WO2022199375A1 - 一种喹唑啉化合物的药物组合物及其制备方法 - Google Patents

一种喹唑啉化合物的药物组合物及其制备方法 Download PDF

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WO2022199375A1
WO2022199375A1 PCT/CN2022/079695 CN2022079695W WO2022199375A1 WO 2022199375 A1 WO2022199375 A1 WO 2022199375A1 CN 2022079695 W CN2022079695 W CN 2022079695W WO 2022199375 A1 WO2022199375 A1 WO 2022199375A1
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pharmaceutical composition
formula
weight
day
quinazoline compound
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PCT/CN2022/079695
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English (en)
French (fr)
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许祖盛
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上海璎黎药业有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • 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
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the invention relates to a pharmaceutical composition of a quinazoline compound and a preparation method thereof.
  • PI3K Phosphatidylinositol 3-kinase (phosphatidylinositol 3-kinase), which is involved in the regulation of various cellular functions such as cell proliferation, differentiation, apoptosis and glucose transport.
  • PI3K can be divided into class I, class II and class III kinases, and the most widely studied is class I PI3K that can be activated by cell surface receptors.
  • Class I PI3Ks in mammalian cells are further divided into class Ia and class Ib according to their structure and receptors, which transmit signals from tyrosine kinase-coupled receptors and G protein-coupled receptors, respectively.
  • Class Ia PI3Ks include PI3K ⁇ , PI3K ⁇ , PI3K ⁇ isoforms, and class Ib PI3Ks include PI3K ⁇ isoforms (Trends. Biochem. Sci., 1997, 22, 267-272).
  • Class Ia PI3K is a dimeric protein composed of a catalytic subunit p110 and a regulatory subunit p85, with dual activities of lipid kinase and protein kinase (Nat. Rev. Cancer 2002, 2, 489-501), and is considered to be related to cell proliferation. It is associated with cancer development, immune diseases and diseases involving inflammation.
  • FL Follicular lymphoma
  • NHL non-Hodgkin lymphoma
  • PI3Kdelta phosphoinositide 3-kinase-delta
  • PI3Kdelta is an intracellular signal transduction component, mainly expressed in blood cell lineages, including cell-induced or mediated malignant hematology sick.
  • PI3K ⁇ inhibitor drugs have been successfully launched in the world, namely Idelalisib, Copanlisib and Duvelisb, all of which are used for the treatment of circulatory system cancers.
  • results of the study showed that the median age of the subjects was 62 years (range 33-84 years), 54% were male and 90% were Caucasian. At inclusion, 92% of patients had a baseline ECOG performance status of 0 or 1; median disease duration was 4-7 years; and median number of prior treatments was 4 (range 2-12).
  • the most common prior regimens were R-CHOP (49%) (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), BR (50%) (bendamustine, tuximab), and R-CVP (28%) (rituximab, cyclophosphamide, vincristine, prednisone). At baseline, 33% of patients had extranodal metastases and 26% had bone marrow metastases.
  • CI confidence interval
  • CR complete response
  • PR partial response
  • the quinazoline compound whose chemical structure is shown in formula A is a PI3K ⁇ small molecule inhibitor, which has been disclosed in the CN104557872A patent (compound 10), Compared with other existing PI3K ⁇ inhibitors, the selectivity to PI3K ⁇ is improved and the activity to PI3K ⁇ is eliminated.
  • Chinese patent CN110950844A discloses two polymorphs of the quinazoline compound represented by formula A.
  • the technical problem to be solved by the present invention is the lack of preparations of the quinazoline compounds shown in formula A in the prior art. Therefore, the present invention provides a pharmaceutical composition of the quinazoline compounds and a preparation method thereof.
  • the pharmaceutical composition has good stability to high temperature, high humidity and light, and can be used in 0.1mol/L hydrochloric acid solution (pH1.2) and pH6.8 phosphate buffer containing 0.2% sodium dodecyl sulfate (SDS) Rapid dissolution is achieved; and the preparation method of the pharmaceutical composition is simple and suitable for industrial production.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising substance X and pharmaceutical excipients
  • the substance X is a quinazoline compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof;
  • the pharmaceutical adjuvant includes a filler, and the filler is one, two or more of microcrystalline cellulose, mannitol and corn starch;
  • the substance X is the only active ingredient.
  • the substance X is in a therapeutically effective amount.
  • the quinazoline compound represented by formula A is the quinazoline compound represented by formula A in free base form, it should be understood that "free base form” is Refers to the case where the quinazoline compound represented by formula A is not in the form of a salt.
  • the quinazoline compound represented by formula A is preferably the crystal form I of the quinazoline compound represented by formula A, wherein the quinazoline compound represented by formula A
  • the crystal form I of the compound can be defined in any way described in Chinese Patent Publication No. CN110950844A.
  • the filler is one or both of microcrystalline cellulose, mannitol and corn starch.
  • the filler is microcrystalline cellulose.
  • the filler is a mixture of microcrystalline cellulose and mannitol.
  • the filler is a mixture of microcrystalline cellulose and cornstarch.
  • the filler is a mixture of microcrystalline cellulose and mannitol and cornstarch.
  • the filler is 10%-90% by weight of the total weight of the pharmaceutical composition, preferably 30%-70%, most preferably 45%-55%.
  • the filler is a mixture of microcrystalline cellulose and mannitol, which is 10%-90% by weight of the total weight of the pharmaceutical composition, preferably 30%-70% %, most preferably 45%-55%.
  • the filler is a mixture of microcrystalline cellulose and mannitol, and the mass ratio of the microcrystalline cellulose and the mannitol is 10:1-1:10 .
  • the filler is a mixture of microcrystalline cellulose and mannitol, and the mass ratio of the microcrystalline cellulose and the mannitol is 6:1-2:1 , preferably 4:1-3:1.
  • the pharmaceutical excipient further includes a disintegrant.
  • the disintegrant is crospovidone and/or croscarmellose sodium.
  • the disintegrant is crospovidone.
  • the disintegrant is croscarmellose sodium.
  • the disintegrant is not low-substituted hydroxypropyl cellulose.
  • the disintegrant is 1%-20% by weight of the total weight of the pharmaceutical composition, preferably 3%-15%, most preferably 4%-8%.
  • the disintegrant is croscarmellose sodium, which is 1%-20% by weight of the total weight of the pharmaceutical composition.
  • the disintegrant is croscarmellose sodium, which is 3%-15% by weight of the total weight of the pharmaceutical composition, preferably 4%-8% %.
  • the pharmaceutical excipients further include lubricants.
  • the lubricant is calcium stearate, glycerol monostearate, glyceryl behenate, magnesium stearate, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, One or more of sodium benzoate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, stearic acid, talc, micropowder silica gel and zinc stearate.
  • the lubricant is magnesium stearate.
  • the lubricant is 0.1%-5.0% by weight of the total weight of the pharmaceutical composition, preferably 0.3%-2.0%, most preferably 0.8%-1.4%.
  • the lubricant is magnesium stearate, which is 0.1%-5.0% by weight of the total weight of the pharmaceutical composition.
  • the lubricant is magnesium stearate, which is 0.3%-2.0% by weight of the total weight of the pharmaceutical composition, preferably 0.8%-1.4%.
  • the pharmaceutical composition comprises the following components by weight:
  • 45%-55% filler which is one, two or more of microcrystalline cellulose, mannitol and cornstarch, preferably a mixture of microcrystalline cellulose and mannitol, most preferably microcrystalline cellulose
  • the mixture of crystalline cellulose and mannitol, and its mass ratio is 4:1-3:1;
  • disintegrant which is at least one of crospovidone and croscarmellose sodium, most preferably croscarmellose sodium;
  • the lubricant is magnesium stearate.
  • the quinazoline compound represented by formula A is 40% by weight of the total weight of the pharmaceutical composition.
  • the filler is 52.8% by weight of the total weight of the pharmaceutical composition.
  • the disintegrant is 6% by weight of the total weight of the pharmaceutical composition.
  • the lubricant is 1.2% by weight of the total weight of the pharmaceutical composition.
  • the pharmaceutical composition comprises the following components by weight:
  • the pharmaceutical composition is composed of the above components.
  • the pharmaceutical composition comprises the following components by weight:
  • the pharmaceutical composition is composed of the above components.
  • the pharmaceutical composition comprises the following components by weight:
  • the pharmaceutical composition is composed of the above components.
  • the pharmaceutical composition comprises the following components by weight:
  • the pharmaceutical composition is composed of the above components.
  • the pharmaceutical composition comprises the following components by weight:
  • the pharmaceutical composition is composed of the above components.
  • the pharmaceutical composition comprises the following components by weight:
  • the pharmaceutical composition is composed of the above components.
  • the pharmaceutical composition comprises the following components by weight:
  • the pharmaceutical composition may be a solid preparation, preferably a solid oral preparation.
  • the pharmaceutical composition may be a tablet or a capsule, preferably a tablet.
  • the tablet is a coated tablet.
  • the coated tablet is a film-coated tablet.
  • the coating agent used for the film-coated tablet is based on hydroxypropyl methylcellulose as the main film-forming agent Film coating premixes for polymers.
  • the coating agent of the film-coated tablet in the film-coated tablet, can be purchased from Colorcon, for example, under the trade name film coating premix.
  • the weight gain of the coating agent is 2%-5%, preferably 2.5%-4.5%, most preferably 3.5% compared to the weight of the tablet core. %.
  • the pharmaceutical composition comprises two parts, a tablet core and a coating, and each contains the following components by weight:
  • 45%-55% filler which is one, two or more of microcrystalline cellulose, mannitol and cornstarch, preferably a mixture of microcrystalline cellulose and mannitol, microcrystalline cellulose
  • the mass ratio of vegan and mannitol is preferably 4:1-3:1;
  • disintegrant which is at least one of crospovidone and croscarmellose sodium, most preferably croscarmellose sodium;
  • the lubricant is magnesium stearate
  • the weight gain of the coating agent is 2%-5%, preferably 2.5%-4.5%, most preferably 3.5%, compared to the tablet core weight.
  • the pharmaceutical composition comprises two parts, a tablet core and a coating, and each contains the following components by weight:
  • the filler is a mixture of microcrystalline cellulose and mannitol, and the mass ratio of microcrystalline cellulose and mannitol is 4:1-3:1;
  • the lubricant is magnesium stearate
  • the weight gain of the coating agent is 3.5% compared to the core weight.
  • the pharmaceutical composition comprises two parts, a tablet core and a coating, and each contains the following components by weight:
  • the weight gain of the coating agent is 3.5% compared to the core weight.
  • the content of the quinazoline compound represented by formula A is 5mg-500mg, preferably 10mg-200mg, most preferably 20mg- 100 mg, such as 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg.
  • the content of the quinazoline compound represented by formula A is 5mg-500mg/tablet.
  • the second aspect of the present invention provides the preparation method of the pharmaceutical composition as described above, which is direct compression of powder.
  • the preparation method of the pharmaceutical composition provided by the present invention comprises the following steps:
  • the quinazoline compound, filler and disintegrating agent shown in formula A are respectively passed through 30 mesh sieves, and lubricant is passed through 60 mesh sieves;
  • the quinazoline compound as shown in formula A obtained according to step 1) is mixed with the filler in a mixer to obtain a premix 1;
  • premix 1 and disintegrant in a mixer to obtain premix 2; use a granulator to sieve premix 2 to obtain premix 3;
  • step 3 compressing the total mixture material obtained according to step 2) to obtain tablet cores;
  • the pharmaceutical composition is a drug for the treatment of B-cell hematoma
  • the pharmaceutical composition is a drug for the treatment of B-cell hematoma
  • the B-cell hematoma is a B-cell lymphoma
  • the B-cell lymphoma is a non-Hodgkin's lymphoma
  • the non-Hodgkin's lymphoma is follicular lymphoma
  • the follicular lymphoma is relapsed and/or refractory follicular lymphoma, eg, relapsed or refractory Bubbly lymphoma.
  • the pharmaceutical composition composition is administered orally.
  • the Substance X is in a therapeutically effective amount.
  • the administration dose of the pharmaceutical composition can be determined according to the body weight of the patient, and in terms of the content of the quinazoline compound shown in formula A, the administration dose of the pharmaceutical composition is: One time 0.33mg/kg-3.33mg/kg, for example, 0.66mg/kg-2.3mg/kg, another example, 1mg/kg, 1.2mg/kg, 1.3mg/kg, 1.33mg/kg, 1.4mg/kg kg, 1.5 mg/kg, 1.6 mg/kg, 1.7 mg/kg, 1.8 mg/kg, 1.9 mg/kg, 2.0 mg/kg, 2.1 mg/kg, 2.2 mg/kg or 2.3 mg/kg.
  • the administration dose of the pharmaceutical composition is 20mg-200mg/day, for example, 20mg/day, 30mg/day, 40mg/day, 50mg/day, 60mg/day, 70mg/day, 80mg/day, 90mg/day, 100mg/day, 110mg/day, 120mg/day, 130mg/day, 140mg/day, 150mg/day, 160mg/day day, 170 mg/day, 180 mg/day, 190 mg/day or 200 mg/day, for another example, 80 mg/day.
  • the frequency of administration of the pharmaceutical composition is 1-5 times/day, eg, 1 time/day, 2 times/day, 3 times/day, 4 times/day or 5 times/day , for another example, 1 time/day.
  • the pharmaceutical composition is administered for a course of 14-84 days/course, eg, 14 days/course, 28 days/course, 42 days/course, 56 days/course, 70 days/course Or 84 days/course, for another example, 28 days/course.
  • the pharmaceutical composition is administered for a total of 1-20 courses of treatment, preferably 10-20 courses of treatment, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 courses of treatment, another example, 12 courses of treatment.
  • the pharmaceutical composition is a tablet.
  • the specification of the pharmaceutical composition is 10mg-120mg/tablet, for example, 20-100mg/tablet, another example is 20mg/tablet, 30mg/tablet, 40mg/tablet, 50mg/tablet, 60mg/tablet, 70mg/tablet, 80mg/tablet, 90mg/tablet or 100mg/tablet, for another example, 20mg/tablet, 80mg/tablet or 100mg/tablet.
  • the pharmaceutical composition is administered to a patient with relapsed or relapsed follicular lymphoma who has received one or more systemic therapy regimens (eg, a patient who has received one or more systemic therapy regimens) Patients with relapsed follicular lymphoma), preferably, the pharmaceutical composition is administered to patients with relapsed or refractory follicular lymphoma who have received two or more systemic treatment regimens (such as , in patients with relapsed follicular lymphoma who have received two or more systemic regimens).
  • systemic therapy regimens eg, a patient who has received one or more systemic therapy regimens
  • the pharmaceutical composition is administered to patients with relapsed or refractory follicular lymphoma who have received two or more systemic treatment regimens (such as , in patients with relapsed follicular lymphoma who have received two or more systemic regimens).
  • the pharmaceutical composition is administered to a patient who has progressed after receiving second-line or more systemic systemic therapy in the previous treatment regimen, and the second-line or more systemic therapy has received CD20 monoclonal antibody and On patients who have progressed after treatment with at least one alkylating agent, including but not limited to bendamustine, cyclophosphamide, ifosfamide, chlorphentermine, melphalan, busulfan, and nitroso .
  • at least one alkylating agent including but not limited to bendamustine, cyclophosphamide, ifosfamide, chlorphentermine, melphalan, busulfan, and nitroso .
  • the pharmaceutical composition administered in the previous treatment regimen is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), BR (bendamole statine, rituximab), and R-CVP (rituximab, cyclophosphamide, vincristine, prednisone).
  • the subject of administration of the pharmaceutical composition is a human.
  • the present invention also provides a method of treating a disease comprising administering to a patient (eg, a human) a therapeutically effective amount of Substance X or a pharmaceutical composition;
  • the disease is B-cell hematoma;
  • the substance X is a quinazoline compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof, or a solvate of a pharmaceutically acceptable salt thereof;
  • the pharmaceutical composition includes the substance X and pharmaceutical excipients.
  • the B-cell hematoma is a B-cell lymphoma
  • the B-cell lymphoma is a non-Hodgkin's lymphoma
  • the non-Hodgkin's lymphoma is a filter Follicular lymphoma
  • the follicular lymphoma is relapsed and/or refractory follicular lymphoma, eg, relapsed or refractory follicular lymphoma.
  • the mode of administration is oral.
  • the administered dose can be determined according to the body weight of the patient, and based on the content of the quinazoline compound shown in formula A, the administered dose is 0.33 mg/kg-3.33 mg once /kg, for example, 0.66mg/kg-2.3mg/kg, another example, 1mg/kg, 1.2mg/kg, 1.3mg/kg, 1.33mg/kg, 1.4mg/kg, 1.5mg/kg, 1.6mg/kg mg/kg, 1.7 mg/kg, 1.8 mg/kg, 1.9 mg/kg, 2.0 mg/kg, 2.1 mg/kg, 2.2 mg/kg or 2.3 mg/kg.
  • the administered dose is 20-200 mg/day, for example, 20 mg/day, 30 mg/day, 40 mg/day, 50mg/day, 60mg/day, 70mg/day, 80mg/day, 90mg/day, 100mg/day, 110mg/day, 120mg/day, 130mg/day, 140mg/day, 150mg/day, 160mg/day, 170mg/day day, 180 mg/day, 190 mg/day or 200 mg/day, for another example, 80 mg/day.
  • the frequency of administration is 1-5 times/day, eg, 1 time/day, 2 times/day, 3 times/day, 4 times/day, or 5 times/day, for example, 1 time/day.
  • the course of administration is 14-84 days/course, eg, 14 days/course, 28 days/course, 42 days/course, 56 days/course, 70 days/course or 84 days/course
  • the course of treatment for another example, is 28 days/course of treatment.
  • the patient receives a total of 1-20 courses of treatment, preferably 10-20 courses of treatment, eg, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 Or 20 courses of treatment, for another example, 12 courses of treatment.
  • the Substance X or pharmaceutical composition is a tablet.
  • the specification of the substance X or the pharmaceutical composition is 10-120mg/tablet, for example, 20-100mg/tablet, and for example, 20mg/tablet, 30mg/tablet, 40mg/tablet, 50mg/tablet Tablet, 60mg/tablet, 70mg/tablet, 80mg/tablet, 90mg/tablet or 100mg/tablet, for another example, 20mg/tablet, 80mg/tablet or 100mg/tablet.
  • the patient is a patient with relapsed follicular lymphoma who has received one or more systemic treatment regimens, preferably, the patient has received two or more systemic treatment regimens of patients with recurrent follicular lymphoma.
  • the patient is a patient who has progressed after receiving second-line or above systemic therapy, preferably, the patient is a patient who has progressed after receiving CD20 monoclonal antibody and at least one alkylating agent,
  • the alkylating agents include, but are not limited to, bendamustine, cyclophosphamide, ifosfamide, chlorphentermine, melphalan, busulfan, nitroso.
  • the patient's previous treatment regimen is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), BR (bendamustine, tuximab), and R-CVP (rituximab, cyclophosphamide, vincristine, prednisone).
  • the pharmaceutical excipients are conventional diluents, excipients, fillers, binders, wetting agents, disintegrating agents, absorption enhancers, surfactants, adsorption carriers, one or more of the lubricants.
  • the invention provides the application of a substance X in the preparation of a B-cell hematoma inhibitor
  • the substance X is a quinazoline compound represented by formula A, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof:
  • the B-cell hematoma is a B-cell lymphoma, preferably, the B-cell lymphoma is a non-Hodgkin's lymphoma, more preferably, the non-Hodgkin's lymphoma is a filter Follicular lymphoma, most preferably, the follicular lymphoma is relapsed and/or refractory follicular lymphoma.
  • the inhibitor in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, such as: providing comparison as a standard sample or a control sample, or making a kit according to conventional methods in the art .
  • fillers used in the present invention, also called “diluent”, refers to a class of adjuvants used to increase the volume and weight of the pharmaceutical composition product dosage form in the scientific context.
  • fillers may be, for example, calcium carbonate, calcium phosphate, calcium hydrogen phosphate, calcium sulfate, cellulose acetate, ethyl cellulose, fructose, lactose, lactitol, maltose, maltodextrin, maltitol, mannitol, Microcrystalline cellulose, polydextrose, polyethylene glycol, sodium bicarbonate, sodium carbonate, sodium chloride, sorbitol, cornstarch, dextrin, sucrose, trehalose and xylitol.
  • the "disintegrant" used in the present invention refers to a class of excipients used in the scientific context to facilitate the breaking of the dosage form of the pharmaceutical composition product into smaller fragments in an aqueous environment.
  • the disintegrant may be, for example: alginic acid, calcium alginate, calcium carboxymethyl cellulose, chitosan, colloidal silicon dioxide, croscarmellose sodium, crospovidone, carboxymethyl cellulose Sodium starch base, low-substituted hydroxypropyl cellulose, hypromellose, glycine, guar gum, hydroxypropyl cellulose, magnesium aluminum silicate, methyl cellulose, povidone, sodium alginate, carboxymethyl Sodium cellulose, sodium starch glycolate and starch.
  • the "lubricant" used in the present invention refers to a class of adjuvants used to improve the processing of pharmaceutical composition product dosage forms under the scientific background.
  • the lubricant can be, for example, calcium stearate, glyceryl monostearate, glyceryl behenate, magnesium stearate, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, benzene Sodium formate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, stearic acid, talc, micronized silica gel and zinc stearate.
  • the "coating agent” or “film coating premix” used in the present invention refers to a class of adjuvants used to improve the appearance of the dosage form of the pharmaceutical composition product under the scientific background.
  • the coating agent may be, for example: sucrose, lactose, hydroxypropyl methylcellulose, hydroxypropylethylcellulose, cellulose acetate phthalate, polyvinyl alcohol, polyvinyl acetate phthalate , hypromellose phthalate and acrylic resin.
  • salts refers to salts of compounds of the present invention prepared with relatively non-toxic, pharmaceutically acceptable acids or bases.
  • base additions can be obtained by contacting neutral forms of such compounds with a sufficient amount of a pharmaceutically acceptable base in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include, but are not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, diethanolamine.
  • acids additions can be obtained by contacting the neutral form of such compounds with a sufficient amount of a pharmaceutically acceptable acid in neat solution or in a suitable inert solvent.
  • a salt is not limited to, lithium, sodium, potassium, calcium, aluminum, magnesium, zinc, bismuth, ammonium, diethanolamine.
  • the pharmaceutically acceptable acids include inorganic acids, including but not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, and the like.
  • Described pharmaceutically acceptable acid includes organic acid, described organic acid includes but is not limited to: acetic acid, propionic acid, oxalic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid , fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, salicylic acid, tartaric acid, methanesulfonic acid, isonicotinic acid, acid citric acid, oleic acid , tannic acid, pantothenic acid, hydrogen tartrate, ascorbic acid, gentisic acid, fumaric acid, gluc
  • solvate refers to a substance formed by combining a compound of the present invention with a stoichiometric or non-stoichiometric amount of a solvent.
  • Solvent molecules in solvates can exist in ordered or non-ordered arrangements.
  • the solvent includes, but is not limited to, water, methanol, ethanol, and the like.
  • “Pharmaceutically acceptable salt” and “solvate” in the term “solvate of a pharmaceutically acceptable salt”, as described above, refer to a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid A substance prepared by combining with a stoichiometric or non-stoichiometric amount of a solvent.
  • therapeutically effective amount refers to an amount of a compound administered to a patient sufficient to be effective in treating a disease.
  • the therapeutically effective amount will vary depending on the compound, the type of disease, the severity of the disease, the age of the patient, etc., but can be adjusted as appropriate by those skilled in the art.
  • pharmaceutical excipients refers to the excipients and additives used in the production of pharmaceuticals and the formulation of prescriptions, and are all substances contained in pharmaceutical preparations other than active ingredients.
  • pharmaceutical preparations other than active ingredients.
  • treatment refers to therapeutic therapy.
  • treatment refers to: (1) ameliorating one or more biological manifestations of the disease or disorder, (2) interfering with (a) one or more points in the biological cascade leading to or causing the disorder or (b) ) one or more biological manifestations of the disorder, (3) amelioration of one or more symptoms, effects or side effects associated with the disorder, or one or more symptoms, effects or side effects associated with the disorder or its treatment, or (4) slowing the progression of the disorder or one or more biological manifestations of the disorder.
  • progressive refers to disease that is not relieved or cured after treatment, or even worsens.
  • patient refers to any animal, preferably a mammal, and most preferably a human, who has been or is about to receive treatment.
  • mammal includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive improvement effect of the present invention is that: the pharmaceutical composition of the present invention has good stability to high temperature, high humidity and light, and is stable in 0.1mol/L hydrochloric acid solution, pH6.8 phosphoric acid containing 0.2% sodium dodecyl sulfate (SDS) Rapid dissolution can be achieved in salt buffer; and the preparation method of the pharmaceutical composition of the present invention is simple and suitable for industrial production.
  • hydrochloric acid solution pH6.8 phosphoric acid containing 0.2% sodium dodecyl sulfate (SDS) Rapid dissolution can be achieved in salt buffer
  • SDS sodium dodecyl sulfate
  • Fig. 1 is the dissolution curve diagram of the pharmaceutical composition of the quinazoline compound represented by formula A provided in the second part of Examples 4 and 5 in 0.1 mol/L hydrochloric acid solution.
  • Figure 2 is a graph showing the dissolution profiles of the pharmaceutical compositions of the quinazoline compounds represented by formula A provided in the second part of Examples 4 and 5 in pH 6.8 phosphate buffer containing 0.2% SDS.
  • the quinazoline compound represented by formula A is prepared according to the preparation method of compound 10 described in patent CN104557872A, and recrystallized according to the method of example 8 in patent CN110950844A.
  • test compound concentrations in and calculate pharmacokinetic parameters The results are shown in Table 1.
  • C max peak drug concentration
  • AUC last area under the concentration-time curve from 0 point to the time point corresponding to the last measurable concentration
  • F% bioavailability
  • the pharmacokinetic studies of the quinazoline compound represented by formula A in mice, rats and dogs show that the oral absorption is good within the effective dose range, and the oral bioavailability is 90%, 65% and 60%, respectively. %above.
  • the exposure of the quinazoline compound shown in formula A in rats and dogs increased to a certain extent, about 1.28-2.20 times that of the first administration, suggesting that the risk of serious drug accumulation is small.
  • the quinazoline compounds of formula A are moderately cleared in rats and relatively slowly in mice and dogs.
  • the quinazoline compound represented by formula A has a wide tissue distribution, and the exposure amount of the quinazoline compound represented by formula A in other tissues is higher than that in plasma except brain tissue.
  • Table 2 Pharmacokinetic results of ICR mice, SD rats, and Beagle dogs after a single oral gavage administration
  • the plasma protein binding rates of the quinazoline compounds represented by formula A in the five species are in descending order: cynomolgus monkey>human>CD1 mouse>SD rat>Beagle dog, among which cynomolgus monkey and Binding was similar in humans (85-90%), SD rats and beagle dogs (50-65%).
  • V ss Steady-state apparent volume of distribution (V ss , L /kg) were 4.22 (male mice), 4.55 (male rats), 5.18 (female rats), 4.70 (male dogs) and 4.08 (female dogs), which were 5.82 (male) of the total body fluid of each animal. mice), 6.80 (male rats), 7.75 (female rats), 7.79 (male dogs), and 6.76 (female dogs) times, suggesting that the quinazoline compound represented by formula A has a wider range in various animals. tissue distribution.
  • the quinazoline compound shown in formula A After gavage administration of 60 mg/kg to SD rats, the quinazoline compound shown in formula A is widely distributed in various tissues and organs, except for brain tissue, the quinazoline compound shown in formula A is in other tissues.
  • the exposures of serotonin were significantly higher than their exposures in plasma, which were about 2-22 times the latter.
  • the plasma and tissue drug concentrations were higher in male rats than in female rats at all time points.
  • the exposure of the quinazoline compound represented by formula A in various tissues of male rats is about 1.49-3.70 times that of female rats.
  • the half-life of the quinazoline compound represented by formula A is about 2.29-5.08 hr in various tissues of male rats, and the half-life in various tissues of female rats is about 2.25-4.45 hr (except brain tissue).
  • quinazoline compounds of formula A had the highest exposure in the stomach, followed by small intestine, liver, kidney, lung, spleen, large intestine, thymus, heart, testis, skeletal muscle, fat , plasma and brain.
  • the highest exposure to quinazoline compounds of formula A was in the small intestine, followed by stomach, liver, spleen, kidney, lung, large intestine, thymus, ovary, uterus, heart, skeletal muscle , fat, plasma and brain.
  • CYP3A4 is the main metabolic enzyme of the quinazoline compound represented by formula A, followed by CYP2C8.
  • the quinazoline compound shown in formula A showed a 20%-30% reduction in the CYP2C8 incubation system, the same phenomenon also occurred in the two incubation systems of -NADPH and + inhibitor, so it cannot be explained that the mother Drug metabolism is dependent on the recombinase CYP2C8.
  • the quinazoline compounds represented by formula A have no significant inhibitory effect on CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4 in human liver microsomes (IC 50 >10 ⁇ M).
  • the quinazoline compound represented by formula A did not show an enhancement effect on enzyme activity or mRNA expression in terms of CYP1A2, CYP2B6 and CYP3A4 at three tested concentrations of 0.4, 4 and 40 ⁇ M.
  • the excretion amounts of quinazoline compound shown in formula A in male rat urine, feces and bile in 0-72hr are respectively: 20.1 ⁇ 6.48%, 24.5 ⁇ 11.1% and 1.68 ⁇ 0.890% of the dose; the excretion in female rat urine, feces and bile from 0-72 hr was 8.11 ⁇ 2.62%, 7.58% of the dose, respectively ⁇ 3.95% and 10.9 ⁇ 1.29%. Therefore, the total excretion rates of the quinazoline compound represented by formula A in the urine, feces and bile of male and female SD rats after oral administration were 46.3% and 26.6%, respectively.
  • the excretion amounts of the quinazoline compound shown in formula A in male dogs' urine and feces were 29.2 ⁇ 29.2 ⁇ of the administration amount, respectively. 13.5% and 19.5 ⁇ 16.2%, and their excretion in female dogs’ urine and feces were 41.4 ⁇ 12.4% and 9.21 ⁇ 7.08% of the administered dose, respectively, so the quinazole shown in formula A after oral administration
  • the total excretion rates of morpholino compounds in male and female beagle dogs were 48.7% and 50.6%, respectively.
  • the effect of quinazoline compounds of formula A on cell proliferation was tested in different tumor cells.
  • the results show that the quinazoline compound represented by formula A has obvious inhibitory activity on some hematological tumor cells.
  • the IC50 value in SU-DHL-6 cells was 0.2337 ⁇ M
  • the IC50 value in SU-DHL-5 cells was 1.7683 ⁇ M.
  • CB17 SCID mice female, weighing 18-22 g.
  • Group administration was started when the average tumor volume reached 95.79 mm 3 .
  • Grouping method animals were weighed before administration, and tumor volume was measured. According to tumor volume random grouping (random grouping design), grouping and dosing schedule are shown in Table 3 below.
  • the antitumor efficacy of the compounds was evaluated by TGI (%). TGI (%) reflects tumor growth inhibition rate.
  • TGI (%) [1-(tumor volume at the end of treatment group administration-tumor volume at the beginning of treatment group administration)/(tumor volume at the end of solvent control group administration-solvent control group administration Tumor volume at the start of the drug)] ⁇ 100%.
  • the results show that by the 15th day of administration, the CAL-101 (that is, Idelalisib) 50mg/kg BID treatment group, the quinazoline compound shown in formula A 60mg/kg QD group, and the quinazoline compound shown in formula A
  • the TGI of the compound 120 mg/kg QD group and the quinazoline compound 240 mg/kg QD group shown in formula A were 42.67%, 71.89%, 81.57% and 86.98%, respectively.
  • results for both tumor volume and weight show quinazoline compound as shown in formula A 60mg/kg QD treatment, quinazoline compound as shown in formula A 120mg/kg QD treatment and quinazoline compound as shown in formula A 240mg/kg QD treatment significantly inhibited the growth of SU-DHL-6 human lymphoma cell subcutaneous xenografts.
  • the patient inclusion criteria were patients with relapsed or refractory B-cell hematological tumors confirmed by histology or cytology. A total of 25 patients were included, including 10 patients with follicular lymphoma.
  • the study is divided into two phases: dose escalation and dose expansion; each phase includes single-dose and multiple-dose studies.
  • Doses in the dose escalation phase included 20 mg/day, 40 mg/day, 80 mg/day, 140 mg/day, 200 mg/day. Except for the 20mg initial dose group, which was only enrolled in 1 group, 3-6 subjects were enrolled in each dose group, 3 subjects were enrolled in the 40 mg dose group, 3 subjects were enrolled in the 80 mg dose group, and 3 subjects were enrolled in the 140 mg dose group. 4 cases were enrolled in the 200 mg dose group; among them, 1 case of follicular lymphoma was enrolled at 40 mg and 200 mg respectively, and 2 cases were enrolled in the 80 mg group.
  • a dose-expansion trial was conducted at a dose of 80 mg/day, and a total of 11 patients were enrolled, including 6 patients with follicular lymphoma. A total of 10 patients with follicular lymphoma were enrolled.
  • the mode of administration is: oral administration, once daily during the continuous administration period, until disease progression or intolerable toxicity.
  • the quinazoline compound tablet represented by formula A is a powder-mixing direct-compression coated tablet, which is prepared according to the process described in the second part of preparation example 1 and preparation example 2.
  • the formulation was that of Example 5 in Part II, and 20 mg or 100 mg tablets were made.
  • the quinazoline compound tablet represented by formula A shows good antitumor activity in patients with relapsed or refractory B cell hematological malignancies, especially in follicular lymphoma.
  • the results are shown in the table below.
  • the best overall curative effect was CR in 5 cases, PR in 11 cases, SD in 2 cases, PD in 7 cases, and the overall optimal curative effect ORR ratio was 64% (16/25) ( 95% CI: 45.2-82.8%), the DCR ratio was 72% (18/25) (95% CI: 54.4-89.6%).
  • the ORR and DCR ratios of the best curative effect in follicular lymphoma were both 90.0% (9/10).
  • the efficacy evaluation criteria for B-cell lymphoma refer to "The efficacy evaluation criteria for lymphoma IRWG (excerpt), the revised criteria for the efficacy evaluation of malignant lymphomas”.
  • the patient inclusion criteria were patients with relapsed or refractory B-cell hematological tumors confirmed by histology or cytology. A total of 25 patients were included, including 10 patients with follicular lymphoma.
  • the study is divided into two phases: dose escalation and dose expansion; each phase includes single-dose and multiple-dose studies. Doses in the dose escalation phase included 20 mg/day, 40 mg/day, 80 mg/day, 140 mg/day, 200 mg/day. Except for the 20mg initial dose group, which was only enrolled in 1 group, 3-6 subjects were enrolled in each dose group, 3 subjects were enrolled in the 40 mg dose group, 3 subjects were enrolled in the 80 mg dose group, and 3 subjects were enrolled in the 140 mg dose group.
  • the quinazoline compounds represented by formula A are safe and tolerable in the dose range of 20-200 mg, can alleviate and control the progression of relapsed or refractory B-cell malignancies, and have also been shown in follicular lymphoma. very good curative effect.
  • the current FDA-approved PI3k ⁇ inhibitor Idelalisib has an objective response rate (ORR) of 39% in the treatment of refractory and relapsed follicular lymphoma, while the PI3K ⁇ , ⁇ inhibitor Duvelisib has an ORR of 42% in the treatment of refractory and relapsed follicular lymphoma; Copanlisib
  • ORR objective response rate
  • the ORR of the quinazoline compound represented by formula A in the clinical phase I treatment of follicular lymphoma was 90.0% (9/10).
  • the quinazoline compound represented by formula A used in the following examples was prepared according to the preparation method of compound 10 described in patent CN104557872A, and recrystallized according to the method of example 8 in patent CN110950844A.
  • the dissolution methods were in accordance with the second method of the 2015 edition of the Chinese Pharmacopoeia, Part Four General Principles 0931, using 900 ml of pH 6.8 phosphate buffer solution containing 0.2% SDS at 37°C as the dissolution medium.
  • the rotation speed was 75 rpm, sampling was performed at appropriate time intervals, the same volume of dissolution medium was replenished, filtered through a 0.45 ⁇ m filter membrane, and the content was determined by high-performance liquid phase to calculate the dissolution rate.
  • the quinazoline compound shown in formula A and each auxiliary material of the recipe quantity are weighed according to the designed prescription composition, and the quinazoline compound shown in formula A, filler and disintegrating agent are respectively passed through a 30-mesh sieve, lubricating pass through a 60-mesh sieve; mix the quinazoline compound shown in formula A and the filler in a mixer to obtain a premix 1; add the disintegrant to the premix 1, and use a mixer to mix uniformly, to obtain premix 2; use a granulator to sieve premix 2 to obtain premix 3; mix premix 3 and lubricant in a mixer to obtain a total mixture; use equipment equipped with 5mm, D-type round die or rotary tableting machine with 11*5.5mm upper punched Half wire bond die to tablet the blended material to form quinazoline containing 20 mg or 100 mg of formula A, respectively Compound cores.
  • the film coating premix powder was added to the stirring purified water, and the stirring was continued for 45 minutes to prepare a coating liquid with a solid content of 10% (w/w) of the film coating premix.
  • the tablet cores manufactured by the process described in Preparation Example 1 above were coated to a coating weight gain ranging from 2% to 5% to form film-coated tablets containing 20 mg or 100 mg of the quinazoline compound represented by Formula A, respectively.
  • Embodiment 1 tablet core prescription F1-F8
  • the type and amount of disintegrant directly affects the disintegration of the tablet and the release rate of the active pharmaceutical ingredient.
  • the formulation compositions F1-F8 of crospovidone, croscarmellose sodium and low-substituted hydroxypropyl cellulose as disintegrants were screened respectively, and the dosage of disintegrants in the formulations was screened.
  • the pharmaceutical composition was manufactured by the process described in the above Preparation Example 1, and tablet cores containing 20 mg of the quinazoline compound represented by formula A were obtained respectively. Taking the smoothness of tableting and the dissolution rate during the tableting process as the investigation indicators, the formulation composition and results are shown in Table 5 below.
  • Embodiment 2 film-coated tablet prescription F9-F10
  • the amount of lubricant used will affect the smoothness of tableting and the dissolution rate of the active pharmaceutical ingredient.
  • the formulation compositions F9 and F10 of different dosages of magnesium stearate as lubricant were screened respectively.
  • the pharmaceutical composition was manufactured by the process described in the above Preparation Example 1, and tablet cores containing 20 mg of the quinazoline compound represented by formula A were obtained respectively.
  • Formulation of Film Coating Premixes A coating liquid with a solid content of 10% (w/w) was used to coat the tablet cores with a high-efficiency coating machine (BGB-5F, Zhejiang Xiaolun Pharmaceutical Machinery Co., Ltd.) to give the formulations F9 and F10, respectively.
  • Example 3A and 3B preparation of film-coated tablets (20 mg specification, 20,000 tablets)
  • the pharmaceutical composition was manufactured by the process described in the above-mentioned preparation example 1, and a tablet core containing 20 mg of the quinazoline compound represented by formula A was obtained.
  • Formulation of Film Coating Premixes
  • the coating liquid with a solid content of 10% (w/w) was used to coat the tablet cores with a coating weight gain range of 2%-5% by using a high-efficiency coating machine (BGB-5F, Zhejiang Xiaolun Pharmaceutical Machinery Co., Ltd.).
  • a powder direct compression process is used to manufacture pilot scale pharmaceutical compositions.
  • the quinazoline compound shown in formula A, the filler and the disintegrating agent were respectively passed through a 30-mesh sieve, and the lubricant was passed through a 60-mesh sieve; Mix evenly in the hopper mixer (HBD200, Nantong Beite Medical Machinery Co., Ltd.) to obtain premix 1; add the disintegrant to premix 1, and use the hopper mixer to mix evenly to obtain premix 2 ; Sieve premix 2 using a granulator (Comil U10, QUADRO, Canada) equipped with a 032R screen and a square impeller to obtain premix 3; mix premix 3 and lubricant in a hopper mixer, The blend was obtained; the blend was tabletted using a rotary tablet press (P2020, Fette, Germany) equipped with a 5mm D-type circular die to form tablets containing 20 mg of the quinazoline compound of formula A core.
  • the coating liquid with a solid content of 10% (w/w) was used to coat the tablet cores with a high-efficiency coating machine (BGB-40F, Zhejiang Xiaolun Pharmaceutical Machinery Co., Ltd.) until the coating weight increased by 3.5%, and a pilot test was obtained.
  • the film-coated tablet batch formulations of Example 4 are shown in Table 9 below.
  • the pharmaceutical composition was manufactured by the method described in Preparation Example 1 above, and a tablet core containing 100 mg of the quinazoline compound represented by formula A was obtained.
  • Formulation of Film Coating Premixes A coating solution with a solid content of 10% (w/w) is used to coat the tablet core with a high-efficiency coating machine until the coating weight is increased by 3.5% to obtain a film containing 100 mg of the quinazoline compound represented by formula A Coated tablet.
  • the film-coated tablet batch formulations of Example 6 are shown in Table 10 below.
  • Test Example 1 Determination of key quality attributes of pharmaceutical compositions
  • the pharmaceutical composition manufactured in the above Example 4 was subjected to the determination of the key quality attributes of the drug, and the assessment items included properties, content uniformity, content, related substances, and dissolution.
  • the assessment results are shown in Table 11 below.
  • Content uniformity Take 10 pieces of the test sample, and measure the relative content xi of each single dose with the labeled amount of 100 according to the high-performance liquid chromatography method under the content determination conditions. According to the content uniformity inspection method (2015 edition of "Chinese Pharmacopoeia” four general chapters 0941), calculate A+2.2S.
  • Dissolution According to the dissolution test method (2015 edition of "Chinese Pharmacopoeia” four general rules 0931 second method), take 900ml of pH6.8 phosphate buffer containing 0.2% SDS as the dissolution medium, the speed is 75 rpm, take 6 Take 1 tablet of the test sample, and put 1 tablet in each dissolution cup. After 30 minutes, take 10 ml of the solution, filter it with a 0.45 ⁇ m filter membrane, measure the content by high-performance liquid phase, and calculate the dissolution rate of the quinazoline compound shown in formula A.
  • Dissolution profile measurements were performed on the pharmaceutical compositions prepared in Examples 4 and 5 above, respectively.
  • the rotation speed is 75 rpm, with 0.1mol/L hydrochloric acid solution (9ml hydrochloric acid, add water to make 1000ml) or pH6 containing 0.2% SDS .8 900ml of phosphate buffer is the dissolution medium, take 6 pieces of the test sample from the film-coated tablets manufactured in each example, and put 1 piece in each dissolution cup, take samples at appropriate time intervals, and rehydrate with the same volume of dissolution medium , filtered through a 0.45 ⁇ m filter membrane, and the cumulative dissolution rate of the quinazoline compound shown in formula A was calculated by high-performance liquid phase determination.
  • the measurement results are shown in Table 12 below and accompanying drawings 1-2.
  • the pharmaceutical composition manufactured in Example 4 was exposed and placed under the influence factors of high temperature (60°C), high humidity (25 ⁇ 2°C, RH92.5%), and light (4500 ⁇ 500Lux) for 30 days.
  • high temperature 60°C
  • high humidity 25 ⁇ 2°C, RH92.5%
  • light 4500 ⁇ 500Lux
  • the test method in 1 assesses the stability of the pharmaceutical composition, and the assessment indicators include properties, related substances, dissolution rate and content. Specific results are shown in Tables 13-15 below.
  • Tables 13-15 show that the pharmaceutical composition of the quinazoline compound represented by the formula A provided by the present invention is measured after being exposed and placed for 5 days, 10 days and 30 days under the conditions of high temperature, high humidity and light influence factors, respectively. , there was no significant change in the evaluation indicators of the pharmaceutical composition compared with those before the influence factor test treatment. When placed under high humidity conditions for 30 days, the pharmaceutical composition has no obvious hygroscopic weight gain.

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Abstract

本发明公开了一种喹唑啉化合物的药物组合物及其制备方法。本发明的药物组合物包含物质X和药用辅料；其中，所述的物质X为如式A所示的喹唑啉化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；所述的药用辅料包括填充剂，所述填充剂为微晶纤维素、甘露醇和玉米淀粉中的一种、两种或多种。本发明的药物组合物稳定性好，溶出度好，并且该药物组合物的制备方法简单，适合工业化生产。

Description

一种喹唑啉化合物的药物组合物及其制备方法 技术领域
本发明涉及一种喹唑啉化合物的药物组合物及其制备方法。
背景技术
PI3K全称为Phosphatidylinositol 3-kinase(磷脂酰肌醇3-激酶)，其参与细胞增殖、分化、凋亡和葡萄糖转运等多种细胞功能的调节。PI3K可分为Ⅰ类、Ⅱ类和Ⅲ类激酶，而研究最广泛的是能被细胞表面受体所激活的Ⅰ类PI3K。哺乳动物细胞中Ⅰ类PI3K根据结构和受体又分为Ⅰa类和Ⅰb类，它们分别传递来自酪氨酸激酶-偶联受体和G蛋白-偶联受体的信号。Ⅰa类PI3K包括PI3Kα、PI3Kβ、PI3Kδ亚型，Ⅰb类PI3K包括PI3Kγ亚型(Trends.Biochem.Sci.,1997,22,267-272)。Ⅰa类PI3K是由催化亚单位p110和调节亚单位p85所组成的二聚体蛋白，具有类脂激酶和蛋白激酶的双重活性(Nat.Rev.Cancer 2002,2,489-501)，被认为与细胞增殖和癌症发生，免疫疾病和涉及炎症的疾病相关。
滤泡性淋巴瘤(FL)是欧美国家第二常见的非霍奇金淋巴瘤(NHL)，约占所有新诊断NHL的22-35％，近年来随着对疾病的认识加深和诊断技术的提高，年发病率由1950s的2-3/100,000逐渐上升至5/100,000左右。与西方国家不同，FL在我国约占B细胞NHL的8％，所占比例较西方国家偏低，发病年龄与国外中位诊断年龄65岁比较相对较低。
尽管滤泡性淋巴瘤在我国只占B细胞淋巴瘤的8％，但由于中国人口基数大，患者人数仍然较多。FL在中老年人群中高发，且随着老龄化进程的加快，近年来中国滤泡性淋巴瘤的发病率呈上升趋势。目前滤泡性淋巴瘤尚无法完全治愈，治疗达到缓解后，FL会反复复发，反复发作容易转成侵袭型。随着复发次数的增多缓解期将越来越短，难治性机率增加，导致总生存期缩短。目前复发、难治的FL尚无统一的标准治疗方法。且目前治疗FL的药物有限，亟需研发出有更佳疗效的药物。
其中，磷酸肌醇3-激酶-δ(PI3Kδ)抑制剂是其中的一个治疗途径，PI3Kδ是一种细胞内信号转导组分，主要表达在血细胞谱系中，包括细胞引起或介导的恶性血液病。
目前全球已有3款PI3Kδ抑制剂药物成功上市，分别为Idelalisib、Copanlisib以及Duvelisb，均用于治疗血液循环系统癌症。
有文献报告了Idelalisib在复发滤泡性B-细胞非霍奇金淋巴瘤(FL)的临床试验结果(临床试验登记号：NCT01282424)，纳入标准为曾用利妥昔单抗联合烷化剂治疗后6个月内复发，并且已曾接受过至少2次系统治疗的FL患者。
研究结果显示，受试者中位年龄为62岁(范围33-84岁)，其中54％为男性，90％为高加索人。在纳入时，92％患者基线ECOG体能状态为0或1；病程中位时间为4-7年；既往治疗中位次数为4次(范围2-12)。最常见既往治疗方案为R-CHOP(49％)(利妥昔单抗、环磷酰胺、阿霉素、长春新碱、强的松)，BR(50％)(苯达莫司汀、利妥昔单抗)，和R-CVP(28％)(利妥昔单抗、环磷酰胺、长春新碱、强的松)。在基线时，33％患者淋巴结外转移，26％有骨髓转移。
给予患者Idelalisib 150mg治疗，每天2次，直至疾病进展或发生不可接受毒性。按照国际工作组 反应标准评估肿瘤恶性淋巴瘤有效性。主要终点是独立评审委员会评估总缓解率(overall response rate，ORR)。
下表为疗效结果：中位反应时间为1.9个月(范围1.6-8.3)。
疗效终点 N＝72
ORR 95％CI 39(54％)(42，66％)
CR 6(8％)
PR 33(46％)
*DOR中位数，月数(范围) 中位数不能评价(0.0+，14.8+)
CI＝可信区间；CR＝完全缓解；PR＝部分缓解；*Kaplan-Meier估计值；
DOR＝Duration of response，缓解持续时间＝PR/CR所持续的时间。
以上数据来源参考文献：Ajay K.Gopal,M.D.,Brad S.Kahl,M.D.,Sven de Vos,M.D.,Ph.D.et al.PI3KδInhibition by Idelalisib in Patients with Relapsed Indolent Lymphoma[J].N Engl J Med.2014March13；370(11):1008–1018.
化学结构如式A所示的喹唑啉化合物是一种PI3Kδ小分子抑制剂，已公开于CN104557872A专利中(化合物10)，
Figure PCTCN2022079695-appb-000001
与现有的其它PI3Kδ抑制剂相比，提高了对PI3Kδ的选择性，并剔除了对PI3Kγ的活性，中国专利CN110950844A公开了如式A所示的喹唑啉化合物的两种多晶型物。
本领域技术人员知道，口服固体制剂给药后，药物活性成分需在胃肠道释放、吸收进入人体后，方可发挥出治疗和/或预防疾病的作用。由于胃(pH 1-3.5)与肠道(pH 4-8)之间的pH值的显著差异，药物活性成分在胃肠道不同位点处的溶解度可能会因pH值的变化而发生变化。研究结果显示，如式A所示的喹唑啉化合物展现出显著的pH依赖溶解度特征，相对于在模拟人工肠液(FaSSIF，pH＝6.5)中，如式A所示的喹唑啉化合物在模拟胃液(SGF，pH＝1.2)中具有约195倍的更高的溶解度。因此，增加如式A所示的喹唑啉化合物在肠道中的溶解度和/或溶出速率，是有望提高其口服吸收最大化的重要途径。
然而，研究发现如式A所示的喹唑啉化合物遇水易聚集成团，为固体口服制剂的有效崩解和/或药物的迅速释放带来困扰。
鉴于如式A所示的喹唑啉化合物在临床前体内外研究中展现出良好的活性和安全性，迫切需要 开发一种溶出迅速、生物利用度良好并且易于生产的口服给药固体剂型，以确保该药物临床使用时的安全性、有效性和质量一致性。
发明内容
本发明所要解决的技术问题是现有技术存在的如式A所示的喹唑啉化合物的制剂缺乏，为此，本发明提供了一种喹唑啉化合物的药物组合物及其制备方法，该药物组合物对高温、高湿和光照稳定性良好，在0.1mol/L盐酸溶液(pH1.2)、含0.2％十二烷基硫酸钠(SDS)的pH6.8磷酸盐缓冲液中均可实现快速溶出；并且该药物组合物制备方法简单，适合工业化生产。
本发明提供了一种药物组合物，其包括物质X和药用辅料；
其中，所述的物质X为如式A所示的喹唑啉化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；
所述的药用辅料包括填充剂，所述填充剂为微晶纤维素、甘露醇和玉米淀粉中的一种、两种或多种；
Figure PCTCN2022079695-appb-000002
本发明的某一个实施方案中，所述的物质X为唯一活性成分。
本发明的某一个实施方案中，所述的物质X为治疗有效量的。
在本发明的某一个实施方案中，所述的如式A所示的喹唑啉化合物为游离碱形式的如式A所示的喹唑啉化合物，应当理解的是，“游离碱形式”是指如式A所示的喹唑啉化合物不是处于盐的形式的情况。
在本发明的某一些实施方案中，所述的如式A所示的喹唑啉化合物优选如式A所示的喹唑啉化合物的晶型Ⅰ形式，其中如式A所示的喹唑啉化合物的晶型Ⅰ可以按中国专利公开号CN110950844A中所描述的任何方式来定义。
在本发明的某一实施方案中，所述的填充剂为微晶纤维素、甘露醇和玉米淀粉中的一种或两种。
在本发明的某一实施方案中，所述的填充剂为微晶纤维素。
在本发明的某一实施方案中，所述的填充剂为微晶纤维素和甘露醇的混合物。
在本发明的某一实施方案中，所述的填充剂为微晶纤维素和玉米淀粉的混合物。
在本发明的某一实施方案中，所述的填充剂为微晶纤维素和甘露醇以及玉米淀粉的混合物。
在本发明的某一实施方案中，所述的填充剂以重量计为所述的药物组合物总重量的10％-90％， 优选30％-70％，最优选45％-55％。
在本发明的某一实施方案中，所述的填充剂为微晶纤维素和甘露醇的混合物，以重量计为所述的药物组合物总重量的10％-90％，优选30％-70％，最优选45％-55％。
在本发明的某一实施方案中，所述的填充剂为微晶纤维素和甘露醇的混合物，所述的微晶纤维素和所述的甘露醇的质量比为10：1-1：10。
在本发明的某一实施方案中，所述的填充剂为微晶纤维素和甘露醇的混合物，所述的微晶纤维素和所述的甘露醇的质量比为6：1-2：1，优选4：1-3：1。
在本发明的某一实施方案中，所述的药用辅料还包括崩解剂。
在本发明的某一实施方案中，所述崩解剂为交联聚维酮和/或交联羧甲基纤维素钠。
在本发明的某一实施方案中，所述的崩解剂为交联聚维酮。
在本发明的某一实施方案中，所述的崩解剂为交联羧甲基纤维素钠。
在本发明的某一实施方案中，所述的崩解剂不为低取代羟丙基纤维素。
在本发明的某一实施方案中，所述的崩解剂以重量计为所述的药物组合物总重量的1％-20％，优选3％-15％，最优选4％-8％。
在本发明的某一实施方案中，所述的崩解剂为交联羧甲基纤维素钠，以重量计为所述的药物组合物总重量的1％-20％。
在本发明的某一实施方案中，所述的崩解剂为交联羧甲基纤维素钠，以重量计为所述的药物组合物总重量的3％-15％，优选4％-8％。
在本发明的某一实施方案中，所述的药用辅料还进一步包括润滑剂。
本发明中，所述的润滑剂为硬脂酸钙、单硬脂酸甘油酯、山嵛酸甘油酯、硬脂酸镁、棕榈酸、泊洛沙姆、聚乙二醇、苯甲酸钾、苯甲酸钠、月桂基硫酸钠、硬脂酸钠、硬脂富马酸钠、硬脂酸、滑石粉、微粉硅胶和硬脂酸锌中的一种或多种。
在本发明的某一实施方案中，所述的润滑剂为硬脂酸镁。
在本发明的某一实施方案中，所述的润滑剂以重量计为所述的药物组合物总重量的0.1％-5.0％，优选0.3％-2.0％，最优选0.8％-1.4％。
在本发明的某一实施方案中，所述的润滑剂为硬脂酸镁，以重量计为药物组合物总重量的0.1％-5.0％。
在本发明的某一实施方案中，所述的润滑剂为硬脂酸镁，以重量计为药物组合物总重量的0.3％-2.0％，优选0.8％-1.4％。
在本发明的某一实施方案中，所述的药物组合物，包括以重量计的如下成分：
1)40％-50％的如式A所示的喹唑啉化合物；
2)45％-55％的填充剂，所述填充剂为微晶纤维素、甘露醇和玉米淀粉中的一种、两种或多种，优选微晶纤维素和甘露醇的混合物，最优选微晶纤维素和甘露醇混合物，且其质量比为4：1-3：1；
3)4％-8％的崩解剂，所述崩解剂为交联聚维酮和交联羧甲基纤维素钠中至少一种，最优选交联羧甲基纤维素钠；
4)0.8％-1.4％的润滑剂，所述润滑剂为硬脂酸镁。
在本发明的某一实施方案中，所述的如式A所示的喹唑啉化合物以重量计为所述的药物组合物总重量的40％。
在本发明的某一实施方案中，所述的填充剂以重量计为所述的药物组合物总重量的52.8％。
在本发明的某一实施方案中，所述的崩解剂以重量计为所述的药物组合物总重量的6％。
在本发明的某一实施方案中，所述的润滑剂以重量计为所述的药物组合物总重量的1.2％。
在本发明的某一实施方案中，所述的药物组合物包括以重量计的如下组分：
组分 重量百分比(％)
如式A所示的喹唑啉化合物 40-50
微晶纤维素 45-55
交联聚维酮 4-8
硬脂酸镁 0.8-1.4
；较佳地，所述的药物组合物由以上组分组成。
在本发明的某一实施方案中，所述的药物组合物包括以重量计的如下组分：
组分 重量百分比(％)
如式A所示的喹唑啉化合物 40-50
微晶纤维素 45-55
交联羧甲基纤维素钠 4-8
硬脂酸镁 0.8-1.4
；较佳地，所述的药物组合物由以上组分组成。
在本发明的某一实施方案中，所述的药物组合物包括以重量计的如下组分：
组分 重量百分比(％)
如式A所示的喹唑啉化合物 40-50
微晶纤维素 30-45
甘露醇 5-15
交联聚维酮 4-8
硬脂酸镁 0.8-1.4
；较佳地，所述的药物组合物由以上组分组成。
在本发明的某一实施方案中，所述的药物组合物包括以重量计的如下组分：
组分 重量百分比(％)
如式A所示的喹唑啉化合物 40-50
微晶纤维素 30-45
甘露醇 5-15
交联羧甲基纤维素钠 4-8
硬脂酸镁 0.8-1.4
；较佳地，所述的药物组合物由以上组分组成。
在本发明的某一实施方案中，所述的药物组合物包括以重量计的如下组分：
组分 重量百分比(％)
如式A所示的喹唑啉化合物 40-50
微晶纤维素 30-45
玉米淀粉 5-15
交联聚维酮 4-8
硬脂酸镁 0.8-1.4
；较佳地，所述的药物组合物由以上组分组成。
在本发明的某一实施方案中，所述的药物组合物包括以重量计的如下组分：
组分 重量百分比(％)
如式A所示的喹唑啉化合物 40-50
微晶纤维素 35-45
玉米淀粉 5-15
交联羧甲基纤维素钠 4-8
硬脂酸镁 0.8-1.4
，较佳地，所述的药物组合物由以上组分组成。
在本发明的某一实施方案中，所述的药物组合物包括以重量计的如下组分：
组分 重量百分比(％)
如式A所示的喹唑啉化合物 40
微晶纤维素 40
甘露醇 12.8
交联羧甲基纤维素钠 6
硬脂酸镁 1.2
。
在本发明的某一实施方案中，所述的药物组合物可以为固体制剂，优选固体口服制剂。
在本发明的某一实施方案中，所述的药物组合物可以为片剂或胶囊，优选片剂。
在本发明的某一实施方案中，所述的片剂为包衣片。
在本发明的某一实施方案中，所述的包衣片为薄膜包衣片。
在本发明的某一实施方案中，当所述的包衣片为薄膜包衣片时，用于所述的薄膜包衣片的包衣剂是基于羟丙基甲基纤维素为主要成膜聚合物的薄膜包衣预混剂。
在本发明的某一实施方案中，所述的薄膜包衣片中，所述的薄膜包衣片的包衣剂可以商购自卡乐康公司(Colorcon)，例如商标名
Figure PCTCN2022079695-appb-000003
的薄膜包衣预混剂。
在本发明的某一实施方案中，所述的薄膜包衣片中，与片芯重量相比，包衣剂的重量增重为2％-5％，优选2.5％-4.5％，最优选3.5％。
在本发明的某一实施方案中，所述的药物组合物，其包括片芯和包衣两部分，并且各自含有以重量计的如下成分：
片芯：
1)40％-50％的如式A所示的喹唑啉化合物；
2)45％-55％的填充剂，所述填充剂为微晶纤维素、甘露醇和玉米淀粉中的一种、两种或多种，优选微晶纤维素和甘露醇的混合物，微晶纤维素和甘露醇的质量比优选为4：1-3：1；
3)4％-8％的崩解剂，所述崩解剂为交联聚维酮和交联羧甲基纤维素钠中的至少一种，最优选交联羧甲基纤维素钠；
4)0.8％-1.4％的润滑剂，所述润滑剂为硬脂酸镁；
包衣：
5)与片芯重量相比，包衣剂的重量增重为2％-5％，优选2.5％-4.5％，最优选3.5％。
在本发明的某一实施方案中，所述的药物组合物，其包括片芯和包衣两部分，并且各自含有以重量计的如下成分：
片芯：
1)40％的如式A所示的喹唑啉化合物；
2)45％-55％的填充剂，所述填充剂为微晶纤维素和甘露醇的混合物，微晶纤维素和甘露醇的质量比为4：1-3：1；
3)4％-8％的崩解剂，所述崩解剂为交联羧甲基纤维素钠；
4)0.8％-1.4％的润滑剂，所述润滑剂为硬脂酸镁；
包衣：
5)与片芯重量相比，包衣剂的重量增重为3.5％。
在本发明的某一实施方案中，所述的药物组合物，其包括片芯和包衣两部分，并且各自含有以重量计的如下成分：
片芯：
1)40％的如式A所示的喹唑啉化合物；
2)40％的微晶纤维素和12.8％的甘露醇；
3)6％的交联羧甲基纤维素钠；
4)1.2％的硬脂酸镁；
包衣：
5)与片芯重量相比，包衣剂的重量增重为3.5％。
在本发明的某一实施方案中，所述的药物组合物的单位剂型中，所述的如式A所示的喹唑啉化合物的含量为5mg-500mg，优选10mg-200mg，最优选20mg-100mg，例如20mg、30mg、40mg、50mg、60mg、70mg、80mg、90mg或100mg。以片剂为例，所述单位剂型中，所述的如式A所示的喹唑啉 化合物的含量为5mg-500mg/片。
本发明的第二方面提供了如上所述的药物组合物的制备方法，其为粉末直接压片。
较佳地，本发明提供的药物组合物的制备方法，包括以下步骤：
1)预处理
将如式A所示的喹唑啉化合物、填充剂、崩解剂分别过30目筛，将润滑剂过60目筛；
2)总混
按处方量，将根据步骤1)得到的如式A所示的喹唑啉化合物与填充剂在混合机中进行混合，得预混物1；
将预混物1与崩解剂在混合机中进行混合，得预混物2；使用整粒机过筛预混物2，得预混物3；
将预混物3和润滑剂在混合机中进行混合，得总混物料；
3)将根据步骤2)得到的总混物料压片，得片芯；
4)配制10％的薄膜包衣预混剂包衣液，将根据步骤3)得到的片芯进行包衣。
在某一方案中，所述药物组合物为治疗B细胞血液瘤的药物；
在某一方案中，所述药物组合物为治疗B细胞血液瘤的药物，所述B细胞血液瘤为B细胞淋巴瘤，较佳地，所述B细胞淋巴瘤为非霍奇金淋巴瘤，更佳地，所述非霍奇金淋巴瘤为滤泡性淋巴瘤，最佳地，所述滤泡性淋巴瘤为复发和/或难治滤泡性淋巴瘤，例如，复发或难治滤泡性淋巴瘤。
在某一方案中，所述药物组合物组合物通过口服使用。
在某一方案中，所述物质X为治疗有效量的。
在某一方案中，所述的药物组合物的施用剂量可以根据患者的体重来确定，以所述如式A所示的喹唑啉化合物的含量计，所述的药物组合物的施用剂量为一次0.33mg/kg-3.33mg/kg，例如，为0.66mg/kg-2.3mg/kg，再例如，为1mg/kg、1.2mg/kg、1.3mg/kg、1.33mg/kg、1.4mg/kg、1.5mg/kg、1.6mg/kg、1.7mg/kg、1.8mg/kg、1.9mg/kg、2.0mg/kg、2.1mg/kg、2.2mg/kg或2.3mg/kg。
在某一方案中，以所述如式A所示的喹唑啉化合物的含量计，所述的药物组合物的施用剂量为20mg-200mg/天，例如，为20mg/天、30mg/天、40mg/天、50mg/天、60mg/天、70mg/天、80mg/天、90mg/天、100mg/天、110mg/天、120mg/天、130mg/天、140mg/天、150mg/天、160mg/天、170mg/天、180mg/天、190mg/天或200mg/天，再例如，为80mg/天。
在某一方案中，所述的药物组合物的施用频率为1-5次/天，例如，为1次/天、2次/天、3次/天、4次/天或5次/天，再例如，为1次/天。
在某一方案中，所述的药物组合物的施用疗程为14-84天/疗程，例如，为14天/疗程、28天/疗程、42天/疗程、56天/疗程、70天/疗程或84天/疗程，再例如，为28天/疗程。
在某一个方案中，所述的药物组合物共计施用1-20个疗程，较佳地，为10-20个疗程，例如，为10、11、12、13、14、15、16、17、18、19或20个疗程，再例如，为12个疗程。
在某一方案中，所述的药物组合物为片剂。
在某一方案中，所述的药物组合物的规格为10mg-120mg/片，例如，为20-100mg/片，再例如为，20mg/片、30mg/片、40mg/片、50mg/片、60mg/片、70mg/片、80mg/片、90mg/片或100mg/片， 再例如，为20mg/片、80mg/片或100mg/片。
在某一方案中，所述的药物组合物施用在接受过一次或一次以上系统性治疗方案的复发或复发滤泡性淋巴瘤的患者上(例如，接受过一次或一次以上系统性治疗方案的复发滤泡性淋巴瘤的患者上)，较佳地，所述的药物组合物施用在接受过二次或二次以上系统性治疗方案的复发或难治滤泡性淋巴瘤的患者上(例如，接受过二次或二次以上系统性治疗方案的复发滤泡性淋巴瘤的患者上)。
在某一方案中，所述的药物组合物施用在既往治疗方案为接受过二线或二线以上全身系统治疗后进展的患者上，所述二线或二线以上全身系统治疗为曾接受过CD20单抗和至少一个烷化剂治疗后进展的患者上，所述烷化剂包括但不限于苯达莫司汀、环磷酰胺、异环磷酰胺、氯苯丁胺、马法兰、白消安和亚硝基。
在某一方案中，所述的药物组合物施用在既往治疗方案为R-CHOP(利妥昔单抗、环磷酰胺、阿霉素、长春新碱、强的松)，BR(苯达莫司汀、利妥昔单抗)，和R-CVP(利妥昔单抗、环磷酰胺、长春新碱、强的松)的患者上。
在某一方案中，所述的药物组合物的施用对象为人类。
本发明还提供了一种治疗疾病的方法，其包括向患者(例如人类)施用治疗有效量的物质X或药物组合物；
所述疾病为B细胞血液瘤；所述物质X为如式A所示的喹唑啉化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；所述药物组合物包括所述物质X和药用辅料。
在某一方案中，所述B细胞血液瘤为B细胞淋巴瘤，较佳地，所述B细胞淋巴瘤为非霍奇金淋巴瘤，更佳地，所述非霍奇金淋巴瘤为滤泡性淋巴瘤，最佳地，所述滤泡性淋巴瘤为复发和/或难治滤泡性淋巴瘤，例如，复发或难治滤泡性淋巴瘤。
在某一方案中，所述施用的方式为口服。
在某一方案中，所述施用的剂量可以根据患者的体重来确定，以所述如式A所示的喹唑啉化合物的含量计，所述施用的剂量为一次0.33mg/kg-3.33mg/kg，例如，为0.66mg/kg-2.3mg/kg，再例如，为1mg/kg、1.2mg/kg、1.3mg/kg、1.33mg/kg、1.4mg/kg、1.5mg/kg、1.6mg/kg、1.7mg/kg、1.8mg/kg、1.9mg/kg、2.0mg/kg、2.1mg/kg、2.2mg/kg或2.3mg/kg。
在某一方案中，以所述如式A所示的喹唑啉化合物的含量计，所述施用的剂量为20-200mg/天，例如，为20mg/天、30mg/天、40mg/天、50mg/天、60mg/天、70mg/天、80mg/天、90mg/天、100mg/天、110mg/天、120mg/天、130mg/天、140mg/天、150mg/天、160mg/天、170mg/天、180mg/天、190mg/天或200mg/天，再例如，为80mg/天。
在某一方案中，所述施用的频率为1-5次/天，例如，为1次/天、2次/天、3次/天、4次/天或5次/天，再例如，为1次/天。
在某一方案中，所述施用的疗程为14-84天/疗程，例如，为14天/疗程、28天/疗程、42天/疗程、56天/疗程、70天/疗程或84天/疗程，再例如，为28天/疗程。
在某一方案中，所述患者共计接受1-20个疗程，较佳地，为10-20个疗程，例如，为10、11、12、13、14、15、16、17、18、19或20个疗程，再例如，为12个疗程。
在某一方案中，所述物质X或药物组合物为片剂。
在某一方案中，所述物质X或药物组合物的规格为10-120mg/片，例如，为20-100mg/片，再例如，为20mg/片、30mg/片、40mg/片、50mg/片、60mg/片、70mg/片、80mg/片、90mg/片或100mg/片，再例如，为20mg/片、80mg/片或100mg/片。
在某一方案中，所述患者为接受过一次或一次以上系统性治疗方案的复发滤泡性淋巴瘤的患者，较佳地，所述患者为接受过二次或二次以上系统性治疗方案的复发滤泡性淋巴瘤的患者。
在某一方案中，所述患者为接受过二线或二线以上全身系统治疗后进展的患者，较佳地，所述患者为曾接受过CD20单抗和至少一个烷化剂治疗后进展的患者，所述烷化剂包括但不限于苯达莫司汀，环磷酰胺，异环磷酰胺，氯苯丁胺，马法兰，白消安，亚硝基。
在某一方案中，所述患者为既往治疗方案为R-CHOP(利妥昔单抗、环磷酰胺、阿霉素、长春新碱、强的松)，BR(苯达莫司汀、利妥昔单抗)，和R-CVP(利妥昔单抗、环磷酰胺、长春新碱、强的松)的患者。
在某一方案中，所述的药用辅料为药学领域常规的稀释剂、赋形剂、填充剂、粘合剂、润湿剂、崩解剂、吸收促进剂、表面活性剂、吸附载体、润滑剂中的一种或多种。
本发明提供了一种物质X在制备B细胞血液瘤抑制剂中的应用；
所述物质X为如式A所示的喹唑啉化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物：
Figure PCTCN2022079695-appb-000004
在某一方案中，所述B细胞血液瘤为B细胞淋巴瘤，较佳地，所述B细胞淋巴瘤为非霍奇金淋巴瘤，更佳地，所述非霍奇金淋巴瘤为滤泡性淋巴瘤，最佳地，所述滤泡性淋巴瘤为复发和/或难治滤泡性淋巴瘤。
在某一方案中，所述抑制剂可用于哺乳动物生物体内；也可用于生物体外，主要作为实验用途，例如：作为标准样或对照样提供比对，或按照本领域常规方法制成试剂盒。
本发明中所使用的“填充剂”，也称“稀释剂”，是指在科学的背景下用于增加药物组合物产品剂型的体积和重量的一类辅料。因此，填充剂可以是，例如：碳酸钙、磷酸钙、磷酸氢钙、硫酸钙、乙酸纤维素、乙基纤维素、果糖、乳糖、乳糖醇、麦芽糖、麦芽糊精、麦芽糖醇、甘露醇、微晶纤维素、聚右旋糖、聚乙二醇、碳酸氢钠、碳酸钠、氯化钠、山梨糖醇、玉米淀粉、糊精、蔗糖、海藻糖和木糖醇。
本发明中所使用的“崩解剂”，是指在科学的背景下用于促进药物组合物产品剂型在水环境中破裂成更小的碎片的一类辅料。因此，崩解剂可以是，例如：海藻酸、海藻酸钙、羧甲基纤维素钙、壳聚糖、胶体二氧化硅、交联羧甲基纤维素钠、交联聚维酮、羧甲基淀粉钠、低取代羟丙基纤维素、羟丙甲纤维素、甘氨酸、瓜尔胶、羟丙基纤维素、硅酸铝镁、甲基纤维素、聚维酮、海藻酸钠、羧甲基纤维素钠、羟基乙酸淀粉钠和淀粉。
本发明中所使用的“润滑剂”，是指在科学的背景下用于改善药物组合物产品剂型加工过程的一类辅料。因此，润滑剂可以是，例如：硬脂酸钙、单硬脂酸甘油酯、山嵛酸甘油酯、硬脂酸镁、棕榈酸、泊洛沙姆、聚乙二醇、苯甲酸钾、苯甲酸钠、月桂基硫酸钠、硬脂酸钠、硬脂富马酸钠、硬脂酸、滑石粉、微粉硅胶和硬脂酸锌。
本发明中所使用的“包衣剂”或“薄膜包衣预混剂”，是指在科学的背景下用于改善药物组合物产品剂型外观的一类辅料。因此，包衣剂可以是，例如：蔗糖、乳糖、羟丙基甲基纤维素、羟丙基乙基纤维素、醋酸纤维素酞酸酯、聚乙烯醇、聚醋酸乙烯邻苯二甲酸酯、邻苯二酸羟丙甲纤维素酯和丙烯酸树脂。
术语“药学上可接受的盐”是指本发明化合物与相对无毒的、药学上可接受的酸或碱制备得到的盐。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括但不限于：锂盐、钠盐、钾盐、钙盐、铝盐、镁盐、锌盐、铋盐、铵盐、二乙醇胺盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的药学上可接受的酸与这类化合物的中性形式接触的方式获得酸加成盐。所述的药学上可接受的酸包括无机酸，所述无机酸包括但不限于：盐酸、氢溴酸、氢碘酸、硝酸、碳酸、磷酸、亚磷酸、硫酸等。所述的药学上可接受的酸包括有机酸，所述有机酸包括但不限于：乙酸、丙酸、草酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、水杨酸、酒石酸、甲磺酸、异烟酸、酸式柠檬酸、油酸、单宁酸、泛酸、酒石酸氢、抗坏血酸、龙胆酸、富马酸、葡糖酸、糖酸、甲酸、乙磺酸、双羟萘酸(即4,4’-亚甲基-双(3-羟基-2-萘甲酸))、氨基酸(例如谷氨酸、精氨酸)等。当本发明的化合物中含有相对酸性和相对碱性的官能团时，可以被转换成碱加成盐或酸加成盐。具体可参见Berge et al.,"Pharmaceutical Salts",Journal of Pharmaceutical Science 66:1-19(1977)、或Handbook of Pharmaceutical Salts:Properties,Selection,and Use(P.Heinrich Stahl and Camille G.Wermuth,ed.,Wiley-VCH,2002)。
术语“溶剂合物”是指本发明化合物与化学计量或非化学计量的溶剂结合形成的物质。溶剂合物中的溶剂分子可以有序或非有序排列的形式存在。所述的溶剂包括但不限于：水、甲醇、乙醇等。
术语“药学上可接受的盐的溶剂合物”中的“药学上可接受的盐”和“溶剂合物”如上所述，是指本发明化合物与相对无毒的、药学上可接受的酸或碱制备得到的，与化学计量或非化学计量的溶剂结合形成的物质。
术语“治疗有效量”是指给予患者的、足以有效治疗疾病的化合物的量。治疗有效量将根据化合物、疾病种类、疾病的严重度、患者的年龄等变化，但可由本领域技术人员视情况调整。
术语“药用辅料”是指生产药品和调配处方时使用的赋形剂和附加剂，是除活性成分以外，包含在药物制剂中的所有物质。具体参见中华人民共和国药典(2020年版)或Handbook of Pharmaceutical Excipients(Raymond C Rowe,2009)。
术语“治疗”指治疗性疗法。涉及具体病症时，治疗指：(1)缓解疾病或者病症的一种或多种生物学表现，(2)干扰(a)导致或引起病症的生物级联中的一个或多个点或(b)病症的一种或多种生物学表现，(3)改善与病症相关的一种或多种症状、影响或副作用，或者与病症或其治疗相关的一种或多种症状、影响或副作用，或(4)减缓病症或者病症的一种或多种生物学表现发展。
术语“进展”指疾病治疗后没有缓解或治愈，甚至反而加重。
术语“患者”指已经或即将接受治疗的任何动物，哺乳动物为优，人类最优。术语“哺乳动物”包括任何哺乳动物。哺乳动物的实例包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人等，以人类为最优。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于：本发明的药物组合物对高温、高湿和光照稳定性良好，在0.1mol/L盐酸溶液、含0.2％十二烷基硫酸钠(SDS)的pH6.8磷酸盐缓冲液中均可实现快速溶出；并且本发明的药物组合物制备方法简单，适合工业化生产。
附图说明
图1为第二部分实施例4和5提供的如式A所示的喹唑啉化合物的药物组合物在0.1mol/L盐酸溶液中的溶出曲线图。
图2为第二部分实施例4和5提供的如式A所示的喹唑啉化合物的药物组合物在含0.2％SDS的pH6.8磷酸盐缓冲液中的溶出曲线图。
具体实施方式
第一部分：
制备实施例1：如式A所示的喹唑啉化合物的合成路线。
如式A所示的喹唑啉化合物按照专利CN104557872A中记载的化合物10的制备方法制备得到，并按照专利CN110950844A中实施例8的方法重结晶。
效果实施例1：如式A所示的喹唑啉化合物及其类似物对于PI3Kδ的体外抑制活性，以及对于其它亚型的选择性。
见CN104557872A说明书[0538]-[0549]段。
效果实施例2：如式A所示的喹唑啉化合物及其类似物的药代动力学评价
实验方法：
选择雄性SD大鼠，分为两组，静脉给药组(iv)剂量为2mg/kg，口服灌胃给药组(po)剂量为10mg/kg。给药后，两组分别在0h，0.083h，0.25h，0.5h，1h，2h，4h，8h，24h时间点采血，分离血 浆，用LCMSMS法测定大鼠静脉和灌胃给药后，血浆中的受试化合物浓度，并计算药代动力学参数。结果见表1。
C max：药物达峰浓度，AUC last：0点到最后可测浓度对应时间点的浓度-时间曲线下面积，F％：生物利用度。
表1：如式A所示的喹唑啉化合物及其类似物对PI3Kδ抑制活性以及选择性、药代动力学数据汇总表
Figure PCTCN2022079695-appb-000005
---表示未测试。
从结果上，尽管几个化合物在体外都表现了很好的PI3Kδ抑制活性，结构也比较接近，但是药代动力学上表现差异很大，如式A所示的喹唑啉化合物在相同剂量下的达峰浓度、0点到最后可测浓度对应时间点的浓度-时间曲线下面积以及生物利用度都更高。
效果实施例3：如式A所示的喹唑啉化合物的药代动力学研究
如式A所示的喹唑啉化合物在小鼠、大鼠和犬的药代动力学研究结果
如式A所示的喹唑啉化合物在小鼠、大鼠和犬的药代动力学研究结果显示，在药效剂量范围内口服吸收良好，口服生物利用度分别在90％、65％和60％以上。连续7天给药后大鼠和犬体内如式A所 示的喹唑啉化合物的暴露量有一定升高，约为首次给药的1.28-2.20倍，提示药物严重蓄积的风险较小。如式A所示的喹唑啉化合物在大鼠体内的清除率为中等，而在小鼠和犬体内的清除率则较慢。如式A所示的喹唑啉化合物具有广泛的组织分布，除脑组织外，如式A所示的喹唑啉化合物在其他组织中的暴露量均高于其在血浆中的暴露量。如式A所示的喹唑啉化合物的组织分布存在一定性别差异。体外抑制、诱导试验和重组酶稳定性试验结果表明如式A所示的喹唑啉化合物对CYP酶没有明显抑制和诱导作用，CYP3A4是如式A所示的喹唑啉化合物的主要代谢酶，其次是CYP2C8。如式A所示的喹唑啉化合物在体内代谢广泛，但主要以原形药物通过尿液和粪便排出体外，约50％。
表2：ICR小鼠、SD大鼠、Beagle犬单次口服灌胃给药后的药代动力学结果
Figure PCTCN2022079695-appb-000006
吸收
如式A所示的喹唑啉化合物灌胃给药后，在小鼠、大鼠和比格犬体内的吸收良好，口服生物利用度分别达到了90％，65％和60％以上。在不同剂量组的大鼠和犬试验中，如式A所示的喹唑啉化合物血浆暴露量以及达峰浓度的增加接近于剂量增加的比例，提示如式A所示的喹唑啉化合物随着剂量的增加，存在线性药代动力学的特征。
分布
体外血浆蛋白结合率试验结果表明，如式A所示的喹唑啉化合物在0.1-30μM浓度范围内其小鼠、大鼠、比格犬和人血浆的蛋白结合率均为中度(51.1-85.6％)；在猴血浆中，低中浓度下(0.1-2μM)其蛋白结合率为中度(89.3-89.6％)，而高浓度下(30μM)的蛋白结合率为高度(90.2％)。如式A所示的喹唑啉化合物在5个种属的血浆蛋白结合率由高到低依次为：食蟹猴>人>CD1小鼠>SD大鼠>比 格犬，其中食蟹猴与人的结合率相似(85-90％)，SD大鼠和比格犬的结合率相似(50-65％)。
ICR小鼠、SD大鼠和比格犬单次静脉注射分别给予10、10和1.0mg/kg剂量后，如式A所示的喹唑啉化合物的稳态表观分布容积(V ss，L/kg)分别为4.22(雄性小鼠)、4.55(雄性大鼠)、5.18(雌性大鼠)、4.70(雄性犬)和4.08(雌性犬)，分别是各动物体内体液总量的5.82(雄性小鼠)、6.80(雄性大鼠)、7.75(雌性大鼠)、7.79(雄性犬)和6.76(雌性犬)倍，提示如式A所示的喹唑啉化合物在各动物体内有较广泛的组织分布。
灌胃给予SD大鼠60mg/kg后，如式A所示的喹唑啉化合物广泛分布至各组织和脏器中，除脑组织外，如式A所示的喹唑啉化合物在其他组织中的暴露量均明显高于其在血浆中的暴露量，约为后者的2-22倍。如式A所示的喹唑啉化合物的组织分布存在一定的性别差异。雄性大鼠在各时间点的血浆和组织药物浓度都高于雌性大鼠。如式A所示的喹唑啉化合物在雄性大鼠各组织中的暴露量约为雌性大鼠的1.49-3.70倍。如式A所示的喹唑啉化合物在雄性大鼠各组织中的半衰期约2.29-5.08hr，在雌性大鼠各组织中的半衰期约2.25-4.45hr(脑组织除外)。对雄性大鼠来说，如式A所示的喹唑啉化合物在胃中的暴露量最高，然后依次为小肠、肝、肾、肺、脾、大肠、胸腺、心、睾丸、骨骼肌、脂肪、血浆和脑。对雌性大鼠来说，如式A所示的喹唑啉化合物的最高暴露量在小肠中，然后依次为胃、肝、脾、肾、肺、大肠、胸腺、卵巢、子宫、心、骨骼肌、脂肪、血浆和脑。
代谢
如式A所示的喹唑啉化合物在小鼠，大鼠，犬和人的肝微粒体中均较为稳定(半衰期>120分钟)，在猴的肝微粒体中为中等代谢(半衰期＝30-120分钟)。此外，如式A所示的喹唑啉化合物在小鼠、大鼠、犬、猴和人的体外肝细胞试验中都未见明显代谢(半衰期>120分钟)。
从各种人重组酶介导下代谢物的生成来看，CYP3A4是如式A所示的喹唑啉化合物的主要代谢酶，其次是CYP2C8。虽然在CYP2C8孵育体系中如式A所示的喹唑啉化合物有20％-30％的减少，但在-NADPH和+抑制剂这两个孵育体系中也发生了同样的现象，故不能说明母药的代谢是依赖于重组酶CYP2C8。
如式A所示的喹唑啉化合物对人肝微粒体内的CYP 1A2、2B6、2C8、2C9、2C19、2D6及3A4无明显抑制作用(IC 50>10μM)。
如式A所示的喹唑啉化合物在0.4，4和40μM 3个测试浓度下，在CYP1A2，CYP2B6及CYP3A4方面，未表现出对酶活或mRNA表达的提高作用。
ICR小鼠、SD大鼠和比格犬单次静脉注射分别给予10、10和1.0mg/kg的剂量后，如式A所示的喹唑啉化合物的总体清除率(CL，L/hr/kg)分别为1.25(雄性小鼠)、1.45(雄性大鼠)、2.18(雌性大鼠)、0.224(雄性犬)和0.191(雌性犬)，分别是各动物体内肝血流量的23.1％(雄性小鼠)、43.8％(雄性大鼠)、66.0％(雌性大鼠)、12.1％(雄性犬)和10.3％(雌性犬)，提示小鼠和犬对如式A所示的喹唑啉化合物的代谢清除能力较弱。
从肝微粒体中代谢物生成的种类及其相对含量，并结合如式A所示的喹唑啉化合物在肝微粒体的代谢稳定性判断，选择大鼠和犬作为啮齿和非啮齿类实验动物的安全性评价，符合药物临床前安全性评价的要求。
排泄
灌胃给予SD大鼠60mg/kg如式A所示的喹唑啉化合物后，如式A所示的喹唑啉化合物在雄性大鼠尿液、粪便及胆汁中0-72hr的排泄量分别为给药量的20.1±6.48％、24.5±11.1％和1.68±0.890％；而其在雌性大鼠尿液、粪便及胆汁中0-72hr的排泄量分别为给药量的8.11±2.62％、7.58±3.95％和10.9±1.29％。故灌胃给药后如式A所示的喹唑啉化合物在雄性和雌性SD大鼠尿粪和胆汁中的总排泄率分别为46.3％和26.6％。
灌胃给予比格犬10mg/kg如式A所示的喹唑啉化合物后，如式A所示的喹唑啉化合物在雄性犬尿液和粪便中的排泄量分别为给药量的29.2±13.5％和19.5±16.2％，其在雌性犬尿液和粪便中的排泄量分别为给药量的41.4±12.4％和9.21±7.08％，故灌胃给药后如式A所示的喹唑啉化合物在雄性和雌性比格犬尿粪中的总排泄率分别为48.7％和50.6％。
效果实施例4：如式A所示的喹唑啉化合物对不同细胞的抑制活性
实验方法：
分别向96孔板中(外围孔除外)加入100μl待测细胞悬液。将培养板放置于二氧化碳培养箱中过夜。往各孔中加入配制好的如式A所示的喹唑啉化合物(50μM为起始浓度，通过3倍稀释，得到10个浓度梯度的如式A所示的喹唑啉化合物)。细胞板在二氧化碳培养箱中孵育72小时。向96孔板中加入25μl的CellTiter Glo试剂，避光震荡2分钟，室温避光静置10分钟，将培养板放入酶标仪中读取化学发光值，利用XLFit绘制药效抑制率曲线并计算IC 50值。
在不同肿瘤细胞中检测了如式A所示的喹唑啉化合物对细胞增殖的影响。结果显示，如式A所示的喹唑啉化合物在一些血液瘤细胞具有明显的抑制活性。比如，在SU-DHL-6细胞中的IC 50值为0.2337μM，在SU-DHL-5细胞中的IC 50值为1.7683μM。
效果实施例5：如式A所示的喹唑啉化合物对SU-DHL-6皮下异种移植瘤模型的动物体内活性评价
实验方法：
CB17 SCID小鼠，雌性，体重18-22克。SU-DHL-6细胞体外悬浮培养，培养条件为RPMI1640培养基中加10％热灭活胎牛血清，100U/ml青霉素及100μg/ml链霉素37℃5％CO 2培养。一周两次传代处理。当细胞呈指数生长期时，收取细胞，用于接种。将含5x 10^6个SU-DHL-6细胞的0.2ml细胞悬液(细胞悬于base RPMI1640培液中，RPMI1640:Matrigel(基质胶)＝100μl:100μl)皮下接种于每只小鼠的右后背。肿瘤平均体积达到95.79mm 3时开始分组给药。分组方法：给药前称重动物，测量瘤体积。根据瘤体积随机分组(随机分组设计)，分组及给药方案见下表3。实验指标是考察肿瘤生长是否可以被抑制、延缓或治愈。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b 2，a和b分别表示肿瘤的长径和短径。化合物的抑瘤疗效用TGI(％)来评价。TGI(％)反映肿瘤生长抑制率。TGI(％)的计算：TGI(％)＝[1-(处理组给药结束时瘤体积-处理组给药开始时瘤体积)/(溶剂对照组给药结束时瘤体积-溶剂对照组给药开始时瘤体积)]×100％。TGI≥58％认为此药有效；TGI≥90％，认为此药极有效。
表3：体内药效实验动物分组及给药方案表
Figure PCTCN2022079695-appb-000007
结果显示，至给药第15天时，CAL-101(即为Idelalisib)50mg/kg BID治疗组、如式A所示的喹唑啉化合物60mg/kg QD组、如式A所示的喹唑啉化合物120mg/kg QD组和如式A所示的喹唑啉化合物240mg/kg QD组的TGI分别为42.67％、71.89％、81.57％和86.98％。Two-way ANOVA统计分析显示CAL-101 50mg/kg BID组、如式A所示的喹唑啉化合物60mg/kg QD组、如式A所示的喹唑啉化合物120mg/kg QD组和如式A所示的喹唑啉化合物240mg/kg QD组在Day15的肿瘤体积均显著小于溶剂对照组(P值均<0.01)。如式A所示的喹唑啉化合物在三个治疗剂量时均可以被荷瘤鼠耐受。肿瘤体积和重量的结果均显示如式A所示的喹唑啉化合物60mg/kg QD治疗、如式A所示的喹唑啉化合物120mg/kg QD治疗和如式A所示的喹唑啉化合物240mg/kg QD治疗对SU-DHL-6人淋巴瘤细胞皮下异种移植瘤生长具有显著的抑制作用。
效果实施例6：如式A所示的喹唑啉化合物的临床I期和II期数据
(1)I期临床方案设计(爬坡和扩展方案)
患者纳入标准为组织学或细胞学确诊的复发或难治B细胞血液肿瘤患者，共计纳入患者25例，其中滤泡性淋巴瘤10例。
本研究分为两个阶段：剂量递增和剂量扩展；每个阶段均包括单次给药和多次给药研究。剂量递增阶段的剂量包括20mg/天、40mg/天、80mg/天、140mg/天、200mg/天。除20mg初始剂量组仅入组1例外，每个剂量组分别入组3-6例受试者，40mg剂量组入组3例，80mg剂量组入组3例，140mg剂量组入组3例，200mg剂量组入组4例；其中，滤泡性淋巴瘤分别在40mg、200mg各入组了1例，80mg入组2例。在耐受性试验结束后，进行剂量扩展试验，剂量为80mg/天，一共入组了11例患者，其中6例滤泡性淋巴瘤患者。共计入组了滤泡性淋巴瘤患者10例。
给药方式为：口服给药，连续给药期间每日1次，直到疾病进展或毒性不可耐受。
如式A所示的喹唑啉化合物片为粉末混合直压工艺的包衣片，按照第二部分制备例1和制备例2中所描述的工艺制备得到。配方为第二部分实施例5的配方，制得20mg或100mg片剂。
(2)I期试验结果与效果
如式A所示的喹唑啉化合物片在复发或难治B细胞恶性血液肿瘤患者中展示了良好的抗肿瘤活性，特别是在滤泡性淋巴瘤中显示了非常好的疗效。结果见下表，25例受试者中最佳整体疗效CR为5例，PR为11例，SD为2例，PD为7例，整体最优疗效ORR比例为64％(16/25)(95％CI：45.2-82.8％)，DCR比例为72％(18/25)(95％CI：54.4-89.6％)。其中滤泡性淋巴瘤最优疗效的ORR和DCR比例均为90.0％(9/10)。
总缓解率(Overall response rate,ORR)；疾病控制率(Disease control rate,DCR)；CR＝完全缓解；PR＝部分缓解；SD＝病情稳定；PD＝疾病进展。
B细胞淋巴瘤的疗效评价标准参考《淋巴瘤的疗效评价标准IRWG(节选)，恶性淋巴瘤疗效评价的修订标准》。
表4：最优疗效统计表
Figure PCTCN2022079695-appb-000008
(3)I期安全性效果数据
患者纳入标准为组织学或细胞学确诊的复发或难治B细胞血液肿瘤患者，共计纳入患者25例，其中滤泡性淋巴瘤10例。本研究分为两个阶段：剂量递增和剂量扩展；每个阶段均包括单次给药和多次给药研究。剂量递增阶段的剂量包括20mg/天、40mg/天、80mg/天、140mg/天、200mg/天。除20mg初始剂量组仅入组1例外，每个剂量组分别入组3-6例受试者，40mg剂量组入组3例，80mg剂量 组入组3例，140mg剂量组入组3例，200mg剂量组入组4例。剂量扩展研究在80mg剂量组中进行。在28天观察期内均未发生剂量限制性毒性(DLT)，从不良事件的发生情况来看，如式A所示的喹唑啉化合物片单次和多次给药耐受性良好。
根据I期临床结果，证明如式A所示的喹唑啉化合物安全性良好可控。
基于临床前结果，在经常规标准治疗无效的或缺乏标准治疗的复发或难治B细胞恶性血液肿瘤患者中开展如式A所示的喹唑啉化合物单臂、开放、单次及多次给药、剂量递增的耐受性及药代动力学I期临床研究，研究结果提示如式A所示的喹唑啉化合物安全性可控，耐受性较好。
综上所述，如式A所示的喹唑啉化合物在20-200mg剂量范围内安全可耐受，可以缓解和控制复发或难治B细胞恶性肿瘤病情进展，在滤泡淋巴瘤中也显示了非常好的疗效。
(4)上市同靶点药物数据对比
目前FDA批准上市的PI3kδ抑制剂Idelalisib治疗难治复发滤泡淋巴瘤的客观缓解率(ORR)为39％，而PI3Kγ，δ抑制剂Duvelisib治疗难治复发滤泡淋巴瘤的ORR为42％；Copanlisib治疗难治复发滤泡淋巴瘤的ORR为59％。(数据从上市药物说明书中获得)。
如式A所示的喹唑啉化合物在临床I期治疗滤泡性淋巴瘤最优疗效的ORR为90.0％(9/10)。如式A所示的喹唑啉化合物治疗复发和/或难治滤泡性淋巴瘤患者的单臂、开放、多中心II期临床试验，入组标准为接受过二线或二线以上全身系统治疗后进展(曾接受过CD20单抗和至少一个烷化剂治疗，烷化剂包括但不限于苯达莫司汀，环磷酰胺，异环磷酰胺，氯苯丁胺，马法兰，白消安，亚硝基)，入组了93例受试者。受试者服用如式A所示的喹唑啉化合物片，每日一次，口服给药，每次20mg片剂4片，直到疾病进展或毒性不可耐受。89例受试者进行了至少一次的影像评估，独立数据评估(淋巴瘤疗效评价标准IRWG)结果显示：如式A所示的喹唑啉化合物在89例(可评估病例)复发/难治滤泡性淋巴瘤的患者中，ORR达80％以上。从统计结果分析来看，ORR从同类药物的50％左右提高到了80％左右，较同类药物有较明显的优势。
第二部分
下列实施例中使用的如式A所示的喹唑啉化合物，按照专利CN104557872A中记载的化合物10的制备方法制备得到，并按照专利CN110950844A中实施例8的方法重结晶。
下列实施例中所用的材料在下表中示出：
Figure PCTCN2022079695-appb-000009
Figure PCTCN2022079695-appb-000010
下列实施例中所用的设备在下表中示出：
Figure PCTCN2022079695-appb-000011
在实施例1、2、3A和3B中，溶出方法均按照2015年版《中国药典》四部通则0931第二法，以37℃、含0.2％SDS的pH6.8磷酸盐缓冲液900ml为溶出介质，转速为75转/分钟，合适时间间隔取样，相同体积溶出介质补液，0.45μm滤膜过滤，高效液相测定含量计算溶出率。
下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
制备例1、片芯制备
按照设计的处方组成称取处方量的如式A所示的喹唑啉化合物和各辅料，将如式A所示的喹唑啉化合物、填充剂和崩解剂分别过30目筛网，润滑剂过60目筛网；将如式A所示的喹唑啉化合物与填充剂在混合机中混合均匀，得预混物1；将崩解剂加入到预混物1中，使用混合机混合均匀，得预混物2；使用整粒机过筛预混物2，得预混物3；将预混物3和润滑剂在混合机中进行混合，得总混物料；使用配备有5mm、D型圆型冲模或11*5.5mm、上冲刻Half线键型冲模的旋转式压片机对总混物料进行压片，以分别形成包含有20mg或100mg如式A所示的喹唑啉化合物的片芯。
制备例2、薄膜包衣片制备
将薄膜包衣预混剂粉末加入到搅拌中的纯化水中，持续搅拌45分钟，配制成薄膜包衣预混剂固含量为10％(w/w)的包衣液，采用高效包衣机对上述制备例1所描述的工艺制造的片芯包衣至包衣增重范围为2％-5％，以分别形成包含20mg或100mg如式A所示的喹唑啉化合物的薄膜包衣片。
实施例1、片芯处方F1-F8
崩解剂的种类和数量直接影响片剂的崩解和药物活性成分的释放速率。分别筛选了交联聚维酮、交联羧甲基纤维素钠和低取代羟丙基纤维素作为崩解剂的处方组成F1-F8，并对处方中崩解剂的用量进行了筛选。采用上述制备例1所描述的工艺来制造药物组合物，分别得到包含20mg如式A所示的喹唑啉化合物的片芯。以压片过程中出片顺畅程度和溶出度作为考察指标，处方组成和结果在下表5中示出。
表5.处方F1-F8及结果
Figure PCTCN2022079695-appb-000012
Figure PCTCN2022079695-appb-000013
―表示未使用。
实验结果：处方F1-F8压片过程顺流畅，均无粘冲现象，仅使用交联聚维酮或仅使用交联羧甲基纤维素钠作为崩解剂的处方F1-F6的片芯崩解迅速，如式A所示的喹唑啉化合物快速溶出，30分钟时的累积溶出均超过90％；崩解剂中加入了低取代羟丙基纤维素的处方F7和F8，片芯崩解迟缓，如式A所示的喹唑啉化合物溶出速率非常慢，30分钟时的累积溶出仅为72％和67％。
实施例2、薄膜包衣片处方F9-F10
润滑剂的用量会影响到压片顺畅程度和药物活性成分的溶出速率。在实施例1中溶出最优处方F5的基础上，分别筛选了不同用量的硬脂酸镁作为润滑剂的处方组成F9和F10。采用上述制备例1所描述的工艺来制造药物组合物，分别得到包含20mg如式A所示的喹唑啉化合物的片芯。配制薄膜包衣预混剂
Figure PCTCN2022079695-appb-000014
固含量为10％(w/w)的包衣液，采用高效包衣机(BGB-5F，浙江小伦制药机械有限公司)对片芯进行包衣，以针对处方F9和F10分别给出包衣增重约为3.5％的包含有20mg如式A所示的喹唑啉化合物的薄膜包衣片。以压片过程中出片顺畅程度和溶出度作为考察指标，实施例2的薄膜包衣片(在包衣之前的)处方组成和结果在下表6中示出。
表6.处方F9-F10及结果
Figure PCTCN2022079695-appb-000015
Figure PCTCN2022079695-appb-000016
实验结果：处方F9和F10压片过程流畅，均无粘冲现象，薄膜包衣片崩解迅速，如式A所示的喹唑啉化合物溶出速率基本一致，30分钟累积溶出分别为88％和92％，均符合成品溶出度放行标准(≥70％)。
实施例3A和3B、薄膜包衣片制备(20mg规格，2万片)
采用上述制备例1所描述的工艺来制造药物组合物，得到包含20mg如式A所示的喹唑啉化合物的片芯。配制薄膜包衣预混剂
Figure PCTCN2022079695-appb-000017
固含量为10％(w/w)的包衣液，采用高效包衣机(BGB-5F，浙江小伦制药机械有限公司)对片芯按包衣增重范围为2％-5％进行包衣，以针对实施例3A给出包衣增重为2.5％的包含有20mg如式A所示的喹唑啉化合物的薄膜包衣片约2万片，和针对实施例3B给出包衣增重为4.5％的包含有20mg如式A所示的喹唑啉化合物的薄膜包衣片约2万片。实施例3A和3B的薄膜包衣片(在包衣之前的)批处方量在下表7中示出。
表7.实施例3A、3B制造的薄膜包衣片(在包衣之前)处方(20mg规格，2万片)
Figure PCTCN2022079695-appb-000018
实施例3A和3B的薄膜包衣片在含0.2％SDS的pH6.8磷酸盐缓冲液中的溶出度结果在下表8中示出。结果表明，包衣增重分别为2.5％和4.5％的20mg规格薄膜包衣片均崩解迅速，如式A所示的喹唑啉化合物溶出速率基本一致，30分钟累积溶出分别为93％和92％，均符合成品溶出度放行标准(≥70％)。
表8.实施例3A、3B制造的薄膜包衣片在0.2％SDS的pH6.8磷酸盐缓冲液中溶出度结果
Figure PCTCN2022079695-appb-000019
实施例4：中试规模薄膜包衣片制备(20mg规格，30万片)
使用粉末直接压片工艺来制造中试规模的药物组合物。将如式A所示的喹唑啉化合物、填充剂和崩解剂分别过30目筛网，润滑剂过60目筛网；将如式A所示的喹唑啉化合物与填充剂在50升的料斗混合机(HBD200型，南通贝特医药机械有限公司)中混合均匀，得预混物1；将崩解剂加入到预混物1中，使用料斗混合机混合均匀，得预混物2；使用安装有032R筛网和方形叶轮的整粒机(Comil U10，加拿大QUADRO)过筛预混物2，得预混物3；将预混物3和润滑剂在料斗混合机中进行混合，得总混物料；使用配备有5mm D型圆型冲模的旋转压片机(P2020，德国Fette)对总混物料进行压片，以形成包含有20mg如式A所示的喹唑啉化合物的片芯。配制薄膜包衣预混剂
Figure PCTCN2022079695-appb-000020
固含量为10％(w/w)的包衣液，采用高效包衣机(BGB-40F，浙江小伦制药机械有限公司)对片芯进行包衣至包衣增重3.5％，得到中试规模的包含有20mg如式A所示的喹唑啉化合物的薄膜包衣片。实施例4的薄膜包衣片批处方量在下表9中示出。
表9.中试规模薄膜包衣片处方(20mg规格，30万片)
Figure PCTCN2022079695-appb-000021
a：制造过程中按50％包衣效率计算，实际批处方使用量为1.050Kg。
b：制造过程中按50％包衣效率计算，实际批处方使用量为9.450Kg，纯化水在包衣过程中除去。
实施例5：100mg规格薄膜包衣片制备
采用上述制备例1所描述的方法来制造药物组合物，得到包含100mg如式A所示的喹唑啉化合物的片芯。配制薄膜包衣预混剂
Figure PCTCN2022079695-appb-000022
固含量为10％(w/w)的包衣液，采用高效包衣机对片芯进行包衣至包衣增重3.5％，得到包含有100mg如式A所示的喹唑啉化合物的薄膜包衣片。实施例6的薄膜包衣片批处方量在下表10中示出。
表10. 100mg规格薄膜包衣片处方
Figure PCTCN2022079695-appb-000023
a：制造过程中按50％包衣效率计算，实际批处方使用量为0.264Kg。
b：制造过程中按50％包衣效率计算，实际批处方使用量为2.376Kg，纯化水在包衣过程中除去。
试验例1：药物组合物关键质量属性测定
对上述实施例4制造的药物组合物进行药物的关键质量属性测定，考核项目包括性状、含量均匀度、含量、有关物质、溶出度，考核结果在下表11中示出。
性状：目视观察，记录薄膜包衣片外观，以及除去包衣后的片芯外观。
含量均匀度：取10片供试品，按照含量测定条件下高效液相色谱方法，分别测定每一个单剂以标示量为100的相对含量xi。照含量均匀度检查法(2015年版《中国药典》四部通则0941)，计算A+2.2S。
有关物质和含量测定：照高效液相色谱法(2015年版《中国药典》四部通则0512)，采用加响应因子的主成分外标法以峰面积计算药物组合物中如式A所示的喹唑啉化合物的各已知杂质和未知杂质及总杂质含量(报告限：0.05％)；采用外标法以峰面积计算药物组合物中如式A所示的喹唑啉化合物的含量。
溶出度：照溶出度测定法(2015年版《中国药典》四部通则0931第二法)，以含0.2％SDS的pH6.8磷酸盐缓冲液900ml为溶出介质，转速为75转/分钟，取6片供试品，且每个溶出杯中放1片，经30分钟时取液10ml，0.45μm滤膜过滤，高效液相测定含量计算如式A所示的喹唑啉化合物的溶出度。
表11.实施例4制造的药物组合物关键质量属性考核结果
Figure PCTCN2022079695-appb-000024
Figure PCTCN2022079695-appb-000025
实验结果：实施例4制造的包含20mg如式A所示的喹唑啉化合物的薄膜包衣片的各关键质量属性的考核结果均符合成品放行质量标准。
试验例2：药物组合物溶出曲线测定
分别对上述实施例4和5制造的药物组合物进行溶出曲线测定。
照溶出度测定法(2015年版《中国药典》四部通则0931第二法)，转速为75转/分钟，以0.1mol/L盐酸溶液(9ml盐酸，加水使成1000ml)或含0.2％SDS的pH6.8磷酸盐缓冲液900ml为溶出介质，从每个实施例制造的薄膜包衣片中取6片供试品，且每个溶出杯中放1片，合适时间间隔取样，相同体积溶出介质补液，0.45μm滤膜过滤，高效液相测定含量计算如式A所示的喹唑啉化合物的累积溶出率，测定结果在下表12和附图1-2中示出。
表12.实施例4、5制造的药物组合物溶出曲线测定结果
Figure PCTCN2022079695-appb-000026
实验结果：在0.1mol/L盐酸溶液中，20mg和100mg规格薄膜包衣片均可迅速且完全溶出，30分钟累积溶出均达到100％。在含0.2％SDS的pH6.8磷酸盐缓冲液中，100mg规格薄膜包衣片的溶出速率稍慢于20mg规格，30分钟累积溶出88％，符合成品溶出度放行标准(≥70％)。
效果实施例1：影响因素试验
采用实施例4制造的药物组合物裸露放置在高温(60℃)、高湿(25±2℃、RH92.5％)、光照(4500±500Lux)影响因素条件下考核30天，照上述试验例1中的测试方法对药物组合物的稳定性进行考核，考核指标包括性状、有关物质、溶出度和含量。具体结果在下表13-15中示出。
表13.实施例4制造的药物组合物高温影响因素试验结果汇总
Figure PCTCN2022079695-appb-000027
Figure PCTCN2022079695-appb-000028
表14.实施例4制造的药物组合物高湿影响因素试验结果汇总
Figure PCTCN2022079695-appb-000029
Figure PCTCN2022079695-appb-000030
a：吸湿增重为高湿影响因素试验的考察项，无限度要求。
表15.实施例4制造的药物组合物光照影响因素试验结果汇总
Figure PCTCN2022079695-appb-000031
Figure PCTCN2022079695-appb-000032
表13-15的结果表明，本发明提供的如式A所示的喹唑啉化合物的药物组合物，在高温、高湿、光照影响因素条件下分别裸露放置5天、10天、30天后测定，药物组合物的各项考核指标与影响因素试验处理前相比，均无明显变化。高湿条件下放置30天，药物组合物无明显的吸湿增重。
应当理解，本发明所述的实施例仅用于说明目的，通过实施例将有助于进一步理解本发明，但不用于限制本发明的内容。对于本领域技术人员而言，对于材料和方法两者的许多改变可在不脱离本发明范围的情况下实施，这些改变或改进包括在本申请的主旨和范围以及所附权利要求的范围内。

Claims (10)

  1. 一种药物组合物，其特征在于，其包含：物质X和药用辅料；其中，所述的物质X为如式A所示的喹唑啉化合物、其药学上可接受的盐、其溶剂合物或其药学上可接受的盐的溶剂合物；
    所述的药用辅料包括填充剂，所述填充剂为微晶纤维素、甘露醇和玉米淀粉中的一种、两种或多种；
    Figure PCTCN2022079695-appb-100001
  2. 如权利要求1所述的药物组合物，其特征在于，所述的物质X为唯一活性成分；
    和/或，所述的物质X为治疗有效量的；
    和/或，所述的药物组合物为治疗B细胞血液瘤的药物；
    和/或，所述的填充剂为微晶纤维素、甘露醇和玉米淀粉中的一种或两种；
    和/或，所述的填充剂以重量计为所述的药物组合物总重量的10％-90％；
    和/或，所述的药用辅料还包括崩解剂；
    和/或，所述的药用辅料还包括润滑剂；
    和/或，所述的药物组合物为片剂或胶囊；
    和/或，以所述如式A所示的喹唑啉化合物的含量计，所述的药物组合物的施用剂量为一次0.33mg/kg-3.33mg/kg；
    和/或，以所述如式A所示的喹唑啉化合物的含量计，所述的药物组合物的施用剂量为20mg-200mg/天；
    和/或，所述的药物组合物的施用频率为1-5次/天；
    和/或，所述的药物组合物的施用疗程为14-84天/疗程；
    和/或，所述的药物组合物共计施用1-20个疗程；
    和/或，所述的药物组合物的单位剂型中，所述的如式A所示的喹唑啉化合物的含量为5mg-500mg；
    和/或，所述的药物组合物施用在既往治疗方案为接受过二线或二线以上全身系统治疗后进展的患者上，所述二线或二线以上全身系统治疗为曾接受过CD20单抗和至少一个烷化剂治疗；
    和/或，所述的药物组合物的施用对象为人类。
  3. 如权利要求2所述的药物组合物，其特征在于，所述的填充剂为微晶纤维素、微晶纤维素和甘露醇的混合物、或、微晶纤维素和玉米淀粉的混合物；
    和/或，所述的填充剂以重量计为药物组合物总重量的30％-70％；
    和/或，当所述的药用辅料还包括崩解剂时，所述的崩解剂为交联聚维酮和/或交联羧甲基纤维素钠；
    和/或，当所述的药用辅料还包括崩解剂时，所述的崩解剂以重量计为所述的药物组合物总重量的1％-20％；
    和/或，当所述的药用辅料还包括润滑剂时，所述的润滑剂为硬脂酸钙、单硬脂酸甘油酯、山嵛酸甘油酯、硬脂酸镁、棕榈酸、泊洛沙姆、聚乙二醇、苯甲酸钾、苯甲酸钠、月桂基硫酸钠、硬脂酸钠、硬脂富马酸钠、硬脂酸、滑石粉、微粉硅胶和硬脂酸锌中的一种或多种；
    和/或，当所述的药用辅料还包括润滑剂时，所述的润滑剂以重量计为所述的药物组合物总重量的0.1％-5.0％；
    和/或，当所述的药物组合物为片剂或胶囊时，所述的片剂为包衣片；
    和/或，当所述的药物组合物为治疗B细胞血液瘤的药物时，所述B细胞血液瘤为B细胞淋巴瘤；
    和/或，以所述如式A所示的喹唑啉化合物的含量计，所述的药物组合物的施用剂量为一次0.66mg/kg-2.3mg/kg；
    和/或，以所述如式A所示的喹唑啉化合物的含量计，所述的药物组合物的施用剂量为20mg/天、30mg/天、40mg/天、50mg/天、60mg/天、70mg/天、80mg/天、90mg/天、100mg/天、110mg/天、120mg/天、130mg/天、140mg/天、150mg/天、160mg/天、170mg/天、180mg/天、190mg/天或200mg/天；
    和/或，所述的药物组合物的施用频率为1次/天、2次/天、3次/天、4次/天或5次/天；
    和/或，所述的药物组合物的施用疗程为14天/疗程、28天/疗程、42天/疗程、56天/疗程、70天/疗程或84天/疗程；
    和/或，所述的药物组合物共计施用10-20个疗程；
    和/或，所述的药物组合物的单位剂型中，所述的如式A所示的喹唑啉化合物的含量为10mg-120mg；
    和/或，所述的药物组合物施用在既往治疗方案为接受过二线或二线以上全身系统治疗后进展的患者上，所述二线或二线以上全身系统治疗为曾接受过CD20单抗和至少一个烷化剂治疗，所述烷化剂包括苯达莫司汀、环磷酰胺、异环磷酰胺、氯苯丁胺、马法兰、白消安和亚硝基。
  4. 如权利要求3所述的药物组合物，其特征在于，所述的填充剂以重量计为药物组合物总重量45％-55％；
    和/或，所述的如式A所示的喹唑啉化合物以重量计为药物组合物总重量40％-50％；
    和/或，当所述的填充剂为微晶纤维素和甘露醇的混合物时，所述的微晶纤维素和所述的甘露醇的质量比为10：1-1：10；
    和/或，当所述的药用辅料还包括崩解剂时，所述的崩解剂为交联聚维酮或交联羧甲基纤维素钠；
    和/或，当所述的药用辅料还包括崩解剂时，所述的崩解剂以重量计为所述的药物组合物总重量的3％-15％；
    和/或，当所述的药用辅料还包括润滑剂时，所述的润滑剂为硬脂酸镁；
    和/或，当所述的药用辅料还包括润滑剂时，所述的润滑剂以重量计为所述的药物组合物总重量的 0.3％-2.0％；
    和/或，当所述的片剂为包衣片时，所述的包衣片为薄膜包衣片；
    和/或，当所述B细胞血液瘤为B细胞淋巴瘤时，所述B细胞淋巴瘤为非霍奇金淋巴瘤；
    和/或，以所述的如式A所示的喹唑啉化合物的含量计，所述的药物组合物的施用剂量为一次1mg/kg、1.2mg/kg、1.3mg/kg、1.33mg/kg、1.4mg/kg、1.5mg/kg、1.6mg/kg、1.7mg/kg、1.8mg/kg、1.9mg/kg、2.0mg/kg、2.1mg/kg、2.2mg/kg或2.3mg/kg；
    和/或，所述的药物组合物共计施用10、11、12、13、14、15、16、17、18、19或20个疗程；
    和/或，所述的药物组合物的单位剂型中，所述的如式A所示的喹唑啉化合物的含量为20-100mg；
    和/或，所述的药物组合物施用在既往治疗方案为接受过R-CHOP、BR和R-CVP中的一种或多种治疗方案的患者上。
  5. 如权利要求4所述的药物组合物，其特征在于，当所述的填充剂为微晶纤维素和甘露醇的混合物时，所述的微晶纤维素和所述的甘露醇的质量比为6：1-2：1，例如，4：1-3：1；
    和/或，当所述的药用辅料还包括崩解剂时，所述的崩解剂以重量计为所述的药物组合物总重量的4％-8％；
    和/或，当所述的药用辅料还包括润滑剂时，所述的润滑剂以重量计为所述的药物组合物总重量的0.8％-1.4％；
    和/或，当所述的包衣片为薄膜包衣片时，所述的薄膜包衣片中，与片芯重量相比，包衣剂的重量增重为2％-5％；
    和/或，当所述的包衣片为薄膜包衣片时，用于所述的薄膜包衣片的包衣剂是基于羟丙基甲基纤维素为主要成膜聚合物的薄膜包衣预混剂；
    和/或，当所述B细胞淋巴瘤为非霍奇金淋巴瘤时，所述非霍奇金淋巴瘤为滤泡性淋巴瘤；
    和/或，所述的药物组合物的单位剂型中，所述的如式A所示的喹唑啉化合物的含量为20mg、30mg、40mg、50mg、60mg、70mg、80mg、90mg或100mg。
  6. 如权利要求5所述的药物组合物，其特征在于，所述的药物组合物，包括以重量计的如下成分：
    1)40％-50％的如式A所示的喹唑啉化合物；
    2)45％-55％的填充剂，所述的填充剂为微晶纤维素、甘露醇和玉米淀粉中的一种、两种或多种；
    3)4％-8％的崩解剂，所述的崩解剂为交联聚维酮和/或交联羧甲基纤维素钠；
    4)0.8％-1.4％的润滑剂，所述的润滑剂为硬脂酸镁；
    和/或，所述的如式A所示的喹唑啉化合物以重量计为所述的药物组合物总重量的40％；
    和/或，所述的填充剂以重量计为所述的药物组合物总重量的52.8％；
    和/或，当所述的药用辅料还包括崩解剂时，所述的崩解剂以重量计为所述的药物组合物总重量的6％；
    和/或，当所述的药用辅料还包括润滑剂时，所述的润滑剂以重量计为所述的药物组合物总重量的1.2％；
    和/或，当所述的包衣片为薄膜包衣片时，用于所述的薄膜包衣片的包衣剂为商购自卡乐康公司，商标名
    Figure PCTCN2022079695-appb-100002
    的薄膜包衣预混剂；
    和/或，当所述的包衣片为薄膜包衣片时，所述的薄膜包衣片中，与片芯重量相比，包衣剂的重量增重2.5％-4.5％，例如，3.5％；
    和/或，当所述非霍奇金淋巴瘤为滤泡性淋巴瘤时，所述滤泡性淋巴瘤为复发和/或难治滤泡性淋巴瘤；
    和/或，所述的药物组合物施用在接受过一次或一次以上系统性治疗方案的复发或难治滤泡性淋巴瘤的患者上(例如，接受过一次或一次以上系统性治疗方案的复发滤泡性淋巴瘤的患者上)，优选接受过二次或二次以上系统性治疗方案的复发或难治滤泡性淋巴瘤的患者上(例如，接受过二次或二次以上系统性治疗方案的复发滤泡性淋巴瘤的患者上)。
  7. 如权利要求1所述的药物组合物，其特征在于，所述的药物组合物，包括以重量计的如下成分：
    组分 重量百分比％ 如式A所示的喹唑啉化合物 40-50 微晶纤维素 45-55 交联聚维酮 4-8 硬脂酸镁 0.8-1.4
    或，
    组分 重量百分比％ 如式A所示的喹唑啉化合物 40-50 微晶纤维素 45-55 交联羧甲基纤维素钠 4-8 硬脂酸镁 0.8-1.4
    或，
    组分 重量百分比％ 如式A所示的喹唑啉化合物 40-50 微晶纤维素 30-45 甘露醇 5-15 交联聚维酮 4-8 硬脂酸镁 0.8-1.4
    或，
    组分 重量百分比％ 如式A所示的喹唑啉化合物 40-50 微晶纤维素 30-45
    甘露醇 5-15 交联羧甲基纤维素钠 4-8 硬脂酸镁 0.8-1.4
    或，
    组分 重量百分比％ 如式A所示的喹唑啉化合物 40-50 微晶纤维素 30-45 玉米淀粉 5-15 交联聚维酮 4-8 硬脂酸镁 0.8-1.4
    或，
    组分 重量百分比％ 如式A所示的喹唑啉化合物 40-50 微晶纤维素 35-45 玉米淀粉 5-15 交联羧甲基纤维素钠 4-8 硬脂酸镁 0.8-1.4
    。
  8. 如权利要求7所述的药物组合物，其特征在于，所述药物组合物由如下组分组成：
    组分 重量百分比％ 如式A所示的喹唑啉化合物 40 微晶纤维素 40 甘露醇 12.8 交联羧甲基纤维素钠 6 硬脂酸镁 1.2
    或，所述的药物组合物，其包括片芯和包衣两部分，并且各自含有以重量计的如下成分：
    片芯：
    1)40％的如式A所示的喹唑啉化合物；
    2)40％的微晶纤维素和12.8％的甘露醇；
    3)6％的交联羧甲基纤维素钠；
    4)1.2％的硬脂酸镁；
    包衣：
    5)与片芯重量相比，包衣剂的重量增重为3.5％。
  9. 一种如权利要求1-8任一项所述的药物组合物的制备方法，其为按如权利要求1-8中任一项所 述的药物组合物的各组分的粉末直接压片制备得到所述的药物组合物。
  10. 如权利要求9所述的制备方法，包括以下步骤：
    1)预处理
    将如式A所示的喹唑啉化合物、填充剂、崩解剂分别过30目筛，将润滑剂过60目筛；
    2)总混
    按处方量，将根据步骤1)得到的如式A所示的喹唑啉化合物与填充剂在混合机中进行混合，得预混物1；
    将预混物1与崩解剂在混合机中进行混合，得预混物2；使用整粒机过筛预混物2，得预混物3；
    将预混物3和润滑剂在混合机中进行混合，得总混物料；
    3)将根据步骤2)得到的总混物料压片，得片芯；
    4)配制10％的薄膜包衣预混剂包衣液，将根据步骤3)得到的片芯进行包衣。
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