH-302, which has good fluidity, better compressibility than mannitol, and particle size and bulk density close to that of mannitol Pearlitol 100sd, which can avoid delamination during tableting.
  • the "glidant” used in the present invention refers to an auxiliary material which is added before the tableting to reduce the friction between the particles, and the addition of the flow aid can improve the fluidity of the powder and achieve the flow aid.
  • the pharmaceutical composition of the present invention may be selected from one, two, three or more glidants. Glidants include, but are not limited to, talc or colloidal silica.
  • the weight ratio of the glidant to the compound of the formula I is (0.04 to 0.2):1, preferably (0.06 to 0.2):1, more preferably (0.08 to 0.15):1.
  • lubricant refers to an auxiliary material which is added before the tableting to reduce the friction between the particles or the tablet and the die.
  • the addition of the lubricant can reduce the friction with the die and increase the slidability of the particles.
  • the filling is good, the density distribution of the tablets is even, and the integrity of the tablet is also ensured.
  • the pharmaceutical composition of the present invention may be selected from one, two, three or more lubricants.
  • Lubricants include, but are not limited to, magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulfate.
  • the lubricant of the present invention is preferably sodium stearyl fumarate.
  • the weight ratio of the lubricant to the compound of the formula I is (0.08 to 0.44): 1, preferably (0.09 to 0.33): 1, more preferably (0.1 to 0.22): 1.
  • the pharmaceutical composition of the present invention may be selected from one, two, three or more disintegrants.
  • a disintegrant is an excipient that causes the tablet to rapidly break into fine particles in the gastrointestinal fluid.
  • Pharmaceutical disintegrating agents include, but are not limited to, dry starch, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone.
  • the present invention preferably uses low-substituted hydroxypropylcellulose and/or croscarmellose sodium as a disintegrant; more preferably, low-substituted hydroxypropylcellulose or croscarmellose sodium is used.
  • the weight ratio of the disintegrant to the compound of the formula I is (0.15 to 0.8):1, preferably (0.18 to 0.7):1, more preferably (0.2 to 0.65):1.
  • the particle size distribution of the drug substance affects the dissolution of the tablet.
  • the present invention can be used in a manner known in the art to control the particle size of the compound of formula I as a component of the tablet.
  • the compound of formula I is treated in a sieved manner; more preferably, formula I The compounds shown are treated by sieving from 80 to 200 mesh.
  • the above pharmaceutical composition is prepared by direct compression molding of a powder, and the direct compression method of the powder comprises: (1) mixing a glidant, a first partial filler, a disintegrant, and sieving; (2) adding sequentially The compound of the formula I and the second part of the filler are uniformly mixed and then added with a lubricant, and the mixture is uniformly mixed to obtain an intermediate powder; (3) the content of the intermediate powder is tested, and the tablet weight is calculated according to the determination result of the intermediate product after passing the test. , for tableting.
  • the second partial filler described in step (2) may be the same as or different from the first partial filler described in step (1).
  • the first portion of the filler refers to a portion of the filler which is added in step (1); the second portion of the filler refers to the remainder of the filler which is added in step (2).
  • the filler is a combination of microcrystalline cellulose and mannitol, preferably, the first partial filler is microcrystalline cellulose, and the second partial filler is mannitol; more preferably microcrystalline cellulose and mannitol are both For direct compression type.
  • the present invention provides a process for the preparation of the above pharmaceutical composition.
  • the preparation method comprises the following steps: (1) first mixing a flow aid, a first partial filler, a disintegrant, and sieving; (2) sequentially adding a compound of the formula I and a second partial filler, mixing uniformly, and then adding The lubricant is continuously mixed to obtain an intermediate powder; (3) the content of the intermediate powder is detected, and after passing the test, the tablet weight is calculated according to the measurement result of the intermediate product, and the tablet is pressed.
  • the glidant is colloidal silica; more preferably colloidal silica corresponding to the particle size distribution of the compound of formula I.
  • the second partial filler described in step (2) may be the same as or different from the first partial filler described in step (1).
  • the first partial filler is microcrystalline cellulose; more preferably, the microcrystalline cellulose is a direct compression type.
  • the disintegrant is croscarmellose sodium.
  • the sieving step in the step of "first mixing the glidant, the first partial filler, the disintegrant, and sieving" in the step (1) is carried out by using a 30-80 mesh sieve; preferably using 40- 60 mesh screen.
  • the particle diameter D 90 of the compound of Formula I is controlled by sieving to be from 30 to 120 ⁇ m.
  • the second partial filler is mannitol; more preferably, the mannitol is directly compressed.
  • step (2) the mixture of "the compound of the formula I and the second partial filler is added in sequence, and the lubricant is added after mixing" is mixed, and the mixing time is 5-25 minutes, and the mixing speed is 10 -25 rpm; more preferably, the mixing time is 10-20 minutes and the mixing speed is 15-20 rpm.
  • the lubricant is sodium stearyl fumarate.
  • the mixing in the "continue mixing is uniform, intermediate powder” is carried out in step (3), the mixing time is 5-15 minutes, the mixing speed is 10-25 rpm; more preferably, the mixing time is 5-10 minutes, mixing speed is 15-20 rpm.
  • the tableting pressure is appropriately adjusted in the step (3) to make the pressed tablet friability and disintegration degree acceptable, and the product does not have the problem of cracking during transportation.
  • the invention also provides a pharmaceutical tablet comprising a pharmaceutical composition as described above.
  • the absolute content of the compound of the formula I in the tablet is from 1 to 2000 mg per tablet, based on the weight of the tablet; more preferably, the absolute content thereof is from 10 to 500 mg per tablet, for example,
  • the absolute content of the compound of I in the tablet may be 10 mg/tablet, 20 mg/tablet, 40 mg/tablet, 80 mg/tablet, 100 mg/tablet, 160 mg/tablet, 240 mg/tablet.
  • a pharmaceutical tablet comprising a core comprising a pharmaceutical composition as described above, the core further having a coating.
  • the coated tablets can be mainly divided into sugar-coated tablets, film-coated tablets, and enteric coated tablets.
  • the coating is a suitable coating which is known to have no adverse effect on the dissolution of the final formulation, preferably a film coating.
  • the film coating can be used to seal the core to protect the patient, the clinical staff, and the contact of the core with air and moisture, and reduce the chance of degradation of the drug.
  • Suitable film coating materials include film formers such as film forming polymers.
  • the film coating material further comprises additional components such as plasticizers, colorants, co-dispersants, and opacifiers.
  • Plasticizers can be used to improve film flexibility and durability as well as adhesion characteristics of film coatings.
  • Preferred film-forming polymers are selected from the group consisting of film-forming vinyl polymers (eg, polyvinyl alcohol), film-forming acrylic polymers (eg, methacrylic acid-methyl methacrylate copolymers), esters of water-soluble cellulose ethers (eg, One or more of hydroxypropylmethylcellulose phthalate) and the like.
  • Suitable plasticizers include, for example, glycerin, acetylated monoglycerides, citrate esters, propylene glycol, polyethylene glycols, triglycerides or phthalates.
  • Suitable opacifiers and colorants include, for example, titanium dioxide, ferric oxide.
  • Suitable co-dispersants include, for example, talc.
  • the coating weight gain may range from 0.5% to 10%, preferably from 1% to 6%, more preferably from 2.5% to 5% by weight of the pharmaceutical composition.
  • a suitable film coating material can be a concentrate which is formulated with water or an organic solvent prior to spraying onto the core. Such concentrates include the Opadry series of coatings available from Colorcon.
  • the invention also provides the use of a pharmaceutical composition or tablet as described above for the manufacture of a medicament for the treatment of cancer in a patient.
  • the cancer is lung cancer, more preferably, the cancer is non-small cell lung cancer, and particularly preferably, the cancer is an EGFR-positive mutant non-cellular lung cancer.
  • the cancer is an EGFR T790M mutant non-small cell lung cancer (NSCLC).
  • a safe and effective amount of a compound of formula I is administered to a patient in need of treatment (e.g., a human), wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight
  • the compound of the formula I is usually administered in a daily dose of from 1 to 2000 mg, preferably from 20 to 500 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • the pharmaceutical composition or tablet of the present invention is generally administered orally, and for patients who have difficulty in swallowing solids, it can be solved by first disintegrating the tablet into a suspension with water and then administering it orally or by nasal feeding. Dosing problem.
  • composition or tablet of the present invention may be administered alone or in combination with other therapeutic agents such as hypoglycemic agents.
  • compositions or tablets of the present invention may be combined with other agents known to treat or ameliorate similar conditions.
  • mode of administration and the dosage of the original drug remain unchanged, while the pharmaceutical composition or tablet of the present invention is administered simultaneously or subsequently.
  • Combinations of drugs also include administration of a pharmaceutical composition or tablet of the invention with one or more other known drugs over an overlapping period of time.
  • the dosage of the pharmaceutical composition/tablet or known drug of the present invention may be lower than when they are administered alone. .
  • Drugs or active ingredients which may be administered in combination with a pharmaceutical composition or tablet of the invention include, but are not limited to, estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxins /Cell inhibitors, antiproliferative agents, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protein kinase inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, cell proliferation and survival signal inhibitors, interfering cells Cycle-level drug and apoptosis inducers, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitors, serine/threonine protein inhibitors, Bcr-Abl inhibitors, c-Kit inhibition Agent, Met inhibitor, Raf inhibitor, MEK inhibitor, MMP inhibitor, topoisomerase inhibitor, histidine deacetylase inhibitor, proteasome inhibitor, CDK inhibitor, Bcl-2 family protein inhibition Agent, MDM2 family protein inhibitor, IAP family protein inhibitor
  • the pharmaceutical composition of the present invention is easy to mold, and a pharmaceutical composition of the compound of the formula I in the form of a tablet having a uniform content and a tablet weight stability can be obtained by a direct tableting method.
  • the pharmaceutical composition of the present invention has a short disintegration time, a fast dissolution rate, and has very good chemical stability.
  • the pharmaceutical composition of the invention has the advantages of convenient processing, short sieving time, less difficulty in filming, sticking and the like in the preparation process, and is very suitable for industrial production.
  • the flowability of the starting material of the compound of formula I was investigated using a Brookfield engineering instrument.
  • the Flow Function Graph shows that the fluidity of the compound of formula I is cohesive under low consolidation stress. Between the cohesive and the easy flowing under the consolidating stress, it indicates that the material of the compound of the formula I has poor fluidity.
  • Table 1 shows the test results of the forced degradation of the compound of the formula I, and the compound of the formula I is stable under high temperature and light conditions, relatively poor in acid and alkali conditions, and easily degraded under oxidizing conditions.
  • the tablet cores of the three batches of the compound of the formula I represented by the formula I were prepared by the direct compression method of the powder in the same formulation (the content of the compound of the formula I in each tablet was 80 mg).
  • the core composition of the core is (w/w): 15% of the compound of formula I, 3% of colloidal silica, 61.5% of mannitol, 8.1% of microcrystalline cellulose, 9.4% of low-substituted hydroxypropylcellulose. Sodium stearyl fumarate 3%.
  • the slowest dissolution was in the 74-05S group.
  • the dissolution rates of the 81-01S group and the 73-06S group were 74% and 68% at 30 minutes, respectively, and the dissolution rates at 79 minutes were 79% and 75%, respectively.
  • the dissolution at 60 minutes was 84% and 80%, respectively. The difference between the two is small.
  • the 74-05S group was still slower than the other two groups.
  • the dissolution rates of the 81-01S group and the 73-06S group at 42 minutes were 42% and 47%, respectively; the dissolution at 60 minutes was 49% and 56%, respectively, and the dissolution of the two groups was relatively close.
  • the particle diameter of the raw material has an influence on the dissolution of the drug.
  • the drug dissolution profiles of the raw material particle diameters D 90 of 37.8 ⁇ m and 77.1 ⁇ m were relatively close, while the dissolution of the raw material particle diameter D 90 of 117 ⁇ m was slow.
  • the dissolution thereof can still satisfy the demand of the present invention.
  • Example 3 Taking the three groups in Example 1, the intermediate powder before tableting, the content uniformity of the compound represented by Formula I was examined; the results are shown in Table 3. The results show that the compounds of formula I drug substance in 37.8 D 90 when 117 ⁇ m, the content of the relative standard deviation of the determination ⁇ RSD less than 5%. Due to the selection of suitable excipients and mixing processes, the effect of particle size distribution on the content uniformity can be reduced.
  • the compound drug substance of the formula I was treated by mechanical pulverization and sieving, and the results are shown in Table 4. It was found that the compound material of the formula I was very easily pulverized, and the mechanical pulverization for 10 seconds resulted in the particle diameter D 90 of the raw material being less than 30 ⁇ m.
  • a tablet core was prepared according to the formulation of Example 1, wherein two different batches of the compound of Formula I were selected from 73-06S and 81-01S, and mannitol having an average particle diameter of 100 ⁇ m and 180 ⁇ m, respectively, was selected.
  • the core formulation is (w/w): 15% of the compound of formula I, 3% of colloidal silica, 9.4% of low-substituted hydroxypropylcellulose, 3% of sodium stearyl fumarate, and 69.6% of mannitol. + microcrystalline cellulose (mass ratio 7.6:1 to 1.8:1) or 69.6% lactose premix.
  • the lactose premix is a commercial Cellactose 80 lactose cellulose with a ratio of lactose to cellulose of about 3:1.
  • the powder direct compression method was used to evaluate the fluidity, compressibility, disintegration and other items of the prescription.
  • the results showed that the combination of mannitol and microcrystalline cellulose as a filler was similar to most of the lactose premixes.
  • the lactose premix formulation has a lower hardness than the mannitol formulation under the same tableting force.
  • each batch of core is (w/w): 15% of the compound of formula I, 0-3% of colloidal silica, 3% of croscarmellose sodium, sodium stearyl fumarate 3 %, the balance is mannitol and microcrystalline cellulose, wherein the mass ratio of mannitol to microcrystalline cellulose is 3.25:1.
  • the amount of colloidal silica is 1.5%, the powder after mixing is passed through a 60 mesh sieve, and no filmination time is long. When the amount is 3%, the first sieving time is prolonged, but it is still industrialized. Acceptable range.
  • each batch of tablets is (w/w): 15% of the compound of formula I, 3% of colloidal silica, 3% of croscarmellose sodium, 0.75% of stearyl fumarate. 3%, the balance is mannitol and microcrystalline cellulose, wherein the mass ratio of mannitol to microcrystalline cellulose is 3.25:1.
  • the tableting process found that when the amount of sodium stearyl fumarate was 0.75%, the tableting process was difficult to produce and the sticking phenomenon appeared. When the amount of sodium stearyl fumarate is 1.5%, the filming is difficult and the sticking phenomenon still occurs, but it has been able to withstand the industrialization process. When the amount of sodium stearyl fumarate was 3%, there was no difficulty in filming and sticking.
  • the effects of different coating weight gain on tablet related substances were investigated, and the effect of coating weight gain on dissolution was investigated.
  • the Opadry 85F640013 was selected as the coating powder.
  • the results showed that the samples with the weight gain of 3% and 4% of the coating were in the dissolution medium of pH 3.8.
  • the dissolution at different time points was very close, and the dissolution rate was 89% in 20 minutes. 88%.
  • colloidal silica, microcrystalline cellulose, croscarmellose sodium are mixed and sieved; then the compound of formula I and mannitol are added in sequence, and after mixing, stearyl fumarate is added, and the mixture is continued. Mix well to obtain an intermediate powder.
  • the content of the intermediate powder was measured. After passing the test, the tablet weight was calculated based on the measurement result of the intermediate product content, and the core was tableted. Timing and hardness are monitored periodically during tableting. For example, it can be compressed into a core between 10 mg and 240 mg.
  • the qualified core is placed in a coating pan, and a coating premix (Opadry 85F640013, 1.3 to 1.4 times the theoretical core weight gain of 1.3 to 1.4 times) is prepared to prepare a coating suspension. After the core weight gain is 3 to 4%, the coating is stopped.
  • a coating premix (Opadry 85F640013, 1.3 to 1.4 times the theoretical core weight gain of 1.3 to 1.4 times) is prepared to prepare a coating suspension. After the core weight gain is 3 to 4%, the coating is stopped.
  • Example 8 Ten pieces of the 80 mg-size tablet prepared in Example 8 were extracted and disintegrated into a suspension with 50 mL of water, respectively, and rapid disintegration was observed (all samples disintegrated in 3 minutes). The dissolution of the suspension after disintegration was measured. The results showed that the dissolution of the suspension after disintegration was slightly faster than that of the same tablet under the normal dissolution conditions, and the dissolution curve of the tablets did not differ at the other time points. The f 2 similarity factor was 53, and the dissolution was consistent.
  • the stability of the film-coated tablet of the compound of the formula I obtained in Example 8 was examined.
  • the film coated tablet is placed in a high-density polyethylene bottle (screw the bottle cap, and the bottle has a medicinal desiccant in a paper bag); the sampling condition is temperature 40 ⁇ 2° C., relative humidity 75 ⁇ 5%; at the beginning of the measurement (0M) And the change in total impurity and content after 1 month (1M), the results are shown in Table 6.
  • the accelerated stability test that has been completed shows that there is no significant change in the single and total impurities in all the six batches, the total impurity of 10 mg is less than 0.6%, the total impurity of the 80 mg specification is less than 0.4%; the dissolution change is less than 10 %, product stability is good.
  • Tablets were prepared by conventional wet granulation tableting according to the following formulation.
  • the prescription is (w/w): 15.4% of the compound of formula I, 47% of mannitol (inward), 18.5% of microcrystalline cellulose (inward), 5.4% of low-substituted hydroxypropylcellulose (inward), 1% hydroxypropyl cellulose (with 3% solution for granulation), microcrystalline cellulose 6.2% (plus), low substituted hydroxypropyl cellulose 4.3% (plus), stearyl fumarate 2.3% (plus).

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Abstract

La présente invention concerne une composition pharmaceutique comprenant du N- ((5-((5-chloro-4-((naphtalén-2-yl) amino))pyrimidine-2-yl) amino)-2-((N-méthyl-N-diméthylaminoéthyl)amino)-4-méthoxyphény) acrylamide, et un procédé de préparation de la composition pharmaceutique.
PCT/CN2018/077435 2017-02-27 2018-02-27 Composition pharmaceutique de composé 2-amino pyrimidine et son procédé de préparation WO2018153379A1 (fr)

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WO2020038434A1 (fr) * 2018-08-23 2020-02-27 江苏奥赛康药业有限公司 Composition pharmaceutique de composés du type 2-aminopyrimidine

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CN1387516A (zh) * 1999-11-04 2002-12-25 巴斯利尔药物股份公司 取代的5－苄基－2,4－二氨基嘧啶
CN101199842A (zh) * 2007-12-21 2008-06-18 郭炳华 乳糖酶片及其制备方法
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CN102740847A (zh) * 2009-12-29 2012-10-17 阿维拉制药公司 杂芳基化合物和其用途
WO2013169401A1 (fr) * 2012-05-05 2013-11-14 Ariad Pharmaceuticals, Inc. Composés pour inhiber la prolifération cellulaire dans les cancers induits par l'egfr
CN103717602A (zh) * 2011-05-17 2014-04-09 加利福尼亚大学董事会 激酶抑制剂
CN105601573A (zh) * 2014-11-24 2016-05-25 中国科学院上海药物研究所 2-氨基嘧啶类化合物及其药物组合物和应用

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CN1387516A (zh) * 1999-11-04 2002-12-25 巴斯利尔药物股份公司 取代的5－苄基－2,4－二氨基嘧啶
CN101199842A (zh) * 2007-12-21 2008-06-18 郭炳华 乳糖酶片及其制备方法
CN102083800A (zh) * 2008-06-27 2011-06-01 阿维拉制药公司 杂芳基化合物和其用途
CN102740847A (zh) * 2009-12-29 2012-10-17 阿维拉制药公司 杂芳基化合物和其用途
CN103717602A (zh) * 2011-05-17 2014-04-09 加利福尼亚大学董事会 激酶抑制剂
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