Pharmaceutical composition, its preparation method and use for treating diseases caused by coronaviruses

Abstract

The present invention provides a pharmaceutical composition comprising a crystalline form of (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione) and fumaric acid, and a physiologically acceptable / pharmaceutically acceptable excipient; a method for its preparation and / or its use in the preparation of a medicament for treating a disease caused by a coronavirus in a subject (including a child, an adult or an elderly person). The pharmaceutical composition described herein has high dissolution, dissolution rate and / or stability.

Description

Technical Field

[0001] The present invention relates to a pharmaceutical composition comprising one or more of a specific compound or its isomers, salts, N-oxides, metabolites, solvates, salts of solvates, polymorphs or prodrugs and a physiologically acceptable / pharmaceutically acceptable excipient, a method for preparing the same, and its use in the preparation of a drug for treating a disease caused by a coronavirus in a subject. Background Art

[0002] Coronaviruses belong to the genus Coronavirus in the systematic classification. Coronaviruses are enveloped positive-strand RNA viruses. Due to the outbreaks of Severe Acute Respiratory Syndrome (SARS) in 2003 and Middle East Respiratory Syndrome (MERS) in 2012, coronaviruses have gradually become a research hotspot in the field of virology. Coronavirus Disease 2019 is a newly emerging acute respiratory infectious disease caused by SARS-CoV-2 (also known as 2019-nCoV).

[0003] On February 11, 2020, the International Committee on Taxonomy of Viruses (ICTV) announced that the official classification name of the novel coronavirus 2019 (2019-nCoV) is severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). On the same day, the World Health Organization (WHO) announced that the official name of the disease caused by this virus is COVID-19. The symptoms of SARS-CoV-2 infection are mainly pneumonia, which can be divided into simple infection, mild pneumonia, severe pneumonia, acute respiratory distress syndrome, sepsis, septic shock, etc. according to the severity of the condition. Patients with simple infection may have non-specific symptoms, such as fever, cough, sore throat, nasal congestion, fatigue, headache, muscle pain or discomfort, and the elderly and immunosuppressed may have atypical symptoms. Patients with mild pneumonia mainly present with cough, dyspnea + tachypnea. Severe pneumonia can be seen in adolescents, adults or children, and the main symptoms are increased respiratory rate, severe respiratory failure or dyspnea, central cyanosis, lethargy, confusion or convulsions, gasping, etc. The lung imaging of acute respiratory distress syndrome shows bilateral ground-glass opacities, but it cannot be fully explained by effusion, lobar exudation, atelectasis or lung mass, and the main symptom is pulmonary edema. At present, for the novel coronavirus infection, the clinical treatment is mainly supportive treatment, and there are no specific antiviral drugs available. In view of the severe situation of the epidemic, there is an urgent need for effective treatment means at present. Summary of the Invention

[0004] In view of the above problems existing in the prior art, the present invention provides a technical solution to solve the above problems.

[0005] In the first aspect of the present invention, there is provided a pharmaceutical composition comprising a crystalline form of (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione) and fumaric acid, and a physiologically acceptable / pharmaceutically acceptable excipient, wherein the crystalline form of (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione) and fumaric acid, using Cu-Kα radiation, the characteristic diffraction peaks of the X-ray powder diffraction pattern represented by 2θ value ±0.2° include any three of 10.94, 19.06, 23.50, and 24.66.

[0006] In the second aspect of the present invention, there is provided a method for preparing the pharmaceutical composition of the present invention, which is characterized in that it comprises the following steps: premixing, granulating and / or total mixing.

[0007] In the third aspect of the present invention, there is provided the use of the pharmaceutical composition of the present invention in the preparation of a drug for treating or preventing a disease caused by a coronavirus in a subject; preferably, wherein the subject is a human, such as a child, an adult or an elderly person.

[0008] Through creative research, the present invention finds that the pharmaceutical composition described herein has the function of inhibiting coronaviruses, especially novel coronaviruses, and has good potential therapeutic effects in the treatment of diseases caused by novel coronaviruses. In addition, the pharmaceutical compounds of the present invention also have high dissolution, dissolution rate and / or stability. Moreover, the pharmaceutical composition of the present invention is suitable for making oral preparations, especially oral solid preparations such as tablets, is suitable for large-scale industrial production, and the obtained products have stable and reliable quality and have good clinical application value. Brief Description of the Drawings

[0009] Figure 1 It is for the powder adhesion phenomenon existing during the tabletting process of the formulation prescription of Example 20.

[0010] Figure 2 It is for the capping phenomenon occurring during the tabletting process of the formulation prescription of Example 22. Detailed Description of the Invention

[0011] In the present application, relative humidity is represented by RH, which represents the percentage of the amount of water vapor (vapor pressure) contained in a gas (usually air) to the saturated water vapor amount (saturated vapor pressure) under the same conditions of the air.

[0012] Depending on their structure, the compounds of the present invention may exist as isomers, for example, in stereoisomeric forms (enantiomers, diastereomers). Therefore, the present invention relates to enantiomers or diastereomers and their respective mixtures. Stereoisomerically pure components can be separated from such mixtures of enantiomers and / or diastereomers in a known manner.

[0013] When the compounds of the present invention can exist as optical isomers, the pharmaceutical compositions provided by the present invention generally contain substantially pure optical isomers.

[0014] If the compounds of the present invention are in tautomeric forms, the present invention encompasses all tautomeric forms.

[0015] In addition, the compounds of the present invention can exist in free form, for example, as a free base or as a free acid or as a zwitterion, or can exist in the form of salts. The salts can be any salts commonly used in pharmacy, organic or inorganic addition salts, especially any physiologically acceptable organic or inorganic addition salts.

[0016] For the purposes of the present invention, preferred salts are the physiologically acceptable salts of the compounds of the present invention. However, salts that are not suitable for pharmaceutical applications per se but can be used, for example, for the separation or purification of the compounds of the present invention are also included.

[0017] The term "physiologically acceptable salts" refers to relatively non-toxic inorganic or organic acid addition salts of the compounds of the present invention, for example, see S.M. Berge et al., "Pharmaceutical Salts", J. Pharm. Sci. 1977, 66, 1-19.

[0018] Physiologically acceptable salts of the compounds of the present invention encompass acid addition salts of inorganic acids, carboxylic acids, and sulfonic acids, such as salts of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, disulfuric acid, sulfamic acid, phosphoric acid, nitric acid, or salts formed with organic acids, said organic acids being, for example, formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, dodecanoic acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)-benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, octanoic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, pantothenic acid, mucic acid, succinic acid, oxalic acid, malonic acid, fumaric acid, malic acid, adipic acid, alginic acid, maleic acid, gluconic acid, mandelic acid, ascorbic acid, glucoheptonic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, or thiocyanic acid. Particularly preferred are fumarates.

[0019] The present invention includes all possible salts of the compounds of the present invention, which are single salts or any mixture of said salts in any proportion.

[0020] For the purposes of the present invention, solvates are those forms of the compounds of the present invention that form complexes by coordination with solvent molecules in solid or liquid form. Hydrates are a specific form of solvates in which coordination occurs with water. Within the scope of the present invention, hydrates are preferably used as solvates.

[0021] The present invention also includes all suitable isotopic variants of the compounds of the present invention. Isotopic variants of the compounds of the present invention are defined as compounds in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually or predominantly present in nature. Examples of isotopes that can be incorporated into the compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, such as 2 H (deuterium), 3 H (tritium), 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I,124 I、 129 I and 131 I. Certain isotopic variants of the compounds of the present invention (e.g., those incorporating one or more radioactive isotopes such as 3 H or 14 C) are suitable for studies of drug and / or matrix tissue distribution. Tritium-labeled and carbon-14 (i.e., 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. In addition, substitution with isotopes such as deuterium can provide certain therapeutic advantages resulting from higher metabolic stability, such as increased in vivo half-life or reduced dose requirements, and may thus be preferred in certain cases. Isotopic variants of the compounds of the present invention can generally be prepared by conventional procedures known to those skilled in the art (e.g., by the exemplary methods or by the preparation methods described in the examples below), using suitable isotopic variants of appropriate reagents.

[0022] In addition, the present invention also encompasses prodrugs of the compounds of the present invention. The term "prodrug" encompasses compounds that may be biologically active or inactive per se, but which are converted (e.g., by metabolism or hydrolysis) into the compounds of the present invention during their residence in the body. Prodrugs of the compounds of the present invention can be generated, for example, by replacing suitable functional groups present in the compounds of the present invention with certain moieties known to those skilled in the art as "pro-moieties" (e.g., as described in Design of Prodrugs by H. Bundgaard (Elsevier, 1985)).

[0023] Furthermore, the present invention includes all possible crystalline forms or polymorphs (single crystal forms, polymorphs, or mixtures of more than one single crystal form in any proportion) of the compounds of the present invention.

[0024] Accordingly, the present invention includes all possible salts, polymorphs, metabolites, hydrates, solvates, prodrugs (e.g., esters), and diastereoisomeric forms of the compounds of the present invention, which are in the form of a single salt, polymorph, metabolite, hydrate, solvate, prodrug (e.g., ester), or diastereoisomer, or are mixtures of more than one salt, polymorph, metabolite, hydrate, solvate, prodrug (e.g., ester), or diastereoisomeric form in any proportion.

[0025] The compounds of the present invention intended for pharmaceutical use can be administered as crystalline or amorphous products, or mixtures thereof. By methods such as precipitation, crystallization, freeze-drying, spray-drying, or evaporation-drying, the compounds of the present invention can be obtained, for example, as solid suppositories, powders, or films. Microwave or radiation drying can be used for this purpose.

[0026] The physiologically acceptable / pharmaceutically acceptable excipients mixed with the compounds of the present invention to form the pharmaceutical compositions of the present invention may depend on the intended method of administration of the said compositions.

[0027] As used herein, the term "physiologically acceptable / pharmaceutically acceptable excipient" refers to an excipient that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the active ingredient administered (such as the compounds described herein or the crystalline form of its fumaric acid).

[0028] The pharmaceutical compositions of the present invention are preferably solid preparations or liquid preparations.

[0029] The pharmaceutical compositions of the present invention can be made into forms suitable for oral, inhalation, topical, nasal, rectal, transdermal or injection administration.

[0030] The pharmaceutical compounds of the present invention can be administered orally.

[0031] The pharmaceutical compositions of the present invention are preferably prepared into dosage forms of oral preparations. The shape of the oral preparations is not particularly limited and can be any one of round, small capsules, doughnut, rectangular, etc.

[0032] For solid preparations, it may involve, for example, tablets, capsules, powders, granules, lozenges, etc.

[0033] Solid preparations can be coated with a coating agent and can have markings and letters for identification and further scoring lines for separation. Coating is carried out under the condition of adding conventional coating media and film-forming agents (generally collectively referred to as coating materials) familiar to those skilled in the art. Coating can be carried out using, for example, sugar coating matrices, water-soluble film coating matrices, enteric film coating matrices, sustained-release film coating matrices, etc. For sugar coating matrices, sucrose and a combination of one or more selected from the following substances can be used: talc, precipitated calcium carbonate, gelatin, gum arabic, amylopectin, carnauba wax, etc. For water-soluble film coating matrices, for example, cellulose polymers such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, etc. can be used; synthetic polymers such as polyvinyl acetal diethylaminoethyl ester, aminoalkyl methacrylate copolymer E [Eudragit E (trade name)], polyvinylpyrrolidone, etc.; polysaccharides such as amylopectin, etc. For enteric film coating matrices, for example, cellulose polymers such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate, etc. can be used; acrylic polymers such as methacrylic acid copolymer L [Eudragit L (trade name)], methacrylic acid copolymer LD [Eudragit L-30D55 (trade name)], methacrylic acid copolymer S [Eudragit S (trade name)], etc.; naturally occurring substances such as shellac, etc. For sustained-release film coating matrices, for example, cellulose polymers such as ethyl cellulose, cellulose acetate, etc. can be used; acrylic polymers such as aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name)], ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trade name)], etc. Two or more of the above coating matrices can be mixed and used in a suitable ratio. Moreover, coating additives can also be used during coating. For coating additives, for example, light masking agents and / or colorants such as titanium oxide, talc, iron oxide, etc. can be used; plasticizers such as polyethylene glycol, triethyl citrate, castor oil, polysorbate, etc.; organic acids such as citric acid, tartaric acid, malic acid, ascorbic acid, etc. Preferably, solid preparations (such as tablets) are not coated with a coating agent.

[0034] Solid preparations can be formulated for immediate release (i.e., rapid release) and / or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

[0035] When the solid preparation is a tablet, any pharmaceutically acceptable excipient commonly used for preparing solid preparations can be used. Tablets can be prepared by compression or molding, optionally using one or more physiologically acceptable / pharmaceutically acceptable excipients. Compressed tablets can also be prepared by compressing the active ingredient in a free-flowing form (such as powder or capsule) in a suitable machine, and the active ingredient is optionally mixed with a binder, a lubricant, a filler, a solubilizer or a disintegrant. Molded tablets can be prepared by molding a mixture of a wetted powdery compound and an inert liquid dispersion medium in a suitable machine. The tablets can be optionally coated or scored and can be formulated to provide a sustained release or controlled release of the active ingredient therein. The formulation of tablets is discussed in detail in "Pharmaceutical Dosage Forms: Tablets, Vol.1", by H. Lieberman and L. Lachman, Marcel Dekker, N.Y., 1980.

[0036] When the solid preparation is a capsule, any conventional encapsulation is suitable, such as using the carriers mentioned above in hard gelatin capsules. When the composition is in the form of soft gelatin capsules, any physiologically acceptable / pharmaceutically acceptable excipient commonly used for preparing dispersants or suspending agents can be considered, and the physiologically acceptable / pharmaceutically acceptable excipient is incorporated into the soft gelatin capsules.

[0037] For liquid preparations, solutions, suspensions, syrups, injections and elixirs can be used. Such preparations can be used as fillers in soft or hard capsules and generally contain a liquid dispersion medium. Solutions can be aqueous solutions of soluble salts or other derivatives of active compounds combined with, for example, sucrose to form syrups. Suspensions can include the active compound of the present invention and water as well as suspending agents and / or flavoring agents. Liquid preparations can also be prepared by rehydrating some solid preparations (such as dry suspensions, etc.) (for example, prepared from sachets).

[0038] The pharmaceutical preparation can be conveniently presented in unit dosage form and can be prepared by any method known in the pharmaceutical art so that a unit dose can be administered to a subject. Preferably, the pharmaceutical composition is in unit dosage form, such as solid preparations (such as tablets, powders, dry suspensions, granules or capsules) or liquid preparations (such as solutions, suspensions, syrups, injections, elixirs).

[0039] As used herein, the term "subject" refers to an animal, including but not limited to primates (e.g., humans), monkeys, cows, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. Specifically, the subject is 0 years old or older, 1 year old or older, 2 years old or older, 4 years old or older, 5 years old or older, 10 years old or older, 12 years old or older, 13 years old or older, 15 years old or older, 16 years old or older, 18 years old or older, 20 years old or older, 25 years old or older, 30 years old or older, 35 years old or older, 40 years old or older, 45 years old or older, 50 years old or older, 55 years old or older, 60 years old or older, 65 years old or older, 70 years old or older, 75 years old or older, 80 years old or older, 85 years old or older, 90 years old or older, 95 years old or older, 100 years old or older, or 105 years old or older.

[0040] As used herein, "novel coronavirus" refers to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or 2019 novel coronavirus (2019-nCoV) published by the International Committee on Taxonomy of Viruses in February 2020. In this application, SARS-CoV-2 has the same meaning as 2019-nCoV, and it also includes all variants of the 2019 novel coronavirus, such as all variants included in NCBI or GISAID (Global Initiative on Sharing All Influenza Data), especially important variants with stronger transmissibility, pathogenicity, or immune escape ability, such as the Alpha, Beta, Gamma, Delta, Eta, Iota, Kappa, or Lambda variants designated by the WHO, and important variants designated subsequently.

[0041] As used herein, the term "starch" generally refers to having the empirical formula (C6H 10 O5) nA substance with n ranging from 300 to 1000 and a molecular weight of 50,000 to 160,000, which consists of amylose and amylopectin, both of which are polysaccharides based on α-glucose units. The starch is derived from plant materials and usually exists in the form of extremely small particles (5 - 25 microns in diameter) composed of layered structures formed by starch molecules around the nucleus. The starch granules can be round, oval, or angular and consist of radially oriented crystalline aggregates of two anhydrous D-glucose polymers (amylose and amylopectin). Amylose is a linear polymer of hundreds of glucose units linked by α-1-4 glycosidic bonds. Amylopectin is a branched polymer of thousands of glucose units with α-1-6 glycosidic bonds at the branching sites and α-1-4 linkages in the linear regions. Individual branches can have 20 - 30 glucose residues. Specifically, the starch is selected from starches with an amylose content in the range of 10% to 40% by weight. Common examples are corn starch, potato starch, rice starch, tapioca starch, and wheat starch.

[0042] As used herein, the term "pre-gelatinized starch" is intended to define starch that has been chemically and / or mechanically processed to rupture all or part of the granules in the presence of water and then dried. Some types of pre-gelatinized starch can be modified to have improved compressibility and flow characteristics. Common pre-gelatinized starch contains 5% free amylose, 15% free amylopectin, and 80% unmodified starch. Pre-gelatinized starch can be corn starch processed by the chemical and / or mechanical methods described above. Starches of other types besides corn starch can be pre-gelatinized, such as rice or potato starch.

[0043] In a first aspect of the present invention, the present invention provides the following specific embodiments and / or any combination thereof.

[0044] In a specific embodiment, the pharmaceutical composition consists of one or more of (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione) or its isomers, salts, N-oxides, metabolites, solvates, salts of solvates, polymorphs, or prodrugs, and a physiologically acceptable / pharmaceutically acceptable excipient.

[0045] Specifically, in the pharmaceutical composition, the active ingredient is one or more of (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione) or its isomers, salts, N-oxides, metabolites, solvates, salts of solvates, polymorphs or prodrugs, preferably (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione) or its crystalline form with fumaric acid.

[0046] Specifically, the pharmaceutical composition consists of (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione) and / or its crystalline form with fumaric acid, and a physiologically acceptable / pharmaceutically acceptable excipient.

[0047] More specifically, (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione) is in crystalline form, preferably anhydrous or hydrated.

[0048] More specifically, the crystalline form of (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione) with fumaric acid is anhydrous or hydrated (such as monohydrate or dihydrate, which may have one or two water of crystallization).

[0049] More specifically, in the crystalline form of (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione) and fumaric acid, the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in 2θ values ±0.2° include any three of 10.94, 19.06, 23.50, 24.66; preferably, it further includes any one or more of 9.5, 13.81, 18.61, 22.59, 23.8, and may further include any one or more of 7.81, 10.14, 11.50, 11.93, 12.31, or may further include any one or more of 14.73, 20.87, 21.49, 21.97, 25.39. More specifically, the XRPD diffraction peak data of the crystalline form of (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione) and fumaric acid are shown in the following table:

[0050]

[0051]

[0052]

[0053] More specifically, in the crystalline form of (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-(2,4,5-trifluorobenzyl)-1,3,5-triazinane-2,4-dione) and fumaric acid, the ratio of (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-(2,4,5-trifluorobenzyl)-1,3,5-triazinane-2,4-dione) to fumaric acid is 1:1.

[0054] In the present application, the crystalline form of (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione) and fumaric acid is sometimes also referred to as the crystalline form A of (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione) and fumaric acid (abbreviated as "crystalline form A"), which is different from other crystalline forms of (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione) and fumaric acid.

[0055] In a specific embodiment, the weight percentage of (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione) or its crystalline form with fumaric acid in the pharmaceutical composition is 15 - 60%, preferably 25 - 45% or 2% - 45%, for example 5% - 29% or 30% - 44%, or, for example, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 40.64%, 41%, 42%, 43%, 44% or 45%.

[0056] In a specific embodiment, after the pharmaceutical composition according to the present invention is placed for 1 month or 3 months under the conditions of accelerated stability test (such as 40°C ± 2°C and RH 75% ± 5%), the maximum single impurity content does not exceed 0.2% (such as not exceeding 0.1%) and / or the total impurity content does not exceed 1% (such as not exceeding 0.25%).

[0057] In a specific embodiment, the physiologically acceptable / pharmaceutically acceptable excipient includes one or more of a filler, a disintegrant, a lubricant, a binder, and a glidant; preferably, the physiologically acceptable / pharmaceutically acceptable excipient is selected from one or more of a filler, a disintegrant, a lubricant, a binder, and a glidant; more preferably, the physiologically acceptable / pharmaceutically acceptable excipient consists of a filler, a disintegrant, a lubricant, a binder, and a glidant.

[0058] Specifically, the filler includes one or more of lactose, anhydrous calcium hydrogen carbonate, sugar alcohols, celluloses, and starches, preferably. For example, the sugar alcohol filler is selected from one or more of mannitol (such as D-mannitol), maltitol, erythritol, lactitol, sorbitol, and xylitol; for example, the cellulose filler is selected from one or more of microcrystalline cellulose, powdered cellulose, and silicified microcrystalline cellulose; for example, the starch filler is selected from one or more of corn starch, potato starch, sweet potato starch, and pregelatinized starch, preferably pregelatinized starch.

[0059] For example, the filler is microcrystalline cellulose, pregelatinized starch, mannitol (such as D-mannitol), or a mixture of two or more thereof (such as, a mixture of microcrystalline cellulose and pregelatinized starch, or, a mixture of microcrystalline cellulose and mannitol (such as D-mannitol)). When the filler is a mixture of microcrystalline cellulose and pregelatinized starch, the weight ratio of the two is in the range of 1.5:1 to 3.5:1, such as 1.9:1, 2:1, 2.1:1, 2.3:1, 2.4:1, 2.5:1, 2.8:1, 2.9:1, or 3:1; when the filler is a mixture of microcrystalline cellulose and mannitol (such as D-mannitol), the weight ratio of the two is in the range of 1:5 to 5:1, such as in the range of 1:3.5 to 3.5:1, such as 3.1:1 or 3.2:1. In the pharmaceutical composition of the present invention, if the weight ratio of the two fillers is lower or higher than the above range, then lamination phenomenon occurs during the preparation (such as tablet preparation by tabletting) of the pharmaceutical composition, and it does not meet the pharmaceutical requirements.

[0060] Specifically, the weight percentage of the filler in the pharmaceutical composition is 10-80%, further 30-70%, preferably 30%-65%, for example 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69% or 70%. Alternatively, the content of the filler in the pharmaceutical composition (such as per unit dose of the pharmaceutical composition) can also be 110 mg-265 mg, preferably 130 mg-245 mg, for example 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 185 mg, 190 mg, 195 mg, 200 mg, 205 mg, 210 mg, 215 mg, 220 mg, 225 mg, 230 mg, 235 mg, 240 mg, 245 mg, 250 mg, 260 mg or 265 mg.

[0061] Specifically, the disintegrant is selected from one or more of crospovidone, sodium croscarmellose, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, corn starch and potato starch; preferably, the disintegrant is selected from one or more of crospovidone, sodium croscarmellose and sodium carboxymethyl starch.

[0062] Specifically, the weight percentage of the disintegrant in the pharmaceutical composition is 1-5%, for example 2%, 3% or 4%. In the pharmaceutical composition of the present invention, the dosage of the disintegrant cannot be too low or too high. If its dosage is too low (such as its weight percentage in the pharmaceutical composition is less than 1%), the dissolution rate of the active ingredient will be too slow, and the dissolution degree within 60 min (such as still not reaching 60%) cannot meet the pharmaceutical requirements; if its dosage is too high (such as its weight percentage in the pharmaceutical composition exceeds 5%), the dissolution rate of the active ingredient will be too fast, and almost all will disintegrate and dissolve within a short time (such as 5-10 min) (dissolution degree is greater than 80% or even 90%), which does not meet the pharmaceutical requirements.

[0063] Alternatively, the content of the disintegrant in the pharmaceutical composition (such as per unit dose of the pharmaceutical composition) can also be 3.5 mg - 19 mg, for example, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 12.5 mg, 13 mg, 13.5 mg, 14 mg, 14.5 mg, 15 mg, 15.5 mg, 16 mg, 16.5 mg, 17 mg, 17.5 mg, 18 mg, 18.5 mg or 19 mg.

[0064] Specifically, the lubricant is selected from one or more of magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oil, glyceryl behenate, stearic acid and sodium stearyl fumarate; preferably, the lubricant is selected from one or more of magnesium stearate, glyceryl behenate and sodium stearyl fumarate. For example, the lubricant is magnesium stearate, or magnesium stearate and sodium stearyl fumarate.

[0065] Specifically, the weight percentage of the lubricant in the pharmaceutical composition is 0.5 - 5%, further 0.5 - 4%, still further 0.5 - 3%, for example, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9% or 3%. In the pharmaceutical composition of the present invention, the dosage of the lubricant cannot be too low or too high. If its dosage is too low or too high (such as its weight percentage in the pharmaceutical composition is less than 0.5% or exceeds 4%), it will cause phenomena such as powder adhesion, sticking to the punch or rough punching during the preparation of the pharmaceutical composition (such as tablet pressing to prepare tablets), not meeting the pharmaceutical requirements.

[0066] Alternatively, specifically, the content of the lubricant in the pharmaceutical composition (such as per unit dose of the pharmaceutical composition) can also be 1.5 mg - 15 mg, for example, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 13 mg or 14 mg.

[0067] Specifically, the binder is selected from one or more of hydroxypropyl methylcellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose and polyvinylpyrrolidone, preferably hydroxypropyl methylcellulose and / or hydroxypropyl cellulose.

[0068] Specifically, the weight percentage of the binder in the pharmaceutical composition is 0-10%, further 1-5%, still further 1-3%, for example 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.1%, 2.2%, 2.3%, 2.4%, 2.5%, 2.6%, 2.7%, 2.8%, 2.9%, 3%, 3.5%, 4%, 4.5%. In the pharmaceutical composition of the present invention, the dosage of the binder cannot be too low or too high. If its dosage is too low or too high (such as its weight percentage in the pharmaceutical composition is less than 1% or exceeds 5%), it will cause the hardness of the obtained tablets to be too low (such as less than 40 N) or too high (such as higher than 80 N) during the tablet preparation process of the pharmaceutical composition, not meeting the pharmaceutical requirements.

[0069] Alternatively, specifically, the binder in the pharmaceutical composition (such as per unit dose of the pharmaceutical composition) can also be 1 mg-15 mg, further preferably 5 mg-8 mg, for example 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 9 mg, 10 mg, 11 mg, 12 mg, 13 mg or 14 mg.

[0070] Specifically, the glidant is selected from colloidal silica and / or talc powder, for example colloidal silica.

[0071] The term "colloidal silica" used in this application is also called "light anhydrous silicic acid".

[0072] Specifically, the weight percentage of the glidant in the pharmaceutical composition is 0.5-5%, further 0.5-4%, still further 0.5-3%, for example 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.5%, 2%, 2.5% or 3%. In the pharmaceutical composition of the present invention, the dosage of the glidant cannot be too low or too high. If its dosage is too low or too high (such as its weight percentage in the pharmaceutical composition is less than 0.5% or exceeds 4%), it will cause the tablet weight of the obtained tablets to be unstable during the tablet preparation process of the pharmaceutical composition, not meeting the pharmaceutical requirements.

[0073] Alternatively, specifically, the content of the glidant in the pharmaceutical composition (such as per unit dose of the pharmaceutical composition) can also be 1.5 mg - 15 mg, for example, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, 10 mg, 10.5 mg, 11 mg, 11.5 mg, 12 mg, 13 mg or 14 mg.

[0074] In a specific embodiment, the physiologically acceptable / pharmaceutically acceptable excipient further comprises a suspending agent and / or a flavoring agent.

[0075] Specifically, the suspending agent is selected from low molecular weight suspending agents, high molecular weight suspending agents, silicate salts, thixotropic gels, or combinations thereof. Specifically, the low molecular weight suspending agents can be selected from glycerol, syrup, or combinations thereof; the high molecular weight suspending agents can be selected from gums (such as gum arabic, tragacanth gum, peach gum, or combinations thereof), vegetable mucilages and polysaccharides (such as sodium alginate, agar, starch, pectin, carrageenan, chitosan, or combinations thereof), cellulose derivatives (such as methylcellulose or its salts, carboxymethylcellulose or its salts, hydroxypropylcellulose or its salts, hydroxyethylcellulose or its salts, or combinations thereof), or combinations thereof; the silicate salts can be selected from bentonite, magnesium aluminum silicate, aluminum silicate, or combinations thereof; and / or, the thixotropic gels can be selected from citrates, hydrogen citrates, tartrates, hydrogen tartrates, phosphates, AlCl3, or combinations thereof; preferably one or more of hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, sodium carboxymethylcellulose, sucrose, glycerol, sorbitol, maltitol, xanthan gum, tragacanth gum, cross-linked polyacrylic acid polymer, polyvinylpyrrolidone, microcrystalline cellulose.

[0076] Specifically, the weight percentage of the suspending agent in the pharmaceutical composition is 0 - 30%, preferably 1 - 20%.

[0077] Specifically, the flavoring agent is selected from ascorbic acid, aspartic acid, aspartame, sucralose, saccharin, D-sorbitol, stevia, acesulfame potassium, thaumatin, advantame, glycine, sodium chloride, magnesium chloride, hydrochloric acid, dilute hydrochloric acid, citric acid and its salts, anhydrous citric acid, L-glutamic acid and its salts, succinic acid and its salts, acetic acid, tartaric acid and its salts, sodium bicarbonate, fumaric acid and its salts, malic acid and its salts, glacial acetic acid, disodium inosinate, honey, reduced maltose syrup (maltitol), licorice, xylitol, etc., preferably ascorbic acid.

[0078] Specifically, the weight percentage of the flavoring agent in the pharmaceutical composition is 0.01-10%, preferably 0.05-7.5%, more preferably 1-5%.

[0079] In a specific embodiment, the weight ratio of (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione or its crystalline form with fumaric acid to the filler is in the range of 1:3 to 3:1, preferably in the range of 1:2 to 2:1, for example in the range of 1:1 to 1:1.5.

[0080] In a specific embodiment, the weight ratio of the disintegrant to the lubricant is in the range of 1:4 to 4:1, preferably in the range of 1:2 to 2:1, for example 1:1.

[0081] In a specific embodiment, the weight ratio of the glidant to the lubricant is in the range of 1:3 to 3:1, preferably in the range of 1:2 to 2:1. For example, in the range of 1:1 to 1.5:1.

[0082] In a specific embodiment, the weight ratio of the binder to the lubricant is in the range of 1:3 to 3:1, preferably in the range of 1:2 to 2:1, for example 1:1.

[0083] In a specific embodiment, the filler is a mixture of microcrystalline cellulose and D-mannitol (for example, the weight ratio of the two is as defined in the present application); the binder is hydroxypropyl cellulose; the disintegrant is croscarmellose sodium; the glidant is colloidal silicon dioxide; and / or, the lubricant is magnesium stearate. Among them, the weight percentage or content of the above specific physiologically acceptable / pharmaceutically acceptable excipients (such as microcrystalline cellulose, mannitol, croscarmellose sodium, hydroxypropyl cellulose, colloidal silicon dioxide and / or magnesium stearate) is as defined above.

[0084] In a specific embodiment, the filler is a mixture of microcrystalline cellulose and pregelatinized starch (for example, the weight ratio of the two is as defined in the present application); the binder is hydroxypropyl cellulose; the disintegrant is croscarmellose sodium; the glidant is colloidal silicon dioxide; and / or, the lubricant is magnesium stearate. Among them, the weight (percentage) ratio of the above specific physiologically acceptable / pharmaceutically acceptable excipients (such as microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, hydroxypropyl cellulose, colloidal silicon dioxide and / or magnesium stearate) in the pharmaceutical composition is as defined above.

[0085] In a specific embodiment of the present invention, the pharmaceutical composition is an oral preparation, preferably an oral solid preparation (such as tablets, powders, dry suspensions, granules or capsules) or an oral liquid preparation (such as solutions, suspensions, syrups, injections or elixirs).

[0086] In a specific embodiment of the present invention, the pharmaceutical composition is in unit dose form, such as a unit dose form of a solid preparation (such as tablets, powders, dry suspensions, granules or capsules) or a liquid preparation (such as solutions, suspensions, syrups, injections or elixirs), preferably tablets, powders, dry suspensions, capsules, solutions, suspensions or syrups.

[0087] When the oral solid preparation of the present invention is preferably a tablet, the tablet may have a film coating for easy swallowing of the tablet; alternatively, the tablet may be without a film coating.

[0088] The "hardness" of a tablet is measured by the force required to break the tablet and is expressed in N (Newtons). In a specific embodiment, the tablets of the present invention have a hardness in the range of 30 N to 90 N, such as in the range of 40 N to 80 N, or for example 70 N. It is well known to those skilled in the art to define a suitable hardness range according to the size and shape of the tablet.

[0089] In a specific embodiment of the present invention, when the pharmaceutical composition of the present invention is in unit dosage form (such as solid preparations (such as tablets, powders, dry suspensions, granules or capsules)), each unit dosage of the pharmaceutical composition contains an active ingredient (i.e., (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione described herein or its crystalline form with fumaric acid), 1 mg - 500 mg, preferably 10 - 300 mg, more preferably 50 - 200 mg, most preferably 120 - 155 mg; for example, each unit dosage of the pharmaceutical composition contains 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 6 mg, 7 mg, 8 mg, 9 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 105 mg, 110 mg, 115 mg, 120 mg, 125 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 151 mg, 152 mg, 152.1 mg, 152.2 mg, 152.3 mg, 152.4 mg, 152.5 mg, 152.6 mg, 152.7 mg, 152.8 mg, 152.9 mg, 153 mg, 154 mg, 155 mg, 160 mg, 165 mg, 170 mg, 170 mg, 180 mg, 185 mg, 190 mg, 195 mg or 200 mg or 250 mg of the active ingredient. It is preferably to add the content measured in the form of the free base to distinguish between the salt form and the free base measurement.

[0090] Specifically, when the pharmaceutical composition of the present invention exists in unit dosage form (such as tablets), the pharmaceutical composition of the present invention in the unit dosage form is in the range of 300 mg - 450 mg, for example, in the range of 350 mg - 400 mg, such as 375 mg.

[0091] In the second aspect of the present invention, the present invention provides the following specific embodiments and / or any combination thereof.

[0092] In a specific embodiment, the preparation method of the pharmaceutical composition of the present invention comprises the following steps:

[0093] (i) Premixing: Mixing (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione or its crystalline form with fumaric acid with a physiologically acceptable / pharmaceutically acceptable excipient;

[0094] (ii) Granulation: Granulating (such as dry granulation or wet granulation) the mixture obtained in step (i) and sieving;

[0095] (iii) Total mixing: Mixing the granules obtained in step (ii) with one or more other physiologically acceptable / pharmaceutically acceptable excipients other than the physiologically acceptable / pharmaceutically acceptable excipient described in step (i).

[0096] Specifically, (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione or its crystalline form with fumaric acid in the pharmaceutical composition, as well as the physiologically acceptable / pharmaceutically acceptable excipient, and their respective dosages are as defined in the present application.

[0097] Specifically, in the preparation method of the pharmaceutical composition of the present invention, step (i) as the premixing step is achieved by the following operations: (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione) or its crystalline form with fumaric acid, a filler, a disintegrant, a binder, and a glidant are sequentially mixed (uniformly). More specifically, step (i) as the premixing step is achieved by the following operations: First, (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione) or its crystalline form with fumaric acid and a first filler are mixed (uniformly), and then a second filler, a disintegrant, a binder, and a glidant are added and mixed (uniformly). Among them, the first filler and the second filler may be the same or different; preferably, the first filler is a cellulose-based filler (such as microcrystalline cellulose) or a sugar alcohol-based filler (such as D-mannitol) described in the present application, and the second filler is a starch-based filler (such as pregelatinized starch) or a cellulose-based filler (such as microcrystalline cellulose) described in the present application; more preferably, when the first filler is a cellulose-based filler (such as microcrystalline cellulose) described in the present application, the second filler is a starch-based filler (such as pregelatinized starch) described in the present application; or, more preferably, when the first filler is a sugar alcohol-based filler (such as D-mannitol) described in the present application, the second filler is a cellulose-based filler (such as microcrystalline cellulose) described in the present application. Preferably, the mixing is achieved by stirring, preferably by manual stirring or stirring in a mixing device (such as a hopper mixer).

[0098] Specifically, step (ii) as the granulation step is achieved by the following operations: The mixture obtained in step (i) is subjected to wet granulation or dry granulation and sieved. Specifically, wet granulation or dry granulation can be carried out by those skilled in the art according to the formulation requirements. Preferably, wet granulation can be carried out once, twice or more times. Preferably, wet granulation is to mix the mixture obtained in step (i) with a solvent (such as water), granulate through a wet granulator or a fluidized bed, sieve, dry (such as drying at 40-80 °C), and optionally perform secondary sieving; or, dry granulation is to granulate the mixture obtained in step (i) through a dry granulator or to granulate by pressing the mixture obtained in step (i) into large tablets, crushing them, and sieving. Preferably, sieving or secondary sieving is achieved through a 20-80 mesh sieve (such as a 40-60 mesh sieve). Preferably, drying is achieved through an oven or a fluidized bed.

[0099] Specifically, the method of adding the binder can be as follows: 1) adding the binder in dry powder form in step (i) or (ii); 2) adding the binder in solution form (preferably an aqueous solution, such as an aqueous solution with a binder concentration of 2-10%) in step (ii); 3) adding a part of the binder in dry powder form and adding another part of the binder in solution form (preferably an aqueous solution, such as an aqueous solution with a binder weight percentage concentration of 2-15%) in step (ii).

[0100] Specifically, (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione) or its crystalline form with fumaric acid is mixed with a solution of a part of the binder (preferably an aqueous solution, such as an aqueous solution with a binder concentration of 2-10%) for granulation, sieved (such as through a 20-80 mesh sieve), dried (such as dried at 40-80 °C), optionally sieved again (such as through a 20-80 mesh sieve), and then mixed (uniformly) with the first filler, the second filler, the disintegrant, the remaining part of the binder, and the glidant.

[0101] Specifically, step (iii) as the total mixing step is achieved by the following operation: mixing (uniformly) the granules obtained in step (ii) with the lubricant. Specifically, the mixing is achieved by stirring, preferably by manual stirring or stirring in a mixing device (such as a hopper mixer).

[0102] Specifically, the preparation method further includes a tableting step. Among them, the tableting step is to tablet the mixture obtained in step (iii); and / or, the tableting step is carried out by a tableting machine (such as a single punch tableting machine).

[0103] In the third aspect of the present invention, the present invention provides the following specific embodiments and / or any combination thereof.

[0104] In a specific embodiment, the subject is a human, preferably a child, an adult or an elderly person, such as a child aged 0-18 years (such as 0-12 years old), an adult aged 19-59 years or an elderly person over 60 years old. Specifically, when the pharmaceutical composition of the present invention is a granule or a dry suspension, the subject is preferably a child (such as a child aged 0-12 years old); when the pharmaceutical composition of the present invention is a tablet or a capsule, the subject is preferably an adult or an elderly person, such as an adult aged 19-59 years or an elderly person over 60 years old; when the pharmaceutical composition of the present invention is an oral liquid preparation, the subject is preferably a child (such as a child aged 0-12 years old) (such as a child aged 0-12 years old), an elderly person or a person with difficulty in swallowing.

[0105] When the pharmaceutical compound of the present invention is an oral preparation (such as tablets, powders, dry suspensions, granules, capsules, oral liquid preparations), it is convenient for the subjects to administer the drug, or improves the medication compliance of the subjects (especially children, the elderly or those with difficulty in swallowing), and also avoids the risks that may be brought by overdose of injectable drugs.

[0106] Unless otherwise specified, the various embodiments or different preferred-level solutions described herein can be arbitrarily combined.

[0107] The pharmaceutical compound of the present invention also has high dissolution rate, dissolution speed and / or stability. Moreover, the pharmaceutical composition of the present invention is suitable for being made into oral preparations, especially oral solid preparations such as tablets (with good compressibility of tablets), suitable for large-scale industrial production, and the obtained products have stable and reliable quality and have good clinical application value.

[0108] The present invention will be illustrated by way of examples below, but it should not be understood that the scope of the subject matter of the present invention is limited to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. The compounds or reagents used in the following examples can be purchased through commercial channels or prepared by conventional methods known to those skilled in the art; the experimental instruments used can be purchased through commercial channels. In the present invention, the content (%) in the examples refers to the weight percentage of each component in the pharmaceutical composition (i.e., the tablets obtained in each example); the value obtained by dividing the dosage (in g) in the examples by the batch size (i.e., the number of tablets) is the specific content of each component in the pharmaceutical composition (such as in mg or g).

[0109] Examples

[0110] I. Preparation and Characterization of Crystalline Form A of the Compound and Fumaric Acid

[0111] Example 1

[0112] Take the fumaric acid solid form of (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-(2,4,5-trifluorobenzyl)-1,3,5-triazinan-2,4-dione (15.2 mg) and add it to 1.0 mL of acetone to prepare a suspension. Stir the suspension at 50 °C for 1 day, separate the suspension, and dry the solid under vacuum to obtain white solid crystalline form A.

[0113] The solid sample obtained in Example 1 was characterized by an X-ray powder diffractometer PANalytical Empyrean (PANalytical, NL). The 2θ scanning angle ranged from 3° to 45°, the scanning step was 0.013°, and the test time was 5 minutes and 8 seconds. When testing the sample, the tube voltage and current were 45 kV and 40 mA respectively, and the sample disk was a zero-background sample disk.

[0114] The XRPD diffraction peak data of the crystalline form A of the compound and fumaric acid are shown in the following table:

[0115]

[0116]

[0117] Among the above diffraction peaks, the main characteristic diffraction peaks are selected from any three of 10.94, 19.06, 23.50, and 24.66, further including any one or more of 9.5, 13.81, 18.61, 22.59, and 23.8, and may also include any one or more of 7.81, 10.14, 11.50, 11.93, and 12.31, or may also include any one or more of 14.73, 20.87, 21.49, 21.97, and 25.39, or are also at 10.94, 19.06, 23.50, 24.66, 9.5, 13.81, 18.61, 22.59, and 23.8.

[0118] After the present inventors determined the crystalline form A of the compound and fumaric acid, they investigated the accelerated stability of the crystalline form A. Specifically, the crystalline form A prepared in Example 1 was placed in a stability test chamber at 40 °C and a relative humidity (RH) of 75% for 2 months. Samples were taken at 1 month and 2 months respectively, the appearance was observed and the purity was detected, and the results were compared with those at 0 day. See the following table for details.

[0119]

[0120]

[0121] Result: Under the conditions of 40 °C and a relative humidity (RH) of 75%, the crystalline form A had good stability, maintaining a stable appearance and purity within 2 months, and no dissociation or crystal transformation occurred in the crystalline form A.

[0122] On the basis of preparing and characterizing the crystalline form A and verifying the stability of the crystalline form A, the present inventors scaled up the preparation of the crystalline form A and continued to explore its formulation further.

[0123] II. Formulation Examples

[0124] Example 1

[0125]

[0126] Preparation method:

[0127] (1) Mix the API (i.e., the crystalline form A of the compound (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-(2,4,5-trifluorobenzyl)-1,3,5-triazinan-2,4-dione) and mannitol evenly;

[0128] (2) Add microcrystalline cellulose, croscarmellose sodium, sodium lauryl sulfate, and colloidal silicon dioxide to the mixture obtained in step (1) and mix evenly;

[0129] (3) Press the mixture obtained in step (2) into large tablets, break them up, and pass through a 20-mesh sieve;

[0130] (4) Mix the granules obtained in step (3) evenly with magnesium stearate and sodium stearyl fumarate;

[0131] (5) Press the mixture obtained in step (4) into tablets using a 9.5 mm round punch, control the average weight difference within ±3%, and the tablet hardness is 85 N to obtain tablets with a tablet weight of 375 mg.

[0132] Example 2

[0133]

[0134] Preparation method:

[0135] (1) Mix the API (i.e., the crystalline form A of the compound (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-(2,4,5-trifluorobenzyl)-1,3,5-triazinan-2,4-dione) and microcrystalline cellulose evenly;

[0136] (2) Add pregelatinized starch, crospovidone, sodium lauryl sulfate, and colloidal silicon dioxide to the mixture obtained in step (1) and mix evenly;

[0137] (3) Press the mixture obtained in step (2) into large tablets, break them up, and pass through a 20-mesh sieve;

[0138] (4) Mix the granules obtained in step (3) evenly with magnesium stearate and sodium stearyl fumarate;

[0139] (5) Press the mixture obtained in step (4) into tablets using a 9.5 mm round punch, control the average weight variation within ±3%, and the tablet hardness at 70 N to obtain tablets with a tablet weight of 375 mg.

[0140] Example 3

[0141]

[0142]

[0143] Preparation method:

[0144] (1) Mix the API (i.e., the crystalline form A of the compound (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-(2,4,5-trifluorobenzyl)-1,3,5-triazinan-2,4-dione and fumaric acid) and microcrystalline cellulose evenly.

[0145] (2) Add pregelatinized starch, croscarmellose sodium, sodium lauryl sulfate, copovidone, and colloidal silicon dioxide to the mixture obtained in step (1) and mix evenly.

[0146] (3) Press the mixture obtained in step (2) into large tablets, break them up, and pass through a 20-mesh sieve.

[0147] (4) Mix the granules obtained in step (3) evenly with magnesium stearate and sodium stearyl fumarate.

[0148] (5) Press the mixture obtained in step (4) into tablets using a 9.5 mm round punch, control the average weight variation within ±3%, and the tablet hardness at 70 N - 80 N to obtain tablets with a tablet weight of 375 mg.

[0149] Example 4

[0150]

[0151] Preparation method:

[0152] (1) Mix the API (i.e., the crystalline form A of the compound (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-(2,4,5-trifluorobenzyl)-1,3,5-triazinan-2,4-dione and fumaric acid) and microcrystalline cellulose evenly.

[0153] (2) Add pregelatinized starch, hydroxypropyl cellulose, croscarmellose sodium, and colloidal silicon dioxide to the mixture obtained in step (1) and mix evenly.

[0154] (3) Wet granulate the mixture obtained in step (2) with purified water, pass through a 20-mesh sieve, dry at 60 °C for 2 h, and screen and size the granules through a 20-mesh sieve;

[0155] (4) Mix the granules obtained in step (3) and magnesium stearate uniformly;

[0156] (5) Compress the mixture obtained in step (4) into tablets using a 9.5 mm round punch, control the average weight variation within ±3%, and the tablet hardness within 70 N - 80 N to obtain tablets with a tablet weight of 375 mg.

[0157] Example 5

[0158]

[0159] Preparation method:

[0160] (1) Premix 1: Mix the API (i.e., (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione), crystalline form A of fumaric acid, and microcrystalline cellulose uniformly by weight percentage;

[0161] (2) Premix 2: Add pregelatinized starch, hydroxypropyl cellulose, croscarmellose sodium, and colloidal silicon dioxide to the mixture obtained in step (1) and mix uniformly by weight percentage;

[0162] (3) Granulation: Granulate the mixture obtained in step (2) using a dry granulator until the granule rate above 60 mesh reaches 70%;

[0163] (4) Total mixing: Mix the granules obtained in step (3) and magnesium stearate uniformly by weight percentage;

[0164] (5) Compression: Compress the mixture obtained in step (4) into tablets using a 9.5 mm round punch, control the average weight variation within ±3%, and the tablet hardness within 70 N - 80 N to obtain tablets with a tablet weight of 375 mg.

[0165] Examples 6 - 9

[0166]

[0167]

[0168] Preparation method:

[0169] (1) Premixing: Mix the API (i.e., (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione), crystalline form A of fumaric acid, microcrystalline cellulose, pregelatinized starch, hydroxypropyl cellulose, croscarmellose sodium, and colloidal silicon dioxide evenly by weight percentage;

[0170] (2) Granulation: Press the mixture obtained in step (2) into large tablets, break them up, and pass through a 20-mesh sieve;

[0171] (3) Total mixing: Mix the granules obtained in step (3) with magnesium stearate evenly by weight percentage;

[0172] (4) Tableting: Tablet the mixture obtained in step (4), using a 9.5 mm round punch, controlling the average weight difference within ±3%, and the tablet hardness between 70 N - 80 N, to obtain tablets with a tablet weight of 375 mg.

[0173] Results: In the tableting process of the formulation prescriptions of Examples 5 - 9, there were no phenomena such as sticking to the punch, sticking to the die, powder adhesion, unstable tablet weight, excessive or insufficient tablet hardness, or capping. Their compressibility was good.

[0174] In the following Examples 10 - 21, the same or similar preparation methods as in Examples 5 - 9 were used, with different formulation prescriptions, to obtain tablets with a tablet weight of 375 mg.

[0175] Examples 10 - 11

[0176]

[0177] Results: Compared with Example 5, the difference in the formulation prescriptions of Examples 10 - 11 was only that pregelatinized starch, one of the fillers, was replaced with calcium carbonate or dibasic calcium phosphate anhydrous. However, there was a phenomenon of sticking to the punch in the tableting process of the formulation prescriptions of Examples 10 - 11, resulting in relatively poor compressibility.

[0178] Examples 12 - 13

[0179]

[0180] Results: Compared with Example 5, the difference in the formulation prescriptions of Examples 12 - 13 was only that hydroxypropyl cellulose, the binder, was replaced with polyvinylpyrrolidone or hydroxyethyl cellulose. However, there was a phenomenon of sticking to the die in the tableting process of the formulation prescriptions of Examples 12 - 13, resulting in relatively poor compressibility.

[0181] Examples 14 - 15

[0182]

[0183] Results: Compared with Example 5, the main differences in the formulation prescriptions of Examples 14 - 15 were that the contents of hydroxypropyl cellulose as a binder were adjusted to 0.7% and 5.3% respectively. However, in the tabletting process of the formulation prescriptions of Examples 14 - 15, there were phenomena of too low tablet hardness (20 N) and too high tablet hardness (95 N) respectively, resulting in relatively poor compressibility.

[0184] Examples 16 - 17

[0185]

[0186] Results: Compared with Example 5, the main differences in the formulation prescriptions of Examples 16 - 17 were that the contents of croscarmellose sodium as a disintegrant were adjusted to 0.8% and 5.5% respectively. However, in the tabletting process of the formulation prescriptions of Examples 16 - 17, there were no phenomena such as sticking punch, picking up, powder adhesion, unstable tablet weight, too high or too low tablet hardness, and capping. Their compressibility was good.

[0187] Examples 18 - 19

[0188]

[0189] Results: Compared with Example 5, the main differences in the formulation prescriptions of Examples 18 - 19 were that the contents of colloidal silicon dioxide as a glidant were adjusted to 0.3% and 4.5% respectively. However, in the tabletting process of the formulation prescriptions of Examples 18 - 19, there was a phenomenon of unstable tablet weight, and their compressibility was relatively poor.

[0190] Examples 20 - 21

[0191]

[0192]

[0193] Results: Compared with Example 5, the main differences in the formulation prescriptions of Examples 20 - 21 were that the contents of magnesium stearate as a lubricant were adjusted to 0.4% and 4.2% respectively. However, in the tabletting process of the formulation prescriptions of Examples 20 - 21, there were phenomena such as powder adhesion, sticking punch, and picking up, and their compressibility was relatively poor. Among them, the powder adhesion phenomenon in the formulation prescription of Example 20 during the tabletting process was as Figure 1 shown.

[0194] Examples 22 - 23

[0195]

[0196] Results: Compared with Example 5, the main differences in the formulation prescriptions of Examples 22 - 23 were that the weight ratios of microcrystalline cellulose and pregelatinized starch as fillers were adjusted to 1.3:1 and 4.4:1 respectively. However, lamination occurred during the tabletting process for the formulation prescriptions of Examples 22 - 23, and their compressibility was relatively poor. The lamination phenomenon during the tabletting process for the formulation prescription of Example 22 was as Figure 2 shown.

[0197] As shown in Examples 5 - 23, on the basis of exploring and studying the influence of changes in the formulation prescription parameters (i.e., component types and / or contents) of the above drug composition on the compressibility of tablets obtained by a preparation method including dry granulation, the inventors further explored and studied the influence of changes in the above formulation prescription parameters on the compressibility of tablets obtained by a preparation method including wet granulation. The results showed that: the influence of the changes in the above formulation prescription parameters also applied to tablets obtained by a preparation method including wet granulation. For example, as shown by the results of the following Examples 24 - 33.

[0198] Example 24

[0199]

[0200] Preparation method:

[0201] (1) Premixing 1: Mix the API (i.e., (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione), crystalline form A) of fumaric acid, and microcrystalline cellulose evenly by weight percentage;

[0202] (2) Premixing 2: Add D-mannitol, hydroxypropyl cellulose, croscarmellose sodium, and colloidal silicon dioxide to the mixture obtained in step (1) and mix evenly by weight percentage;

[0203] (3) Granulation: Granulate the mixture obtained in step (2) with purified water in a wet granulator, pass through a 20-mesh sieve, dry at 60 °C for 2 h, and screen and size the granules through a 20-mesh sieve;

[0204] (4) Final mixing: Mix the granules obtained in step (3) and magnesium stearate evenly by weight percentage;

[0205] (5) Tabletting: Tablet the mixture obtained in step (4), use a 9.5 mm round punch, control the average weight difference within ±3%, and the tablet hardness is 70 N - 80 N to obtain tablets with a tablet weight of 375 mg.

[0206] Results: During the tabletting process of the formulation of Example 24, there were no phenomena such as sticking to the punch, adhesion to the punch, powder adhesion, unstable tablet weight, too high or too low tablet hardness, or tablet splitting. Its compressibility was good.

[0207] Examples 25 - 28

[0208]

[0209]

[0210] Preparation method:

[0211] (1) Premixing: Mix the API (i.e., (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione), crystalline form A of fumaric acid, microcrystalline cellulose, D-mannitol, hydroxypropyl cellulose, croscarmellose sodium, and colloidal silicon dioxide evenly by weight percentage;

[0212] (2) Granulation: Granulate the mixture obtained in step (2) by wet granulation manually with purified water, pass through a 20-mesh sieve, dry at 60 °C for 2 h, and screen and size the granules through a 20-mesh sieve;

[0213] (3) Final mixing: Mix the granules obtained in step (3) and magnesium stearate evenly by weight percentage;

[0214] (4) Tabletting: Tablet the mixture obtained in step (4), use a 9.5 mm round punch, control the average weight difference within ±3%, and the tablet hardness within 70 N - 80 N to obtain tablets with a tablet weight of 375 mg.

[0215] Results: During the tabletting process of the formulations of Examples 25 - 28, there were no phenomena such as sticking to the punch, adhesion to the punch, powder adhesion, unstable tablet weight, too high or too low tablet hardness, etc. Their compressibility was good.

[0216] In the following Examples 29 - 33, the same or similar preparation methods as those in Examples 25 - 28 were used, different formulation prescriptions were used, and tablets with a tablet weight of 375 mg were obtained.

[0217] Examples 29 - 31

[0218]

[0219]

[0220] Results: During the tabletting process of the formulation of Example 29, there were no phenomena such as sticking to the punch, adhesion to the punch, powder adhesion, unstable tablet weight, too high or too low tablet hardness, etc. Its compressibility was good.

[0221] Compared with Examples 27-28, the main differences in the formulation prescriptions of Examples 30-31 are that the contents of colloidal silicon dioxide as the glidant and magnesium stearate as the lubricant are adjusted respectively. However, during the tabletting process of the formulation prescriptions of Examples 30-31, there are phenomena such as powder adhesion, sticking or picking, and their compressibility is relatively poor.

[0222] Examples 32-33

[0223]

[0224] Results: Compared with Example 25, the main differences in the formulation prescriptions of Examples 32-33 are that the weight ratios of microcrystalline cellulose to D-mannitol as the fillers are adjusted to 5.3:1 and 1:5.3 respectively. However, during the tabletting process of the formulation prescriptions of Examples 32-33, there are lamination phenomena, and their compressibility is relatively poor.

[0225] Example 34

[0226]

[0227]

[0228] Preparation method:

[0229] (1) Premixing 1: Mix API (i.e., (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione), self-made) and microcrystalline cellulose evenly by weight percentage;

[0230] (2) Premixing 2: Add D-mannitol, hydroxypropyl cellulose, cross-linked carboxymethyl cellulose sodium, and colloidal silicon dioxide to the mixture obtained in step (1) and mix evenly by weight percentage;

[0231] (3) Granulation: Granulate the mixture obtained in step (2) manually by wet granulation with purified water, pass through a 20-mesh sieve, dry at 60 °C for 2 h, and screen and size the granules through a 20-mesh sieve;

[0232] (4) Total mixing: Mix the granules obtained in step (3) and magnesium stearate evenly by weight percentage;

[0233] (5) Tabletting: Tablet the mixture obtained in step (4), use a 9.5 mm round punch, control the average weight difference within ±3%, and the tablet hardness is 70 N - 80 N to obtain tablets with a tablet weight of 347.6 mg.

[0234] Result: During the tabletting process of the formulation of Example 34, there were no phenomena such as sticking to the punch, capping, powder adhesion, unstable tablet weight, excessive or insufficient tablet hardness, or lamination. It had good compressibility.

[0235] Example 35

[0236]

[0237] Preparation method:

[0238] (1) Mix the API (i.e., (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione), which was self-prepared and from the same batch as the API in Example 34), D-mannitol, microcrystalline cellulose, and hypromellose evenly by weight percentage;

[0239] (2) Add cross-linked carboxymethyl cellulose sodium and mix it evenly with the mixture obtained in step (1);

[0240] (3) Pass magnesium stearate through a 40-mesh sieve and mix it evenly with the mixture obtained in step (2);

[0241] (4) Tablet the mixture obtained in step (3) using a 10-mm round punch, control the average weight difference within ±3%, and the tablet hardness at 50 - 60 N.

[0242] For the convenience of children's taking, the inventors of the present application also explored the dosage forms and dosages suitable for children, specifically Examples 36 - 37.

[0243] Example 36

[0244] Component Content (g) Content (%) API 6.005 20.32 D-Mannitol 24.349 72.68 Sucrose 1.675 5.00 Ascorbic Acid 0.67 2.00

[0245] Preparation method:

[0246] (1) Mix the API (i.e., (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione) with crystalline form A of fumaric acid and mannitol evenly by weight percentage;

[0247] (2) Add sucrose and ascorbic acid and mix them evenly with the mixture obtained in step (1) by weight percentage;

[0248] (3) Grind the mixture obtained in step (2) into fine powder;

[0249] (4) Pass the fine powder obtained in step (3) through a 120-mesh sieve, and pack it into packaging materials (such as small bags) to obtain powder or dry suspension.

[0250] Example 37

[0251] Component Content (g) Content (%) API 6.005 20.32 Microcrystalline Cellulose 25.094 80.46 Sucrose 0.67 2.00 Ascorbic Acid 0.67 2.00

[0252] Preparation method:

[0253] (1) Mix the API (i.e., (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione), crystalline form A of fumaric acid, and microcrystalline cellulose evenly by weight percentage;

[0254] (2) Add sucrose and ascorbic acid, and mix them evenly with the mixture obtained in step (1);

[0255] (3) Grind the mixture obtained in step (2), and pass it through a 60-mesh sieve;

[0256] (4) Pack the sieved mixture obtained in step (3) into packaging materials (such as gelatin capsules) to obtain capsules.

[0257] Example 38

[0258] 1. In vitro dissolution experiment

[0259] 1.1 The dissolution medium is pH 1.2 + 0.2% Tween 80

[0260] The experimental method is as follows: Use the paddle method, the rotation speed is 75 revolutions per minute, and 900 ml of dissolution medium. Measure the dissolution curves of the products obtained in Examples 1-4 in the dissolution medium, i.e., purified water pH 1.2 + 0.2% Tween 80. Take appropriate amounts of the dissolution solution at 5 min, 10 min, 15 min, 30 min, 45 min, and 60 min respectively, filter, and take the subsequent filtrate as the test solution to measure the in vitro dissolution rate.

[0261] The specific measurement results are shown in the following table:

[0262]

[0263] Conclusion: In the dissolution medium of purified water pH 1.2 + 0.2% Tween 80, the products of Examples 1-4 using crystalline form A have a faster dissolution rate and a higher in vitro dissolution rate, which can meet the dissolution requirements and are suitable for subsequent formulation development.

[0264] 1.2 The dissolution medium is purified water + 0.1% CTAB

[0265] The experimental method is as follows: The paddle method is adopted, with a rotation speed of 75 revolutions per minute and 900 ml of dissolution medium. The dissolution curves of the pharmaceutical compositions obtained in Examples 1, 16, 17, and 24 were respectively determined in the dissolution medium, i.e., purified water + 0.1% CTAB. Appropriate amounts of the dissolution solution were taken at 5 min, 10 min, 15 min, 30 min, 45 min, and 60 min respectively, filtered, and the subsequent filtrate was taken as the test solution for determining the in vitro dissolution rate.

[0266] The specific measurement results are shown in the following table:

[0267]

[0268]

[0269] Conclusion: In the dissolution medium of purified water + 0.1% CTAB, the pharmaceutical compositions prepared in Examples 5 and 24 can reach a dissolution rate of more than 80% within 30 min and more than 90% within 60 min, that is, their dissolution rate is relatively fast and the in vitro dissolution rate is relatively high, which can meet the dissolution requirements. In contrast, the dissolution rate of the pharmaceutical composition prepared in Example 16 still did not reach 60% within 60 min; although the pharmaceutical composition prepared in Example 17 meets the dissolution requirements, its dissolution rate is too fast, reaching more than 80% within 5 min and more than 90% within 10 min.

[0270] 2. Stability experiment

[0271] 2.1 Stability experiment of the crystalline form A of the compound and fumaric acid during the preparation of the preparation

[0272] This study focused on investigating the stability of the crystalline form A of the compound and fumaric acid during the preparation of the preparation in the above-mentioned preparation examples, which was determined by sampling at different time points during the preparation process of the preparation. Specifically, taking Example 2 in the preparation examples as an example, samples were taken before the start of the preparation of the preparation, after step (3) and before step (4) of the preparation of the preparation, and after step (5) of the preparation of the preparation, and the samples were analyzed with an X-ray powder diffractometer PANalytical Empyrean (PANalytical, NL) (where the 2θ scanning angle ranges from 3° to 45°, the scanning step size is 0.013°, and the test time is 5 minutes and 8 seconds; when testing the sample, the tube voltage and current are 45 kV and 40 mA respectively, and the sample disk is a zero-background sample disk).

[0273] Conclusion: The X-ray powder diffraction patterns of the blank excipients, the compound and the crystalline form A of fumaric acid (hereinafter simply referred to as crystalline form A) before the preparation of the preparation, the particles containing the compound and the crystalline form A of fumaric acid obtained in step (3) (hereinafter simply referred to as the preparation intermediate made of crystalline form A), and the tablets containing the compound and the crystalline form A of fumaric acid obtained (hereinafter simply referred to as the preparation made of crystalline form A) indicate that during the preparation process of the preparation, the crystalline form A of the compound and fumaric acid is stable and no crystal transformation occurs. This shows that the compatibility of each excipient component with the crystalline form A of the compound and fumaric acid in the preparation is good, and each excipient component does not affect the stability of the crystalline form A of the compound and fumaric acid during the preparation process.

[0274] 2.2. Stability experiments of the preparation containing the crystalline form A of the compound and fumaric acid

[0275] The products of Examples 1-4 were respectively packaged in oral high-density polyethylene bottles (specification 60 ml), with 1 bag of silica gel desiccant (specification 2.0 g) in solid pharmaceutical paper bags added inside, and then subjected to stress testing to investigate the effects on the content of each component in the product after being placed for 5 days and 10 days under the conditions of light (total illuminance not less than 1.2×10 6 Lux·hr, near-ultraviolet energy not less than 200 w·hr / m 2 ), high temperature (60 °C), and high humidity (92.5% RH, 25 °C).

[0276] Conclusion: Under the stress testing conditions of light (total illuminance not less than 1.2×10 6 Lux·hr, near-ultraviolet energy not less than 200 w·hr / m 2 ), high temperature (60 °C), and high humidity (92.5% RH, 25 °C), the products of Examples 1-4 are relatively stable, and the content of each component (including the crystalline form A of the compound of formula (I) and fumaric acid) is basically unchanged. This indicates that no crystal transformation occurs to the crystalline form A of the compound of formula (I) and fumaric acid in the products of Examples 1-4, and the compatibility between the crystalline form A of the compound of formula (I) and fumaric acid and each excipient is good, making the products of Examples 1-4 relatively stable under the conditions of light, high temperature, and high humidity.

[0277] The drug compositions prepared in representative Examples 5 and 24 were respectively tested using oral high-density polyvinyl chloride bags as the inner packaging to investigate the effects on the content of related substances in the tested drug compositions after being placed in a stability test chamber for 1 month and 3 months under the conditions of 40 °C ± 2 °C and RH 75% ± 5%.

[0278]

[0279] Results: Under the accelerated stability test conditions, there were no obvious changes in the related substances of the pharmaceutical compositions prepared in Examples 5 and 24, meeting the requirements of the quality standards, indicating that the pharmaceutical compositions of the present invention are stable.

[0280] The specific embodiments described above have further elaborated on the purpose, technical solutions, and beneficial effects of the present invention. It should be understood that the above are only specific embodiments of the present invention and are not used to limit the protection scope of the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and gist of the present invention shall be included in the protection scope of the present invention.

Claims

1. A pharmaceutical composition comprising a crystalline form of (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione) and fumaric acid, and a physiologically acceptable / pharmaceutically acceptable excipient, wherein, The crystalline form of (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione) and fumaric acid, using Cu-Kα radiation, the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed as 2θ values ±0.2° include any three of 10.94, 19.06, 23.50, 24.

66. The physiologically acceptable / pharmaceutically acceptable excipients include fillers, disintegrants, lubricants, binders, and glidants. Among them, The weight ratio of the crystalline form of the compound of formula (I) and fumaric acid to the filler is in the range of 1:3 to 3:1; The weight ratio of the disintegrant to the lubricant is in the range of 1:1 to 2:1; The weight ratio of the binder to the lubricant is in the range of 1:1 to 2:1; and, The weight ratio of the glidant to the lubricant is in the range of 1:2 to 2:1; Among them, the filler is a mixture of microcrystalline cellulose and pre-gelatinized starch or a mixture of microcrystalline cellulose and mannitol; the binder is hydroxypropyl cellulose; the disintegrant is croscarmellose sodium; the glidant is colloidal silicon dioxide; the lubricant is magnesium stearate; When the filler is a mixture of microcrystalline cellulose and mannitol, the weight ratio of the two is in the range of 1:5 to 5:1; When the filler is a mixture of microcrystalline cellulose and pre-gelatinized starch, the weight ratio of microcrystalline cellulose to pre-gelatinized starch is in the range of 1.5:1 to 3.5:1; Among them, the weight percentage of the lubricant in the pharmaceutical composition is 1% - 2%.

2. The pharmaceutical composition according to claim 1, characterized in that: The weight percentage of the crystalline form of (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione) and fumaric acid in the pharmaceutical composition is 15 - 60%.

3. The pharmaceutical composition according to claim 1, characterized in that: The weight percentage of the crystalline form of (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione) and fumaric acid in the pharmaceutical composition is 2 - 45%.

4. The pharmaceutical composition according to claim 1, wherein: The crystalline form of (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione) and fumaric acid, using Cu-Kα radiation, the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed as 2θ values ±0.2° also include any one or more of 9.5, 13.81, 18.61, 22.59, 23.

8.

5. The pharmaceutical composition according to claim 2, characterized in that: The crystalline form of (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione) and fumaric acid, using Cu-Kα radiation, the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in 2θ values ±0.2° further include any one or more of 7.81, 10.14, 11.50, 11.93, 12.

31.

6. The pharmaceutical composition according to claim 1, wherein: The mannitol described above is D-mannitol.

7. The pharmaceutical composition according to any one of claims 1-6, characterized in that: The pharmaceutical composition is an oral preparation, or the pharmaceutical composition is in unit dose form.

8. The pharmaceutical composition according to claim 7, characterized in that: When the pharmaceutical composition is an oral preparation, the pharmaceutical composition is an oral solid preparation or an oral liquid preparation.

9. The pharmaceutical composition according to claim 8, wherein: The oral solid preparation is selected from one of tablets, powders, dry suspensions, granules and capsules.

10. The pharmaceutical composition according to claim 8, wherein: The oral liquid preparation is selected from one of solutions, suspensions, syrups and elixirs.

11. The pharmaceutical composition according to claim 7, wherein: When the pharmaceutical composition is in unit dose form, the pharmaceutical composition is a solid preparation in unit dose form or a liquid preparation in unit dose form.

12. The pharmaceutical composition according to claim 11, wherein: The solid preparation in unit dose form is selected from one of tablets, powders, dry suspensions, granules and capsules.

13. The pharmaceutical composition according to claim 11, characterized in that: The liquid preparation in unit dose form is selected from one of solutions, suspensions, syrups, injections and elixirs.

14. The pharmaceutical composition according to claim 7, characterized in that: When the pharmaceutical composition is in unit dose form, the pharmaceutical composition is selected from one of tablets, powders, dry suspensions, capsules, solutions, suspensions and syrups.

15. The pharmaceutical composition according to claim 7, wherein: The pharmaceutical composition is in unit dose form, and each unit dose of the pharmaceutical composition contains the active ingredient, and the crystalline form of (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione) and fumaric acid is 1 - 500 mg.

16. The pharmaceutical composition according to claim 15, wherein: Each unit dose of the pharmaceutical composition contains 10 - 300 mg of the active ingredient.

17. The pharmaceutical composition according to claim 15, wherein: Each unit dose of the pharmaceutical composition contains 50 - 200 mg of the active ingredient.

18. A method for preparing a pharmaceutical composition according to any one of claims 1-17, characterized in that: It includes the following steps: Premixing, granulating and / or total mixing.

19. According to the preparation method described in claim 18, characterized in that: It includes the following steps: (i) Premixing: Mixing the crystalline form of (6E)-6-[(6-chloro-2-methyl-2H-indazol-5-yl)imino]-3-[(1-methyl-1H-1,2,4-triazol-3-yl)methyl]-1-[(2,4,5-trifluorophenyl)methyl]-1,3,5-triazine-2,4-dione) and fumaric acid with a physiologically acceptable / pharmaceutically acceptable excipient; (ii) Granulating: Granulating the mixture obtained in step (i) and sieving. (iii) Total mixing: Mix the granules obtained in step (ii) with one or more other physiologically acceptable / pharmaceutically acceptable excipients other than the physiologically acceptable / pharmaceutically acceptable excipients described in step (i).

20. The preparation method according to claim 18 or 19, characterized in that: The granulation described is dry granulation or wet granulation.

21. Use of a pharmaceutical composition according to any one of claims 1-17 in the preparation of a medicament for treating or preventing a disease caused by novel coronavirus in a subject, characterized in that: The subject is a human.

22. The use according to claim 21, characterized in that: The subject is selected from one of the following: children, adults aged 19 - 59 years, and the elderly aged 60 years and above.

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