Pharmaceutical composition of pyrimidine derivative

Abstract

Disclosed are a pharmaceutical composition of N-(2-((2-(dimethylamino)ethyl)(methyl)amino)-4-methoxy-5-((4-(1-deuteromethyl-1H-indol-3-yl)pyrimidin-2-yl)amino)phenyl)acrylamide methanesulfonate (TY-9591), a method for preparing same, and use thereof. The pharmaceutical composition is a coated tablet, with a tablet core comprising TY-9591, mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, and sodium stearyl fumarate. By optimizing the formula and the preparation process, the composition exhibits excellent storage stability, accelerated stability, and dissolution performance.

Description

A pharmaceutical composition of pyrimidine derivatives Technical Field

[0001] The present invention relates to the field of medicine, and in particular to a pharmaceutical composition of pyrimidine derivatives. Background Art

[0002] The chemical name of TY-9591 free base is N-(2-((2-(dimethylamino)ethyl)(methyl)amine)-4-methoxy-5-((4-(1-deuteromethyl-1H-indol-3-yl)pyrimidin-2-yl)amine)phenyl)acrylamide, and its structural formula is shown in Formula I.

[0003] The compound represented by formula I and its pharmaceutically acceptable salts are hereinafter referred to as "agents".

[0004] TY-9591 is the monomethanesulfonate salt of the compound represented by Formula I.

[0005] TY-9591 is potentially useful in treating diseases or conditions involving EGFR or other protein kinases that are inhibited by TY-9591. TY-9591 is disclosed in CN 104140418 B, which is incorporated herein by reference. Example 3 of CN 104140418 B describes the synthesis of TY-9591 and indicates that the product is obtained in solid form. Several free base polymorphic forms of TY-9591 are described in CN 110950847 B, which is incorporated herein by reference. Crystalline forms of TY-9591 are described in CN 108558835 A, which is incorporated herein by reference.

[0006] Chinese Patent No. 201280033773.9 discloses the compound AZD9291 of Formula II, which is effective against T790M EGFR mutant tumors. However, it is easily metabolized and demethylated in vivo, increasing the metabolic burden on the liver, causing hepatotoxicity, increasing the toxicity of its metabolites, and resulting in a shorter pharmacokinetic half-life in vivo, ultimately affecting the drug's anticancer activity. TY-9591, on the other hand, can mitigate these side effects. To deliver the therapeutic benefits of TY-9591 to patients in need, it is necessary to formulate TY-9591 into a pharmaceutical composition, particularly a solid dosage form suitable for oral administration. Therefore, a stable, high-quality TY-9591 pharmaceutical formulation with excellent in vivo dissolution, high bioavailability, storage stability, and accelerated stability is needed.

[0007] Chinese patent 201810017685.9 discloses a pharmaceutical preparation of a deuterated derivative of AZD9291, which is a rapid-release tablet of a deuterated derivative of AZD9291. However, the patent requires the D90 of the active ingredient to be 20-280 μm when preparing the tablets. This is mainly because the preparation process of the tablets cannot guarantee the stability of small particle sizes (<20 μm). When the active ingredient particles become smaller and the specific surface area increases, it is easy to cause decomposition, deliquescence and other phenomena, resulting in a decrease in the solubility of the prepared pharmaceutical preparation and instability of the prepared pharmaceutical preparation. When D90 is greater than 280 μm, since the deuterated derivative of AZD9291 itself is poorly soluble, the drug particles are too large, resulting in a low solubility of the prepared pharmaceutical preparation (for example, when the API particle size in Example 1 (e) is D90 = 320 μm, the dissolution rate of the resulting tablet within 60 minutes is only 90%). Control of particle size is not conducive to the scale-up production of the preparation.

[0008] Based on this, the present invention breaks through the limitation of particle size and can prepare preparations with good stability and rapid dissolution within the range of active ingredient particle size less than 20 μm and greater than 280 μm.

[0009] Patent CN105848647A discloses a pharmaceutical composition of AZD9291, which is a rapid-release tablet of AZD9291 or its salt, but the patent is designed for AZD9291. In addition, the patent adopts a long mixing time in the preparation process (such as the three mixing times in Example 8 of Patent CN105848647A totaling 73 minutes). In the scale-up production of the preparation, the long mixing time is not conducive to the stability control of the drug, and the preparation production capacity is limited, and the production cost is high. The present invention optimizes the preparation process parameters based on the patent. The mixing speed of the three mixings is lower than the parameters in the patent, and the mixing time is shortened to one-third of that in the patent, significantly shortening the preparation production cycle, reducing production costs, and at the same time helping to protect the stability of the drug. In addition, the present invention adopts a lower coating weight gain (3-4% VS Patent CN105848647A Example 9 has a coating weight gain of 5% at the same specification of 40mg), which also achieves the effect of improving drug stability. At the same time, the preparation prepared by the process of the present invention has a faster dissolution rate, especially in the early stage of drug dissolution (5 min and 10 min), and the drug dissolution rate is significantly improved compared with Example 9 of patent CN105848647A.

[0010] Summary of the Invention

[0011] The object of the present invention is to provide a TY-9591 pharmaceutical preparation with good in vivo dissolution, high bioavailability, good storage stability (under long-term conditions and accelerated conditions) and stable quality, as well as a preparation method and use thereof in treating tumors.

[0012] In a first aspect of the present invention, a pharmaceutical composition is provided, wherein the pharmaceutical composition is a tablet, comprising a tablet core and a coating located outside the tablet core;

[0013] The core comprises the following components:

[0014] The coating completely covers the tablet core, and the mass of the coating is 1-6 wt% (preferably 2.5-5 wt%, more preferably 2-4 wt%) of the mass of the tablet core;

[0015] The pharmaceutical composition is prepared as follows:

[0016] 1) providing a mesylate salt of a compound of formula I, mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, sodium stearyl fumarate, and a coating suspension;

[0017] 2) mixing the mesylate salt of the compound of formula I, mannitol, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose to obtain a first mixture;

[0018] 3) mixing the sodium stearyl fumarate for internal addition with the first mixture to obtain a second mixture;

[0019] 4) dry granulating the second mixture to obtain first granules;

[0020] 5) mixing the first particles with sodium stearyl fumarate for external addition to obtain a third mixture;

[0021] 6) tableting the third mixture to obtain plain tablets;

[0022] 7) coating the plain tablets with the coating suspension to obtain the pharmaceutical composition.

[0023] In another preferred embodiment, the D90 of the active ingredient is 1-500 μm (preferably 3-495 μm).

[0024] In another preferred embodiment, the methanesulfonate of the compound of formula I is a crystalline form of the monomethanesulfonate of the compound of formula I.

[0025] In another preferred embodiment, the X-ray powder diffraction of the crystalline form at 2θ angle (the unit of 2θ angle is °) is: 7.1±0.2, 8.5±0.2, 9.4±0.2, 10.3±0.2, 12.6±0.2, 14.4±0.2, 15.1±0.2, 15.6±0.2, 16.3±0.2, 17.0±0.2, 17.3±0.2, 17.7±0.2, 18.2±0.2, 18.7±0.2, 19.4±0.2, 19.7±0.2, 20.2±0.2, 20.7±0.2, 21. There are diffraction peaks at 6±0.2, 22.0±0.2, 22.8±0.2, 23.5±0.2, 24.2±0.2, 24.8±0.2, 25.6±0.2, 26.0±0.2, 26.9±0.2, 27.7±0.2, 28.2±0.2, 29.5±0.2, 30.7±0.2, 31.7±0.2, 32.5±0.2, 33.1±0.2, 33.8±0.2, 34.6±0.2, 34.9±0.2, 35.6±0.2, 37.9±0.2, and 38.7±0.2.

[0026] In another preferred embodiment, the coating comprises a stabilizing substance and a polymer.

[0027] In another preferred embodiment, the stabilizing substance is selected from the following group: titanium dioxide, talc, red iron oxide, or a combination thereof.

[0028] In another preferred embodiment, the polymer is selected from the group consisting of polyvinyl alcohol, polyethylene glycol, or a combination thereof.

[0029] In another preferred embodiment, the pharmaceutical composition has one or more characteristics selected from the following group:

[0030] 1) In a pH 1.2 hydrochloric acid and sodium chloride buffer solution, the solubility of the active ingredient in the pharmaceutical composition is ≥50% (preferably ≥70%, more preferably ≥90%) after 10 minutes;

[0031] 2) In a pH 1.2 hydrochloric acid and sodium chloride buffer solution, the solubility of the active ingredient in the pharmaceutical composition is ≥80% (preferably ≥90%, more preferably ≥93%) after 15 minutes;

[0032] 3) In a pH 1.2 hydrochloric acid and sodium chloride buffer solution, the solubility of the active ingredient in the pharmaceutical composition is ≥85% (preferably ≥90%, more preferably ≥94%) after 20 minutes;

[0033] 4) In a pH 1.2 hydrochloric acid and sodium chloride buffer solution, the solubility of the active ingredient in the pharmaceutical composition is ≥90% (preferably ≥92%, more preferably ≥95%) after 30 minutes;

[0034] 5) In a pH 1.2 hydrochloric acid and sodium chloride buffer solution, the solubility of the active ingredient in the pharmaceutical composition is ≥96% (preferably ≥97%) after 45 minutes;

[0035] 6) In a pH 1.2 hydrochloric acid and sodium chloride buffer solution, the dissolution rate of the active ingredient in the pharmaceutical composition is ≥ 100% after 60 minutes;

[0036] 7) After storage for 3 years at 25±2°C and 60%±5% RH, the dissolution rate of the active ingredient in the pharmaceutical composition in a pH 1.3 hydrochloric acid and sodium chloride buffer solution is ≥95% at 30 minutes;

[0037] 8) The pharmaceutical composition is stored at 40±2°C and 75%±5% RH for 6 months. In a pH 1.3 hydrochloric acid and sodium chloride buffer solution, the solubility of the active ingredient in the pharmaceutical composition is ≥95% after 30 minutes.

[0038] In another preferred embodiment, the pharmaceutical composition is an oral preparation.

[0039] The second aspect of the present invention provides a method for preparing the pharmaceutical composition according to the first aspect of the present invention, comprising the steps of:

[0040] 1) providing a mesylate salt of a compound of formula I, mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, sodium stearyl fumarate, and a coating suspension;

[0041] 2) mixing the mesylate salt of the compound of formula I, mannitol, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose to obtain a first mixture;

[0042] 3) mixing the sodium stearyl fumarate for internal addition with the first mixture to obtain a second mixture;

[0043] 4) dry granulating the second mixture to obtain first granules;

[0044] 5) mixing the first particles with sodium stearyl fumarate for external addition to obtain a third mixture;

[0045] 6) tableting the third mixture to obtain plain tablets;

[0046] 7) coating the plain tablets with the coating suspension to obtain the pharmaceutical composition.

[0047] In another preferred embodiment, the method has one or more characteristics selected from the following group:

[0048] 1) In step 2), the mixing speed is 4-14 rpm (preferably 8-12 rpm);

[0049] 2) In step 2), the mixing time is 10-20 min (preferably 14-16 min);

[0050] 3) In step 3), the mixing speed is 4-14 rpm (preferably 8-12 rpm);

[0051] 4) In step 3), the mixing time is 2-9 minutes (preferably 4-6 minutes);

[0052] 5) In step 4), the roller spacing of the dry granulation is 1.5-2.5 mm;

[0053] 6) In step 4), the speed of the roller in the dry granulation process is 7.0-10.0 rpm;

[0054] 7) In step 4), the oil pressure of the dry granulation is 35-50 bar;

[0055] 8) In step 5), the mixing speed is 4-14 rpm (preferably 8-12 rpm);

[0056] 9) In step 5), the mixing time is 2-10 min (preferably 3-7 min).

[0057] In another preferred embodiment, the hardness of the plain sheet is 70-120N (preferably 95-105N).

[0058] The third aspect of the present invention provides a use of the pharmaceutical composition according to the first aspect of the present invention for preparing an anti-tumor drug.

[0059] In another preferred embodiment, the tumor is lung cancer.

[0060] In another preferred embodiment, the lung cancer is non-small cell lung cancer.

[0061] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0062] FIG1 is the dissolution curve of the tablets obtained in Examples 1 to 6.

[0063] FIG2 is the dissolution curve of the tablets obtained in Examples 7 to 10.

[0064] FIG3 is the dissolution curves of the tablets obtained in Examples 11 to 13.

[0065] FIG4 is the dissolution curves of the tablets obtained in Examples 3, 14, and 15.

[0066] FIG5 is the dissolution curves of the tablets obtained in Examples 16 to 19.

[0067] Figure 6 is the dissolution curve of the tablets obtained in Examples 3 and 21.

[0068] Figures 7 and 8 are the content and dissolution curves of the long-term stability test of the tablets obtained in Example 22 (the dissolution medium is pH 1.3 hydrochloric acid sodium chloride buffer, and the dissolution time is 30 min).

[0069] Figures 9 and 10 are the content and dissolution curves of the accelerated stability test of the tablets obtained in Example 22 (the dissolution medium is pH 1.3 sodium chloride hydrochloric acid buffer and the dissolution time is 30 min).

[0070] FIG11 is the dissolution curves of the tablets obtained in Example 3 and Comparative Examples 1 and 2. The dissolution medium is a pH 1.3 hydrochloric acid sodium chloride buffer solution, 0.2% NaCl + 4 ml hydrochloric acid. DETAILED DESCRIPTION

[0071] After long and in-depth research, the inventors have obtained a pharmaceutical composition with excellent dissolution performance, pharmacokinetic properties and storage stability by optimizing the composition and / or process. On this basis, the inventors have completed the present invention.

[0072] As used herein, the terms "comprising" or "including" may be open, semi-closed, or closed. In other words, the terms also include "consisting essentially of" or "consisting of."

[0073] Following oral administration, drugs can be absorbed at many different sites along the gastrointestinal tract (including via the stomach, duodenum, jejunum, ileum, and colon). As the pH varies significantly between the stomach (pH 1-3.5) and the small intestine (pH 4-8), the pH differs at each absorption site. Our studies have shown that TY-9591 exhibits significant pH-dependent solubility and moderate permeability. For example, TY-9591 has been found to have higher solubility at pH 1 (hydrochloric acid) relative to pH 6.8 (sodium hydroxide-monobasic sodium phosphate buffer, 25 mM). In such cases, where the solubility of a drug varies with pH, ​​and particularly when solubility is highest at acidic pH, there is a problem in that the drug can precipitate from solution as it passes through the gastrointestinal tract. The drug needs to be in solution in order to be absorbed, but such precipitation can affect the extent and rate of absorption of the drug. Compounds with pH-dependent solubility, particularly basic compounds, can exhibit undesirable pharmacokinetic properties, such as poor absorption or low bioavailability, which can lead to significant inter- and intra-patient variability.

[0074] Therefore, there is a need to find improved TY-9591 dosage forms that have favorable dissolution and pharmacokinetic profiles and exhibit good storage stability. At the same time, we have found that the solid dosage form according to the present invention exhibits excellent storage stability.

[0075] The present invention relates to pharmaceutical compositions suitable for oral administration, and more particularly to pharmaceutical compositions (and pharmaceutically acceptable tablets) comprising TY-9591.

[0076] The present invention provides a solution to one or more of the above problems and relates to novel pharmaceutical compositions comprising the agent. The pharmaceutical compositions of the present invention can be formed into tablets that exhibit improved dissolution properties under physiologically relevant conditions and / or higher total release of the agent on physiologically relevant indicators.

[0077] Since the compound of the present invention has excellent anti-tumor activity, the pharmaceutical composition containing the compound of the present invention as the main active ingredient can be used to treat, prevent and alleviate tumor-related diseases.

[0078] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 10-1000 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0079] "Pharmaceutically acceptable carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as Tween ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0080] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0081] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administration routes include (but are not limited to): oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0082] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0083] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a specific portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0084] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0085] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0086] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0087] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0088] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0089] The composition of the present invention can be administered alone or in combination with other pharmaceutically acceptable compositions (such as anti-tumor drugs).

[0090] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0091] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is administered to a mammal (e.g., a human) in need of treatment, wherein the dosage is a pharmaceutically effective dosage. For a 60 kg human, the daily dosage is generally 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage will also take into account factors such as the route of administration and the patient's health condition, all of which are within the skill of a skilled physician.

[0092] The specific examples of the present invention specifically describe the preparation methods of the pharmaceutical compositions of the present invention, but these specific methods do not constitute any limitation to the present invention. The pharmaceutical compositions of the present invention can also be conveniently prepared by optionally combining various preparation methods described in this specification or known in the art.

[0093] Typically, the raw materials and reagents used in the process for preparing the pharmaceutical composition of the present invention can be purchased through commercial channels.

[0094] It should be understood that for film coating premixes, similar technical effects of the present invention can be achieved by using commercially available and well-known coating premixes in the art.

[0095] Crystal form

[0096] A drug's crystal form is the solid state in which it exists. Research on drug crystal forms is the study of the drug's fundamental state. Only with a comprehensive understanding of the crystal forms of chemical drugs can we identify the most suitable crystal forms for treating diseases. A drug's crystal form can influence its physical and chemical properties, directly impacting its clinical therapeutic efficacy. Different crystal forms of the same drug can significantly differ in appearance, solubility, melting point, dissolution rate, and bioavailability, thus affecting the drug's stability, bioavailability, and efficacy. Therefore, studying the stable crystal forms of a compound is of great significance.

[0097] The active ingredient of the same drug generally exists in two or more crystal forms, which are called drug polymorphs. Different crystal forms have different solubilities and dissolution rates, which affect the drug's clinical therapeutic effects by causing changes in in vivo bioavailability. Differences in drug crystal forms may affect its dissolution and absorption in the body, thereby affecting the drug's bioavailability, clinical efficacy and safety. At the same time, the stability of the drug crystal form is also very important. In order to improve the bioavailability of the drug, reduce toxicity, and enhance the therapeutic effect, more attention should be paid to the stability of the drug crystal form. Crystal forms with good stability can ensure the physicochemical stability of the drug preparation during preparation and storage, maintain good solubility and bioavailability of the drug preparation, and ensure the equivalence between each batch of drugs. The same drug often has multiple crystal forms. Currently, the crystal form with better therapeutic effect and the most clinically applicable is called the dominant drug crystal form.

[0098] The crystal form of TY-9591 in the present invention is the crystal form described in patent CN 108558835 A.

[0099] Specifically, the X-ray powder diffraction of the TY-9591 crystal form of the present invention measured using Cu-Kα radiation at 2θ angles (the unit of 2θ angles is °) is: 7.1±0.2, 8.5±0.2, 9.4±0.2, 10.3±0.2, 12.6±0.2, 14.4±0.2, 15.1±0.2, 15.6±0.2, 16.3±0.2, 17.0±0.2, 17.3±0.2, 17.7±0.2, 18.2±0 .2, 18.7±0.2, 19.4±0.2, 19.7±0.2, 20.2±0.2, 20.7±0.2, 21.6±0.2, 22.0±0.2, 22.8±0.2, 23.5±0.2, 24.2±0.2, 24.8±0.2, 25.6±0.2, 26.0±0.2, 26.9±0.2, 27.7±0.2, 28.2±0.2, 29.5±0.2, 30.7±0.2, 31.7 There are diffraction peaks at 32.5±0.2, 33.1±0.2, 33.8±0.2, 34.6±0.2, 34.9±0.2, 35.6±0.2, 37.9±0.2, and 38.7±0.2.

[0100] More specifically, the crystal form of TY-9591 of the present invention has the X-ray powder diffraction data shown in Table A below.

[0101] Table A

[0102] Compared with the prior art, the present invention has the following main advantages:

[0103] (1) The pharmaceutical composition has excellent dissolution performance, pharmacokinetic properties and storage stability;

[0104] (2) The pharmaceutical composition has stable quality;

[0105] (3) The preparation process of the pharmaceutical composition is simple and easy to implement, and is convenient for industrial production;

[0106] (4) The pharmaceutical composition is easy to administer, safe and reliable to use, easily accepted by patients, and has high social and economic value.

[0107] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the present invention. The experimental methods in the following examples, for which specific conditions are not specified, were generally performed under conventional conditions such as those described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0108] Unless otherwise defined, all technical and scientific terms used herein have the same meanings as those familiar to those skilled in the art. Furthermore, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred embodiments and materials described herein are for illustrative purposes only.

[0109] General raw materials

[0110] General Methods

[0111] Dissolution performance

[0112] Dissolution rate refers to the rate and extent of drug dissolution from solid dosage forms, such as tablets, in a specified solvent. Dissolution rate is a key indicator for tablet quality control, and poorly soluble drugs are generally subject to dissolution testing. The dissolution test involves placing a specific amount of a solid dosage form in the rotating basket (or dissolution cup) of a dissolution apparatus. Operating the apparatus at a constant temperature of 37°C ± 0.5°C, at a specified rotational speed and in a specified dissolution medium, the apparatus then samples the solution within a specified time period and measures the amount dissolved.

[0113] The dissolution test conditions are as follows:

[0114] Dissolution medium: pH 1.2 hydrochloric acid sodium chloride buffer (0.2% NaCl + 7ml hydrochloric acid) or pH 1.3 hydrochloric acid sodium chloride buffer (0.2% NaCl + 4ml hydrochloric acid)

[0115] Dissolution medium volume: 900ml

[0116] Speed: 50rpm

[0117] Water bath temperature: 37±0.5℃

[0118] Sampling time points: 5, 10, 15, 20, 30, 45, 60-90 min (maximum speed 150 rpm)

[0119] Sampling method: automatic sampling 1.5ml without rehydration, gain 3.5ml, rinse 10ml

[0120] A pH 1.2 hydrochloric acid and sodium chloride buffer solution can make the solubility of the TY-9591 raw material meet the sink condition. The dissolution curve of the TY-9591 tablets tested in a pH 1.2 hydrochloric acid and sodium chloride buffer solution shows a parabolic growth with no inflection point or sudden release in the middle. The dissolution rate is around 80% in 15 minutes and greater than 85% in 45-60 minutes.

[0121] Determination of impurity B content

[0122] Impurity B (RRT 1.5, i.e., relative retention time 1.5) is a degradation impurity in the stability study of this formulation and is a specific impurity that requires key control. Systematic research has found that impurity B (RRT 1.5) is very unstable under neutral and slightly alkaline conditions and easily degrades into the API and other impurities. It is relatively stable under slightly acidic conditions. Therefore, the study of the content of impurity B is also an important part of the present invention.

[0123] The method for determining the content of impurity B is as follows:

[0124] 1. Chromatographic conditions (HPLC):

[0125] Gradient table:

[0126] 2. Reagents and reference substances

[0127] Heptafluorobutyric acid: chromatographically pure water: ultrapure water Ammonia: chromatographically pure or analytically pure

[0128] Acetonitrile: chromatographic grade Methanol: chromatographic grade

[0129] TY-9591 reference substance: self-made or purchased from outside

[0130] 3. Solution preparation

[0131] Diluent: methanol: water: heptafluorobutyric acid = 50:50:0.1 (V / V / V)

[0132] Blank solution: diluent

[0133] Standard solution: Prepare a solution containing TY-9591 reference substance at a concentration of 0.5 mg / mL (for example, weigh 50 mg of TY-9591 reference substance, accurately weigh it in a 100 ml volumetric flask, dissolve it in diluent and dilute to the mark, and mix well).

[0134] Working check solution: Prepare a solution containing 0.45 mg / mL of TY-9591 (for example, weigh 45 mg of TY-9591 reference substance, accurately weigh it in a 100 mL volumetric flask, dissolve it in diluent and make up to the mark, then mix thoroughly).

[0135] Reference solution: Prepare a solution containing 1.0 μg / mL of TY-9591 reference substance (for example: weigh 50 mg of TY-9591 reference substance, accurately weigh it into a 50 mL volumetric flask, dissolve it and dilute it to the mark with diluent, and mix it thoroughly; then accurately pipette 5.0 mL of this solution into a 100 mL volumetric flask, dilute it to the mark with diluent, and mix it thoroughly; then accurately pipette 1.0 mL of this solution into a 50 mL volumetric flask, dilute it to the mark with diluent, and mix it thoroughly).

[0136] Sensitivity solution: Prepare a solution containing TY-9591 reference substance at a concentration of 0.5 μg / mL (for example, accurately pipette 5.0 mL of reference solution into a 10 mL volumetric flask, dilute to the mark with diluent, and mix thoroughly).

[0137] Related substance test solution: Prepare a solution containing the test substance at a concentration of 1.0 mg / mL (for example, weigh 50 mg of the test substance, accurately weigh it in a 50 mL volumetric flask, dissolve it in the diluent and dilute it to the scale, and mix well).

[0138] Assay solution: Prepare a test solution containing TY-9591 at a concentration of 0.5 mg / mL (for example, weigh 50 mg of TY-9591 sample, accurately weigh it in a 100 mL volumetric flask, dissolve it with diluent and dilute to the mark, then mix well).

[0139] Prepare two test sample solutions with the same concentration.

[0140] Program control solution: standard solution.

[0141] 4. Calculation

[0142] in:

[0143] At---peak area of ​​unknown impurities in the test solution;

[0144] Ar---average peak area of ​​the main peak in the reference solution;

[0145] Cr---concentration of reference solution (mg / mL);

[0146] Ct---concentration of the test solution (mg / mL);

[0147] P---The content of TY-9591 reference substance

[0148] The content of impurity B is calculated using the above formula.

[0149] Example 1 Tablet 1 and its preparation (prescription composition (40 mg))

[0150] Note: The TY-9591 used contains a methanesulfonic acid. 47.6 mg of the salt form drug is equivalent to 40 mg of the free base of TY-9591.

[0151] TY-9591 was micronized to control its particle size D90 to be within 20 μm (actual D90 was 4.8 μm). Tablet 1 was manufactured using a dry mixing / rolling process using the materials listed in the table above. TY-9591, mannitol, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose were added sequentially to a 5L mixing hopper, the mixing speed was set to 10 rpm, and the mixture was mixed for 15 minutes. Sodium stearyl fumarate (added internally) was added to a 5L mixing hopper, the mixing speed was set to 10 rpm, and the mixture was mixed for 5 minutes to obtain a premix. The premix was added to a dry granulator for dry granulation, with a roller spacing of 1.5-2.5 mm, specifically 1.9-2.0 mm, a roller speed of 7.0-11.0 rpm, specifically 9 rpm, and an oil pressure of 35-45 bar (specifically 45 bar) to obtain dry granulated particles. The granules collected after dry granulation and the converted sodium stearyl fumarate (external addition) were added to a 5 L mixing hopper, the speed was set to 10 rpm, and the mixing time was 5 minutes (i.e., the total mixing time). The mixture was tableted using a punch to produce a plain tablet 1 (hardness 98.8-109.8N).

[0152] The film coating premix (7.5 mg / tablet) was prepared into a 20% (w / w) coating suspension (whose main components are polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, and red iron oxide), and the plain tablet 1 was coated with 3.8% of the weight of the plain tablet to form a tablet 1 of approximately 260 mg.

[0153] The dissolution results of Tablet 1 obtained (dissolution medium: pH 1.2 hydrochloric acid sodium chloride buffer, 0.2% NaCl + 7 ml hydrochloric acid) are shown in Table 1 and Figure 1 below. Tablet 1 was completely dissolved under the above dissolution conditions, and the solubility reached 95% of the labeled amount at 45 minutes, meeting the standard.

[0154] Examples 2-6 Tablets 2-6

[0155] Same as Example 1, except that the particle size of TY-9591 is different, as shown in the following table.

[0156] The dissolution results of the obtained tablets 2 to 6 (the dissolution medium was pH 1.2 hydrochloric acid sodium chloride buffer solution, 0.2% NaCl + 7 ml hydrochloric acid) are shown in Table 1 and Figure 1.

[0157] Table 1

[0158] As can be seen from the data in Table 1, this prescription is not only suitable for particle sizes with a D90 of 20-280 μm, but also meets the dissolution standards for small-particle TY-9591 (D90 < 20 μm) and large-particle TY-9591 (D90 > 300 μm). The advantage of this prescription is that it can completely release micronized drugs (D90 < 5 μm) under conditions of large specific surface area and easy decomposition and deliquescence. However, the formulation reported in patent CN 110013468 B cannot completely dissolve the drug when D90 < 20 μm (Comparative Example 1 (a)). In the large particle size range (Example 6, D90 = 494 μm > 280 μm), the drug can also be completely dissolved due to the internal and external addition of lubricants to promote drug dissolution. Moreover, the tablets prepared by the formulation of the present invention (such as Examples 1-6) can also be completely dissolved in the dissolution medium pH 6.8 phosphate buffer. Therefore, compared with the solution reported in patent CN 110013468B, the present invention has obvious advantages in both small and large particle size ranges.

[0159] Examples 7 to 10

[0160] To investigate the effects of internal and external lubricant addition on tablets, Examples 7 to 10 investigated the ratio of internal and external lubricant addition. The API particle size used was D90 = 222 μm, and the specific ratios are shown in the table below (the dissolution medium was pH 1.2 hydrochloric acid sodium chloride buffer solution, 0.2% NaCl + 7 ml hydrochloric acid).

[0161] As shown in Table 2 and Figure 2, under the conditions of this formulation (D90 = 222 μm), the addition of lubricant to both internal and external agents had no significant effect on drug dissolution within this particle size range. However, considering the need for drug dissolution in a larger particle size range, the internal and external addition method (1:3) is preferred. This method uses 2% lubricant, while the formulation reported in patent CN 110013468B uses 1% lubricant. Therefore, this method produces powders with improved flowability and is more suitable for scale-up production.

[0162] Table 2

[0163] Examples 11, 12, 13 Tablets 11, 12, 13

[0164] Same as Example 3, except that the coating weight gain is different and the particle size D90 of the TY-9591 used is 112 μm, as shown in the following table.

[0165] The dissolution results of the obtained tablets 11, 12, and 13 (the dissolution medium was pH 1.2 hydrochloric acid sodium chloride buffer solution, 0.2% NaCl + 7 ml hydrochloric acid) are shown in Table 3 and Figure 3.

[0166] Table 3

[0167] It can be seen from Table 3 and Figure 3 that the dissolution of the coated tablets with different coating weight gains is basically the same and meets the standards.

[0168] Examples 14, 15 Tablets 14, 15

[0169] Same as Example 3, except that the hardness of the plain sheets 14 and 15 is different, as shown in the following table.

[0170] The dissolution results of the obtained tablets 14 and 15 (the dissolution medium was pH 1.2 hydrochloric acid sodium chloride buffer solution, 0.2% NaCl + 7 ml hydrochloric acid) are shown in Table 4 and Figure 4.

[0171] Table 4

[0172] From Table 4 and Figure 4, we can see that there are certain differences in the dissolution of tablets with different hardness, mainly in the 5-15 min dissolution. As the hardness of the tablet increases, the dissolution and release slows down, but it is basically completely released at 30 min, which meets the standard.

[0173] Example 16-19 Tablets 16-19

[0174] The same as Example 3, except that the feed speed, roller spacing, roller speed and oil pressure of the dry granulation are different, and the particle size D90 of the TY-9591 used is 112 μm, as shown in Table 5 below.

[0175] Table 5

[0176] The dissolution results of the obtained tablets 16-19 (dissolution medium: pH 1.2 sodium chloride hydrochloride buffer solution, 0.2% NaCl + 7 ml hydrochloric acid) are shown in Table 6 and Figure 5.

[0177] Table 6

[0178] From Table 5 and Figure 5, we can see that changing the feeding speed, roller spacing, roller speed and oil pressure of the dry granulation process resulted in similar dissolution results, with the dissolution exceeding 80% within 15 minutes, which met the standards.

[0179] Example 20 Tablet 20

[0180] Same as Example 3, except that the amounts of each component are different, as shown in the table below.

[0181] Given its strong binding force and good compressibility, microcrystalline cellulose, also known as a "dry binder," is known to improve tablet compressibility by increasing its proportion. Therefore, Tablet 20 was designed by increasing the proportion of microcrystalline cellulose by 5% compared to Tablet 3. Tablet compression data for Examples 3 and 20 are summarized in Table 7 below.

[0182] Table 7

[0183] The data in the table above show that, at the same tablet thickness, the two formulations achieve tablets with similar hardness (around 80 N) and consistent primary tablet thickness, indicating similar compressibility. Tablet 20 achieves a maximum hardness of around 140 N, demonstrating some improvement in compressibility. However, due to the increased proportion of microcrystalline cellulose, the powder mix flowability is slightly worse than that of Tablet 3.

[0184] Example 21 Tablet 21 and its preparation (prescription composition (10 mg))

[0185] Note: The TY-9591 used contains a methanesulfonic acid. 11.9 mg of the salt form drug is equivalent to 10 mg of the free base of TY-9591.

[0186] Tablet 21 was prepared using a dry mixing / rolling process using the materials listed in the table above. TY-9591 mesylate, mannitol, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose were added sequentially to a 5L mixing hopper, the mixing speed was set to 10 rpm, and the mixture was mixed for 15 minutes. Sodium stearyl fumarate (added internally) was added to a 5L mixing hopper, the mixing speed was set to 10 rpm, and the mixture was mixed for 5 minutes. The premix was added to a dry granulator for dry granulation, with a roller spacing of 1.5-2.5 mm, a roller speed of 7.0-11.0 rpm, and an oil pressure of 35-45 bar. The granules collected after dry granulation and the converted sodium stearyl fumarate (added externally) were added to a 5L mixing hopper, the speed was set to 10 rpm, and the mixing time was 5 minutes. The mixture was used for tableting, and punches were used to press plain tablets 21 (hardness 98.8-109.8N).

[0187] The film coating premix was prepared into a 20% (w / w) coating suspension, and the plain tablet 21 was coated with 3% of the weight of the plain tablet to form a 64.4 mg tablet 21.

[0188] The dissolution curve of tablet 21 in a pH 1.3 sodium chloride hydrochloride dissolution medium is shown in FIG6 . The dissolution results are similar to those of the 40 mg tablet, with the dissolution rate exceeding 80% in 15 minutes, meeting the standard.

[0189] Example 22: The present inventors scaled up production according to the formulation in Example 1 to produce Tablets 22. This batch of TY-9591 was not micronized, with a particle size D90 of 145 μm. The manufacturing process parameters, such as mixing speed and time, were identical to those in Example 1, except for the use of a 30L mixing hopper and a coating weight gain of 3.2%. Data on the relevant substances, content, and dissolution under long-term conditions (25°C ± 2°C / 60% ± 5% RH) and accelerated conditions (40°C ± 2°C / 75% ± 5% RH) were collected, as shown in Tables 7 and 8 below. The data from the three-year long-term and six-month accelerated data indicate that Tablets 22 obtained according to the formulation in Example 1 exhibit good storage stability.

[0190] Table 8 is a summary of the long-term stability test results of Tablet 22 (specification 40 mg), the dissolution medium being pH 1.3 hydrochloric acid sodium chloride buffer solution, 0.2% NaCl + 4 ml hydrochloric acid.

[0191] Table 8

[0192] From Table 8, we can see that the main indicators of long-term stability fluctuate within a certain range, and there is no significant difference in the data at each time point, indicating good stability.

[0193] 1) In terms of content, the test results fluctuate within the normal range.

[0194] 2) As far as the relevant substances are concerned, although the detection results of impurity B, single unknown impurity and total impurities fluctuated, the fluctuation range was small and there was no significant difference at different time points.

[0195] 3) As for dissolution, the test results fluctuated within the normal range and were in compliance with the Chinese Pharmacopoeia.

[0196] FIG7 and FIG8 are the content and dissolution curves of the tablet 22 obtained according to the formulation of Example 1 in the long-term stability test.

[0197] As shown in Figure 7, in the long-term stability test, although the content at each time point fluctuated to a certain extent, it was all within the acceptable standard range.

[0198] As shown in Figure 8, in the long-term stability test, although the dissolution rate at each time point fluctuated to a certain extent, it was all within the acceptable standard range and in compliance with the Chinese Pharmacopoeia.

[0199] Table 9 is a summary of the stability test results of Tablet 22 (40 mg) under accelerated conditions, where the dissolution medium was a pH 1.3 sodium chloride buffered saline solution.

[0200] Table 9

[0201] From Table 9, we can see that the main indicators of accelerated stability fluctuate within a certain range, and there is no significant difference in the data at each time point, indicating good stability.

[0202] 1) In terms of content, the test results fluctuate within the normal range.

[0203] 2) As far as the relevant substances are concerned, although the detection results of impurity B, single unknown impurity and total impurities fluctuated, the fluctuation range was small and there was no significant difference at different time points.

[0204] 3) As for dissolution, the test results fluctuated within the normal range and were in compliance with the Chinese Pharmacopoeia.

[0205] FIG9 and FIG10 are the content and dissolution curves of the tablet 22 obtained according to the formulation of Example 1 in the accelerated stability test.

[0206] As shown in Figure 9, in the accelerated stability test, although the content at each time point fluctuated to a certain extent, it was all within the acceptable standard range.

[0207] As shown in Figure 10, in the long-term stability test, although the dissolution rate at each time point fluctuated to a certain extent, it was all within the acceptable standard range and in compliance with the Chinese Pharmacopoeia.

[0208] The stability of the micronized sample Example 1 and the 10 mg sample also met the standards.

[0209] Example 23

[0210] In vivo exposure levels of Tablet 22

[0211] A single-dose study was conducted in healthy volunteers, and the pharmacokinetic data are shown in Table 10 below. The results showed that a single oral dose of 80 mg tablets 22 (40 mg x 2 tablets, calculated as TY-9591 free base) resulted in favorable in vivo exposure, with comparable pharmacokinetic data in subjects on a fasting diet and after a high-fat meal. Dosage was not affected by the feeding state, and the drug could be taken on an empty stomach or after a meal.

[0212] Table 10

[0213] Comparative Example 1

[0214] Same as Example 3, except that: no coating.

[0215] Table 11

[0216] As shown in Table 11 and Figure 11, the dissolution of the plain tablets was slightly faster than that of the coated tablet 3, with no significant difference. However, after coating, as shown in Table 12 below, the impurity B content of the plain tablets increased slightly after 20 days at room temperature, while that of the coated tablets remained essentially unchanged, indicating that coating improved their stability.

[0217] Table 12

[0218] Table 13 summarizes the hardness-disintegration time of the tablets obtained in Example 3 and Comparative Example 1.

[0219] Table 13

[0220] As shown in Table 13, the disintegration time of Example 3 did not change significantly with the change in hardness, while the disintegration time of Comparative Example 1 was significantly prolonged with the increase in hardness.

[0221] Comparative Example 2

[0222] Same as Example 1, except that the preparation process follows the parameters of Example 9 of patent CN105848647A. The details are as follows:

[0223] AZD9291 mesylate, mannitol, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose were added sequentially to a 25 L mixing hopper at a mixing speed of 15 rpm for 58 minutes. Sodium stearyl fumarate (0.5%) was added to the mixing hopper at a mixing speed of 15 rpm for 9.5 minutes. The premix was added to a dry granulator for dry granulation with a roller spacing of 2 mm, a roller speed of 10.1-10.2 rpm (25 mm roller), and a screw speed of 22.4-22.9 rpm. The resulting ribbon was milled using a Comil U3 with a granulator speed of 100 rpm and a mesh size of 1.27 mm. The granules collected after granulation and the converted sodium stearyl fumarate (added externally) were added to the mixing hopper at a mixing speed of 15 rpm for 5 minutes. The tablet cores were compressed using a tablet press equipped with a 9 mm punch (40 mg specification).

[0224] The film coating premix was prepared into a 20% (w / w) coating suspension, and the plain tablets were coated at 5% of the weight of the plain tablets to form 262.5 mg coated tablets.

[0225] A comparison of the dissolution curves of Example 9 of Patent CN105848647A in pH 1.3 hydrochloric acid and sodium chloride buffer salts with those of Example 3 of the present invention is shown in Figure 11. The dissolution rate of Example 3 of the present invention at 5 minutes is significantly higher than that of the comparative example at 7.5 minutes. The optimized preparation process of the present invention has the advantage of significantly faster dissolution rate, greatly shortens the preparation process time, and reduces production costs.

[0226] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A pharmaceutical composition, characterized in that The pharmaceutical composition is a tablet, comprising a tablet core and a coating located outside the tablet core; The core comprises the following components: The coating completely covers the tablet core, and the mass of the coating is 1-6wt% of the mass of the tablet core; The pharmaceutical composition is prepared as follows: 1) providing a mesylate salt of a compound of formula I, mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, sodium stearyl fumarate and a coating suspension; 2) mixing the mesylate salt of the compound of formula I, mannitol, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose to obtain a first mixture; 3) mixing the sodium stearyl fumarate for internal addition with the first mixture to obtain a second mixture; 4) dry granulating the second mixture to obtain first granules; 5) mixing the first particles with sodium stearyl fumarate for external addition to obtain a third mixture; 6) tableting the third mixture to obtain plain tablets; 7) coating the plain tablets with the coating suspension to obtain the pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, characterized in that The D90 of the active ingredient is 1-500 μm.

3. The pharmaceutical composition according to claim 1, characterized in that The methanesulfonate salt of the compound of formula I is a crystalline form of the monomethanesulfonate salt of the compound of formula I.

4. The pharmaceutical composition according to claim 3, characterized in that The X-ray powder diffraction of the crystal form at 2θ angle (the unit of 2θ angle is °) is: 7.1±0.2, 8.5±0.2, 9.4±0.2, 10.3±0.2, 12.6±0.2, 14.4±0.2, 15.1±0.2, 15.6±0.2, 16.3±0.2, 17.0±0.2, 17.3±0.2, 17 .7±0.2, 18.2±0.2, 18.7±0.2, 19.4±0.2, 19.7±0.2, 20.2±0.2, 20.7±0.2, 21.6±0.2, 22.0±0.2, 22.8±0.2, 23.5±0.2, 24.2±0.2, 24.8±0.2, 25.6±0.2, 26.0 There are diffraction peaks at 26.9±0.2, 27.7±0.2, 28.2±0.2, 29.5±0.2, 30.7±0.2, 31.7±0.2, 32.5±0.2, 33.1±0.2, 33.8±0.2, 34.6±0.2, 34.9±0.2, 35.6±0.2, 37.9±0.2, and 38.7±0.

2.

5. The pharmaceutical composition according to claim 1, characterized in that The pharmaceutical composition has one or more characteristics selected from the following group: 1) In a pH 1.2 hydrochloric acid and sodium chloride buffer, the solubility of the active ingredient in the pharmaceutical composition is ≥50% at 10 min; 2) In a pH 1.2 hydrochloric acid and sodium chloride buffer, the solubility of the active ingredient in the pharmaceutical composition is ≥ 80% at 15 min; 3) In a pH 1.2 hydrochloric acid and sodium chloride buffer, the solubility of the active ingredient in the pharmaceutical composition is ≥ 85% at 20 min; 4) In a pH 1.2 hydrochloric acid and sodium chloride buffer, the solubility of the active ingredient in the pharmaceutical composition is ≥ 90% at 30 min; 5) In a pH 1.2 hydrochloric acid and sodium chloride buffer, the solubility of the active ingredient in the pharmaceutical composition is ≥ 96% at 45 min; 6) In a pH 1.2 hydrochloric acid and sodium chloride buffer, the dissolution rate of the active ingredient in the pharmaceutical composition is ≥ 100% at 60 min; 7) After the pharmaceutical composition is stored at 25±2°C and 60%±5%RH for 3 years, the dissolution rate of the active ingredient in the pharmaceutical composition in a pH 1.3 hydrochloric acid and sodium chloride buffer solution is ≥95% at 30 minutes; 8) The pharmaceutical composition is stored at 40±2°C and 75%±5% RH for 6 months. In a pH 1.3 hydrochloric acid and sodium chloride buffer, the solubility of the active ingredient in the pharmaceutical composition is ≥95% at 30 minutes.

6. A method for preparing the pharmaceutical composition according to claim 1, characterized in that: Includes steps: 1) providing a mesylate salt of a compound of formula I, mannitol, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, sodium stearyl fumarate and a coating suspension; 2) mixing the mesylate salt of the compound of formula I, mannitol, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose to obtain a first mixture; 3) mixing the sodium stearyl fumarate for internal addition with the first mixture to obtain a second mixture; 4) dry granulating the second mixture to obtain first granules; 5) mixing the first particles with sodium stearyl fumarate for external addition to obtain a third mixture; 6) tableting the third mixture to obtain plain tablets; 7) coating the plain tablets with the coating suspension to obtain the pharmaceutical composition.

7. The method according to claim 6, characterized in that: The method has one or more characteristics selected from the following group: 1) In step 2), the mixing speed of the mixing is 4-14 rpm; 2) In step 2), the mixing time is 10-20 min; 3) In step 3), the mixing speed of the mixing is 4-14 rpm; 4) In step 3), the mixing time of the mixing is 2-9 min; 5) In step 4), the roller spacing of the dry granulation is 1.5-2.5 mm; 6) In step 4), the speed of the roller for dry granulation is 7.0-10.0 rpm; 7) In step 4), the oil pressure of the dry granulation is 35-50 bar; 8) In step 5), the mixing speed of the mixing is 4-14 rpm; 9) In step 5), the mixing time is 2-10 min.

8. The method according to claim 6, characterized in that: The hardness of the plain sheet is 70-120N.

9. A use of the pharmaceutical composition according to claim 1, characterized in that: Used for the preparation of anti-tumor drugs.

10. The use according to claim 9, characterized in that The tumor is lung cancer.

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