CN115120732A

CN115120732A - Pharmaceutical composition of quinazoline compound and preparation method thereof

Info

Publication number: CN115120732A
Application number: CN202210227702.8A
Authority: CN
Inventors: 许祖盛
Original assignee: Shanghai Yingli Pharmaceutical Co Ltd
Current assignee: Shanghai Yingli Pharmaceutical Co Ltd
Priority date: 2021-03-26
Filing date: 2022-03-08
Publication date: 2022-09-30
Also published as: WO2022199375A1

Abstract

The invention discloses a pharmaceutical composition of a quinazoline compound and a preparation method thereof. The pharmaceutical composition of the present invention comprises substance X and a pharmaceutical excipient; wherein the substance X is a quinazoline compound shown as a formula A, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof; the pharmaceutic adjuvant comprises a filler, wherein the filler is one or two or more of microcrystalline cellulose, mannitol and corn starch. The pharmaceutical composition has good stability and dissolution rate, and the preparation method of the pharmaceutical composition is simple and is suitable for industrial production.

Description

Pharmaceutical composition of quinazoline compound and preparation method thereof

Technical Field

The invention relates to a quinazoline compound pharmaceutical composition and a preparation method thereof.

Background

PI3K is collectively called Phosphatidylinositol 3-kinase (Phosphatidylinositol 3-kinase) and 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, with the most widely studied being class i PI3K which is activated by cell surface receptors. Class i PI3K is further classified in mammalian cells by structure and receptor into class ia and class ib, which transmit signals from tyrosine kinase-coupled receptors and G protein-coupled receptors, respectively. Class ia PI3K includes the PI3K α, PI3K β, PI3K δ subtypes, and class ib PI3K includes the PI3K γ subtype (trends biochem sci, 1997,22, 267-272). Class Ia PI3K is a dimeric protein consisting of a catalytic subunit p110 and a regulatory subunit p85, has dual activity of lipid kinases and protein kinases (nat. Rev. cancer 2002,2,489-501), and is thought to be associated with cell proliferation and carcinogenesis, immune disorders and diseases involving inflammation.

Follicular Lymphoma (FL), the second most common non-hodgkin lymphoma (NHL) in europe and america, accounts for about 22-35% of all newly diagnosed NHLs, and in recent years, with the deepening of understanding of diseases and the improvement of diagnostic techniques, the annual incidence rate gradually increases from 2-3/100,000 of 1950s to about 5/100,000. Unlike western countries, FL accounts for about 8% of B cell NHL in our country, is lower in proportion than that in western countries, and has a relatively low onset age compared with the foreign median diagnostic age of 65 years.

Although follicular lymphoma accounts for only 8% of B cell lymphoma in China, the number of patients is still large due to the large population base in China. FL is highly developed in middle-aged and elderly people, and along with the acceleration of aging process, the incidence rate of Chinese follicular lymphoma is in an increasing trend in recent years. At present, follicular lymphoma can not be completely cured, FL can relapse after the treatment achieves remission, and the relapse is easy to be converted into invasive type. As the number of relapses increases, the remission period becomes shorter and shorter, and the probability of refractory treatment increases, resulting in a shortened overall survival. At present, there is no unified standard treatment method for relapsed and refractory FL. In addition, there are limited drugs available for FL treatment, and there is a need to develop drugs with better therapeutic effects.

Among them, phosphoinositide 3-kinase-delta (PI3K delta) inhibitors are one of the therapeutic approaches, and PI3K delta is an intracellular signal transduction component, primarily expressed in the blood cell lineage, including hematologic malignancies, which are caused or mediated by cells.

At present, 3 PI3K delta inhibitor drugs are successfully marketed globally, namely Idelalisib, Copalisib and Duvelisb, which are all used for treating cancers of the blood circulation system.

The results of clinical trials of Idelalisib on relapsed follicular B-cell non-Hodgkin lymphoma (FL) (clinical trial accession number: NCT01282424) have been reported in the literature, with inclusion criteria for FL patients who had relapsed within 6 months after treatment with rituximab in combination with alkylating agent and who had received at least 2 systemic treatments.

The results of the study showed that the median age of the subjects was 62 years (range 33-84 years), of which 54% were males and 90% were caucasians. Upon admission, 92% of patients had baseline ECOG performance status of 0 or 1; the median time of the course of the disease is 4-7 years; the median frequency of the previous treatment was 4 times (range 2-12). The most common previous treatment regimens were R-CHOP (49%) (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), BR (50%) (bendamustine, rituximab), and R-CVP (28%) (rituximab, cyclophosphamide, vincristine, prednisone). At baseline, 33% of patients had extralymph node metastases and 26% had bone marrow metastases.

The patient is given 150mg of Idelalisib treatment 2 times daily until disease progression or unacceptable toxicity occurs. The effectiveness of the malignant tumor was evaluated according to the international working group response criteria. The primary endpoint was the independent review board assessment of total remission rate (ORR).

The following table shows the therapeutic results: the median reaction time was 1.9 months (range 1.6-8.3).

End of therapeutic effect	N＝72
		ORR 95％CI	39(54％)(42，66％)
CR	6(8％)
		PR	33(46％)
DOR median, number of months (range)	Median was not evaluated (0.0+, 14.8+)

CI is a credible interval; CR is complete remission; PR ═ partial remission; Kaplan-Meier estimate;

DOR, Duration of relaxation, PR/CR, Duration of relaxation.

The above data source references: ajay K.Gopal, M.D., Brad S.Kahl, M.D., Sven de Vos, M.D., Ph.D.et al.PI3K.delta. Inhibition by Idelalisib in Patients with modified Indolent Lymphoma [ J ]. N Engl J Med.2014March 13; 370(11):1008-1018.

The quinazoline compound with the chemical structure shown as the formula A is a PI3K delta small molecule inhibitor and is disclosed in CN104557872A patent (compound 10),

compared with other existing PI3K delta inhibitors, the quinazoline compound has improved selectivity to PI3K delta and eliminates activity to PI3K gamma, and Chinese patent CN110950844A discloses two polymorphic forms of the quinazoline compound shown as the formula A.

As known to those skilled in the art, after oral solid preparations are administered, the active pharmaceutical ingredients are released from the gastrointestinal tract and absorbed into the human body, so as to exert the effect of treating and/or preventing diseases. Due to the significant difference in pH between the stomach (pH 1-3.5) and the intestinal tract (pH 4-8), the solubility of the pharmaceutically active ingredient at different sites in the gastrointestinal tract may change due to changes in pH. The results of the study show that the quinazoline compound shown in formula a exhibits a significant pH dependent solubility profile, with about 195 times higher solubility in simulated gastric fluid (SGF, pH ═ 1.2) relative to that in simulated artificial intestinal fluid (FaSSIF, pH ═ 6.5). Therefore, increasing the solubility and/or dissolution rate of the quinazoline compound shown in the formula A in the intestinal tract is an important way for hopefully improving the maximization of the oral absorption of the quinazoline compound.

However, researches find that the quinazoline compound shown as the formula A is easy to agglomerate when meeting water, and brings trouble to effective disintegration of solid oral preparations and/or quick release of medicines.

In view of the fact that the quinazoline compound shown as the formula A shows good activity and safety in clinical precursor internal and external research, the development of an oral administration solid dosage form which is rapid in dissolution, good in bioavailability and easy to produce is urgently needed so as to ensure the safety, effectiveness and quality consistency of the drug in clinical use.

Disclosure of Invention

The invention aims to solve the technical problem that the prior art lacks a quinazoline compound preparation shown as a formula A, so that the invention provides a quinazoline compound pharmaceutical composition and a preparation method thereof, wherein the pharmaceutical composition has good stability to high temperature, high humidity and illumination, and can be quickly dissolved out in 0.1mol/L hydrochloric acid solution (pH1.2) and pH6.8 phosphate buffer solution containing 0.2% of Sodium Dodecyl Sulfate (SDS); and the preparation method of the pharmaceutical composition is simple and is suitable for industrial production.

The invention provides a pharmaceutical composition, which comprises a substance X and pharmaceutic adjuvants;

wherein the substance X is a quinazoline compound shown as a formula A, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof;

the pharmaceutic adjuvant comprises a filler, wherein the filler is one, two or more of microcrystalline cellulose, mannitol and corn starch;

in one embodiment of the present invention, the substance X is the only active ingredient.

In one embodiment of the present invention, the substance X is in a therapeutically effective amount.

In one embodiment of the present invention, the quinazoline compound represented by the formula a is a quinazoline compound represented by the formula a in a free base form, and it is to be understood that the term "free base form" refers to a case where the quinazoline compound represented by the formula a is not in a salt form.

In certain embodiments of the present invention, the quinazoline compound of the formula a is preferably the crystalline form i form of the quinazoline compound of the formula a, wherein the crystalline form i of the quinazoline compound of the formula a may be defined in any of the ways described in chinese patent publication No. CN 110950844A.

In one embodiment of the present invention, the filler is one or two of microcrystalline cellulose, mannitol, and corn starch.

In one embodiment of the present invention, the filler is microcrystalline cellulose.

In one embodiment of the invention, the filler is a mixture of microcrystalline cellulose and mannitol.

In one embodiment of the invention, the filler is a mixture of microcrystalline cellulose and corn starch.

In one embodiment of the invention, the filler is a mixture of microcrystalline cellulose and mannitol and corn starch.

In one embodiment of the invention, the filler is present in an amount of 10% to 90%, preferably 30% to 70%, most preferably 45% to 55% by weight based on the total weight of the pharmaceutical composition.

In one embodiment of the invention, the filler is a mixture of microcrystalline cellulose and mannitol in an amount of 10% to 90%, preferably 30% to 70%, most preferably 45% to 55% by weight based on the total weight of the pharmaceutical composition.

In one embodiment of the present invention, the filler is a mixture of microcrystalline cellulose and mannitol, and the mass ratio of the microcrystalline cellulose to the mannitol is 10: 1-1: 10.

in one embodiment of the present invention, the filler is a mixture of microcrystalline cellulose and mannitol, and the mass ratio of the microcrystalline cellulose to the mannitol is 6: 1-2: 1, preferably 4: 1-3: 1.

in one embodiment of the present invention, the pharmaceutical excipient further comprises a disintegrant.

In a certain embodiment of the invention, the disintegrant is crospovidone and/or croscarmellose sodium.

In one embodiment of the present invention, the disintegrant is crospovidone.

In one embodiment of the present invention, the disintegrant is croscarmellose sodium.

In one embodiment of the invention, the disintegrant is not low-substituted hydroxypropylcellulose.

In one embodiment of the invention, the disintegrant is present in an amount of 1% to 20%, preferably 3% to 15%, most preferably 4% to 8% by weight of the total weight of the pharmaceutical composition.

In one embodiment of the present invention, the disintegrant is croscarmellose sodium, and is 1% to 20% by weight of the total weight of the pharmaceutical composition.

In one embodiment of the invention, the disintegrant is croscarmellose sodium, representing from 3% to 15% by weight, preferably from 4% to 8% by weight of the total weight of the pharmaceutical composition.

In one embodiment of the present invention, the pharmaceutical excipient further comprises a lubricant.

In the invention, the lubricant is one or more of calcium stearate, glyceryl monostearate, glyceryl behenate, magnesium stearate, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, stearic acid, talcum powder, micro-powder silica gel and zinc stearate.

In one embodiment of the invention, the lubricant is magnesium stearate.

In one embodiment of the invention, the lubricant is present in an amount of 0.1% to 5.0%, preferably 0.3% to 2.0%, most preferably 0.8% to 1.4% by weight based on the total weight of the pharmaceutical composition.

In one embodiment of the present invention, the lubricant is magnesium stearate, which is 0.1% to 5.0% by weight of the total weight of the pharmaceutical composition.

In one embodiment of the invention, the lubricant is magnesium stearate, which is present in an amount of 0.3% to 2.0%, preferably 0.8% to 1.4% by weight, based on the total weight of the pharmaceutical composition.

In one embodiment of the present invention, the pharmaceutical composition comprises the following components by weight:

1) 40-50% of quinazoline compound shown as formula A;

2) 45-55% of a filler, wherein the filler is one, two or more of microcrystalline cellulose, mannitol and corn starch, a mixture of microcrystalline cellulose and mannitol is preferred, a mixture of microcrystalline cellulose and mannitol is most preferred, and the mass ratio of the filler to the filler is 4: 1-3: 1;

3) 4% -8% of a disintegrant, wherein the disintegrant is at least one of crospovidone and croscarmellose sodium, and most preferably croscarmellose sodium;

4) 0.8% -1.4% of a lubricant, wherein the lubricant is magnesium stearate.

In one embodiment of the present invention, the weight of the quinazoline compound represented by the formula a is 40% of the total weight of the pharmaceutical composition.

In one embodiment of the present invention, the filler is 52.8% by weight of the total weight of the pharmaceutical composition.

In one embodiment of the present invention, the disintegrant is 6% by weight of the total weight of the pharmaceutical composition.

In one embodiment of the present invention, the lubricant is 1.2% by weight of the total weight of the pharmaceutical composition.

components	Weight percent (%)
		Quinazoline compounds of formula A	40-50
Microcrystalline cellulose	45-55
		Cross-linked polyvidone	4-8
Magnesium stearate	0.8-1.4

(ii) a Preferably, the pharmaceutical composition consists of the components.

components	Weight percent (%)
		Quinazoline compounds of formula A	40-50
Microcrystalline cellulose	45-55
		Croscarmellose sodium	4-8
Magnesium stearate	0.8-1.4

(ii) a Preferably, the pharmaceutical composition consists of the components.

components	Weight percent (%)
		Quinazoline compounds of formula A	40-50
Microcrystalline cellulose	30-45
		Mannitol	5-15
Cross-linked polyvidone	4-8
		Magnesium stearate	0.8-1.4

(ii) a Preferably, the pharmaceutical composition consists of the components.

(ii) a Preferably, the pharmaceutical composition consists of the components.

components	Weight percent (%)
		Quinazoline compounds of formula A	40-50
Microcrystalline cellulose	30-45
		Corn starch	5-15
Cross-linked polyvidone	4-8
		Magnesium stearate	0.8-1.4

(ii) a Preferably, the pharmaceutical composition consists of the components.

components	Weight percent (%)
		Quinazoline compounds of formula A	40-50
Microcrystalline cellulose	35-45
		Corn starch	5-15
Croscarmellose sodium	4-8
		Magnesium stearate	0.8-1.4

Preferably, the pharmaceutical composition consists of the components.

components	Weight percent (%)
		Quinazoline compounds of formula A	40
Microcrystalline cellulose	40
		Mannitol	12.8
Croscarmellose sodium	6
		Magnesium stearate	1.2

。

In one embodiment of the present invention, the pharmaceutical composition may be a solid formulation, preferably a solid oral formulation.

In one embodiment of the invention, the pharmaceutical composition may be a tablet or capsule, preferably a tablet.

In one embodiment of the invention, the tablet is a coated tablet.

In one embodiment of the invention, the coated tablet is a film coated tablet.

In one embodiment of the present invention, when the coated tablet is a film-coated tablet, the coating agent for the film-coated tablet is a film-coated premix based on hydroxypropyl methylcellulose as a main film-forming polymer.

In one embodiment of the invention, the film-coated tablet may be coated with a coating agent commercially available from Colorcon, Inc. (Colorcon), such as the trade name'

Ⅰ(

I) "film coated premix.

In a certain embodiment of the invention, the film-coated tablets have a weight gain of the coating agent of 2% to 5%, preferably 2.5% to 4.5%, most preferably 3.5% compared to the weight of the tablet core.

In one embodiment of the present invention, the pharmaceutical composition comprises a tablet core and a coating, and each comprises the following components by weight:

tablet core:

1) 40-50% of quinazoline compound shown as formula A;

2) 45-55% of a filler, wherein the filler is one, two or more of microcrystalline cellulose, mannitol and corn starch, preferably a mixture of microcrystalline cellulose and mannitol, and the mass ratio of the microcrystalline cellulose to the mannitol is preferably 4: 1-3: 1;

4) 0.8% -1.4% of a lubricant, wherein the lubricant is magnesium stearate;

coating:

5) the weight gain of the coating agent compared to the weight of the tablet core is 2% to 5%, preferably 2.5% to 4.5%, most preferably 3.5%.

tablet core:

1) 40% of quinazoline compound shown as formula A;

2) 45% -55% of a filler, wherein the filler is a mixture of microcrystalline cellulose and mannitol, and the mass ratio of the microcrystalline cellulose to the mannitol is 4: 1-3: 1;

3) 4% -8% of a disintegrating agent, wherein the disintegrating agent is croscarmellose sodium;

4) 0.8% -1.4% of a lubricant, wherein the lubricant is magnesium stearate;

coating:

5) the weight gain of the coating agent compared to the tablet core weight was 3.5%.

tablet core:

1) 40% of quinazoline compound shown as formula A;

2) 40% microcrystalline cellulose and 12.8% mannitol;

3) 6% croscarmellose sodium;

4) 1.2% magnesium stearate;

coating:

In one embodiment of the invention, the amount of the quinazoline compound according to formula a in the unit dosage form of the pharmaceutical composition is 5mg to 500mg, preferably 10mg to 200mg, most preferably 20mg to 100mg, for example 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg or 100 mg. Taking tablets as an example, in the unit dosage form, the content of the quinazoline compound shown as the formula A is 5mg-500mg per tablet.

A second aspect of the invention provides a process for the preparation of a pharmaceutical composition as described above, which is a powder direct compression.

Preferably, the preparation method of the pharmaceutical composition provided by the invention comprises the following steps:

1) pretreatment of

Respectively sieving the quinazoline compound shown as the formula A, the filling agent and the disintegrating agent by a 30-mesh sieve, and sieving the lubricating agent by a 60-mesh sieve;

2) total mixing

Mixing the quinazoline compound shown as the formula A obtained in the step 1) and a filling agent in a mixer according to the prescription amount to obtain a premix 1;

mixing the premix 1 and the disintegrant in a mixer to obtain a premix 2; sieving premix 2 using a granulator to obtain premix 3;

mixing the premix 3 and the lubricant in a mixer to obtain a total mixed material;

3) tabletting the total mixed material obtained in the step 2) to obtain a tablet core;

4) preparing 10% of film coating premix coating liquid, and coating the tablet core obtained according to the step 3).

In a certain embodiment, the pharmaceutical composition is a medicament for treating a B cell hematological neoplasm;

in one embodiment, the pharmaceutical composition is a medicament for treating a B cell hematologic tumor, preferably, the B cell lymphoma is a non-hodgkin's lymphoma, more preferably, the non-hodgkin's lymphoma is a follicular lymphoma, and most preferably, the follicular lymphoma is a relapsed and/or refractory follicular lymphoma, e.g., a relapsed or refractory follicular lymphoma.

In a certain embodiment, the pharmaceutical composition is administered orally.

In one embodiment, the substance X is in a therapeutically effective amount.

In a certain embodiment, the dosage of the pharmaceutical composition may be determined according to the body weight of the patient, and the dosage of the pharmaceutical composition may be 0.33mg/kg to 3.33mg/kg, such as 0.66mg/kg to 2.3mg/kg, and further such as 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 or 2.3mg/kg at a time based on the amount of the quinazoline compound represented by the formula A.

In a certain embodiment, the pharmaceutical composition is administered in an amount of 20mg to 200mg per day, for example, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, or 200mg per day, and further for example, 80mg per day, based on the amount of the quinazoline compound represented by formula A.

In a certain embodiment, the pharmaceutical composition is administered at a frequency of 1-5 times per day, e.g., 1 time/day, 2 times/day, 3 times/day, 4 times/day, or 5 times/day, and further e.g., 1 time/day.

In a certain embodiment, the pharmaceutical composition is administered for a course of 14-84 days/course, e.g., 14 days/course, 28 days/course, 42 days/course, 56 days/course, 70 days/course, or 84 days/course, e.g., 28 days/course.

In a certain embodiment, the pharmaceutical composition is administered for a total of 1-20 courses, preferably 10-20 courses, e.g., 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 courses, and further e.g., 12 courses.

In one embodiment, the pharmaceutical composition is a tablet.

In a certain embodiment, the pharmaceutical composition has a size of 10mg to 120mg per tablet, for example, 20 to 100mg per tablet, further for example, 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg or 100mg per tablet, further for example, 20mg, 80mg or 100mg per tablet.

In one embodiment, the pharmaceutical composition is administered to a patient who has received one or more systemic treatment regimens for relapsed or relapsed follicular lymphoma (e.g., a patient who has received one or more systemic treatment regimens for relapsed follicular lymphoma), preferably, the pharmaceutical composition is administered to a patient who has received two or more systemic treatment regimens for relapsed or refractory follicular lymphoma (e.g., a patient who has received two or more systemic treatment regimens for relapsed follicular lymphoma).

In one embodiment, the pharmaceutical composition is administered to a patient who has progressed following a previous treatment regimen with two or more lines of systemic treatment with patients who have progressed following treatment with CD20 mab and at least one alkylating agent, including but not limited to bendamustine, cyclophosphamide, ifosfamide, chlrobenzamide, maflan, busulfan, and nitroso.

In one embodiment, the pharmaceutical composition is administered to a patient having a previous treatment regimen of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), BR (bendamustine, rituximab), and R-CVP (rituximab, cyclophosphamide, vincristine, prednisone).

In one embodiment, the subject to which the pharmaceutical composition is administered is a human.

The invention also provides a method of treating a disease comprising administering to a patient (e.g. a human) a therapeutically effective amount of substance X or a pharmaceutical composition;

the disease is a B cell hematological tumor; the substance X is a quinazoline compound shown as a formula A, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof; the pharmaceutical composition comprises the substance X and pharmaceutic adjuvant.

In one embodiment, the B cell hematologic tumor is a B cell lymphoma, preferably the B cell lymphoma is a non-hodgkin lymphoma, more preferably the non-hodgkin lymphoma is a follicular lymphoma, most preferably the follicular lymphoma is a relapsed and/or refractory follicular lymphoma, e.g., a relapsed or refractory follicular lymphoma.

In a certain embodiment, the mode of administration is oral.

In a certain embodiment, the dose administered may be determined based on the body weight of the patient, and the dose administered is 0.33mg/kg to 3.33mg/kg, for example, 0.66mg/kg to 2.3mg/kg, and further for example, 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 or 2.3mg/kg at a time based on the amount of the quinazoline compound represented by the formula A.

In a certain embodiment, the administration is at a dose of 20-200 mg/day, for example, 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day, or 200 mg/day, and further for example, 80 mg/day, based on the amount of the quinazoline compound represented by formula A.

In a certain regimen, the frequency of administration is 1-5 times/day, e.g., 1 time/day, 2 times/day, 3 times/day, 4 times/day, or 5 times/day, and still e.g., 1 time/day.

In a certain regimen, the course of administration is 14-84 days/course, e.g., 14 days/course, 28 days/course, 42 days/course, 56 days/course, 70 days/course or 84 days/course, e.g., 28 days/course.

In a certain regimen, the patient receives a total of 1-20 courses, preferably 10-20 courses, for example, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 courses, and further for example, 12 courses.

In a certain embodiment, the substance X or pharmaceutical composition is a tablet.

In a certain embodiment, the substance X or pharmaceutical composition has a size of 10-120 mg/tablet, e.g., 20-100 mg/tablet, further e.g., 20 mg/tablet, 30 mg/tablet, 40 mg/tablet, 50 mg/tablet, 60 mg/tablet, 70 mg/tablet, 80 mg/tablet, 90 mg/tablet or 100 mg/tablet, further e.g., 20 mg/tablet, 80 mg/tablet or 100 mg/tablet.

In one embodiment, the patient is a patient who has received one or more systemic treatment regimens of recurrent follicular lymphoma, preferably the patient is a patient who has received two or more systemic treatment regimens of recurrent follicular lymphoma.

In one embodiment, the patient is a patient who has progressed on treatment with systemic therapy of two or more lines, preferably the patient has progressed on treatment with CD20 mab and at least one alkylating agent including, but not limited to, bendamustine, cyclophosphamide, ifosfamide, chlobenzamide, melphalan, busulfan, nitroso.

In one embodiment, the patient is a patient for whom the previous treatment regimen was R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), BR (bendamustine, rituximab), and R-CVP (rituximab, cyclophosphamide, vincristine, prednisone).

In a certain scheme, the pharmaceutical adjuvant is one or more of diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorption carriers and lubricants which are conventional in the pharmaceutical field.

The invention provides an application of a substance X in preparing a B cell hemangioma inhibitor;

the substance X is a quinazoline compound shown as a formula A, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof:

in one embodiment, the B cell hematologic tumor is a B cell lymphoma, preferably the B cell lymphoma is a non-hodgkin lymphoma, more preferably the non-hodgkin lymphoma is follicular lymphoma, most preferably the follicular lymphoma is relapsed and/or refractory follicular lymphoma.

In a certain embodiment, the inhibitor is useful in a mammalian organism; also useful in vitro, primarily for experimental purposes, for example: the comparison is provided as a standard or control, or a kit is prepared according to methods routine in the art.

"bulking agents", also known as "diluents", as used herein, refer to a class of excipients used in the scientific context to increase the volume and weight of a product dosage form of a pharmaceutical composition. Thus, the filler 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, corn starch, dextrin, sucrose, trehalose, and xylitol.

As used herein, "disintegrant" refers to a class of excipients used in the scientific context to facilitate the breaking of a pharmaceutical composition product dosage form into smaller pieces in an aqueous environment. Thus, the disintegrant may be, for example: alginic acid, calcium alginate, carboxymethylcellulose calcium, chitosan, colloidal silicon dioxide, croscarmellose sodium, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, hypromellose, glycine, guar gum, hydroxypropyl cellulose, magnesium aluminum silicate, methylcellulose, povidone, sodium alginate, carboxymethylcellulose sodium, sodium starch glycolate, and starch.

As used herein, "lubricant" refers to a class of excipients used in the scientific context to improve the processing of pharmaceutical product dosage forms of pharmaceutical compositions. Thus, the lubricant may be, for example: calcium stearate, glyceryl monostearate, glyceryl behenate, magnesium stearate, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, stearic acid, talcum powder, superfine silica gel and zinc stearate.

As used herein, "coating agent" or "film-coated premix" refers to a class of excipients used in the scientific context to improve the appearance of pharmaceutical composition product dosage forms. Thus, the coating agent may be, for example: sucrose, lactose, hydroxypropyl methylcellulose, hydroxypropyl ethylcellulose, cellulose acetate phthalate, polyvinyl alcohol, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and acrylic resins.

The term "pharmaceutically acceptable salt" refers to salts prepared from the compounds of the present invention with relatively nontoxic, pharmaceutically acceptable acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the 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 salt, sodium salt, potassium salt, calcium salt, aluminum salt, magnesium salt, zinc salt, bismuth salt, ammonium salt, and diethanolamine salt. When compounds of the present invention contain relatively basic functional groups, acid addition salts 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. The pharmaceutically acceptable acid includes 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. The pharmaceutically acceptable acids include organic acids including, but 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, gluconic acid, saccharic acid, formic acid, ethanesulfonic acid, pamoic acid (i.e. 4, 4' -methylene-bis (3-hydroxy-2-naphthoic acid)), amino acids (e.g. glutamic acid, arginine), and the like. When compounds of the present invention contain relatively acidic and relatively basic functional groups, they may be converted to base addition salts or acid addition salts. See in particular Berge et al, "Pharmaceutical Salts", Journal of Pharmaceutical Science 66:1-19(1977), or Handbook of Pharmaceutical Salts: Properties, Selection, and Use (P.Heinrich Stahl and Camile G.Wermuth, ed., Wiley-VCH, 2002).

The term "solvate" refers to a substance formed by combining a compound of the present invention with a stoichiometric or non-stoichiometric amount of a solvent. The solvent molecules in the solvate may be present in ordered or unordered arrangements. Such solvents include, but are not limited to: water, methanol, ethanol, and the like.

The terms "pharmaceutically acceptable salt" and "solvate" of the "solvate of a pharmaceutically acceptable salt" as used herein refer to a substance formed by combining a compound of the present invention with a stoichiometric or non-stoichiometric amount of a relatively non-toxic, pharmaceutically acceptable acid or base, as prepared.

The term "therapeutically effective amount" refers to an amount of a compound administered to a patient sufficient to effectively treat 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, and the like, but can be adjusted as appropriate by one of ordinary skill in the art.

The term "pharmaceutical excipient" refers to excipients and additives used in the manufacture of pharmaceutical products and in the formulation of pharmaceutical formulations, and is intended to include all substances in a pharmaceutical formulation, except for the active ingredient. See in particular the pharmacopoeia of the people's republic of China (2020 edition) or the Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009).

The term "treatment" refers to therapeutic therapy. Where specific conditions are involved, treatment refers to: (1) relieving one or more biological manifestations of a disease or disorder, (2) interfering with (a) one or more points in a biological cascade that causes or leads to a disorder or (b) one or more biological manifestations of a disorder, (3) ameliorating one or more symptoms, effects, or side effects associated with a disorder, or one or more symptoms, effects, or side effects associated with a disorder or treatment thereof, or (4) slowing the progression of one or more biological manifestations of a disorder or disorder.

The term "progression" means that the disease is not alleviated or cured, or even exacerbated, following treatment.

The term "patient" refers to any animal, preferably a mammal, most preferably a human, that has been or is about to be treated. The term "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, and the like, with humans being most preferred.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

The positive progress effects of the invention are as follows: the pharmaceutical composition has good stability to high temperature, high humidity and illumination, and can be quickly dissolved out in 0.1mol/L hydrochloric acid solution and 0.2 percent Sodium Dodecyl Sulfate (SDS) -containing phosphate buffer solution with pH of 6.8; the preparation method of the pharmaceutical composition is simple and is suitable for industrial production.

Drawings

FIG. 1 is a graph showing the dissolution profile of the pharmaceutical composition of the quinazoline compound shown in the formula A in a 0.1mol/L hydrochloric acid solution provided in the second partial examples 4 and 5.

FIG. 2 is a graph showing the dissolution profile of the pharmaceutical composition of the quinazoline compound shown in the formula A provided in the second part of examples 4 and 5 in a phosphate buffer containing 0.2% SDS and having a pH of 6.8.

Detailed Description

A first part:

preparation example 1: the synthetic route of the quinazoline compound shown as the formula A.

The quinazoline compound represented by the formula a was prepared according to the preparation method of the compound 10 described in patent CN104557872A, and recrystallized according to the method of example 8 in patent CN 110950844A.

Effect example 1: the quinazoline compound shown as the formula A and the analogues thereof have in-vitro inhibitory activity on PI3K delta and selectivity on other subtypes.

See paragraphs [0538] - [0549] of the specification of CN 104557872A.

Effect example 2: pharmacokinetic evaluation of quinazoline compounds and analogs thereof as shown in formula A

The experimental method comprises the following steps:

male SD rats were selected and divided into two groups, the intravenous (iv) dose was 2mg/kg and the oral gavage (po) dose was 10 mg/kg. After administration, the two groups were bled at time points 0h, 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 8h, and 24h, respectively, plasma was separated, the concentration of the test compound in the plasma was determined by LCMSMS after intravenous and intragastric administration to rats, and pharmacokinetic parameters were calculated. The results are shown in Table 1.

C _max : peak concentration of drug, AUC _last : area under the concentration-time curve from 0 to the last measurable concentration versus time point, F%: and (4) bioavailability.

Table 1: a summary table of the inhibitory activity, selectivity and pharmacokinetic data of quinazoline compounds and analogs thereof on PI3K delta shown in formula A

- - -means not tested.

From the results, although several compounds showed excellent PI3K δ inhibitory activity in vitro and the structures were relatively close, the pharmacokinetics were very different, and the peak concentration, the area under the concentration-time curve from 0 to the last measurable concentration corresponding to the time point, and the bioavailability of the quinazoline compound represented by formula a were higher at the same dose.

Effect example 3: pharmacokinetic study of quinazoline Compounds represented by formula A

The pharmacokinetic research result of the quinazoline compound shown as the formula A in mice, rats and dogs

The pharmacokinetic research result of the quinazoline compound shown as the formula A in mice, rats and dogs shows that the quinazoline compound is well absorbed by oral administration within the range of pharmacodynamic dose, and the oral bioavailability is respectively over 90%, 65% and 60%. After 7 consecutive days of administration, the amount of exposure of the quinazoline compound of the formula a in rats and dogs increased somewhat, approximately 1.28-2.20 times that of the first administration, suggesting that there was less risk of severe accumulation of the drug. The quinazoline compound of formula a has moderate clearance in rats and slower clearance in mice and dogs. The quinazoline compound shown in the formula A has wide tissue distribution, and the exposure amount of the quinazoline compound shown in the formula A in other tissues except brain tissues is higher than that of the quinazoline compound shown in the formula A in blood plasma. There is a certain gender difference in the tissue distribution of the quinazoline compound shown in formula a. The results of in vitro inhibition, induction test and recombinase stability test show that the quinazoline compound shown in the formula A has no obvious inhibition and induction effects on CYP enzyme, CYP3A4 is the main metabolic enzyme of the quinazoline compound shown in the formula A, and CYP2C8 is followed. The quinazoline compound shown as the formula A is widely metabolized in vivo, but is mainly excreted in vitro in a crude form through urine and feces, and is about 50%.

Table 2: pharmacokinetic results after single oral gavage administration of ICR mice, SD rats and Beagle dogs

Absorption of

After the quinazoline compound shown in the formula A is administrated by gastric lavage, the quinazoline compound is well absorbed in mice, rats and beagle dogs, and the oral bioavailability respectively reaches 90%, 65% and more than 60%. In rat and dog experiments of different dose groups, the plasma exposure and peak concentration of the quinazoline compound shown in the formula A are increased by a ratio close to the dose increase, which indicates that the quinazoline compound shown in the formula A has a linear pharmacokinetic characteristic along with the increase of the dose.

Distribution of

The results of in vitro plasma protein binding rate tests show that the protein binding rates of mice, rats, beagle dogs and human plasma of the quinazoline compound shown in the formula A are all neutral (51.1-85.6%) within the concentration range of 0.1-30 mu M; in monkey plasma, the protein binding rate was medium (89.3-89.6%) at low-to-medium concentration (0.1-2. mu.M) and high (90.2%) at high concentration (30. mu.M). The quinazoline compound shown in the formula A has the following plasma protein binding rates in 5 species from high to low: cynomolgus monkey > human > CD1 mouse > SD rat > beagle dog, wherein the binding rate of cynomolgus monkey to human is similar (85-90%), the binding rate of SD rat and beagle dog is similar (50-65%).

The steady state apparent volume distribution (V) of the quinazoline compound shown in the formula A after single intravenous injection of 10, 10 and 1.0mg/kg doses in ICR mice, SD rats and beagle dogs respectively _ss L/kg) was 4.22 (male mouse), 4.55 (male rat), 5.18 (female rat), 4.70 (male dog) and 4.08 (female dog), respectively, which were 5.82 (male mouse), 6.80 (male rat), 7.75 (female rat), 7.79 (male dog) and 6.76 (female dog), respectively, of the total amount of body fluid in each animal, suggesting that the quinazoline compound represented by the formula A had a broader tissue distribution in each animal.

After 60mg/kg of the quinazoline compound shown in the formula A is administrated to SD rats by stomach filling, the quinazoline compound shown in the formula A is widely distributed in each tissue and organ, except brain tissue, the exposure of the quinazoline compound shown in the formula A in other tissues is obviously higher than that of the quinazoline compound shown in the formula A in blood plasma, and is about 2-22 times of that of the quinazoline compound shown in the formula A in the latter tissues. The tissue distribution of the quinazoline compound shown in the formula A has a certain sex difference. The plasma and tissue drug concentrations were higher in male rats than in female rats at each time point. The exposure of the quinazoline compound of the formula a in the 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 to 5.08hr in each tissue of male rats and about 2.25 to 4.45hr in each tissue of female rats (excluding brain tissue). For male rats, the quinazoline compound represented by the formula a was exposed to the highest amount in the stomach, followed by small intestine, liver, kidney, lung, spleen, large intestine, thymus, heart, testis, skeletal muscle, fat, plasma and brain in this order. For female rats, the highest exposure of the quinazoline compound according to formula a is in the small intestine, followed in turn by the stomach, liver, spleen, kidney, lung, large intestine, thymus, ovary, uterus, heart, skeletal muscle, fat, plasma and brain.

Metabolism

The quinazoline compounds of formula a are stable in liver microsomes in mice, rats, dogs and humans (half-life >120 min) and are moderately metabolized in liver microsomes in monkeys (half-life 30-120 min). Furthermore, the quinazoline compound shown in formula a was not significantly metabolized in vitro hepatocyte assays in mice, rats, dogs, monkeys and humans (half-life >120 min).

From the viewpoint of the production of metabolites mediated by various human recombinant enzymes, CYP3a4 is the main metabolic enzyme of quinazoline compounds represented by the formula a, and CYP2C8 is secondly. Although the quinazoline compound shown in the formula A is reduced by 20-30% in the CYP2C8 incubation system, the same phenomenon occurs in the-NADPH and + inhibitor incubation systems, so that the dependence of the metabolism of the parent drug on the recombinase CYP2C8 cannot be explained.

The quinazoline compound shown as the formula A has no obvious inhibition effect (IC) on CYP1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4 in human liver microsomes (IC) ₅₀ >10μM)。

The quinazoline compound shown as the formula A does not show the effect of improving enzyme activity or mRNA expression in the aspects of CYP1A2, CYP2B6 and CYP3A4 under the test concentrations of 0.4, 4 and 40 mu M3.

After single intravenous injection of 10, 10 and 1.0mg/kg doses in ICR mice, SD rats and beagle dogs, respectively, the total clearance rates (CL, L/hr/kg) of the quinazoline compound represented by the formula a were 1.25 (male mice), 1.45 (male rats), 2.18 (female rats), 0.224 (male dogs) and 0.191 (female dogs), respectively, which were 23.1% (male mice), 43.8% (male rats), 66.0% (female rats), 12.1% (male dogs) and 10.3% (female dogs), respectively, of the hepatic blood flow in each animal, suggesting that the mice and dogs had poor metabolic clearance of the quinazoline compound represented by the formula a.

The type and relative content of metabolites in the liver microsome are combined with the judgment of the metabolic stability of the quinazoline compound shown as the formula A in the liver microsome, rats and dogs are selected as rodent and non-rodent experimental animals for safety evaluation, and the safety evaluation meets the requirement of preclinical safety evaluation of medicaments.

Excretion device

After 60mg/kg of the quinazoline compound shown in the formula A is administered to SD rats by intragastric administration, the excretion of the quinazoline compound shown in the formula A in urine, feces and bile of male rats for 0-72hr is respectively 20.1 +/-6.48%, 24.5 +/-11.1% and 1.68 +/-0.890% of the administration amount; the excretion amount of the composition in urine, feces and bile of female rat is 8.11 + -2.62%, 7.58 + -3.95% and 10.9 + -1.29% of the administration amount respectively. Therefore, after the gastric lavage, the total excretion rates of the quinazoline compound shown in the formula A in the urine feces and the bile of male SD rats and female SD rats are 46.3 percent and 26.6 percent respectively.

After the stomach-irrigation administration of 10mg/kg of the quinazoline compound shown in the formula A to the beagle dog, the excretion of the quinazoline compound shown in the formula A in the urine and the excrement of the male dog is respectively 29.2 +/-13.5% and 19.5 +/-16.2% of the administration amount, and the excretion of the quinazoline compound shown in the formula A in the urine and the excrement of the female dog is respectively 41.4 +/-12.4% and 9.21 +/-7.08% of the administration amount, so that the total excretion rate of the quinazoline compound shown in the formula A in the urine and the excrement of the male and female beagle dogs after the stomach-irrigation administration is respectively 48.7% and 50.6%.

Effect example 4: the inhibitory activity of the quinazoline compound shown as the formula A on different cells

The experimental method comprises the following steps:

100. mu.l of the test cell suspension was added to each 96-well plate (except for the peripheral wells). The plates were placed in a carbon dioxide incubator overnight. Adding the prepared quinazoline compound shown as the formula A (50 mu M is the initial concentration, and obtaining the quinazoline compound shown as the formula A with 10 concentration gradients by 3-fold dilution) into each hole. The cell plates were incubated in a carbon dioxide incubator for 72 hours. Adding 25 μ l CellTiter Glo reagent into 96-well plate, shaking in dark for 2 min, standing in dark at room temperature for 10 min, placing the culture plate in microplate reader to read chemiluminescence value, drawing drug effect inhibition rate curve by using XLFit and calculating IC ₅₀ The value is obtained.

The influence of the quinazoline compound shown as the formula A on cell proliferation is detected in different tumor cells. The results show that the quinazoline compound shown as the formula A has obvious inhibitory activity on some blood tumor cells. For example, IC in SU-DHL-6 cells ₅₀ A value of 0.23IC in SU-DHL-5 cells at 37. mu.M ₅₀ The value was 1.7683. mu.M.

Effect example 5: evaluation of in vivo Activity of quinazoline Compounds represented by formula A on SU-DHL-6 subcutaneous xenograft tumor model in animals

The experimental method comprises the following steps:

CB17 SCID mice, female, weighing 18-22 grams. SU-DHL-6 cells are cultured in vitro in suspension by adding 10% heat inactivated fetal calf serum, 100U/ml penicillin and 100 μ g/ml streptomycin 5% CO at 37 deg.C into RPMI1640 medium ₂ And (5) culturing. Twice a week for subculture. When the cells are in the exponential growth phase, the cells are harvested for inoculation. A cell suspension (5X 10^6 SU-DHL-6 cells, cells suspended in a base RPMI1640 medium, RPMI1640: Matrigel (Matrigel): 100. mu.l) in 0.2ml of the cell suspension was subcutaneously inoculated on the right back of each mouse. The average tumor volume reaches 95.79mm ³ The grouped administration is started. The grouping method comprises the following steps: animals were weighed before dosing and tumor volumes were measured. The tumor volumes were randomly grouped (randomized block design), and the grouping and dosing schedule is shown in table 3 below. The experimental criteria were to investigate whether tumor growth could be inhibited, retarded or cured. Tumor diameters were measured twice weekly using a vernier caliper. The tumor volume was calculated as: v is 0.5a × b ² And a and b represent the major and minor diameters of the tumor, respectively. The tumor-inhibiting therapeutic effect of the compounds TGI (%) was evaluated. TGI (%) reflects the tumor growth inhibition rate. Calculation of TGI (%): TGI (%) - (1- (tumor volume at the end of treatment group administration-tumor volume at the start of treatment group administration)/(tumor volume at the end of solvent control group administration-tumor volume at the start of solvent control group administration)]X100%. The medicine is effective when the TGI is more than or equal to 58 percent; the TGI is more than or equal to 90 percent, and the medicine is considered to be extremely effective.

Table 3: in vivo efficacy experiment animal grouping and administration schedule

The results show that by day15 of dosing, the TGIs of CAL-101 (i.e., Idelalisib)50mg/kg BID treatment group, the quinazoline compound of formula a of 60mg/kg QD group, the quinazoline compound of formula a of 120mg/kg QD group, and the quinazoline compound of formula a of 240mg/kg QD group were 42.67%, 71.89%, 81.57%, and 86.98%, respectively. Two-way ANOVA statistical analysis shows that the tumor volumes of CAL-10150 mg/kg BID group, quinazoline compound 60mg/kg QD group shown in formula A, quinazoline compound 120mg/kg QD group shown in formula A and quinazoline compound 240mg/kg QD group shown in formula A in Day15 are all significantly smaller than those of solvent control group (P values are all less than 0.01). The quinazoline compound shown in the formula A can be tolerated by tumor-bearing mice at three therapeutic doses. The results of the tumor volume and the weight show that the quinazoline compound shown in the formula A in 60mg/kg QD treatment, the quinazoline compound shown in the formula A in 120mg/kg QD treatment and the quinazoline compound shown in the formula A in 240mg/kg QD treatment have remarkable inhibition effects on the growth of SU-DHL-6 human lymphoma subcutaneous xenograft tumors.

Effect example 6: clinical phase I and II data for quinazoline compounds of formula A

(1) Phase I clinical protocol design (climbing and extension scheme)

Patients were enrolled as histologically or cytologically confirmed relapsed or refractory B-cell hematological tumor patients for a total of 25 patients, of which 10 were follicular lymphomas.

The study is divided into two phases: dose escalation and dose extension; each phase included single dose and multiple dose studies. The dosage of the up-dosing phase includes 20 mg/day, 40 mg/day, 80 mg/day, 140 mg/day, 200 mg/day. With the exception of the 20mg initial dose group which was only group 1, each dose group was divided into 3-6 subjects, 3 subjects with a 40mg dose group, 3 subjects with a 80mg dose group, 3 subjects with a 140mg dose group, and 4 subjects with a 200mg dose group; of these, follicular lymphoma was administered in 1 case at 40mg and 200mg, and in 2 cases at 80mg, respectively. After the end of the tolerability test, a dose extension test was carried out at a dose of 80 mg/day, for a total of 11 patients, 6 patients with follicular lymphoma. A total of 10 patients with follicular lymphoma were enrolled.

The administration mode is as follows: oral administration, 1 time daily for a continuous period of administration, until disease progression or intolerable toxicity.

The quinazoline compound tablet represented by the formula a was a coated tablet prepared by the powder mixing direct compression process according to the processes described in the second partial preparation example 1 and preparation example 2. The formulation was the second part of the formulation of example 5, making 20mg or 100mg tablets.

(2) Phase I test results and Effect

The quinazoline compound tablet shown as the formula A shows good anti-tumor activity in patients with relapsed or refractory B cell malignant hematological tumors, and particularly shows good curative effect in follicular lymphoma. The results are shown in the following table, where the optimal overall therapeutic effect among 25 subjects was CR in 5 cases, PR in 11 cases, SD in 2 cases, and PD in 7 cases, the overall optimal therapeutic effect was ORR ratio of 64% (16/25) (95% CI: 45.2-82.8%), and DCR ratio of 72% (18/25) (95% CI: 54.4-89.6%). The ORR and DCR ratios for optimal therapeutic effect of follicular lymphoma were both 90.0% (9/10).

Total remission rate (ORR); disease Control Rate (DCR); CR is complete remission; PR ═ partial remission; SD stable; PD-disease progression.

The evaluation criteria for the therapeutic effect of B cell lymphoma refer to "evaluation criteria for therapeutic effect of lymphoma IRWG (selection), and revision criteria for the evaluation of therapeutic effect of malignant lymphoma".

Table 4: statistical table of optimal curative effect

(3) Phase I security effect data

Patients were enrolled as histologically or cytologically confirmed relapsed or refractory B-cell hematological tumor patients for a total of 25 patients, of which 10 were follicular lymphomas. The study is divided into two phases: dose escalation and dose extension; each phase included single dose and multiple dose studies. The dosage of the up-dosing phase includes 20 mg/day, 40 mg/day, 80 mg/day, 140 mg/day, 200 mg/day. With the exception of the 20mg initial dose group which was only group 1, each dose group was divided into 3-6 subjects, 3 subjects with a 40mg dose group, 3 subjects with a 80mg dose group, 3 subjects with a 140mg dose group, and 4 subjects with a 200mg dose group. The dose extension study was performed in the 80mg dose group. Dose-limiting toxicity (DLT) did not occur during the 28-day observation period, and the quinazoline compound tablet shown in the formula A has good tolerance in single and multiple administration in view of occurrence of adverse events.

According to the phase I clinical result, the quinazoline compound shown as the formula A is proved to be good and controllable in safety.

Based on preclinical results, single-arm, open, single-time and multi-time administration and dose-increasing tolerance and pharmacokinetics phase I clinical research of the quinazoline compound shown in the formula A is developed in patients with recurrent or refractory B cell hematological malignancies which are ineffective or lack of standard treatment through conventional standard treatment, and research results suggest that the quinazoline compound shown in the formula A has controllable safety and better tolerance.

In conclusion, the quinazoline compound shown in the formula A is safe and tolerable in the dosage range of 20-200mg, can relieve and control the disease progress of relapsed or refractory B cell malignant tumors, and also shows very good curative effect in follicular lymphoma.

(4) Comparison of marketed drug data with targeted drug data

The PI3k delta inhibitor Idelalisib currently approved by the FDA for marketing has an Objective Remission Rate (ORR) of 39% for refractory relapsed follicular lymphoma, whereas PI3K gamma, the delta inhibitor Duvelisib has an ORR of 42% for refractory relapsed follicular lymphoma; ORR of Copalisib treatment refractory relapsed follicular lymphoma was 59%. (data obtained from the marketed drug insert).

The ORR of the quinazoline compound shown in the formula A in the clinical stage I for treating follicular lymphoma is 90.0% (9/10). The one-armed, open, multicenter phase II clinical trial of a quinazoline compound according to formula a on patients with relapsed and/or refractory follicular lymphoma was performed on 93 subjects who had been treated with systemic therapy of second or more lines (once treated with CD20 mab and at least one alkylating agent including, but not limited to, bendamustine, cyclophosphamide, ifosfamide, chlrobamine, melphalan, busulfan, nitroso). The subjects took tablets of the quinazoline compound shown in formula a once daily, orally, 4 tablets of 20mg each time, until the disease progressed or toxicity was not tolerated. 89 subjects performed at least one imaging evaluation and the results of independent data evaluation (lymphoma efficacy assessment criteria IRWG) showed: the quinazoline compound shown in the formula A has an ORR of more than 80% in 89 (evaluable cases) patients with relapsed/refractory follicular lymphoma. From the analysis of statistical results, the ORR is improved from about 50% to about 80% of the similar medicines, and has obvious advantages compared with the similar medicines.

The second part

The quinazoline compound represented by the formula a used in the following examples was prepared according to the method for producing compound 10 described in patent CN104557872A, and recrystallized according to the method of example 8 in patent CN 110950844A.

The materials used in the following examples are shown in the table below:

the equipment used in the following examples is shown in the table below:

in examples 1, 2, 3A and 3B, the dissolution rate was calculated by measuring the content in high performance liquid phase using 900ml of a phosphate buffer solution of pH6.8 containing 0.2% SDS as a dissolution medium at 37 ℃ and 75 rpm in accordance with the second method 0931, the general rule of the four ministry of China, published by 2015 edition, and sampling at appropriate time intervals, supplementing the dissolution medium at the same volume, filtering with a 0.45 μm filter membrane, and measuring the content.

The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.

Preparation example 1 preparation of tablet core

Weighing a quinazoline compound shown as a formula A and various auxiliary materials according to the designed prescription composition, respectively sieving the quinazoline compound shown as the formula A, a filling agent and a disintegrating agent with a 30-mesh sieve, and sieving a lubricating agent with a 60-mesh sieve; uniformly mixing a quinazoline compound shown as a formula A and a filler in a mixer to obtain a premix 1; adding the disintegrant into the premix 1, and uniformly mixing by using a mixer to obtain a premix 2; sieving premix 2 using a granulator to obtain premix 3; mixing the premix 3 and the lubricant in a mixer to obtain a total mixed material; the total blend was tabletted using a rotary tablet press equipped with 5mm, D-type circular dies or 11 x 5.5mm, up-cut Half-line dies to form tablet cores containing 20mg or 100mg, respectively, of a quinazoline compound according to formula a.

Preparation example 2 preparation of film-coated tablet

Adding the film coating premix powder into the purified water which is stirred for 45 minutes continuously to prepare a coating solution with the solid content of the film coating premix of 10 percent (w/w), and coating the tablet core manufactured by the process described in the preparation example 1 by a high-efficiency coating machine until the weight gain range of the coating is 2 to 5 percent so as to respectively form a film coating tablet containing 20mg or 100mg of the quinazoline compound shown as the formula A.

Example 1 tablet core formulation F1-F8

The type and amount of disintegrant directly affects the disintegration of the tablet and the release rate of the pharmaceutically active ingredient. The prescription composition of crospovidone, croscarmellose sodium and low-substituted hydroxypropyl cellulose as the disintegrating agent is F1-F8 respectively, and the dosage of the disintegrating agent in the prescription is screened. The pharmaceutical compositions were manufactured using the process described in preparation example 1 above, resulting in tablet cores containing 20mg of the quinazoline compound according to formula a, respectively. The smoothness and dissolution rate of tablets during tabletting were used as the index for investigation, and the formulation and results are shown in table 5 below.

TABLE 5 recipes F1-F8 and results

Which means not used.

The experimental results are as follows: the tabletting process of the prescription F1-F8 is smooth, no sticky impact phenomenon exists, the tablet core of the prescription F1-F6 which only uses the crospovidone or only uses the croscarmellose sodium as a disintegrant is disintegrated quickly, the quinazoline compound shown in the formula A is dissolved out quickly, and the accumulative dissolution in 30 minutes is more than 90%; the formulas F7 and F8 of low-substituted hydroxypropyl cellulose are added into the disintegrant, so that the tablet core is slowly disintegrated, the dissolution rate of the quinazoline compound shown as the formula A is very slow, and the cumulative dissolution at 30 minutes is only 72 percent and 67 percent.

Example 2 film-coated tablet formulation F9-F10

The amount of lubricant used will affect the smoothness of the compressed tablet and the rate of dissolution of the pharmaceutically active ingredient. On the basis of the dissolution optimum formulation F5 in example 1, formulation compositions F9 and F10 were respectively screened for different amounts of magnesium stearate as a lubricant. The pharmaceutical compositions were manufactured using the process described in preparation example 1 above, resulting in tablet cores containing 20mg of the quinazoline compound according to formula a, respectively. Preparing film coating premix (

I) coating liquid with solid content of 10% (w/w), coating the tablet core by using a high-efficiency coating machine (BGB-5F, pharmaceutical machinery, Inc. of Zhejiang Torontis) to respectively provide a film-coated tablet containing 20mg of quinazoline compound shown as formula A with coating weight increment of about 3.5% according to formulas F9 and F10. The formulation composition of the film-coated tablets of example 2 (before coating) and the results are shown in Table 6 below, using the smoothness and dissolution rate of tablets during compression as an index for investigation.

TABLE 6 recipes F9-F10 and results

The experimental results are as follows: the tabletting processes of the formulas F9 and F10 are smooth, no sticking phenomenon exists, the film coated tablet disintegrates rapidly, the dissolution rates of the quinazoline compound shown in the formula A are basically consistent, the 30-minute accumulated dissolution rates are respectively 88 percent and 92 percent, and the dissolution rates of the finished product are in accordance with the release standard (more than or equal to 70 percent) of the dissolution rate of the finished product.

Examples 3A and 3B, film coated tablet preparation (20mg size, 2 ten thousand tablets)

The pharmaceutical composition was manufactured using the process described in preparation example 1 above to give a tablet core containing 20mg of the quinazoline compound according to formula a. Preparing film coating premix (

I) a coating solution having a solid content of 10% (w/w), coating the core tablet with a high-efficiency coating machine (BGB-5F, zhejiang ceren pharmaceutical machinery, ltd) in a coating weight gain range of 2% to 5%, giving about 2 ten thousand film-coated tablets containing 20mg of the quinazoline compound represented by the formula a having a coating weight gain of 2.5% for example 3A, and about 2 ten thousand film-coated tablets containing 20mg of the quinazoline compound represented by the formula a having a coating weight gain of 4.5% for example 3B. The batch formula amounts of the film coated tablets of examples 3A and 3B (prior to coating) are shown in table 7 below.

TABLE 7 film coated tablets (before coating) made in examples 3A, 3B were formulated (20mg size, 2 ten thousand tablets)

The dissolution results of the film-coated tablets of examples 3A and 3B in a phosphate buffer ph6.8 containing 0.2% SDS are shown in table 8 below. The result shows that 20mg film coated tablets with the coating weight increment of 2.5 percent and 4.5 percent respectively are disintegrated rapidly, the quinazoline compound shown as the formula A has basically consistent dissolution rate, the 30-minute accumulated dissolution is 93 percent and 92 percent respectively, and the quinazoline compound meets the finished product dissolution rate release standard (more than or equal to 70 percent).

TABLE 8 dissolution results of film-coated tablets manufactured in examples 3A and 3B in 0.2% SDS-pH 6.8 phosphate buffer

Example 4: Pilot-Scale film coated tablet preparation (20mg size, 30 ten thousand tablets)

Pilot scale pharmaceutical compositions were manufactured using a powder direct compression process. Respectively sieving the quinazoline compound shown as the formula A, the filling agent and the disintegrating agent by a 30-mesh sieve, and sieving the lubricating agent by a 60-mesh sieve; uniformly mixing a quinazoline compound shown as a formula A and a filling agent in a hopper mixer (HBD200 type, Nantong medicinal machinery Co., Ltd.) of 50 liters to obtain a premix 1; adding the disintegrant into the premix 1, and uniformly mixing by using a hopper mixer to obtain a premix 2; premix 2 was sieved using a granulator (Comil U10, quaduro, canada) equipped with a 032R screen and a square impeller to give premix 3; mixing the premix 3 and the lubricant in a hopper mixer to obtain a total mixed material; the total blend was tabletted using a rotary tablet press (P2020, Fette, germany) equipped with a 5mm circular die to form tablet cores containing 20mg of the quinazoline compound according to formula a. Preparing film coating premix (

I) coating liquid with solid content of 10% (w/w), coating the tablet core by using a high-efficiency coating machine (BGB-40F, pharmaceutical machinery, Inc. of Zhejiang Torontis) until the coating weight is increased by 3.5%, and obtaining a pilot scale film coated tablet containing 20mg of quinazoline compound shown as formula A.

The film coated tablet lot formula amounts for example 4 are shown in table 9 below.

TABLE 9 Pilot scale film coated tablet formulation (20mg size, 30 ten thousand tablets)

^a : the dosage of the actual batch is 1.050Kg calculated according to 50 percent coating efficiency in the manufacturing process.

^b : the preparation process includes 50% coating efficiency, 9.450Kg of purified water is eliminated during the coating process.

Example 5: preparation of 100mg specification film coated tablets

The pharmaceutical composition was manufactured as described in preparation example 1 above, resulting in a tablet core containing 100mg of the quinazoline compound according to formula a. Preparing film coating premix (

I) coating liquid with solid content of 10% (w/w), and coating the tablet core by using a high-efficiency coating machine until the coating weight is increased by 3.5%, so as to obtain a film-coated tablet containing 100mg of the quinazoline compound shown as the formula A. The film coated tablet lot formula amounts for example 6 are shown in table 10 below.

Film coated tablet prescription of table 10.100 mg specification

^a : the dosage of the actual batch is 0.264Kg calculated according to the 50 percent coating efficiency in the manufacturing process.

^b : the preparation process includes coating with 50% coating efficiency, 2.376Kg of purified water is eliminated in the coating process.

Test example 1: determination of key quality attributes of pharmaceutical compositions

The pharmaceutical composition manufactured in example 4 was subjected to determination of key quality attributes of the drug, and the evaluation items include properties, content uniformity, content, related substances, and dissolution rate, and the evaluation results are shown in table 11 below.

The characteristics are as follows: visual observations were made to record the appearance of the film-coated tablets, as well as the appearance of the cores after removal of the coating.

Content uniformity: taking 10 test samples, and respectively measuring the relative content xi of each single agent with the labeled amount as 100 according to a high performance liquid chromatography method under the condition of content measurement. A +2.2S was calculated according to content uniformity inspection (2015 edition "Chinese pharmacopoeia", 0941, the general rules of four departments).

Related substances and content determination: calculating the content of each known impurity, unknown impurity and total impurity of the quinazoline compound shown in the formula A in the pharmaceutical composition by adopting a main component external standard method with a response factor according to a high performance liquid chromatography (2015 edition, China pharmacopoeia, general guidelines 0512) and a peak area (report limit: 0.05%); and calculating the content of the quinazoline compound shown as the formula A in the pharmaceutical composition by using the peak area by adopting an external standard method.

Dissolution rate: according to a dissolution determination method (2015 edition, Chinese pharmacopoeia, second method of 0931, the general rule of four departments, the edition), 900ml of phosphate buffer solution with the pH value of 6.8 containing 0.2% SDS is used as a dissolution medium, the rotating speed is 75 revolutions per minute, 6 samples are taken, 1 sample is put in each dissolution cup, 10ml of solution is taken after 30 minutes, the solution is filtered by a 0.45 mu m filter membrane, and the dissolution of the quinazoline compound shown in the formula A is calculated by measuring the content by a high performance liquid phase.

TABLE 11 assessment results of key quality attributes of the pharmaceutical compositions manufactured in example 4

The experimental results are as follows: the assessment results of each key quality attribute of the film-coated tablets manufactured in example 4 and containing 20mg of the quinazoline compound according to formula a met the end product release quality standards.

Test example 2: determination of dissolution Curve of pharmaceutical composition

The pharmaceutical compositions manufactured in examples 4 and 5 above were subjected to the measurement of the dissolution profile, respectively.

Taking 6 test pieces from the film-coated tablets produced in each example using 0.1mol/L hydrochloric acid solution (9ml hydrochloric acid, 1000ml by adding water) or 900ml of pH6.8 phosphate buffer solution containing 0.2% SDS as a dissolution medium according to a dissolution method (2015 edition, second method of 0931, national ministry of general rules of Chinese pharmacopoeia), taking 1 piece in each dissolution cup, sampling at appropriate time intervals, supplementing the dissolution medium at the same volume, filtering with a 0.45 μm filter membrane, calculating the cumulative dissolution rate of the quinazoline compound represented by the formula A according to the content measured by high performance liquid chromatography, and the measurement results are shown in the following table 12 and attached fig. 1-2.

TABLE 12 measurement results of dissolution curves of the pharmaceutical compositions produced in examples 4 and 5

The experimental results are as follows: in 0.1mol/L hydrochloric acid solution, 20mg and 100mg specification film coating tablets can be quickly and completely dissolved out, and the cumulative dissolution in 30 minutes reaches 100 percent. In a phosphate buffer solution with 0.2 percent SDS and pH6.8, the dissolution rate of a film-coated tablet with 100mg specification is slightly slower than that of a film-coated tablet with 20mg specification, the cumulative dissolution in 30 minutes is 88 percent, and the dissolution rate of a finished product meets the release standard (more than or equal to 70 percent).

Effect example 1: test for influencing factor

The pharmaceutical composition manufactured in example 4 was exposed and examined for 30 days under the influence of high temperature (60 ℃), high humidity (25 ± 2 ℃, RH 92.5%), and light (4500 ± 500Lux), and the stability of the pharmaceutical composition was examined according to the test method in the above test example 1, wherein the examination indexes include properties, related substances, dissolution rate, and content. Specific results are shown in tables 13-15 below.

TABLE 13 summary of the test results for high temperature influencing factor of the pharmaceutical composition manufactured in example 4

TABLE 14 summary of test results for high humidity Effect factor of the pharmaceutical composition produced in example 4

^a : the moisture absorption weight gain is an investigation item of a high-humidity influence factor test and has no limit requirement.

TABLE 15 summary of the test results for light influencing factors for the pharmaceutical compositions manufactured in example 4

The results in tables 13-15 show that the pharmaceutical composition of the quinazoline compound shown in the formula A provided by the invention is determined after being respectively exposed and placed for 5 days, 10 days and 30 days under the conditions of high temperature, high humidity and illumination influence factors, and each evaluation index of the pharmaceutical composition has no obvious change compared with that before the influence factor test treatment. The medicinal composition is placed under high humidity condition for 30 days, and has no obvious moisture absorption weight gain.

It should be understood that the examples described herein are for illustrative purposes only and are not intended to limit the scope of the present invention, which will be described in further detail herein. It will be apparent to those skilled in the art that many changes in both materials and methods may be made without departing from the scope of the invention, and such changes or modifications are intended to be included within the spirit and scope of this application and the scope of the appended claims.

Claims

1. A pharmaceutical composition, comprising: substance X and a pharmaceutical excipient; wherein the substance X is a quinazoline compound shown as a formula A, a pharmaceutically acceptable salt thereof, a solvate thereof or a solvate of a pharmaceutically acceptable salt thereof;

2. the pharmaceutical composition according to claim 1, wherein substance X is the only active ingredient;

and/or, said substance X is in a therapeutically effective amount;

and/or, the pharmaceutical composition is a medicament for treating B cell hemangioma;

and/or the filler is one or two of microcrystalline cellulose, mannitol and corn starch;

and/or, the filler accounts for 10% -90% of the total weight of the pharmaceutical composition by weight;

and/or, the pharmaceutic adjuvant also comprises a disintegrant;

and/or, the pharmaceutic adjuvant also comprises a lubricant;

and/or, the pharmaceutical composition is a tablet or capsule;

and/or, the administration dosage of the pharmaceutical composition is 0.33mg/kg to 3.33mg/kg once based on the content of the quinazoline compound shown in the formula A;

and/or the administration dosage of the pharmaceutical composition is 20mg to 200mg per day based on the content of the quinazoline compound shown in the formula A;

and/or, the frequency of administration of said pharmaceutical composition is 1-5 times per day;

and/or the administration course of the pharmaceutical composition is 14-84 days per course;

and/or, the pharmaceutical composition is administered for a total of 1-20 treatment periods;

and/or, in the unit dosage form of the pharmaceutical composition, the quinazoline compound shown in the formula A is 5mg-500 mg;

and/or, said pharmaceutical composition is administered to a patient who has progressed on a previous treatment regimen after receiving a second or more lines of systemic treatment that has been treated with CD20 mab and at least one alkylating agent;

and/or, the subject to which the pharmaceutical composition is administered is a human.

3. The pharmaceutical composition of claim 2, wherein the filler is microcrystalline cellulose, a mixture of microcrystalline cellulose and mannitol, or a mixture of microcrystalline cellulose and corn starch;

and/or, the filler accounts for 30% -70% of the total weight of the pharmaceutical composition by weight;

and/or, when the pharmaceutic adjuvant further comprises a disintegrant, the disintegrant is crospovidone and/or croscarmellose sodium;

and/or, when the pharmaceutic adjuvant further comprises a disintegrant, the disintegrant accounts for 1-20% of the total weight of the pharmaceutical composition by weight;

and/or, when the pharmaceutic adjuvant further comprises a lubricant, the lubricant is one or more of calcium stearate, glyceryl monostearate, glyceryl behenate, magnesium stearate, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, stearic acid, talcum powder, micro-powder silica gel and zinc stearate;

and/or, when the pharmaceutic adjuvant further comprises a lubricant, the lubricant accounts for 0.1-5.0% of the total weight of the pharmaceutical composition by weight;

and/or, when the pharmaceutical composition is a tablet or capsule, the tablet is a coated tablet;

and/or, when the pharmaceutical composition is a medicament for treating a B cell hematological tumor, the B cell hematological tumor is a B cell lymphoma;

and/or, the administration dosage of the pharmaceutical composition is 0.66mg/kg-2.3mg/kg once based on the content of the quinazoline compound shown in the formula A;

and/or, based on the content of the quinazoline compound shown in the formula A, the administration dosage of the pharmaceutical composition is 20 mg/day, 30 mg/day, 40 mg/day, 50 mg/day, 60 mg/day, 70 mg/day, 80 mg/day, 90 mg/day, 100 mg/day, 110 mg/day, 120 mg/day, 130 mg/day, 140 mg/day, 150 mg/day, 160 mg/day, 170 mg/day, 180 mg/day, 190 mg/day or 200 mg/day;

and/or, the pharmaceutical composition is administered at a frequency of 1, 2, 3, 4, or 5 times per day;

and/or the administration course of the pharmaceutical composition is 14 days/course, 28 days/course, 42 days/course, 56 days/course, 70 days/course or 84 days/course;

and/or, the pharmaceutical composition is administered for a total of 10-20 courses;

and/or, in the unit dosage form of the pharmaceutical composition, the quinazoline compound shown in the formula A is 10mg-120 mg;

and/or, the pharmaceutical composition is administered to a patient who has progressed on a previous treatment regimen after receiving a second or more line of systemic treatment that has been treated with CD20 mab and at least one alkylating agent including bendamustine, cyclophosphamide, ifosfamide, chlrobutylamine, melphalan, busulfan, and nitroso.

4. The pharmaceutical composition of claim 3, wherein the filler is present in an amount of 45% to 55% by weight of the total weight of the pharmaceutical composition;

and/or, the quinazoline compound shown in the formula A accounts for 40-50% of the total weight of the pharmaceutical composition by weight;

and/or, when the filler is a mixture of microcrystalline cellulose and mannitol, the mass ratio of the microcrystalline cellulose to the mannitol is 10: 1-1: 10;

and/or, when the pharmaceutic adjuvant further comprises a disintegrant, the disintegrant is crospovidone or croscarmellose sodium;

and/or, when the pharmaceutic adjuvant further comprises a disintegrant, the disintegrant accounts for 3-15% of the total weight of the pharmaceutical composition by weight;

and/or, when the pharmaceutical excipients also comprise a lubricant, the lubricant is magnesium stearate;

and/or, when the pharmaceutical excipients also comprise a lubricant, the lubricant accounts for 0.3 to 2.0 percent of the total weight of the pharmaceutical composition by weight;

and/or, when the tablet is a coated tablet, the coated tablet is a film coated tablet;

and/or, when the B cell hematological tumor is a B cell lymphoma, the B cell lymphoma is non-hodgkin's lymphoma;

and/or, based on the content of the quinazoline compound shown in the formula A, the administration dosage of the pharmaceutical composition is 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 or 2.3mg/kg at a time;

and/or, said pharmaceutical composition is administered for a total of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 treatment sessions;

and/or, in the unit dosage form of the pharmaceutical composition, the content of the quinazoline compound shown in the formula A is 20-100 mg;

and/or, the pharmaceutical composition is administered to a patient who has received one or more of R-CHOP, BR, and R-CVP in a previous treatment regimen.

5. The pharmaceutical composition according to claim 4, wherein when the filler is a mixture of microcrystalline cellulose and mannitol, the mass ratio of microcrystalline cellulose to mannitol is 6: 1-2: 1, e.g., 4: 1-3: 1;

and/or, when the pharmaceutic adjuvant further comprises a disintegrant, the disintegrant accounts for 4-8% of the total weight of the pharmaceutical composition by weight;

and/or, when the pharmaceutical excipients also comprise a lubricant, the lubricant accounts for 0.8 to 1.4 percent of the total weight of the pharmaceutical composition by weight;

and/or, when the coated tablet is a film coated tablet, the weight gain of the coating agent in the film coated tablet is 2% -5% compared with the weight of the tablet core;

and/or, when the coating tablet is a film coating tablet, the coating agent used for the film coating tablet is a film coating premix taking hydroxypropyl methylcellulose as a main film forming polymer;

and/or, when the B cell lymphoma is non-hodgkin's lymphoma, the non-hodgkin's lymphoma is follicular lymphoma;

and/or, in a unit dosage form of the pharmaceutical composition, the quinazoline compound shown in the formula A is contained in an amount of 20mg, 30mg, 40mg, 50mg, 60mg, 70mg, 80mg, 90mg or 100 mg.

6. The pharmaceutical composition of claim 5, wherein the pharmaceutical composition comprises, by weight:

1) 40-50% of quinazoline compound shown as formula A;

2) 45-55% of filler, wherein the filler is one, two or more of microcrystalline cellulose, mannitol and corn starch;

3) 4% -8% of a disintegrating agent, wherein the disintegrating agent is crospovidone and/or croscarmellose sodium;

4) 0.8% -1.4% of a lubricant, wherein the lubricant is magnesium stearate;

and/or the quinazoline compound shown as the formula A accounts for 40% of the total weight of the pharmaceutical composition by weight;

and/or, the filler is 52.8% of the total weight of the pharmaceutical composition by weight;

and/or, when the pharmaceutic adjuvant further comprises a disintegrant, the disintegrant accounts for 6 percent of the total weight of the pharmaceutical composition by weight;

and/or, when the pharmaceutic adjuvant further comprises a lubricant, the lubricant accounts for 1.2 percent of the total weight of the pharmaceutical composition by weight;

and/or, when said coated tablet is a film coated tablet, the coating agent for said film coated tablet is commercially available from Coloconggong, trade name "

The film-coated premix of I';

and/or, when the coated tablet is a film coated tablet, the weight of the coating agent in the film coated tablet is increased by 2.5% to 4.5%, e.g. 3.5%, compared to the weight of the tablet core;

and/or, when the non-hodgkin's lymphoma is follicular lymphoma, the follicular lymphoma is relapsed and/or refractory follicular lymphoma;

and/or, the pharmaceutical composition is administered to a patient who has received one or more systemic treatment regimens of relapsed or refractory follicular lymphoma (e.g., a patient who has received one or more systemic treatment regimens of relapsed follicular lymphoma), preferably to a patient who has received two or more systemic treatment regimens of relapsed or refractory follicular lymphoma (e.g., a patient who has received two or more systemic treatment regimens of relapsed follicular lymphoma).

7. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises, by weight:

components The weight percentage is% Quinazoline compounds of formula A 40-50 Microcrystalline cellulose 45-55 Cross-linked polyvidone 4-8 Magnesium stearate 0.8-1.4

Or the like, or, alternatively,

components The weight percentage is% Quinazoline compounds of formula A 40-50 Microcrystalline cellulose 45-55 Croscarmellose sodium 4-8 Magnesium stearate 0.8-1.4

Or the like, or, alternatively,

components Percentage by weight% Quinazoline compounds of formula A 40-50 Microcrystalline cellulose 30-45 Mannitol 5-15 Cross-linked polyvidone 4-8 Magnesium stearate 0.8-1.4

Or the like, or, alternatively,

or the like, or, alternatively,

components The weight percentage is% Quinazoline compounds of formula A 40-50 Microcrystalline cellulose 30-45 Corn starch 5-15 Cross-linked polyvidone 4-8 Magnesium stearate 0.8-1.4

Or the like, or, alternatively,

components The weight percentage is% Quinazoline compounds of formula A 40-50 Microcrystalline cellulose 35-45 Corn starch 5-15 Croscarmellose sodium 4-8 Magnesium stearate 0.8-1.4

。

8. The pharmaceutical composition of claim 7, wherein the pharmaceutical composition consists of:

components The weight percentage is% As shown in formula AQuinazoline compound of (4) 40 Microcrystalline cellulose 40 Mannitol 12.8 Croscarmellose sodium 6 Magnesium stearate 1.2

Or, the pharmaceutical composition comprises a tablet core and a coating, and each comprises the following components by weight:

tablet core:

1) 40% of quinazoline compound shown as formula A;

2) 40% microcrystalline cellulose and 12.8% mannitol;

3) 6% croscarmellose sodium;

4) 1.2% magnesium stearate;

coating:

9. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 8, by direct compression of a powder of the components of a pharmaceutical composition according to any one of claims 1 to 8.

10. The method of claim 9, comprising the steps of:

1) pretreatment of

2) total mixing