A pharmaceutical composition of a quinazoline compound and a preparation method thereof

Abstract

The present 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 pharmaceutical excipients; wherein, the substance X is a quinazoline compound represented by formula A, its pharmaceutically acceptable salt, its solvate or a solvate of its pharmaceutically acceptable salt; the pharmaceutical excipients include fillers, and the fillers are one, two or more of microcrystalline cellulose, mannitol and corn starch. The pharmaceutical composition of the present invention has good stability and dissolution rate, and the preparation method of the pharmaceutical composition is simple and suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition of a quinazoline compound and a preparation method thereof. Background Art

[0002] PI3K is short for Phosphatidylinositol 3-kinase, and it participates 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. In mammalian cells, class I PI3K is further divided into class Ia and class Ib according to structure and receptor, and they respectively transmit signals from tyrosine kinase-coupled receptors and G protein-coupled receptors. Class Ia PI3K includes PI3Kα, PI3Kβ, and PI3Kδ subtypes, and class Ib PI3K includes PI3Kγ subtype (Trends. Biochem. Sci., 1997, 22, 267-272). Class Ia PI3K is a dimer protein composed of a catalytic subunit p110 and a regulatory subunit p85, and has dual activities of lipid kinase and protein kinase (Nat. Rev. Cancer 2002, 2, 489-501), and is considered to be related to cell proliferation, cancer occurrence, immune diseases, and diseases involving inflammation.

[0003] Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma (NHL) in European and American countries, accounting for about 22-35% of all newly diagnosed NHL. In recent years, with the deepening of the understanding of the disease and the improvement of diagnostic techniques, the annual incidence has gradually increased from 2-3 / 100,000 in the 1950s to about 5 / 100,000. Different from Western countries, FL accounts for about 8% of B-cell NHL in China, and the proportion is relatively lower than that in Western countries, and the onset age is relatively lower compared with the median diagnosis age of 65 years abroad.

[0004] Although follicular lymphoma only accounts for 8% of B-cell lymphoma in China, due to the large population base in China, the number of patients is still relatively large. FL is highly prevalent in the middle-aged and elderly populations, and with the acceleration of the aging process, the incidence of follicular lymphoma in China has shown an upward trend in recent years. At present, follicular lymphoma cannot be completely cured. After treatment reaches remission, FL will relapse repeatedly, and repeated relapses are likely to turn into an aggressive type. As the number of relapses increases, the remission period will become shorter and shorter, the probability of being refractory increases, resulting in a shortened overall survival period. At present, there is no unified standard treatment method for relapsed and refractory FL. And currently, the drugs for treating FL are limited, and there is an urgent need to develop drugs with better efficacy.

[0005] Among them, phosphoinositide 3-kinase-delta (PI3Kδ) inhibitors are one of the treatment approaches. PI3Kδ is an intracellular signal transduction component mainly expressed in the hematopoietic cell lineage, including malignant hematological diseases caused or mediated by cells.

[0006] Currently, 3 PI3Kδ inhibitor drugs have been successfully launched globally, namely Idelalisib, Copanlisib, and Duvelisib, all of which are used to treat cancers of the circulatory system.

[0007] The clinical trial results of Idelalisib in relapsed follicular B-cell non-Hodgkin lymphoma (FL) (clinical trial registration number: NCT01282424) have been reported in the literature. The inclusion criteria were FL patients who relapsed within 6 months after treatment with rituximab combined with alkylating agents and had received at least 2 systemic treatments.

[0008] The research results showed that the median age of the subjects was 62 years (range 33 - 84 years), 54% were male, and 90% were Caucasian. At the time of inclusion, 92% of the patients had a baseline ECOG performance status of 0 or 1; the median disease course was 4 - 7 years; the median number of previous treatments was 4 (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 the patients had extranodal metastases and 26% had bone marrow metastases.

[0009] Patients were treated with Idelalisib 150 mg twice a day until disease progression or unacceptable toxicity occurred. The effectiveness of malignant lymphoma was evaluated according to the International Working Group response criteria. The primary endpoint was the overall response rate (ORR) evaluated by the independent review committee.

[0010] The following table shows the efficacy results: The median response time was 1.9 months (range 1.6 - 8.3).

[0011] Efficacy endpoint N＝72 ORR 95% CI 39(54％)(42，66％) CR 6(8％) PR 33(46％) *Median DOR, months (range) Median not evaluable (0.0+, 14.8+)

[0012] CI = confidence interval; CR = complete remission; PR = partial remission; *Kaplan-Meier estimate;

[0013] DOR = Duration of response, the duration of remission = the duration of PR / CR.

[0014] The above data source: Ajay K. Gopal, M.D., Brad S. Kahl, M.D., Sven de Vos, M.D., Ph.D. et al. PI3Kδ Inhibition by Idelalisib in Patients with Relapsed Indolent Lymphoma[J]. N Engl J Med. 2014 March 13; 370(11): 1008–1018.

[0015] The quinazoline compound with the chemical structure shown in Formula A is a small molecule inhibitor of PI3Kδ and has been disclosed in the patent CN104557872A (Compound 10). Compared with other existing PI3Kδ inhibitors, the selectivity for PI3Kδ is improved and the activity against PI3Kγ is eliminated. The Chinese patent CN110950844A discloses two polymorphs of the quinazoline compound shown in Formula A.

[0016] Those skilled in the art know that after oral solid dosage forms are administered, the active pharmaceutical ingredient needs to be released and absorbed into the human body in the gastrointestinal tract before it can play a role in treating and / or preventing diseases. Due to the significant difference in pH values between the stomach (pH 1 - 3.5) and the intestine (pH 4 - 8), the solubility of the active pharmaceutical ingredient at different sites in the gastrointestinal tract may change due to the change in pH value. The research results show that the quinazoline compound shown in Formula A exhibits significant pH-dependent solubility characteristics. Compared with that in simulated artificial intestinal fluid (FaSSIF, pH = 6.5), the quinazoline compound shown in Formula A has approximately 195 times higher solubility in simulated gastric fluid (SGF, pH = 1.2). Therefore, increasing the solubility and / or dissolution rate of the quinazoline compound shown in Formula A in the intestine is an important way to maximize its oral absorption.

[0017] However, it is found that the quinazoline compound shown in Formula A is prone to aggregate into clusters when exposed to water, which brings trouble to the effective disintegration of solid oral dosage forms and / or the rapid release of drugs.

[0018] In view of the good activity and safety shown by the quinazoline compound shown in Formula A in preclinical in vitro and in vivo studies, there is an urgent need to develop an oral solid dosage form with rapid dissolution, good bioavailability and easy production to ensure the safety, effectiveness and quality consistency of the drug during clinical use. Summary of the Invention

[0019] The technical problem to be solved by the present invention is the lack of preparations of quinazoline compounds represented by formula A in the prior art. Therefore, the present invention provides a pharmaceutical composition of a quinazoline compound and a preparation method thereof. The pharmaceutical composition has good stability to high temperature, high humidity and light, and can achieve rapid dissolution in 0.1 mol / L hydrochloric acid solution (pH 1.2) and pH 6.8 phosphate buffer solution containing 0.2% sodium dodecyl sulfate (SDS); and the preparation method of the pharmaceutical composition is simple and suitable for industrial production.

[0020] The present invention provides a pharmaceutical composition, which comprises substance X and pharmaceutical excipients;

[0021] Wherein, the substance X is a quinazoline compound represented by formula A, its pharmaceutically acceptable salt, its solvate or a solvate of its pharmaceutically acceptable salt;

[0022] The pharmaceutical excipients include fillers, and the fillers are one, two or more of microcrystalline cellulose, mannitol and corn starch;

[0023]

[0024] In one embodiment of the present invention, the substance X is the only active ingredient.

[0025] In one embodiment of the present invention, the substance X is in a therapeutically effective amount.

[0026] In one embodiment of the present invention, the quinazoline compound represented by formula A is the quinazoline compound represented by formula A in free base form. It should be understood that the "free base form" means the case where the quinazoline compound represented by formula A is not in the form of a salt.

[0027] In some embodiments of the present invention, the quinazoline compound represented by formula A is preferably in the form of polymorph I of the quinazoline compound represented by formula A, and the polymorph I of the quinazoline compound represented by formula A can be defined in any manner described in Chinese Patent Publication No. CN110950844A.

[0028] In one embodiment of the present invention, the filler is one or two of microcrystalline cellulose, mannitol and corn starch.

[0029] In one embodiment of the present invention, the filler is microcrystalline cellulose.

[0030] In one embodiment of the present invention, the filler is a mixture of microcrystalline cellulose and mannitol.

[0031] In one embodiment of the present invention, the filler is a mixture of microcrystalline cellulose and corn starch.

[0032] In one embodiment of the present invention, the filler is a mixture of microcrystalline cellulose, mannitol and corn starch.

[0033] In one embodiment of the present invention, the filler accounts for 10%-90% by weight of the total weight of the pharmaceutical composition, preferably 30%-70%, and most preferably 45%-55%.

[0034] In one embodiment of the present invention, the filler is a mixture of microcrystalline cellulose and mannitol, accounting for 10%-90% by weight of the total weight of the pharmaceutical composition, preferably 30%-70%, and most preferably 45%-55%.

[0035] 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.

[0036] 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.

[0037] In one embodiment of the present invention, the pharmaceutical excipient further includes a disintegrant.

[0038] In one embodiment of the present invention, the disintegrant is crospovidone and / or sodium croscarmellose.

[0039] In one embodiment of the present invention, the disintegrant is crospovidone.

[0040] In one embodiment of the present invention, the disintegrant is sodium croscarmellose.

[0041] In one embodiment of the present invention, the disintegrant is not low-substituted hydroxypropyl cellulose.

[0042] In one embodiment of the present invention, the disintegrant accounts for 1%-20% by weight of the total weight of the pharmaceutical composition, preferably 3%-15%, and most preferably 4%-8%.

[0043] In one embodiment of the present invention, the disintegrant is sodium croscarmellose, accounting for 1%-20% by weight of the total weight of the pharmaceutical composition.

[0044] In one embodiment of the present invention, the disintegrant is sodium carboxymethylcellulose cross-linked, which is 3%-15% by weight of the total weight of the pharmaceutical composition, preferably 4%-8%.

[0045] In one embodiment of the present invention, the pharmaceutical excipient further includes a lubricant.

[0046] In the present invention, the lubricant is one or more of calcium stearate, glycerol monostearate, glyceryl behenate, magnesium stearate, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, stearic acid, talc, colloidal silicon dioxide and zinc stearate.

[0047] In one embodiment of the present invention, the lubricant is magnesium stearate.

[0048] In one embodiment of the present invention, the lubricant is 0.1%-5.0% by weight of the total weight of the pharmaceutical composition, preferably 0.3%-2.0%, and most preferably 0.8%-1.4%.

[0049] In one embodiment of the present invention, the lubricant is magnesium stearate, which is 0.1%-5.0% by weight of the total weight of the pharmaceutical composition.

[0050] In one embodiment of the present invention, 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%.

[0051] In one embodiment of the present invention, the pharmaceutical composition comprises the following components by weight:

[0052] 1) 40%-50% of the quinazoline compound shown in Formula A;

[0053] 2) 45%-55% of a filler, the filler being one, two or more of microcrystalline cellulose, mannitol and corn starch, preferably a mixture of microcrystalline cellulose and mannitol, most preferably a mixture of microcrystalline cellulose and mannitol, and the mass ratio thereof being 4:1-3:1;

[0054] 3) 4%-8% of a disintegrant, the disintegrant being at least one of cross-linked povidone and sodium carboxymethylcellulose cross-linked, most preferably sodium carboxymethylcellulose cross-linked;

[0055] 4) 0.8%-1.4% of a lubricant, the lubricant being magnesium stearate.

[0056] In one embodiment of the present invention, the quinazoline compound shown in Formula A is 40% by weight of the total weight of the pharmaceutical composition.

[0057] In one embodiment of the present invention, the filler is 52.8% by weight of the total weight of the pharmaceutical composition.

[0058] In one embodiment of the present invention, the disintegrant is 6% by weight of the total weight of the pharmaceutical composition.

[0059] In one embodiment of the present invention, the lubricant is 1.2% by weight of the total weight of the pharmaceutical composition.

[0060] In one embodiment of the present invention, the pharmaceutical composition comprises the following components by weight:

[0061] Component Weight percentage (%) Quinazoline compound as shown in Formula A 40-50 Microcrystalline cellulose 45-55 Crospovidone 4-8 Magnesium stearate 0.8-1.4

[0062] Preferably, the pharmaceutical composition consists of the above components.

[0063] In one embodiment of the present invention, the pharmaceutical composition comprises the following components by weight:

[0064] Component Weight percentage (%) Quinazoline compound as shown in Formula A 40-50 Microcrystalline cellulose 45-55 Croscarmellose sodium 4-8 Magnesium stearate 0.8-1.4

[0065] Preferably, the pharmaceutical composition consists of the above components.

[0066] In one embodiment of the present invention, the pharmaceutical composition comprises the following components by weight:

[0067] Component Weight percentage (%) Quinazoline compound as shown in Formula A 40-50 Microcrystalline cellulose 30-45 Mannitol 5-15 Crospovidone 4-8 Magnesium stearate 0.8-1.4

[0068] Preferably, the pharmaceutical composition consists of the above components.

[0069] In one embodiment of the present invention, the pharmaceutical composition comprises the following components by weight:

[0070]

[0071]

[0072] Preferably, the pharmaceutical composition consists of the above components.

[0073] In one embodiment of the present invention, the pharmaceutical composition comprises the following components by weight:

[0074] Component Weight percentage (%) Quinazoline compound as shown in Formula A 40-50 Microcrystalline cellulose 30-45 Corn starch 5-15 Crospovidone 4-8 Magnesium stearate 0.8-1.4

[0075] Preferably, the pharmaceutical composition consists of the above components.

[0076] In one embodiment of the present invention, the pharmaceutical composition comprises the following components by weight:

[0077] Component Weight percentage (%) Quinazoline compound as shown in Formula A 40-50 Microcrystalline cellulose 35-45 Corn starch 5-15 Croscarmellose sodium 4-8 Magnesium stearate 0.8-1.4

[0078] Preferably, the pharmaceutical composition consists of the above components.

[0079] In one embodiment of the present invention, the pharmaceutical composition comprises the following components by weight:

[0080] Component Weight percentage (%) Quinazoline compound as shown in Formula A 40 Microcrystalline cellulose 40 Mannitol 12.8 Croscarmellose sodium 6 Magnesium stearate 1.2

[0081] In one embodiment of the present invention, the pharmaceutical composition may be a solid preparation, preferably a solid oral preparation.

[0082] In one embodiment of the present invention, the pharmaceutical composition may be a tablet or a capsule, preferably a tablet.

[0083] In one embodiment of the present invention, the tablet is a coated tablet.

[0084] In one embodiment of the present invention, the coated tablet is a film-coated tablet.

[0085] 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 coating premix based on hydroxypropyl methylcellulose as the main film-forming polymer.

[0086] In one embodiment of the present invention, in the film-coated tablet, the coating agent of the film-coated tablet can be commercially purchased from Colorcon, for example, the film coating premix with the trade name " Ⅰ( Ⅰ)".

[0087] In one embodiment of the present invention, in the film-coated tablet, compared with the weight of the tablet core, the weight gain of the coating agent is 2% - 5%, preferably 2.5% - 4.5%, and most preferably 3.5%.

[0088] In one embodiment of the present invention, the pharmaceutical composition, which comprises two parts: a tablet core and a coating, and each contains the following components by weight:

[0089] Tablet core:

[0090] 1) 40% - 50% of the quinazoline compound shown in Formula A;

[0091] 2) 45%-55% filler, the filler being one, two or more of microcrystalline cellulose, mannitol and corn starch, preferably a mixture of microcrystalline cellulose and mannitol, and the mass ratio of microcrystalline cellulose to mannitol preferably being 4:1 - 3:1;

[0092] 3) 4%-8% disintegrant, the disintegrant being at least one of crospovidone and croscarmellose sodium, most preferably croscarmellose sodium;

[0093] 4) 0.8%-1.4% lubricant, the lubricant being magnesium stearate;

[0094] Coating:

[0095] 5) Compared with the weight of the tablet core, the weight gain of the coating agent is 2%-5%, preferably 2.5%-4.5%, most preferably 3.5%.

[0096] In a certain embodiment of the present invention, the pharmaceutical composition comprises two parts, a tablet core and a coating, and each contains the following components by weight:

[0097] Tablet core:

[0098] 1) 40% of the quinazoline compound shown in formula A;

[0099] 2) 45%-55% filler, the filler being a mixture of microcrystalline cellulose and mannitol, and the mass ratio of microcrystalline cellulose to mannitol being 4:1 - 3:1;

[0100] 3) 4%-8% disintegrant, the disintegrant being croscarmellose sodium;

[0101] 4) 0.8%-1.4% lubricant, the lubricant being magnesium stearate;

[0102] Coating:

[0103] 5) Compared with the weight of the tablet core, the weight gain of the coating agent is 3.5%.

[0104] In a certain embodiment of the present invention, the pharmaceutical composition comprises two parts, a tablet core and a coating, and each contains the following components by weight:

[0105] Tablet core:

[0106] 1) 40% of the quinazoline compound shown in formula A;

[0107] 2) 40% microcrystalline cellulose and 12.8% mannitol;

[0108] 3) 6% croscarmellose sodium;

[0109] 4) Magnesium stearate 1.2%;

[0110] Coating:

[0111] 5) Compared with the weight of the tablet core, the weight gain of the coating agent is 3.5%.

[0112] In one embodiment of the present invention, in the unit dosage form of the pharmaceutical composition, the content of the quinazoline compound shown in Formula A is 5 mg - 500 mg, preferably 10 mg - 200 mg, most preferably 20 mg - 100 mg, such as 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg or 100 mg. Taking tablets as an example, in the unit dosage form, the content of the quinazoline compound shown in Formula A is 5 mg - 500 mg / tablet.

[0113] The second aspect of the present invention provides a preparation method of the pharmaceutical composition as described above, which is direct powder compression.

[0114] Preferably, the preparation method of the pharmaceutical composition provided by the present invention includes the following steps:

[0115] 1) Pretreatment

[0116] Pass the quinazoline compound shown in Formula A, the filler, and the disintegrant through a 30-mesh sieve respectively, and pass the lubricant through a 60-mesh sieve;

[0117] 2) Total mixing

[0118] According to the prescription amount, mix the quinazoline compound shown in Formula A obtained in step 1) with the filler in a mixer to obtain premix 1;

[0119] Mix premix 1 with the disintegrant in a mixer to obtain premix 2; Sieve premix 2 through a granulator to obtain premix 3;

[0120] Mix premix 3 and the lubricant in a mixer to obtain the total mixed material;

[0121] 3) Compress the total mixed material obtained in step 2) into tablets to obtain tablet cores;

[0122] 4) Prepare a 10% film coating premix coating solution and coat the tablet cores obtained in step 3).

[0123] In one scheme, the pharmaceutical composition is a drug for treating B-cell hematological tumors;

[0124] In one embodiment, the pharmaceutical composition is a medicament for treating B-cell hematological malignancies, the B-cell hematological malignancy being B-cell lymphoma. Preferably, the B-cell lymphoma is non-Hodgkin lymphoma. More preferably, the non-Hodgkin lymphoma is follicular lymphoma. Most preferably, the follicular lymphoma is relapsed and / or refractory follicular lymphoma, for example, relapsed or refractory follicular lymphoma.

[0125] In one embodiment, the pharmaceutical composition is administered orally.

[0126] In one embodiment, Substance X is present in a therapeutically effective amount.

[0127] In one embodiment, the dosage of the pharmaceutical composition can be determined according to the patient's body weight. Calculated based on the content of the quinazoline compound shown in Formula A, the dosage of the pharmaceutical composition is 0.33 mg / kg - 3.33 mg / kg per administration, for example, 0.66 mg / kg - 2.3 mg / kg. Further examples include 1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.33 mg / kg, 1.4 mg / 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.

[0128] In one embodiment, calculated based on the content of the quinazoline compound shown in Formula A, the dosage of the pharmaceutical composition is 20 mg - 200 mg per 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. Further examples include 80 mg / day.

[0129] In one embodiment, the administration frequency of the pharmaceutical composition is 1 - 5 times per day, for example, 1 time per day, 2 times per day, 3 times per day, 4 times per day, or 5 times per day. Further examples include 1 time per day.

[0130] In one embodiment, the treatment course of the pharmaceutical composition is 14 - 84 days per course, for example, 14 days per course, 28 days per course, 42 days per course, 56 days per course, 70 days per course, or 84 days per course. Further examples include 28 days per course.

[0131] In one embodiment, the pharmaceutical composition is administered for 1 to 20 treatment courses, preferably 10 to 20 treatment courses. For example, it can be 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 treatment courses. For another example, it can be 12 treatment courses.

[0132] In one embodiment, the pharmaceutical composition is a tablet.

[0133] In one embodiment, the specification of the pharmaceutical composition is 10mg - 120mg per tablet. For example, it can be 20 - 100mg per tablet. For another example, it can be 20mg / tablet, 30mg / tablet, 40mg / tablet, 50mg / tablet, 60mg / tablet, 70mg / tablet, 80mg / tablet, 90mg / tablet or 100mg / tablet. For yet another example, it can be 20mg / tablet, 80mg / tablet or 100mg / tablet.

[0134] In one embodiment, the pharmaceutical composition is administered to patients with relapsed or refractory follicular lymphoma who have received one or more systemic treatment regimens (e.g., patients with relapsed follicular lymphoma who have received one or more systemic treatment regimens). Preferably, the pharmaceutical composition is administered to patients with relapsed or refractory follicular lymphoma who have received two or more systemic treatment regimens (e.g., patients with relapsed follicular lymphoma who have received two or more systemic treatment regimens).

[0135] In one embodiment, the pharmaceutical composition is administered to patients who have progressed after a prior treatment regimen of second-line or higher-line systemic treatment, where the second-line or higher-line systemic treatment is for patients who have progressed after receiving CD20 monoclonal antibody and at least one alkylating agent. The alkylating agents include, but are not limited to, bendamustine, cyclophosphamide, ifosfamide, chlorambucil, melphalan, busulfan and nitrosoureas.

[0136] In one embodiment, the pharmaceutical composition is administered to patients with a prior treatment regimen of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), BR (bendamustine, rituximab), and R-CVP (rituximab, cyclophosphamide, vincristine, prednisone).

[0137] In one embodiment, the administration subject of the pharmaceutical composition is human.

[0138] The present invention also provides a method for treating a disease, which includes administering a therapeutically effective amount of substance X or the pharmaceutical composition to a patient (e.g., a human).

[0139] The disease is B-cell hematoma; the substance X is a quinazoline compound represented by formula A, its pharmaceutically acceptable salt, its solvate or a solvate of its pharmaceutically acceptable salt; the pharmaceutical composition comprises the substance X and pharmaceutical excipients.

[0140] In one embodiment, the B-cell hematoma is B-cell lymphoma. Preferably, the B-cell lymphoma is non-Hodgkin lymphoma. More preferably, the non-Hodgkin lymphoma is follicular lymphoma. Most preferably, the follicular lymphoma is relapsed and / or refractory follicular lymphoma, for example, relapsed or refractory follicular lymphoma.

[0141] In one embodiment, the administration mode is oral administration.

[0142] In one embodiment, the administration dose can be determined according to the patient's body weight. Calculated by the content of the quinazoline compound represented by formula A, the administration dose is 0.33 mg / kg - 3.33 mg / kg per administration, for example, 0.66 mg / kg - 2.3 mg / kg, and for another example, 1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.33 mg / kg, 1.4 mg / 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.

[0143] In one embodiment, calculated by the content of the quinazoline compound represented by formula A, the administration dose is 20 - 200 mg per day, for example, 20 mg per day, 30 mg per day, 40 mg per day, 50 mg per day, 60 mg per day, 70 mg per day, 80 mg per day, 90 mg per day, 100 mg per day, 110 mg per day, 120 mg per day, 130 mg per day, 140 mg per day, 150 mg per day, 160 mg per day, 170 mg per day, 180 mg per day, 190 mg per day or 200 mg per day, and for another example, 80 mg per day.

[0144] In one embodiment, the administration frequency is 1 - 5 times per day, for example, 1 time per day, 2 times per day, 3 times per day, 4 times per day or 5 times per day, and for another example, 1 time per day.

[0145] In one embodiment, the administration course is 14 - 84 days per course, for example, 14 days per course, 28 days per course, 42 days per course, 56 days per course, 70 days per course or 84 days per course, and for another example, 28 days per course.

[0146] In one embodiment, the patient receives a total of 1 to 20 treatment courses, preferably 10 to 20 treatment courses. For example, the number of treatment courses can be 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20. As another example, the number of treatment courses is 12.

[0147] In one embodiment, the substance X or the pharmaceutical composition is a tablet.

[0148] In one embodiment, the specification of the substance X or the pharmaceutical composition is 10 - 120 mg / tablet. For example, it can be 20 - 100 mg / tablet. As another example, it can be 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. As yet another example, it can be 20 mg / tablet, 80 mg / tablet, or 100 mg / tablet.

[0149] In one embodiment, the patient is a patient with relapsed follicular lymphoma who has received one or more systemic treatment regimens. Preferably, the patient is a patient with relapsed follicular lymphoma who has received two or more systemic treatment regimens.

[0150] In one embodiment, the patient is a patient who has progressed after receiving second-line or above second-line systemic treatment. Preferably, the patient is a patient who has progressed after receiving CD20 monoclonal antibody and at least one alkylating agent, and the alkylating agent includes but is not limited to bendamustine, cyclophosphamide, ifosfamide, chlorambucil, melphalan, busulfan, nitrosourea.

[0151] In one embodiment, the patient's previous treatment regimens are R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone), BR (bendamustine, rituximab), and R-CVP (rituximab, cyclophosphamide, vincristine, prednisone).

[0152] In one embodiment, the pharmaceutical excipients are one or more of the conventional diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption promoters, surfactants, adsorption carriers, and lubricants in the pharmaceutical field.

[0153] The present invention provides an application of substance X in the preparation of an inhibitor for B-cell hematological tumors;

[0154] The substance X is a quinazoline compound represented by formula A, its pharmaceutically acceptable salt, its solvate, or a solvate of its pharmaceutically acceptable salt:

[0155]

[0156] In one embodiment, the B-cell hematologic tumor is B-cell lymphoma. Preferably, the B-cell lymphoma is non-Hodgkin lymphoma. More preferably, the non-Hodgkin lymphoma is follicular lymphoma. Most preferably, the follicular lymphoma is relapsed and / or refractory follicular lymphoma.

[0157] In one embodiment, the inhibitor can be used in mammalian organisms; it can also be used in vitro, mainly for experimental purposes, such as providing a comparison as a standard sample or control sample, or being made into a kit according to conventional methods in the art.

[0158] The "filler" used in the present invention, also known as "diluent", refers to a class of excipients used to increase the volume and weight of the pharmaceutical composition product dosage form in a scientific context. Therefore, the filler can 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.

[0159] The "disintegrant" used in the present invention refers to a class of excipients used to promote the pharmaceutical composition product dosage form to break into smaller fragments in an aqueous environment in a scientific context. Therefore, the disintegrant can be, for example: alginic acid, calcium alginate, calcium carboxymethylcellulose, chitosan, colloidal silicon dioxide, croscarmellose sodium, crospovidone, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, hypromellose, glycine, guar gum, hydroxypropyl cellulose, magnesium aluminum silicate, methyl cellulose, povidone, sodium alginate, sodium carboxymethylcellulose, sodium starch glycolate and starch.

[0160] The "lubricant" used in the present invention refers to a class of excipients used to improve the processing of the pharmaceutical composition product dosage form in a scientific context. Therefore, the lubricant can be, for example: calcium stearate, glycerol monostearate, glyceryl behenate, magnesium stearate, palmitic acid, poloxamer, polyethylene glycol, potassium benzoate, sodium benzoate, sodium lauryl sulfate, sodium stearate, sodium stearyl fumarate, stearic acid, talc, colloidal silica and zinc stearate.

[0161] The "coating agent" or "film coating premix" used in the present invention refers to a class of excipients used to improve the appearance of the pharmaceutical composition product dosage form in a scientific context. Therefore, the coating agent can be, for example: sucrose, lactose, hypromellose, hydroxypropyl ethyl cellulose, cellulose acetate phthalate, polyvinyl alcohol, polyvinyl acetate phthalate, hypromellose phthalate and acrylic resin.

[0162] The term "pharmaceutically acceptable salt" refers to a salt prepared from a compound of the present invention and a relatively non-toxic, pharmaceutically acceptable acid or base. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of a pharmaceutically acceptable base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include, but are not limited to: lithium salts, sodium salts, potassium salts, calcium salts, aluminum salts, magnesium salts, zinc salts, bismuth salts, ammonium salts, diethanolamine salts. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of a pharmaceutically acceptable acid in a pure solution or a suitable inert solvent. The pharmaceutically acceptable acids include inorganic acids, which include, but are not limited to: hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, phosphoric acid, phosphorous acid, sulfuric acid, etc. The pharmaceutically acceptable acids include organic acids, which include, but are 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, 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 (such as glutamic acid, arginine), etc. When a compound of the present invention contains both relatively acidic and relatively basic functional groups, it can be converted into a base addition salt or an acid addition salt. For details, see 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 Camille G. Wermuth, ed., Wiley-VCH, 2002).

[0163] The term "solvate" refers to a substance formed by the combination of a compound of the present invention with a stoichiometric or non-stoichiometric amount of a solvent. The solvent molecules in the solvate can exist in an ordered or disordered arrangement. The solvents include, but are not limited to: water, methanol, ethanol, etc.

[0164] The "pharmaceutically acceptable salt" and "solvate" in the term "solvate of a pharmaceutically acceptable salt" are as described above, and refer to a substance formed by the combination of a compound of the present invention with a relatively non-toxic, pharmaceutically acceptable acid or base and a stoichiometric or non-stoichiometric amount of a solvent.

[0165] The term "therapeutically effective amount" refers to the amount of a compound administered to a patient that is 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, etc., but can be adjusted by those skilled in the art according to the circumstances.

[0166] The term "pharmaceutical excipient" refers to excipients and additives used in the production of drugs and the formulation of prescriptions, and is all substances contained in pharmaceutical preparations except the active ingredient. For details, refer to the Pharmacopoeia of the People's Republic of China (2020 Edition) or Handbook of Pharmaceutical Excipients (Raymond C Rowe, 2009).

[0167] The term "treatment" refers to therapeutic treatment. When referring to a specific disease or disorder, treatment means: (1) alleviating one or more biological manifestations of the disease or disorder, (2) interfering with (a) one or more points in the biological cascade that causes or gives rise to the disorder or (b) one or more biological manifestations of the disorder, (3) improving 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.

[0168] The term "progression" refers to the situation where there is no remission or cure after the treatment of a disease, and instead, the condition even worsens.

[0169] The term "patient" refers to any animal that has received or is about to receive treatment, preferably a mammal, and most preferably a human. 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, etc., with humans being the most preferred.

[0170] On the basis of not violating the common knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain various preferred examples of the present invention.

[0171] The reagents and raw materials used in the present invention are all commercially available.

[0172] The positive and progressive effects of the present invention are as follows: The pharmaceutical composition of the present invention has good stability to high temperature, high humidity, and light, and can achieve rapid dissolution in 0.1 mol / L hydrochloric acid solution and pH 6.8 phosphate buffer solution containing 0.2% sodium dodecyl sulfate (SDS); moreover, the preparation method of the pharmaceutical composition of the present invention is simple and suitable for industrial production. Description of the Drawings

[0173] Figure 1 Dissolution curve of the pharmaceutical composition of the quinazoline compound shown by formula A provided for Examples 4 and 5 in the second part in 0.1 mol / L hydrochloric acid solution.

[0174] Figure 2 Dissolution curve of the pharmaceutical composition of the quinazoline compound shown in formula A provided for Examples 4 and 5 of the second part in a pH 6.8 phosphate buffer containing 0.2% SDS. Detailed implementation mode

[0175] First part:

[0176] Preparation Example 1: Synthetic route of the quinazoline compound shown in formula A.

[0177] The quinazoline compound shown in formula A 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.

[0178] Effect Example 1: In vitro inhibitory activity of the quinazoline compound shown in formula A and its analogs against PI3Kδ, and selectivity for other subtypes.

[0179] See paragraphs

[0538] -

[0549] of the specification of CN104557872A.

[0180] Effect Example 2: Pharmacokinetic evaluation of the quinazoline compound shown in formula A and its analogs

[0181] Experimental method:

[0182] Male SD rats were selected and divided into two groups. The intravenous administration group (iv) had a dose of 2 mg / kg, and the oral gavage administration group (po) had a dose of 10 mg / kg. After administration, blood samples were collected from both groups at time points of 0 h, 0.083 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h. Plasma was separated, and the concentration of the test compound in plasma after intravenous and gavage administration to rats was determined by LCMSMS method, and pharmacokinetic parameters were calculated. The results are shown in Table 1.

[0183] C max : Peak drug concentration, AUC last : Area under the concentration-time curve from 0 to the time point corresponding to the last measurable concentration, F%: Bioavailability.

[0184] Table 1: Summary table of inhibitory activity, selectivity and pharmacokinetic data of the quinazoline compound shown in formula A and its analogs against PI3Kδ

[0185]

[0186] --- indicates not tested.

[0187] In terms of the results, although several compounds all showed good PI3Kδ inhibitory activity in vitro and their structures were relatively close, there were significant differences in pharmacokinetics. For example, the quinazoline compound shown in Formula A had higher peak concentration at the same dose, area under the concentration-time curve from 0 to the last measurable concentration time point, and bioavailability.

[0188] Effect Example 3: Pharmacokinetic study of the quinazoline compound shown in Formula A

[0189] Results of the pharmacokinetic study of the quinazoline compound shown in Formula A in mice, rats and dogs

[0190] The results of the pharmacokinetic study of the quinazoline compound shown in Formula A in mice, rats and dogs showed good oral absorption within the effective dose range, and the oral bioavailability was above 90%, 65% and 60% respectively. After continuous administration for 7 days, 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 dose, indicating a relatively low risk of serious drug accumulation. The clearance rate of the quinazoline compound shown in Formula A in rats was moderate, while that in mice and dogs was slow. The quinazoline compound shown in Formula A had a wide tissue distribution. Except for the brain tissue, the exposure of the quinazoline compound shown in Formula A in other tissues was higher than that in plasma. There were certain gender differences in the tissue distribution of the quinazoline compound shown in Formula A. The results of in vitro inhibition, induction tests and recombinant enzyme stability tests showed that the quinazoline compound shown in Formula A had no obvious inhibitory or inductive effect on CYP enzymes. CYP3A4 was the main metabolic enzyme of the quinazoline compound shown in Formula A, followed by CYP2C8. The quinazoline compound shown in Formula A was extensively metabolized in vivo, but mainly excreted in vitro as the original drug through urine and feces, about 50%.

[0191] Table 2: Pharmacokinetic results after single oral gavage in ICR mice, SD rats and Beagle dogs

[0192]

[0193] Absorption

[0194] After gavage administration of the quinazoline compound shown in Formula A, it was well absorbed in mice, rats and Beagle dogs, and the oral bioavailability reached above 90%, 65% and 60% respectively. In the rat and dog experiments of different dose groups, the increase in plasma exposure and peak concentration of the quinazoline compound shown in Formula A was close to the proportion of dose increase, indicating that the quinazoline compound shown in Formula A had the characteristics of linear pharmacokinetics with the increase of dose.

[0195] Distribution

[0196] The results of in vitro plasma protein binding rate tests showed that for the quinazoline compounds represented by Formula A, the protein binding rates in mouse, rat, beagle dog, and human plasma were moderate (51.1 - 85.6%) within the concentration range of 0.1 - 30 μM; in monkey plasma, the protein binding rates were moderate (89.3 - 89.6%) at low and medium concentrations (0.1 - 2 μM), while the protein binding rate at high concentration (30 μM) was high (90.2%). The order of plasma protein binding rates of the quinazoline compounds represented by Formula A in five species from high to low was: cynomolgus monkey > human > CD1 mouse > SD rat > beagle dog, where the binding rates of cynomolgus monkey and human were similar (85 - 90%), and the binding rates of SD rat and beagle dog were similar (50 - 65%).

[0197] After single intravenous injection of 10, 10, and 1.0 mg / kg doses to ICR mice, SD rats, and beagle dogs respectively, the steady-state apparent volume of distribution (V ss , L / kg) of the quinazoline compounds represented by Formula A were 4.22 (male mice), 4.55 (male rats), 5.18 (female rats), 4.70 (male dogs), and 4.08 (female dogs) respectively, which were 5.82 (male mice), 6.80 (male rats), 7.75 (female rats), 7.79 (male dogs), and 6.76 (female dogs) times the total body fluid volume of each animal, indicating that the quinazoline compounds represented by Formula A had a relatively wide tissue distribution in each animal body.

[0198] After intragastric administration of 60 mg / kg to SD rats, the quinazoline compounds represented by Formula A were widely distributed to various tissues and organs. Except for the brain tissue, the exposure levels of the quinazoline compounds represented by Formula A in other tissues were significantly higher than those in plasma, about 2 - 22 times that of the latter. There were certain gender differences in the tissue distribution of the quinazoline compounds represented by Formula A. The plasma and tissue drug concentrations of male rats at each time point were higher than those of female rats. The exposure levels of the quinazoline compounds represented by Formula A in various tissues of male rats were about 1.49 - 3.70 times that of female rats. The half-lives of the quinazoline compounds represented by Formula A in various tissues of male rats were about 2.29 - 5.08 hr, and the half-lives in various tissues of female rats were about 2.25 - 4.45 hr (except for brain tissue). For male rats, the highest exposure level of the quinazoline compounds represented by Formula A was in the stomach, followed by small intestine, liver, kidney, lung, spleen, large intestine, thymus, heart, testis, skeletal muscle, fat, plasma, and brain. For female rats, the highest exposure level of the quinazoline compounds represented by 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.

[0199] Metabolism

[0200] The quinazoline compound shown in Formula A is relatively stable in the liver microsomes of mice, rats, dogs and humans (half-life > 120 minutes), and is moderately metabolized in the liver microsomes of monkeys (half-life = 30 - 120 minutes). In addition, no obvious metabolism was observed in the in vitro hepatocyte tests of the quinazoline compound shown in Formula A in mice, rats, dogs, monkeys and humans (half-life > 120 minutes).

[0201] Judging from the generation of metabolites mediated by various human recombinant enzymes, CYP3A4 is the main metabolic enzyme of the quinazoline compound shown in Formula A, followed by CYP2C8. Although there is a 20% - 30% reduction of the quinazoline compound shown in Formula A in the CYP2C8 incubation system, the same phenomenon also occurs in the two incubation systems of -NADPH and + inhibitor. Therefore, it cannot be explained that the metabolism of the parent drug depends on the recombinant enzyme CYP2C8.

[0202] The quinazoline compound shown in Formula A has no obvious inhibitory effect on CYP 1A2, 2B6, 2C8, 2C9, 2C19, 2D6 and 3A4 in human liver microsomes (IC 50 > 10 μM).

[0203] The quinazoline compound shown in Formula A did not show an enhancing effect on enzyme activity or mRNA expression in terms of CYP1A2, CYP2B6 and CYP3A4 at the three test concentrations of 0.4, 4 and 40 μM.

[0204] After single intravenous injection of doses of 10, 10 and 1.0 mg / kg to ICR mice, SD rats and beagle dogs respectively, the total clearance rates (CL, L / hr / kg) of the quinazoline compound shown in 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) of the hepatic blood flow in each animal body respectively, suggesting that mice and dogs have relatively weak metabolic clearance ability for the quinazoline compound shown in Formula A.

[0205] Judging from the types and relative contents of metabolites generated in liver microsomes and combining with the metabolic stability of the quinazoline compound shown in Formula A in liver microsomes, the selection of rats and dogs for the safety evaluation of rodent and non-rodent experimental animals meets the requirements of preclinical safety evaluation of drugs.

[0206] Excretion

[0207] After intragastric administration of 60 mg / kg of the quinazoline compound shown in Formula A to SD rats, the excretion amounts of the quinazoline compound shown in Formula A in male rat urine, feces, and bile within 0 - 72 hours were 20.1 ± 6.48%, 24.5 ± 11.1%, and 1.68 ± 0.890% of the administered dose, respectively; while its excretion amounts in female rat urine, feces, and bile within 0 - 72 hours were 8.11 ± 2.62%, 7.58 ± 3.95%, and 10.9 ± 1.29% of the administered dose, respectively. Therefore, the total excretion rates of the quinazoline compound shown in Formula A in male and female SD rats' urine, feces, and bile after intragastric administration were 46.3% and 26.6%, respectively.

[0208] After intragastric administration of 10 mg / kg of the quinazoline compound shown in Formula A to beagle dogs, the excretion amounts of the quinazoline compound shown in Formula A in male dog urine and feces were 29.2 ± 13.5% and 19.5 ± 16.2% of the administered dose, respectively, and its excretion amounts in female dog urine and feces were 41.4 ± 12.4% and 9.21 ± 7.08% of the administered dose, respectively. Therefore, the total excretion rates of the quinazoline compound shown in Formula A in male and female beagle dogs' urine and feces after intragastric administration were 48.7% and 50.6%, respectively.

[0209] Effect Example 4: Inhibitory Activity of the Quinazoline Compound Shown in Formula A against Different Cells

[0210] Experimental Method:

[0211] Add 100 μl of the cell suspension to be tested (except for the peripheral wells) into a 96-well plate. Place the culture plate in a carbon dioxide incubator overnight. Add the prepared quinazoline compound shown in Formula A (starting concentration of 50 μM, and 10 concentration gradients of the quinazoline compound shown in Formula A are obtained by 3-fold dilution) to each well. Incubate the cell plate in a carbon dioxide incubator for 72 hours. Add 25 μl of CellTiter Glo reagent to the 96-well plate, shake it in the dark for 2 minutes, let it stand in the dark at room temperature for 10 minutes, put the culture plate into a microplate reader to read the chemiluminescence value, and use XLFit to draw the pharmacodynamic inhibition rate curve and calculate the IC 50 value.

[0212] The effect of the quinazoline compound shown in Formula A on cell proliferation was detected in different tumor cells. The results showed that the quinazoline compound shown in Formula A had obvious inhibitory activity in some hematological tumor cells. For example, the IC 50 value in SU-DHL-6 cells was 0.2337 μM, and the IC 50 value in SU-DHL-5 cells was 1.7683 μM.

[0213] Effect Example 5: In Vivo Activity Evaluation of Quinazoline Compounds Shown by Formula A against SU-DHL-6 Subcutaneous Xenograft Tumor Model

[0214] Experimental Method:

[0215] CB17 SCID mice, female, weighing 18 - 22 g. SU-DHL-6 cells were cultured in suspension in vitro. The culture conditions were RPMI1640 medium supplemented with 10% heat-inactivated fetal bovine serum, 100 U / ml penicillin, and 100 μg / ml streptomycin at 37°C with 5% CO 2 cultivation. Passage was carried out twice a week. When the cells were in the exponential growth phase, the cells were harvested for inoculation. A 0.2 ml cell suspension containing 5 x 10^6 SU-DHL-6 cells (the cells were suspended in base RPMI1640 medium, RPMI1640:Matrigel = 100 μl:100 μl) was subcutaneously inoculated into the right back of each mouse. When the average tumor volume reached 95.79 mm 3 treatment began. Grouping method: The animals were weighed before dosing, and the tumor volume was measured. Random grouping was performed according to the tumor volume (random grouping design). The grouping and dosing regimens are shown in Table 3 below. The experimental index was to examine whether tumor growth could be inhibited, delayed, or cured. The tumor diameter was measured twice a week with a vernier caliper. The formula for calculating the tumor volume was: V = 0.5a × b 2 , where a and b represent the long and short diameters of the tumor, respectively. The antitumor efficacy of the compound was evaluated by TGI (%). TGI (%) reflects the tumor growth inhibition rate. Calculation of TGI (%): TGI (%) = [1 - (tumor volume at the end of treatment in the treatment group - tumor volume at the start of treatment in the treatment group) / (tumor volume at the end of treatment in the solvent control group - tumor volume at the start of treatment in the solvent control group)] × 100%. A drug was considered effective when TGI ≥ 58%; a drug was considered highly effective when TGI ≥ 90%.

[0216] Table 3: Table of Animal Grouping and Dosing Regimens for In Vivo Pharmacodynamic Experiments

[0217]

[0218] Results showed that on day 15 after dosing, the TGI of the CAL-101 (i.e., Idelalisib) 50 mg / kg BID treatment group, the quinazoline compound as shown in formula A 60 mg / kg QD group, the quinazoline compound as shown in formula A 120 mg / kg QD group, and the quinazoline compound as shown in formula A 240 mg / kg QD group were 42.67%, 71.89%, 81.57% and 86.98% respectively. Two-way ANOVA statistical analysis showed that the tumor volumes of the CAL-101 50 mg / kg BID group, the quinazoline compound as shown in formula A 60 mg / kg QD group, the quinazoline compound as shown in formula A 120 mg / kg QD group, and the quinazoline compound as shown in formula A 240 mg / kg QD group on Day 15 were significantly smaller than those of the vehicle control group (P values were all < 0.01). The quinazoline compound as shown in formula A could be tolerated by tumor-bearing mice at three treatment doses. The results of tumor volume and weight both showed that the treatment with the quinazoline compound as shown in formula A at 60 mg / kg QD, the quinazoline compound as shown in formula A at 120 mg / kg QD, and the quinazoline compound as shown in formula A at 240 mg / kg QD had a significant inhibitory effect on the growth of subcutaneous xenograft tumors of SU-DHL-6 human lymphoma cells.

[0219] Effect Example 6: Clinical Phase I and Phase II data of the quinazoline compound as shown in formula A

[0220] (1) Design of Phase I clinical protocol (escalation and expansion protocol)

[0221] The inclusion criteria for patients were patients with histologically or cytologically confirmed relapsed or refractory B-cell hematological malignancies. A total of 25 patients were included, among which 10 had follicular lymphoma.

[0222] This study was divided into two phases: dose escalation and dose expansion; each phase included single-dose and multiple-dose studies. The 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 20 mg initial dose group with only 1 subject enrolled, each dose group enrolled 3 - 6 subjects respectively, the 40 mg dose group enrolled 3 subjects, the 80 mg dose group enrolled 3 subjects, the 140 mg dose group enrolled 3 subjects, and the 200 mg dose group enrolled 4 subjects; among them, 1 case of follicular lymphoma was enrolled in the 40 mg and 200 mg groups respectively, and 2 cases were enrolled in the 80 mg group. After the tolerance test was completed, a dose expansion test 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.

[0223] The administration method is: oral administration, once a day during continuous administration until disease progression or intolerable toxicity.

[0224] The quinazoline compound tablets as shown in Formula A are coated tablets prepared by a direct compression process of powder mixing, and are prepared according to the processes described in Preparation Example 1 and Preparation Example 2 in Part Two. The formulation is the formulation of Example 5 in Part Two, and 20 mg or 100 mg tablets are prepared.

[0225] (2) Results and effects of Phase I trial

[0226] The quinazoline compound tablets as shown in Formula A demonstrated good anti-tumor activity in patients with relapsed or refractory B-cell malignant hematological tumors, especially showed very good efficacy in follicular lymphoma. The results are shown in the following table. Among 25 subjects, the best overall efficacy: 5 cases of CR, 11 cases of PR, 2 cases of SD, 7 cases of PD. The overall optimal efficacy ORR ratio was 64% (16 / 25) (95% CI: 45.2 - 82.8%), and the DCR ratio was 72% (18 / 25) (95% CI: 54.4 - 89.6%). Among them, the ORR and DCR ratios of the optimal efficacy in follicular lymphoma were both 90.0% (9 / 10).

[0227] Overall response rate (ORR); Disease control rate (DCR); CR = Complete remission; PR = Partial remission; SD = Stable disease; PD = Progressive disease.

[0228] The efficacy evaluation criteria for B-cell lymphoma refer to "Efficacy Evaluation Criteria for Lymphoma IRWG (Excerpt), Revised Criteria for Efficacy Evaluation of Malignant Lymphoma".

[0229] Table 4: Statistical Table of Optimal Efficacy

[0230]

[0231] (3) Phase I safety effect data

[0232] The inclusion criteria for patients were those with histologically or cytologically confirmed relapsed or refractory B-cell hematological malignancies. A total of 25 patients were included, among whom 10 had follicular lymphoma. This study was divided into two phases: dose escalation and dose expansion; each phase included single-dose and multiple-dose studies. The doses in the dose escalation phase included 20 mg / day, 40 mg / day, 80 mg / day, 140 mg / day, and 200 mg / day. Except for the initial dose group of 20 mg which only enrolled 1 case, each dose group enrolled 3 - 6 subjects respectively. The 40 mg dose group enrolled 3 cases, the 80 mg dose group enrolled 3 cases, the 140 mg dose group enrolled 3 cases, and the 200 mg dose group enrolled 4 cases. The dose expansion study was conducted in the 80 mg dose group. No dose-limiting toxicity (DLT) occurred during the 28-day observation period. From the occurrence of adverse events, the quinazoline compound tablets shown in Formula A had good tolerance for single-dose and multiple-dose administrations.

[0233] According to the results of Phase I clinical trials, it was demonstrated that the quinazoline compound shown in Formula A had good and controllable safety.

[0234] Based on preclinical results, a single-arm, open-label, single-dose and multiple-dose, dose-escalation tolerance and pharmacokinetics Phase I clinical study of the quinazoline compound shown in Formula A was carried out in patients with relapsed or refractory B-cell hematological malignancies who were ineffective under conventional standard treatment or lacked standard treatment. The study results indicated that the quinazoline compound shown in Formula A had controllable safety and good tolerance.

[0235] In summary, the quinazoline compound shown in Formula A was safe and tolerable within the dose range of 20 - 200 mg, could relieve and control the progression of relapsed or refractory B-cell malignancies, and also showed very good efficacy in follicular lymphoma.

[0236] (4) Comparison of data of marketed drugs with the same target

[0237] Currently, the objective response rate (ORR) of the PI3kδ inhibitor Idelalisib approved by the FDA for the treatment of relapsed and refractory follicular lymphoma is 39%, while the ORR of the PI3Kγ,δ inhibitor Duvelisib for the treatment of relapsed and refractory follicular lymphoma is 42%; the ORR of Copanlisib for the treatment of relapsed and refractory follicular lymphoma is 59%. (Data obtained from the product labels of marketed drugs).

[0238] The ORR of the quinazoline compound shown in Formula A for the optimal efficacy in the treatment of follicular lymphoma in Phase I clinical trials was 90.0% (9 / 10). In a single-arm, open-label, multicenter Phase II clinical trial of the quinazoline compound shown in Formula A for the treatment of patients with relapsed and / or refractory follicular lymphoma, the inclusion criteria were progression after receiving second-line or above systemic treatment (had received CD20 monoclonal antibody and at least one alkylating agent, and the alkylating agents included but were not limited to bendamustine, cyclophosphamide, ifosfamide, chlorambucil, melphalan, busulfan, nitrosourea), and 93 subjects were enrolled. The subjects took the quinazoline compound tablets shown in Formula A once a day, administered orally, 4 tablets of 20 mg each time, until disease progression or intolerable toxicity. Imaging evaluations were performed on at least one occasion for 89 subjects, and the results of independent data evaluation (IRWG lymphoma efficacy evaluation criteria) showed that the quinazoline compound shown in Formula A had an ORR of more than 80% in 89 patients with relapsed / refractory follicular lymphoma (evaluable cases). From the statistical analysis, the ORR increased from about 50% of similar drugs to about 80%, showing a significant advantage over similar drugs.

[0239] The second part

[0240] The quinazoline compound shown in 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.

[0241] The materials used in the following examples are shown in the following table:

[0242]

[0243]

[0244] The equipment used in the following examples is shown in the following table:

[0245]

[0246] In Examples 1, 2, 3A, and 3B, the dissolution method was carried out according to Method 2 of General Chapter 0931 in Volume IV of the Chinese Pharmacopoeia (2015 Edition), using 900 ml of pH 6.8 phosphate buffer containing 0.2% SDS at 37°C as the dissolution medium, with a rotation speed of 75 revolutions per minute. Samples were taken at appropriate time intervals, the same volume of dissolution medium was replenished, filtered through a 0.45 μm filter membrane, and the dissolution rate was calculated by high-performance liquid chromatography to determine the content.

[0247] For the experimental methods without specific conditions indicated in the following examples, they were carried out according to conventional methods and conditions, or selected according to the product instructions.

[0248] Preparation Example 1, Preparation of tablet cores

[0249] Weigh the prescription amounts of the quinazoline compound shown in Formula A and each excipient according to the designed prescription composition. Pass the quinazoline compound shown in Formula A, the filler, and the disintegrant through a 30-mesh sieve respectively, and pass the lubricant through a 60-mesh sieve; mix the quinazoline compound shown in Formula A and the filler evenly in a mixer to obtain Premix 1; add the disintegrant to Premix 1 and mix evenly using a mixer to obtain Premix 2; sieve Premix 2 using a granulator to obtain Premix 3; mix Premix 3 and the lubricant in a mixer to obtain the total mixed material; use a rotary tablet press equipped with a 5-mm, D-type round die or an 11*5.5-mm, upper punch engraved with a Half-line key die to press the total mixed material to form tablet cores containing 20 mg or 100 mg of the quinazoline compound shown in Formula A respectively.

[0250] Preparation Example 2, Preparation of Film-Coated Tablets

[0251] Add the film coating premix powder to the purified water under stirring and continuously stir for 45 minutes to prepare a coating solution with a solid content of 10% (w / w) of the film coating premix. Use a high-efficiency coating machine to coat the tablet cores manufactured by the process described in Preparation Example 1 above until the coating weight gain ranges from 2% to 5% to form film-coated tablets containing 20 mg or 100 mg of the quinazoline compound shown in Formula A respectively.

[0252] Example 1, Tablet Core Prescriptions F1-F8

[0253] The type and amount of the disintegrant directly affect the disintegration of the tablets and the release rate of the drug active ingredient. The prescription compositions F1-F8 with crospovidone, sodium carboxymethylcellulose cross-linked, and low-substituted hydroxypropyl cellulose as the disintegrant were screened respectively, and the amount of the disintegrant in the prescription was screened. Use the process described in Preparation Example 1 above to manufacture the pharmaceutical composition to obtain tablet cores containing 20 mg of the quinazoline compound shown in Formula A respectively. Taking the smoothness of tablet ejection during the tableting process and the dissolution rate as the evaluation indexes, the prescription compositions and results are shown in Table 5 below.

[0254] Table 5. Prescriptions F1-F8 and Results

[0255]

[0256]

[0257] ― indicates not used.

[0258] Experimental results: The tabletting process of Formulations F1 - F8 was smooth and there was no sticking phenomenon. The cores of Formulations F1 - F6, which used only crospovidone or only sodium carboxymethylcellulose as the disintegrant, disintegrated rapidly, and the quinazoline compound shown in Formula A dissolved quickly, with the cumulative dissolution exceeding 90% at 30 minutes; for Formulations F7 and F8 in which low-substituted hydroxypropyl cellulose was added to the disintegrant, the core disintegration was slow, and the dissolution rate of the quinazoline compound shown in Formula A was very slow, with the cumulative dissolution only being 72% and 67% at 30 minutes.

[0259] Example 2, Film-Coated Tablet Formulations F9 - F10

[0260] The amount of lubricant can affect the smoothness of tabletting and the dissolution rate of the active pharmaceutical ingredient. Based on the optimal dissolution Formulation F5 in Example 1, different amounts of magnesium stearate were screened as the lubricant for Formulation Compositions F9 and F10. The drug compositions were manufactured using the process described in Preparation Example 1 above to obtain cores containing 20 mg of the quinazoline compound shown in Formula A. A film coating premix was prepared ( Ⅰ) A coating solution with a solids content of 10% (w / w) was used to coat the cores with a high-efficiency coating machine (BGB-5F, Zhejiang Xiaolun Pharmaceutical Machinery Co., Ltd.) to give film-coated tablets containing 20 mg of the quinazoline compound shown in Formula A with a coating weight gain of approximately 3.5% for Formulations F9 and F10 respectively. Using the smoothness of tablet ejection during tabletting and dissolution as the evaluation indicators, the formulation compositions and results of the film-coated tablets in Example 2 (before coating) are shown in Table 6 below.

[0261] Table 6. Formulations F9 - F10 and Results

[0262]

[0263]

[0264] Experimental results: The tabletting process of Formulations F9 and F10 was smooth and there was no sticking phenomenon. The film-coated tablets disintegrated rapidly, and the dissolution rates of the quinazoline compound shown in Formula A were basically the same, with the cumulative dissolution being 88% and 92% at 30 minutes respectively, both meeting the release standard for finished product dissolution (≥70%).

[0265] Example 3A and 3B, Preparation of Film-Coated Tablets (20 mg specification, 20,000 tablets)

[0266] The drug compositions were manufactured using the process described in Preparation Example 1 above to obtain cores containing 20 mg of the quinazoline compound shown in Formula A. A film coating premix was prepared ( Ⅰ) A film coating solution with a solid content of 10% (w / w) was used. An efficient film coating machine (BGB-5F, Zhejiang Xiaolun Pharmaceutical Machinery Co., Ltd.) was employed to coat the tablet cores with a coating weight gain range of 2% - 5%. Approximately 20,000 film-coated tablets containing 20 mg of the quinazoline compound shown in Formula A with a coating weight gain of 2.5% were prepared for Example 3A, and approximately 20,000 film-coated tablets containing 20 mg of the quinazoline compound shown in Formula A with a coating weight gain of 4.5% were prepared for Example 3B. The batch prescription amounts of the film-coated tablets of Example 3A and 3B (before coating) are shown in Table 7 below.

[0267] Table 7. Prescription of Film-Coated Tablets Manufactured in Example 3A and 3B (Before Coating) (20 mg Specification, 20,000 Tablets)

[0268]

[0269] The dissolution results of the film-coated tablets of Example 3A and 3B in a pH 6.8 phosphate buffer solution containing 0.2% SDS are shown in Table 8 below. The results indicate that the 20 mg specification film-coated tablets with coating weight gains of 2.5% and 4.5% respectively disintegrate rapidly, and the dissolution rates of the quinazoline compound shown in Formula A are basically the same. The cumulative dissolutions at 30 minutes are 93% and 92% respectively, both meeting the release standard of the finished product dissolution (≥70%).

[0270] Table 8. Dissolution Results of Film-Coated Tablets Manufactured in Example 3A and 3B in a pH 6.8 Phosphate Buffer Solution Containing 0.2% SDS

[0271]

[0272] Example 4: Preparation of Pilot-Scale Film-Coated Tablets (20 mg Specification, 300,000 Tablets)

[0273] The powder direct compression process was used to manufacture the pilot-scale pharmaceutical composition. The quinazoline compound shown in Formula A, the filler, and the disintegrant were each passed through a 30-mesh sieve, and the lubricant was passed through a 60-mesh sieve; the quinazoline compound shown in Formula A and the filler were mixed evenly in a 50-liter hopper mixer (Model HBD200, Nantong Bete Pharmaceutical Machinery Co., Ltd.) to obtain Premix 1; the disintegrant was added to Premix 1 and mixed evenly using the hopper mixer to obtain Premix 2; Premix 2 was sieved using a granulator (Comil U10, QUADRO, Canada) equipped with a 032R sieve and a square impeller to obtain Premix 3; Premix 3 and the lubricant were mixed in the hopper mixer to obtain the total mixed material; the total mixed material was compressed into tablet cores containing 20 mg of the quinazoline compound shown in Formula A using a rotary tablet press (P2020, Fette, Germany) equipped with 5 mm D-type round punches. A film coating premix was prepared ( Ⅰ) A film coating solution 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 gain reached 3.5%, obtaining pilot-scale film-coated tablets containing 20 mg of the quinazoline compound shown in Formula A.

[0274] The batch prescription amounts of the film-coated tablets of Example 4 are shown in Table 9 below.

[0275] Table 9. Prescription of Pilot-Scale Film-Coated Tablets (20 mg Specification, 300,000 tablets)

[0276]

[0277] a : Calculated at a coating efficiency of 50% during the manufacturing process, the actual batch prescription usage amount is 1.050 Kg.

[0278] b : Calculated at a coating efficiency of 50% during the manufacturing process, the actual batch prescription usage amount is 9.450 Kg, and the purified water is removed during the coating process.

[0279] Example 5: Preparation of 100 mg Specification Film-Coated Tablets

[0280] The method described in Preparation Example 1 above was used to manufacture the pharmaceutical composition, obtaining tablet cores containing 100 mg of the quinazoline compound shown in Formula A. A film coating premix was prepared ( Ⅰ) A film coating solution with a solid content of 10% (w / w) was used to coat the tablet cores with a high-efficiency coating machine until the coating weight gain reached 3.5%, obtaining film-coated tablets containing 100 mg of the quinazoline compound shown in Formula A. The batch prescription amounts of the film-coated tablets of Example 6 are shown in Table 10 below.

[0281] Table 10. Prescription of 100 mg Specification Film-Coated Tablets

[0282]

[0283] a : Calculated at a coating efficiency of 50% during the manufacturing process, the actual batch prescription usage amount is 0.264 Kg.

[0284] b : Calculated at a coating efficiency of 50% during the manufacturing process, the actual batch prescription usage amount is 2.376 Kg, and the purified water is removed during the coating process.

[0285] Test Example 1: Determination of Key Quality Attributes of the Pharmaceutical Composition

[0286] The key quality attributes of the drug were determined for the pharmaceutical composition prepared in Example 4 above. The assessment items included appearance, content uniformity, content, related substances, and dissolution. The assessment results are shown in Table 11 below.

[0287] Appearance: Visually observe and record the appearance of the film-coated tablets and the core tablets after removing the coating.

[0288] Content uniformity: Take 10 test samples and, according to the high-performance liquid chromatography method under the content determination conditions, determine the relative content xi of each single dose with a labeled amount of 100. According to the content uniformity test method (General Chapter 0941, Volume IV, Chinese Pharmacopoeia 2015 Edition), calculate A + 2.2S.

[0289] Related substances and content determination: According to the high-performance liquid chromatography method (General Chapter 0512, Volume IV, Chinese Pharmacopoeia 2015 Edition), the main component external standard method with response factor addition is used to calculate the contents of known impurities, unknown impurities, and total impurities of the quinazoline compound shown in Formula A in the pharmaceutical composition by peak area (reporting limit: 0.05%); the external standard method is used to calculate the content of the quinazoline compound shown in Formula A in the pharmaceutical composition by peak area.

[0290] Dissolution: According to the dissolution test method (Second Method in General Chapter 0931, Volume IV, Chinese Pharmacopoeia 2015 Edition), use 900 ml of pH 6.8 phosphate buffer solution containing 0.2% SDS as the dissolution medium, with a rotation speed of 75 revolutions per minute. Take 6 test samples and place 1 sample in each dissolution cup. After 30 minutes, take 10 ml of the solution, filter it through a 0.45 μm filter membrane, and determine the content by high-performance liquid chromatography to calculate the dissolution of the quinazoline compound shown in Formula A.

[0291] Table 11. Assessment Results of Key Quality Attributes of the Pharmaceutical Composition Prepared in Example 4

[0292]

[0293]

[0294] Experimental results: The assessment results of each key quality attribute of the film-coated tablets containing 20 mg of the quinazoline compound shown in Formula A prepared in Example 4 all meet the quality standards for finished product release.

[0295] Test Example 2: Determination of the dissolution curve of the pharmaceutical composition

[0296] The dissolution curves of the pharmaceutical compositions prepared in Examples 4 and 5 above were determined respectively.

[0297] According to the dissolution test method (the second method in General Chapter 0931, Volume IV of the Chinese Pharmacopoeia (2015 Edition)), the rotation speed is 75 revolutions per minute. Using 0.1 mol / L hydrochloric acid solution (9 ml of hydrochloric acid, diluted with water to 1000 ml) or 900 ml of pH 6.8 phosphate buffer solution containing 0.2% SDS as the dissolution medium, 6 tablets of the test samples are taken from the film-coated tablets manufactured in each example, and 1 tablet is placed in each dissolution cup. Samples are taken at appropriate time intervals, and the same volume of dissolution medium is added for compensation. The samples are filtered through a 0.45 μm filter membrane, and the cumulative dissolution rate of the quinazoline compound shown in Formula A is calculated by high-performance liquid chromatography. The test results are shown in Table 12 below and in the appendix Figure 1 - 2 as shown.

[0298] Table 12. Dissolution Curve Test Results of the Pharmaceutical Compositions Manufactured in Examples 4 and 5

[0299]

[0300] Experimental Results: In 0.1 mol / L hydrochloric acid solution, the film-coated tablets of 20 mg and 100 mg specifications can be dissolved rapidly and completely, and the cumulative dissolution reaches 100% in 30 minutes. In the pH 6.8 phosphate buffer solution containing 0.2% SDS, the dissolution rate of the film-coated tablets of 100 mg specification is slightly slower than that of 20 mg specification, and the cumulative dissolution is 88% in 30 minutes, meeting the release standard of the finished product dissolution (≥70%).

[0301] Effect Example 1: Stress Test

[0302] The pharmaceutical composition manufactured in Example 4 was placed naked under the stress conditions of high temperature (60 °C), high humidity (25 ± 2 °C, RH 92.5%), and light (4500 ± 500 Lux) for 30 days for assessment. The stability of the pharmaceutical composition was evaluated according to the test method in Test Example 1 above, and the evaluation indicators included appearance, related substances, dissolution, and content. The specific results are shown in Tables 13 - 15 below.

[0303] Table 13. Summary of High Temperature Stress Test Results of the Pharmaceutical Composition Manufactured in Example 4

[0304]

[0305]

[0306] Table 14. Summary of High Humidity Stress Test Results of the Pharmaceutical Composition Manufactured in Example 4

[0307]

[0308]

[0309] aMoisture absorption weight gain is an inspection item for the high humidity influencing factor test, without limit requirements.

[0310] Table 15. Summary of the results of the light influencing factor test of the pharmaceutical composition prepared in Example 4

[0311]

[0312]

[0313] The results in Tables 13 - 15 show that for the pharmaceutical composition of the quinazoline compound shown by Formula A provided by the present invention, after being placed naked for 5 days, 10 days, and 30 days respectively under the conditions of high temperature, high humidity, and light influencing factors, when measured, all the assessment indicators of the pharmaceutical composition have no obvious changes compared with those before the influencing factor test. After being placed for 30 days under high humidity conditions, the pharmaceutical composition has no obvious moisture absorption weight gain.

[0314] It should be understood that the embodiments described in the present invention are only for illustrative purposes. Through the embodiments, it will be helpful to further understand the present invention, but not for limiting the content of the present invention. For those skilled in the art, many changes to both materials and methods can be implemented without departing from the scope of the present invention, and these changes or improvements are included within the gist and scope of this application and the scope of the appended claims.

Claims

1. A pharmaceutical composition, characterized in that, the pharmaceutical composition comprises the following components by weight: 1) 40%-50% of a quinazoline compound represented by formula A; 2) 45%-55% of a filler, and the filler is one, two or more of microcrystalline cellulose, mannitol and corn starch; 3) 4%-8% of a disintegrant, and the disintegrant is crospovidone and / or sodium carboxymethylcellulose crosslinked; 4) 0.8%-1.4% of a lubricant, and the lubricant is magnesium stearate; 2. The pharmaceutical composition according to claim 1, characterized in that, the pharmaceutical composition is a medicament for treating B-cell hematological tumors; and / or, the pharmaceutical composition is a tablet; and / or, based on the content of the quinazoline compound represented by formula A, the administration dose of the pharmaceutical composition is 0.33 mg / kg - 3.33 mg / kg per time; and / or, based on the content of the quinazoline compound represented by formula A, the administration dose of the pharmaceutical composition is 20 mg - 200 mg per day; and / or, the administration frequency of the 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 1 - 20 courses in total; and / or, in the unit dosage form of the pharmaceutical composition, the content of the quinazoline compound represented by formula A is 5 mg - 500 mg; and / or, the pharmaceutical composition is administered to patients whose previous treatment regimen was progressive after receiving systemic treatment above the second line, and the systemic treatment above the second line was receiving CD20 monoclonal antibody and at least one alkylating agent; and / or, the administration object of the pharmaceutical composition is human.

3. The pharmaceutical composition according to claim 2, characterized in that, when the pharmaceutical composition is a tablet, the tablet is a coated tablet; and / or, when the pharmaceutical composition is a medicament for treating B-cell hematological tumors, the B-cell hematological tumor is B-cell lymphoma; and / or, based on the content of the quinazoline compound represented by formula A, the administration dose of the pharmaceutical composition is 0.66 mg / kg - 2.3 mg / kg per time; and / or, based on the content of the quinazoline compound represented by formula A, the administration dose of the pharmaceutical composition is 20 mg per day, 30 mg per day, 40 mg per day, 50 mg per day, 60 mg per day, 70 mg per day, 80 mg per day, 90 mg per day, 100 mg per day, 110 mg per day, 120 mg per day, 130 mg per day, 140 mg per day, 150 mg per day, 160 mg per day, 170 mg per day, 180 mg per day, 190 mg per day or 200 mg per day; and / or, the administration frequency of the pharmaceutical composition is 1 time per day, 2 times per day, 3 times per day, 4 times per day or 5 times per day; and / or, the administration course of the pharmaceutical composition is 14 days per course, 28 days per course, 42 days per course, 56 days per course, 70 days per course or 84 days per course; And / or, the pharmaceutical composition is administered for a total of 10 - 20 treatment courses; And / or, in the unit dosage form of the pharmaceutical composition, the content of the quinazoline compound shown in formula A is 10 mg - 120 mg; And / or, the pharmaceutical composition is administered to patients whose previous treatment regimen was progressive after receiving systemic treatment above the second line. The systemic treatment above the second line was receiving CD20 monoclonal antibody and at least one alkylating agent, and the alkylating agents include bendamustine, cyclophosphamide, ifosfamide, chlorambucil, melphalan, and busulfan.

4. The pharmaceutical composition according to claim 3, wherein, 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, the disintegrant is crospovidone or croscarmellose sodium; And / or, when the tablet is a coated tablet, the coated tablet is a film-coated tablet; And / or, when the B-cell hematologic tumor is B-cell lymphoma, the B-cell lymphoma is non-Hodgkin lymphoma; And / or, based on the content of the quinazoline compound shown in formula A, the administration dose of the pharmaceutical composition is 1 mg / kg, 1.2 mg / kg, 1.3 mg / kg, 1.33 mg / kg, 1.4 mg / 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 per time; And / or, the pharmaceutical composition is administered for a total of 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 treatment courses; And / or, in the unit dosage form of the pharmaceutical composition, the content of the quinazoline compound shown in formula A is 20 - 100 mg; And / or, the pharmaceutical composition is administered to patients whose previous treatment regimen was receiving one or more of the treatment regimens of R-CHOP, BR, and R-CVP.

5. The pharmaceutical composition according to claim 4, wherein, when the filler is a mixture of microcrystalline cellulose and mannitol, the mass ratio of the microcrystalline cellulose to the mannitol is 6:1 - 2:1; And / or, when the coated tablet is a film-coated tablet, in the film-coated tablet, the weight gain of the coating agent compared to the weight of the tablet core is 2% - 5%; And / or, when the B-cell lymphoma is non-Hodgkin lymphoma, the non-Hodgkin lymphoma is follicular lymphoma; And / or, in the unit dosage form of the pharmaceutical composition, the content of the quinazoline compound shown in formula A is 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg.

6. The pharmaceutical composition according to claim 5, wherein, the quinazoline compound shown in formula A accounts for 40% of the total weight of the pharmaceutical composition by weight; And / or, the filler is 52.8% by weight of the total weight of the pharmaceutical composition; And / or, the disintegrant is 6% by weight of the total weight of the pharmaceutical composition; And / or, the lubricant is 1.2% by weight of the total weight of the pharmaceutical composition; And / or, when the coated tablet is a film-coated tablet, in the film-coated tablet, the weight gain of the coating agent is 2.5% - 4.5% compared to the weight of the tablet core; And / or, when the non-Hodgkin lymphoma is follicular lymphoma, the follicular lymphoma is relapsed and / or refractory follicular lymphoma; And / or, the pharmaceutical composition is administered to patients with relapsed or refractory follicular lymphoma who have received more than one systemic treatment regimen.

7. The pharmaceutical composition according to claim 1, wherein, the pharmaceutical composition comprises the following components by weight: or, or, or, or, or, 。 8. The pharmaceutical composition according to claim 7, wherein, the pharmaceutical composition consists of the following components as follows: or, the pharmaceutical composition, which comprises two parts: a tablet core and a coating, and each contains the following components by weight: Tablet core: 1) 40% of the quinazoline compound shown in formula A; 2) 40% of microcrystalline cellulose and 12.8% of mannitol; 3) 6% of croscarmellose sodium; 4) 1.2% of magnesium stearate; Coating: 5) The weight gain of the coating agent is 3.5% compared to the weight of the tablet core.

9. A method for preparing a pharmaceutical composition according to any one of claims 1-8, which is prepared by direct tableting of the powders of the components of the pharmaceutical composition according to any one of claims 1-8 to obtain the pharmaceutical composition.

10. The preparation method according to claim 9, comprising the following steps: 1) Pretreatment Pass the quinazoline compound shown in formula A, the filler, and the disintegrant through a 30-mesh sieve respectively, and pass the lubricant through a 60-mesh sieve; 2) Total mixing According to the prescription amount, mix the quinazoline compound shown in formula A obtained in step 1) with the filler in a mixer to obtain premix 1; Mix premix 1 with the disintegrant in a mixer to obtain premix 2; pass premix 2 through a sieve using a granulator to obtain premix 3; Mix premix 3 and the lubricant in a mixer to obtain the total mixed material; 3) Tablet the total mixed material obtained in step 2) to obtain the tablet core; 4) Prepare a 10% film coating premix coating solution and coat the tablet core obtained in step 3).

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