WO2018153379A1 - 一种2-氨基嘧啶类化合物的药用组合物及其制备方法 - Google Patents

一种2-氨基嘧啶类化合物的药用组合物及其制备方法 Download PDF

Info

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
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
compound
formula
filler
mannitol
Prior art date
Application number
PCT/CN2018/077435
Other languages
English (en)
French (fr)
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
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 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/zh

Links

Images

Classifications

    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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).

Abstract

一种包含N-((5-((5-氯-4-((萘-2-基)氨基))嘧啶-2-基)氨基)-2-((N-甲基-N-二甲氨基乙基)氨基)-4-甲氧基苯基)丙烯酰胺的药用组合物，以及制备所述药用组合物的方法。

Description

一种2-氨基嘧啶类化合物的药用组合物及其制备方法 技术领域
本发明属于药物制剂领域，具体地说，本发明涉及化合物N-((5-((5-氯-4-((萘-2-基)氨基))嘧啶-2-基)氨基)-2-((N-甲基-N-二甲氨基乙基)氨基)-4-甲氧基苯基)丙烯酰胺的药用组合物，以及制备该药用组合物的方法。
背景技术
表皮生长因子受体(EGFR)，一种受体酪氨酸蛋白激酶，调控了细胞的增殖、存活、粘连、迁移与分化。EGFR在多种肿瘤细胞中过度活化或持续活化，比如肺癌、乳腺癌、***癌等。阻断EGFR和Erb-B2的活化已被临床验证为主导的方法来靶向***细胞。两种靶向EGFR的小分子抑制剂，吉非替尼和厄洛替尼，得到了美国FDA的快速批准用于治疗晚期非小细胞肺癌(NSCLC)患者，这些患者对常规化疗已经失去反应。
EGFR活化突变阳性的NSCLC患者对EGFR-TKI(EGFR-酪氨酸激酶抑制剂)的反应率显著高于EGFR野生型NSCLC患者，无进展生存(PFS)期和总生存(OS)期也显著延长。但尽管如此，大部分EGFR突变阳性患者的PFS不超过12～14个月，即对TKI发生了耐药。获得性耐药的机制及其临床应对策略成为靶向治疗领域的又一研究热点。
Figure PCTCN2018077435-appb-000001
N-((5-((5-氯-4-((萘-2-基)氨基))嘧啶-2-基)氨基)-2-((N-甲基-N-二甲氨基乙基)氨基)-4-甲氧基苯基)丙烯酰胺，化学结构如式I所示。式I所示化合物是选择性抑制EGFR T790M突变的EGFR抑制剂，可以克服现有药物吉非替尼、厄洛替尼等诱发的耐药，对野生型EGFR抑制活性弱。然而，本领域尚缺乏适应N-((5-((5-氯-4-((萘-2-基)氨基))嘧啶-2-基)氨基)-2-((N-甲基-N-二甲氨基乙基)氨基)-4-甲氧基苯基)丙烯酰胺给药的药用组合物。
发明内容
本发明的目的是提供一种适应N-((5-((5-氯-4-((萘-2-基)氨基))嘧啶-2-基)氨 基)-2-((N-甲基-N-二甲氨基乙基)氨基)-4-甲氧基苯基)丙烯酰胺给药的药用组合物。
本发明的第一方面，提供了一种含有式I所示化合物的药用组合物，
Figure PCTCN2018077435-appb-000002
所述药用组合物经由粉末直接压片法制备，所述药用组合物包括式I化合物、填充剂、助流剂、润滑剂、崩解剂。
在另一优选例中，所述填充剂选自下组：淀粉、蔗糖、糊精、乳糖、预胶化淀粉、微晶纤维素、硫酸钙、磷酸氢钙、山梨醇、甘露醇，或其组合；和/或
所述助流剂为滑石粉或胶态二氧化硅；优选胶态二氧化硅；和/或
所述润滑剂选自下组：硬脂酸镁、硬脂酸钙、硬脂酸锌、硬脂酸钠、硬脂酸、硬脂富马酸钠、聚乙二醇、十二烷基硫酸钠，或其组合；优选硬脂富马酸钠；和/或
所述崩解剂选自下组：干淀粉、羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠、交联聚维酮中的一种或多种；优选低取代羟丙基纤维素和/或交联羧甲基纤维素钠；更优选地为低取代羟丙基纤维素或交联羧甲基纤维素钠。
在另一优选例中，在所述的药用组合物中，所述的式I化合物的粒径为10-150μm，优选为30-100μm。
在另一优选例中，所述填充剂为甘露醇和微晶纤维素；优选地，所述的填充剂中，甘露醇和微晶纤维素的重量比为(1.5～9)：1，优选地为(1.8～8)：1，更优选地为(3～7.6)：1。
在另一优选例中，所述填充剂与式I化合物的重量比为3～7)：1，优选地为(4～6)：1，更优选地为(4.5～5.5)：1；和/或
所述助流剂与式I化合物的重量比为(0.04～0.2)：1，优选地为(0.06～0.2)：1，更优选地为(0.08～0.15)：1；
所述润滑剂与式I化合物的重量比为(0.08～0.44)：1，优选地为(0.09～0.33)：1，更优选地为(0.1～0.22)：1；
所述崩解剂与式I化合物的重量比为(0.15～0.8)：1，优选地为(0.18～0.7)：1，更优选地为(0.2～0.65)：1。
在另一优选例中，所述药用组合物包括：
在另一优选例中，所述药用组合物包括：
Figure PCTCN2018077435-appb-000004
且所述的填充剂包括甘露醇和微晶纤维素，且所述的甘露醇和微晶纤维素的重量比为(1.8～8)：1；
且所述的崩解剂选自下组：低取代羟丙基纤维素，或交联羧甲基纤维素钠。
在另一优选例中，所述药用组合物由以下组分组成：
Figure PCTCN2018077435-appb-000005
且所述的填充剂包括甘露醇和微晶纤维素，且所述的甘露醇和微晶纤维素的重量比为(1.8～8)：1；
且所述的崩解剂选自下组：低取代羟丙基纤维素，或交联羧甲基纤维素钠。
在另一优选例中，所述的药用组合物是通过直接压片法制备的。
本发明的第二方面，提供了一种制备本发明第一方面所述药用组合物的方法，所述制备方法包括：
(1)先将助流剂、第一部分填充剂、崩解剂混合，过筛；
(2)再加入式I所示化合物和第二部分填充剂，混合均匀后加入润滑剂，继续混合均匀，得中间体粉末；
(3)进行中间体粉末的含量检测，根据中间品含量测定结果计算片重，进行压片。
在另一优选例中，所述的式I所示化合物为粉末形式。
在另一优选例中，所述的式I化合物粉末通过机械粉碎式I化合物原料药获得。
在另一优选例中，所述的填充剂为甘露醇和微晶纤维素，且所述的第一部分填充剂为微晶纤维素，第二部分填充剂为甘露醇。
在另一优选例中，所述的药用组合物在制备用于在患者中治疗癌症的药物，优选地，所述癌症为EGFR T790M突变的非小细胞肺癌(NSCLC)。
本发明的第三方面，提供了一种药用片剂，所述的药用片剂包括如本发明第一方面所述的药用组合物。
在另一优选例中，所述的药用片剂包括：片芯，所述的片芯为本发明第一方面所述的药用组合物，和包覆于所述片芯外的包衣。
在另一优选例中，所述的包衣与片芯的重量比为2-5：100，优选为3-4:100。
在另一优选例中，所述的药用片剂用于制备用于在患者中治疗癌症的药物，优选地，所述癌症为EGFR T790M突变的非小细胞肺癌(NSCLC)。
本发明的第四方面，提供了一种药盒，所述的药盒包括：
如本发明第一方面所述的药用组合物；和
用于与所述的药用组合物联用的第二治疗剂。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选地技术方案。限于篇幅，在此不再一一累述。
附图说明
图1为实施例1制备的三批片芯在pH1.2溶出介质中的溶出曲线；
图2为实施例1制备的三批片芯在pH4.5溶出介质中的溶出曲线；
图3为实施例1制备的三批片芯在FASSIF溶出介质中的溶出曲线；
图4为实施例8制备的三批10mg规格片剂在pH3.8溶出介质中的溶出曲线；
图5为实施例8制备的三批80mg规格片剂在pH3.8溶出介质中的溶出曲线。
具体实施方式
本发明人经过长期而深入的研究，提供了一种适合N-((5-((5-氯-4-((萘-2-基)氨基))嘧啶-2-基)氨基)-2-((N-甲基-N-二甲氨基乙基)氨基)-4-甲氧基苯基)丙烯酰胺给药的药用组合物。所述的药用组合物具有优异的溶出度和化学稳定性。基于上述发现，发明人完成了本发明。
术语
如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”或“由…构成”。
如本文所用，术语“……规格片芯”或“……规格片剂”具有如下含义：每一片芯或每一片剂中含一定数量的式I所示化合物；例如10mg规格片芯代表每一片芯中含有约10mg的式I所示化合物。
N-((5-((5-氯-4-((萘-2-基)氨基))嘧啶-2-基)氨基)-2-((N-甲基-N-二甲氨基乙基)氨基)-4-甲氧基苯基)丙烯酰胺药用组合物
本发明的目的在于提供化合物N-((5-((5-氯-4-((萘-2-基)氨基))嘧啶-2-基)氨基)-2-((N-甲基-N-二甲氨基乙基)氨基)-4-甲氧基苯基)丙烯酰胺的适宜工业化生产、符合临床使用需求的药用组合物。
本发明的发明人在研究式I所示化合物适宜工业化生产、符合临床使用需求的药用组合物的过程中，碰到多个技术难题。例如，(1)式I所示化合物的流动性差，影响了药用组合物的含量均匀度、批间溶出度一致性等；(2)式I所示化合物易被氧化，需要工艺快速简便，尽量缩短制备时间；(3)非小细胞肺癌患者，尤其晚期患者，呼吸***的障碍使得吞咽困难，需要药物能够通过鼻饲等方式给药。
本领域人员已知，根据压片的工艺路线不同，可以把压片方法分为两大类，即制粒压片法与直接压片法。进一步的又可以将制粒压片法分为湿法制粒压片法、干法制粒压片法两小类，将直接压片法分为粉末直接压片法、半干式颗粒压片法两小类。
粉末直接压片法(direct compression method)是不经过制粒过程，直接把药物和辅料的混合物进行压片的方法。直接压片法具有粉末流动性差、含量均匀度差、片重差异大的缺点；因此对于原料药的流动性要求比较高。式I所示化合物原料药流动性差，并且发明人的研究表明流动性差与原料药的晶体结构无关。对于本领域技术人员而言，粉末直接压片法不适于制造式I所示化合物适宜工业化生产、符合临床使用需求的药用组合物。
然而发明人在对四小类压片方法进行大量尝试后，惊喜地发现通过本发明，可以克服流动性差的缺陷，利用粉末直接压片法，获得含量均匀、片重稳定的片剂形式的式I所示化合物的药用组合物。更令人惊喜的是，通过本发明提供的粉末直接压片法制得片剂形式药用组合物崩解时间短，溶出速度快。
因此，本发明第一方面提供了一种适宜工业化生产、符合临床使用需求的式I所示化合物的药用组合物形式；式I所示化合物的药用组合物优选为片剂形式。该药用组合物经由粉末直接压片法制备，包含式I所示化合物、填充剂、助流剂、润滑剂及崩解剂。
所述式I所示化合物作为药用组合物中的活性成分存在，其含量通常可依据给药方式的需要灵活设置。
本发明的药用组合物可以选择一种、两种、三种或更多种填充剂。填充剂，也可称为稀释剂，主要作用是用来增加药用组合物的重量和/或体积；同时可以减少活性成分的剂量偏差、改善压缩成形性。药用填充剂包括但不限于淀粉、蔗糖、糊精、乳糖、预胶化淀粉、微晶纤维素、硫酸钙、磷酸氢钙、山梨醇、甘露醇中的一种或多种。
本发明中，填充剂与式I化合物的重量比为(3～7)：1，优选的为(4～6)：1，更优选的为(4.5～5.5)：1。
本发明中，优选使用甘露醇和微晶纤维素作为填充剂。其中，甘露醇和微晶纤维素的重量比例为(1.5～9)：1；优选地，重量比例为(1.8～8)：1；更优选地，重量比例为(3～7.6)：1。
本发明中，优选使用适于直接压片的材料。
合适的甘露醇的平均粒径为50～200μm，优选为100～200μm，其可以商购获得，如Roquette公司的Pearlitol 100sd和Pearlitol 200sd。本发明优选使用Pearlitol 100sd，其流动性好，可以满足压片及含量均匀度的要求。
适合的微晶纤维素的平均粒径为20～200μm，优选与甘露醇的粒径接近，其 可以商购获得，如FMC公司的Avicel PH-102、Avicel HFE-102、Avicel PH-301、Avicel PH-302、Avicel PH-200。本发明优选使用Avicel PH-302，其流动性好，可压性优于甘露醇，粒径和堆密度与甘露醇Pearlitol 100sd接近，可以避免压片过程中的分层。
本发明中所用的“助流剂”是指在压片前加入，以降低颗粒之间摩擦力的辅料，加入助流剂可以改善粉体流动性，达到助流作用。本发明的药用组合物可以选择一种、两种、三种或更多种助流剂。助流剂包括但不限于滑石粉或胶态二氧化硅。本发明中，助流剂与式I化合物的重量比为(0.04～0.2)：1，优选的为(0.06～0.2)：1，更优选的为(0.08～0.15)：1。
本发明中所使用的“润滑剂”是指在压片前加入，用以降低颗粒或片剂与冲模之间摩擦力的辅料，加入润滑剂可以减少与冲模的摩擦，增加颗粒的滑动性，使填充良好、片剂的密度分布均匀，也保证了推出片剂的完整性。本发明的药用组合物可以选择一种、两种、三种或更多种润滑剂。润滑剂包括但不限于硬脂酸镁、硬脂酸钙、硬脂酸锌、硬脂酸钠、硬脂酸、硬脂富马酸钠、聚乙二醇、十二烷基硫酸钠。本发明润滑剂优选硬脂富马酸钠。本发明中，润滑剂与式I化合物的重量比为(0.08～0.44)：1，优选的为(0.09～0.33)：1，更优选的为(0.1～0.22)：1。
本发明的药用组合物可以选择一种、两种、三种或更多种崩解剂。崩解剂是促使片剂在胃肠液中迅速碎裂成细小颗粒的辅料。药用崩解剂包括但不限于干淀粉、羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠、交联聚维酮。本发明优选使用低取代羟丙基纤维素和/或交联羧甲基纤维素钠作为崩解剂；更优选的使用低取代羟丙基纤维素或交联羧甲基纤维素钠。本发明中，崩解剂与式I化合物的重量比为(0.15～0.8)：1，优选的为(0.18～0.7)：1，更优选的为(0.2～0.65)：1。
原料药的粒径分布影响片剂的溶出度。为了保证活性药物式I所示化合物的溶出度，在本发明中，优选地，控制式I所示化合物的粒径D 90为30～120μm；更优选地，控制粒径D 90为30～85μm。本发明可采用本领域已知的方式来控制作为片剂成分之一的原料式I所示化合物颗粒大小，优选地，将式I所示化合物按过筛方式进行处理；更优选地，式I所示化合物的处理方式为过筛80～200目。
上述药用组合物经由粉末直接压片法制备，所述粉末直接压片法包括：(1)先将助流剂、第一部分填充剂、崩解剂混合，过筛；(2)再依次加入式I所示化合物和第二部分填充剂，混合均匀后加入润滑剂，继续混合均匀，得中间体粉末；(3) 进行中间体粉末的含量检测，合格后根据中间品含量测定结果计算片重，进行压片。根据本发明，步骤(2)中所述的第二部分填充剂可与步骤(1)中所述的第一部分填充剂可相同或不同。第一部分填充剂是指填充剂的一部分，该部分填充剂在步骤(1)中加入；第二部分填充剂是指填充剂中的剩余部分，该剩余的填充剂在步骤(2)中加入。当填充剂为微晶纤维素与甘露醇的组合时，优选地，所述第一部分填充剂为微晶纤维素，第二部分填充剂为甘露醇；更优选的微晶纤维素与甘露醇均为直接压片型。
第二方面，本发明提供上述药用组合物的制备方法。所述制备方法包括：(1)先将助流剂、第一部分填充剂、崩解剂混合，过筛；(2)再依次加入式I所示化合物和第二部分填充剂，混合均匀后加入润滑剂，继续混合均匀，得中间体粉末；(3)进行中间体粉末的含量检测，合格后根据中间品含量测定结果计算片重，进行压片。
优选地，根据本发明的一个实施方案，所述助流剂为胶态二氧化硅；更优选与式I所示化合物粒径分布相当的胶态二氧化硅。
根据本发明，步骤(2)中所述的第二部分填充剂可与步骤(1)中所述的第一部分填充剂可相同或不同。
优选地，根据本发明的一个实施方案，所述第一部分填充剂为微晶纤维素；更优选地，微晶纤维素为直接压片型。
优选地，根据本发明的一个实施方案，所述崩解剂为交联羧甲基纤维素钠。
根据本发明，步骤(1)所述“先将助流剂、第一部分填充剂、崩解剂混合，过筛”中的过筛步骤使用30-80目筛网进行过筛；优选使用40-60目筛网。
优选地，根据本发明的一个实施方案，通过过筛控制式I所示化合物粒径D 90为30～120μm。
优选地，根据本发明的一个实施方案，所述第二部分填充剂为甘露醇；更优选地，甘露醇为直接压片型。
优选地，步骤(2)所述“再依次加入式I所示化合物和第二部分填充剂，混合均匀后加入润滑剂”中进行的混合，其混合时间为5-25分钟，混合速度为10-25转/分钟；更优选地，混合时间为10-20分钟，混合速度为15-20转/分钟。
优选地，根据本发明的一个实施方案，所述润滑剂为硬脂富马酸钠。
优选地，步骤(3)所述“继续混合均匀，得中间体粉末”中进行的混合，其混合时间为5-15分钟，混合速度为10-25转/分钟；更优选地，混合时间为5-10分钟， 混合速度为15-20转/分钟。
根据本发明，步骤(3)中适当调节压片压力，使压制的片剂脆碎度和崩解度合格，保证产品在运输过程中不出现裂片问题。
药用片剂及其制备
本发明还提供了一种药用片剂，所述药用片剂包括如上所述的药用组合物。优选地，在本发明中，基于片剂的重量，式I所示化合物在片剂中的绝对含量为1-2000mg/片；更优选地，其绝对含量为10-500mg/片，例如，式I所示化合物在片剂中的绝对含量可以为10mg/片、20mg/片、40mg/片、80mg/片、100mg/片、160mg/片、240mg/片。
在本发明的一个实施方案中，提供了一种药用片剂，包括片芯，该片芯包括如上所述的药用组合物，该片芯还具有包衣。
依据包衣材料的不同，可将包衣的片剂主要分为糖衣片、薄膜衣片、肠溶衣片。本发明中，所述包衣为已知不会对最终制剂的溶出度有负面影响的合适包衣，优选为薄膜包衣。通过薄膜包衣可以使片芯具备密封包衣，以达到保护患者、临床人员以及阻挡片芯与空气、水分的接触，减少药物发生降解的机会。
合适薄膜包衣材料包括成膜剂，例如成膜聚合物。优选地，薄膜包衣材料还包括另外的组分，例如，增塑剂、着色剂、助分散剂和遮光剂。可以使用增塑剂来改进薄膜包衣的薄膜柔性和耐久性以及粘附特性。优选的成膜聚合物选自成膜乙烯基聚合物(例如聚乙烯醇)、成膜丙烯酸聚合物(例如甲基丙烯酸-甲基丙烯酸甲酯共聚物)、水溶性纤维素醚的酯(例如羟丙基甲基纤维素邻苯二甲酸酯)等中的一种或多种。适合的增塑剂包括例如甘油、乙酰化的甘油单酯、柠檬酸酯、丙二醇、聚乙二醇、三酸甘油酯或邻苯二甲酸酯。适合的遮光剂和着色剂包括例如二氧化钛、三氧化二铁。适合的助分散剂包括例如滑石。
包衣增重按重量计可以是药用组合物的0.5％至10％，优选是1％至6％，更优选是2.5％至5％。适合的薄膜包衣材料可为浓缩物，在喷涂至片芯之前用水或有机溶剂配制包衣液。此类浓缩物包括购自卡乐康公司(Colorcon)的欧巴代(Opadry)系列包衣。
药用组合物的用途
最后，本发明还提供了上述药用组合物或片剂在制备用于在患者中治疗癌症 的药物中的用途。优选地，所述癌症为肺癌，更优选地，所述癌症为非小细胞肺癌，特别优选地，所述癌症为EGFR阳性突变的非细胞肺癌。在本发明的一个实施例中，所述癌症为EGFR T790M突变的非小细胞肺癌(NSCLC)。
使用药用组合物时，是将安全有效量的式I所示化合物施用于需要治疗的患者(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，式I所示化合物的日给药剂量通常为1～2000mg，优选20～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。本发明的药用组合物或片剂一般通过口服方式进行给药，对于固体吞咽有困难的患者，可通过先将片剂用水崩解成混悬液，再口服或经鼻饲给药，从而解决给药问题。
本发明药用组合物或片剂可以单独给药，或者与其他治疗药物(如降糖药)联合给药。
本发明的药用组合物或片剂可以与已知的治疗或改进相似病状的其它药物联用。联合给药时，原来药物的给药方式和剂量保持不变，而同时或随后服用本发明的药用组合物或片剂。药物联用也包括在重叠的时间段服用本发明的药用组合物或片剂与其它一种或几种已知药物。当本发明的药用组合物或片剂与其它一种或几种药物进行药物联用时，本发明的药用组合物/片剂或已知药物的剂量可能比它们单独用药时的剂量较低。
可以与本发明的药用组合物或片剂进行药物联用的药物或活性成分包括但不局限为：***受体调节剂、雄激素受体调节剂、视网膜样受体调节剂、细胞毒素/细胞抑制剂、抗增殖剂、蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂、HIV蛋白激酶抑制剂、逆转录酶抑制剂、血管生成抑制剂、细胞增殖及生存信号抑制剂、干扰细胞周期关卡的药物和细胞凋亡诱导剂，细胞毒类药物、酪氨酸蛋白抑制剂、EGFR抑制剂、VEGFR抑制剂、丝氨酸/苏氨酸蛋白抑制剂、Bcr-Abl抑制剂、c-Kit抑制剂、Met抑制剂、Raf抑制剂、MEK抑制剂、MMP抑制剂、拓扑异构酶抑制剂、组氨酸去乙酰化酶抑制剂、蛋白酶体抑制剂、CDK抑制剂、Bcl-2家族蛋白抑制剂、MDM2家族蛋白抑制剂、IAP家族蛋白抑制剂、STAT家族蛋白抑制剂、PI3K抑制剂、AKT抑制剂、整联蛋白阻滞剂、干扰素-α、白介素-12、COX-2抑制剂、p53、p53激活剂、VEGF抗体、EGF抗体等。
本发明的主要优点在于：
(1)本发明的药用组合物成型容易，可以利用粉末直接压片法获得含量均匀、片重稳定的片剂形式的式I所示化合物的药用组合物。
(2)本发明的药用组合物崩解时间短，溶出速度快，且具有非常好的化学稳定性。
(3)本发明的药用组合物加工方便，过筛时间短，制备过程中较少出现出片困难、粘冲等现象，非常适合用于工业化生产。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
试验例1 式I所示化合物的流动性研究
使用Brookfield engineering仪器考察了式I所示化合物原料的流动性，流动函数图(Flow Function Graph)显示式I所示化合物的流动性在低固结应力(consolidating stress)下为粘结(cohesive)，在中固结应力(consolidating stress)下介于粘结(cohesive)与容易流动(easy flowing)之间，表明式I所示化合物原料的流动性较差。
通过电镜观察式I所示化合物，发现式I所示化合物大多呈现不规则的柱状结构，没有出现针状晶体结构，所以晶体结构并不是引起粉末流动性差的原因。
试验例2 式I所示化合物的化学稳定性
表1为对式I所示化合物原料药强制降解的试验结果，式I所示化合物在高温、光照条件下稳定，在酸、碱条件稳定性相对较差，在氧化条件易降解。
表1
项目 强制降解条件 总杂
未破坏 未破坏 0.15％
酸破坏 HCl 60℃，3h 2.37％
碱破坏 NaOH 60℃，5h 1.28％
高温破坏 100℃，7h 0.17％
光照破坏 6h 0.16％
氧化破坏 1％H 2O 2，1h 5.35％
实施例1 原料药的粒度对制剂溶出度的影响
取3个批号的式I所示化合物原料药，测定粒径分布，结果如表2所示。将3个批号的式I所示化合物原料药以相同的处方，通过粉末直接压片法制备片芯(每片中式I所示化合物的含量为80mg)。片芯的处方组成为(w/w)：式I所示化合物15％、胶态二氧化硅3％、甘露醇61.5％、微晶纤维素8.1％、低取代羟丙基纤维素9.4％、硬脂富马酸钠3％。
表2
式I所示化合物批号 D 50μm D 90μm 片芯批号
73-06S 18.1 37.8 20160106
74-05S 51.2 117 20160201
81-01S 26.6 77.1 20160202
在pH1.2、4.5的溶出介质以及FASSIF介质中，采用浆法，以每分钟75转的转速测定各批号片芯的溶出曲线，结果如图1～3所示。从不同粒径制备的式I所示化合物片芯在3种不同pH值介质中的溶出度结果中可以看到：
pH1.2的酸性介质中，由于药物在此介质中的溶解度很大，所以不同粒径的3条溶出曲线几乎没有区别。
pH4.5的溶出介质中，溶出最慢的是74-05S组。81-01S组和73-06S组在30分钟的溶出度分别为74％、68％，45分钟时的溶出度分别为79％、75％；60分钟时的溶出度分别为84％、80％，两者相差不大。
在pH6.5的人工肠液FASSIF介质中，74-05S组还是慢于其他2组。81-01S组和73-06S组在45分钟时的溶出度分别为42％、47％；60分钟时的溶出度分别为49％、56％，两者溶出比较接近。
所以，在pH4.5以上的介质中，原料的粒径对药物的溶出有影响。在30分钟至60分钟时间段中，原料粒径D 90为37.8μm和77.1μm的药物溶出曲线比较接近，而原料粒径D 90为117μm的溶出则较慢。但原料粒径D 90为117μm时，其溶出仍能满足本发明的需求。
实施例2 含量均匀度考察
取实施例1中3个组别，在压片前的中间体粉末，考察式I所示化合物的含量均匀性；结果如表3所示。结果显示式I所示化合物原料药D 90在37.8～117μm时，含量测定结果的相对标准偏差RSD均小于5％。由于选用了合适的辅料以及混合工艺， 原料粒径分布对含量均匀度的影响可以降低。
表3
组别 含量 RSD
73-06S 13.99％ 2.55％
74-05S 14.86％ 3.19％
81-01S 14.10％ 1.62％
实施例3 原料药处理方式的考察
将式I所示化合物原料药按机械粉碎和过筛两种方式进行处理，结果如表4所示。发现式I所示化合物物料非常容易粉碎，机械粉碎10秒就会使原料的粒径D 90小于30μm。
表4
Figure PCTCN2018077435-appb-000006
实施例4A 片芯填充剂的考察
按照实施例1的处方制备片芯，其中选择73-06S、81-01S两个不同批次的式I所示化合物，选择平均粒径分别为100μm、180μm两种规格的甘露醇。
当式I所示化合物为73-06S(D 90＝37.8μm)，甘露醇平均粒径为180μm时，抽取压制的片芯20片，称量片重。结果显示：与平均片重相比，所有片重差异均小于5％、19片片重差异小于4％、16片片重差异小于3％。抽取压制的片芯10片，测定式I所示化合物的含量，相对标准偏差RSD为2.55％。
当式I所示化合物为81-01S(D 90＝77.1μm)，甘露醇平均粒径为180μm时，抽取压 片开始、中间、结束三个阶段的片芯各10片，分别测定式I所示化合物的含量。开始、中间、结束3个阶段的相对标准偏差RSD分别为0.8％、0.4％、2.8％。
当式I所示化合物为81-01S(D 90＝77.1μm)，甘露醇平均粒径为100μm时，抽取压片开始、中间、结束三个阶段的片芯各10片，分别测定式I所示化合物的含量。开始、中间、结束3个阶段的相对标准偏差RSD分别为0.1％、0.1％、0.2％。
结果表明，依据本发明的处方，使得甘露醇的粒径和密度对片剂品质不会产生显著影响。
实施例4B 片芯填充剂的考察
片芯处方组成为(w/w)：式I所示化合物15％、胶态二氧化硅3％、低取代羟丙基纤维素9.4％、硬脂富马酸钠3％、69.6％甘露醇+微晶纤维素(质量比7.6:1～1.8:1)或者69.6％乳糖预混剂。乳糖预混剂选用商品化Cellactose 80乳糖纤维素，乳糖与纤维素比例约为3：1。
采用粉末直接压片法，评估处方的流动性、可压性、崩解性等项目。结果表明，甘露醇与微晶纤维素组合作为填充剂与乳糖预混剂大部分项目结果相似。但乳糖预混剂处方相同压片力下硬度小于甘露醇处方。
还考察了不同比例的甘露醇和微晶纤维素作为填充剂对溶出度的影响，结果见表5。在pH4.5的溶出介质中，溶出度的筛选结果表明：甘露醇与微晶纤维素的比例为36：10或76：10时，溶出没有明显的变化，但在甘露醇：微晶纤维素(w/w)为18：10时，溶出有所下降，但20min时溶出度仍然达到了57％。
表5
Figure PCTCN2018077435-appb-000007
实施例5 片芯助流剂的考察
由于式I所示化合物流动性较差，考察助流剂对片芯生产工艺的影响。当使用胶态二氧化硅为助流剂时，可以提高粉末的流动性；但同时也会堵塞筛网，使混合粉末第一次过筛的时间延长。
《药用辅料手册(第四版)》(Handbook of Pharmaceutical Excipients,4 th edition,edited by Raymond C Rowe,Paul J Sheskey,and Paul J Weller)中记载了胶态二氧化硅作为助流剂改善干粉流动性时，用量一般为0.1～0.5％。
各批次片芯的处方为(w/w)：式I所示化合物15％、胶态二氧化硅0～3％、交联羧甲基纤维素钠3％、硬脂富马酸钠3％、余量为甘露醇与微晶纤维素，其中甘露醇与微晶纤维素的质量比为3.25：1。
压片过程发现，不加助流剂的处方可压性变差，增加压片力后容易出现死冲。当胶态二氧化硅的用量为0.6％时，处方可压性得到了显著改善。
当胶态二氧化硅的用量为1.5％或3％时，片重差异、含量均匀度无显著差别。其中二氧化硅的用量为1.5％时，抽取10片10mg规格片芯，片重的相对标准偏差RSD为2.3％；用量为3％时，相应的相对标准偏差RSD为4.5％。两个不同胶态二氧化硅含量的片芯，式I所示化合物的含量测定结果皆显示含量均匀度稳定。
胶态二氧化硅的用量为3％时，比用量为1.5％的崩解和溶出有所降低，但崩解时间仍然不足2分钟，而且20分钟溶出也达到了57.4％(溶出介质pH＝4.5，75rpm)。
胶态二氧化硅的用量为1.5％时，混合后粉末过60目筛，未出现过筛时间长的现象；用量为3％时，观察到第一次过筛时间延长，但仍在产业化所能接受范围内。
实施例6 硬脂富马酸钠的考察
各批次片芯的处方为(w/w)：式I所示化合物15％、胶态二氧化硅3％、交联羧甲基纤维素钠3％、硬脂富马酸钠0.75％～3％、余量为甘露醇与微晶纤维素，其中甘露醇与微晶纤维素的质量比为3.25：1。
《药用辅料手册(第四版)》(Handbook of Pharmaceutical Excipients,4 th edition,edited by Raymond C Rowe,Paul J Sheskey,and Paul J Weller)中记载了硬脂富马酸钠作为片剂或胶囊剂的润滑剂，用量一般为0.5～2.0％。
压片过程发现，当硬脂富马酸钠用量为0.75％时，压片过程出现出片困难，并有粘冲现象出现。当硬脂富马酸钠用量为1.5％时，出片困难、粘冲现象仍有出现，但已为产业化过程所能承受。当硬脂富马酸钠用量为3％时，未出现出片困难、粘冲现 象。
实施例7 包衣增重对片剂的影响
考察不同包衣增重对片剂有关物质的影响，同时考察包衣增重对溶出度的影响。选择欧巴代85F640013作为包衣粉，结果显示包衣增重3％和4％时的样品在pH3.8的溶出介质中，不同时间点的溶出度非常接近，20分钟溶出度分别为89％、88％。在60℃，75％RH条件下放置10天，有关物质的变化也很接近。
实施例8 示例性产业化处方与工艺
精确称取式I所示化合物222.0g、胶态二氧化硅22.0g、甘露醇863.5g、微晶纤维素265.76g、硬脂富马酸钠44.0g、交联羧甲基纤维素钠51.26g、欧巴代薄膜包衣预混粉61.6g，称量时检查原辅料是否存在颗粒或结块现象，若存在，首先将其过筛，再称量。
先将胶态二氧化硅、微晶纤维素、交联羧甲基纤维素钠混合，过筛；再依次加入式I所示化合物和甘露醇，混合均匀后加入硬脂富马酸钠，继续混合均匀，得中间体粉末。
进行中间体粉末的含量检测，合格后根据中间品含量测定结果计算片重，压片芯。压片过程中定时监控片重和硬度。例如可以压制成10mg～240mg规格之间的片芯。
将合格的片芯置于包衣锅内，取包衣预混剂(欧巴代85F640013，按理论片芯增重3％的1.3～1.4倍取样)，配制包衣混悬液。片芯增重3～4％后，停止包衣。
实施例9 溶出度考察
取按照实施例8制备的10mg、80mg规格片剂每批次各6片，进行溶出度考察(溶出介质pH＝3.8，75rpm)，结果如图4和5所示。按照实施例8制备片剂30分钟的溶出达到90％以上。
抽取实施例8制备的80mg规格片剂10片，分别用50mL水崩解成混悬液，观察到崩解迅速(所有样品在3分钟内全部崩解)。测定崩解后混悬液的溶出，结果表明崩解后混悬液的溶出比相同片剂在正常溶出条件下，刚开始的5分钟溶出稍快，其余时间点和片剂的溶出曲线没有差异；f 2相似因子为53，溶出度一致。
实施例10 稳定性考察
对实施例8中获得式I所示化合物薄膜包衣片的稳定性进行考察。薄膜包衣片置于高密度聚乙烯瓶(旋紧瓶盖，瓶内有纸袋装药用干燥剂)；放样条件为温度40±2℃、相对湿度75±5％；测定开始时(0M)与1个月后(1M)总杂与含量的变化，结果如表6所示。已经完成的加速稳定性试验表明，所有6批样品中的单杂和总杂均没有明显的变化，10mg的总杂均小于0.6％，80mg规格的总杂均小于0.4％；溶出度变化小于10％，产品稳定性良好。
表6
Figure PCTCN2018077435-appb-000008
对比例1 湿法制粒压片法
按照以下处方，通过常规湿法制粒压片法制备片剂。处方为(w/w)：式I所示化合物15.4％、甘露醇47％(内加)、微晶纤维素18.5％(内加)、低取代羟丙基纤维素5.4％(内加)、1％羟丙基纤维素(配成3％溶液用于制粒)、微晶纤维素6.2％(外加)、低取代羟丙基纤维素4.3％(外加)、硬脂富马酸钠2.3％(外加)。
与实施例8中片剂相比，湿法制粒压片流动性好且硬度大；但是崩解慢，10分钟的溶出明显小于粉末直接压片法，10分钟的溶出仅为7.6％(pH＝4.5，75rpm)。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (12)

  1. 一种含有式I所示化合物的药用组合物，
    Figure PCTCN2018077435-appb-100001
    其特征在于，所述药用组合物经由粉末直接压片法制备，所述药用组合物包括式I化合物、填充剂、助流剂、润滑剂、崩解剂。
  2. 如权利要求1所述的药用组合物，其特征在于，所述填充剂选自下组：淀粉、蔗糖、糊精、乳糖、预胶化淀粉、微晶纤维素、硫酸钙、磷酸氢钙、山梨醇、甘露醇，或其组合；和/或
    所述助流剂为滑石粉或胶态二氧化硅；优选胶态二氧化硅；和/或
    所述润滑剂选自下组：硬脂酸镁、硬脂酸钙、硬脂酸锌、硬脂酸钠、硬脂酸、硬脂富马酸钠、聚乙二醇、十二烷基硫酸钠，或其组合；优选硬脂富马酸钠；和/或
    所述崩解剂选自下组：干淀粉、羧甲基淀粉钠、低取代羟丙基纤维素、交联羧甲基纤维素钠、交联聚维酮中的一种或多种；优选低取代羟丙基纤维素和/或交联羧甲基纤维素钠；更优选地为低取代羟丙基纤维素或交联羧甲基纤维素钠。
  3. 如权利要求2所述的药用组合物，其特征在于，所述填充剂为甘露醇和微晶纤维素；优选地，所述填充剂中，甘露醇和微晶纤维素的重量比为(1.5～9)：1，优选地为(1.8～8)：1，更优选地为(3～7.6)：1。
  4. 如权利要求1所述的药用组合物，其特征在于，所述填充剂与式I化合物的重量比为(3～7)：1，优选地为(4～6)：1，更优选地为(4.5～5.5)：1；和/或
    所述助流剂与式I化合物的重量比为(0.04～0.2)：1，优选地为(0.06～0.2)：1，更优选地为(0.08～0.15)：1；和/或
    所述润滑剂与式I化合物的重量比为(0.08～0.44)：1，优选地为(0.09～0.33)：1，更优选地为(0.1～0.22)：1；和/或
    所述崩解剂与式I化合物的重量比为(0.15～0.8)：1，优选地为(0.18～0.7)：1，更优选地为(0.2～0.65)：1。
  5. 如权利要求1-3任一项所述的药用组合物，其特征在于，所述药用组合物包括：
    Figure PCTCN2018077435-appb-100002
  6. 如权利要求1-3任一项所述的药用组合物，其特征在于，所述药用组合物包括：
    Figure PCTCN2018077435-appb-100003
    且所述填充剂包括甘露醇和微晶纤维素，且所述甘露醇和微晶纤维素的重量比为(1.8～8)：1；
    且所述崩解剂选自下组：低取代羟丙基纤维素，或交联羧甲基纤维素钠。
  7. 如权利要求1-3任一项所述的药用组合物，其特征在于，所述药用组合物由以下组分组成：
    Figure PCTCN2018077435-appb-100004
    且所述填充剂包括甘露醇和微晶纤维素，且所述甘露醇和微晶纤维素的重量比为(1.8～8)：1；
    且所述崩解剂选自下组：低取代羟丙基纤维素，或交联羧甲基纤维素钠。
  8. 一种制备权利要求1-7任一项所述药用组合物的方法，其特征在于，所述制备方法包括：
    (1)先将助流剂、第一部分填充剂、崩解剂混合，过筛；
    (2)再加入式I化合物和第二部分填充剂，混合均匀后加入润滑剂，继续混合均匀，得中间体粉末；
    (3)进行中间体粉末的含量检测，根据中间品含量测定结果计算片重，进行压片。
  9. 如权利要求8所述的方法，其特征在于，所述填充剂为甘露醇和微晶纤维素，且所述第一部分填充剂为微晶纤维素，第二部分填充剂为甘露醇。
  10. 一种药用片剂，其特征在于，所述药用片剂包括如权利要求1至7中任一项所述的药用组合物。
  11. 如权利要求10所述的药用片剂，其特征在于，所述药用片剂包括：片芯，所述片芯为权利要求1至7中任一项所述的药用组合物，和包覆于所述片芯外的包衣。
  12. 一种药盒，其特征在于，所述药盒包括：
    如权利要求1至7中任一项所述药用组合物；和
    用于与所述的药用组合物联用的第二治疗剂。
PCT/CN2018/077435 2017-02-27 2018-02-27 一种2-氨基嘧啶类化合物的药用组合物及其制备方法 WO2018153379A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201880014402.3A CN110446701B (zh) 2017-02-27 2018-02-27 一种2-氨基嘧啶类化合物的药用组合物及其制备方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201710108703.XA CN108498477A (zh) 2017-02-27 2017-02-27 一种2-氨基嘧啶类化合物的药用组合物及其制备方法
CN201710108703.X 2017-02-27

Publications (1)

Publication Number Publication Date
WO2018153379A1 true WO2018153379A1 (zh) 2018-08-30

Family

ID=63252405

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2018/077435 WO2018153379A1 (zh) 2017-02-27 2018-02-27 一种2-氨基嘧啶类化合物的药用组合物及其制备方法

Country Status (2)

Country Link
CN (2) CN108498477A (zh)
WO (1) WO2018153379A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110856719B (zh) * 2018-08-23 2021-08-10 江苏奥赛康药业有限公司 一种2-氨基嘧啶类化合物的药用组合物

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2013169401A1 (en) * 2012-05-05 2013-11-14 Ariad Pharmaceuticals, Inc. Compounds for inhibiting cell proliferation in egfr-driven cancers
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

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2013169401A1 (en) * 2012-05-05 2013-11-14 Ariad Pharmaceuticals, Inc. Compounds for inhibiting cell proliferation in egfr-driven cancers
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

Also Published As

Publication number Publication date
CN108498477A (zh) 2018-09-07
CN110446701A (zh) 2019-11-12
CN110446701B (zh) 2022-09-30

Similar Documents

Publication Publication Date Title
JP5401327B2 (ja) 溶出性の改善された錠剤
JP6888226B2 (ja) オラパリブの経口徐放性医薬組成物及びその使用
EP2422783A1 (en) Pharmaceutical Composition
WO2022022369A1 (zh) 一种托法替布或其盐的缓释制剂及其制备方法
KR20210147082A (ko) 디메틸푸마레이트를 포함하는 일일 저용량 투여용 약제학적 조성물
WO2018108160A1 (zh) 一种尼拉帕尼缓控释药物组合物及其用途
JP7195345B2 (ja) 薬物の時間放出のためのプログラム可能な医薬組成物
WO2018108157A1 (zh) 一种瑞卡帕布口服缓控释药物组合物及其用途
EP3437645B1 (en) Film-coated tablet having high chemical stability of active ingredient
JP2013253093A (ja) ローラーコンパクターを使用した多微粒子の製造方法
WO2018153379A1 (zh) 一种2-氨基嘧啶类化合物的药用组合物及其制备方法
WO2020038434A1 (zh) 一种2-氨基嘧啶类化合物的药用组合物
JP7419333B2 (ja) メタ亜ヒ酸塩を含む医薬組成物および製造方法
CN110913843B (zh) 药物组合物
EP4169508A1 (en) Pharmaceutical compositions comprising alpelisib
CN113116840B (zh) 一种硫酸羟氯喹片的制备方法
CN117442577B (zh) 一种坎地沙坦酯微片及制备方法和应用
WO2022138717A1 (ja) 経口固形製剤
CN113350350A (zh) 一种含有盐酸培唑帕尼的药物组合物的制备方法
CN107115308B (zh) 一种氢化可的松双相缓释片剂组合物
EP4082533A1 (en) Jak kinase inhibitor pharmaceutical composition
WO2024061267A1 (zh) 一种药物组合物及其制备方法和用途
TW202206074A (zh) 藥物配製物
CN116270482A (zh) 一种阿普米司特药物组合物及其制备方法
CN107837273A (zh) 一种肠溶替吉奥缓释制剂及其制备方法

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: 18757697

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 18757697

Country of ref document: EP

Kind code of ref document: A1