WO2021115425A1 - Pharmaceutical composition containing bpi-7711 and preparation method thereof - Google Patents

Abstract

Disclosed is a pharmaceutical composition containing a pharmaceutically acceptable salt of the compound of formula I, a diluent, a disintegrant and a lubricant. The pharmaceutical composition can dissolve extremely quickly, has high drug bioavailability and stable quality. In addition, the pharmaceutical composition can be prepared by a direct powder filling method, which is suitable for industrial production.

Description

Medicinal composition containing BPI-7711 and preparation method thereof Technical field

The invention relates to a pharmaceutical composition containing BPI-7711 and a preparation method thereof, and belongs to the technical field of pharmaceutical preparations.

Background technique

Epidermal growth factor receptors (EGFR, Her1, ErbB1) are the main members of the ErbB family of four structurally related cell surface receptors. Other members are Her2 (Neu, ErbB2), Her3 (ErbB3) and Her4 (ErbB4). EGFR exerts its main cellular functions through its inherent catalytic tyrosine protein kinase activity. The receptor is activated by binding to growth factor ligands, such as epidermal growth factor (EGF) and transforming growth factor-α (TGF-α). The catalytically inactive EGFR monomer is transformed into a catalytically active homopolymer and Heterodimer. These catalytically active dimers then initiate intracellular tyrosine kinase activity, which leads to autophosphorylation of specific EGFR tyrosine residues and elicits downstream activation of signaling proteins. Subsequently, the signal protein initiates multiple signal transduction cascades (MAPK, Akt, and JNK), which ultimately regulate the basic biological processes of cell growth, proliferation, motility, and survival.

EGFR has been found to have abnormally high levels on the surface of many types of cancer cells, and elevated EGFR levels have been associated with advanced disease, cancer spread, and poor clinical prognosis. Mutations in EGFR can lead to overexpression of the receptor, permanent activation or continuous hyperactivity, leading to uncontrolled cell growth, which is cancer. Therefore, EGFR mutations have been identified in several types of malignant tumors, including metastatic lung cancer, head and neck cancer, colorectal cancer, and pancreatic cancer. In brain cancer, mutations mainly occur in exons 18-21, which encode the adenosine triphosphate (ATP)-binding pocket of the kinase domain. The most clinically relevant drug-sensitive EGFR mutations are deletions in exon 19 and point mutations in exon 21. The former eliminates a common amino acid motif (LREA), and the latter results in position 858 (L858R). The arginine is replaced by leucine. Together, these two mutations account for nearly 85% of the EGFR mutations observed in lung cancer. Both mutations have permanent tyrosine kinase activity, so they are carcinogenic. In at least 50% of patients who initially responded to current therapies, the progression of the disease is related to the development of a secondary mutation, T790M (also known as the goalkeeper mutation) in exon 20 of EGFR.

BPI-7711 is a third-generation EGFR-TKI compound developed by Beida Pharmaceuticals and disclosed in International Patent No. WO2017/218892. It is the N-(2-(2-(dimethylamino) )Ethoxy)-4-methoxy-5-((4-(1-methyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide methanesulfonic acid salt:

Need to develop improved properties containing N-(2-(2-(dimethylamino)ethoxy)-4-methoxy-5-((4-(1-methyl-1H-indole-3 -Yl)pyrimidin-2-yl)amino)phenyl)acrylamide pharmaceutically acceptable salt, especially the pharmaceutical composition of BPI-7711 and its use, and the preparation of said pharmaceutical composition suitable for large-scale production method.

Summary of the invention

The object of the present invention is to provide a N-(2-(2-(dimethylamino)ethoxy)-4-methoxy-5-((4-(1-methyl-1H-indole) -3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide pharmaceutically acceptable salt pharmaceutical composition and preparation method thereof to improve the solubility of active ingredients-pH dependence and light instability and other defects . The pharmaceutical composition provided by the invention has fast dissolution, good quality, stable product and good clinical curative effect. The pharmaceutical composition and the preparation method thereof are suitable for continuous and stable large-scale industrial production.

In order to achieve the above object, the present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable salt of the compound of the following formula I, a diluent, a disintegrant and a lubricant:

According to the present invention, the chemical name of the compound of formula I is N-(2-(2-(dimethylamino)ethoxy)-4-methoxy-5-((4-(1-methyl- 1H-Indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide.

According to a preferred embodiment of the present invention, the pharmaceutically acceptable salt of the compound of formula I is the methanesulfonate salt, which has the structure shown in the following formula:

In the context of the present invention, BPI-7711 represents the mesylate salt of the compound of formula I described above.

According to an embodiment of the present invention, the pharmaceutical composition comprises the following components in terms of weight percentage:

According to an embodiment of the present invention, the weight percentage content of the pharmaceutically acceptable salt of the compound of formula I may be selected from 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%.

According to an embodiment of the present invention, the weight percentage content of the diluent may be selected from 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%.

According to an embodiment of the present invention, the weight percentage content of the disintegrant may be selected from 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0 %.

According to an embodiment of the present invention, the weight percentage content of the lubricant may be selected from 0.5%, 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%.

As an example, the pharmaceutical composition contains the following components by weight percentage:

Preferably, the pharmaceutically acceptable salt, diluent, disintegrant and lubricant of the compound of formula I are all in powder form.

Preferably, the particle size of the powder of the pharmaceutically acceptable salt of the compound of formula I is 5 to 250 μm, more preferably 60 to 200 μm. _{For example, the D 90} of the powder of the pharmaceutically acceptable salt of the compound of formula I is 5 to 250 μm, more preferably 60 to 200 μm, such as 60 μm, 70 μm, 80 μm, 90 μm, 100 μm, 110 μm, 120 μm, 130 μm, 140 μm, 150μm, 160μm, 170μm, 180μm, 190μm, 200μm.

Preferably, the particle size of the diluent powder is 100-250 μm. For example, the D ₉₀ of the diluent is 100-250 μm, such as 100 μm, 110 μm, 120 μm, 130 μm, 140 μm, 150 μm, 160 μm, 170 μm, 180 μm, 190 μm, 200 μm, 210 μm, 220 μm, 230 μm, 240 μm, 250 μm.

Preferably, the diluent is selected from microcrystalline cellulose, lactose, calcium carbonate, calcium phosphate, calcium sulfate, cellulose acetate, erythritol, ethyl cellulose, silicified microcrystalline cellulose, fructose, inulin , Isomalt, lactitol, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, polydextrose, polyethylene glycol, pullulan, simethicone, sodium bicarbonate, sodium carbonate One, two or more of, sodium chloride, sorbitol, starch, sucrose, trehalose and xylitol, more preferably one or a combination of two of lactose and microcrystalline cellulose.

More preferably, the selected lactose is lactose monohydrate, and the selected microcrystalline cellulose is microcrystalline cellulose PH102.

According to an embodiment of the present invention, when the diluent is multiple of the above-mentioned diluents, the particle size of the diluent of each diluent and the other diluents may be the same or different, and are independently selected from the above-mentioned diluents. The particle size range of the powder.

According to an embodiment of the present invention, when the diluent is selected from a combination of two of the above-mentioned diluents (such as a combination of lactose and microcrystalline cellulose), its ratio can be varied within a relatively large range. For example, the weight ratio of two diluents (such as lactose and microcrystalline cellulose) can be 1:2 to 2:1, such as 1:1.5 to 1.5:1, for example, 1.4:1 to 1:1.4, 1.3:1 to 1:1.3, 1.2:1 to 1:1.2, 1.1:1 to 1:1.1, such as 1:1.

Preferably, the disintegrant is selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose methyl cellulose, povidone, glycolic acid One, two or more of sodium starch, more preferably croscarmellose sodium.

Preferably, the lubricant is selected from one, two or more of magnesium stearate, silicon dioxide, sodium stearyl fumarate, calcium stearate, sodium lauryl sulfate and talc, More preferred is one or a combination of both magnesium stearate and colloidal silica.

According to an embodiment of the present invention, when the lubricant is selected from a combination of two of the above-mentioned lubricants (such as a combination of magnesium stearate and colloidal silica), the ratio can be varied within a relatively large range. For example, the weight ratio of two lubricants (such as magnesium stearate and colloidal silica) can be 1:2 to 2:1, such as 1:1.5 to 1.5:1, for example, 1.4:1 to 1:1.4, 1.3:1 to 1:1.3, 1.2:1 to 1:1.2, 1.1:1 to 1:1.1, such as 1:1.

The present invention also provides a capsule, which comprises a capsule and a capsule shell, wherein the capsule contains the pharmaceutical composition.

Preferably, the capsule shell is selected from gelatin hollow capsules, hydroxypropylcellulose hollow capsules, and more preferably gelatin hollow capsules.

The present invention also provides a preparation method of the above-mentioned pharmaceutical composition, which comprises mixing the pharmaceutically acceptable salt of the compound of formula I, a diluent, a disintegrant and a lubricant.

According to an embodiment of the present invention, the preparation method includes sieving the pharmaceutically acceptable salt of the compound of formula I, a diluent and a disintegrant, and mixing, and then mixing with a lubricant.

According to an embodiment of the present invention, the preparation method includes the following steps:

1) After sieving the required weight percentage of the pharmaceutically acceptable salt, diluent, and disintegrant of the compound of formula I, respectively, they are mixed;

2) Add lubricant to the material obtained in step 1) and continue mixing.

According to an embodiment of the present invention, preferably, the sieving described in step 1) is a 20-60 mesh sieve, more preferably a 30-45 mesh sieve.

According to a preferred embodiment of the present invention, in step 2), when the lubricant is selected from a combination of magnesium stearate and colloidal silica, silica is first added to the material obtained in step 1) and mixed, and then added The magnesium stearate continues to mix.

According to an embodiment of the present invention, the preparation method may further include filling a mixture of a pharmaceutically acceptable salt of the compound of formula I, a diluent, a disintegrant and a lubricant into the capsule shell.

The present invention also provides a method for treating diseases or disorders related to EGFR activity, which comprises administering a therapeutically effective amount of the pharmaceutical composition or capsule to a patient in need of treatment.

The present invention also provides the use of the pharmaceutical composition or capsule for the treatment of diseases or disorders related to EGFR activity.

The present invention also provides the use of the pharmaceutical composition in the preparation of medicines for the treatment of diseases or disorders related to EGFR activity.

In one embodiment, the disease or condition is associated with one or more mutants of EGFR.

In another embodiment, the one or more mutants of EGFR are selected from L858R activating mutants L858R, delE746-A750, G719S; Exon 19 deletion activating mutants; and T790M resistance mutants.

In another embodiment, the disease or condition is cancer.

In another embodiment, the cancer is selected from brain cancer, lung cancer, kidney cancer, bone cancer, liver cancer, bladder cancer, head and neck cancer, esophageal cancer, gastric cancer, colon cancer, rectal cancer, breast cancer, ovarian cancer, melanin Tumor, skin cancer, adrenal cancer, cervical cancer, lymphoma and thyroid tumor and their complications.

In another embodiment, the cancer is brain cancer or lung cancer.

In another embodiment, the cancer is metastatic brain cancer.

In another embodiment, any embodiment of the method of treating a disease or condition is used in combination with administering a second therapeutic agent to the patient.

In another embodiment, the second therapeutic agent is a chemotherapeutic agent.

In another embodiment, the second therapeutic agent is an EGFR modulator other than BPI-7711.

In another aspect, the present application provides a method of inhibiting a mutant of EGFR in an individual, comprising contacting a biological sample of the individual with the pharmaceutical composition or capsule.

The term "patient" or "individual" includes humans and other mammals.

The term "mammal" or "mammal" includes but is not limited to: humans, dogs, cats, horses, pigs, cows, monkeys, rabbits and mice. The preferred mammal is human.

The term "therapeutically effective amount" refers to an amount of a compound or composition that, when administered to an individual to treat a disease, is sufficient to achieve the treatment of the disease. The "therapeutically effective amount" may vary according to the compound, the disease and its severity, and the age, weight, or other factors of the patient being treated. When applied to the administration of a single active ingredient alone, the term refers to that single ingredient. When applied to a combination, the term refers to the combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, consecutively, or simultaneously.

The term "treatment" (verb) or "treatment" (noun) refers to: (i) inhibiting a disease, disorder or condition, that is, preventing its development; (ii) alleviating a disease, disorder or condition, that is, causing the disease, disorder, and Or the condition subsides; or (iii) prevent the disease, disorder or condition from occurring in an individual who may be susceptible to the disease, condition, or condition but has not yet been diagnosed with it. Therefore, in one embodiment, "treating" (verb) or "treating" (noun) refers to ameliorating a disease or condition, which may include an improved physical parameter or parameters, although the individual being treated may be indistinguishable. In another embodiment, "treating" (verb) or "treating" (noun) includes modulating a disease or condition, either physically (e.g., stabilization of discernible symptoms) or physiological (e.g., stabilization of a physical parameter) or both Both. In another embodiment, "treating" (verb) or "treating" (noun) includes delaying the onset of a disease or condition.

The beneficial effects of the present invention are as follows:

The inventors found that some pharmaceutically acceptable salts of compounds of formula I, especially BPI-7711, have hygroscopicity, photosensitivity and pH dependence of solubility. The hygroscopicity of the drug will cause the medicament to gradually absorb moisture during storage and use. Excessive water content will accelerate the degradation of the medicament and increase the risk of excessive microorganisms in the medicament. The photosensitivity of the medicament usually causes degradation of the medicament due to exposure to strong light during the manufacturing, storage and use of the medicament, making the medicament difficult to industrially produce and store for a long time. Generally, after oral administration, the drug needs to be dissolved into the digestive juice and then absorbed in different parts of the gastrointestinal tract (including the stomach, duodenum, jejunum, ileum and colon). The digestive juices of different absorption sites have different pH values, such as the stomach (pH 1-3.5) and the small intestine (pH 4-8). Since the pharmaceutically acceptable salt of the compound of formula I (for example, BPI-7711) is a gastric-soluble drug, the dissolution rate of the drug in the stomach has a great influence on the bioavailability of the drug.

The pharmaceutical composition provided by the present invention solves the problem by controlling the particle size of the pharmaceutically acceptable salt of the compound of formula I in the range of 5 to 250 microns, preferably 60 to 200 microns, and the diluent in the range of 100 to 250 microns. The pharmaceutically acceptable salt of the compound of formula I, especially BPI-7711, due to its solubility-pH dependence, leads to the problem of too slow dissolution in high pH media, and at the same time avoids the mixing failure caused by the too small particle size of the active ingredient. Uniformity and stratification during the production process realize the balance between the rapid dissolution and manufacturability of the pharmaceutically acceptable salt of the compound of formula I, especially BPI-7711.

The preparation method of the pharmaceutical composition of the present invention adopts a powder direct filling process, has the characteristics of simple process and accurate filling quantity, and greatly reduces the time and cost of production. At the same time, due to the short production time, the exposure of drugs to light, humidity and heat is avoided, and the stability and controllability of the product in the production process are effectively ensured.

Detailed ways

The following examples are used to further describe the beneficial effects of the present invention. The examples are only for illustrative purposes and do not limit the scope of protection of the present invention. At the same time, changes and modifications made by persons of ordinary skill in the art according to the present invention are also included in Within the protection scope of the present invention.

In the following examples, BPI-7711 represents N-(2-(2-(dimethylamino)ethoxy)-4-methoxy-5-((4-(1-methyl-1H-indyl Dol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide methanesulfonate.

Example 1

According to 1000 capsules, the composition of the capsule is as follows:

Among them: BPI-7711 particle size D ₉₀ : 200 μm, microcrystalline cellulose particle size pH 102D ₉₀ : 204 μm, lactose monohydrate particle size D ₉₀ : 200 μm.

Prepared according to the following process:

a. Sieving: Pass the microcrystalline cellulose pH102, lactose monohydrate, and croscarmellose sodium through a 45-mesh sieve; use another 45-mesh sieve to pass BPI-7711, and then weigh the prescription amount of BPI-7711 ；

b. Premixing: Put the sieved materials into a 1L hopper mixer, set the mixer speed to 20 rpm, and mix for 24 minutes;

c. Mixing: Pass the colloidal silica through a 45-mesh sieve and add it to the b-step mixer, set the mixer speed to 20 rpm, and continue mixing for 14 minutes;

d. Lubrication: After passing the magnesium stearate through a 45-mesh sieve, add it to the c-step mixer, set the mixer speed to 20 rpm, and continue mixing for 3 minutes;

e. Use an automatic capsule filling machine to fill the powder into No. 5 gelatin capsules to make 1000 capsules.

Example 2

According to 1000 capsules, the composition of the capsule is as follows:

Among them: BPI-7711 particle size D ₉₀ 60 μm, microcrystalline cellulose particle size D ₉₀ : 100 μm, lactose particle size D ₉₀ : 105 μm.

Prepared according to the following process:

a. Sieving: Pass the microcrystalline cellulose, lactose monohydrate, and croscarmellose sodium through a 45-mesh sieve; use another 45-mesh sieve to pass BPI-7711, and weigh the prescription amount of BPI-7711 after sieving;

b. Premixing: Put the sieved materials into a 500L hopper mixer, set the mixer speed to 20 rpm, and mix for 24 minutes;

c. Mixing: Pass the colloidal silica through a 45-mesh sieve and add it to the b-step mixer, set the mixer speed to 20 rpm, and continue mixing for 14 minutes;

d. Lubrication: After passing the magnesium stearate through a 45-mesh sieve, add it to the c-step mixer, set the mixer speed to 20 rpm, and continue mixing for 3 minutes;

e. Use an automatic capsule filling machine to fill the mixed powder into No. 1 capsules to make 1000 capsules.

Example 3

According to 1000 capsules, the composition of the capsule is as follows:

Among them: BPI-7711 particle size D ₉₀ : 120 μm, microcrystalline cellulose pH 102 particle size D ₉₀ : 200 μm, lactose particle size D ₉₀ : 205 μm.

Prepared according to the following process:

a. Sieving: Pass the microcrystalline cellulose PH102, lactose monohydrate, and croscarmellose sodium through a 45-mesh sieve; use another 45-mesh sieve to pass BPI-7711, and then weigh the prescription amount of BPI-7711 ；

b. Premixing: Put the sieved materials into a 1L hopper mixer, set the mixer speed to 20 rpm, and mix for 24 minutes;

c. Mixing: Pass the colloidal silica through a 45-mesh sieve and add it to the b-step mixer, set the mixer speed to 20 rpm, and continue mixing for 14 minutes;

d. Lubrication: After passing the magnesium stearate through a 45-mesh sieve, add it to the c-step mixer, set the mixer speed to 20 rpm, and continue mixing for 3 minutes;

e. Use an automatic capsule filling machine to fill the powder into No. 4 gelatin capsules to make 1000 capsules.

Example 4

According to 1000 capsules, the composition of the capsule is as follows:

Among them: BPI-7711 particle size D ₉₀ : 80 μm, microcrystalline cellulose particle size D ₉₀ : 100 μm, lactose particle size D ₉₀ : 110 μm.

Prepared according to the following process:

a. Sieving: Pass the microcrystalline cellulose, lactose monohydrate, and croscarmellose sodium through a 45-mesh sieve; use another 45-mesh sieve to pass BPI-7711, and weigh the prescription amount of BPI-7711 after sieving;

b. Premixing: Put the sieved materials into a 1L hopper mixer, set the mixer speed to 20 rpm, and mix for 24 minutes;

c. Lubrication: After passing the magnesium stearate through a 45-mesh sieve, add it to the c-step mixer, set the mixer speed to 20 rpm, and continue mixing for 3 minutes;

d. Use an automatic capsule filling machine to fill the powder into No. 4 gelatin capsules to make 1000 capsules.

Example 5

According to 1000 capsules, the composition of the capsule is as follows:

Among them: BPI-7711 particle size D ₉₀ : 80 μm, microcrystalline cellulose particle size D ₉₀ : 100 μm, lactose monohydrate particle size D ₉₀ : 110 μm.

Prepared according to the following process:

a. Sieving: Pass the microcrystalline cellulose, lactose monohydrate, and croscarmellose sodium through a 45-mesh sieve; use another 45-mesh sieve to pass BPI-7711, and weigh the prescription amount of BPI-7711 after sieving;

b. Premixing: Put the sieved materials into a 1L hopper mixer, set the mixer speed to 20 rpm, and mix for 24 minutes;

c. Mixing: Pass the colloidal silica through a 45-mesh sieve and add it to the b-step mixer, set the mixer speed to 20 rpm, and continue mixing for 14 minutes;

d. Lubrication: After passing the magnesium stearate through a 45-mesh sieve, add it to the c-step mixer, set the mixer speed to 20 rpm, and continue mixing for 3 minutes;

Use a fully automatic capsule filling machine to fill the powder into No. 3 gelatin capsules to make 1000 capsules.

Product effect evaluation

1. Dissolution test of Examples 1-5

Experimental method: Refer to the dissolution test method (Chinese Pharmacopoeia 2015 Edition Four General Rules 0931 Method 2).

according to:

Dissolution method: slurry method; dissolution apparatus: Distek 6300 dissolution apparatus (ADS-DIS-012);

Speed: 50 rpm;

Medium volume: 900 ml; medium temperature: 37 degrees Celsius;

Sampling method: automatic sampling; sampling volume: 1.5 ml;

Sampling time points: 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes and 60 minutes.

The dissolution curves of the samples in pH 1.2 hydrochloric acid solution, pH 4.5 phosphate buffer, pH 6.8 phosphate buffer (containing 0.5% Tween 80), and water (containing 0.5% Tween 80) were detected respectively.

The results are as follows:

Table 1: Dissolution rate in pH1.2 hydrochloric acid solution

Table 2: Dissolution in pH4.5 phosphate buffer

according to:

Dissolution method: slurry method; dissolution apparatus: Agilent 708-DS dissolution apparatus;

Speed: 75 rpm;

Medium volume: 900 ml; medium temperature: 37 degrees Celsius;

Sampling method: automatic sampling; sampling volume: 5 ml;

Sampling time points: 5 minutes, 10 minutes, 20 minutes, 30 minutes, 45 minutes and 60 minutes.

The dissolution curves of the samples in water (containing 0.5% Tween 80) and pH 6.8 buffer (containing 0.5% Tween 80) were detected respectively.

The results are as follows:

Table 3: Dissolution curve in water (containing 0.5% Tween 80)

Table 4: Dissolution in pH6.8 phosphate buffer (containing 0.5% Tween 80)

2. Stability test of Examples 1-5

Experimental method: Place the samples of Examples 1-5 in a stability box at 25°C ± 2°C 60 ± 5% RH, and perform long-term stability experiments. Samples were taken at 0, 1, 3, 6, 9, and 12 months to investigate the appearance, content, impurities, moisture, and dissolution rate of the samples in a hydrochloric acid solution of pH 1.2 at 30 minutes.

The results are as follows:

Table 5: Stability data under long-term stability conditions (25℃±2℃60±5%RH)

The experimental results show that the maximum single impurity of the samples of the examples is no more than 0.09% and the total impurities are no more than 0.13% in the stability experiment at 0 days, which are far below the limit requirements, indicating that the samples of the examples can be maintained well during the preparation process. The stability avoids degradation caused by hygroscopicity and light instability. At the same time, the samples of the examples have a moisture content of no more than 5% and a content of 97%-103% on the 0th day of the stability experiment, and the quality is good. During the 0 days and 12 months of the stability experiment, the release rate of the samples of each example in the pH 1.2 hydrochloric acid was greater than 90% in 30 minutes, indicating that the product has a rapid dissolution performance in gastric acid. The long-term stability data for 12 months showed that the maximum single impurities and total impurities did not increase significantly during the storage process of the samples of each example, indicating that the samples of each example had better stability. In summary, it is shown that the present invention has the advantages of extremely rapid drug dissolution, high drug bioavailability, stable quality, and suitability for industrial production.

Claims (12)

1. A pharmaceutical composition comprising a pharmaceutically acceptable salt of the compound of the following formula I, a diluent, a disintegrant and a lubricant:

   
2. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition comprises the following components in terms of weight percentage:

   
3. The pharmaceutical composition according to claim 2, wherein the pharmaceutical composition comprises the following components in terms of weight percentage:

   
4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the pharmaceutically acceptable salt, diluent, disintegrant and lubricant of the compound of formula I are all in powder form;

   Preferably, the particle size of the powder of the pharmaceutically acceptable salt of the compound of formula I is 5 to 250 μm, more preferably 60 to 200 μm; the particle size of the diluent powder is 100 to 250 μm.
5. The pharmaceutical composition according to any one of claims 1 to 4, wherein the pharmaceutically acceptable salt of the compound of formula I is selected from the mesylate salt of the compound of formula I.
6. The pharmaceutical composition according to any one of claims 1-5, wherein the diluent is selected from the group consisting of microcrystalline cellulose, lactose, calcium carbonate, calcium phosphate, calcium sulfate, cellulose acetate, erythritol, ethyl acetate Base cellulose, silicified microcrystalline cellulose, fructose, inulin, isomalt, lactitol, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, polydextrose, polyethylene glycol, One, two or more of pullulan, simethicone, sodium bicarbonate, sodium carbonate, sodium chloride, sorbitol, starch, sucrose, trehalose and xylitol, preferably lactose, microcrystalline One or a combination of two of cellulose; more preferably, the selected lactose is lactose monohydrate, and the selected microcrystalline cellulose is microcrystalline cellulose PH102.
7. The pharmaceutical composition according to any one of claims 1 to 6, wherein the disintegrant is selected from the group consisting of croscarmellose sodium, sodium carboxymethyl starch, hydroxypropyl cellulose, low-substituted hydroxypropyl cellulose One, two or more of base cellulose methyl cellulose, povidone, and sodium starch glycolate, more preferably croscarmellose sodium.
8. The pharmaceutical composition according to any one of claims 1-7, wherein the lubricant is selected from the group consisting of magnesium stearate, silicon dioxide, sodium stearyl fumarate, calcium stearate, sodium lauryl sulfate, One, two or more of talc, more preferably one or a combination of two of magnesium stearate and colloidal silica.
9. A capsule comprising a capsule and a capsule shell, wherein the capsule comprises the pharmaceutical composition according to any one of claims 1-8;

   Preferably, the capsule shell is selected from gelatin hollow capsules, hydroxypropylcellulose hollow capsules, and more preferably gelatin hollow capsules.
10. The preparation method of the pharmaceutical composition according to any one of claims 1-8 or the capsule according to claim 9, comprising mixing a pharmaceutically acceptable salt of the compound of formula I, a diluent, a disintegrant and a lubricant;

    Preferably, the preparation method includes the following steps:

    1) After sieving the required weight percentage of the pharmaceutically acceptable salt, diluent, and disintegrant of the compound of formula I, respectively, they are mixed;

    2) Add lubricant to the material obtained in step 1) and continue to mix;

    Preferably, the sieving described in step 1) is a 20-60 mesh sieve, more preferably a 30-45 mesh sieve;

    Preferably, in step 2), when the lubricant is selected from the combination of magnesium stearate and colloidal silica, first add silica to the material obtained in step 1) and mix, and then add magnesium stearate to continue mixing;

    Preferably, the preparation method further includes the following steps:

    3) Fill the material obtained in step 2) into the capsule shell.
11. A method of treating diseases or disorders related to EGFR activity includes administering a therapeutically effective amount of the pharmaceutical composition according to any one of claims 1 to 8 or the capsule according to claim 9 to a patient in need of treatment.
12. A method of inhibiting a mutant of EGFR in an individual comprises contacting a biological sample of the individual with the pharmaceutical composition according to any one of claims 1-8 or the capsule according to claim 9.