Pharmaceutical composition of a multi-targeted protein kinase inhibitor and uses thereof

Abstract

The application discloses a pharmaceutical composition containing a multi-target protein kinase inhibitor compound and application thereof. The pharmaceutical composition contains a compound shown in formula II, formula A or formula B as an active ingredient and an excipient. The pharmaceutical composition has the characteristics of simple preparation method, smooth preparation process and suitability for industrialized production. An oral preparation, especially an oral solid preparation made from the pharmaceutical composition has advantageous dissolution, content uniformity and other preparation properties and excellent stability, and is suitable for use and storage as a medicine.

Description

[0001] Citation of relevant applications

[0002] This invention claims priority to two Chinese patent applications filed on December 31, 2020, entitled "A pharmaceutical composition of a multi-target protein kinase inhibitor and its application therein", application number 202011642452.1, and July 22, 2021, entitled "A pharmaceutical composition of a multi-target protein kinase inhibitor and its application therein", application number 202110829596.6, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This application belongs to the field of pharmaceutical formulation technology, specifically relating to a pharmaceutical composition of a multi-target protein kinase inhibitor and its application. Background Technology

[0004] Malignant tumors are among the most serious diseases threatening human life and health, and have become the second leading cause of death after cardiovascular diseases. Chemotherapy is the most important treatment for malignant tumors besides surgery and radiotherapy. Traditional chemotherapy drugs mainly act on common components related to the life and death of all cells, such as DNA, RNA, and microtubules, resulting in low selectivity and high toxicity. Targeted therapy drugs, on the other hand, act on key molecules and signal transduction pathways that regulate cell growth and proliferation in tumor cells and are significantly different from those in normal cells. They have advantages such as high selectivity for tumor cells and low toxicity to normal tissues, and have become a hot topic in anti-tumor drug research.

[0005] Among the numerous molecules regulating cell signal transduction pathways, the protein kinase family is the most important. Studies have shown that the occurrence and development of many tumors are related to gene abnormalities or overactivation of protein kinases. Therefore, protein kinases have become the most important targets for anti-tumor therapy. Among the members of the protein kinase family, tyrosine and serine / threonine protein kinases such as EGFR (Epidermal Growth Factor Receptor), VEGFR (Vascular Endothelial Growth Factor Receptor), PDGFR (Platelet-Derived Growth Factor Receptor), c-Kit, c-SRC, MET, BTK, ALK, Abl, and FLT3 are the most important and have been classified as oncogenes or oncoproteins.

[0006] Currently, several small molecule inhibitors targeting these tyrosine and serine / threonine protein kinases are used in clinical cancer treatment. Typical examples include: two EGFR inhibitors, gefitinib and erlotinib, mainly used to treat non-small cell lung cancer; two angiogenesis inhibitors (mainly targeting VEGFR and PDGFR, etc.), sunitinib and sorafenib, used for anti-angiogenic therapy of solid tumors; and the Bcr-Abl kinase inhibitor imatinib, mainly used to treat Philadelphia chromosome-positive chronic myeloid leukemia (CML).

[0007] As more and more targeted anti-tumor drugs are applied in clinical practice, some issues have gradually attracted attention. On the one hand, anti-tumor drugs targeting single or a few kinase oncogenes or oncoproteins face drawbacks such as low efficacy and easy development of drug resistance. Typical examples are EGFR kinase inhibitors gefitinib and erlotinib. These two drugs are only effective in 10-20% of non-small cell lung cancer patients. Studies on their mechanism of action have found that gefitinib and erlotinib are selective EGFR kinase inhibitors, and they are most sensitive to patients with EGFR exon 19 deletion mutations and exon 21 L858R point mutations (EGFR exon 19 deletion mutations and exon 21 L858R point mutations are collectively referred to as EGFR-sensitive mutations). Even for patients with these EGFR-sensitive mutations, the vast majority develop drug resistance after 6-9 months of treatment with gefitinib and erlotinib. Studies have shown that there are multiple reasons for drug resistance, including (1) secondary mutations on the basis of EGFR sensitive mutations, namely the T790M mutation of EGFR; and (2) amplification of the MET gene (MET is a tyrosine kinase). On the other hand, existing protein kinase inhibitors are still concentrated on a small number of kinase targets such as EGFR, FGFR, VEGFR, JAK, PI3K and CDK, and the exploration of other kinase members is still insufficient. There is still a lot of room for exploration in terms of inhibitor backbone structure and mechanism of action. In addition, although targeted drugs have the characteristics of low toxicity and high specificity compared with traditional anti-tumor drugs, different degrees of toxic side effects have been observed in the clinical trials of small molecule kinase inhibitors. For example, it has been reported that the common adverse reactions of Midostaurin in the treatment of acute myeloid leukemia (AML) include: leukopenia, nausea and vomiting, mucositis, headache, petechiae, musculoskeletal pain, epistaxis, hyperglycemia, and upper respiratory tract infection.

[0008] Researching new anti-tumor drugs to address the low efficacy, drug resistance, and safety issues of small molecule kinase inhibitors is a current focus of anti-tumor targeted drug development. Currently, researchers are exploring effective solutions, with the most promising approaches including: (1) multi-kinase inhibitors that simultaneously target multiple kinases related to tumor development. For example, EGFR is overexpressed or abnormally overactivated in various human tumor tissues. If a small molecule kinase inhibitor can not only inhibit EGFR activity but also inhibit the activity of key kinases regulating angiogenesis or other cell growth and proliferation, such as c-Kit, c-SRC, MET, BTK, ALK, Abl, FLT3, and other kinase oncogenes or oncoproteins, it could improve the efficacy of tumor treatment and reduce the incidence of drug resistance; (2) directly targeting kinases that produce drug resistance mutations. For example, as mentioned earlier, after using EGFR inhibitors gefitinib and erlotinib, EGFR itself is prone to secondary mutations on the basis of the original mutation (i.e., EGFR sensitive mutation), namely the T790M mutation of EGFR. The occurrence of this mutation is one of the main reasons for the failure of EGFR inhibitors gefitinib and erlotinib. Therefore, developing EGFR kinase inhibitors that directly target drug resistance mutations, i.e., T790M mutations, is a direct way to overcome drug resistance in this type of tumor.

[0009] Patent WO2011147066A1 discloses compound I, its preparation method and uses. It is a novel multi-target protein kinase inhibitor with main targets including FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, etc., and can be used for the treatment of tumor diseases.

[0010] Summary of the Invention

[0011] Technical issues

[0012] Based on compound I, this application further discovers hydrochloride salts (e.g., formula II, formula A) of compound I that exhibit better druggability than compound I. These hydrochloride salts not only possess superior solubility and stability compared to compound I, but also, considering solubility, hygroscopicity, and stability, are more suitable for drug preparation than other salts of compound I. The corresponding research and screening process is described in patent application PCT / CN2021 / 073285, the entire contents of which are incorporated herein by reference. Given the promising application prospects of compound I in the treatment of tumor diseases, seeking a pharmaceutical composition containing compound I or its pharmaceutically acceptable salts (e.g., formula II, formula A) with excellent formulation properties has become a pressing problem for those skilled in the art.

[0013]

[0014] One technical problem to be solved by this application is to provide a pharmaceutical composition that meets the needs of oral administration and contains a compound of Formula II, particularly a compound of Formula A, as an active ingredient.

[0015] Solution

[0016] In the course of ongoing research into pharmaceutical compositions and / or oral formulations containing compounds of Formula II, particularly those of Formula A, the inventors of this application have conducted meticulous screening experiments on the components of the pharmaceutical compositions and have discovered that the formulation of specific pharmaceutical compositions can solve the above-mentioned technical problems, thereby completing this application.

[0017] On one hand, this application provides a pharmaceutical composition comprising: a compound of formula II as an active ingredient and an excipient.

[0018]

[0019] Wherein, m is 1 to 5, preferably 1 to 3; n is 0 to 10, preferably 0 to 5, further preferably 3 to 5, further preferably 3, 3.5, 4, 4.5 or 5, and even more preferably 5.

[0020] Secondly, this application provides a pharmaceutical composition comprising: a compound of formula A as an active ingredient and an excipient.

[0021]

[0022] Wherein, n is 0 to 10, preferably 0 to 5, more preferably 3 to 5, more preferably 3, 3.5, 4, 4.5 or 5, and even more preferably 5.

[0023] Thirdly, this application provides a pharmaceutical composition comprising: a compound of formula B as an active ingredient and an excipient.

[0024]

[0025] In some embodiments of this application, the compound represented by Formula B, when irradiated with Cu-Kα, exhibits characteristic peaks in X-ray powder diffraction at 8.5±0.2°, 11.8±0.2°, 19.6±0.2°, 25.2±0.2°, and 27.2±0.2° in 2θ angles; preferably, the compound represented by Formula B, when irradiated with Cu-Kα, exhibits characteristic peaks in X-ray powder diffraction at 8.5±0.2°, 11.8±0.2°, 12.6±0.2°, 19.6±0.2°, 20.0±0.2°, and 23.7±0.2° in 2θ angles. Characteristic peaks are observed at 0.2°, 25.2±0.2°, and 27.2±0.2°. More preferably, the compound represented by Formula B, when subjected to Cu-Kα radiation, exhibits X-ray powder diffraction at 7.3±0.2°, 8.5±0.2°, 9.0±0.2°, 11.8±0.2°, 12.6±0.2°, 14.3±0.2°, 18.1±0.2°, 19.6±0.2°, 20.0±0.2°, 21.1±0.2°, 21.9±0.2°, 23.7±0.2°, and 25.2±0.2°. Characteristic peaks are present at 26.1±0.2°, 27.2±0.2° or 7.3±0.2°, 8.5±0.2°, 9.1±0.2°, 11.8±0.2°, 12.6±0.2°, 14.3±0.2°, 18.1±0.2°, 19.6±0.2°, 20.0±0.2°, 21.1±0.2°, 21.9±0.2°, 23.7±0.2°, 25.2±0.2°, 26.1±0.2°, and 27.2±0.2°; more preferably, the compound represented by Formula B, when irradiated with Cu-Kα, exhibits substantially the following characteristics. Figure 1 The X-ray powder diffraction pattern shown is shown.

[0026] In some embodiments of this application, the single crystal of the compound represented by Formula B is subjected to Cu-Kα radiation and belongs to the triclinic crystal system. The space group has the following unit cell parameters:

[0027] In some embodiments of this application, the components and their weight percentages in the aforementioned (first aspect, second aspect, third aspect) pharmaceutical compositions are as follows:

[0028] The active ingredient, by weight percentage, is 0.5%–90%; or 1%–90%; or 0.5%–85%; or 0.5%–80%; or 1%–80%; or 5%–80%; or 5%–75%; or 5%–70%; or 5%–65%; or 5%–60%; or 5%–55%; or 5%–50%; or 5%–45%; or 5%–40%; or 10%–70%; or 10%–65%; or 10%–60%; or 15%–60%; or 20%–60%; or 25%–60%; or 25%–50%; or 25%–45%; or 25%–40%; with the balance being excipients.

[0029] In some embodiments of this application, the components and their weight percentages of the aforementioned (first aspect, second aspect, third aspect) pharmaceutical compositions are as follows:

[0030] The active ingredient has a weight percentage of 1% to 90%, preferably 5% to 80%, 5% to 65%, 5% to 55%, 5% to 45%, or 5% to 40%;

[0031] The excipients have a weight percentage of 1% to 99%, preferably 5% to 95%, 10% to 90%, 20% to 80%, or 30% to 70%; and the sum of the weight percentages of the above components is 100%.

[0032] In some embodiments of this application, the components and their weight percentages in the aforementioned (first aspect, second aspect, third aspect) pharmaceutical compositions are as follows:

[0033] The active ingredient comprises, by weight, 5%–90%; or 10%–90%; or 10%–80%; or 15%–80%; or 20%–70%; or 25%–60%; or 25%–50%; or 25%–45%; or 25%–40%; with the remainder being excipients.

[0034] The term "excipient" as used in this application, also known as "pharmaceuticalally acceptable excipient," "excipient," or "additional agent," refers to the collective term for all additional materials used in formulating prescriptions and manufacturing pharmaceuticals, excluding the active ingredient. These are generally pharmaceutically acceptable inert ingredients that have undergone reasonable safety assessments. Examples of excipients, without limitation, include binders, disintegrants, lubricating excipients (lubricants, flow aids, anti-adhesion agents), stabilizers, fillers (or diluents), as well as flavoring agents, thickeners, dispersants, colorants, antibacterial agents, antioxidants, pH adjusters, surfactants, fragrances, and coating materials (plasticizers, opacifiers, pigments), etc. For example, excipients can enhance the operational characteristics of pharmaceutical formulations, such as by increasing flowability and / or adhesion to ensure the formulation meets process requirements. Furthermore, the "excipient" should possess good compatibility with the active ingredient, meaning that the excipient itself or its impurities will not chemically react with the structural groups in the active ingredient or cause degradation of the active ingredient, resulting in a decrease in the content of the active ingredient.

[0035] In some embodiments of this application, the excipient comprises one or more of fillers, binders, disintegrants, flavoring agents, lubricants, antibacterial agents, antioxidants, pH adjusters, surfactants, fragrances, solvents, or coating materials.

[0036] In some embodiments of this application, the excipient comprises a filler, and optionally, further comprises one or more of a binder, disintegrant, flavoring agent, lubricant, antibacterial agent, antioxidant, surfactant, fragrance, or coating material.

[0037] In some embodiments of this application, the excipient comprises a filler and optionally further comprises one or more of a disintegrant, binder, or lubricant. In one embodiment, the excipient comprises a filler and a lubricant and optionally further comprises a disintegrant and / or a binder. In one embodiment, the excipient consists of a filler and a lubricant. In another embodiment, the excipient consists of a filler, a lubricant, and a disintegrant. In yet another embodiment, the excipient consists of a filler, a lubricant, a disintegrant, and a binder.

[0038] The pharmaceutical composition of this application may also contain other excipients besides fillers, lubricating agents, and disintegrants. Specific examples include: binders, flavoring agents, antibacterial agents, pH adjusters, pigments, thickeners, dispersants, colorants, antioxidants, stabilizers, coating materials, and fragrances. Preferably, the other excipients constitute 0% to 25% by weight in the pharmaceutical composition, more preferably 0% to 20%, 0% to 15%, 0% to 10%, or 0% to 5%.

[0039] The term "filler" or "diluent" as used in this application refers to an excipient used to increase the weight and volume of a pharmaceutical composition to facilitate shaping and dispensing. The filler described in this application may be a single filler or a mixture of two or more fillers. In some embodiments of this application, the filler is selected from one or more of starch, pregelatinized starch, powdered sugar, magnesium hydroxide, lactose, microcrystalline cellulose, sugar alcohols, or inorganic calcium salts; preferably, the sugar alcohol is selected from one or more of xylitol, sorbitol, and mannitol; preferably, the inorganic calcium salt is selected from one or more of calcium phosphate, dicalcium phosphate, calcium carbonate, and calcium sulfate. In one embodiment, the filler is selected from one of pregelatinized starch, anhydrous dicalcium phosphate, calcium carbonate, microcrystalline cellulose, and mannitol, or a combination of pregelatinized starch and mannitol, or a combination of microcrystalline cellulose and lactose, or a combination of pregelatinized starch and lactose, or a combination of pregelatinized starch and anhydrous dicalcium phosphate, or a combination of pregelatinized starch and calcium carbonate. In one embodiment, the filler is a combination of pregelatinized starch and mannitol, a combination of microcrystalline cellulose and lactose, a combination of pregelatinized starch and anhydrous dicalcium phosphate, or pregelatinized starch and calcium carbonate. In the combination of two fillers, the weight ratio of the two fillers is 1:10 to 10:1; or 1:7 to 7:1; or 1:6 to 6:1; or 1:5 to 5:1; or 1:4 to 4:1; or 1:3 to 3:1; or 1:2 to 2:1; or 1:1.

[0040] The "adhesive" or "adhesive" described in this application refers to a viscous excipient that enables non-sticky or low-sticky materials or excipients to aggregate and bind into granules or be compressed into molds. It can be a solid powder or a viscous liquid. In some embodiments of this application, the adhesive is selected from one or more of starch paste, copovidone, cellulose derivatives, powdered sugar, syrup, polyvinylpyrrolidone, adhesive, polyethylene glycol 4000, and dextrin; the cellulose derivative includes methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethylcellulose, or sodium carboxymethyl cellulose; the dextrin includes maltodextrin; the polyvinylpyrrolidone, also known as povidone, includes povidone K30, povidone K25, povidone K90, etc.; the copovidone includes copovidone VA64, copovidone VA64 Fine, etc.; the adhesive includes gum arabic paste, gelatin paste, etc.

[0041] The term "disintegrant" as used in this application refers to an excipient used to promote the disintegration of a pharmaceutical composition in the gastrointestinal tract and increase the dissolution rate of the active ingredient. In some embodiments of this application, the pharmaceutical composition does not contain a disintegrant. In some embodiments of this application, the pharmaceutical composition contains a disintegrant, and the disintegrant is selected from one or more of the following: dry starch, sodium carboxymethyl cellulose, microcrystalline cellulose, powdered cellulose, methyl cellulose, potassium plucklein, sodium alginate, sodium starch glycolate, polyvinylpyrrolidone, maltodextrin, magnesium aluminum silicate, corn starch, pregelatinized starch, crospovidone, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, effervescent disintegrant, sodium carboxymethyl starch, and sodium crospovidone carboxymethyl cellulose. Preferably, the disintegrant is selected from one or more of the following: dry starch, pregelatinized starch, crospovidone, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, and sodium crospovidone carboxymethyl cellulose. In one embodiment, the disintegrant is preferably one or more of pregelatinized starch, crospovidone, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, or sodium crospovidone carboxymethyl cellulose; more preferably crospovidone, sodium carboxymethyl starch, or sodium crospovidone carboxymethyl cellulose; and even more preferably sodium carboxymethyl starch. The crospovidone includes crospovidone CL-M, crospovidone CL-SF, crospovidone CL-F, crospovidone CL, etc.

[0042] The "flavoring agent" or "taste enhancer" mentioned in this application refers to a pharmaceutical excipient used to improve or mask the unpleasant odor and taste of a drug, making it difficult for the user to detect the drug's odor or taste. It can be further classified into sweeteners, flavoring agents, gelling agents, and effervescent agents, etc. In some embodiments of this application, the flavoring agent includes one or more of sweeteners, flavoring agents, gelling agents, or effervescent agents.

[0043] In some embodiments of this application, the sweetener is selected from one or more of sorbitol, xylose, xylitol, glycerol, disodium glycyrrhizate, mannose, galactose, maltose, lactose, fructose, aspartame, sodium saccharin, steviol glycosides, glucose, sucrose, sucralose, aspartame, and neotame.

[0044] In some embodiments of this application, the fragrance agent is selected from natural volatile aromatic oils and artificial synthetic fragrances, such as one or more of fennel oil, rose oil, peppermint oil, orange peel oil, lemon oil, rose essence, lemon essence, vanilla essence, vanillin, banana essence, pineapple essence, and apple essence.

[0045] In some embodiments of this application, the adhesive is selected from one or more of starch, gum arabic, tragacanth gum, carboxymethyl cellulose, methyl cellulose, sodium alginate, pectin, and agar.

[0046] The "lubricating excipient" described in this application is a broad term for lubricants, referring to excipients used to reduce friction between particles and between particles and die orifices in a pharmaceutical composition, thereby improving force transmission and distribution. Based on their functions of reducing friction, increasing particle flowability, and preventing adhesion between the die orifice and pharmaceutical particles, lubricating excipients are further classified into lubricants, flow aids, and anti-adhesion agents.

[0047] In some embodiments of this application, the lubricating additive comprises a lubricant and / or a flow aid.

[0048] In some embodiments of this application, the lubricant is selected from one or more of stearic acid, magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitate stearate, sodium benzoate, sodium lauryl sulfate, talc, silica, zinc stearate, sodium stearoyl fumarate, magnesium stearoyl fumarate, magnesium lauryl sulfate, hydrogenated vegetable oil, sodium lauryl sulfate, magnesium lauryl sulfate, or polyethylene glycol. Preferably, it is one or more of talc, magnesium stearate, calcium stearate, or sodium stearate fumarate; more preferably, it is magnesium stearate.

[0049] In some embodiments of this application, the flow aid is selected from one or more of colloidal silica or aluminum hydroxide. Colloidal silica is preferred.

[0050] In some embodiments of this application, the pH adjuster is selected from one or more of sodium hydroxide, sodium carbonate, sodium bicarbonate, or potassium hydroxide.

[0051] In some embodiments of this application, the antibacterial agent is selected from one or more of sodium benzoate, potassium sorbate, hexamethylenetetramine, ethanol, benzyl alcohol, parabens, benzoic acid, sorbic acid, benzyl alcohol, or phenylethanol.

[0052] In some embodiments of this application, the antioxidant is selected from one or more of sodium bisulfite, sodium metabisulfite, sodium sulfite, dried sodium sulfite, sodium thiosulfate, ascorbic acid, methionine, thiourea, disodium ethylenediaminetetraacetate, phosphoric acid, citric acid, tert-butyl-p-hydroxyanisole, tert-butyl-p-cresol, tocopherol, nordihydroguaiacol, tocopherol, or gallate esters.

[0053] The "coating material," "coating powder," "coating agent," or "coating premix" mentioned in this application are mixtures of various pharmaceutical excipients, whose main functions are coloring, masking odor, light protection, extending shelf life, and improving appearance. The "film-coated tablet" or "film-coated tablet" mentioned in this application refers to a tablet with a film coating on the tablet core (which is prepared by compression of the pharmaceutical composition of this application). The film coating can be prepared using coating materials and methods commonly used in the art. For example, film coating materials typically contain one or more of the following: film-forming agents (or polymeric materials), plasticizers, pore-forming agents, colorants, light-blocking agents, and certain solid materials; furthermore, the coating material can be dissolved in a solvent to form a coating solution. The polymer material can be selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethylcellulose, acrylic resin, ethylcellulose, cellulose acetate, cellulose acetate phthalate, polyvinyl alcohol phthalate, cellulose acetate triterpenoid, hydroxypropyl methylcellulose phthalate, and polyvinyl alcohol; the plasticizer can be selected from glycerol, propylene glycol, polyethylene glycol, glycerol monoacetate, glycerol triacetate, dibutyl sebacate, dibutyl phthalate, diethyl phthalate, castor oil, silicone oil, corn oil, liquid paraffin, etc.; the pore-forming agent (also known as the release rate regulator) can be selected from sucrose, sodium chloride, surfactant, etc.; the solid material can be selected from talc, magnesium stearate, colloidal silica, etc.; the light-blocking agent includes titanium dioxide; and conventional colorants in the art can also be used as appropriate, such as the colorant selected from one or more of amaranth, carmine, tartrazine, soluble indigo, orange G, eosin, fuchsin, methylene blue, Sudan yellow, or mercurochrome. Alternatively, commercially available premixed coating powders, such as Obadai, can be used directly as coating materials. Series of coating powders, Yake Yi Series of coating powders, Suteri Series of coating powders, Sulis Series of wrap-around pink, Aidoshow A series of coating powders, etc. The coating material can be a gastrointestinal or enteric coating material. The film coating weight gain accounts for 1-5% of the tablet core weight, preferably 1.5-4%, more preferably 1.5%-3%. The coating solvent is selected from water and ethanol, preferably water, which can be removed during drying and does not remain in the final product. For example, Opadry... The series of coating powder models include: Opal 85G64788, 85F18422, 0366507, 8568918, 85F12252, 03F58908, etc.

[0054] In some embodiments of this application, the solvent is selected from one or more of water, ethanol, or vegetable oil.

[0055] In some embodiments of this application, the surfactant is selected from one or more of polyethylene glycols, polysorbates, sorbitan monolaurates, polyoxyethylene lauryl ethers, emulsifiers OP, lactone A, Sismaco-1000, protonil, glyceryl monooleate, glyceryl monostearate, soft soap, hard soap, aluminum monostearate, calcium stearate, triethanolamine oleate, sodium lauryl sulfate, sodium cetyl sulfate, sulfated castor oil, sodium dioctyl succinate sulfonate, benzalkonium chloride, benzalkonium chloride, benzyl chloride, and hexadecanetrimethylamine bromide.

[0056] In some embodiments of this application, the aforementioned (first aspect, second aspect, third aspect) pharmaceutical compositions are formulated into oral preparations; preferably, the oral preparations comprise oral solid preparations and / or oral liquid preparations; more preferably, the oral solid preparations are selected from one or more of capsules, tablets, granules, fine granules and powders; the oral liquid preparations are selected from oral solutions.

[0057] Fourthly, this application provides a pharmaceutical composition comprising: a compound of formula II, formula A or formula B as an active ingredient and an excipient comprising a filler, and optionally, further comprising a lubricating agent, a disintegrant and / or a binder.

[0058] In some embodiments of this application, the excipient comprises fillers and lubricating agents, and optionally, further comprises disintegrants and / or binders.

[0059] In some embodiments of this application, the excipient comprises fillers, lubricating agents, and disintegrants, and optionally, further comprises adhesives.

[0060] In some embodiments of this application, the excipient comprises fillers, lubricating agents, disintegrants, and binders.

[0061] In some embodiments of this application, the lubricating agent is a lubricant, and optionally, further includes a flow aid.

[0062] In some embodiments of this application, the lubricating additives are lubricants and flow aids.

[0063] In some embodiments of this application, the filler is selected from one or more of starch, powdered sugar, magnesium hydroxide, pregelatinized starch, lactose, microcrystalline cellulose, sugar alcohols, and inorganic calcium salts; preferably, the sugar alcohol filler is selected from one or more of mannitol, sorbitol, and xylitol, and the inorganic calcium salt filler is selected from one or more of calcium phosphate, dicalcium phosphate, calcium sulfate, and calcium carbonate; preferably, the filler is selected from one or more of pregelatinized starch, lactose, microcrystalline cellulose, mannitol, sorbitol, anhydrous dicalcium phosphate, calcium sulfate dihydrate, and calcium carbonate; more preferably, the filler is selected from one or more of pregelatinized starch, lactose, microcrystalline cellulose, mannitol, anhydrous dicalcium phosphate, and calcium carbonate; more preferably, the filler is selected from one or more of pregelatinized starch, lactose, microcrystalline cellulose, anhydrous dicalcium phosphate, or mannitol; more preferably, the filler is selected from one or more of pregelatinized starch, lactose, microcrystalline cellulose, or mannitol.

[0064] In some embodiments of this application, the filler is selected from one of pregelatinized starch, anhydrous dicalcium phosphate, calcium carbonate, and microcrystalline cellulose, or a combination of pregelatinized starch and mannitol, or a combination of microcrystalline cellulose and lactose, or a combination of pregelatinized starch and anhydrous dicalcium phosphate, or a combination of pregelatinized starch and calcium carbonate, or a combination of pregelatinized starch and lactose; preferably, the filler is selected from one of pregelatinized starch, anhydrous dicalcium phosphate, and microcrystalline cellulose, or a combination of pregelatinized starch and mannitol, or a combination of microcrystalline cellulose and lactose. Alternatively, the filler may be a combination of pregelatinized starch and anhydrous dicalcium phosphate, or a combination of pregelatinized starch and calcium carbonate; more preferably, the filler is selected from: one of pregelatinized starch or microcrystalline cellulose, or a combination of pregelatinized starch and mannitol, or a combination of microcrystalline cellulose and lactose, or a combination of pregelatinized starch and anhydrous dicalcium phosphate, or a combination of pregelatinized starch and calcium carbonate; more preferably, the filler is selected from: one of pregelatinized starch or microcrystalline cellulose, or a combination of pregelatinized starch and mannitol, or a combination of microcrystalline cellulose and lactose.

[0065] In some embodiments of this application, the weight ratio of the two fillers in the combination of pregelatinized starch and mannitol, the combination of microcrystalline cellulose and lactose, the combination of pregelatinized starch and anhydrous dicalcium phosphate, the combination of pregelatinized starch and lactose, or the combination of pregelatinized starch and calcium carbonate is 1:10 to 10:1; or 1:7 to 7:1; or 1:6 to 6:1; or 1:5 to 5:1; or 1:4 to 4:1; or 1:3 to 3:1; or 1:2 to 2:1; or 1:1.

[0066] In some embodiments of this application, the lubricant is selected from one or more of stearic acid, magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitate, sodium benzoate, sodium lauryl sulfate, hydrogenated vegetable oil, talc, silica, zinc stearate, sodium stearoyl fumarate, magnesium stearoyl fumarate, magnesium lauryl sulfate, sodium lauryl sulfate, magnesium lauryl sulfate, or polyethylene glycol; preferably, stearic acid, magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitate, sodium benzoate, sodium lauryl sulfate, talc, silica, zinc stearate, or stearoyl fumarate. Sodium, magnesium stearoyl fumarate, magnesium lauryl sulfate, polyethylene glycol 4000, polyethylene glycol 6000, sodium lauryl sulfate, or magnesium lauryl sulfate; more preferably, stearic acid, magnesium stearate, calcium stearate, palmitic acid, glyceryl palmitate stearate, sodium benzoate, sodium lauryl sulfate, talc, silica, zinc stearate, sodium stearoyl fumarate, magnesium stearoyl fumarate, or magnesium lauryl sulfate; more preferably, talc, magnesium stearate, calcium stearate, or sodium stearoyl fumarate; and even more preferably, magnesium stearate.

[0067] In some embodiments of this application, the flow aid is selected from one or more of colloidal silica or aluminum hydroxide; preferably colloidal silica.

[0068] In some embodiments of this application, the lubricating additive is a combination of lubricant and flow aid, wherein the weight ratio of the flow aid to the lubricant is 1:6 to 6:1; or 1:5 to 5:1; or 1:4 to 4:1; or 1:3 to 3:1; or 1:2 to 2:1; or 1:1, 1:2, 1:1.5, 2:1, 2:3, 3:1, 3:2, 4:3 or 5:3.

[0069] In some embodiments of this application, the pharmaceutical composition comprises a disintegrant selected from one or more of the following: dry starch, carboxymethyl cellulose, microcrystalline cellulose, powdered cellulose, methyl cellulose, potassium plucklein, sodium alginate, sodium starch glycolate, polyvinylpyrrolidone, maltodextrin, magnesium aluminum silicate, corn starch, pregelatinized starch, crospovidone, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, effervescent disintegrant, sodium carboxymethyl starch, or sodium crospovidone; preferably one or more of the following: dry starch, pregelatinized starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, sodium crospovidone, or crospovidone; more preferably one or more of the following: crospovidone, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, or sodium crospovidone; further preferably crospovidone, sodium carboxymethyl starch, or sodium crospovidone; more preferably sodium carboxymethyl starch or sodium crospovidone.

[0070] In some embodiments of this application, the pharmaceutical composition comprises a binder selected from one or more of starch paste, copovidone, powdered sugar, syrup, polyvinylpyrrolidone, cellulose derivatives, adhesives, polyethylene glycol 4000, and dextrin; preferably, the cellulose derivative is selected from methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethylcellulose, and sodium carboxymethyl cellulose; more preferably, copovidone, powdered sugar, polyvinylpyrrolidone, hydroxypropyl methylcellulose, and sodium carboxymethyl cellulose; and even more preferably, copovidone VA64 and polyvinylpyrrolidone.

[0071] In some embodiments of this application, the filler is selected from one of pregelatinized starch, microcrystalline cellulose, anhydrous dicalcium phosphate, or a combination of pregelatinized starch and mannitol, or a combination of microcrystalline cellulose and lactose, or a combination of pregelatinized starch and anhydrous dicalcium phosphate, or a combination of pregelatinized starch and calcium carbonate; the lubricating agent is a lubricant and / or a flow aid, wherein the lubricant is magnesium stearate and the flow aid is colloidal silica; optionally, the disintegrant is selected from sodium carboxymethyl starch and croscarmellose sodium; optionally, the binder is selected from copovidone.

[0072] In some embodiments of this application, the pharmaceutical composition comprises an active ingredient, a filler, a lubricant, and a flow aid, wherein the filler is pregelatinized starch or microcrystalline cellulose; preferably, the flow aid is colloidal silica; more preferably, the lubricant is magnesium stearate; and more preferably, the pharmaceutical composition further comprises a disintegrant selected from sodium carboxymethyl starch or croscarmellose sodium.

[0073] In some embodiments of this application, the pharmaceutical composition comprises an active ingredient, a filler, a lubricant, and a flow aid, wherein the filler is pregelatinized starch and mannitol; preferably, the flow aid is colloidal silica; and more preferably, the lubricant is magnesium stearate.

[0074] In some embodiments of this application, the pharmaceutical composition comprises an active ingredient, a filler, and a lubricant, wherein the filler is microcrystalline cellulose; preferably, the lubricant is magnesium stearate.

[0075] In some embodiments of this application, the pharmaceutical composition comprises an active ingredient, a filler, a lubricant, a flow aid, and a disintegrant, wherein the filler is microcrystalline cellulose and lactose; preferably, the flow aid is selected from colloidal silica; more preferably, the disintegrant is selected from sodium carboxymethyl starch or croscarmellose sodium; and even more preferably, the lubricant is magnesium stearate or sodium stearoyl fumarate.

[0076] In some embodiments of this application, the pharmaceutical composition comprises an active ingredient, a filler, a lubricant, and a flow aid, wherein the filler is anhydrous calcium hydrogen phosphate or a combination of anhydrous calcium hydrogen phosphate and pregelatinized starch; preferably, the flow aid is selected from colloidal silica; more preferably, the lubricant is magnesium stearate; and even more preferably, the pharmaceutical composition further comprises a disintegrant selected from sodium carboxymethyl starch or croscarmellose sodium.

[0077] In some embodiments of this application, the pharmaceutical composition comprises an active ingredient, a filler, a lubricant, and a flow aid, wherein the filler is calcium carbonate or a combination of calcium carbonate and pregelatinized starch; preferably, the flow aid is selected from colloidal silica; more preferably, the lubricant is magnesium stearate; even more preferably, the pharmaceutical composition further comprises a disintegrant selected from sodium carboxymethyl starch or croscarmellose sodium; even more preferably, the pharmaceutical composition further comprises a binder selected from copovidone.

[0078] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows:

[0079] The active ingredient, by weight percentage, is 0.5%–90%; or 1%–90%; or 0.5%–85%; or 5%–80%; or 5%–75%; or 5%–70%; or 10%–70%; or 5%–65%; or 5%–60%; or 5%–55%; or 5%–50%; or 5%–45%; or 5%–40%; or 10%–65%; or 10%–60%; or 15%–60%; or 20%–60%; or 25%–60%; or 25%–50%; or 25%–45%; or 25%–40%.

[0080] The filler, by weight percentage, is 5%–99%; or 10%–95%; or 15%–95%; or 15%–90%; or 15%–85%; or 15%–80%; or 20%–80%; or 25%–90%; or 25%–75%; or 30%–70%; or 35%–90%; or 35%–70%; or 40%–90%; or 40%–70%; or 45%–70%; or 50%–90%; or 50%–70%; or 55%–70%.

[0081] The disintegrant has a weight percentage of 0%–20%; 0%–15%; or 0%–10%; or 0%–8%; or 0%–6%; or 0%–5%; or 0%–4%; or 0%–3%; or 0.5%–3%; or 1%–3%; or 1.5%–3%; or 2%–3%;

[0082] The adhesive, by weight percentage, is 0%–10%; or 0%–6%; or 0%–5%; or 0%–4%; or 0%–3%; or 0%–2%;

[0083] The weight percentage of lubricating additives is 0%–18%; or 0.1%–18%; or 0%–15%; or 0.1%–15%; or 0%–10%; or 0.1%–10%; or 0%–8%; or 0%–7%; or 0%–6%; or 1%–6%; or 0.5%–6%; or 0%–5%; or 1%–5%; or 1.5%–4.5%; or 2%–4%; or 2%–3.5%; or 2%–3%; or 2.5%–5%; or 3.5%–5%; or 4%–5%.

[0084] Other excipients, by weight percentage, are 0%–25%; or 0%–20%; or 0%–15%; or 0%–10%; or 0%–5%; and

[0085] The sum of the weight percentages of all the above components is 100%.

[0086] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows:

[0087] The active ingredient has a weight percentage of 1% to 90%, preferably 5% to 80%, 5% to 65%, 5% to 55%, 5% to 45%, or 5% to 40%;

[0088] The filler has a weight percentage of 10% to 95%, preferably 25% to 90%, 35% to 90%, 40% to 90%, or 50% to 90%;

[0089] The disintegrant has a weight percentage of 0% to 15%, preferably 0% to 10%, 0% to 6%, 0% to 5%, or 0% to 3%;

[0090] The lubricating additives have a weight percentage of 0% to 18%, preferably 0.1% to 18%, 0% to 15%, 0% to 10%, 0% to 6%, 0% to 5%, 0.1% to 15%, 0.1% to 10%, 0.5% to 0%, 1% to 5%, 2.5% to 5%, 3.5% to 5%, or 4% to 5%.

[0091] Other excipients, in weight percentages of 0% to 25%, preferably 0% to 20%, 0% to 15%, 0% to 10%, or 0% to 5%; and the sum of the weight percentages of all the above components is 100%.

[0092] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows:

[0093] The active ingredient, by weight percentage, is 5%–90%; or 10%–90%; or 10%–80%; or 15%–80%; or 20%–70%; or 25%–60%; or 25%–50%; or 25%–45%; or 25%–40%.

[0094] The filler, by weight percentage, is 5%–90%; or 15%–90%; or 15%–85%; or 25%–85%; or 25%–80%; or 35%–75%; or 35%–70%; or 50%–70%; or 55%–70%.

[0095] The disintegrant has a weight percentage of 0% to 5%; or 0% to 4%; or 0.5% to 4%; or 1% to 3%;

[0096] The adhesive, by weight percentage, is 0% to 5%; or 0% to 4%; or 0% to 3%;

[0097] The lubricating additives, by weight percentage, are 2%–7%; or 2%–6%; or 2.5%–6%; or 3%–5%; or 3%–6%; or 3.5%–6%; or 4%–6%; or 4%–5%; or 5%–6%.

[0098] Other excipients, by weight percentage, are 0% to 10%; or 0% to 5%; and the sum of the weight percentages of the above components is 100%.

[0099] In some embodiments of this application, the lubricating additive is a lubricant.

[0100] In some embodiments of this application, the lubricating additive is a combination of lubricant and flow aid, wherein the weight ratio of the flow aid to the lubricant is 1:6 to 6:1; or 1:5 to 5:1; or 1:4 to 4:1; or 1:3 to 3:1; or 1:2 to 2:1; or 1:1, 1:2, 1:1.5, 2:1, 2:3, 3:1, 3:2, 4:3 or 5:3.

[0101] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows:

[0102] The active ingredient, by weight percentage, is 0.5%–90%; or 1%–90%; or 0.5%–85%; or 5%–80%; or 5%–75%; or 5%–70%; or 10%–70%; or 5%–65%; or 5%–60%; or 5%–55%; or 5%–50%; or 5%–45%; or 5%–40%; or 10%–65%; or 10%–60%; or 15%–60%; or 20%–60%; or 25%–60%; or 25%–50%; or 25%–45%; or 25%–40%.

[0103] The filler, by weight percentage, is 5%–99%; or 10%–95%; or 15%–95%; or 15%–90%; or 15%–85%; or 15%–80%; or 20%–80%; or 25%–90%; or 25%–75%; or 30%–70%; or 35%–90%; or 35%–70%; or 40%–90%; or 40%–70%; or 45%–70%; or 50%–90%; or 50%–70%; or 55%–70%.

[0104] The disintegrant has the following weight percentages: 0%–20%; 0%–15%; or 0%–10%; or 0%–8%; or 0%–6%; or 0%–5%; or 0%–4%; or 0%–3%; or 0.5%–0.00%; or 1%–3%; or 1.5%–3%; or 2%–3%.

[0105] The adhesive, by weight percentage, is 0%–10%; or 0%–6%; or 0%–5%; or 0%–4%; or 0%–3%; or 0%–2%;

[0106] The lubricant, by weight percentage, is 0%–10%; or 0%–8%; or 0.1%–8%; or 0%–6%; or 0%–5%; or 0.1%–5%; or 0%–4%; or 0.1%–4%; or 0%–3%; or 1%–5%; or 2%–4%; or 2%–3%; or 1%–4%; or 1%–3.5%; or 0.5%–3%; or 1%–3%; or 1%–2.5%; or 1%–2%; or 2%–2.5%.

[0107] The glialization agent, by weight percentage, is 0%–10%; or 0.5%–10%; or 0%–8%; or 0.5%–8%; or 0%–6%; or 0%–5%; or 0.5%–5%; or 1%–5%; or 0%–4%; or 1%–4%; or 0%–3.5%; or 0%–3%; or 1%–3%; or 1%–2.5%; or 1%–2%; or 1.5%–3%; or 2%–3%; or 3%;

[0108] Other excipients, by weight percentage, are 0%–25%; or 0%–20%; or 0%–15%; or 0%–10%; or 0%–5%; and

[0109] The sum of the weight percentages of all the above components is 100%.

[0110] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows:

[0111] The active ingredient has a weight percentage of 1% to 90%, preferably 5% to 80%, 5% to 65%, 5% to 55%, 5% to 45%, or 5% to 40%;

[0112] The filler has a weight percentage of 10% to 95%, preferably 25% to 90%, 35% to 90%, 40% to 90%, or 50% to 90%;

[0113] The disintegrant has a weight percentage of 0% to 15%, preferably 0% to 10%, 0% to 6%, 0% to 5%, or 0% to 3%;

[0114] The lubricant has a weight percentage of 0.1% to 8%, preferably 0.1% to 5%, 0.1% to 4%, 0.5% to 3%, or 1% to 3%;

[0115] The gliding agent has a weight percentage of 0% to 10%, preferably 0% to 8%, 0% to 5%, 0% to 4%, or 0% to 3%;

[0116] Other excipients, in weight percentages of 0% to 25%, preferably 0% to 20%, 0% to 15%, 0% to 10%, or 0% to 5%; and the sum of the weight percentages of all the above components is 100%.

[0117] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows:

[0118] The active ingredient has a weight percentage of 1% to 90%, preferably 5% to 80%, 5% to 65%, 5% to 55%, 5% to 45%, or 5% to 40%;

[0119] The filler has a weight percentage of 10% to 95%, preferably 25% to 90%, 35% to 90%, 40% to 90%, or 50% to 90%;

[0120] The disintegrant has a weight percentage of 0% to 15%, preferably 0% to 10%, 0.00% to 6%, 0% to 5%, or 0% to 3%;

[0121] The lubricant has a weight percentage of 0.1% to 8%, preferably 0.1% to 5%, 0.1% to 4%, 0.5% to 3%, or 1% to 3%;

[0122] The gliding agent has a weight percentage of 0.5% to 10%, preferably 0.5% to 8%, 0.5% to 5%, 1% to 5%, 1% to 4%, or 1% to 3%;

[0123] Other excipients, in weight percentages of 0% to 25%, preferably 0% to 20%, 0% to 15%, 0% to 10%, or 0% to 5%; and the sum of the weight percentages of all the above components is 100%.

[0124] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows:

[0125] The active ingredient has a weight percentage of 1% to 90%, preferably 5% to 80%, 5% to 65%, 5% to 55%, 5% to 45%, or 5% to 40%;

[0126] The filler has a weight percentage of 10% to 95%, preferably 25% to 90%, 35% to 90%, 40% to 90%, or 50% to 90%;

[0127] The disintegrant has a weight percentage of 0% to 15%, preferably 0% to 10%, 0% to 6%, 0% to 5%, or 0% to 3%;

[0128] The lubricant has a weight percentage of 1% to 5%, preferably 2% to 4%, 2% to 3%, or 2% to 2.5%;

[0129] The gliding agent has a weight percentage of 1% to 5%, preferably 1% to 4%, 1% to 3%, 1.5% to 3%, 2% to 3% or 3%;

[0130] Other excipients, in weight percentages of 0% to 25%, preferably 0% to 20%, 0% to 15%, 0% to 10%, or 0% to 5%; and the sum of the weight percentages of all the above components is 100%.

[0131] In some embodiments of the present invention, the components of the pharmaceutical composition and their weight percentages are as follows:

[0132] The active ingredient has a weight percentage of 1% to 90%, preferably 5% to 80%, 5% to 65%, 5% to 55%, 5% to 45%, or 5% to 40%;

[0133] Microcrystalline cellulose, with a weight percentage of 10% to 95%, preferably 25% to 90%, 35% to 90%, 40% to 90%, or 50% to 90%;

[0134] The disintegrant has a weight percentage of 0% to 15%, preferably 0% to 10%, 0% to 6%, 0% to 5%, or 0% to 3%;

[0135] The lubricant has a weight percentage of 0.1% to 8%, preferably 0.1% to 5%, 0.1% to 4%, 0.5% to 3%, or 1% to 2%;

[0136] Other excipients, in weight percentages of 0% to 25%, preferably 0% to 20%, 0% to 15%, 0% to 10%, or 0% to 5%;

[0137] Furthermore, the sum of the weight percentages of all the above components is 100%.

[0138] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows:

[0139] The active ingredient, by weight percentage, is 5%–90%; or 10%–90%; or 10%–80%; or 15%–80%; or 20%–70%; or 25%–60%; or 25%–50%; or 25%–45%; or 25%–40%.

[0140] The filler, by weight percentage, is 5%–90%; or 15%–90%; or 15%–85%; or 25%–85%; or 25%–80%; or 35%–75%; or 35%–70%; or 50%–70%; or 55%–70%.

[0141] The disintegrant has a weight percentage of 0% to 5%; or 0% to 4%; or 0.5% to 4%; or 1% to 3%;

[0142] The adhesive, by weight percentage, is 0% to 5%; or 0% to 4%; or 0% to 3%;

[0143] The lubricant comprises 1% to 5% by weight; or 1% to 4%; or 2% to 4%; or 2% to 3% by weight.

[0144] The glialization agent, by weight percentage, is 0%–5%; or 0%–4%; or 1%–4%; or 1%–3%; or 0%–3%; or 2%–4%; or 3%–4%; or 2%–3%;

[0145] Other excipients, by weight percentage, are 0% to 10%; or 0% to 5%; the sum of the weight percentages of the above components is 100%.

[0146] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows:

[0147] 0.5%–90% active ingredient, 5%–99% filler, 0%–20% disintegrant, 0%–10% binder, 0.1%–15% lubricant, and 0%–25% other excipients; or

[0148] 5%–80% active ingredient, 10%–95% filler, 0%–15% disintegrant, 0%–6% binder, 0.50%–10% lubricating agent, and 0%–15% other excipients; or

[0149] 5%–80% active ingredient, 15%–85% filler, 0%–5% disintegrant, 0%–4% binder, 0%–7% lubricant, and 0%–10% other excipients; or

[0150] 5%–80% active ingredient, 15%–80% filler, 0%–4% disintegrant, 0%–3% binder, 1%–6% lubricant, and 0%–5% other excipients; the sum of the weight percentages of the above components is 100%.

[0151] In some embodiments of this application, the components of the aforementioned pharmaceutical composition and their weight percentages are as follows:

[0152] 5%–90% active ingredient, 5%–90% filler, 0%–5% disintegrant, 0%–5% binder, 1%–7% lubricating agent, and 0%–5% other excipients; or

[0153] 10%–90% active ingredient, 15%–90% filler, 0%–5% disintegrant, 0%–4% binder, 1%–6% lubricant, and 0%–5% other excipients; or

[0154] 10%–80% active ingredient, 15%–85% filler, 0%–5% disintegrant, 0%–4% binder, 3%–5% lubricant, and 0%–5% other excipients; or

[0155] 10%–80% active ingredient, 15%–85% filler, 0%–5% disintegrant, 0%–4% binder, 3.5%–6% lubricating agent, and 0%–5% other excipients; or

[0156] 10%–80% active ingredient, 15%–85% filler, 0%–5% disintegrant, 0%–4% binder, 4%–6% lubricant, and 0%–5% other excipients; or

[0157] 25%–60% active ingredient, 35%–70% filler, 0%–4% disintegrant, 0%–3% binder, 5%–6% lubricant, and 0%–5% other excipients; or

[0158] The sum of the weight percentages of all the above components is 100%.

[0159] In some embodiments of this application, the filler is selected from: pregelatinized starch, microcrystalline cellulose, anhydrous dicalcium phosphate, calcium carbonate, or a combination of pregelatinized starch and mannitol, or a combination of microcrystalline cellulose and lactose, or a combination of pregelatinized starch and anhydrous dicalcium phosphate, or a combination of pregelatinized starch and calcium carbonate; the lubricating agent is a lubricant and / or a flow aid, wherein the lubricant is magnesium stearate and the flow aid is colloidal silica; the disintegrant is selected from sodium carboxymethyl starch and croscarmellose sodium; the binder is selected from copovidone; preferably copovidone VA64 and / or copovidone VA64Fine.

[0160] In some embodiments of this application, the filler is selected from a combination of pregelatinized starch and mannitol, a combination of microcrystalline cellulose and lactose, a combination of pregelatinized starch and anhydrous dicalcium phosphate, a combination of pregelatinized starch and lactose, or a combination of pregelatinized starch and calcium carbonate. In this case, the weight ratio of the two fillers is 1:10 to 10:1, preferably 1:7 to 7:1, more preferably 1:6 to 6:1, more preferably 1:5 to 5:1, more preferably 1:4 to 4:1, more preferably 1:3 to 3:1, even more preferably 1:2 to 2:1, and even more preferably 1:1.

[0161] In some embodiments of this application, the lubricating additive is a lubricant.

[0162] In some embodiments of this application, the lubricating additive is a combination of lubricant and flow aid, wherein the weight ratio of the flow aid to the lubricant is 1:6 to 6:1; or 1:5 to 5:1; or 1:4 to 4:1; or 1:3 to 3:1; or 1:2 to 2:1; or 1:1, 1:2, 1:1.5, 2:1, 2:3, 3:1, 3:2, 4:3 or 5:3.

[0163] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows:

[0164] 0.50%–90% active ingredient, 5%–99% filler, 0%–20% disintegrant, 0%–10% binder, 0%–10% lubricant, 0%–10% flow aid, and 0%–25% other excipients; or

[0165] 5%–80% active ingredient, 10%–95% filler, 0%–10% disintegrant, 0%–6% binder, 0%–5% lubricant, 0%–5% flow aid, and 0%–25% other excipients; or

[0166] 5%–80% active ingredient, 15%–85% filler, 0%–6% disintegrant, 0%–5% binder, 1%–4% lubricant, 0%–4% flow aid, and 0%–15% other excipients; or

[0167] 5%–80% active ingredient, 15%–80% filler, 0%–5% disintegrant, 0%–4% binder, 1%–3.50% lubricant, 0%–3.50% flow aid, and 0%–10% other excipients; or

[0168] 5%–80% active ingredient, 15%–80% filler, 0%–4% disintegrant, 0%–3% binder, 1%–3% lubricant, 0%–3% flow aid, and 0%–5% other excipients; the sum of the weight percentages of the above components is 100%.

[0169] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows:

[0170] 5%–90% active ingredient, 5%–90% filler, 0%–5% disintegrant, 0%–5% binder, 1%–5% lubricant, 0%–5% flow aid, and 0%–5% other excipients; or

[0171] 5%–90% active ingredient, 5%–90% filler, 0%–5% disintegrant, 0%–5% binder, 1%–4% lubricant, 0%–4% flow aid, and 0%–5% other excipients; or

[0172] 10%–90% active ingredient, 15%–90% filler, 0%–5% disintegrant, 0%–4% binder, 1%–3% lubricant, 0%–3% flow aid, and 0%–5% other excipients; or

[0173] 10%–90% active ingredient, 15%–90% filler, 0%–4% disintegrant, 0%–3% binder, 1%–3% lubricant, 0%–3% flow aid, and 0%–5% other excipients; or

[0174] The sum of the weight percentages of all the above components is 100%.

[0175] In some embodiments of this application, the filler is selected from one of: pregelatinized starch, microcrystalline cellulose, anhydrous dicalcium phosphate, calcium carbonate, or a combination of pregelatinized starch and mannitol, or a combination of microcrystalline cellulose and lactose, or a combination of pregelatinized starch and anhydrous dicalcium phosphate, or a combination of pregelatinized starch and calcium carbonate; the lubricant is selected from one or more of magnesium stearate or sodium stearate fumarate; the flow aid is colloidal silica; the disintegrant is selected from sodium carboxymethyl starch and croscarmellose sodium; and the binder is copovidone, preferably copovidone VA64.

[0176] In some embodiments of this application, the filler is selected from a combination of pregelatinized starch and mannitol, a combination of microcrystalline cellulose and lactose, a combination of pregelatinized starch and anhydrous dicalcium phosphate, a combination of pregelatinized starch and lactose, or a combination of pregelatinized starch and calcium carbonate. Preferably, the weight ratio of the two fillers is 1:10 to 10:1, more preferably 1:7 to 7:1, further preferably 1:6 to 6:1, more preferably 1:5 to 5:1, more preferably 1:4 to 4:1, more preferably 1:3 to 3:1, even more preferably 1:2 to 2:1, and even more preferably 1:1.

[0177] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows:

[0178] 5%–45% active ingredient, 50%–90% filler, 0%–5% disintegrant, 0%–5% binder, 1%–5% lubricant, 0%–5% flow aid, and 0%–5% other excipients; or

[0179] 5%–40% active ingredient, 50%–90% filler, 0%–5% disintegrant, 0%–3% binder, 2%–4% lubricant, 1%–4% flow aid, and 0%–5% other excipients; or

[0180] 5%–40% active ingredient, 50%–90% filler, 0%–5% disintegrant, 0%–3% binder, 2%–3% lubricant, 2%–4% flow aid, and 0%–5% other excipients; or

[0181] 5%–40% active ingredient, 50%–90% filler, 0%–5% disintegrant, 0%–3% binder, 2%–3% lubricant, 3%–4% flow aid, and 0%–5% other excipients; or

[0182] 20%–45% active ingredient, 50%–75% filler, 0%–5% disintegrant, 0%–3% binder, 2%–3% lubricant, 3%–4% flow aid, and 0%–5% other excipients; or

[0183] 25%–40% active ingredient, 50%–70% filler, 0%–4% disintegrant, 0%–3% binder, 2%–3% lubricant, 3%–4% flow aid, and 0%–5% other excipients; or

[0184] 25%–40% active ingredient, 50%–70% filler, 2%–3% lubricant, and 3%–4% flow aid;

[0185] The sum of the weight percentages of all the above components is 100%.

[0186] In some embodiments of this application, the filler is selected from: pregelatinized starch or microcrystalline cellulose, or a combination of pregelatinized starch and mannitol, or a combination of microcrystalline cellulose and lactose; the lubricant is selected from one or more of magnesium stearate or sodium stearate fumarate; the flow aid is colloidal silica; the disintegrant is selected from sodium carboxymethyl starch and croscarmellose sodium; and the binder is copovidone, preferably copovidone VA64.

[0187] In some embodiments of this application, the filler is selected from a combination of pregelatinized starch and mannitol, or a combination of microcrystalline cellulose and lactose. Preferably, the weight ratio of the two fillers is 1:10 to 10:1, more preferably 1:7 to 7:1, further preferably 1:6 to 6:1, more preferably 1:5 to 5:1, more preferably 1:4 to 4:1, more preferably 1:3 to 3:1, even more preferably 1:2 to 2:1, and even more preferably 1:1.

[0188] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows:

[0189] 5%–45% active ingredient, 50%–90% filler, 0%–5% disintegrant, 0%–5% binder, 1%–5% lubricant, 0%–5% flow aid, and 0%–5% other excipients; or

[0190] 15%–45% active ingredient, 50%–70% filler, 1%–5% disintegrant, 0%–3% binder, 2%–4% lubricant, 3%–4% flow aid, and 0%–5% other excipients; or

[0191] 25%–40% active ingredient, 50%–70% filler, 1%–3% disintegrant, 0%–3% binder, 2%–3% lubricant, 2%–4% flow aid, and 0%–5% other excipients; or

[0192] 25%–40% active ingredient, 50%–70% filler, 1%–3% disintegrant, 2%–3% lubricant, and 2%–4% flow aid;

[0193] The sum of the weight percentages of all the above components is 100%.

[0194] In some embodiments of this application, the filler is selected from a combination of microcrystalline cellulose and lactose; preferably, the weight ratio of the two fillers is 1:10 to 10:1, more preferably 1:7 to 7:1, further preferably 1:6 to 6:1, further preferably 1:5 to 5:1, further preferably 1:4 to 4:1, further preferably 1:3 to 3:1, even more preferably 1:2 to 2:1, and even more preferably 1:1; the lubricant is selected from one or more of magnesium stearate or sodium stearate fumarate; the flow aid is colloidal silica; the disintegrant is selected from sodium carboxymethyl starch and croscarmellose sodium; the binder is copovidone, preferably copovidone VA64.

[0195] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows:

[0196] 10%–90% active ingredient, 5%–90% filler, 0%–5% disintegrant, 0%–5% binder, 1%–4% lubricant, 1%–4% flow aid, and 0%–5% other excipients; or

[0197] 10%–90% active ingredient, 5%–90% filler, 0%–5% disintegrant, 0%–4% binder, 1%–3% lubricant, 1%–3% flow aid, and 0%–5% other excipients; or

[0198] 15%–70% active ingredient, 20%–80% filler, 0%–5% disintegrant, 0%–4% binder, 1%–3% lubricant, 1%–3% flow aid, and 0%–5% other excipients; or

[0199] 15%–70% active ingredient, 20%–80% filler, 0%–4% disintegrant, 0%–3% binder, 2%–3% lubricant, 2%–3% flow aid, and 0%–5% other excipients; or

[0200] 15%–70% active ingredient, 20%–80% filler, 0%–4% disintegrant, 0%–3% binder, 2%–3% lubricant, and 2%–3% flow aid;

[0201] The sum of the weight percentages of all the above components is 100%.

[0202] In some embodiments of this application, the filler is selected from: anhydrous dicalcium phosphate or calcium carbonate, or a combination of pregelatinized starch and anhydrous dicalcium phosphate, or a combination of pregelatinized starch and calcium carbonate; the lubricant is selected from one or more of magnesium stearate or sodium stearate fumarate; the flow aid is colloidal silica; the disintegrant is selected from sodium carboxymethyl starch and croscarmellose sodium; and the binder is copovidone, preferably copovidone VA64.

[0203] In some embodiments of this application, the filler is selected from a combination of pregelatinized starch and anhydrous dicalcium phosphate, or a combination of pregelatinized starch and calcium carbonate. Preferably, the weight ratio of the two fillers is 1:10 to 10:1, more preferably 1:7 to 7:1, further preferably 1:6 to 6:1, more preferably 1:5 to 5:1, more preferably 1:4 to 4:1, more preferably 1:3 to 3:1, even more preferably 1:2 to 2:1, and even more preferably 1:1.

[0204] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows:

[0205] 0.50%–90% active ingredient, 5%–99% filler, 0%–20% disintegrant, 0%–10% binder, 0%–10% lubricant, 0%–10% flow aid, and 0%–25% other excipients; or

[0206] 5%–80% active ingredient, 10%–95% filler, 0%–10% disintegrant, 0%–6% binder, 0%–5% lubricant, 0%–5% flow aid, and 0%–25% other excipients; or

[0207] 5%–80% active ingredient, 15%–85% filler, 0%–6% disintegrant, 0%–5% binder, 1%–4% lubricant, 0%–4% flow aid, and 0%–15% other excipients; or

[0208] 5%–80% active ingredient, 15%–80% filler, 0%–5% disintegrant, 0%–4% binder, 1%–3.50% lubricant, 0%–3.50% flow aid, and 0%–10% other excipients; or

[0209] 5%–80% active ingredient, 15%–80% filler, 0%–4% disintegrant, 0%–3% binder, 1%–3% lubricant, 0%–3% flow aid, and 0%–5% other excipients; or

[0210] 5%–80% active ingredient, 15%–80% filler, 0%–4% disintegrant, 0%–3% binder, 1%–3% lubricant, 1%–5% flow aid, and 0%–5% other excipients; or

[0211] 5%–80% active ingredient, 15%–80% filler, 0%–4% disintegrant, 0%–3% binder, 1%–3% lubricant, 1%–3% flow aid, and 0%–5% other excipients; or

[0212] The sum of the weight percentages of the above components is 100%; wherein, the filler is pregelatinized starch; the lubricant is magnesium stearate; the flow aid is colloidal silica; the disintegrant is selected from sodium carboxymethyl starch and / or cross-linked sodium carboxymethyl cellulose; and the binder is copovidone.

[0213] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows:

[0214] 20%–45% active ingredient, 40%–80% filler, 0%–5% disintegrant, 0%–5% binder, 2%–5% lubricant, 1%–5% flow aid, and 0%–5% other excipients; or

[0215] 20%–45% active ingredient, 40%–80% filler, 0%–3% disintegrant, 0%–3% binder, 2%–4% lubricant, 1%–4% flow aid, and 0%–5% other excipients; or

[0216] 20%–45% active ingredient, 40%–80% filler, 0%–3% disintegrant, 0%–3% binder, 2%–3% lubricant, 2%–4% flow aid, and 0%–5% other excipients; or

[0217] 20%–45% active ingredient, 40%–80% filler, 0%–3% disintegrant, 0%–3% binder, 2%–3% lubricant, 3%–4% flow aid, and 0%–5% other excipients; or

[0218] 25%–40% active ingredient, 50%–75% filler, 0%–3% disintegrant, 0%–3% binder, 2%–3% lubricant, 3%–4% flow aid, and 0%–5% other excipients; or

[0219] 25%–40% active ingredient, 50%–70% filler, 0%–3% disintegrant, 0%–3% binder, 2%–3% lubricant, 3%–4% flow aid, and 0%–5% other excipients; or

[0220] The sum of the weight percentages of the above components is 100%; wherein, the filler is pregelatinized starch; the lubricant is magnesium stearate; the flow aid is colloidal silica; the disintegrant is selected from sodium carboxymethyl starch and / or cross-linked sodium carboxymethyl cellulose; and the binder is copovidone.

[0221] In some embodiments of the present invention, the components of the pharmaceutical composition and their weight percentages are as follows:

[0222] 5%–65% active ingredient, 35%–90% pregelatinized starch, 0%–6% disintegrant, 0.1%–5% lubricant, 1%–5% glidant, and 0%–25% other excipients; or

[0223] 5%–55% active ingredient, 40%–90% pregelatinized starch, 0%–5% disintegrant, 0.1%–4% lubricant, 1%–5% glidant, and 0%–20% other excipients; or

[0224] 5%–40% active ingredient, 50%–90% pregelatinized starch, 0%–3% disintegrant, 1%–3% lubricant, 1%–5% flow aid, and 0%–15% other excipients; or 5%–40% active ingredient, 50%–90% pregelatinized starch, 0%–3% disintegrant, 1%–3% lubricant, 1%–5% colloidal silica, and 0%–10% other excipients; or 5%–40% active ingredient, 50%–90% pregelatinized starch, 0%–3% disintegrant, 1%–3% magnesium stearate, 1%–5% colloidal silica, and 0%–5% other excipients; or

[0225] 5%–40% active ingredients, 50%–90% pregelatinized starch, 0%–3% sodium carboxymethyl starch or croscarmellose sodium, 1%–3% magnesium stearate, and 1%–5% colloidal silica;

[0226] The sum of the weight percentages of all the above components is 100%.

[0227] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows:

[0228] 20%–45% active ingredient, 40%–80% pregelatinized starch, 0%–5% disintegrant, 0%–5% binder, 2%–5% lubricant, 1%–5% flow aid, and 0%–5% other excipients; or

[0229] 20%–45% active ingredient, 40%–80% pregelatinized starch, 0%–3% disintegrant, 0%–3% binder, 2%–4% lubricant, 1%–4% flow aid, and 0%–5% other excipients; or

[0230] 20%–45% active ingredient, 40%–80% pregelatinized starch, 0%–3% disintegrant, 0%–3% binder, 2%–3% lubricant, 2%–4% colloidal silica, and 0%–5% other excipients; or

[0231] 20%–45% active ingredient, 40%–80% pregelatinized starch, 0%–3% disintegrant, 0%–3% binder, 2%–3% lubricant, 3%–4% colloidal silica, and 0%–5% other excipients; or

[0232] 25%–40% active ingredient, 50%–75% pregelatinized starch, 0%–3% disintegrant, 0%–3% binder, 2%–3% lubricant, 3%–4% colloidal silica, and 0%–5% other excipients; or

[0233] 25%–40% active ingredient, 50%–70% pregelatinized starch, 0%–3% disintegrant, 0%–3% binder, 2%–3% lubricant, and 3%–4% colloidal silica; the sum of the weight percentages of the above components is 100%.

[0234] Preferably, the lubricant is selected from one or more of magnesium stearate or sodium stearate fumarate; preferably, the flow aid is selected from colloidal silica; preferably, the disintegrant is selected from one or two of sodium carboxymethyl starch and croscarmellose sodium; preferably, the binder is copovidone, more preferably copovidone VA64.

[0235] In some embodiments of the present invention, the components of the pharmaceutical composition and their weight percentages are as follows:

[0236] 5%–65% active ingredient, 10%–95% filler (pregelatinized starch and mannitol), 0%–6% disintegrant, 0.1%–5% lubricant, 1%–5% flow aid, and 0%–25% other excipients; or

[0237] 5%–65% active ingredient, 5%–30% pregelatinized starch, 5%–65% mannitol, 0%–6% disintegrant, 0.1%–5% lubricant, 1%–5% glidant, and 0%–20% other excipients; or

[0238] 5%–55% active ingredient, 5%–30% pregelatinized starch, 5%–65% mannitol, 0%–5% disintegrant, 0.1%–4% lubricant, 1%–5% glidant, and 0%–15% other excipients; or

[0239] 5%–40% active ingredient, 5%–30% pregelatinized starch, 5%–65% mannitol, 0%–3% disintegrant, 1%–3% lubricant, 1%–5% glidant, and 0%–10% other excipients; or

[0240] 5%–40% active ingredient, 5%–30% pregelatinized starch, 5%–65% mannitol, 0%–3% disintegrant, 1%–3% lubricant, 1%–5% colloidal silica, and 0%–10% other excipients; or

[0241] 5%–40% active ingredient, 5%–30% pregelatinized starch, 5%–65% mannitol, 0%–3% disintegrant, 1%–3% magnesium stearate, 1%–5% colloidal silica, and 0%–5% other excipients; or

[0242] 5%–40% active ingredient, 5%–30% pregelatinized starch, 5%–65% mannitol, 0%–3% sodium carboxymethyl starch or croscarmellose sodium, 1%–3% magnesium stearate, and 1%–5% colloidal silica.

[0243] The sum of the weight percentages of all the above components is 100%;

[0244] Preferably, the weight ratio of pregelatinized starch to mannitol is 1:10 to 10:1, more preferably 1:7 to 7:1, even more preferably 1:6 to 6:1, even more preferably 1:5 to 5:1, even more preferably 1:4 to 4:1, even more preferably 1:3 to 3:1, and even more preferably 1:2 to 2:1.

[0245] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows:

[0246] 5%–45% active ingredient, 50%–90% filler (pregelatinized starch and mannitol), 0%–3% disintegrant, 0%–4% binder, 2%–4% lubricant, 2.5%–5% flow aid, and 0%–5% other excipients; or

[0247] 5%–45% active ingredient, 5%–60% pregelatinized starch, 5%–65% mannitol, 0%–3% disintegrant, 0%–3% binder, 2%–4% lubricant, 2.5%–5% flow aid, and 0%–5% other excipients; or

[0248] 25%–45% active ingredient, 5%–55% pregelatinized starch, 5%–65% mannitol, 0%–3% disintegrant, 0%–3% binder, 2%–4% lubricant, 3%–4% flow aid, and 0%–5% other excipients; the sum of the weight percentages of the above components is 100%.

[0249] Preferably, the weight ratio of pregelatinized starch to mannitol is 1:10 to 10:1, more preferably 1:7 to 7:1, further preferably 1:6 to 6:1, further preferably 1:5 to 5:1, further preferably 1:4 to 4:1, further preferably 1:3 to 3:1, and even more preferably 1:2 to 2:1; preferably, the lubricant is selected from one or more of magnesium stearate or sodium stearate fumarate; preferably, the flow aid is selected from colloidal silica; preferably, the disintegrant is selected from one or two of sodium carboxymethyl starch and croscarmellose sodium; preferably, the binder is copovidone, preferably copovidone VA64.

[0250] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows:

[0251] 5%–65% active ingredient, 10%–95% filler (microcrystalline cellulose and lactose), 0%–6% disintegrant, 0.1%–5% lubricant, 0.5%–5% flow aid, and 0%–25% other excipients; or

[0252] 5%–65% active ingredient, 5%–50% microcrystalline cellulose, 5%–45% lactose, 0%–6% disintegrant, 0.1%–5% lubricant, 0.5%–5% glidant, and 0%–20% other excipients; or

[0253] 5%–55% active ingredient, 15%–45% microcrystalline cellulose, 10%–45% lactose, 0%–5% disintegrant, 0.1%–4% lubricant, 0.5%–5% flow aid, and 0%–15% other excipients; or

[0254] 5%–40% active ingredient, 15%–45% microcrystalline cellulose, 10%–45% lactose, 0%–3% disintegrant, 1%–2% lubricant, 0.5%–5% glidant, and 0%–10% other excipients; or

[0255] 5%–40% active ingredient, 15%–45% microcrystalline cellulose, 10%–45% lactose, 0%–3% disintegrant, 1%–2% lubricant, 0.5%–5% colloidal silica, and 0%–10% other excipients; or

[0256] 5%–40% active ingredient, 15%–45% microcrystalline cellulose, 10%–45% lactose, 0%–3% disintegrant, 1%–2% magnesium stearate, 0.5%–5% colloidal silica, and 0%–5% other excipients; or

[0257] 5%–40% active ingredient, 15%–45% microcrystalline cellulose, 10%–45% lactose, 0%–3% sodium carboxymethyl starch or croscarmellose sodium, 1%–2% magnesium stearate, and 0.5%–5% colloidal silica;

[0258] The sum of the weight percentages of all the above components is 100%;

[0259] Preferably, the weight ratio of microcrystalline cellulose to lactose is 1:10 to 10:1, more preferably 1:7 to 7:1, even more preferably 1:6 to 6:1, even more preferably 1:5 to 5:1, even more preferably 1:4 to 4:1, even more preferably 1:3 to 3:1, and even more preferably 1:2 to 2:1.

[0260] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows:

[0261] 20%–45% active ingredient, 50%–75% filler (microcrystalline cellulose and lactose), 0%–5% disintegrant, 0%–5% binder, 2%–4% lubricant, 2%–4% flow aid, and 0%–5% other excipients; or

[0262] 20%–45% active ingredient, 50%–75% filler (microcrystalline cellulose and lactose), 1%–4% disintegrant, 0%–4% binder, 2%–3% lubricant, 3%–4% flow aid, and 0%–5% other excipients; or

[0263] 20%–45% active ingredient, 15%–50% microcrystalline cellulose, 15%–45% lactose, 1%–4% disintegrant, 0%–3% binder, 2%–3% lubricant, 3%–4% flow aid, and 0%–5% other excipients; or

[0264] 25%–45% active ingredient, 15%–50% microcrystalline cellulose, 15%–45% lactose, 1%–3% disintegrant, 0%–3% binder, 2%–3% lubricant, 3%–4% flow aid, and 0%–5% other excipients; or the sum of the weight percentages of the above components is 100%.

[0265] Preferably, the lubricant is selected from one or more of magnesium stearate or sodium stearate fumarate; preferably, the flow aid is selected from colloidal silica; preferably, the disintegrant is selected from one or two of sodium carboxymethyl starch and croscarmellose sodium; preferably, the binder is copovidone, more preferably copovidone VA64.

[0266] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows:

[0267] 10%–90% active ingredient, 5%–85% anhydrous dicalcium phosphate, 0%–3% disintegrant, 0%–3% binder, 2%–3% lubricant, 1%–3% flow aid, and 0%–5% other excipients; or

[0268] 10%–80% active ingredient, 15%–85% anhydrous dicalcium phosphate, 0%–3% disintegrant, 0%–3% binder, 2%–3% lubricant, 1%–3% flow aid, and 0%–5% other excipients; and the sum of the weight percentages of the above components is 100%;

[0269] Preferably, the lubricant is selected from one or more of magnesium stearate or sodium stearate fumarate; preferably, the flow aid is selected from colloidal silica; preferably, the disintegrant is selected from one or two of sodium carboxymethyl starch and croscarmellose sodium; preferably, the binder is copovidone, more preferably copovidone VA64.

[0270] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows:

[0271] 15%–80% active ingredient, 5%–20% anhydrous dicalcium phosphate, 5%–60% pregelatinized starch, 0%–3% disintegrant, 0%–3% binder, 1.5%–3% lubricant, 2%–3% flow aid, and 0%–5% other excipients;

[0272] Furthermore, the sum of the weight percentages of all the above components is 100%;

[0273] Preferably, the lubricant is selected from one or more of magnesium stearate or sodium stearate fumarate; preferably, the flow aid is selected from colloidal silica; preferably, the disintegrant is selected from one or two of sodium carboxymethyl starch and croscarmellose sodium; preferably, the binder is copovidone, more preferably copovidone VA64.

[0274] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows:

[0275] 10%–80% active ingredient, 15%–75% calcium carbonate, 0%–5% disintegrant, 0%–3% binder, 2%–3% lubricant, 2%–3% flow aid, and 0%–5% other excipients; or

[0276] 10%–80% active ingredient, 15%–75% calcium carbonate, 0.5%–4% disintegrant, 0%–3% binder, 2%–3% lubricant, 2%–3% flow aid, and 0%–5% other excipients;

[0277] Furthermore, the sum of the weight percentages of all the above components is 100%;

[0278] Preferably, the lubricant is selected from one or more of magnesium stearate or sodium stearate fumarate; preferably, the flow aid is selected from colloidal silica; preferably, the disintegrant is selected from one or two of sodium carboxymethyl starch and croscarmellose sodium; preferably, the binder is copovidone, more preferably copovidone VA64.

[0279] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows:

[0280] 10%–80% active ingredient, 5%–40% calcium carbonate, 5%–60% pregelatinized starch, 0%–2% disintegrant, 0%–3% binder, 2%–3% lubricant, 2%–3% flow aid, and 0%–5% other excipients; or

[0281] 10%–80% active ingredient, 5%–40% calcium carbonate, 5%–60% pregelatinized starch, 0%–2% disintegrant, 0%–2% binder, 2%–3% lubricant, 2%–3% flow aid, and 0%–5% other excipients;

[0282] Furthermore, the sum of the weight percentages of all the above components is 100%;

[0283] Preferably, the lubricant is selected from one or more of magnesium stearate or sodium stearate fumarate; preferably, the flow aid is selected from colloidal silica; preferably, the disintegrant is selected from one or two of sodium carboxymethyl starch and croscarmellose sodium; preferably, the binder is copovidone, more preferably copovidone VA64.

[0284] In some embodiments of the present invention, the components of the pharmaceutical composition and their weight percentages are as follows:

[0285] 5%–65% active ingredient, 10%–95% microcrystalline cellulose, 0%–6% disintegrant, 0.1%–5% lubricant, 0%–10% flow aid, and 0%–25% other excipients; or

[0286] 5%–55% active ingredient, 20%–85% microcrystalline cellulose, 0%–5% disintegrant, 0.1%–4% lubricant, 0%–8% flow aid, and 0%–20% other excipients; or

[0287] 5%–45% active ingredient, 30%–75% microcrystalline cellulose, 0%–4% disintegrant, 1%–3% lubricant, 0%–3% flow aid, and 0%–10% other excipients;

[0288] The sum of the weight percentages of all the above components is 100%.

[0289] In some embodiments of this application, the pharmaceutical composition described above (fourth aspect) may also contain excipients other than those of the type described above. These other excipients are selected from: binders, flavoring agents, antibacterial agents, pH adjusters, pigments, thickeners, dispersants, colorants, antioxidants, stabilizers, fragrances, and coating materials, etc. In embodiments of this application, the weight percentage of the other excipients in the pharmaceutical composition is 0% to 25%, preferably 0% to 20%, 0% to 15%, 0% to 10%, or 0% to 5%.

[0290] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are: 10% to 70% of the active ingredient, 30% to 80% of the pregelatinized starch, 0% to 5% of the colloidal silica, 0% to 5% of the magnesium stearate, and 0% to 5% of the sodium carboxymethyl starch and / or the sodium cross-linked carboxymethyl cellulose, the sum of the weight percentages of the components being 100%.

[0291] Preferably, the components of the pharmaceutical composition and their weight percentages are: 15% to 60% of the active ingredient, 40% to 80% of the pregelatinized starch, 1% to 5% of the colloidal silica, 1% to 5% of the magnesium stearate, and 0% to 5% of the sodium carboxymethyl starch and / or the sodium cross-linked carboxymethyl cellulose, and the sum of the weight percentages of the components is 100%.

[0292] Preferably, the components of the pharmaceutical composition and their weight percentages are: 20% to 50% of the active ingredient, 45% to 75% of pregelatinized starch, 1% to 4% of colloidal silica, 1% to 5% of magnesium stearate, and 0% to 5% of sodium carboxymethyl starch and / or croscarmellose sodium, the sum of the weight percentages of each component being 100%.

[0293] Preferably, the components of the pharmaceutical composition and their weight percentages are: 25% to 45% of the active ingredient, 50% to 70% of pregelatinized starch, 1% to 4% of colloidal silica, 1% to 4% of magnesium stearate, and 0% to 4% of sodium carboxymethyl starch and / or croscarmellose sodium, the sum of the weight percentages of each component being 100%.

[0294] Preferably, the components of the pharmaceutical composition and their weight percentages are: 25% to 40% of the active ingredient, 56% to 68% of pregelatinized starch, 1% to 4% of colloidal silica, 2% to 4% of magnesium stearate, and 0% to 4% of sodium carboxymethyl starch and / or croscarmellose sodium, the sum of the weight percentages of the components being 100%.

[0295] Preferably, the components of the pharmaceutical composition and their weight percentages are: 25% to 40% of the active ingredient, 56% to 68% of pregelatinized starch, 1% to 3% of colloidal silica, 2% to 3% of magnesium stearate, and 0% to 4% of sodium carboxymethyl starch and / or croscarmellose sodium, and the sum of the weight percentages of the components is 100%.

[0296] Preferably, the components of the pharmaceutical composition and their weight percentages are: 25% to 40% of the active ingredient, 56% to 68% of the pregelatinized starch, 3% to 5% of the colloidal silica, and 2% to 3% of the magnesium stearate, and the sum of the weight percentages of the components is 100%.

[0297] Preferably, the components of the pharmaceutical composition and their weight percentages are: 25% to 40% of the active ingredient, 56% to 68% of the pregelatinized starch, 3% to 4% of the colloidal silica, and 2% to 3% of the magnesium stearate, and the sum of the weight percentages of the components is 100%.

[0298] In some other embodiments of this application, the components of the pharmaceutical composition and their weight percentages are: 25% to 50% of the active ingredient, 50% to 75% of microcrystalline cellulose, 0% to 5% of colloidal silica, 0% to 3% of magnesium stearate, and 0% to 5% of sodium carboxymethyl starch and / or croscarmellose sodium, the sum of the weight percentages of each component being 100%.

[0299] Preferably, the components of the pharmaceutical composition and their weight percentages are: 25% to 40% of the active ingredient, 55% to 75% of microcrystalline cellulose, 0% to 5% of colloidal silica, 1% to 3% of magnesium stearate, and 0% to 5% of sodium carboxymethyl starch and / or croscarmellose sodium, the sum of the weight percentages of each component being 100%.

[0300] Preferably, the components of the pharmaceutical composition and their weight percentages are: 30% to 35% of the active ingredient, 60% to 70% of microcrystalline cellulose, 0% to 3% of colloidal silica, 1% to 2% of magnesium stearate, and 0% to 4% of sodium carboxymethyl starch and / or croscarmellose sodium, and the sum of the weight percentages of each component is 100%.

[0301] Preferably, the components of the pharmaceutical composition and their weight percentages are: 30% to 35% of the active ingredient, 60% to 70% of microcrystalline cellulose, 0% to 3% of colloidal silica, and 1% to 2% of magnesium stearate, and the sum of the weight percentages of the components is 100%.

[0302] In some other embodiments of this application, the components of the pharmaceutical composition and their weight percentages are: 5% to 50% of the active ingredient, 5% to 55% of pregelatinized starch, 5% to 70% of mannitol, 0% to 5% of colloidal silica, 1% to 3% of magnesium stearate, and 0% to 5% of sodium carboxymethyl starch and / or croscarmellose sodium, the sum of the weight percentages of the components being 100%.

[0303] Preferably, the components of the pharmaceutical composition and their weight percentages are as follows: 20%–50% of the active ingredient, 5%–55% of pregelatinized starch, 5%–70% of mannitol, 1%–5% of colloidal silica, 1%–3% of magnesium stearate, and 0%–5% of sodium carboxymethyl starch and / or croscarmellose sodium, the sum of the weight percentages of the components being 100%.

[0304] Preferably, the components of the pharmaceutical composition and their weight percentages are: 25% to 40% of the active ingredient, 10% to 50% of pregelatinized starch, 5% to 63% of mannitol, 1% to 4% of colloidal silica, 1% to 3% of magnesium stearate, and 0% to 5% of sodium carboxymethyl starch and / or croscarmellose sodium, the sum of the weight percentages of the components being 100%.

[0305] Preferably, the components of the pharmaceutical composition and their weight percentages are: 25% to 40% of the active ingredient, 10% to 50% of pregelatinized starch, 5% to 63% of mannitol, 1% to 3% of colloidal silica, 1% to 3% of magnesium stearate, and 0% to 5% of sodium carboxymethyl starch and / or croscarmellose sodium, the sum of the weight percentages of each component being 100%.

[0306] Preferably, the components of the pharmaceutical composition and their weight percentages are: 25% to 40% of the active ingredient, 10% to 50% of pregelatinized starch, 5% to 63% of mannitol, 3% to 4% of colloidal silica, 2% to 3% of magnesium stearate, and 0% to 5% of sodium carboxymethyl starch and / or croscarmellose sodium, the sum of the weight percentages of each component being 100%.

[0307] Preferably, the components of the pharmaceutical composition and their weight percentages are: 25% to 40% of the active ingredient, 10% to 50% of the pregelatinized starch, 5% to 63% of mannitol, 3% to 4% of colloidal silica, and 2% to 3% of magnesium stearate, and the sum of the weight percentages of the components is 100%.

[0308] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows: 23%–50% of the active ingredient, 10%–55% of microcrystalline cellulose, 10%–50% of lactose, 0%–5% of colloidal silica, 1%–4% of magnesium stearate or sodium stearate fumarate, and 0%–5% of sodium carboxymethyl starch and / or croscarmellose sodium, the sum of the weight percentages of each component being 100%.

[0309] Preferably, the components of the pharmaceutical composition and their weight percentages are as follows: 23%–40% of the active ingredient, 10%–50% of microcrystalline cellulose, 10%–50% of lactose, 1%–5% of colloidal silica, 1%–4% of magnesium stearate or sodium stearate fumarate, and 0%–5% of sodium carboxymethyl starch and / or croscarmellose sodium, the sum of the weight percentages of each component being 100%.

[0310] Preferably, the components of the pharmaceutical composition and their weight percentages are as follows: 28%–35% of the active ingredient, 15%–45% of microcrystalline cellulose, 15%–45% of lactose, 1%–4% of colloidal silica, 2%–3% of magnesium stearate or sodium stearate fumarate, and 1%–4% of sodium carboxymethyl starch and / or croscarmellose sodium, the sum of the weight percentages of each component being 100%.

[0311] Preferably, the components of the pharmaceutical composition and their weight percentages are as follows: 28%–35% of the active ingredient, 15%–45% of microcrystalline cellulose, 15%–45% of lactose, 1%–3% of colloidal silica, 2%–3% of magnesium stearate or sodium stearate fumarate, and 1%–4% of sodium carboxymethyl starch and / or croscarmellose sodium, the sum of the weight percentages of each component being 100%.

[0312] Preferably, the components of the pharmaceutical composition and their weight percentages are as follows: 28%–35% of the active ingredient, 15%–45% of microcrystalline cellulose, 15%–45% of lactose, 3%–5% of colloidal silica, 2%–4% of magnesium stearate or sodium stearate fumarate, and 1%–4% of sodium carboxymethyl starch and / or croscarmellose sodium, the sum of the weight percentages of each component being 100%.

[0313] Preferably, the components of the pharmaceutical composition and their weight percentages are as follows: 28%–35% of the active ingredient, 15%–45% of microcrystalline cellulose, 15%–45% of lactose, 3%–4% of colloidal silica, 2%–3% of magnesium stearate or sodium stearate fumarate, and 1%–3% of sodium carboxymethyl starch and / or croscarmellose sodium, the sum of the weight percentages of each component being 100%.

[0314] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are: 10% to 90% of the active ingredient, 5% to 85% of anhydrous dicalcium phosphate, 1% to 5% of colloidal silica, 1% to 4% of magnesium stearate, and 0% to 5% of sodium carboxymethyl starch and / or croscarmellose sodium, the sum of the weight percentages of the components being 100%.

[0315] Preferably, the components of the pharmaceutical composition and their weight percentages are: 10% to 80% of the active ingredient, 15% to 85% of anhydrous dicalcium phosphate, 1% to 4% of colloidal silica, 2% to 3% of magnesium stearate, and 0% to 4% of sodium carboxymethyl starch and / or croscarmellose sodium, the sum of the weight percentages of the components being 100%.

[0316] Preferably, the components of the pharmaceutical composition and their weight percentages are: 50% to 60% of the active ingredient, 35% to 40% of anhydrous dicalcium phosphate, 1% to 3% of colloidal silica, 2% to 3% of magnesium stearate, and 0% to 4% of sodium carboxymethyl starch and / or croscarmellose sodium, the sum of the weight percentages of the components being 100%.

[0317] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows: 10% to 85% of the active ingredient, 5% to 23% of anhydrous dicalcium phosphate, 5% to 70% of pregelatinized starch, 1% to 4% of colloidal silica, 1% to 4% of magnesium stearate, and 0% to 4% of sodium carboxymethyl starch and / or croscarmellose sodium, the sum of the weight percentages of the components being 100%.

[0318] Preferably, the components of the pharmaceutical composition and their weight percentages are as follows: 15% to 80% of the active ingredient, 7% to 18% of anhydrous dicalcium phosphate, 7% to 63% of pregelatinized starch, 1% to 3% of colloidal silica, 2% to 3% of magnesium stearate, and 0% to 4% of sodium carboxymethyl starch and / or croscarmellose sodium, the sum of the weight percentages of each component being 100%.

[0319] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows: 10% to 82% of the active ingredient, 10% to 85% of calcium carbonate, 1% to 4% of colloidal silica, 1% to 4% of magnesium stearate, 0-5% of copovidone VA64, and 0% to 4% of sodium carboxymethyl starch and / or croscarmellose sodium, the sum of the weight percentages of the components being 100%.

[0320] Preferably, the components of the pharmaceutical composition and their weight percentages are as follows: 12%–80% of the active ingredient, 15%–78% of calcium carbonate, 1%–3% of colloidal silica, 2%–3% of magnesium stearate, 0–3% of copovidone VA64, and 0.5%–4% of sodium carboxymethyl starch and / or croscarmellose sodium, the sum of the weight percentages of each component being 100%.

[0321] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows: 10%–83% of the active ingredient, 5%–50% of calcium carbonate, 5%–68% of pregelatinized starch, 1%–4% of colloidal silica, 1%–4% of magnesium stearate, 0–3% of copovidone VA64, and 0%–2% of sodium carboxymethyl starch and / or croscarmellose sodium, the sum of the weight percentages of the components being 100%.

[0322] Preferably, the components of the pharmaceutical composition and their weight percentages are as follows: 12%–80% of the active ingredient, 7%–45% of calcium carbonate, 7%–65% of pregelatinized starch, 1%–3% of colloidal silica, 1.5%–3% of magnesium stearate, 0–2% of copovidone VA64, and 0%–1% of sodium carboxymethyl starch and / or croscarmellose sodium, the sum of the weight percentages of each component being 100%.

[0323] Preferably, the components of the pharmaceutical composition and their weight percentages are as follows: 12%–80% of the active ingredient, 7%–45% of calcium carbonate, 7%–65% of pregelatinized starch, 2%–3% of colloidal silica, 2%–3% of magnesium stearate, 0–2% of copovidone VA64, and 0%–1% of sodium carboxymethyl starch and / or croscarmellose sodium, the sum of the weight percentages of each component being 100%.

[0324] In some embodiments of this application, the pharmaceutical composition is formulated as an oral solid dosage form; preferably, the oral solid dosage form is selected from capsules, tablets, powders, and granules; more preferably, capsules, tablets, and granules; even more preferably, capsules and tablets; and even more preferably, capsules.

[0325] In some embodiments of this application, the tablet is selected from film-coated tablets or uncoated tablets.

[0326] Fifthly, this application provides a pharmaceutical composition comprising, as an active ingredient, a compound of formula II, formula A or formula B, and an excipient comprising a filler and a binder, and optionally, further comprising a flavoring agent.

[0327] In some embodiments of this application, the excipient comprises fillers, binders, and flavoring agents.

[0328] In some embodiments of this application, the flavoring agent comprises a flavoring agent, and optionally, further comprises a sweetener.

[0329] In some embodiments of this application, the filler is selected from one or more sugar alcohols; preferably, the sugar alcohol filler is selected from one or more of lactose, mannitol and sorbitol; preferably, the filler is selected from mannitol.

[0330] In some embodiments of this application, the adhesive is selected from one or more of copovidone, powdered sugar, syrup, polyvinylpyrrolidone, cellulose derivatives, glue, and dextrin; preferably, the cellulose derivative is selected from hydroxypropyl methylcellulose and / or sodium carboxymethyl cellulose; more preferably, copovidone, powdered sugar, polyvinylpyrrolidone, hydroxypropyl methylcellulose and / or sodium carboxymethyl cellulose; even more preferably, copovidone and / or polyvinylpyrrolidone.

[0331] In some embodiments of this application, the sweetener is selected from sorbitol, xylose, xylitol, glycerol, disodium glycyrrhizate, mannose, galactose, maltose, lactose, fructose, aspartame, sodium saccharin, steviol glycosides, glucose, sucrose, sucralose, aspartame, and neotame; preferably xylitol, sucralose, aspartame, and neotame.

[0332] In some embodiments of this application, the fragrance agent is one or more of oils or fragrances; preferably one or more of fennel oil, rose oil, peppermint oil, orange peel oil, lemon oil, rose essence, lemon essence, vanilla essence, vanillin, banana essence, pineapple essence, or apple essence; more preferably one or more of lemon essence, pineapple essence, or apple essence.

[0333] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows:

[0334] The active ingredient, by weight percentage, is 0.50%–30%; or 0.60%–25%; or 0.70%–20%; or 0.80%–15%; or 1%–10%; or 1.50%–8%; or 2%–6%; or 2.50%–5%; or 3%–4.50%.

[0335] The filler, by weight percentage, is 50%–99.90%; or 60%–99.50%; or 70%–99%; or 80%–99%; or 85%–99%.

[0336] The adhesive, by weight percentage, is 0% to 10%; or 0% to 6%; or 0% to 5%; or 0% to 4%; or 0% to 3%; or 0% to 2%;

[0337] Flavoring agent, by weight percentage, is 0%–10%; or 0%–6%; or 0%–5%; or 0%–4%; or 0%–3%; or 0%–2%; or 0%–1%;

[0338] Other excipients, by weight percentage, are 0%–25%; or 0%–20%; or 0%–15%; or 0%–10%; or 0%–5%; or 0.10%–3%; or 0.10%–2%; or 0.10%–1%; the sum of the weight percentages of the above components is 100%.

[0339] In some embodiments of this application, the filler is selected from mannitol; the binder is selected from copovidone; preferably copovidone VA64 or copovidone VA64 Fine; the flavoring agent is selected from sweeteners and / or flavoring agents; the sweetener is selected from xylitol, sucralose, aspartame, and / or neotame; the flavoring agent is selected from lemon flavoring; the components of the pharmaceutical composition and their weight percentages are as follows:

[0340] 0.50%–30% active ingredient, 50%–99.90% filler, 0%–10% binder, 0%–10% flavoring agent, and 0%–25% other excipients; or

[0341] 0.60%–25% active ingredient, 60%–99.50% filler, 0%–8% binder, 0%–6% flavoring agent, and 0%–15% other excipients; or

[0342] 0.70%–20% active ingredient, 70%–99% filler, 2%–8% binder, 0%–3% flavoring agent, and 0%–10% other excipients; or

[0343] 1%–10% active ingredients, 85%–99% fillers, 3%–8% binders, 0%–1% flavoring agents, and 0%–2% other excipients;

[0344] 1%–5% active ingredients, 85%–95% fillers, 4%–8% binders, 0%–1% flavoring agents, and 0%–2% other excipients;

[0345] The sum of the weight percentages of all the above components is 100%.

[0346] Preferably, in the pharmaceutical composition, the filler is selected from mannitol; the binder is selected from copovidone; preferably copovidone VA64; and the flavoring agent is selected from lemon flavoring.

[0347] In some embodiments of this application, the pharmaceutical compositions described in the above aspects may also contain excipients other than those of the types described above. Specific examples include disintegrants, antibacterial agents, thickeners, dispersants, antioxidants, and stabilizers. In embodiments of this application, the other excipients constitute 0% to 25% by weight in the pharmaceutical composition, preferably 0% to 20%, 0% to 15%, 0% to 10%, or 0% to 5%.

[0348] In some embodiments of this application, the pharmaceutical composition is formulated as an oral solid dosage form; preferably, the oral solid dosage form is selected from granules, powders, and fine granules; more preferably, it is granules.

[0349] In a sixth aspect, the present invention provides a pharmaceutical composition comprising, as an active ingredient, a compound of formula II or formula A, and an excipient comprising a solvent, and optionally, further comprising one or more of a flavoring agent, an antibacterial agent, or a pH adjuster.

[0350] In some embodiments of this application, the excipient comprises a solvent and a flavoring agent, and optionally, further comprises one or more of an antibacterial agent or a pH adjuster.

[0351] In some embodiments of this application, the excipient comprises a solvent, a flavoring agent, and a pH adjuster, and optionally, further comprises an antibacterial agent.

[0352] In some embodiments of this application, the flavoring agent comprises a sweetener, and optionally, further comprises a flavoring agent.

[0353] In some embodiments of this application, the aforementioned sweetener is selected from one or more of sorbitol, xylose, xylitol, glycerol, disodium glycyrrhizate, mannose, galactose, maltose, lactose, fructose, aspartame, sodium saccharin, steviol glycosides, glucose, sucrose, sucralose, aspartame, and / or neotame; preferably one or more of xylitol, sucralose, aspartame, and / or neotame.

[0354] In some embodiments of this application, the aforementioned fragrance agent is one or more of oils or fragrances; preferably, it is one or more of fennel oil, rose oil, peppermint oil, orange peel oil, lemon oil, rose essence, lemon essence, vanilla essence, vanillin, banana essence, pineapple essence, or apple essence; more preferably, it is one or more of lemon essence, pineapple essence, or apple essence.

[0355] In some embodiments of this application, the aforementioned solvent is selected from water, ethanol, and vegetable oil; preferably water; more preferably purified water.

[0356] In some embodiments of this application, the aforementioned antibacterial agent is selected from one or more of sodium benzoate, potassium sorbate, hexamethylenetetramine, ethanol, benzyl alcohol, or parabens; preferably one or more of sodium benzoate, potassium sorbate, hexamethylenetetramine, ethanol, benzyl alcohol, methylparaben, ethylparaben, or propylparaben; more preferably one or more of sodium benzoate, potassium sorbate, methylparaben, ethylparaben, or propylparaben.

[0357] In some embodiments of this application, the aforementioned pH adjuster is one or more of sodium hydroxide, sodium bicarbonate, and sodium carbonate.

[0358] In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows:

[0359] The active ingredient, by weight percentage, is 0.10%–40%; or 0.10%–35%; or 0.10%–30%; or 0.50%–25%; or 0.50%–20%; or 1%–10%.

[0360] The solvent has a weight percentage of 90%–99.99%; or 95%–99.99%; or 96%–99.99%; or 97%–99.99%;

[0361] Sweeteners, in the following weight percentages: 0%–5%; or 0.01%–4%; or 0.05%–3%; or 0.10%–2%; or 0.10%–1%; or 0.10%–0.50%;

[0362] Fragrance, in the following weight percentages: 0%–5%; or 0.01%–4%; or 0.05%–3%; or 0.05%–2%; or 0.05%–1.50%; or 0.05%–1%.

[0363] The antibacterial agent has a weight percentage of 0%–6%; or 0%–5%; or 0%–4%; or 0%–3%; or 0%–2.50%; or 0%–2%; or 0%–1.50%; or 0%–1%; or 0%–0.50%.

[0364] Other excipients, in weight percentages of 0%–25%; or 0%–20%; or 0%–15%; or 0%–10%; or 0%–5%;

[0365] And pH adjusters;

[0366] The amount of pH adjuster used should be based on the actual amount required to achieve pH = 4 to 6, and the sum of the weight percentages of the above components is 100%.

[0367] In some embodiments of this application, the solvent is water; the flavoring agent is lemon flavoring; the sweetener is neotame; and the pH adjuster is sodium hydroxide. In some embodiments of this application, the components of the pharmaceutical composition and their weight percentages are as follows:

[0368] 0.10%–10% of the active ingredient, 90%–99.99% of the solvent, 0%–5% of the sweetener, 0%–5% of the flavoring agent, 0%–6% of the antibacterial agent, and 0%–25% of other excipients; or

[0369] 0.10%–5% of the active ingredient, 95%–99.99% of the solvent, 0.05%–3% of the sweetener, 0.05%–3% of the flavoring agent, 0%–4% of the antibacterial agent, and 0%–25% of other excipients; or

[0370] 0.50%–4% of the active ingredient, 96%–99.99% of the solvent, 0.10%–2% of the sweetener, 0.05%–2% of the flavoring agent, 0%–2.50% of the antibacterial agent, and 0%–25% of other excipients; or

[0371] 1%–3% of active ingredient, 97%–99.99% of solvent, 0.10%–1% of sweetener, 0%–1% of flavoring agent, 0%–1% of antibacterial agent, and 0%–25% of other excipients;

[0372] And pH adjusters;

[0373] The amount of pH adjuster used should be based on the actual amount required to achieve pH = 4 to 6, and the sum of the weight percentages of the above components is 100%.

[0374] In some embodiments of this application, the pharmaceutical compositions described in the above aspects may also contain excipients other than those of the types described above. Specific examples include thickeners, dispersants, surfactants, antioxidants, stabilizers, etc. In embodiments of this application, the other excipients constitute 0% to 25% by weight in the pharmaceutical composition, preferably 0% to 20%, 0% to 15%, 0% to 10%, or 0% to 5%.

[0375] In some embodiments of this application, the pharmaceutical composition is formulated as an oral solution.

[0376] In some embodiments of this application, the pharmaceutical composition may be prepared in a single-dose or multi-dose form.

[0377] In some embodiments of this application, the oral solution is in the form of a single dose of 1-30 mL, preferably 1-20 mL, more preferably 1-15 mL, more preferably 1-10 mL, and even more preferably 1 mL, 2 mL, 3 mL, 4 mL, 5 mL, 6 mL, 7 mL, 8 mL, 9 mL, or 10 mL.

[0378] In some embodiments of this application, the oral solution is in multiple doses of 2-500 mL, preferably 2-250 mL, more preferably 5-250 mL, more preferably 10-200 mL, more preferably 15-150 mL, more preferably 20-100 mL, more preferably 20-50 mL, and more preferably 30-50 mL.

[0379] In some embodiments of this application, the pharmaceutical compositions described above (first to sixth aspects) contain 0.001-1000 mg of an active ingredient, preferably 0.1-800 mg, more preferably 1-500 mg, more preferably 10-300 mg, more preferably 10-200 mg, and even more preferably 10-100 mg. For example, a single-dose pharmaceutical composition may contain 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 500 mg, etc. of the active ingredient; wherein the active ingredient is in the form of a hydrochloride salt (e.g., in some embodiments of this application, in the form of C...). 24 H 29 (N9·3HCl) is used as a metric.

[0380] In some embodiments of this application, each dosage unit of the oral formulation, oral solid dosage form, or oral solution described above (first to sixth aspects) may contain 0.001-1000 mg of active ingredient, preferably 0.1-800 mg, more preferably 1-500 mg, more preferably 10-300 mg, more preferably 10-200 mg, and even more preferably a dose range of 10-100 mg. For example, a single-dose oral formulation may contain active ingredient in doses of 5 mg, 10 mg, 20 mg, 25 mg, 30 mg, 50 mg, 60 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 500 mg, etc.; wherein the active ingredient is in the form of a hydrochloride salt (e.g., in some embodiments of this application, in the form of C...). 24 H 29 (N9·3HCl) is used as a metric.

[0381] In a seventh aspect, this application provides a method for preparing the above-mentioned pharmaceutical composition, which includes: (1) weighing: weighing the active ingredient and excipient according to the prescription amount; (2) mixing: mixing the active ingredient and excipient evenly in a mixing container.

[0382] In some embodiments of this application, the pharmaceutical composition is prepared into capsules, and the preparation method includes: (1) weighing the active ingredient and excipient according to the prescription amount; (2) adding the active ingredient and excipient to a mixing container and mixing to produce a mixed powder; and (3) filling capsules with the above mixed powder.

[0383] In some embodiments of this application, the excipients of the pharmaceutical composition include an external lubricant; the pharmaceutical composition is made into capsules, and the preparation method includes: (1) weighing the active ingredient and the excipient according to the prescription amount; (2) adding the active ingredient and the excipient other than the external lubricant into a mixing container and mixing to produce a mixed powder; (3) granulating the above mixed powder; (4) mixing the granules obtained in step (3) with the external lubricant; and (5) filling the mixture obtained in step (4) into capsules.

[0384] In some embodiments of this application, the pharmaceutical composition is prepared into tablets, the preparation method comprising: (1) weighing the active ingredient and excipient according to the prescribed amount; (2) adding the active ingredient and excipient to a mixing container for mixing to produce a mixed powder; (3) granulating the mixed powder; (4) mixing the granules obtained in step (3) with an external lubricant; (5) compressing the tablets; and optionally, further comprising a coating step.

[0385] In some embodiments of this application, the pharmaceutical composition is prepared into granules, and the preparation method includes: (1) weighing the active ingredient and excipient according to the prescription amount; (2) adding the excipient and active ingredient into a mixing container to mix and produce a premix; (3) adding water to form a soft mass; (4) granulating and drying; and (5) sizing.

[0386] In some embodiments of this application, the pharmaceutical composition is prepared into an oral liquid formulation, the preparation method comprising: (1) weighing the active ingredient and excipients according to the prescription amount; (2) adding the excipients and active ingredient into a mixing container and stirring to mix evenly; (3) sterilizing; and (4) filling.

[0387] Some embodiments of this application provide a method for preparing the above-mentioned solid oral dosage form, which includes: packaging the pharmaceutical composition obtained by the above preparation method into packaging bags according to the packaging dosage to form a powder or granules. The term "mixing container" should be interpreted broadly, including both flexible mixers (including but not limited to flexible bags such as clean plastic bags, self-sealing bags, etc.) and rigid mixers (including but not limited to mixers, hopper mixers, etc.). Those skilled in the art can select a suitable mixer for the corresponding premixing and total mixing operations according to the batch size and weight.

[0388] The aforementioned "granulation" step should be interpreted broadly, including granulation using a mortar and pestle, optionally supplemented by sieving for granulation or to ensure the granules meet requirements, as well as granulation using machinery such as a dry granulator. Those skilled in the art can select appropriate tools or machinery based on batch size and weight to perform the corresponding granulation operation.

[0389] Eighthly, this application provides the use of the aforementioned pharmaceutical composition or the aforementioned solid oral formulation for inhibiting the activity of one or more of the following kinases: FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, VEGFR2, ALK, BTK, c-KIT, c-SRC, FGFR1, KDR, MET, and PDGFRα.

[0390] Ninthly, this application provides the use of the aforementioned pharmaceutical composition or the aforementioned oral formulation for preparation as a medicine.

[0391] In some embodiments of this application, the drug is used to treat or prevent diseases mediated by protein kinases, wherein the protein kinases are selected from one or more of the following: FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, VEGFR2, ALK, BTK, c-KIT, c-SRC, FGFR1, KDR, MET, and PDGFRα kinases.

[0392] In some embodiments of this application, the protein kinase-mediated disease is a neoplastic disease, preferably a hematologic malignancy or solid tumor, more preferably leukemia or lung cancer, and more preferably acute myeloid leukemia such as FLT3 mutation-positive acute myeloid leukemia (further such as FLT3-ITD mutation or FLT3-TKD mutation-positive acute myeloid leukemia), chronic myeloid leukemia (such as Ph-positive chronic myeloid leukemia), or non-small cell lung cancer (such as EGFR activating mutation-positive non-small cell lung cancer). In some embodiments of this application, the drug is used to treat or prevent acute myeloid leukemia; preferably, the acute myeloid leukemia is selected from relapsed and / or refractory acute myeloid leukemia, or, the acute myeloid leukemia is selected from acute myeloid leukemia with FLT3-ITD mutation and / or TKD mutation, relapsed and / or refractory acute myeloid leukemia that has failed treatment with type II FLT3 inhibitors (e.g., sorafenib), or, acute myeloid leukemia with both DEK-CAN positivity and FLT3-ITD mutation; more preferably, the acute myeloid leukemia is acute myeloid leukemia with FLT3-ITD high mutation; and / or the acute myeloid leukemia has 0 to 2 adverse prognostic factors; and / or the acute myeloid leukemia is classified as M2, M4, or M5, preferably M5. Furthermore, the aforementioned use in the preparation of a medicament for the treatment or prevention of acute myeloid leukemia is detailed in patent application PCT / CN2020 / 127449, the disclosure of which is incorporated herein by reference as disclosed in this application.

[0393] In a tenth aspect, this application provides the use of the aforementioned pharmaceutical composition or the aforementioned oral formulation for the preparation of a protein kinase inhibitor drug, wherein the protein kinase is selected from one or more of the following kinases: FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, VEGFR2, ALK, BTK, c-KIT, c-SRC, FGFR1, KDR, MET, and PDGFRα.

[0394] In some embodiments of this application, the protein kinase inhibitor drug is an anti-tumor drug, wherein the tumor is preferably a solid tumor or hematologic malignancy, more preferably leukemia or lung cancer, and more preferably acute myeloid leukemia such as FLT3 mutation-positive acute myeloid leukemia (further such as FLT3-ITD mutation or FLT3-TKD mutation-positive acute myeloid leukemia), chronic myeloid leukemia (such as Ph-positive chronic myeloid leukemia), or non-small cell lung cancer (such as EGFR activating mutation-positive non-small cell lung cancer).

[0395] In some embodiments of this application, the protein kinase inhibitor drug is an anti-tumor drug, and the tumor is selected from non-small cell lung cancer, acute myeloid leukemia, chronic myeloid leukemia, chronic myeloid leukemia, epidermal squamous cell carcinoma, breast cancer, colorectal cancer, liver cancer, gastric cancer, and malignant melanoma; more preferably, the disease is selected from human non-small cell lung cancer, human acute myeloid leukemia, human chronic myeloid leukemia, human chronic myeloid leukemia, human epidermal squamous cell carcinoma, human breast cancer, human colorectal cancer, human liver cancer, human gastric cancer, and human malignant melanoma.

[0396] In one aspect, this application provides the use of the aforementioned pharmaceutical composition or the aforementioned oral formulation in the preparation of a medicament for treating or preventing a disease; preferably, the disease is caused by one or more of the following kinases: FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, VEGFR2, ALK, BTK, c-KIT, c-SRC, FGFR1, KDR, MET, and PDGFRα; more preferably, the disease is selected from non-small cell lung cancer, acute myeloid leukemia, chronic myeloid leukemia, chronic myeloid leukemia, squamous cell carcinoma of the epidermis, breast cancer, colorectal cancer, liver cancer, gastric cancer, and malignant melanoma; even more preferably, the disease is selected from human non-small cell lung cancer, human acute myeloid leukemia, human chronic myeloid leukemia, human chronic myeloid leukemia, human squamous cell carcinoma of the epidermis, human breast cancer, human colorectal cancer, human liver cancer, human gastric cancer, and human malignant melanoma.

[0397] In a twelfth aspect, this application provides the above-described pharmaceutical composition or oral formulation for treating protein kinase-related diseases, wherein the protein kinase is selected from one or more of the following: FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, VEGFR2, ALK, BTK, c-KIT, c-SRC, FGFR1, KDR, MET, and PDGFRα kinases.

[0398] In some embodiments of this application, the protein kinase-related diseases are selected from non-small cell lung cancer, acute myeloid leukemia, chronic myeloid leukemia, chronic myeloid leukemia, squamous cell carcinoma of the epidermis, breast cancer, colorectal cancer, liver cancer, gastric cancer, and malignant melanoma; more preferably, the diseases are selected from human non-small cell lung cancer, human acute myeloid leukemia, human chronic myeloid leukemia, human chronic myeloid leukemia, human squamous cell carcinoma of the epidermis, human breast cancer, human colorectal cancer, human liver cancer, human gastric cancer, and human malignant melanoma.

[0399] In a thirteenth aspect, this application provides a method for treating a protein kinase-mediated disease, comprising administering the aforementioned pharmaceutical composition or the aforementioned oral formulation to a subject in need, wherein the protein kinase is selected from one or more of FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, VEGFR2, ALK, BTK, c-KIT, c-SRC, FGFR1, KDR, MET, and PDGFRα kinases.

[0400] In some embodiments of this application, the protein kinase-related diseases are selected from non-small cell lung cancer, acute myeloid leukemia, chronic myeloid leukemia, chronic myeloid leukemia, squamous cell carcinoma of the epidermis, breast cancer, colorectal cancer, liver cancer, gastric cancer, and malignant melanoma; more preferably, the diseases are selected from human non-small cell lung cancer, human acute myeloid leukemia, human chronic myeloid leukemia, human chronic myeloid leukemia, human squamous cell carcinoma of the epidermis, human breast cancer, human colorectal cancer, human liver cancer, human gastric cancer, and human malignant melanoma.

[0401] When the aforementioned drugs, oral preparations, oral solid preparations, or oral solutions exert their therapeutic effects, the therapeutically effective amount of the active ingredient is 0.001–1000 mg, preferably 1–800 mg, or 1–500 mg, or 20–400 mg, or 100–350 mg, most preferably 150–310 mg, wherein the therapeutically effective amount is in the form of hydrochloride (e.g., in some embodiments of this application, in C...). 24 H 29 (N9·3HCl). It can be administered as a single dose or in multiple doses.

[0402] Unless otherwise specified, all percentages are given as weight percent of the total weight of the pharmaceutical composition and its oral formulation.

[0403] The term "oral preparation" as used in this application refers to a pharmaceutical preparation intended for oral administration.

[0404] The term "oral solid dosage form" as used in this application refers to a solid pharmaceutical preparation intended for oral administration.

[0405] The “oral solution preparation” or “oral solution formulation” mentioned in this application refers to a pharmaceutical preparation in solution form for oral administration.

[0406] In the embodiments of this application, the drug administration target can be a human or a non-human mammal, more preferably a human.

[0407] In embodiments of this application, the terms "comprising," "including," and "containing" generally have an open meaning, but within their scope also include closed meanings defined by "composed of." For example, "a pharmaceutical composition comprising: a compound as an active ingredient, as shown in Formula II, Formula A, or Formula B, and an excipient" also includes "a pharmaceutical composition comprising a compound as an active ingredient, as shown in Formula II, Formula A, or Formula B, and an excipient."

[0408] Within the scope of this application, various options for any feature can be combined with various options for other features to form many different embodiments. This application is intended to include all possible embodiments composed of various options for all technical features.

[0409] Within the scope of this application, the amount of a compound or its pharmaceutically acceptable salt represented by Formula I, Formula II, Formula A or Formula B, or the ratio (mass ratio) with the excipient, may be appropriately adjusted in the formulation to obtain pharmaceutical compositions or oral formulations containing different strengths or different drug weights, which also fall within the scope of this application.

[0410] Through meticulous research and experimentation, this application has achieved one or more of the following beneficial technical effects:

[0411] (1) The preparation method of the pharmaceutical composition is simple and the formulation process is smooth. There are no strict requirements on the instruments, equipment and operating technology used, which makes it more suitable for industrial production. (2) After screening, it was found that some of the pharmaceutical compositions described in this application are suitable for direct mixing or dry granulation, which can simplify the preparation process of solid dosage forms. (3) Compared with other formulations, oral dosage forms made from the above pharmaceutical compositions meet the formulation standards and requirements. For example, oral solid dosage forms (e.g., capsules, tablets) have good dissolution, content uniformity and stability. (4) The pharmaceutical compositions and / or oral dosage forms, especially oral solid dosage forms, also have excellent stability. In the influence factor test, accelerated test and / or long-term test, the maximum single impurity, total impurity, content, crystal form, etc. of the examined pharmaceutical compositions and / or oral dosage forms (especially oral solid dosage forms, e.g., capsules and tablets, more particularly capsules) did not change significantly, so they are suitable for long-term storage. Attached Figure Description

[0412] Figure 1 XRPD spectrum of compound B obtained in Preparation Example 2.

[0413] Figure 2 Differential thermal-thermal gravity (DSC-TGA) chromatogram of the compound of formula B obtained in Preparation Example 2. Detailed Implementation

[0414] Detection method:

[0415] 1. Content (Detection of free base content of compound B)

[0416] Testing instrument: High Performance Liquid Chromatograph / Waters e2695-2489

[0417] Analysis method:

[0418] The column was filled with octadecylsilane-bonded silica gel (pH range greater than 10.0), and the mobile phase was 20 mmol / L disodium hydrogen phosphate solution (pH adjusted to 10.0 with sodium hydroxide) - acetonitrile (65:35). The detection wavelength was 287 nm, and the column temperature was 30 °C. The theoretical plate number should be no less than 3000.

[0419] For the assay, accurately weigh approximately 20 mg of sample and place it in a 100 mL volumetric flask. Add diluent (50% methanol-water) to dissolve and dilute to the mark. Shake well, accurately measure 10 μL, and inject it into the liquid chromatograph. Record the chromatogram. Separately, take an appropriate amount of reference standard and determine it using the same method. Calculate the result based on the peak area using the external standard method.

[0420] 2. Moisture content (determination of moisture content in compound B)

[0421] Testing instrument: Carbide moisture titrator / 915KF Ti-Touch

[0422] Test method: After the instrument is balanced, take an appropriate amount of the test sample (about 200 mg), weigh it accurately, add it to the titration cup, use anhydrous methanol as solvent, and directly measure it with water titrant. Each test sample is measured twice and the average value is taken.

[0423] 3. Solubility

[0424] Testing instrument: Ultraviolet spectrophotometer / Evolution 300

[0425] Test method:

[0426] pH 1.2, pH 4.5, pH 6.8, and water were selected as solvents. The specific solvent preparation method is as follows:

[0427] (1) pH 1.2 hydrochloric acid solution: 7.65 ml hydrochloric acid, add 1000 ml water, shake well, and you will get the solution.

[0428] (2) pH 4.5 phosphate buffer: Take 6.8g of potassium dihydrogen phosphate, dilute with water to 1000ml, and shake well.

[0429] (3) pH 6.8 phosphate buffer: Take 6.8g of potassium dihydrogen phosphate and 0.896g of sodium hydroxide, dilute with water to 1000ml, and shake well.

[0430] (4) Water: Purified water

[0431] Sample preparation:

[0432] Take a stoppered test tube and precisely add 10 ml of dissolution medium at each pH value. Add excess raw material until a supersaturated solution is formed. Record the amount added, shake well, stopper tightly, and shake in a shaker for 24 hours. Take 2 ml of solution at different time points, centrifuge, collect the supernatant, filter, and collect the filtrate for later use.

[0433] Take the saturated solutions in different solvents mentioned above, dilute them with solvent to a certain volume, and measure the absorbance at a wavelength of 287 nm.

[0434] Preparation of reference solution: Take an appropriate amount of the reference standard of compound 1, accurately weigh it, add solvent to dissolve and dilute it to prepare a solution containing about 10 μg of compound 1 per ml, measure the absorbance at a wavelength of 287 nm and calculate it.

[0435] 4. Hygroscopicity

[0436] Testing instrument: XPE105DR

[0437] Test method:

[0438] (1) Take a dry stoppered glass weighing bottle and place it in a suitable 25℃±1℃ constant temperature desiccator (with ammonium chloride or ammonium sulfate saturated solution at the bottom) or artificial climate chamber (set temperature 25℃±1℃, relative humidity 80%±2%) one day before the test, and accurately weigh it (m1).

[0439] (2) Take an appropriate amount of the test sample and spread it evenly in the weighing bottle. The thickness of the test sample is generally about 1 mm. Accurately weigh the sample (m2).

[0440] (3) Leave the weighing bottle open and place it together with the bottle cap under the above constant temperature and humidity conditions for 24 hours.

[0441] (4) Close the weighing bottle cap and accurately weigh the weight (m3).

[0442] Weight gain percentage = (m3-m2) / (m2-m1)×100%

[0443] (5) Description of hygroscopic characteristics and definition of hygroscopic weight gain:

[0444] Deliquescence: The process of absorbing sufficient water to form a liquid.

[0445] Extremely hygroscopic: the weight gain due to moisture absorption is not less than 15%.

[0446] It has hygroscopic properties: the weight gain due to moisture absorption is less than 15% but not less than 2%.

[0447] Slightly hygroscopic: the weight gain due to moisture absorption is less than 2% but not less than 0.2%.

[0448] It has little or no hygroscopicity: the weight gain due to moisture absorption is less than 0.2%.

[0449] 5. X-ray Powder Diffraction (XRPD)

[0450] Testing instrument: PANalytical Empyrean powder X-ray diffractometer

[0451] Test conditions:

[0452] X-ray tube type: Cu target, metal-ceramic X-ray tube;

[0453] X-ray wavelength: CuKα, Kα2 / Kα1 strength ratio: 0.5;

[0454] Voltage and current: 45kV, 40mA;

[0455] Scan range: 3-40°2θ;

[0456] Total scan time: approximately 5 minutes.

[0457] 6. Differential thermal analysis-thermogravimetric analysis (DSC-TGA)

[0458] Testing instrument: NETZSCH STA 449F3

[0459] Test conditions:

[0460] Temperature range: 20℃-350℃;

[0461] Heating rate: 10.0 (K / min);

[0462] Sample holder / thermocouple: DSC / TG Cp S / S

[0463] Crucible: DSC / TG pan Al2O3

[0464] Atmosphere: N2, 20.0 ml / min / N2, 50.0 ml / min

[0465] Calibration / Measurement Range: 020 / 5000μV

[0466] 7. Nuclear Magnetic Resonance Spectroscopy (NMRS)

[0467] Detection instrument: AVIII BRUKER 600 superconducting nuclear magnetic resonance spectrometer

[0468] Contents and test solvents: 1 H-NMR, with H2D as the test solvent.

[0469] 8. Single crystal

[0470] Single-crystal diffraction data were obtained using Rigaka XtaLAB Synergy-R (Micro-Max007HF Cu mode). The samples were collected at 120.00 (10) K using a Hypix 6000HE detector single-crystal diffractometer. Micrographs of the single-crystal samples were taken using a Shanghai Cewei PXS9-T stereomicroscope.

[0471] 9. Dissolution rate

[0472] Test method: Dissolution and release determination, method II (with sedimentation basket) (Chinese Pharmacopoeia 2020 Edition, Part IV, General Chapter 0931)

[0473] Take 6 tablets of this product and dissolve and release them according to Method II of the Dissolution and Release Test, using 900 mL of pH 1.2 hydrochloric acid solution as the dissolution medium and a rotation speed of 50 rpm. After 30 minutes, take 10 mL of the solution, filter it, and take the filtrate. Dilute the filtrate with pH 1.2 hydrochloric acid solution to a concentration equivalent to 10 μg / mL of API to prepare the test solution. Separately, accurately weigh approximately 25 mg of compound B reference standard, place it in a 100 mL volumetric flask, dissolve it with pH 1.2 hydrochloric acid solution, and dilute to the mark. Shake well to prepare the reference standard stock solution. Accurately measure the reference standard stock solution and dilute it to a concentration of 10 μg / mL to prepare the reference standard solution.

[0474] Determination method: Take appropriate amounts of the reference solution and the test solution respectively, and measure the absorbance at a wavelength of 287 nm using ultraviolet-visible spectrophotometry. Calculate the dissolution amount per particle based on the absorbance using the external standard method.

[0475] 10. Raw material and auxiliary material compatibility test

[0476] Conditions and timing for raw material compatibility testing

[0477]

[0478] 11. Influencing Factor Experiment

[0479] Influencing factors, experimental conditions and time

[0480]

[0481] 12. Accelerated and long-term stability tests

[0482] Stability test conditions and time

[0483]

[0484] The present application will be described in detail below with reference to some embodiments, but the present application is not limited to the embodiments described below. Any modifications that are obvious to those skilled in the art fall within the scope of the claims of this application.

[0485] Unless otherwise specified in the examples, standard conditions or manufacturer-recommended conditions shall apply. Reagents or instruments whose manufacturers are not specified are all commercially available products. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art.

[0486] Compound I of this application can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining it with other chemical synthetic methods, and equivalent substitutions that are obvious to those skilled in the art. Preferred embodiments include, but are not limited to, the preparation examples of this application.

[0487] In order to obtain the compounds of this application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction process based on existing embodiments.

[0488] Preparation of Compound I (Example 1)

[0489]

[0490] 100g of the compound of Formula I was prepared by referring to the method described in Example 90 of Patent Document WO 2011 / 147066.

[0491] Preparation of Compound B in Example 2

[0492] The aromatic aminopurine derivative (90 g, 0.203 mol) obtained in Preparation Example 1, along with 800 mL of purified water and 400 mL of acetone, were added to a reactor. After stirring and heating to 40 ± 5 °C, concentrated hydrochloric acid (74 g, 0.731 mol) was added to the reactor. After the concentrated hydrochloric acid was added, 2 L of acetone was added, and the temperature was maintained at 40 ± 5 °C for 1 h. Then, the temperature was stirred and cooled to 10 ± 5 °C for 2 h to crystallize. The mixture was then filtered, and the filter cake was washed with 300 mL of acetone to obtain 74.7 g of yellow or pale yellow hydrochloride. 1¹H-NMR (600MHz, D₂O) δ: 1.556 (d, 6H), 2.896 (s, 3H), 3.058 (t, 2H), 3.187 (t, 2H), 3.586 (d, 2H), 3.749 (d, 2H), 4.701 (s, 1H), 7.062 (d, 2H), 7.377 (d, 2H), 7.968 (t, 1H), 8.086 (s, 1H), 8.431 (d, 1H), 8.636 (d, 1H), 9.171 (s, 1H). The obtained hydrochloride exhibits good crystallinity, and its XRPD characterization spectrum is attached. Figure 1 As shown, the main diffraction peak data are as follows:

[0493] 7.300 20.96 20.027 26.40 8.504 40.4 21.140 22.06 9.052 14.65 21.913 14.4 11.814 34.65 23.701 25.54 12.579 13.44 25.162 62.26 14.300 15.86 26.137 15.54 18.136 18.09 27.165 100 19.641 29.87

[0494] Samples were taken for DSC and TGA testing, and the spectra are shown in the attached figures. Figure 2 As shown in the figure. The DSC spectrum shows no obvious melting point, while the TGA spectrum shows that the sample begins to lose water of crystallization at around 40℃ and begins to lose acid at around 140℃.

[0495] By calculating the free base content and determining the moisture content using HPLC (see table below), it can be deduced that the base / acid / H2O ratio of this hydrochloride is 1:3:5.

[0496]

[0497] The sample from Preparation Example 2 was cultured into a single crystal (according to the method in PCT / CN2021 / 073285). The X-ray diffraction characterization results of the single crystal showed that the crystal belongs to the triclinic crystal system. The space group has the following unit cell parameters: The asymmetric unit cell of this crystal consists of a cation of compound 1, three chloride ions, and five water molecules. Furthermore, the XRPD pattern of this single crystal is compared with... Figure 1 Basically the same.

[0498] Example 1: Capsules of Compound B

[0499] Table 1. Formula for Example 1 (makes 100 pills)

[0500]

[0501]

[0502] The dry granulation process is used, and the specific method is as follows: 1) Weighing or preparing materials: Weigh the active ingredient (API) compound B and the corresponding fillers, gliding agents, and lubricants (internal or external) according to the prescription amount; 2) Premixing 1: Add the active ingredient, filler, gliding agent, and lubricant (internal) to the mixing container in sequence for premixing; 3) Depolymerization: Depolymerize the obtained powder mixture; 4) Premixing 2: Add the depolymerized powder mixture to the mixing container and premix again; 5) Dry granulation: Press the premixed powder mixture into tablets using a tablet press, and granulate after pressing; 6) Final mixing: Add the granules obtained in step 5) to the mixing container, add the lubricant (external), and mix; 7) Capsule filling: Select the appropriate type of capsule shell for filling according to the dosage.

[0503] Table 2 Detection Results of Example 1

[0504]

[0505] The results showed that the pre-granulation tableting process was smooth, non-stick, and dissolved quickly, meeting the formulation requirements and the prescription was qualified.

[0506] Capsules of Compound B in Examples 2-5

[0507] Following the preparation method of Example 1, the ratio of glidant and lubricant was adjusted, and the amounts of API and pregelatinized starch were adjusted according to the total amount (API: pregelatinized starch (w / w) = 1:1.58) to obtain the following pharmaceutical composition. Specific formulations and test results are shown in Table 3.

[0508] Table 3. Prescriptions and test results for Examples 2-5

[0509]

[0510] Note: ① The weight percentage of added magnesium stearate is 1%; ② The data in the table are weight percentages, and the same applies below.

[0511] The results showed that, within the scope of this application, adjusting the weight percentage of colloidal silica and magnesium stearate (added internally) resulted in formulations that did not exhibit phenomena such as sticking, flakes, agglomeration, and / or stratification. The tableting process before granulation was smooth, indicating that the tableting process met the requirements, dissolution was rapid, and the formulation requirements were met. All formulations were qualified.

[0512] Capsules of Compound B in Examples 6-9

[0513] Following the preparation method of Example 1, by adjusting the amount of filler, the following pharmaceutical composition can be obtained. Specific formulations and test results are shown in Table 4.

[0514] Table 4. Prescriptions and test results for Examples 6-9

[0515]

[0516] Note: The weight percentage of magnesium stearate (added internally) and magnesium stearate (added externally) is 1% each; each formulation is made into 100 tablets, with a total weight of 16g.

[0517] The results showed that, based on the formulation of Example 1, within the scope of this application, adjusting the amount of pregelatinized starch had no significant impact on the tableting phenomenon and dissolution results. That is, the tableting process before granulation of the obtained formulation was smooth, with slight sticking or no sticking, and no phenomena such as flakes, agglomeration and / or delamination occurred. In other words, the tableting process met the requirements, dissolution was rapid, and the formulation requirements were met. All formulations were qualified.

[0518] Example 10: Capsules of Compound B

[0519] Following the preparation method of Example 1, adding a disintegrant in step 6) yields the following pharmaceutical composition. Specific formulations and test results are shown in Table 5.

[0520] Table 5. Prescription for Example 10 (made into 100 tablets) and test results.

[0521]

[0522] The results showed that, based on Example 1, the formulation obtained by adding a disintegrant proceeded smoothly during the tableting process before granulation, with slight sticking or no sticking, and no issues such as flakes, agglomeration, and / or delamination occurred. This indicates that the tableting process met the requirements, dissolution was rapid, and the formulation was qualified; therefore, the effect was comparable to that without the disintegrant. Thus, the addition of a disintegrant has little impact on the effectiveness of formulations with a single filler (pregelatinized starch).

[0523] Capsules of Compound B in Examples 11-14

[0524] Referring to the formulation and preparation method of Example 1, using pregelatinized starch and mannitol as composite fillers, the following pharmaceutical composition can be obtained. Specific formulations and test results are shown in Table 6.

[0525] Table 6. Prescriptions and test results for Examples 11-14

[0526]

[0527] Note: The weight percentage of magnesium stearate (added internally) and magnesium stearate (added externally) is 1% each; each formulation is made into 100 tablets, with a total weight of 16g.

[0528] The results showed that using a combination filler composed of pregelatinized starch and mannitol, within the scope of this application, adjusting the weight ratio of the two had no significant impact on the tableting phenomenon and dissolution results. That is, the tableting process before granulation of the obtained formulation was smooth, with slight sticking or no sticking, and no phenomena such as flakes, agglomeration and / or delamination occurred. In other words, the tableting process met the requirements and the formulation was qualified. Moreover, rapid dissolution could be achieved without the addition of disintegrants.

[0529] Example 15: Capsules of Compound B

[0530] Following the preparation method of Example 1, using microcrystalline cellulose and lactose as combined fillers, the following pharmaceutical composition can be obtained. Specific formulations and test results are shown in Tables 7 and 8, respectively.

[0531] Table 7. Formula for Example 15 (makes 100 tablets)

[0532]

[0533]

[0534] Note: The weight percentage of magnesium stearate (internal) and magnesium stearate (external) is 1%;

[0535] Table 8. Test Results of Example 15

[0536]

[0537] The results showed that the tableting process before granulation was smooth and did not stick to the granulator when using a combination of microcrystalline cellulose and lactose as fillers. No tableting defects, agglomeration, or delamination were observed. In other words, the tableting process met the requirements, dissolution was rapid, and the formulation requirements were met. All formulations were qualified.

[0538] Examples 16-17: Capsules of Compound B

[0539] Following the preparation method and dosage of Example 15, microcrystalline cellulose was used as a single filler, and the pharmaceutical composition was prepared according to the formulation and weight percentages in Table 9. The specific formulation and experimental results are shown in Table 9 below.

[0540] Table 9. Prescriptions and test results for Examples 16-17

[0541]

[0542] Note: Each prescription is made into 100 pills, with a total weight of 18g.

[0543] The results showed that when microcrystalline cellulose was used as a single filler, the resulting formulation (Example 16) met the requirements in the granulation process without the addition of a disintegrant; moreover, even without the addition of a flow aid (colloidal silica), the resulting formulation (Example 17) still met the requirements in the granulation process, that is, the granulation process of the resulting formulation was smooth before granulation, with slight sticking or no sticking, and no phenomena such as flakes, agglomeration and / or delamination occurred.

[0544] For the formulations of Examples 16 and 17, the dissolution results showed that although dissolution was slightly slower at 15 min, the dissolution rate met the requirements at 30 min, and the choice could be made according to the medication needs.

[0545] Examples 18-19: Capsules of Compound B

[0546] Referring to the formulation and preparation method of Example 15, by adjusting the weight ratio of the combined filler, the following pharmaceutical composition (100 capsules) can be obtained. The specific formulation and test results are shown in Table 10.

[0547] Table 10. Prescriptions and test results for Examples 18-19

[0548]

[0549]

[0550] Note: The weight percentage of magnesium stearate (added internally) and magnesium stearate (added externally) is 1% each; each formulation is made into 100 tablets, with a total weight of 18g.

[0551] The results showed that by adjusting the ratio of the two fillers in the combined filler, within the scope of this application, the resulting formulation underwent a smooth tableting process before granulation, without sticking or clumping, and no issues such as flakes, agglomeration, or delamination occurred. This indicates that the tableting process met the requirements and satisfied the formulation requirements. When using a 1:1 weight ratio of lactose / microcrystalline cellulose (Example 18), dissolution was faster within 15 minutes; when using a 2:1 weight ratio of lactose / microcrystalline cellulose (Example 19), dissolution was slightly slower within 15 minutes, but the dissolution rate met the requirements within 30 minutes.

[0552] Examples 20-21: Capsules of Compound B

[0553] Referring to the formulation and preparation method of Example 15, by changing the type of disintegrant and adjusting the ratio of the two fillers, the following drug composition (100 capsules) can be obtained. The specific formulation and test results are shown in Table 11.

[0554] Table 11 Prescriptions and test results for Examples 20-21

[0555]

[0556] Note: The weight percentage of magnesium stearate (added internally) and magnesium stearate (added externally) is 1% each; each formulation is made into 100 tablets, with a total weight of 18g.

[0557] The results showed that when sodium carboxymethyl starch was used as the disintegrant, the tableting process before granulation was smooth, without sticking or clumping, and no tablet fragmentation, agglomeration, or delamination occurred. This indicates that the tableting process met the requirements, and the resulting formulations all exhibited good dissolution effects, satisfying the formulation requirements and thus were qualified. Therefore, provided that the compatibility of raw materials and excipients is satisfied, the disintegrant can be selected and replaced according to the medication requirements.

[0558] Examples 22-23: Capsules of Compound B

[0559] Referring to the preparation method of Example 15 and the formulation of Example 20, using sodium carboxymethyl starch as a disintegrant and adjusting its dosage, the following pharmaceutical composition (100 tablets) can be obtained. Specific formulation composition and test results are shown in Table 12.

[0560] Table 12 Prescriptions and test results for Examples 22-23

[0561]

[0562] Note: The weight percentage of magnesium stearate (added internally) and magnesium stearate (added externally) is 1% each; each formulation is made into 100 tablets, with a total weight of 18g.

[0563] The results showed that after adjusting the amount of disintegrant, the tableting process before granulation of the obtained formulations was smooth and did not stick together. No tablet fragments, agglomeration, or delamination were observed. In other words, the tableting process met the requirements, and the obtained formulations all had good dissolution effects, met the formulation requirements, and were all qualified.

[0564] Example 24: Capsules of Compound B

[0565] Referring to the preparation method of Example 15 and the formulation composition of Example 20, by changing the type of lubricant, the following composition (100 capsules) can be obtained. The specific formulation and test results are shown in Table 13.

[0566] Table 13. Prescription and test results for Example 24

[0567]

[0568] Note: Sodium stearate fumarate (added internally) and magnesium stearate (added externally) are both 1% by weight;

[0569] The results showed that, compared with Example 20, changing the lubricant had no significant impact on the granulation process (non-sticking, no flakes, agglomeration and / or stratification) and dissolution results. In terms of price, magnesium stearate was preferred.

[0570] Example 25: Capsules of Compound B

[0571] Referring to the formulation and preparation method of Example 1, by changing the filler, the following pharmaceutical composition (100 capsules) can be obtained. The specific formulation and test results are shown in Table 14.

[0572] Table 14. Prescription and test results for Example 25

[0573]

[0574] Note: The weight percentage of magnesium stearate (added internally) and magnesium stearate (added externally) is 1% each; 100 tablets are prepared according to the prescription, with a total weight of 10g each.

[0575] The results showed that, compared with Example 1, replacing the filler with calcium salt (e.g., anhydrous dicalcium phosphate) had no effect on the granulation process (no sticking, no flakes, agglomeration and / or stratification) and dissolution results, and the formulation was qualified.

[0576] Examples 26-29: Capsules of Compound B

[0577] Referring to the preparation method of Example 1 and the formulation of Example 25, by adjusting the proportions of each component or further increasing the disintegrant, the following pharmaceutical composition can be obtained. Specific formulations and test results are shown in the table.

[0578] Table 15 Prescriptions and test results for Examples 26-29

[0579]

[0580]

[0581] Note: The weight percentage of magnesium stearate (internal) and magnesium stearate (external) is 1%; each formulation is made into 100 tablets, and the total weight is calculated based on the amount per tablet; " / " indicates not tested.

[0582] The results showed that, compared with Example 25, adjusting the proportion of each component or further increasing the disintegrant had no effect on the granulation process (slight sticking or non-sticking, no flakes, agglomeration and / or stratification). Although the dissolution rate was low at 15 min, more than 80% dissolution could be achieved at 30 min. The choice can be made according to actual needs, and all formulations were qualified.

[0583] Capsules of Compound B (Examples 30-32)

[0584] Referring to the preparation method of Example 1 or Example 15, and the formulation composition of Example 25, by replacing the single filler with a combination of two fillers, the following pharmaceutical composition can be obtained. Specific formulations and test results are shown in Table 16.

[0585] Table 16 Prescriptions and test results for Examples 30-32

[0586]

[0587] Note: In Examples 30 and 31, the weight percentage of magnesium stearate (internal) and magnesium stearate (external) is 1%; in Example 32, the weight percentages of magnesium stearate (internal) and magnesium stearate (external) are 0.5% and 1%, respectively; 100 tablets are prepared according to the formula, and the total weight is calculated based on the amount per tablet.

[0588] The results showed that, compared with Example 25, the use of a combination of two fillers (e.g., a combination of anhydrous dicalcium phosphate and pregelatinized starch), or further adjustment of the proportions of each component, had no effect on the granulation process (no sticking, no flakes, agglomeration and / or stratification) or the dissolution results, and all formulations were qualified.

[0589] Capsules of Compound B (Examples 33-34)

[0590] Referring to the formulations and preparation methods of Examples 1, 15, or 30, by changing the filler, or by further adding and / or replacing the disintegrant, or by further increasing the binder, the following pharmaceutical compositions can be obtained. Specific formulations and test results are shown in Table 17.

[0591] Table 17 Prescriptions and test results for Examples 33-34

[0592]

[0593] Note: The weight percentage of magnesium stearate (added internally) and magnesium stearate (added externally) is 1% each; each formulation is made into 100 tablets, and the total weight is calculated based on the amount per tablet.

[0594] The results showed that the adjustment of the above formulation composition and proportion had no effect on the granulation process (no sticking, no flakes, agglomeration and / or stratification) or dissolution results, and all formulations were qualified.

[0595] Capsules of Compound B (Examples 35-38)

[0596] Referring to the formulations and preparation methods of Examples 1, 15, or 30, by adding a second filler, or further adding a disintegrant and / or binder, the following pharmaceutical compositions can be obtained. Specific formulations and test results are shown in Table 18.

[0597] Table 18 Prescriptions and test results for Examples 35-38

[0598]

[0599] Note: The weight percentage of magnesium stearate (added internally) and magnesium stearate (added externally) is 1% each; each formulation is made into 100 tablets, and the total weight is calculated based on the amount per tablet.

[0600] The results showed that the adjustment of the above formulation composition and proportion had no effect on the granulation process (no sticking, no flakes, agglomeration and / or stratification) or dissolution results, and all formulations were qualified.

[0601] Example 39: Capsules of Compound B

[0602] The above-mentioned qualified pharmaceutical composition formulations can be formulated into preparations containing active ingredients of different strengths. An exemplary formulation includes (preparing 100 tablets):

[0603] Table 19 Example 39 Formulation (Single Filler)

[0604]

[0605] Note: Refer to the formulation and preparation method of Example 1. The filler ratio and gelatin empty capsules can be adjusted appropriately according to the required specifications and dosage. The formulations of Examples 39-2 are the same as those of Example 1.

[0606] Table 20 Example 39 Formulation (Combination Filler)

[0607]

[0608] Note: Referring to the formulation of Example 11 and the preparation method of Example 1, the filler ratio and gelatin empty capsules can be adjusted appropriately according to the required specifications and dosage; Examples 39-5 have the same formulation as Example 11.

[0609] Table 21 Formulation of Example 39 (Combination Filler)

[0610]

[0611]

[0612] Note: Examples 39-8 and 39-9 are prepared according to the method of Example 1. The filler ratio and gelatin empty capsules can be adjusted appropriately according to the required specifications and dosage.

[0613] Examples 39-7 were prepared using a direct mixing process, specifically as follows: 1) Preparation: Weigh the active ingredient (API) compound B and various excipients according to the prescribed amount; 2) Premixing 1: Sieve and mix the colloidal silica and active ingredient, and place them in a mixing container; 3) Premixing 2: Add pregelatinized starch and mannitol to the above mixed powder, and shake to mix evenly; 4) Final mixing: Add magnesium stearate to the mixed powder obtained in step 3), and shake to mix evenly; 5) Capsule filling: Select an appropriate type of capsule shell for filling according to the filling amount.

[0614] Table 22 Example 39 Formulation (Combination Filler)

[0615]

[0616] Note: Referring to the formulation and preparation method of Example 15, the filler ratio and gelatin empty capsules can be adjusted appropriately according to the required specifications and dosage.

[0617] Table 23 Example 39 Formulation (Single Filler)

[0618]

[0619] Note: Refer to the formulation and preparation method of Example 1. The filler ratio and gelatin empty capsules can be adjusted appropriately according to the required specifications and dosage.

[0620] Example 40: Tablets of Compound B

[0621] Table 24 Example 40 Prescription (makes 100 tablets)

[0622]

[0623]

[0624] Note: Each prescription is made into 100 tablets; the weight percentage of the coating powder is the weight of the coating powder / the total weight of the tablet core; the coating powder model is: Obadai 85G68918, and its specific composition is polyvinyl alcohol, titanium dioxide, talc, polyethylene glycol, and soybean lecithin.

[0625] The dry granulation process is used, and the specific method is as follows: 1) Material preparation: Weigh the active ingredient (API) compound A and the corresponding filler, gliding agent and lubricant according to the prescription amount; 2) Premixing 1: Add the active ingredient, filler, gliding agent and lubricant (added internally) to the mixing container in sequence for premixing; 3) Depolymerization: Depolymerize the obtained powder mixture; 4) Premixing 2: Add the depolymerized powder mixture to the mixing container and premix again; 5) Granulation; 6) Final mixing: Mix the granules obtained in step 5) with the lubricant (added externally); 7) Tableting: Compress the tablets using a tablet press; 8) Coating: Coat the tablets obtained in step 5).

[0626] Table 25 Detection Results of Example 40

[0627]

[0628] The results showed that the prepared tablets had uniform content, no obvious wear on the edges, met the hardness requirements, and dissolved rapidly, indicating that the formulation was qualified.

[0629] Example 41: Granules of Compound B

[0630] Table 26 Example 41 Prescription (makes 100 bags)

[0631]

[0632] The specific method is as follows: 1) Preparation: Weigh the active ingredient (API) compound B and the corresponding excipients according to the prescription amount; 2) Premixing 1: Add the active ingredient and various excipients to the mixing container in sequence for premixing; 3) Making the soft material: Add an appropriate amount of water to make a suitable soft material; 4) Granulation: Granulate using the solution; 5) Drying: Dry at 45℃; 6) Granulation.

[0633] Table 27 Detection Results of Example 41

[0634]

[0635] The results showed that the prepared granules had uniform content, good solubility, and clear solution, indicating that the formulation was qualified.

[0636] Example 42: Oral solution of compound B

[0637] Table 28 Example 42 Prescription (makes 100 mL)

[0638]

[0639] The specific method is as follows: 1) Weighing: Weigh the active ingredient (API) compound B and the corresponding sweetener according to the prescription amount; 2) Solution preparation: First, place the active ingredient and sweetener in a beaker, add the solvent while stirring, and after stirring evenly, use sodium hydroxide to adjust the pH of the solution to 4-5; 3) Filtration: Filter the prepared solution to remove bacteria; 4) Filling: Fill the filtered solution according to the required dosage; 5) Crimping.

[0640] Table 29 Detection Results of Example 42

[0641] Example 42 Clear solution 99.7％ 4.55

[0642] The results showed that the prepared oral solution had a uniform content, was clear and transparent, and met the prescription requirements.

[0643] Test Example 1: Solubility Test

[0644] The solubility of the salt obtained in Preparation Example 2 and the sample from Preparation Example 1 were tested in the following media, and the results are shown in the table below:

[0645]

[0646] Test Example 2: Hygroscopicity Test

[0647] The salt obtained in Preparation Example 2 and the sample from Preparation Example 1 were subjected to hygroscopicity tests at 25±1℃ and a relative humidity of 80%±2%. The results are shown in the table below:

[0648]

[0649] Test Example 3: Accelerated Stability Test

[0650] The salt obtained from Preparation Example 2 was subjected to accelerated testing at 25±2℃ and 60%±5%RH for 10 days in an open container and at 40±2℃ and 75%±5%RH for 10 days in an open container. The results are as follows:

[0651]

[0652] Test Example 4: Long-term stability test

[0653] An appropriate amount of the salt sample obtained in Preparation Example 2 was packaged in a pharmaceutical low-density polyethylene bag as the inner packaging and a polyester / aluminum / polyethylene pharmaceutical packaging composite bag as the outer packaging. Samples were taken at the end of the 3rd, 6th, 9th, 12th, and 18th months at a temperature of 25±2℃ and a relative humidity of 60%±5%. After comparing the appearance, other indicators were tested. The results were compared with those at 0 months. The experimental results are shown in the table below:

[0654] October Yellow crystalline powder 13.9 3.1 0.33 100.9 March Yellow crystalline powder 13.9 3.3 0.34 100.4 June Yellow crystalline powder 14.3 3.3 0.34 100.8 September Yellow crystalline powder 14.3 3.3 0.31 101.7 December Yellow crystalline powder 13.9 3.3 0.34 99.6 18 months Yellow crystalline powder 14.2 3.3 0.26 100.2

[0655] Test Example 5: Bioactivity Test

[0656] The salt sample obtained in Preparation Example 2 was tested according to the kinase inhibitory activity evaluation described in the biological evaluation of patent application WO 2011 / 147066. The test results showed that the sample could inhibit the activity of FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, VEGFR2, ALK, BTK, c-KIT, c-SRC, FGFR1, KDR, MET, and PDGFRα kinases. Some kinase test results are shown in the table below.

[0657] FLT3(h) 26 Lyn(h) 7 FLT3-ITD(h) 3-10 Ret(h) 10 EGFR(h) 42 Yes 4 Abl(h) 25 c-SRC(h) 176 Fyn(h) 34 FGFR1(h) 247

[0658] Lck(h) 37

[0659] According to the in vivo antitumor experiments described in the biological evaluation of patent application WO 2011 / 147066, the salt samples obtained in Preparation Example 2 were tested (specifically targeting FLT3-ITD acute myeloid leukemia, EGFR activating mutation non-small cell lung cancer, or Ph-positive chronic myeloid leukemia, respectively). The test results showed that in the MV4-11 (FLT3-ITD mutation) subcutaneous tumor model experiment (referring to Example 4 of WO2011 / 147066 for model establishment), the sample (orally administered once daily for 21 days) could completely inhibit tumor growth at a dose of 5 mg / kg, and could induce complete tumor regression at doses of 10 mg / kg and 20 mg / kg. In a non-small cell lung cancer model (model established according to Example 3 of WO 2011 / 147066), the sample dose-dependently inhibited the growth of human non-small cell lung cancer HCC827, causing tumor shrinkage (compared to the initial tumor) in three dosage groups: 7.5 mg / kg, 15 mg / kg, and 30 mg / kg (oral administration once daily for 30 days). The 30 mg / kg group resulted in near-complete tumor regression. In a K562 (BCR-Abl gene rearrangement) subcutaneous tumor model (model established similarly to the MV4-11 subcutaneous tumor model), the sample (oral administration once daily for 18 days) effectively inhibited tumor growth at a dose of 70 mg / kg, achieving a tumor inhibition rate of 71.3%.

[0660] Studies on the hydrochloride salt and other salt forms of compound I have been described in patent application PCT / CN202I / 073285, the entire contents of which are incorporated herein by reference.

[0661] Experimental Example 1: Raw Material Compatibility Test

[0662] The active ingredient (compound B) was mixed evenly with each of the excipients mentioned in this application and placed in a 10 ml injection vial. The vials were then placed under the following conditions for 14 days, 28 days, or 30 days: light intensity of 4500 lux ± 500 lux / peripheral humidity, high temperature of 60℃ ± 2℃ / peripheral humidity, high humidity of 90% ± 5% RH, and temperature of 25℃ ± 2℃. The impurity content was then tested to verify the compatibility between the active ingredient and the various excipients.

[0663] The results showed that after 14 days and 28 days or 30 days of accelerated compatibility testing, the active ingredient was compatible with the various excipients mentioned in this application, and there was no significant increase in the maximum single impurity or total impurity. Except for the calcium carbonate sample which showed a slight discoloration, the colors of the other mixed samples did not change significantly.

[0664] Experiment Example 2 Accelerated Test

[0665] Capsule samples from Examples 39-1, 39-2, 39-7, 39-8, and 39-9, and tablet samples from Example 40, were placed in a constant temperature and humidity chamber at 40℃±2℃ and 75%RH±5%RH for a 6-month accelerated test, according to the example packaging conditions (aluminum foil and polyamide / aluminum / polyvinyl chloride cold-stamped solid pharmaceutical composite hard sheet packaging). Samples were taken at the end of 0, 1, 2, 3, and 6 months for key item investigation. The test results of representative examples (Examples 39-2, 39-7, 39-8, and Example 40) (other examples were scaled up or adjusted proportionally, and not all data are presented, but the results are similar) are shown in Tables 30-33.

[0666] Table 30 Batch Accelerated Test Results of Example 39-2 (Aluminum-Aluminum Packaging)

[0667]

[0668] Table 31 Batch Accelerated Test Results of Example 39-7 (Aluminum-Aluminum Packaging)

[0669]

[0670]

[0671] Table 32 Batch Accelerated Test Results of Example 39-8 (Aluminum-Aluminum Packaging)

[0672]

[0673] Table 33 Batch Accelerated Test Results of Example 40 (Aluminum-Aluminum Packaging)

[0674]

[0675] The results showed that, under accelerated testing, the drug compositions of the three examples, after being placed in the packaging at 40±2℃ and 75%RH±5%RH for 6 months, showed no increase or a slight increase in related substances, and the content remained essentially unchanged. All other test items at each time point met the requirements, and the crystal form of the active ingredient did not change. The capsule samples of Examples 39-1 and 39-9 also remained stable in the accelerated test, with no significant changes in drug properties, related substances, drug content, dissolution rate, or microbial limits. The tablet sample of Example 40 also remained stable in the accelerated test, with no significant changes in drug properties, related substances, drug content, or microbial limits.

[0676] Experimental Example 3: Long-term test

[0677] Capsule samples from Examples 39-1, 39-2, 39-7, 39-8, and 39-9 were placed in a constant temperature and humidity chamber at 30℃±2℃ and 65%RH±5%RH for 30 months, according to the example packaging conditions (aluminum foil and polyamide / aluminum / polyvinyl chloride cold stamping solid pharmaceutical composite hard sheet packaging). Samples were taken at the end of 3, 6, 9, 12, 18, 24, and 30 months. The test results of representative examples (Examples 39-7 and 39-8) are shown in Tables 34-35 (other examples are scaled up or adjusted proportionally, and not all data are presented).

[0678] Table 34 Batch Long-Term Test Results of Example 39-7 (Aluminum-Aluminum Packaging)

[0679]

[0680]

[0681] Table 35 Batch Long-Term Test Results of Example 39-8 (Aluminum-Aluminum Packaging)

[0682]

[0683] The results showed that, after long-term testing, the drug compositions of the two examples, placed in the packaging at 30±2℃ and 65%RH±5%RH for 30 months, showed no increase or a slight increase in related substances, and the content remained essentially unchanged; other test items at each time point met the requirements. The capsule samples of Examples 39-1, 39-2, and 39-9 also remained stable during the long-term test, with no significant changes in drug properties, related substances, drug content, dissolution rate, or microbial limits.

Claims

1. A pharmaceutical composition comprising a compound of formula (B) as an active ingredient and an excipient, ； in, The compound shown in formula (B) was subjected to X-ray powder diffraction at 2θ angles of 7.3±0.2°, 8.5±0.2°, 9.0±0.2°, 11.8±0.2°, 12.6±0.2°, 14.3±0.2°, 18.1±0.2°, 19.6±0.2°, 20.0±0.2°, 21.1±0.2°, 21.9±0.2°, 23.7±0.2°, 25.2±0.2°, and 26.1±0.2° using Cu-Kα radiation. It has a characteristic peak at 27.2±0.2°; or, it has characteristic peaks at 7.3±0.2°, 8.5±0.2°, 9.1±0.2°, 11.8±0.2°, 12.6±0.2°, 14.3±0.2°, 18.1±0.2°, 19.6±0.2°, 20.0±0.2°, 21.1±0.2°, 21.9±0.2°, 23.7±0.2°, 25.2±0.2°, 26.1±0.2°, and 27.2±0.2°. The excipients include fillers and lubricating agents, and optionally further include disintegrants and / or binders; The lubricating additives are lubricants and flow aids; The active ingredient is 5% to 45% by weight. The filler has a weight percentage of 50% to 90%; The lubricant has a weight percentage of 2% to 3%; The weight percentage of the glial agent is 2% to 3%; The weight percentage of the disintegrant is 0% to 5%; The adhesive has a weight percentage of 0% to 3%; Other excipients, in weight percentages of 0% to 10%; Furthermore, the sum of the weight percentages of all the above components is 100%; The filler is pregelatinized starch; or the filler is a combination of pregelatinized starch and mannitol, and the weight ratio of the two fillers is 1:6 to 6:

1. The lubricant is selected from one or more of magnesium stearate, calcium stearate, zinc stearate, sodium stearoyl fumarate, and magnesium stearoyl fumarate. The flow aid is colloidal silica.

2. The pharmaceutical composition according to claim 1, characterized in that, The components of the pharmaceutical composition and their weight percentages are as follows: The active ingredient, by weight, is 25% to 45%; The filler, by weight, comprises 50% to 70%; Lubricant, comprising 2% by weight; The gliding agent, by weight, is 3%. Disintegrant, with a weight percentage of 0% to 3%; The adhesive, by weight, is 0%. Other excipients, in weight percentages of 0% to 10%; Furthermore, the sum of the weight percentages of all the above components is 100%.

3. The pharmaceutical composition according to claim 1, characterized in that, The compound represented by formula (B) exhibits an X-ray powder diffraction pattern substantially as shown in Figure 1 when subjected to Cu-Kα radiation.

4. The pharmaceutical composition according to claim 1, characterized in that, The other excipients are selected from flavoring agents, antibacterial agents, stabilizers, coating materials, and flavorings.

5. The pharmaceutical composition according to any one of claims 1-4, characterized in that, The filler is pregelatinized starch.

6. The pharmaceutical composition according to any one of claims 1-4, characterized in that, The lubricant is selected from magnesium stearate and sodium stearoyl fumarate.

7. The pharmaceutical composition according to any one of claims 1-4, characterized in that, The lubricant is selected from magnesium stearate.

8. The pharmaceutical composition according to any one of claims 1-4, characterized in that, The disintegrant is selected from one or more of the following: dry starch, carboxymethyl cellulose, microcrystalline cellulose, powdered cellulose, methyl cellulose, potassium polaclin, sodium alginate, polyvinylpyrrolidone, maltodextrin, magnesium aluminum silicate, pregelatinized starch, crospovidone, low-substituted hydroxypropyl cellulose, calcium carboxymethyl cellulose, effervescent disintegrant, sodium carboxymethyl starch, and sodium crospovidone carboxymethyl cellulose.

9. The pharmaceutical composition according to any one of claims 1-4, characterized in that, The disintegrant is selected from sodium carboxymethyl starch and sodium croscarmellose.

10. The pharmaceutical composition according to any one of claims 1-4, characterized in that, The adhesive is selected from one or more of starch paste, copovidone, powdered sugar, syrup, polyvinylpyrrolidone, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, polyethylene glycol 4000, hydroxypropyl cellulose, ethylcellulose and dextrin.

11. The pharmaceutical composition according to any one of claims 1-4, characterized in that, The adhesive is selected from copolyvinylpyrrolidone VA64 and polyvinylpyrrolidone.

12. The pharmaceutical composition according to any one of claims 1-4, characterized in that, Other excipients constitute 0% to 5% by weight in the pharmaceutical composition.

13. The pharmaceutical composition according to any one of claims 1-4, characterized in that, The filler is pregelatinized starch; or the filler is a combination of pregelatinized starch and mannitol, and the weight ratio of the two fillers is 1:6 to 6:

1. The lubricating additives are lubricants and flow aids; The lubricant is selected from magnesium stearate; The disintegrant is selected from sodium carboxymethyl starch and sodium croscarmellose. The adhesive is copolyvinyl ketone; The flow aid is colloidal silica.

14. The pharmaceutical composition according to any one of claims 1-4, characterized in that, The components of the pharmaceutical composition and their weight percentages are as follows: The active ingredient, by weight, is 25% to 45%; The filler, by weight, comprises 50% to 70%; Lubricant, comprising 2% by weight; The gliding agent, by weight, is 3%. Disintegrant, with a weight percentage of 0% to 3%; The adhesive, by weight, is 0%. The filler is pregelatinized starch; or the filler is a combination of pregelatinized starch and mannitol, and the weight ratio of the two fillers is 1:6 to 6:

1. The lubricating additives are lubricants and flow aids; The lubricant is selected from magnesium stearate; The flow aid is colloidal silica; The disintegrant is selected from sodium carboxymethyl starch and sodium croscarmellose.

15. The pharmaceutical composition according to any one of claims 1-4, wherein, The pharmaceutical composition comprises an active ingredient, a filler, a lubricant, and a flow aid, wherein the filler is pregelatinized starch; the flow aid is colloidal silica; and the lubricant is magnesium stearate.

16. The pharmaceutical composition according to any one of claims 1-4, characterized in that, The components of the pharmaceutical composition and their weight percentages are as follows: 25%~40% of the active ingredient, 56%~68% of the pregelatinized starch, 3% of the colloidal silica and 2% of the magnesium stearate, and the sum of the weight percentages of the components is 100%.

17. The pharmaceutical composition according to any one of claims 1-4, characterized in that, The components of the pharmaceutical composition and their weight percentages are as follows: 25% to 40% of the active ingredient, 10% to 50% of the pregelatinized starch, 5% to 63% of mannitol, 3% of colloidal silica, and 2% to 3% of magnesium stearate, with the sum of the weight percentages of each component being 100%.

18. The pharmaceutical composition according to any one of claims 1-4, characterized in that, The components of the pharmaceutical composition and their weight percentages are as follows: 29.08% active ingredient, 65.92% pregelatinized starch, 3% colloidal silica, 1% internally added magnesium stearate, and 1% externally added magnesium stearate, the sum of the weight percentages of each component being 100%; or, The components of the pharmaceutical composition and their weight percentages are as follows: 36.34% of the active ingredient, 58.66% of the pregelatinized starch, 3% of the colloidal silica, 1% of the internally added magnesium stearate and 1% of the externally added magnesium stearate, and the sum of the weight percentages of the components is 100%.

19. A pharmaceutical composition comprising a compound of formula (B) as an active ingredient and an excipient, ； in, The compound shown in formula (B) was subjected to X-ray powder diffraction at 2θ angles of 7.3±0.2°, 8.5±0.2°, 9.0±0.2°, 11.8±0.2°, 12.6±0.2°, 14.3±0.2°, 18.1±0.2°, 19.6±0.2°, 20.0±0.2°, 21.1±0.2°, 21.9±0.2°, 23.7±0.2°, 25.2±0.2°, and 26.1±0.2° using Cu-Kα radiation. It has a characteristic peak at 27.2±0.2°; or, it has characteristic peaks at 7.3±0.2°, 8.5±0.2°, 9.1±0.2°, 11.8±0.2°, 12.6±0.2°, 14.3±0.2°, 18.1±0.2°, 19.6±0.2°, 20.0±0.2°, 21.1±0.2°, 21.9±0.2°, 23.7±0.2°, 25.2±0.2°, 26.1±0.2°, and 27.2±0.2°. The excipients include fillers, lubricating agents, and disintegrants; The lubricating additive is a combination of lubricant and flow aid; The active ingredient has a weight percentage of 25% to 45%; The filler has a weight percentage of 50% to 70%; The lubricant has a weight percentage of 2%; The glidin agent has a weight percentage of 3%; The weight percentage of the disintegrant is 1% to 3%; Other excipients, in weight percentages of 0% to 5%; Furthermore, the sum of the weight percentages of all the above components is 100%; The filler is a combination of microcrystalline cellulose and lactose, with a weight ratio of 1:2 to 2:

1. The lubricant is selected from magnesium stearate or sodium stearyl fumarate; The flow aid is colloidal silica; The disintegrant is sodium carboxymethyl starch.

20. A pharmaceutical composition comprising a compound of formula (B) as an active ingredient and an excipient, ； in, The compound shown in formula (B) was subjected to X-ray powder diffraction at 2θ angles of 7.3±0.2°, 8.5±0.2°, 9.0±0.2°, 11.8±0.2°, 12.6±0.2°, 14.3±0.2°, 18.1±0.2°, 19.6±0.2°, 20.0±0.2°, 21.1±0.2°, 21.9±0.2°, 23.7±0.2°, 25.2±0.2°, and 26.1±0.2° using Cu-Kα radiation. It has a characteristic peak at 27.2±0.2°; or, it has characteristic peaks at 7.3±0.2°, 8.5±0.2°, 9.1±0.2°, 11.8±0.2°, 12.6±0.2°, 14.3±0.2°, 18.1±0.2°, 19.6±0.2°, 20.0±0.2°, 21.1±0.2°, 21.9±0.2°, 23.7±0.2°, 25.2±0.2°, 26.1±0.2°, and 27.2±0.2°. The excipients include fillers, lubricating agents, and disintegrants; The lubricating additive is a combination of lubricant and flow aid; The active ingredient has a weight percentage of 25% to 45%; The filler has a weight percentage of 50% to 70%; The lubricant has a weight percentage of 2%; The glidin agent has a weight percentage of 3%; The disintegrant has a weight percentage of 3%; Other excipients, in weight percentages of 0% to 5%; Furthermore, the sum of the weight percentages of all the above components is 100%; The filler is a combination of microcrystalline cellulose and lactose, with a weight ratio of 1:1 or 2:1 between the two fillers; The lubricant is selected from magnesium stearate or sodium stearyl fumarate; The flow aid is colloidal silica; The disintegrant is sodium carboxymethyl starch or croscarmellose sodium.

21. The pharmaceutical composition according to claim 19 or 20, characterized in that, The compound represented by formula (B) exhibits an X-ray powder diffraction pattern substantially as shown in Figure 1 when subjected to Cu-Kα radiation.

22. The pharmaceutical composition according to claim 19 or 20, characterized in that, The components of the pharmaceutical composition and their weight percentages are as follows: 25% to 45% of the active ingredient, 15% to 50% of microcrystalline cellulose, 15% to 45% of lactose, 3% of the disintegrant, 2% of the lubricant, 3% of the flow aid, and 0% to 5% of other excipients, the sum of the weight percentages of the components being 100%.

23. The pharmaceutical composition according to claim 19 or 20, characterized in that, The components of the pharmaceutical composition and their weight percentages are as follows: 28%~35% of the active ingredient, 15%~45% of microcrystalline cellulose, 15%~45% of lactose, 3% of colloidal silica, 2% of magnesium stearate or sodium stearoyl fumarate, and 3% of sodium carboxymethyl starch, with the sum of the weight percentages of each component being 100%.

24. A pharmaceutical composition comprising, as an active ingredient, a compound of formula (B), ； in, The compound shown in formula (B) was subjected to X-ray powder diffraction at 2θ angles of 7.3±0.2°, 8.5±0.2°, 9.0±0.2°, 11.8±0.2°, 12.6±0.2°, 14.3±0.2°, 18.1±0.2°, 19.6±0.2°, 20.0±0.2°, 21.1±0.2°, 21.9±0.2°, 23.7±0.2°, 25.2±0.2°, and 26.1±0.2° using Cu-Kα radiation. It has a characteristic peak at 27.2±0.2°; or, it has characteristic peaks at 7.3±0.2°, 8.5±0.2°, 9.1±0.2°, 11.8±0.2°, 12.6±0.2°, 14.3±0.2°, 18.1±0.2°, 19.6±0.2°, 20.0±0.2°, 21.1±0.2°, 21.9±0.2°, 23.7±0.2°, 25.2±0.2°, 26.1±0.2°, and 27.2±0.2°. The components of the pharmaceutical composition and their weight percentages are as follows: 50% to 60% of the active ingredient, 35% to 40% of anhydrous dicalcium phosphate, 1% to 3% of colloidal silica, 2% to 3% of magnesium stearate, and 0% to 4% of sodium carboxymethyl starch and / or croscarmellose sodium, the sum of the weight percentages of the components being 100%.

25. A pharmaceutical composition comprising a compound of formula (B) as an active ingredient, ； in, The compound shown in formula (B) was subjected to X-ray powder diffraction at 2θ angles of 7.3±0.2°, 8.5±0.2°, 9.0±0.2°, 11.8±0.2°, 12.6±0.2°, 14.3±0.2°, 18.1±0.2°, 19.6±0.2°, 20.0±0.2°, 21.1±0.2°, 21.9±0.2°, 23.7±0.2°, 25.2±0.2°, and 26.1±0.2° using Cu-Kα radiation. It has a characteristic peak at 27.2±0.2°; or, it has characteristic peaks at 7.3±0.2°, 8.5±0.2°, 9.1±0.2°, 11.8±0.2°, 12.6±0.2°, 14.3±0.2°, 18.1±0.2°, 19.6±0.2°, 20.0±0.2°, 21.1±0.2°, 21.9±0.2°, 23.7±0.2°, 25.2±0.2°, 26.1±0.2°, and 27.2±0.2°. The components of the pharmaceutical composition and their weight percentages are as follows: 15%–80% of the active ingredient, 5%–20% of anhydrous dicalcium phosphate, 5%–60% of pregelatinized starch, 0%–3% of disintegrant, 0% of binder, 1.5%–3% of lubricant, 2%–3% of flow aid, and 0%–5% of other excipients; and the sum of the weight percentages of all components is 100%. The lubricant is selected from magnesium stearate or sodium stearyl fumarate; The flow aid is colloidal silica; The disintegrant is selected from sodium carboxymethyl starch and / or croscarmellose sodium.

26. A pharmaceutical composition comprising a compound of formula (B) as an active ingredient, ； in, The compound shown in formula (B) was subjected to X-ray powder diffraction at 2θ angles of 7.3±0.2°, 8.5±0.2°, 9.0±0.2°, 11.8±0.2°, 12.6±0.2°, 14.3±0.2°, 18.1±0.2°, 19.6±0.2°, 20.0±0.2°, 21.1±0.2°, 21.9±0.2°, 23.7±0.2°, 25.2±0.2°, and 26.1±0.2° using Cu-Kα radiation. It has a characteristic peak at 27.2±0.2°; or, it has characteristic peaks at 7.3±0.2°, 8.5±0.2°, 9.1±0.2°, 11.8±0.2°, 12.6±0.2°, 14.3±0.2°, 18.1±0.2°, 19.6±0.2°, 20.0±0.2°, 21.1±0.2°, 21.9±0.2°, 23.7±0.2°, 25.2±0.2°, 26.1±0.2°, and 27.2±0.2°. The components of the pharmaceutical composition and their weight percentages are as follows: 10%–80% active ingredient, 15%–75% calcium carbonate, 0.5%–4% disintegrant, 0%–3% binder, 2%–3% lubricant, 2%–3% flow aid, and 0%–5% other excipients; and the sum of the weight percentages of all components is 100%. The lubricant is selected from magnesium stearate or sodium stearyl fumarate; The flow aid is colloidal silica; The disintegrant is selected from sodium carboxymethyl starch and / or croscarmellose sodium; The adhesive is copolyvinylpyrrolidone.

27. The pharmaceutical composition of claim 26, characterized in that, The adhesive is copovidone VA64.

28. A pharmaceutical composition comprising a compound of formula (B) as an active ingredient, ； in, The compound shown in formula (B) was subjected to X-ray powder diffraction at 2θ angles of 7.3±0.2°, 8.5±0.2°, 9.0±0.2°, 11.8±0.2°, 12.6±0.2°, 14.3±0.2°, 18.1±0.2°, 19.6±0.2°, 20.0±0.2°, 21.1±0.2°, 21.9±0.2°, 23.7±0.2°, 25.2±0.2°, and 26.1±0.2° using Cu-Kα radiation. It has a characteristic peak at 27.2±0.2°; or, it has characteristic peaks at 7.3±0.2°, 8.5±0.2°, 9.1±0.2°, 11.8±0.2°, 12.6±0.2°, 14.3±0.2°, 18.1±0.2°, 19.6±0.2°, 20.0±0.2°, 21.1±0.2°, 21.9±0.2°, 23.7±0.2°, 25.2±0.2°, 26.1±0.2°, and 27.2±0.2°. The components of the pharmaceutical composition and their weight percentages are as follows: 10%–80% active ingredient, 5%–40% calcium carbonate, 5%–60% pregelatinized starch, 0%–2% disintegrant, 0%–2% binder, 2%–3% lubricant, 2%–3% flow aid, and 0%–5% other excipients; and the sum of the weight percentages of all components is 100%. The lubricant is selected from magnesium stearate or sodium stearyl fumarate; The flow aid is colloidal silica; The disintegrant is selected from sodium carboxymethyl starch and / or croscarmellose sodium; The adhesive is copolyvinylpyrrolidone.

29. The pharmaceutical composition of claim 28, characterized in that, The adhesive is copovidone VA64.

30. A pharmaceutical composition comprising a compound of formula (B) as an active ingredient, ； in, The compound shown in formula (B) was subjected to X-ray powder diffraction at 2θ angles of 7.3±0.2°, 8.5±0.2°, 9.0±0.2°, 11.8±0.2°, 12.6±0.2°, 14.3±0.2°, 18.1±0.2°, 19.6±0.2°, 20.0±0.2°, 21.1±0.2°, 21.9±0.2°, 23.7±0.2°, 25.2±0.2°, and 26.1±0.2° using Cu-Kα radiation. It has a characteristic peak at 27.2±0.2°; or, it has characteristic peaks at 7.3±0.2°, 8.5±0.2°, 9.1±0.2°, 11.8±0.2°, 12.6±0.2°, 14.3±0.2°, 18.1±0.2°, 19.6±0.2°, 20.0±0.2°, 21.1±0.2°, 21.9±0.2°, 23.7±0.2°, 25.2±0.2°, 26.1±0.2°, and 27.2±0.2°. The components of the pharmaceutical composition and their weight percentages are as follows: 12%~80% of the active ingredient, 7%~45% of calcium carbonate, 7%~65% of pregelatinized starch, 3% of colloidal silica, 2% of magnesium stearate, 0-2% of copovidone VA64, and 0%~1% of sodium carboxymethyl starch and / or cross-linked sodium carboxymethyl cellulose, the sum of the weight percentages of each component being 100%.

31. The pharmaceutical composition according to any one of claims 24-30, characterized in that, The compound represented by formula (B) exhibits an X-ray powder diffraction pattern substantially as shown in Figure 1 when subjected to Cu-Kα radiation.

32. An oral solid dosage form, characterized in that, It is made from the pharmaceutical composition as described in any one of claims 1-31.

33. The oral solid dosage form as described in claim 32, characterized in that, The oral solid dosage form is selected from capsules and tablets.

34. The oral solid dosage form as described in claim 32, characterized in that, The oral solid dosage form is a capsule.

35. The oral solid dosage form as described in claim 33, characterized in that, The tablets are film-coated tablets or uncoated tablets.

36. The oral solid dosage form according to any one of claims 32-35, characterized in that, Each unit of the oral solid dosage form may contain 1 to 500 mg of active ingredient, which is expressed as hydrochloride.

37. The oral solid dosage form as described in claim 36, characterized in that, Each unit of the oral solid dosage form may contain 10 to 300 mg of active ingredient, which is expressed as hydrochloride.

38. The oral solid dosage form as described in claim 36, characterized in that, Each unit of the oral solid dosage form may contain 10 to 100 mg of active ingredient, wherein the active ingredient is in the form of hydrochloride.

39. Use of the pharmaceutical composition of any one of claims 1-31, or the oral solid dosage form of any one of claims 32-38, for the preparation of a medicament, wherein the medicament is for the treatment or prevention of a protein kinase-mediated disease, the protein kinase being selected from one or more of FLT3, EGFR, Abl, Fyn, Hck, Lck, Lyn, Ret, Yes, ALK, BTK, c-KIT, c-SRC, FGFR1, KDR, MET, and PDGFRα kinases, and the protein kinase-mediated disease is a neoplastic disease.

40. The use as described in claim 39, wherein, The tumor disease is a solid tumor or a hematologic tumor.

41. The use as described in claim 39, wherein, The tumor disease is either leukemia or lung cancer.

42. The use as described in claim 39, wherein, The tumor disease is acute myeloid leukemia, chronic myeloid leukemia, or non-small cell lung cancer.

43. The use as described in claim 39, wherein, The tumor diseases mentioned are selected from non-small cell lung cancer, acute myeloid leukemia, chronic myeloid leukemia, chronic myeloid leukemia, epidermal squamous cell carcinoma, breast cancer, colorectal cancer, liver cancer, gastric cancer, and malignant melanoma.

44. The use as described in claim 42 or 43, wherein, The acute myeloid leukemia is selected from relapsed and / or refractory acute myeloid leukemia.

45. The use as described in claim 42 or 43, wherein, The acute myeloid leukemia mentioned is selected from FLT3 mutation-positive acute myeloid leukemia.

46. ​​The use as described in claim 42 or 43, wherein, The acute myeloid leukemia is selected from acute myeloid leukemia with FLT3-ITD mutation or FLT3-TKD mutation, the chronic myeloid leukemia is Ph-positive chronic myeloid leukemia, and the non-small cell lung cancer is non-small cell lung cancer with EGFR activating mutation.

Images