Pharmaceutical composition of pyrimidine derivatives

Abstract

The invention relates to a pharmaceutical composition of pyrimidine derivatives, and by optimizing a formula and a preparation process, the composition has excellent storage stability, acceleration stability and dissolution performance.

Description

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-(dimethylamine)ethyl)(methyl)amine)-4-methoxy-5-((4-(1-deuterated methyl-1H-indol-3-yl)pyrimidin-2-yl)amine)phenyl)acrylamide, and its structural formula is shown in Formula I.

[0003]

[0004] The compounds of formula I and their pharmaceutically acceptable salts are hereinafter referred to as "agents".

[0005] TY-9591 is the monomethanesulfonate salt of the compound represented by formula I.

[0006] TY-9591 can potentially be used to treat diseases or conditions involving EGFR or other protein kinases inhibited by TY-9591. TY-9591 is disclosed in CN 104140418 B, which is incorporated herein by reference. Example 3 of CN 104140418B describes the synthesis of TY-9591 and states that the product is obtained in the form of a solid. Several free base polymorphic forms of TY-9591 are described in CN 110950847B, which is incorporated herein by reference. Crystal forms of TY-9591 are described in CN 108558835 A, which is incorporated herein by reference.

[0007]

[0008] Chinese patent 201280033773.9 discloses a compound of formula II, AZD9291, which is effective against T790M EGFR mutant tumors, but it is easily metabolized and demethylated in vivo, which increases the metabolic burden of the liver, causes hepatotoxicity, increases the toxicity of metabolites, and causes a shorter half-life of the pharmacokinetic properties in vivo, and ultimately affects the anticancer activity of the drug. TY-9591 can reduce the occurrence of this side effect. In order to deliver the therapeutic benefits of TY-9591 to patients in need, TY-9591 needs to be formulated into a pharmaceutical composition, especially a solid dosage form suitable for oral administration. Therefore, a TY-9591 pharmaceutical preparation with good in vivo dissolution, high bioavailability, good storage stability and accelerated stability and stable quality is needed.

[0009] 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 that the D90 of the active ingredient be 20-280 μm when preparing the tablet. This is mainly because the preparation process of the tablet cannot guarantee the stability of small particle sizes (<20 μm). When the particles of the active ingredient 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 drug preparation and instability of the prepared drug 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 drug preparation (such as Example 1 (e) when the API particle size is D90 = 320 μm, the dissolution of the resulting tablet within 60 min is only 90%). Control of particle size is not conducive to the scale-up production of preparations.

[0010] 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.

[0011] 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 up to 73min). In the scaled-up production of the preparation, the long mixing 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 on the basis of the patent, and 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 the patent, which significantly shortens the preparation production cycle, reduces production costs, and is beneficial to the protection of drug stability. 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 (5min and 10min), and the drug dissolution rate is significantly improved compared with Example 9 of patent CN105848647A. Summary of the invention

[0012] 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.

[0013] In a first aspect of the present invention, a pharmaceutical composition is provided, wherein the pharmaceutical composition is a tablet, and the pharmaceutical composition comprises a tablet core and a coating located outside the tablet core;

[0014] The core comprises the following components:

[0015] Weight Function Methanesulfonate of the compound of formula I 18.5-19.5 (preferably 19-19.1, more preferably 19.04) Active ingredients Mannitol 57-60 (preferably 58-59, more preferably 58.96) First diluent Microcrystalline Cellulose 12-17 (preferably 14-16, more preferably 15) Second diluent Low substituted hydroxypropyl cellulose 3-7 (preferably 4-6, more preferably 5) Disintegrants Sodium stearyl fumarate (added) 0.3-0.7 (preferably 0.4-0.6, more preferably 0.5) First lubricant Sodium stearyl fumarate (added) 1.3-1.7 (preferably 1.4-1.6, more preferably 1.5) Second lubricant

[0016] The coating completely covers the tablet core, and the mass of the coating is 1-6wt% (preferably 2.5-5wt%, more preferably 2-4wt%) of the mass of the tablet core;

[0017]

[0018] The pharmaceutical composition is prepared as follows:

[0019] 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;

[0020] 2) mixing the mesylate salt of the compound of formula I, mannitol, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose to obtain a first mixture;

[0021] 3) mixing the sodium stearyl fumarate for internal addition with the first mixture to obtain a second mixture;

[0022] 4) dry granulating the second mixture to obtain first granules;

[0023] 5) mixing the first particles with sodium stearyl fumarate for external addition to obtain a third mixture;

[0024] 6) tableting the third mixture to obtain plain tablets;

[0025] 7) coating the plain tablets with the coating suspension to obtain the pharmaceutical composition.

[0026] In another preferred embodiment, the D90 of the active ingredient is 1-500 μm (preferably 3-495 μm).

[0027] In another preferred embodiment, the mesylate salt of the compound of formula I is a crystalline form of the mono-mesylate salt of the compound of formula I.

[0028] In another preferred embodiment, 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. 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.

[0029] In another preferred embodiment, the coating comprises a stabilizing substance and a polymer.

[0030] In another preferred embodiment, the stabilizing substance is selected from the following group: titanium dioxide, talc, red iron oxide, or a combination thereof.

[0031] In another preferred embodiment, the polymer is selected from the group consisting of polyvinyl alcohol, polyethylene glycol, or a combination thereof.

[0032] In another preferred embodiment, the pharmaceutical composition has one or more characteristics selected from the following group:

[0033] 1) In a pH 1.2 hydrochloric acid and sodium chloride buffer, the solubility of the active ingredient in the pharmaceutical composition is ≥50% (preferably ≥70%, more preferably ≥90%) at 10 min;

[0034] 2) In a pH 1.2 hydrochloric acid and sodium chloride buffer, at 15 min, the solubility of the active ingredient in the pharmaceutical composition is ≥80% (preferably ≥90%, more preferably ≥93%);

[0035] 3) In a pH 1.2 hydrochloric acid and sodium chloride buffer, the solubility of the active ingredient in the pharmaceutical composition is ≥85% (preferably ≥90%, more preferably ≥94%) at 20 min;

[0036] 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%) at 30 min;

[0037] 5) In a pH 1.2 hydrochloric acid and sodium chloride buffer, the solubility of the active ingredient in the pharmaceutical composition is ≥96% (preferably ≥97%) at 45 min;

[0038] 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;

[0039] 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;

[0040] 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.

[0041] In another preferred embodiment, the pharmaceutical composition is an oral preparation.

[0042] 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:

[0043] 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;

[0044] 2) mixing the mesylate salt of the compound of formula I, mannitol, microcrystalline cellulose, and low-substituted hydroxypropyl cellulose to obtain a first mixture;

[0045] 3) mixing the sodium stearyl fumarate for internal addition with the first mixture to obtain a second mixture;

[0046] 4) dry granulating the second mixture to obtain first granules;

[0047] 5) mixing the first particles with sodium stearyl fumarate for external addition to obtain a third mixture;

[0048] 6) tableting the third mixture to obtain plain tablets;

[0049] 7) coating the plain tablets with the coating suspension to obtain the pharmaceutical composition.

[0050] In another preferred embodiment, the method has one or more characteristics selected from the following group:

[0051] 1) In step 2), the mixing speed of the mixing is 4-14 rpm (preferably 8-12 rpm);

[0052] 2) In step 2), the mixing time is 10-20 min (preferably 14-16 min);

[0053] 3) In step 3), the mixing speed of the mixing is 4-14 rpm (preferably 8-12 rpm);

[0054] 4) In step 3), the mixing time is 2-9 min (preferably 4-6 min);

[0055] 5) In step 4), the roller spacing of the dry granulation is 1.5-2.5 mm;

[0056] 6) In step 4), the speed of the roller for dry granulation is 7.0-10.0 rpm;

[0057] 7) In step 4), the oil pressure of the dry granulation is 35-50 bar;

[0058] 8) In step 5), the mixing speed of the mixing is 4-14 rpm (preferably 8-12 rpm);

[0059] 9) In step 5), the mixing time is 2-10 min (preferably 3-7 min).

[0060] In another preferred embodiment, the hardness of the plain sheet is 70-120N (preferably 95-105N).

[0061] 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.

[0062] In another preferred embodiment, the tumor is lung cancer.

[0063] In another preferred embodiment, the lung cancer is non-small cell lung cancer.

[0064] 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 specifically described below (such as embodiments) can be combined with each other to form a new or preferred technical solution. Due to space limitations, they will not be described one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0065] Figure 1 The dissolution curves of the tablets obtained in Examples 1 to 6 are shown below.

[0066] Figure 2 The dissolution curves of the tablets obtained in Examples 7 to 10 are shown.

[0067] Figure 3 The dissolution curves of the tablets obtained in Examples 11 to 13 are shown.

[0068] Figure 4 The dissolution curves of the tablets obtained in Examples 3, 14 and 15 are shown.

[0069] Figure 5 The dissolution curves of the tablets obtained in Examples 16 to 19 are shown.

[0070] Figure 6 This is the dissolution curve of the tablets obtained in Examples 3 and 21.

[0071] Figure 7 , Figure 8 The content and dissolution curve 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).

[0072] Fig. 9 , Fig.10 The content and dissolution curve of the accelerated 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).

[0073] Fig.11 The dissolution curves of the tablets obtained in Example 3 and Comparative Examples 1 and 2 are shown in FIG. 1 . The dissolution medium is a pH 1.3 sodium chloride hydrochloride buffer solution, 0.2% NaCl + 4 ml hydrochloric acid. DETAILED DESCRIPTION

[0074] After long-term and in-depth research, the inventors have obtained a pharmaceutical composition with excellent dissolution performance, pharmacokinetic performance and storage stability by optimizing the composition and / or process. On this basis, the inventors have completed the present invention.

[0075] As used herein, the term "comprising" or "including (comprising)" may be open, semi-closed and closed. In other words, the term also includes "consisting essentially of" or "consisting of".

[0076] Drugs can be absorbed at many different sites along the gastrointestinal tract (including via the stomach, duodenum, jejunum, ileum and colon) after oral administration. The pH is different at each absorption site as the pH varies significantly between the stomach (pH 1-3.5) and the small intestine (pH 4-8). According to our research, TY-9591 exhibits significant pH-dependent solubility and moderate permeability. For example, it has been found that TY-9591 has a higher solubility in pH 1 (hydrochloric acid) relative to pH 6.8 (sodium hydroxide-monobasic sodium phosphate buffer, 25mM). In such cases, where the solubility of the drug varies with pH, ​​and specifically when the solubility is highest at acidic pH, there is a problem that the drug can precipitate from the solution as it passes through the gastrointestinal tract; the drug needs to be in solution in order to be absorbed, but such precipitation may affect the degree and rate of absorption of the drug. Compounds with pH-dependent solubility, particularly basic compounds, may exhibit undesirable pharmacokinetic properties, such as poor absorption or low bioavailability, which can lead to significant inter- and intra-patient variability.

[0077] Therefore, there is a need to find an improved TY-9591 dosage form having a favorable dissolution and pharmacokinetic profile and showing good storage stability. At the same time, we have found that the solid dosage form according to the present invention shows excellent storage stability.

[0078] The present invention relates to pharmaceutical compositions suitable for oral administration, and more particularly to pharmaceutical compositions (and pharmaceutical tablets) comprising TY-9591.

[0079] The present invention provides a solution to one or more of the above problems and relates to a novel pharmaceutical composition comprising the agent. The pharmaceutical composition of the present invention can be formed into a tablet, which exhibits improved dissolution properties under physiologically relevant conditions and / or a higher total release of the agent on physiologically relevant indicators.

[0080] Since the compound of the present invention has excellent anti-tumor activity, the pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used to treat, prevent and alleviate tumor-related diseases.

[0081] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention or a pharmacologically acceptable salt thereof and a pharmacologically acceptable excipient or carrier. Wherein "safe and effective amount" means: the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, and more preferably, contains 10-1000 mg of the compound of the present invention per dose. Preferably, the "one dose" is a capsule or tablet.

[0082] "Pharmaceutically acceptable carrier" refers 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 ), wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0083] The pharmaceutical composition is in the form of injection, capsule, tablet, pill, powder or granule.

[0084] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), and topical administration.

[0085] 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 starch 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.

[0086] Solid dosage forms such as tablets, pills, 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 opacifiers, and the release of the active compound or compounds in such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can also be formed into microencapsulated form with one or more of the above-mentioned excipients.

[0087] 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, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, in particular cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or mixtures of these substances.

[0088] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0089] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methanol and agar, or mixtures of these substances, and the like.

[0090] Compositions for parenteral injection may include 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.

[0091] Dosage forms for topical administration of the compounds of the 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.

[0092] The composition of the present invention can be administered alone or in combination with other pharmaceutically acceptable compositions (such as anti-tumor drugs).

[0093] The treatment method of the present invention can be used alone or in combination with other treatment methods or therapeutic drugs.

[0094] When using the pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (such as a human) in need of treatment, wherein the dosage during administration is a pharmaceutically effective dosage, and for a person weighing 60 kg, the daily dosage is usually 1 to 2000 mg, preferably 50 to 1000 mg. Of course, the specific dosage should also take into account factors such as the route of administration and the health status of the patient, which are all within the skill of a skilled physician.

[0095] The specific embodiments of the present invention specifically describe the preparation methods of the pharmaceutical composition of the present invention, but these specific methods do not constitute any limitation to the present invention. The pharmaceutical composition of the present invention can also be conveniently prepared by optionally combining various preparation methods described in this specification or known in the art.

[0096] 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.

[0097] It should be understood that for film coating premixes, any commercially available and well-known coating premixes in the art can achieve similar technical effects of the present invention.

[0098] Crystal form

[0099] Crystal form is the solid state of a drug. The study of drug crystal form is the study of the basic state of the drug. Only when we have a relatively full and comprehensive understanding of the crystal state of chemical drugs can we find more suitable drug crystal solid substances for treating diseases. The crystal form of a drug can affect the physical and chemical properties of the drug and directly affect the basis for the drug to play a role in treating diseases in clinical practice. Different crystal forms of the same drug may have significant differences in appearance, solubility, melting point, dissolution, bioavailability, etc., thereby affecting the stability, bioavailability and efficacy of the drug. Therefore, it is of great significance to study the stable crystal form of the compound.

[0100] The active ingredients of the same drug generally exist in two or more crystal forms, which are called drug polymorphs. Different crystal forms have different solubility and dissolution rates, which affect the clinical therapeutic effect of the drug by causing changes in bioavailability in the body. The difference in drug crystal forms may affect its dissolution and absorption in the body, and then affect the bioavailability, clinical efficacy and safety of the drug. 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. At present, the crystal form with better therapeutic effect and the most suitable clinically is called the dominant drug crystal form.

[0101] The crystal form of TY-9591 in the present invention is the crystal form described in patent CN 108558835 A.

[0102] Specifically, the X-ray powder diffraction of the TY-9591 crystal form of the present invention measured by Cu-Kα ray at a 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, 20.3±0.2, 21.4±0.2 The diffraction peaks are at .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±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.

[0103] More specifically, the crystal form of TY-9591 of the present invention has the X-ray powder diffraction data shown in Table A below.

[0104] Table A

[0105]

[0106]

[0107] Compared with the prior art, the present invention has the following main advantages:

[0108] (1) The pharmaceutical composition has excellent dissolution performance, pharmacokinetic properties and storage stability;

[0109] (2) The pharmaceutical composition has stable quality;

[0110] (3) The preparation process of the pharmaceutical composition is simple and easy to implement, and is convenient for industrial production;

[0111] (4) The pharmaceutical composition is easy to administer, safe and reliable to use, easily accepted by patients, and has high social and economic value.

[0112] 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 where specific conditions are not specified are 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 under conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0113] Unless otherwise defined, all professional and scientific terms used herein have the same meanings as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein can be applied to the methods of the present invention. The preferred implementation methods and materials described herein are for demonstration purposes only.

[0114] General raw materials

[0115] Material Name model The crystal form of TY-9591, the drug substances used in the examples of the present invention are all of this crystal form N / A Mannitol 100SD Microcrystalline Cellulose VIVAPUR101 Low substituted hydroxypropyl cellulose LH-21 Sodium stearyl fumarate PRUV Film coating premix 85F94245-CN

[0116] General Methods

[0117] Dissolution performance

[0118] Dissolution refers to the speed and degree of drug dissolution from solid preparations such as tablets in a specified solvent. Dissolution is an important indicator for tablet quality control, and poorly soluble drugs should generally be tested for dissolution. The dissolution test method is to place a certain amount of a solid preparation in the rotating basket (or dissolution cup) of the dissolution instrument, operate it according to the law at a constant temperature of 37℃±0.5℃, at a specified speed and dissolution medium, take samples within a specified time and measure the dissolution amount.

[0119] The dissolution test conditions are as follows:

[0120] Dissolution medium: pH 1.2 sodium chloride hydrochloride buffer (0.2% NaCl + 7ml hydrochloric acid) or pH 1.3 sodium chloride hydrochloride buffer (0.2% NaCl + 4ml hydrochloric acid)

[0121] Dissolution medium volume: 900ml

[0122] Speed: 50rpm

[0123] Water bath temperature: 37±0.5℃

[0124] Sampling time points: 5, 10, 15, 20, 30, 45, 60-90 min (maximum speed 150 rpm)

[0125] Sampling method: automatic sampling 1.5ml without rehydration, gain 3.5ml, rinse 10ml

[0126] pH 1.2 hydrochloric acid and sodium chloride buffer solution can make the solubility of TY-9591 raw material meet the sink condition; the dissolution curve of TY-9591 tablets detected by 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 solubility is around 80% in 15 minutes, and the dissolution is greater than 85% in 45-60 minutes.

[0127] Determination of impurity B content

[0128] Impurity B (impurity RRT1.5, i.e., relative retention time 1.5) is a degradation impurity in the stability study of this preparation and is a unique impurity that needs to be focused on. Through systematic research, it was found that impurity B (impurity RRT1.5) is very unstable under neutral and alkaline conditions, easily degraded into raw materials and other impurities, and relatively stable under acidic conditions. Therefore, the study of the content of impurity B is also an important content of the present invention.

[0129] The method for determining the content of impurity B is as follows:

[0130] 1. Chromatographic conditions (HPLC):

[0131]

[0132]

[0133] Gradient table:

[0134] Time (min) Mobile phase A (% V / V) Mobile phase B (% V / V) 0 70 30 40 35 65 45 20 80 45.1 70 30 55 70 30

[0135] 2. Reagents and reference substances

[0136] Heptafluorobutyric acid: chromatographic pure water: ultrapure water Ammonia: chromatographic pure or analytical pure

[0137] Acetonitrile: Chromatographic grade Methanol: Chromatographic grade

[0138] TY-9591 reference substance: self-made or purchased

[0139] 3. Solution preparation

[0140] Diluent: methanol: water: heptafluorobutyric acid = 50:50:0.1 (V / V / V)

[0141] Blank solution: diluent

[0142] 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 scale, and mix well).

[0143] Working test 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 with diluent and make up to the mark, and mix well).

[0144] Reference solution: Prepare a solution containing TY-9591 reference substance at a concentration of 1.0 μg / mL (for example: weigh 50 mg of TY-9591 reference substance, accurately weigh it in a 50 mL volumetric flask, dissolve it with diluent and dilute it to the mark, mix it; then accurately transfer 5.0 mL of the solution to a 100 mL volumetric flask, dilute it to the mark with diluent, mix it; then accurately transfer 1.0 mL of the solution to a 50 mL volumetric flask, dilute it to the mark with diluent, mix it).

[0145] Sensitivity solution: Prepare a solution containing TY-9591 reference substance at a concentration of 0.5 μg / mL (for example: accurately transfer 5.0 mL of reference solution into a 10 mL volumetric flask, dilute to the mark with diluent, and mix well).

[0146] Related substance test sample solution: Prepare a solution containing the test sample at a concentration of 1.0 mg / mL (for example: weigh 50 mg of the test sample, accurately weigh it in a 50 mL volumetric flask, dissolve it in the diluent and dilute it to the scale, and mix well).

[0147] Content Test 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 make up to the mark, and mix well).

[0148] Prepare two test sample solutions with the same concentration.

[0149] Program control solution: standard solution.

[0150] 4. Calculation

[0151]

[0152] in:

[0153] At---peak area of ​​unknown impurities in the test solution;

[0154] Ar---average peak area of ​​the main peak in the reference solution;

[0155] Cr---concentration of reference solution (mg / mL);

[0156] Ct---concentration of the test solution (mg / mL);

[0157] P---Content of TY-9591 reference substance

[0158] The content of impurity B is calculated by the above formula.

[0159] Example 1 Tablet 1 and its preparation (prescription composition (40 mg))

[0160] Name of raw materials Specific gravity %(w / w) mg / tablet Function TY-9591(D90=4.8μm) 19.04 47.60 Drug substances Mannitol 58.96 147.40 Thinner Microcrystalline Cellulose 15.00 37.50 Thinner Low substituted hydroxypropyl cellulose 5.00 12.50 Disintegrants Sodium stearyl fumarate (added) 0.50 1.25 Lubricants Sodium stearyl fumarate (added) 1.50 3.75 Lubricants total 100 250

[0161] Note: The TY-9591 used contains a methanesulfonic acid, and 47.6 mg of the salt drug is equivalent to 40 mg of TY-9591 free base.

[0162] TY-9591 was micronized to control its particle size D90 within 20 μm (the actual D90 was 4.8 μm). Tablet 1 was manufactured using a dry mixing / rolling process using the materials listed in the above table. TY-9591, mannitol, microcrystalline cellulose and low-substituted hydroxypropyl cellulose were added to a 5L mixing hopper in sequence, the mixing speed was set to 10 rpm, and the mixture was mixed for 15 min. Sodium stearyl fumarate (internal addition) was added to a 5L mixing hopper, the mixing speed was set to 10 rpm, and the mixture was mixed for 5 min to obtain a premix. The premix was added to a dry granulator for dry granulation, with a roller spacing (1.5-2.5 mm, specifically 1.9-2.0 mm), a roller speed (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 into a 5L 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, and a plain tablet 1 (hardness 98.8-109.8N) was pressed using a punch.

[0163] The film coating premix (7.5 mg / tablet) is 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 is coated with 3.8% of the weight of the plain tablet to form a tablet 1 of about 260 mg.

[0164] The dissolution results of the obtained tablet 1 (the dissolution medium is pH 1.2 hydrochloric acid sodium chloride buffer, 0.2% NaCl + 7ml hydrochloric acid) are shown in Table 1 and Figure 1 As shown, tablet 1 can be completely dissolved under the above dissolution conditions, and the dissolution rate has reached 95% of the labeled amount at 45 minutes, which meets the standard.

[0165] Examples 2 to 6 Tablets 2 to 6

[0166] Same as Example 1, except that the particle size of TY-9591 is different, as shown in the following table.

[0167] Example TY-9591 particle size (D90) Example 2 16μm Example 3 95μm Example 4 195μm Example 5 246μm Example 6 494μm

[0168] The dissolution results of the obtained tablets 2 to 6 (the dissolution medium is pH 1.2 hydrochloric acid sodium chloride buffer, 0.2% NaCl + 7ml hydrochloric acid) are shown in Table 1. Figure 1 shown.

[0169] Table 1

[0170]

[0171] As can be seen from the data in Table 1, this prescription is not only suitable for particle size ranges of D90 of 20-280μm, but also meets the standards for dissolution of small particle size TY-9591 (D90<20μm) and large particle size TY-9591 (D90>300μm). The advantage of this prescription is that it can completely release micronized drugs (D90<5μm) under the condition of large specific surface area and easy decomposition and deliquescence. However, the preparation formula reported in patent CN110013468 B cannot completely dissolve the drug when D90<20μm (Comparative Example 1(a)). In the large particle size range (Example 6, D90=494μm>280μm), the drug can also be completely dissolved because the internal and external addition of lubricants promotes the dissolution of the drug. And the tablets prepared by the preparation prescription 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.

[0172] Embodiments 7 to 10

[0173] In order to study the effect of internal and external addition of lubricants on tablets, Examples 7 to 10 investigated the ratio of internal and external addition of lubricants. The particle size of the API used was D90 = 222 μm, and the specific ratio is shown in the following table (the dissolution medium was pH 1.2 hydrochloric acid sodium chloride buffer, 0.2% NaCl + 7 ml hydrochloric acid).

[0174]

[0175] As shown in Table 2, Figure 2 As shown, under the conditions of the present formulation (D90 = 222 μm), the addition of lubricants to the inside and outside of the formulation has no significant effect on the drug dissolution in the particle size range. However, considering the need for drug dissolution in a large particle size range, the internal and external addition method (1:3) is preferred. The amount of lubricant used in this method is 2%, while the amount of lubricant used in the formulation formula reported in patent CN 110013468B is 1%. Therefore, the powder prepared by this method has better fluidity and is more conducive to the scale-up production of the formulation.

[0176] Table 2

[0177]

[0178] Examples 11, 12, 13 Tablets 11, 12, 13

[0179] 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.

[0180]

[0181]

[0182] The dissolution results of the obtained tablets 11, 12, and 13 (the dissolution medium is pH 1.2 hydrochloric acid sodium chloride buffer, 0.2% NaCl + 7ml hydrochloric acid) are shown in Table 3 and Figure 3 shown.

[0183] Table 3

[0184]

[0185] From Table 3 and Figure 3 It can be seen that the dissolution of coated tablets with different coating weight gains is basically the same and meets the standards.

[0186] Example 14, 15 Tablets 14, 15

[0187] The same as the embodiment 3, except that the hardness of the plain sheets 14 and 15 is different, as shown in the following table.

[0188] Hardness of blank sheet (N) Example 3 100 Embodiment 14 70 Embodiment 15 130

[0189] The dissolution results of the obtained tablets 14 and 15 (the dissolution medium is pH 1.2 hydrochloric acid sodium chloride buffer, 0.2% NaCl + 7ml hydrochloric acid) are shown in Tables 4 and Figure 4 shown.

[0190] Table 4

[0191]

[0192] From Table 4 and Figure 4 It can be seen that there are certain differences in the dissolution of tablets of different hardness, mainly in the 5-15min dissolution. As the hardness of the tablet increases, the dissolution release slows down, but it is basically completely released at 30min, which meets the standard.

[0193] Example 16-19 Tablets 16-19

[0194] Same as Example 3, except that the feeding speed, roller spacing, roller speed and oil pressure of dry granulation are different, and the particle size D90 of the TY-9591 used is 112 μm, as shown in Table 5 below.

[0195] Table 5

[0196]

[0197]

[0198] The dissolution results of the obtained tablets 16-19 (the dissolution medium is pH 1.2 hydrochloric acid sodium chloride buffer, 0.2% NaCl + 7ml hydrochloric acid) are shown in Tables 6 and Figure 5 shown.

[0199] Table 6

[0200]

[0201] From Table 5 and Figure 5 It can be seen that changing the feeding speed, roller spacing, roller speed and oil pressure of dry granulation results in similar dissolution results, with the dissolution rate exceeding 80% in 15 minutes, which meets the standard.

[0202] Example 20 Tablet 20

[0203] Same as Example 3, except that the dosage of each component is different, as shown in the table below.

[0204] Name of raw materials Specific gravity %(w / w) mg / tablet Function TY-9591 19.04 47.60 Drug substances Mannitol 53.96 134.90 Thinner Microcrystalline Cellulose 20.00 50.00 Thinner Low substituted hydroxypropyl cellulose 5.00 12.50 Disintegrants Sodium stearyl fumarate (added) 0.50 1.25 Lubricants Sodium stearyl fumarate (added) 1.50 3.75 Lubricants total 100 250

[0205] In view of the fact that microcrystalline cellulose has strong binding force and good compressibility, it is also known as a "dry binder". Increasing its proportion is helpful to improve the compressibility of the tablet. Therefore, Tablet 20 is designed, that is, the proportion of microcrystalline cellulose is increased by 5% on the basis of Tablet 3. The summary information of the tableting data of Examples 3 and 20 is shown in Table 7 below.

[0206] Table 7

[0207]

[0208] From the data in the table above, it can be seen that under the same tablet thickness, the tablet hardness obtained by pressing the two prescriptions is close (about 80N), and the main tablet thickness is consistent, indicating that the compressibility of the two prescriptions is similar. The maximum hardness of tablet 20 can reach about 140N, and the compressibility has been improved to a certain extent, but the proportion of microcrystalline cellulose is increased, and the mixed powder fluidity is slightly worse than that of tablet 3.

[0209] Example 21 Tablet 21 and its preparation (prescription composition (10 mg))

[0210] Name of raw materials Specific gravity %(w / w) mg / tablet Function TY-9591 19.04 11.9 Drug substances Mannitol 58.96 36.85 Thinner Microcrystalline Cellulose 15.00 9.375 Thinner Low substituted hydroxypropyl cellulose 5.00 3.125 Disintegrants Sodium stearyl fumarate (added) 0.50 0.3125 Lubricants Sodium stearyl fumarate (added) 1.50 0.9375 Lubricants total 100 62.5

[0211] Note: The TY-9591 used contains a methanesulfonic acid, and 11.9 mg of the salt drug is equivalent to 10 mg of TY-9591 free base.

[0212] 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 to a 5L mixing hopper in sequence, the mixing speed was set to 10rpm, and the mixture was mixed for 15min. Sodium stearyl fumarate (internal addition) was added to a 5L mixing hopper, the mixing speed was set to 10rpm, and the mixture was mixed for 5min. The premix was added to a dry granulator for dry granulation, with a roller spacing (1.5-2.5mm), a roller speed (7.0-11.0rpm), and an oil pressure of 35-45bar. The granules collected after dry granulation and the converted sodium stearyl fumarate (external addition) were added to a 5L mixing hopper, the speed was set to 10rpm, and the mixing time was 5 minutes. The mixture was used for tableting, and a punch was used to press the plain tablet 21 (hardness 98.8-109.8N).

[0213] The film coating premix was prepared into a 20% (w / w) coating suspension, and the plain tablet 21 was coated at 3% of the weight of the plain tablet to form a 64.4 mg tablet 21.

[0214] The dissolution curve of tablet 21 in the sodium chloride hydrochloride dissolution medium of pH 1.3 is as follows Figure 6 As shown, the dissolution results were similar to those of the 40 mg tablets, with more than 80% dissolution in 15 minutes, which met the standards.

[0215] Example 22 The inventors carried out scaled-up production according to the prescription in Example 1 to obtain tablets 22. The batch of TY-9591 was not micronized, and the particle size D90 was 145 μm. Except for the use of a 30L mixing hopper and a coating weight gain of 3.2%, the preparation process parameters such as mixing speed and mixing time were the same as those in Example 1. The inventors collected data on the relevant substances, content and dissolution under long-term conditions (25°C ± 2°C / 60%RH ± 5%RH) and accelerated conditions (40°C ± 2°C / 75%RH ± 5%RH), as shown in Tables 7 and 8 below. From the data under long-term conditions for 3 years and accelerated conditions for 6 months, it can be concluded that the tablets 22 obtained according to the prescription of Example 1 have good storage stability.

[0216] Table 8 is a summary table of the long-term stability test results of Tablet 22 (specification 40 mg), the dissolution medium is pH 1.3 sodium chloride hydrochloric acid buffer, 0.2% NaCl + 4 ml hydrochloric acid.

[0217] Table 8

[0218]

[0219] From Table 8, we can see that the main indicators in long-term stability fluctuate within a certain range, and there is no obvious difference in the data at each time point, indicating good stability.

[0220] 1) In terms of content, the test results fluctuate within the normal range.

[0221] 2) As far as the relevant substances are concerned, although the detection results of impurity B, single unknown impurities and total impurities fluctuate, the fluctuation range is small and there is no obvious difference at different time points.

[0222] 3) As for dissolution, the test results fluctuated within the normal range and were in line with the Chinese Pharmacopoeia.

[0223] Figure 7 , Figure 8 The content and dissolution curve of the tablet 22 obtained according to the formulation of Example 1 in the long-term stability test.

[0224] from Figure 7 It can be seen that in the long-term stability test, although the content at each time point has certain fluctuations, it is still within the acceptable standard range.

[0225] from Figure 8 It can be seen that: in the long-term stability test, although the dissolution rate at each time point has certain fluctuations, it is all within the acceptable standard range and in line with the Chinese Pharmacopoeia.

[0226] Table 9 is a summary of the stability test results of Tablet 22 (Specification 40 mg) under accelerated conditions, where the dissolution medium is sodium chloride buffer with a pH of 1.3.

[0227] Table 9

[0228]

[0229]

[0230] From Table 9, we can see that the main indicators of accelerated stability fluctuate within a certain range, and there is no obvious difference in the data at each time point, indicating good stability.

[0231] 1) In terms of content, the test results fluctuate within the normal range.

[0232] 2) As far as the relevant substances are concerned, although the detection results of impurity B, single unknown impurities and total impurities fluctuate, the fluctuation range is small and there is no obvious difference at different time points.

[0233] 3) As for dissolution, the test results fluctuated within the normal range and were in line with the Chinese Pharmacopoeia.

[0234] Fig. 9 , Fig.10The content and dissolution curve of the tablet 22 obtained according to the formulation of Example 1 were obtained by accelerated stability testing.

[0235] from Fig. 9 It can be seen that: in the accelerated stability test, although the content at each time point has certain fluctuations, it is still within the acceptable standard range.

[0236] from Fig.10 It can be seen that: in the long-term stability test, although the dissolution rate at each time point has certain fluctuations, it is all within the acceptable standard range and in line with the Chinese Pharmacopoeia.

[0237] The stability of the micronized sample Example 1 and the 10 mg sample also met the standards.

[0238] Embodiment 23

[0239] In vivo exposure level of Tablet 22

[0240] A single-dose study was conducted in healthy volunteers, and the pharmacokinetic data are shown in Table 10. The results showed that the in vivo exposure of a single oral dose of 80 mg tablet 22 (40 mg*2 tablets based on TY-9591 free base) was good, and the pharmacokinetic data in subjects with and without a high-fat meal were comparable. The medication was not affected by the eating state, and the medication could be taken on an empty stomach or after a meal.

[0241] Table 10

[0242]

[0243]

[0244] Comparative Example 1

[0245] Same as Example 3, except that there is no coating.

[0246] Table 11

[0247]

[0248] Tablet dissolution is shown in Table 11. Fig.11 As shown in Table 12, the dissolution rate of the coated tablets was slightly faster than that of the coated tablets 3, but there was no significant difference. However, after coating, as shown in Table 12 below, the impurity B of the plain tablets increased after being placed at room temperature for 20 days, while the impurity B of the coated tablets remained basically unchanged, indicating that coating can improve its stability.

[0249] Table 12

[0250]

[0251] Table 13 summarizes the hardness-disintegration time of the tablets obtained in Example 3 and Comparative Example 1.

[0252] Table 13

[0253]

[0254]

[0255] It can be seen from Table 13 that the disintegration time of Example 3 does not change significantly with the hardness, while the disintegration time of Comparative Example 1 is significantly prolonged with the increase of hardness.

[0256] Comparative Example 2

[0257] Same as Example 1, except that the preparation process is in accordance with the parameters of Example 9 of patent CN105848647A.

[0258] The details are as follows:

[0259] AZD9291 mesylate, mannitol, microcrystalline cellulose and low-substituted hydroxypropyl cellulose were added to a 25L mixing hopper in sequence, the mixing speed was set to 15 rpm, and the mixture was mixed for 58 minutes. Sodium stearyl fumarate (0.5%) was added to the mixing hopper, the mixing speed was set to 15 rpm, and the mixture was mixed for 9.5 minutes. The premix was added to a dry granulator for dry granulation, the roller spacing was 2 mm, the roller speed was 10.1-10.2 rpm (25 mm roller), and the screw speed was 22.4-22.9 rpm. The resulting ribbon was milled using a Comil U3 with a granulator speed of 100 rpm and a sieve size of 1.27 mm. The granules collected after granulation and the converted sodium stearyl fumarate (added) were added to the mixing hopper, the speed was set to 15 rpm, and the mixing time was 5 minutes. The tablet cores were compressed using a tablet press equipped with a 9 mm punch (40 mg specification).

[0260] 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.

[0261] The dissolution curve of Example 9 of Patent CN105848647A in pH 1.3 sodium chloride buffer salt is compared with the dissolution curve of Example 3 of the present invention. Fig.11 As shown, 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 preparation process optimized by the present invention has the advantage of significantly fast dissolution rate, greatly shortens the preparation process time, and reduces production costs.

[0262] All documents mentioned in the present invention are cited as references in this application, just as each document is cited as reference individually. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the claims attached to this application.

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. There are diffraction peaks at 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.

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 min.

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 to prepare anti-tumor drugs.

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

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