WO2020038434A1 - Composition pharmaceutique de composés du type 2-aminopyrimidine - Google Patents

Composition pharmaceutique de composés du type 2-aminopyrimidine Download PDF

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Publication number
WO2020038434A1
WO2020038434A1 PCT/CN2019/101970 CN2019101970W WO2020038434A1 WO 2020038434 A1 WO2020038434 A1 WO 2020038434A1 CN 2019101970 W CN2019101970 W CN 2019101970W WO 2020038434 A1 WO2020038434 A1 WO 2020038434A1
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Prior art keywords
pharmaceutical composition
filler
tablet
compound
composition according
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PCT/CN2019/101970
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English (en)
Chinese (zh)
Inventor
陈庆财
宋婷婷
孙敏
仇海镇
田帅华
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江苏奥赛康药业有限公司
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Publication of WO2020038434A1 publication Critical patent/WO2020038434A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • 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
    • C07D239/48—Two nitrogen atoms
    • 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
    • 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 invention belongs to the field of pharmaceutical preparations, and in particular, the invention relates to a compound N-((5-((5-chloro-4-((naphthalene-2-yl) amino)) pyrimidin-2-yl) amino) -2 -((N-methyl-N-dimethylaminoethyl) amino) -4-methoxyphenyl) acrylamide or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition for preparing the same method.
  • EGFR Epidermal growth factor receptor
  • NSCLC non-small cell lung cancer
  • EGFR-activated mutation-positive NSCLC have significantly higher response rates to EGFR-TKI (EGFR-tyrosine kinase inhibitor) than patients with EGFR wild-type NSCLC, and their progression-free survival (PFS) and overall survival (OS) periods have also been significantly extended.
  • PFS progression-free survival
  • OS overall survival
  • the compound of formula I is an EGFR inhibitor that selectively inhibits the EGFR T790M mutation. It can overcome the resistance induced by the existing drugs gefitinib, erlotinib, etc., and has weak inhibitory activity against wild-type EGFR.
  • the unpublished Chinese invention patent application CN201710108703.X describes a pharmaceutical composition of a compound of formula I; the unpublished Chinese invention patent application CN201810332187.3 describes a pharmaceutically acceptable salt of a compound of formula I.
  • the object of the present invention is to provide a suitable N-((5-((5-chloro-4-((naphthalene-2-yl) amino)) pyrimidin-2-yl) amino) -2-((N-methyl -N-dimethylaminoethyl) amino) -4-methoxyphenyl) acrylamide or a pharmaceutical composition for administration thereof.
  • a pharmaceutical composition comprising a compound of Formula I or a pharmaceutically acceptable salt thereof, the pharmaceutical composition comprising an active ingredient, a filler, a lubricant, and a disintegrant, via Direct powder compression method;
  • the active ingredient is a compound of formula I or a pharmaceutically acceptable salt thereof;
  • the disintegrant is crospovidone.
  • the pharmaceutical composition may further contain a glidant; the glidant is preferably talc or colloidal silica.
  • the weight ratio of the glidant to the active ingredient is 0.005: 1 to 0.2: 1, preferably 0.01: 1 to 0.1: 1.
  • 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 a combination thereof.
  • the filler is a combination of a first filler and a second filler, the first filler is mannitol and / or lactose, and the second filler is microcrystalline cellulose.
  • the weight ratio of the first filler and the second filler is preferably 9: 1 to 1: 9, and more preferably 9: 1 to 1: 3.
  • the weight ratio of the filler to the active ingredient is 99: 1 to 1: 9, preferably 8: 1 to 1: 1, and more preferably 4: 1 to 2: 1.
  • the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulfate, Or a combination thereof; sodium stearyl fumarate is preferred.
  • the weight ratio of the lubricant to the active ingredient is 1: 1 to 1: 200, preferably 1: 2 to 1:50, and more preferably 1: 5 to 1:15.
  • the weight ratio of the disintegrant to the active ingredient is 1: 1 to 1:90, preferably 1: 1 to 1:30, and more preferably 1: 2 to 1:15.
  • the pharmaceutical composition is used for preparing a medicament for treating cancer in a patient.
  • the cancer is EGFR T790M mutant non-small cell lung cancer (NSCLC).
  • the pharmaceutical composition is used to treat cancer in a patient.
  • the cancer is EGFR T790M mutant non-small cell lung cancer (NSCLC).
  • a pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof, the pharmaceutical composition comprising an active ingredient, a filler, a lubricant, and a disintegrant, via Direct powder compression method;
  • the active ingredient is a compound of formula I or a pharmaceutically acceptable salt thereof;
  • the pharmaceutical composition is free of colloidal silica.
  • 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 a combination thereof.
  • the filler is a combination of a first filler and a second filler, the first filler is mannitol and / or lactose, and the second filler is microcrystalline cellulose.
  • the weight ratio of the first filler and the second filler is preferably 9: 1 to 1: 9, and more preferably 9: 1 to 1: 3.
  • the weight ratio of the filler to the active ingredient is 99: 1 to 1: 9, preferably 8: 1 to 1: 1, and more preferably 4: 1 to 2: 1.
  • the lubricant is selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, sodium stearate, stearic acid, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulfate, Or a combination thereof; sodium stearyl fumarate is preferred.
  • the weight ratio of the lubricant to the active ingredient is 1: 1 to 1: 200, preferably 1: 2 to 1:50, and more preferably 1: 5 to 1:15.
  • the disintegrant is crospovidone, low-substituted hydroxypropyl cellulose, or a combination thereof.
  • the weight ratio of the disintegrant to the active ingredient is 1: 1 to 1:90, preferably 1: 1 to 1:30, and more preferably 1: 2 to 1:15.
  • the pharmaceutical composition is used for preparing a medicament for treating cancer in a patient.
  • the cancer is EGFR T790M mutant non-small cell lung cancer (NSCLC).
  • the pharmaceutical composition is used to treat cancer in a patient.
  • the cancer is EGFR T790M mutant non-small cell lung cancer (NSCLC).
  • a method for preparing the pharmaceutical composition according to the first or second aspect of the present invention includes: (1) combining an active ingredient, a filler, a lubricant, and a The dissolving agent is mixed uniformly to obtain an intermediate powder; (2) tabletting is performed according to the tablet weight.
  • the preparation method includes: (1) mixing the active ingredient, filler, lubricant, disintegrant, and glidant uniformly to obtain an intermediate powder; (2) ) Compression according to tablet weight.
  • the active ingredient is in a powder form.
  • the active ingredient powder is obtained by mechanically pulverizing a drug substance of the compound of Formula I or a pharmaceutically acceptable salt thereof.
  • the active ingredient powder is obtained by sieving a drug substance of Compound I or a pharmaceutically acceptable salt thereof.
  • the active ingredient powder is obtained by mechanically pulverizing the drug substance of the compound of Formula I or a pharmaceutically acceptable salt thereof, and sieving the pulverized drug substance.
  • a pharmaceutical tablet is provided, and the pharmaceutical tablet includes the pharmaceutical composition according to the first aspect or the second aspect of the present invention.
  • the medicinal tablet includes a tablet core and a coating covering the tablet core, and the tablet core is the medicinal combination according to the first aspect or the second aspect of the present invention. Thing.
  • the pharmaceutical tablet is used for preparing a medicament for treating cancer in a patient.
  • the cancer is EGFR T790M mutant non-small cell lung cancer (NSCLC).
  • the pharmaceutical tablet is used for treating cancer in a patient.
  • the cancer is EGFR T790M mutant non-small cell lung cancer (NSCLC).
  • FIG. 1 is a dissolution curve of three batches of 10 mg tablets in Comparative Example 1 in a pH 3.8 dissolution medium;
  • Example 3 is a dissolution curve of the tablets of Group A, Group B, Group C, and Group D in a dissolution medium at pH 3.8 in Comparative Example 3;
  • FIG. 4 is a dissolution curve of the tablets in Examples 3 to 6 in a pH3.8 dissolution medium.
  • the inventors have provided a suitable N-((5-((5-chloro-4-((naphthalene-2-yl) amino)) pyrimidin-2-yl) amino) -2 after long and intensive research.
  • -((N-methyl-N-dimethylaminoethyl) amino) -4-methoxyphenyl) acrylamide A pharmaceutical composition for administration of a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition has excellent dissolution and chemical stability. Based on the above findings, the inventors have completed the present invention.
  • the term “about” means that the value can vary from the recited value by no more than 1%.
  • 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 (comprising)” may be open, semi-closed, and closed. In other words, the term also includes “consisting essentially of” or “consisting of.”
  • each core or tablet contains a certain amount of a compound of formula I; for example, 10 mg standard core represents each core It contains about 10 mg of a compound of formula I.
  • a pharmaceutically acceptable salt of a compound of formula I is converted according to a compound of formula I.
  • the pharmaceutically acceptable salt of Compound I is an inorganic or organic salt formed from Compound I and any acid.
  • the salt may be selected from the group consisting of phosphate, hydrochloride, hydrobromide, sulfate, mesylate, p-toluenesulfonate, fumarate, tartrate, citrate, succinate, hexanoate Diacids, maleates, lactates, malates, camphor sulfonates, nitrates, acetates and benzoates.
  • the acid includes any of its optical isomers, racemates, and mesomers.
  • tartaric acid may be L-tartaric acid, D-tartaric acid, and DL-tartaric acid.
  • the camphorsulfonic acid may be D-camphorsulfonic acid, L-camphorsulfonic acid, DL-camphorsulfonic acid, and the like.
  • the phosphate of the compound I is composed of a compound I with a phosphate molar ratio of about 3: 1, or about 2: 1, or about 1: 1.
  • the sulfate of Compound I is composed of Compound I and sulfuric acid at a molar ratio of about 2: 1, or about 1: 1.
  • the salts, benzoates, hydrobromides, lactates and nitrates consist of a compound with a molar ratio of about 1: 1 to the corresponding acid.
  • the method for preparing a pharmaceutically acceptable salt of Compound I may be a conventional salt formation method in the art, and includes a step of salting Compound I with a corresponding acid.
  • the pharmaceutically acceptable salt of Compound I is preferably a phosphate of Compound I (for example, a molar ratio of Compound I to phosphoric acid is about 1: 1, that is, a dihydrogen phosphate), a sulfate (for example, a molar ratio of Compound I to sulfuric acid is about It is 1: 1, ie, hydrogen sulfate), hydrobromide or camphorsulfonate, more preferably phosphate (such as dihydrogen phosphate) and sulfate (such as hydrogen sulfate).
  • a phosphate of Compound I for example, a molar ratio of Compound I to phosphoric acid is about 1: 1, that is, a dihydrogen phosphate
  • a sulfate for example, a molar ratio of Compound I to sulfuric acid is about It is 1: 1, ie, hydrogen sulfate
  • hydrobromide or camphorsulfonate more preferably phosphate (
  • An object of the present invention is to provide a compound N-((5-((5-chloro-4-((naphthalene-2-yl) amino)) pyrimidin-2-yl) amino) -2-((N-methyl- N-dimethylaminoethyl) amino) -4-methoxyphenyl) acrylamide or a pharmaceutically acceptable salt thereof is a medicinal composition suitable for industrial production and meeting the requirements of clinical use.
  • the inventor of the present invention encountered a number of technical difficulties in the process of studying the pharmaceutical composition of the compound of formula I or a pharmaceutically acceptable salt thereof suitable for industrial production and meeting the requirements of clinical use.
  • the poor fluidity of the compound of formula I affects the uniformity of the content of the pharmaceutical composition, the consistency of the dissolution between batches, etc .
  • the compound of formula I is easily oxidized, and the process needs to be fast and simple to minimize the preparation time
  • Dissolution decreases after long-term storage.
  • tableting methods can be divided into two categories, namely, pelletizing and direct tableting methods. Further, the granulation and tableting method can be divided into two categories: wet granulation and tableting method, dry granulation and tableting method, and direct tableting method into powder direct tableting method and semi-dry granule tableting method. Small class.
  • the direct compression method is a method of directly compressing a mixture of a drug and an excipient without a granulation process.
  • the direct compression method has the disadvantages of poor powder flowability, poor content uniformity, and large differences in tablet weight; therefore, the requirements for the fluidity of the drug substance are relatively high.
  • the drug substance of the compound of formula I has poor fluidity, and research by the inventors shows that the poor fluidity has nothing to do with the crystal structure of the drug substance.
  • the direct powder tableting method is not suitable for manufacturing a pharmaceutical composition of the compound of formula I suitable for industrial production and meeting the requirements of clinical use.
  • the inventor made a lot of experiments on the four types of tableting methods, and surprisingly found that the invention can overcome the defect of poor fluidity, and use the powder direct tableting method to obtain a formula in the form of tablets with uniform content and stable tablet weight.
  • the pharmaceutical composition in the form of a tablet prepared by the direct compression method of the powder provided by the present invention has a short disintegration time and a fast dissolution rate. It has also been found that good dissolution performance can still be guaranteed after long-term storage.
  • the present invention provides a pharmaceutical composition of the compound of formula I or a pharmaceutically acceptable salt thereof which is suitable for industrial production and meets the requirements of clinical use; the pharmaceutical composition is preferably in the form of a tablet.
  • the pharmaceutical composition is prepared by a direct powder tableting method, and is composed of a compound of formula I or a pharmaceutically acceptable salt thereof, a filler, a lubricant, and a disintegrant.
  • the compound of formula I or a pharmaceutically acceptable salt thereof exists as an active ingredient in a pharmaceutical composition, and its content can generally be flexibly set according to the needs of the mode of administration.
  • the pharmaceutical composition of the present invention may be selected from one, two, three or more fillers.
  • the filler also known as a diluent, is mainly used to increase the weight and / or volume of the pharmaceutical composition; at the same time, it can reduce the dose deviation of the active ingredient and improve compression moldability.
  • 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, and mannitol.
  • the weight ratio of the filler to the active ingredient is 99: 1 to 1: 9, preferably 8: 1 to 1: 1, and more preferably 4: 1 to 2: 1
  • the filler is preferably a combination of a first filler and a second filler, the first filler is mannitol and / or lactose, and the second filler is microcrystalline cellulose.
  • the weight ratio of the first filler and the second filler is preferably 9: 1 to 1: 9, and more preferably 9: 1 to 1: 3.
  • Suitable microcrystalline cellulose has an average particle size of 20-200 ⁇ m, and it is commercially available, such as Avicel PH-102, Avicel HFE-102, Avicel PH-301, Avicel PH-302, and Avicel PH-200 from FMC.
  • the "lubricant" used in the present invention refers to an auxiliary material added before tabletting to reduce the friction between particles or tablets and the die. Adding a lubricant can reduce the friction with the die and increase the sliding properties of the particles. The filling is good, the density distribution of the tablets is uniform, and the integrity of the ejected tablets is also guaranteed.
  • 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 active ingredient is 1: 1 to 1: 200, preferably 1: 2 to 1:50, and more preferably 1: 5 to 1:15.
  • Disintegrants are excipients that promote the rapid fragmentation of tablets into fine particles in the gastrointestinal fluid.
  • Common pharmaceutical disintegrants include, but are not limited to, dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, and crospovidone.
  • the present invention preferably uses low-substituted hydroxypropyl cellulose and / or crospovidone as a disintegrant; more preferably uses low-substituted hydroxypropyl cellulose or crospovidone; even more preferably uses crospovidone .
  • the weight ratio of the disintegrant to the active ingredient is 1: 1 to 1:90, preferably 1: 1 to 1:30, and more preferably 1: 2 to 1:15.
  • the particle size distribution of the drug substance affects the dissolution of the tablet.
  • the particle diameter D90 of the active ingredient is preferably controlled to be 30 to 200 ⁇ m, and the particle diameter D90 of the active ingredient is preferably controlled to be 30 to 120 ⁇ m.
  • the present invention can adopt methods known in the art to control the particle size of the compound of formula I or a pharmaceutically acceptable salt thereof.
  • the active ingredient is processed by pulverization and / or sieving; more preferably, the The treatment method is sieving 80-200 mesh (optionally, crushing before sieving).
  • the above medicinal composition is prepared through a direct powder tableting method, which includes: (1) mixing the active ingredients, fillers, lubricants, and disintegrating agents uniformly to obtain an intermediate powder; (2) according to Tablets are compressed. After the intermediate powder is obtained, the content can be detected, and the tablet weight can be calculated by calculating the tablet weight as a result of the content measurement.
  • the present invention also provides a pharmaceutical tablet comprising the pharmaceutical composition as described above.
  • the absolute content of the compound of formula I or a pharmaceutically acceptable salt thereof in the tablet is 1-2000 mg / tablet; more preferably, the absolute content thereof is 10-500 mg / Tablets, for example, the absolute content of a compound of formula I or a pharmaceutically acceptable salt thereof in a 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 including a core comprising the pharmaceutical composition as described above, and the core further having a coating.
  • 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 not to adversely affect the dissolution of the final formulation, and is preferably a film coating.
  • the tablet core can be provided with a sealed coating, so as to protect patients, clinical personnel, and block the tablet core from contact with air and moisture, and reduce the chance of drug degradation.
  • Suitable film coating materials include film-forming agents, such as film-forming polymers.
  • the film coating material also includes additional components, such as plasticizers, colorants, co-dispersants, and opacifiers.
  • Plasticizers can be used to improve film flexibility and durability and adhesion properties of film coatings.
  • Preferred film-forming polymers are selected from film-forming vinyl polymers (such as polyvinyl alcohol), film-forming acrylic polymers (such as methacrylic acid-methyl methacrylate copolymers), and esters of water-soluble cellulose ethers (such as One or more of hydroxypropyl methylcellulose phthalate).
  • Suitable plasticizers include, for example, glycerol, acetylated monoglycerides, citrates, propylene glycol, polyethylene glycol, triglycerides or phthalates.
  • Suitable sunscreens and colorants include, for example, titanium dioxide, iron oxide.
  • Suitable co-dispersants include, for example, talc.
  • the weight gain of the coating may be 0.5% to 10%, preferably 1% to 6%, and more preferably 2.5% to 5% by weight of the pharmaceutical composition.
  • a suitable film coating material may be a concentrate, and the coating solution is formulated with water or an organic solvent before spraying onto the tablet core. Such concentrates include the Opadry series coatings available from Colorcon.
  • the present invention also provides the use of the above-mentioned pharmaceutical composition or tablet in the manufacture of a medicament for treating cancer in a patient.
  • the present invention also provides the use of the above pharmaceutical composition or tablet for treating 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 EGFR-positive non-cell lung cancer.
  • the cancer is EGFR T790M mutant non-small cell lung cancer (NSCLC).
  • a safe and effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof is administered to a patient (such as a human) in need of treatment, wherein the dose at the time of administration is a pharmaceutically considered effective dose for 60 kg
  • the daily dose of the compound of formula I or a pharmaceutically acceptable salt thereof is usually 1 to 2000 mg, preferably 20 to 500 mg.
  • the specific dosage should also consider factors such as the route of administration, the patient's health, etc., which are all within the skill of a skilled physician.
  • the medicinal composition or tablet of the present invention is generally administered orally. For patients who have difficulty swallowing solids, the tablets can be disintegrated into a suspension by water and then administered orally or by nasal feeding. Dosing problems.
  • composition or tablet of the present invention may be administered alone or in combination with other therapeutic drugs such as a hypoglycemic agent.
  • the pharmaceutical composition or tablet of the present invention can be used in combination with other drugs known to treat or ameliorate similar conditions.
  • the combination is administered, the original drug is administered in the same manner and dosage, while the pharmaceutical composition or tablet of the present invention is taken simultaneously or subsequently.
  • Drug combinations also include taking the pharmaceutical composition or tablet of the invention with one or more other known drugs over overlapping periods of time.
  • the dosage of the pharmaceutical composition / tablet or known drug of the present invention may be lower than when they are used alone .
  • the drugs or active ingredients that can be used in combination with the pharmaceutical composition or tablet of the present invention include, but are not limited to: estrogen receptor modulators, androgen receptor modulators, retinal receptor modulators, cytotoxins / Cell inhibitors, antiproliferative agents, protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protein kinase inhibitors, reverse transcriptase inhibitors, angiogenesis inhibitors, inhibitors of cell proliferation and survival signals, interfering cells Cycle checkpoint drugs and apoptosis inducers, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitors, serine / threonine protein inhibitors, Bcr-Abl inhibitors, c-Kit inhibitors Agent, Met inhibitor, Raf inhibitor, MEK inhibitor, MMP inhibitor, topoisomerase inhibitor, histidine deacetylase inhibitor, proteasome inhibitor, CDK inhibitor, Bcl-2 family protein inhibitor Agent, MDM2 family protein inhibitor, IAP family protein
  • the pharmaceutical composition of the present invention is easy to form, and a pharmaceutical composition of the compound of Formula I or a pharmaceutically acceptable salt thereof in the form of a tablet having a uniform content and a stable tablet weight can be obtained by a direct powder 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 medicinal composition of the present invention is convenient to process, has short sieving time, and has fewer problems such as tableting difficulties and stickiness during the preparation process, which is very suitable for industrial production.
  • the Brookfield engineering equipment was used to examine the fluidity of the compound of Formula I.
  • the Flow Function Graph showed that the fluidity of the compound of Formula I was cohesive under low consolidation stress and consolidated in medium consolidation.
  • the stress (consolidating stress) is between cohesive and easy flowing, which indicates that the compound of formula I has poor fluidity.
  • Table 1 shows the test results of forced degradation of the compounds of formula I.
  • the compounds of formula I are stable under high temperature and light conditions, relatively poor stability under acid and alkali conditions, and easily degrade under oxidizing conditions.
  • the raw materials of the compound of formula I were processed by mechanical crushing and sieving. The results are shown in Table 2. It is found that the material of the compound of formula I is very easy to pulverize. The mechanical pulverization for 10 seconds will make the particle size D90 of the raw material less than 30 ⁇ m.
  • colloidal silica, microcrystalline cellulose, and croscarmellose sodium are mixed and sieved; then the compound of formula I and mannitol are added sequentially, and after mixing, sodium stearyl fumarate is added, and the mixture is continued to be mixed uniformly To obtain intermediate powder.
  • the content of the intermediate powder is measured, and the tablet weight is calculated according to the intermediate product content determination result, and the tablet core is compressed.
  • Monitor tablet weight and hardness regularly during tabletting For example, it can be compressed into tablets with a size between 10 mg and 240 mg.
  • the qualified tablet cores were placed in a coating pan, and a coating premix (Opadry 85F640013, which was sampled at 1.3 to 1.4 times the theoretical core weight gain of 3%) was prepared to prepare a coating suspension. After the tablet core gains 3 to 4%, the coating is stopped.
  • a coating premix (Opadry 85F640013, which was sampled at 1.3 to 1.4 times the theoretical core weight gain of 3%) was prepared to prepare a coating suspension. After the tablet core gains 3 to 4%, the coating is stopped.
  • Tablets were prepared by the conventional wet granulation and compression method according to the following prescription.
  • the prescription is (w / w): 15.4% of the compound of formula I, 47% (manned) of mannitol, 18.5% of microcrystalline cellulose (added), 5.4% of low-substituted hydroxypropyl cellulose (added), 1% hydroxypropyl cellulose (3% solution for granulation), microcrystalline cellulose 6.2% (extra), low-substituted hydroxypropyl cellulose 4.3% (extra), sodium stearyl fumarate 2.3% (Plus).
  • wet granulation and tableting have good fluidity and hardness; but disintegration is slow, and the dissolution in 10 minutes is significantly smaller than that in the powder direct compression method.
  • Component Proportion /% 1 tablet content / mg Compound of formula I 25 80 lactose 16.75 53.60 Microcrystalline cellulose 50.25 160.80 Crospovidone 3.5 11.20 Sodium stearyl fumarate 3 9.60 Colloidal silica 1.5 4.80
  • Tableting Calculate the standard tablet weight according to the determination results of the intermediate content, control the tablet weight ⁇ 3%, hardness 90 ⁇ 120N, and tablet.
  • Coating The concentration of the coating solution is 12%, and the weight gain of the coating is 3-4%.
  • Component Proportion /% 1 tablet content / mg Compound of formula I 25 80 Mannitol 50.25 160.80 Microcrystalline cellulose 16.75 53.60 Crospovidone 3.5 11.20 Sodium stearyl fumarate 3 9.60 Colloidal silica 1.5 4.80
  • Tableting Calculate the standard tablet weight according to the determination results of the intermediate content, control the tablet weight ⁇ 3%, hardness 90 ⁇ 120N, and tablet.
  • Coating The concentration of the coating solution is 12%, and the weight gain of the coating is 3-4%.
  • Tableting Calculate the standard tablet weight according to the determination result of the intermediate content, control the tablet weight ⁇ 3%, hardness 90 ⁇ 120N, and tablet.
  • Coating The concentration of the coating solution is 12%, and the weight gain of the coating is 3-4%.
  • Tableting Calculate the standard tablet weight according to the determination results of the intermediate content, control the tablet weight ⁇ 3%, hardness 90 ⁇ 120N, and tablet.
  • Coating The concentration of the coating solution is 12%, and the weight gain of the coating is 3-4%.
  • the first filler is mannitol
  • the second filler is microcrystalline cellulose
  • the weight ratio of mannitol to microcrystalline cellulose is 7.6: 1 to 1.8: 1
  • the pharmaceutical composition was prepared by a direct powder tableting method, and was similar to Example 4 in terms of fluidity, compressibility, and disintegrability.
  • Tablet pressing DPMODP020 tablet pressing machine, using 10mm round punch. Tablet weight 320mg, hardness control 105.00N ⁇ 15.00N, compressed.
  • Coating SOLID LAB 02 high-efficiency coating machine, 2.5L coating pan.
  • the film coating premix was slowly added to the purified water to prepare a coating solution with a solid content of 12%. After the weight gain of the coating reached 3.0% ⁇ 1%, the coating was stopped.
  • the prepared coated tablets were taken for dissolution examination. Samples were taken at 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes, and 60 minutes, and the average cumulative dissolution percentage was calculated. See Table 7 for dissolution results. For each dissolution medium, 15 coated tablets were taken and divided into 3 portions.
  • Example 9 Take the sample prepared in Example 9, and use high-density polyethylene (HDPE) and thick cold aluminum to simulate the packaging. After packaging, stake out at accelerated stability (temperature 40 °C ⁇ 2 °C, relative humidity 75% ⁇ 5%), and examine The changes in the content and related substances are shown in Table 8.
  • HDPE high-density polyethylene
  • Table 8 The changes in the content and related substances are shown in Table 8.
  • Example 9 Five 80 mg tablets prepared in Example 9 were extracted and disintegrated into suspensions with 50 mL of water, and rapid disintegration was observed (all samples disintegrated within 3 minutes). The dissolution of the suspension after disintegration was measured, and the results showed that the dissolution of the suspension after disintegration was slightly faster than that of the same tablet under normal dissolution conditions in the first 5 minutes. ; F2 similarity factor is greater than 50, the dissolution behavior is consistent.

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Abstract

L'invention concerne une composition pharmaceutique de composés du type 2-aminopyrimidine ou de sels pharmaceutiquement acceptables de ceux-ci. L'invention concerne plus particulièrement une composition pharmaceutique comprenant le N-((5-((5-chloro-4-((naphtalèn-1-yl)amino))pyrimidin-2-yl)amino)-2-((N-méthyl-N-diméthylaminoéthyl)amino)-4-méthoxy-phényl)acrylamide ou des sels pharmaceutiquement acceptables de celui-ci. L'invention concerne également un procédé de préparation de la composition pharmaceutique.
PCT/CN2019/101970 2018-08-23 2019-08-22 Composition pharmaceutique de composés du type 2-aminopyrimidine WO2020038434A1 (fr)

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CN102048736A (zh) * 2010-12-02 2011-05-11 深圳海王药业有限公司 一种达沙替尼的药物组合物及其制备方法
WO2013157754A1 (fr) * 2012-04-18 2013-10-24 제일약품주식회사 Procédé de préparation d'une formulation d'entécavir faiblement dosée à administrer par voie orale
CN104055745A (zh) * 2014-06-11 2014-09-24 连云港杰瑞药业有限公司 一种甲磺酸伊马替尼片的制备方法
CN104337782A (zh) * 2013-08-02 2015-02-11 山东新时代药业有限公司 一种甲磺酸伊马替尼片剂
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
CN108498477A (zh) * 2017-02-27 2018-09-07 江苏奥赛康药业股份有限公司 一种2-氨基嘧啶类化合物的药用组合物及其制备方法

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Publication number Priority date Publication date Assignee Title
US20150166591A1 (en) * 2012-05-05 2015-06-18 Ariad Pharmaceuticals, Inc. Methods and compositions for raf kinase mediated diseases
WO2017202311A1 (fr) * 2016-05-23 2017-11-30 中国科学院上海药物研究所 Forme polycristalline de 2-aminopyrimidine

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102048736A (zh) * 2010-12-02 2011-05-11 深圳海王药业有限公司 一种达沙替尼的药物组合物及其制备方法
WO2013157754A1 (fr) * 2012-04-18 2013-10-24 제일약품주식회사 Procédé de préparation d'une formulation d'entécavir faiblement dosée à administrer par voie orale
CN104337782A (zh) * 2013-08-02 2015-02-11 山东新时代药业有限公司 一种甲磺酸伊马替尼片剂
CN104055745A (zh) * 2014-06-11 2014-09-24 连云港杰瑞药业有限公司 一种甲磺酸伊马替尼片的制备方法
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
CN108498477A (zh) * 2017-02-27 2018-09-07 江苏奥赛康药业股份有限公司 一种2-氨基嘧啶类化合物的药用组合物及其制备方法

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