CN114787151B - Use of quinazoline derivatives or salts thereof, or pharmaceutical compositions thereof - Google Patents

Use of quinazoline derivatives or salts thereof, or pharmaceutical compositions thereof Download PDF

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CN114787151B
CN114787151B CN202080071551.0A CN202080071551A CN114787151B CN 114787151 B CN114787151 B CN 114787151B CN 202080071551 A CN202080071551 A CN 202080071551A CN 114787151 B CN114787151 B CN 114787151B
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formula
compound
pharmaceutically acceptable
acceptable salt
pharmaceutical composition
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CN114787151A (en
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杨朝强
封帆
葛琪
李琳
唐晓闻
王训强
尚磊
何佳丽
晏彩霞
董平
周杰
孙迎迎
许易
陈智林
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Capital Pharmaceutical Holdings Beijing Co ltd
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Lianyungang Runzhong Pharmaceutical Co Ltd
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Capital Pharmaceutical Holdings Beijing Co ltd
Chia Tai Tianqing Pharmaceutical Group Co Ltd
Lianyungang Runzhong Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • 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

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  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Use of quinazoline derivatives or pharmaceutically acceptable salts thereof, or solid pharmaceutical compositions thereof, in particular N shown in formula (I) 6 - (1-propenoylazepan-4-yl) -N 4 Use of- (3-chloro-4-fluorophenyl) -7-methoxyquinazoline-4, 6-diamine or a pharmaceutically acceptable salt thereof, or a solid pharmaceutical composition thereof.

Description

Use of quinazoline derivatives or salts thereof, or pharmaceutical compositions thereof
Cross Reference to Related Applications
The present application claims priority and equity to chinese patent application No. 201911059471.9 filed on month 11 and 01 of 2019 to the chinese national intellectual property agency, the disclosure of which is incorporated herein by reference in its entirety.
Technical Field
The application belongs to the technical field of medicines, relates to application of quinazoline derivatives or pharmaceutically acceptable salts thereof or pharmaceutical compositions thereof, in particular to application of quinazoline derivatives containing N 6 - (1-propenoylazepan-4-yl) -N 4 Use of- (3-chloro-4-fluorophenyl) -7-methoxyquinazoline-4, 6-diamine or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.
Background
EGFR (epidermal growth factor receptor, epithelial growth factor receptor) is a tyrosine kinase receptor, one of the HER/ErbB family members, which family includes EGFR, HER2, HER3 and HER4, consisting of three parts: extracellular ligand binding domain, transmembrane domain composed of single strands, and intracellular tyrosine kinase domain. EGFR is widely distributed on the surface of mammalian epithelial cells, fibroblasts, glial cells, keratinocytes and other cells. The EGFR signaling pathway plays an important role in physiological processes such as cell growth, proliferation and differentiation. The abnormal activity of key factors in EGFR and other protein tyrosine kinase functions or related signal paths or abnormal cell localization can cause the occurrence of tumors, diabetes, immunodeficiency and cardiovascular diseases.
The compound of formula (I) disclosed in WO2015043515A is a selective EGF receptor inhibitor, can block the interaction of the receptor with ATP by competitively combining with phosphorylation sites of intracellular tyrosine kinase, inhibit tyrosine phosphorylation and a series of downstream signal transduction, and then inhibit the growth of tumor cells, and can be used for treating various malignant tumors such as non-small cell lung cancer, breast cancer and the like. Wherein the chemical name of the compound of formula (I) is N 6 - (1-propenoylazepan-4-yl) -N 4 - (3-chloro-4-fluorophenyl) -7-methoxyquinazoline-4, 6-diamine.
Disclosure of Invention
In one aspect, the present application provides a method for preventing or treating cancer comprising administering to a subject in need thereof a compound of formula (I) or a pharmaceutically acceptable salt thereof
Wherein the cancer is selected from lung adenocarcinoma, lung squamous carcinoma, pharyngeal squamous carcinoma or esophageal carcinoma.
In another aspect, the present application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prevention or treatment of a cancer selected from lung adenocarcinoma, lung squamous carcinoma, pharyngeal squamous carcinoma or esophageal carcinoma.
In yet another aspect, the present application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the prevention or treatment of cancer selected from lung adenocarcinoma, lung squamous carcinoma, pharyngeal squamous carcinoma, or esophageal carcinoma.
In a further aspect, the present application provides a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of cancer, wherein the cancer is selected from lung adenocarcinoma, lung squamous carcinoma, pharyngeal squamous carcinoma or esophageal carcinoma.
In some embodiments, the cancer is selected from lung adenocarcinoma. In some embodiments, the cancer is selected from lung squamous carcinoma. In some embodiments, the cancer is selected from pharyngeal squamous carcinoma. In some embodiments, the cancer is selected from esophageal cancer.
In some embodiments, the lung adenocarcinoma contains mutant EGFR. In some embodiments, the mutants include, but are not limited to, exon18 point mutation of EGFR (G719A), exon 19 deletion mutation of EGFR (Del 19, e.g., E746-A750), exon 20 point mutation of EGFR (S768I), exon 21 point mutation of EGFR (L858R). In some embodiments, the EGFR mutants described above may be involved in one or both of a plurality of mutation types, for example, in one, two, three or four mutations.
In yet another aspect, the present application provides a method for preventing or treating lung cancer comprising administering to a subject in need thereof a compound of formula (I), or a pharmaceutically acceptable salt thereof, wherein the lung cancer comprises EGFR of one or more mutant forms selected from: EGFR No. 18 exon point mutation (G719A), EGFR No. 19 exon deletion mutation (Del 19, e.g., E746-A750), EGFR No. 20 exon point mutation (S768I), EGFR No. 21 exon point mutation (L858R).
In yet another aspect, the present application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the prevention or treatment of lung cancer, wherein the lung cancer comprises one or more mutant EGFR, the mutant selected from: EGFR No. 18 exon point mutation (G719A), EGFR No. 19 exon deletion mutation (Del 19, e.g., E746-A750), EGFR No. 20 exon point mutation (S768I), EGFR No. 21 exon point mutation (L858R).
In yet another aspect, the present application provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the prevention or treatment of lung cancer, wherein the lung cancer comprises EGFR in one or more mutant forms selected from: EGFR No. 18 exon point mutation (G719A), EGFR No. 19 exon deletion mutation (Del 19, e.g., E746-A750), EGFR No. 20 exon point mutation (S768I), EGFR No. 21 exon point mutation (L858R).
In yet another aspect, the present application provides a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment of lung cancer, wherein the lung cancer comprises EGFR in one or more mutant forms selected from the group consisting of: EGFR No. 18 exon point mutation (G719A), EGFR No. 19 exon deletion mutation (Del 19, e.g., E746-A750), EGFR No. 20 exon point mutation (S768I), EGFR No. 21 exon point mutation (L858R) EGFR.
In some embodiments, the EGFR mutant described above is an EGFR exon18 point mutation (G719A). In some embodiments, the EGFR mutant is an EGFR 19 exon deletion mutation (Del 19, e.g., E746-A750). In some embodiments, the EGFR mutant described above is an EGFR exon 20 point mutation (S768I). In some embodiments, the EGFR mutant described above is an EGFR exon 21 point mutation (L858R).
In some embodiments, the mutant is a combination of an EGFR 18 exon point mutation (G719A) and an EGFR 20 exon point mutation (S768I).
In some embodiments, the lung cancer is selected from non-small cell lung cancer.
In some embodiments, the lung cancer is selected from lung adenocarcinoma or lung squamous carcinoma.
In some embodiments, the individual with lung cancer (e.g., lung adenocarcinoma or lung squamous carcinoma) is selected from patients who have received prior treatment (e.g., prior chemical treatment).
In some embodiments, the lung cancer individual has received prior treatment selected from gefitinib, bevacizumab, pemetrexed, platinum-based drugs (e.g., carboplatin), and combinations thereof.
In some embodiments, the lung cancer individual is selected from patients who have previously been treated with gefitinib and/or bevacizumab.
In some embodiments, the lung cancer individual is selected from patients who have previously received combination therapy of pemetrexed, carboplatin, and bevacizumab, or combination therapy of pemetrexed and bevacizumab.
In some embodiments, the lung cancer individual is selected from patients who have previously received oral gefitinib 0.25g qd targeted therapy.
In some embodiments, the lung cancer individual is selected from patients who have previously received 100mg chest injections of bevacizumab.
In some embodiments of any of the above aspects, the lung adenocarcinoma is non-small cell lung adenocarcinoma.
In some embodiments of any of the above aspects, the lung adenocarcinoma includes, but is not limited to, advanced lung adenocarcinoma.
In some embodiments of any of the above aspects, the lung adenocarcinoma described above includes, but is not limited to, lung adenocarcinoma that fails or recurs after lacking conventional effective treatment methods or conventional methods of treatment.
In some embodiments of any of the above aspects, the lung squamous carcinoma is non-small cell lung squamous carcinoma.
In some embodiments of any of the above aspects, the lung squamous carcinoma includes, but is not limited to, advanced lung squamous carcinoma.
In some embodiments of any of the above aspects, the lung squamous carcinoma includes, but is not limited to, lung squamous carcinoma that fails or recurs after lacking conventional effective treatment methods or conventional methods of treatment.
The amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof administered may be determined according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the patient. In some embodiments, the daily dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, administered is from 0.2mg to 60 mg, or from 0.5mg to 40 mg, or from 1.0mg to 40 mg, or from 1.5mg to 40 mg, or from 2mg to 40 mg, or from 4mg to 40 mg, or from 5mg to 40 mg, or from 6 mg to 40 mg, or from 7mg to 40 mg, or from 8mg to 30 mg, or from 8mg to 25mg, or from 8mg to 20 mg, or from 8mg to 16 mg, calculated as the compound of formula (I).
In a particular embodiment, the daily dose of the compound of formula (I), or a pharmaceutically acceptable salt thereof, is selected from 0.2mg, 0.5mg, 1 mg, 1.5mg, 2mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0mg, 4.5 mg, 5mg, 5.5 mg, 6 mg, 6.5 mg, 7mg, 7.5 mg, 8mg, 8.5 mg, 9 mg, 9.5 mg, 10mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg or 18 mg calculated for the compound of formula (I). In a particular embodiment, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 8mg calculated for the compound of formula (I). In a particular embodiment, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered at a dose of 10mg calculated for the compound of formula (I). In a particular embodiment, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 12 mg calculated for the compound of formula (I). In a particular embodiment, the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is 16 mg calculated for the compound of formula (I).
The compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered by a variety of routes including, but not limited to, the following: oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, buccal, intranasal, inhaled, vaginal, intraocular, topical, subcutaneous, intraadipose, intra-articular, intraperitoneal and intrathecal. In a particular embodiment, the administration is by oral administration.
The compound of formula (I) or a pharmaceutically acceptable salt thereof may be administered one or more times daily. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered 1 time per day. The compounds of formula (I) or pharmaceutically acceptable salts thereof may also be administered in single or multiple dose forms. In one embodiment, the administration is 1 time per day in a single dose.
In one embodiment, the oral solid formulation is administered 1 time per day in a single dose. In one embodiment, the administration is 1 time per day in multiple doses.
The method of administration can be determined comprehensively based on the activity, toxicity, tolerance of the patient, etc.
In one embodiment, the individual is administered once daily with an oral solid pharmaceutical composition at a dose of 8mg, the solid pharmaceutical composition being administered in a single dose of 2mg. In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered alone to the patient as the sole active ingredient.
A compound of formula (I) or a pharmaceutically acceptable salt thereof
The compounds of formula (I) of the present application may be administered in the form of their free base, or in the form of their salts, hydrates and prodrugs which are converted in vivo to the free base form of the compounds of formula (I). For example, pharmaceutically acceptable salts of the compounds of formula (I) are within the scope of the invention, which salts may be produced from various organic and inorganic acids according to methods well known in the art.
The pharmaceutically acceptable salts described herein are selected from the group consisting of maleates, hydrochlorides, hydrobromides, sulphates, phosphates, nitrates, acetates, lactates, malonates, succinates, fumarates, malates, mandelates, tartrates, citrates, ascorbates, palmitates, benzoates, phenylacetates, cinnamates, salicylates, methanesulfonates, benzenesulfonates, or methylbenzenesulfonates.
In some embodiments, the pharmaceutically acceptable salt is selected from the group consisting of maleate, malate, fumarate, tartrate, citrate, lactate, phosphate, or acetate.
In some embodiments, the pharmaceutically acceptable salt is selected from the group consisting of maleates.
Regarding pharmaceutically acceptable salts of the compounds of formula (I) described herein, the molar ratio of the compound of formula (I) to the acid ion forming the pharmaceutically acceptable salt may be selected from 1:1.
A pharmaceutically acceptable salt of a compound of formula (I) as described herein, selected from the group consisting of a compound of formula (I) or a maleate salt of a compound of formula (I).
Pharmaceutically acceptable salts of the compounds of formula (I) described herein are compounds of formula (II)
The "compound of formula (I) or a pharmaceutically acceptable salt thereof" described herein may be replaced by "compound of formula (II)"; for example, the above-described "administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof" may be replaced by "administering a compound of formula (II) to a subject in need thereof".
Pharmaceutical composition
The "compound of formula (I) or a pharmaceutically acceptable salt thereof" described herein may be "a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof", and further "a pharmaceutical composition comprising the compound of formula (II)". For example, the above-mentioned "administering a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof" may be "administering a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof to a subject in need thereof", and further, may be "administering a pharmaceutical composition comprising a compound of formula (II) to a subject in need thereof". In some embodiments, the above pharmaceutical composition further comprises a pharmaceutically acceptable excipient.
In some embodiments, the pharmaceutical composition is in a single dose of 0.2mg to 60 mg, or 0.5mg to 40 mg, or 1.0mg to 40 mg, or 1.5mg to 40 mg, or 2mg to 40 mg, or 4mg to 40 mg, or 5mg to 40 mg, or 6 mg to 40 mg, or 7mg to 40 mg, or 8mg to 30 mg, or 8mg to 25mg, or 8mg to 20 mg, or 8mg to 16 mg, calculated as compound of formula (I).
In some embodiments, the present application provides a pharmaceutical composition of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for preventing or treating lung adenocarcinoma, lung squamous carcinoma, pharyngeal squamous carcinoma, and esophageal carcinoma, in a single dose of 0.2mg, 0.5mg, 1 mg, 1.5mg, 2mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0mg, 4.5 mg, 5mg, 5.5 mg, 6 mg, 6.5 mg, 7mg, 7.5 mg, 8mg, 8.5 mg, 9 mg, 9.5 mg, 10mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 17 mg, 17.5 mg, or 18 mg, calculated as the compound of formula (I).
In some embodiments, the single dose of the pharmaceutical composition is 8mg, 10mg, 12 mg or 16 mg, calculated as compound of formula (I); in some particular embodiments, the single dose is 8 milligrams; in some particular embodiments, the single dose is 10 milligrams; in some particular embodiments, the single dose is 12 milligrams; in some particular embodiments, the single dose is 16 milligrams.
Each of the pharmaceutical compositions of the present application may be a solid pharmaceutical composition that may be in a variety of dosage forms intended to be formed into a formulation suitable for oral administration to a patient (e.g., a human), including, for example, tablets, pills, capsules, powders, granules, or the like.
The above pharmaceutical composition may be administered one or more times daily. In some embodiments, the above pharmaceutical composition is administered 1 time per day. The above pharmaceutical compositions may also be administered in single or multiple dose form.
In one embodiment, the administration is 1 time per day.
In one embodiment, the administration is 1 time per day in a single dose. In one embodiment, the administration is 1 time per day in multiple doses.
The method of administration can be determined comprehensively based on the activity, toxicity, tolerance of the patient, etc.
In some embodiments, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is administered alone to the patient as the sole active ingredient.
In some embodiments, the above pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof and a polymethacrylate.
In some embodiments, the above pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, a polymethacrylate, and an acid.
In some embodiments, the above pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, a polymethacrylate, and a surface stabilizer.
In some embodiments, the above pharmaceutical compositions comprise a compound of formula (I) or a pharmaceutically acceptable salt thereof, a polymethacrylate, an acid, a surface stabilizer, a dispersant, and a carrier.
In some embodiments, the above pharmaceutical composition comprises a compound of formula (II), a polymethacrylate, an acid, a surface stabilizer, a dispersant, and a carrier.
In some embodiments, the polymethacrylate is
In some embodiments, the polymethacrylate is selected from And combinations thereof.
In some embodiments, the polymethacrylate is selected from
In some embodiments, the weight ratio of polymethacrylate to the compound of formula (I) or a pharmaceutically acceptable salt thereof in the above pharmaceutical composition is 50-0.5:1, or 45-1:1, or 40-1.5:1, or 35-2:1, or 30-3:1, or 25-4:1, or 20-5:1, or 18-5.5:1, or 16-5.7:1, or 14-5.9:1, or 12-6.1:1, or 10-6.3:1, or 8.5-6.5:1, or 8.5-7:1, or 8.5-7.5:1.
In some embodiments, the weight ratio of polymethacrylate to the compound of formula (II) in the above pharmaceutical composition is 8:1.
In some embodiments, the acid is selected from the group consisting of maleic acid, malic acid, fumaric acid, tartaric acid, citric acid, lactic acid, phosphoric acid, acetic acid, and combinations thereof.
In some embodiments, the acid is maleic acid.
In some embodiments, the above pharmaceutical composition is 0.1 to 50wt%, alternatively 0.1 to 20wt%, alternatively 0.1 to 10wt%, alternatively 0.1 to 5wt%, alternatively 0.1 to 4wt% of the total mass of the solid pharmaceutical composition of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
In some embodiments, the surface stabilizer is selected from the group consisting of hydroxypropyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl-cellulose phthalate, amorphous cellulose, and combinations thereof.
In some embodiments, the surface stabilizer is selected from hydroxypropyl cellulose (e.g., HPC-SL type).
In some embodiments, the weight ratio of surface stabilizer to compound of formula (I) or a pharmaceutically acceptable salt thereof in the above pharmaceutical composition is 0.06 to 1:1, alternatively 0.07 to 0.9:1, alternatively 0.08 to 0.8:1, alternatively 0.09 to 0.7:1, alternatively 0.10 to 0.6:1, alternatively 0.11 to 0.5:1, alternatively 0.12 to 0.7:1, alternatively 0.13 to 0.6:1, alternatively 0.14 to 0.5:1, alternatively 0.15 to 0.4:1, alternatively 0.15 to 0.3:1, alternatively 0.15 to 0.2:1.
In some embodiments, the weight ratio of surface stabilizer to compound of formula (II) in the above pharmaceutical composition is 0.16:1.
In some embodiments, the dispersant is selected from sucrose, lactose, or mannitol.
In some embodiments, the dispersant is selected from sucrose.
In some embodiments, the weight ratio of dispersant to compound of formula (I) or a pharmaceutically acceptable salt thereof in the above pharmaceutical composition is 0.5-50:1, or 0.8-45:1, or 1.1-40:1, or 1.4-35:1, or 1.7-30:1, or 2-25:1, or 2.3-20:1, or 2.8-15:1, or 3.1-10:1, or 3.4-9:1, or 3.7-8:1, or 4.0-7:1, or 4.3-6:1, or 4.5-5.5:1,
in some embodiments, the weight ratio of dispersant to compound of formula (II) in the above pharmaceutical composition is 5:1.
In some embodiments, the carrier is selected from the group consisting of cellulose spheres, mannitol cores, tartaric acid cores, lactose/microcrystalline cores, sucrose cores, starch cores, and combinations thereof.
In some embodiments, the carrier is selected from a cellulose pellet or a sucrose pellet core.
In some embodiments, the carrier is selected from the group consisting of sucrose pellets (e.g., 0.6-0.8 mm).
In some embodiments, the carrier comprises a proportion ranging from 0.1 to 99wt%, 0.5 to 99wt%, 1 to 99wt%, 5 to 99wt%, 10 to 99wt%, 15 to 99wt%, 20 to 99wt%, 25 to 99wt%, 30 to 99wt%, 35 to 99wt%, 40 to 99wt%, or 45 to 99wt% of the pharmaceutical composition.
In some embodiments, the pharmaceutical compositions comprise a compound of formula (II), hydroxypropyl cellulose (e.g., HPC-SL type), sucrose, polymethacrylate (e.g.) Maleic acid, sucrose pellets (e.g., 0.6-0.8 mm).
The pharmaceutical composition comprises the following components in parts by weight:
in specific embodiments, the solid pharmaceutical composition above, wherein the polymethacrylate, acid, surface stabilizer, dispersant and carrier are each as defined above.
The pharmaceutical composition comprises the following components in parts by weight:
the pharmaceutical composition comprises the following components in parts by weight:
the pharmaceutical composition comprises the following components in parts by weight:
the pharmaceutical composition comprises the following components in parts by weight:
the pharmaceutical composition comprises the following components in parts by weight:
the particle size of each of the above-mentioned pharmaceutical compositions of the present application, the compound of formula (I) or a pharmaceutically acceptable salt thereof, ranges from D50 < 10 μm to D90 < 20 μm; or D50 < 5 μm and D90 < 10 μm; or D50 < 2 μm and D90 < 4 μm.
In some embodiments, the particle size of the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the range D50 < 2 μm and D90 < 4 μm.
The above-mentioned pharmaceutical compositions of the present application, wherein the acid is added in an amount, for example, to make the pharmaceutical composition acidic in water.
In some embodiments, each of the above pharmaceutical compositions, wherein the maleic acid is added in an appropriate amount. In some embodiments, the acid may be used as a pH adjuster in each of the above pharmaceutical compositions, for example during the preparation of a solid pharmaceutical composition, to adjust the pH in a range, for example in an aqueous solution, more particularly, for example in an aqueous solution having a pH of between 3.0 and 3.5 or between 2.0 and 3.0.
Each of the above-described pharmaceutical compositions of the present application may be formulated into various dosage forms intended to be suitable for oral administration to a patient (e.g., a human), including, for example, tablets, pills, capsules, powders, granules, or the like.
In some embodiments, the pharmaceutical compositions of the present application are administered orally.
In some embodiments, each of the above pharmaceutical compositions is a solid pharmaceutical composition.
In some embodiments, the solid pharmaceutical compositions of the present application are formulated in capsules.
In some embodiments, the above-described capsules are filled with micropellet particles comprising a solid pharmaceutical composition as described above.
In some embodiments, the capsule is a hard capsule or a soft capsule.
Capsules may be prepared by loading pellets of the aforementioned compound of formula (I) or a pharmaceutically acceptable salt thereof into hard capsules made of gelatin, hydroxypropyl methylcellulose, polyvinyl alcohol, etc., or into gelatin-based soft capsules according to known methods.
The pharmaceutical compositions of the present application may be manufactured by methods well known in the art, such as conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, freeze-drying, and the like.
The solid oral compositions may be prepared by conventional mixing, filling or tabletting methods. For example, it can be obtained by the following method: the active compound is mixed with solid auxiliary materials, the resulting mixture is optionally milled, if desired with other suitable auxiliary materials, and the mixture is then processed to granules, giving a tablet or dragee core. Suitable excipients include, but are not limited to: binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
In another aspect, the present application provides a method of preparing a solid composition comprising the process of:
preparing a suspension comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof; adding an acid and a polymethacrylate to the suspension; and (3) carrying out fluidized bed drug loading on the obtained suspension on a carrier to obtain drug-containing pellets.
The treatment scheme has better curative effect in treating lung adenocarcinoma, lung squamous carcinoma, pharyngeal squamous carcinoma or esophageal carcinoma. Wherein there is prominent effect data at least in at least one of ORR, DCR, doR, PFS or OS; and the patient has good tolerance and small side effect.
The solid pharmaceutical composition containing the compound shown in the formula (I) and the pharmaceutically acceptable salt thereof has low maximum single impurity content, less total impurities, no obvious change of active ingredients and the impurity content, good stability, high bioavailability and higher dissolution rate, and is suitable for industrial production, storage and clinical use.
Definition and description
The words "comprise" or "include" and variations thereof such as "comprises" or "comprising" are to be interpreted in an open, non-exclusive sense, i.e. "including but not limited to.
The term "optionally" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not. Which means that it may alternatively be used interchangeably with "or".
The term "patient" refers to a mammal, preferably a human. In some embodiments, the patient is a patient who has failed standard therapy or lacks standard therapy.
The term "pharmaceutically acceptable" or "pharmaceutically acceptable" refers to the use thereof in the preparation of pharmaceutical compositions which are generally safe, non-toxic and neither biologically nor otherwise undesirable, and which are included as being acceptable for human pharmaceutical use. The terms "pharmaceutically acceptable" and "pharmaceutically acceptable" are used interchangeably herein.
The term "therapeutically effective amount" means an amount of a compound that, when administered to a human being for treating a disease, is sufficient to effect treatment of the disease.
The term "treatment" means administration of a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
(i) Inhibiting a disease or disease state, i.e., inhibiting its progression;
(ii) The disease or condition is alleviated, even if the disease or condition subsides.
The term "preventing" means that a compound or formulation described herein is administered to prevent a disease or one or more symptoms associated with the disease, including: preventing a disease or a disease state from occurring in a mammal, particularly when such mammal is susceptible to the disease state, but has not been diagnosed as having the disease state.
The term "pharmaceutically acceptable excipients" refers to those excipients which do not significantly stimulate the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to the person skilled in the art, such as carbohydrates, waxes, water soluble and/or water swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water and the like.
The term "single dose" refers to the smallest packaging unit containing a quantity of a drug, e.g., a box of seven capsules, each capsule being a single dose; or a single dose per bottle of injectate.
The application uses the following abbreviations:
PD: disease progression (progressive disease), at least an increase of 20% or more in the sum of the maximum diameters of target lesions, or the appearance of new lesions.
PR: partial response, the sum of the maximum diameters of target lesions is reduced by 30% or more, for at least 4 weeks.
OS: total survival (over all survivinal), time from the start of randomization to death (for any reason).
SD: disease stabilization (stable disease), the sum of the maximum diameters of target lesions is reduced by less than PR, or increased by less than PD.
PO: is orally taken.
Description of the embodiments
The following specific examples are intended to provide those skilled in the art with a more clear understanding and practice of the present application. They should not be considered as limiting the scope of the application, but merely as being illustrative and representative of the application.
Example 1
1) Adding hydroxypropyl cellulose into water 1 Adding the compound of formula (II) into the mixture under stirring after dissolving, dispersing uniformly, and sieving;
2) Homogenizing the drug-containing suspension at high pressure, and controlling the particle size of a compound of a formula (II): d50 < 2 μm and D90 < 4 μm;
3) Preparing maleic acid water with the concentration of 0.5mol/L 2 The solution is prepared by dissolving half of the prepared maleic acid aqueous solution into the prescriptionAdding the suspension obtained in the step 2) after the solution is clear, and then adjusting the pH value of the suspension to be 3.0-3.5 by using the residual maleic acid aqueous solution to obtain the suspension;
4) Coating the suspension prepared in the step 3) on a sucrose blank pellet core in a fluidized bed to obtain a drug-containing pellet;
5) Adding the drug-containing pellets into a hopper mixer for uniform mixing;
6) Filling the capsule.
The composition of a specific pharmaceutical capsule formulation is shown in table 1 below.
TABLE 1
Water and its preparation method 1 :26.67mg; water and its preparation method 2 ：20mg。
Examples 2-5 the procedure of example 1 was followed to prepare specific pharmaceutical capsule formulations having the compositions shown in table 2 below.
TABLE 2
Note that:
example 2 Water 1 :66.67mg; water and its preparation method 2 ：50mg；
Example 3 Water 1 :266.68mg; water and its preparation method 2 ：200mg；
Example 4 Water 1 :666.7mg; water and its preparation method 2 ：500mg；
Example 5 Water 1 :1333.4mg; water and its preparation method 2 ：1000mg。
Example 6
Reference to steps 1) -6) of example 1), except that in step 3) the pH of the suspension is adjusted to a pH of 2.0.ltoreq.pH < 3.0, and water 1 :25mg; water and its preparation method 2 ：50mg。
The composition of a particular pharmaceutical capsule formulation is shown in table 3 below.
TABLE 3 Table 3
Experimental example 1 cell Activity
Sulfonyl rhodamine B protein staining method (SRB method)
Human pharyngeal squamous carcinoma cells (FaDu cells) (purchased from Shanghai Seisakusho of China academy of sciences of life) were cultured with RPMI 1640 medium containing 10% FBS.
The preparation method of the sample comprises the following steps: prepared to 10mM with dimethyl sulfoxide (DMSO) and stored at-80 ℃.
A number of logarithmic growth phase cells were seeded in 96 well plates. After 24 hours of adherent growth, samples to be tested with different concentrations are added. After the drug action is completed, the cells are fixed with trichloroacetic acid. SRB solution (Sigma) was then stained; finally, adding Tris solution to dissolve SRB, measuring OD value under the wavelength of 510nm by using an enzyme label instrument, and calculating the cell growth inhibition rate according to the following formula:
inhibition = (OD control well-OD dosing well)/OD control well x 100%
Based on the concentration inhibition ratios, the median inhibition concentration IC was calculated 50 。
The results are shown in Table 4 below.
TABLE 4 Table 4
Experimental example 2 in vivo efficacy in mice
BALB/cA-nude mice, 6-7 weeks, females, purchased from Shanghai Laek laboratory animal Limited. Production license number: SCXK 2012-0002; animal pass number 2007000570156. Feeding environment: SPF stage. Nude mice were inoculated subcutaneously with human pharyngeal squamous carcinoma FaDu cells until tumors grew to 80-150mm 3 Animals were then randomly grouped (D0). The dosage and regimen are shown in Table 4. Tumor volumes were measured 2 times per week, mice were weighed, and data were recorded.
BALB/cA-nude mice, 6-7 weeks, females, were purchased from Shanghai Ling Biotechnology Co. Production license number: SCXK 2013-0018; pass number: 2013001802999. feeding environment: SPF stage. Nude mice are inoculated with human esophageal cancer Eca-109 cells subcutaneously and the tumor grows to 100-300mm 3 Animals were then randomly grouped (D0). The dosage and regimen are shown in Table 4. Tumor volumes were measured 2 times per week, mice were weighed, and data were recorded.
BALB/cA-nude mice, 6-7 weeks, females, purchased from Shanghai Laek laboratory animal Limited. Production license number: SCXK 2012-0002; animal pass number 2007000570541. Feeding environment: SPF stage. Subcutaneously inoculating HCC827 cells of human non-small cell lung cancer into nude mice, and growing tumor to 100-200mm 3 Animals were then randomly grouped (D0). The dosage and regimen are shown in Table 4. Tumor volumes were measured 2 times per week, mice were weighed, and data were recorded.
The tumor volume (V) was calculated as:
V＝1/2×a×b 2 the method comprises the steps of carrying out a first treatment on the surface of the Wherein a and b respectively represent the length and width of the tumor.
The relative tumor volume (relative tumor volume, RTV) is calculated from the measurements as:
RTV＝V t /V 0 the method comprises the steps of carrying out a first treatment on the surface of the Wherein V is 0 Tumor volume measured at the time of divided administration (i.e., D0); v (V) t Tumor volume at each measurement.
T/C(％)＝(T-T 0 )/(C-C 0 ) X 100%; wherein T, C is the tumor volume of the experimental and control groups at the end of the experiment; t (T) 0 、C 0 For the experiment to open
Tumor volumes of the initial experimental and control groups.
Tumor inhibition rate (%) =100% -T/C (%).
Tumor inhibition (%) =100% - (T-T) when tumor regression occurs 0 )/T 0 ×100％。
The preparation method of the sample comprises the following steps: all formulated with 0.4% Tween-80/0.5% CMC.
The test results are shown in Table 5.
TABLE 5
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D0: randomly grouping, and performing first administration time; d0-6 means 6 days of administration; d0-20 means administration for 20 days; PO: stomach lavage
Experimental example 3 study of curative effects
3.1 inclusion criteria:
1. patients with advanced malignant solid tumors, diagnosed pathologically and/or cytologically, lack conventional effective treatment methods or fail or recur after treatment by conventional methods; the case expansion phase, EGFR positivity (including common mutation of 18-2l exons and rare mutation) meeting the conditions is entered into a group;
2.18 to 70 years old; ECOG physical condition: 0 to 1 minute; the expected lifetime exceeds 3 months;
3. the major organs function normally, i.e. meet the following criteria:
a) Blood routine examination: hb 90g/L (no transfusion within 14 days before starting treatment); ANC is more than or equal to 1.5X109/L; PLT is more than or equal to 100X 109/L
b) Biochemical examination: serum creatinine < 1.5 times upper normal limit, total bilirubin < 1.5 times upper normal limit, aspartate Aminotransferase (AST) or alanine Aminotransferase (ALT) < 3 times upper normal limit (ULN) (if associated with liver metastasis, < 5 times upper normal limit)
c) Doppler ultrasound assessment: left Ventricular Ejection Fraction (LVEF) is greater than or equal to 50%;
4. women should agree that contraceptive measures (such as intrauterine device [ IUD ], contraceptive or condoms) must be taken during the study period and within 6 months after the end of the study; serum or urine pregnancy tests are negative within 7 days prior to study entry and must be non-lactating patients; men should agree to patients who must take contraceptive measures during the study period and within 6 months after the end of the study period;
5. patients voluntarily added the study, signed informed consent, and compliance was good.
3.2 test drug
A compound capsule of formula (II): is provided by the pharmaceutical company of the pharmaceutical industry group, inc.
Specification (calculated as compound of formula (I)): 0.2mg, 0.5mg, 2mg, 5mg, 10mg; shading, sealing, storing at 20 ℃ or below, and valid period: for 24 months.
(1) Single administration dose increment method:
starting at 0.2 mg/day, the second dose group was 0.5 mg/day, the third dose group was 1.0 mg/day, the fourth dose group was 1.5 mg/day, the fifth dose group was 2.0 mg/day, the sixth dose group was 4.0 mg/day, the seventh dose group was 8.0 mg/day, the eighth dose group was 10.0 mg/day, the ninth dose group was 12.0 mg/day, and the tenth dose group was 16.0 mg/day.
(2) Continuous dosing increment method:
taking part in single administration patients, and after taking the medicine for 3 days, starting to take continuous medicine with single administration dosage once daily under the condition of ensuring safety and controllability. If the drug half-life exceeds 24 hours, the subsequent dose groups are administered directly in succession. The first two dose groups were dosed with reference to the doses of the first two dose groups of a single dose, i.e. starting from 0.2 mg/day, the second dose group was 0.5 mg/day, the third dose group was 1.0 mg/day, the fourth dose group was 1.5 mg/day, the fifth dose group was 2.0 mg/day, the sixth dose group was 4.0 mg/day, the seventh dose group was 8.0 mg/day, the eighth dose group was 10.0 mg/day, the ninth dose group was 12.0 mg/day, and the tenth dose group was 16.0 mg/day until DLT was reached.
3.3 evaluation criteria
The main efficacy index evaluates efficacy according to RECIST1.1 standard.
3.4 efficacy assessment
Objective Remission Rate (ORR): only the objective tumor remission rate of patients measurable according to RECIST version 1.1 disease was calculated. Objective remission rate is defined as the ratio of complete remission to partial remission of the patient. Patients who have not been tumor assessed after baseline will be considered to have no objective relief.
Disease Control Rate (DCR): disease control rate is defined as the proportion of patients who are fully and partially relieved and stable to disease.
Remission (DoR): remission is defined as the time from the initial appearance of complete or partial remission to the appearance of disease progression in a patient with objective remission. If the patient has not died or had disease progression at the end of the study, or the patient is out of visit, remission statistics will be up to the time of the last tumor evaluation.
Progression Free Survival (PFS): PFS is defined as the time from the first study treatment to the onset of disease progression or death in a patient. If the patient is still not dying or developing disease progression at the end of the study, or the patient is not interviewed, the PFS statistics will be up to the time of the last tumor evaluation.
Improvement or worsening of general status is indicated by changes in ECOG scores before and after treatment.
3.5 therapeutic Effect
3.5.1 therapeutic effects on non-small cell lung adenocarcinoma
A 58 year old female, 4 th 2018 thoracocentesis, hydrothorax cytology: a large number of malignant cells are seen, considered as adenocarcinomas. The transcranial MRI did not see signs of metastasis. The gene detection of the hydrothorax cell shows that: EGFR exon 20S 7688I mutation, exon 18G 719A mutation.
Oral gefitinib 0.25g qd targeted therapy 25 days after 2018, 04 months. The first bevacizumab 100mg chest injection was given 5 months 2018. Chest CT was reviewed at 5.30 a 2018 (compared to 10 a 2018 at 4): the patch of the right lung portal area is reduced more than before, the double lung multiple nodule is approximately the same as before, the right chest metastasis is reduced more than before, and the right pleural effusion is reduced more than before. Patients on the right side with chest distress and dyspnea with cough and white phlegm appear again on day 6 and 20 of 2018. Chest CT review at 7.3.2018: the right lung gate occupies a space with lesions, and the two lungs are disseminated with multiple metastasis nodules, and the right pleural thickening is accompanied by right pleural effusion. The 7 th and 9 th 2018 th positioning of hydrothorax shows the right middle-volume effusion, and the injection of bevacizumab into the chest cavity controls hydrothorax. A review of 8.2.2018 suggests disease progression and stop taking gefitinib therapy. A review of 31 days 8 and 31 years 2018 suggests that the nodule in the lung is enlarged before and that the chest water is increased before, suggesting that the disease PD. Treatment with 4-cycle pemetrexed+carboplatin+bevacizumab regimen was performed at 9/20/2018 to 12/21/2018, with 1 degree decrease in leukocytes and neutrophils following chemotherapy. 18 days of 2019, 1 cycle of pemetrexed and bevacizumab regimen treatment, optimal efficacy SD. Cough and chest distress of later patients are gradually aggravated before, and comprehensive evaluation considers disease progression.
8.0mg (2 mg per capsule, 4 total capsules based on the compound of formula (I)) of the compound of formula (II) prepared in the above example was orally administered once daily (3 days of single administration), and 8.0mg (based on the compound of formula (I)) of the compound of formula (II) was orally administered once daily (one treatment cycle per 28 days of continuous administration) starting on 4 months of 2019.
Patients on day 4 and 30 of 2019 receive treatment for 1 period, and the CT is enhanced to prompt the lower right lung door tumor to shrink more than before; the upper right leaf is transferred to the same front node; liver S2 lesions, reduced anteriorly; PR was evaluated as RECIST1.1, with a total target lesion of 37mm, a 17mm reduction from baseline.
Patient enhancement CT at 6 months and 27 days 2019 suggests a slightly smaller right lower lung door tumor. The total target lesions were 28mm.
The 22-day enhancement CT in 2019, 8, suggests that the lesions do not change much more than before, and the total target lesions are 28mm.
Day-enhanced CT suggests less focal changes than before, maintaining PR, 10 months, 21 days 2020.
Adverse patient reactions are essentially tolerated and continue to receive treatment.

Claims (32)

1. The use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the prophylaxis or treatment of cancer,
wherein the cancer is selected from pharyngeal squamous carcinoma or esophageal carcinoma.
2. The use of claim 1, wherein: the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered orally.
3. The use of claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof, is administered one or more times daily.
4. The use according to claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in single or multiple dose form.
5. The use of claim 1, wherein: the compounds of formula (I) may be administered in the form of their free bases or in the form of their salts.
6. The use of claim 1, wherein the pharmaceutically acceptable salt is selected from the group consisting of maleate, hydrochloride, hydrobromide, sulfate, phosphate, nitrate, acetate, lactate, malonate, succinate, fumarate, malate, mandelate, tartrate, citrate, ascorbate, palmitate, benzoate, phenylacetate, cinnamate, salicylate, methanesulfonate, benzenesulfonate, and methylbenzenesulfonate.
7. The use of claim 6, wherein the pharmaceutically acceptable salt is selected from the group consisting of maleate, malate, fumarate, tartrate, citrate, lactate, phosphate, and acetate.
8. The use of claim 7, wherein the pharmaceutically acceptable salt is selected from the group consisting of maleates.
9. The use of claim 6, wherein the molar ratio of the compound of formula (I) to the acid ion forming the pharmaceutically acceptable salt in the pharmaceutically acceptable salt of the compound of formula (I) is 1:1.
10. The use according to claim 1, wherein the pharmaceutically acceptable salt of the compound of formula (I) is a compound of formula (II)
11. The use of claim 1, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is in the form of a pharmaceutical composition comprising the compound of formula (I) or a pharmaceutically acceptable salt thereof.
12. The use of claim 11, wherein the pharmaceutical composition of the compound of formula (I) or a pharmaceutically acceptable salt thereof is a solid pharmaceutical composition.
13. The use of claim 1, wherein the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is from 0.2mg to 60 mg, or from 0.5mg to 40 mg, or from 1.0mg to 40 mg, or from 1.5mg to 40 mg, or from 2mg to 40 mg, or from 4mg to 40 mg, or from 5mg to 40 mg, or from 6 mg to 40 mg, or from 7mg to 40 mg, or from 8mg to 30 mg, or from 8mg to 25mg, or from 8mg to 20 mg, or from 8mg to 16 mg, calculated as the compound of formula (I).
14. The use of claim 11, wherein the daily dose of the pharmaceutical composition is from 0.2mg to 60 mg, or from 0.5mg to 40 mg, or from 1.0mg to 40 mg, or from 1.5mg to 40 mg, or from 2mg to 40 mg, or from 4mg to 40 mg, or from 5mg to 40 mg, or from 6 mg to 40 mg, or from 7mg to 40 mg, or from 8mg to 30 mg, or from 8mg to 25mg, or from 8mg to 20 mg, or from 8mg to 16 mg, calculated as compound of formula (I).
15. The use of claim 1, wherein the daily dose of the compound of formula (I) or a pharmaceutically acceptable salt thereof is selected from 0.2mg, 0.5mg, 1 mg, 1.5mg, 2mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0mg, 4.5 mg, 5mg, 5.5 mg, 6 mg, 6.5 mg, 7mg, 7.5 mg, 8mg, 8.5 mg, 9 mg, 9.5 mg, 10mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg or 18 mg, calculated as the compound of formula (I).
16. The use of claim 11, wherein the daily dose of the pharmaceutical composition is selected from 0.2mg, 0.5mg, 1 mg, 1.5mg, 2mg, 2.5 mg, 3.0 mg, 3.5 mg, 4.0mg, 4.5 mg, 5mg, 5.5 mg, 6 mg, 6.5 mg, 7mg, 7.5 mg, 8mg, 8.5 mg, 9 mg, 9.5 mg, 10mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg or 18 mg calculated as the compound of formula (I).
17. The use of claim 11, wherein: the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, a polymethacrylate and an acid.
18. The use of claim 17, wherein: the pharmaceutical composition comprises a compound of formula (I) or a pharmaceutically acceptable salt thereof, a polymethacrylate, an acid, a surface stabilizer, a dispersing agent and a carrier.
19. The use according to claim 18, wherein the pharmaceutical composition comprises a compound of formula (II), a polymethacrylate, an acid, a surface stabilizer, a dispersant and a carrier,
20. the use of claim 17, wherein: the polymethacrylate in the pharmaceutical composition is
21. The use of claim 20, wherein the polymethacrylate is selected from the group consisting of Or a combination thereof.
22. The use of claim 21, wherein the polymethacrylate is selected from the group consisting of
23. The use of claim 17, wherein the acid in the pharmaceutical composition is selected from the group consisting of maleic acid, malic acid, fumaric acid, tartaric acid, citric acid, lactic acid, phosphoric acid, acetic acid, and combinations thereof.
24. The use of claim 23, wherein the acid is maleic acid.
25. The use of claim 18, wherein the surface stabilizer in the pharmaceutical composition is selected from the group consisting of hydroxypropyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl-cellulose phthalate, amorphous cellulose, and combinations thereof.
26. The use of claim 25, wherein the surface stabilizer is selected from hydroxypropyl cellulose.
27. The use of claim 18, wherein the dispersant in the pharmaceutical composition is selected from the group consisting of sucrose, lactose, mannitol, and combinations thereof.
28. The use of claim 27, wherein the dispersant is selected from sucrose.
29. The use of claim 18, wherein the carrier in the pharmaceutical composition is selected from the group consisting of cellulose spheres, mannitol cores, tartaric acid cores, lactose/microcrystalline cores, sucrose cores or, starch cores, and combinations thereof.
30. The use according to claim 29, wherein the carrier is selected from the group consisting of cellulose spheres and sucrose cores.
31. The use of claim 30, wherein the carrier is selected from the group consisting of sucrose pellets.
32. The use of claim 19, wherein the pharmaceutical composition comprises a compound of formula (II), hydroxypropyl cellulose, sucrose, polymethacrylate, maleic acid, sucrose pellet core.
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WO2016150340A1 (en) * 2015-03-20 2016-09-29 正大天晴药业集团股份有限公司 Salts of quinazoline derivative and method for preparing same
WO2018036539A1 (en) * 2016-08-25 2018-03-01 正大天晴药业集团股份有限公司 Crystal of salt of quinazoline derivative

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WO2016150340A1 (en) * 2015-03-20 2016-09-29 正大天晴药业集团股份有限公司 Salts of quinazoline derivative and method for preparing same
WO2018036539A1 (en) * 2016-08-25 2018-03-01 正大天晴药业集团股份有限公司 Crystal of salt of quinazoline derivative

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