Crystal form of compound and fumaric acid, pharmaceutical composition and method for treating coronavirus-induced diseases

Abstract

To provide a crystal form of a compound and fumaric acid, an active pharmaceutical ingredient and a pharmaceutical composition containing the same, and a method for treating coronavirus-induced diseases using the same.SOLUTION: A crystal form of this invention includes a compound of formula (I) and fumaric acid, and has a specific X-ray powder diffraction pattern. The inventive crystal form is characterized by high purity, excellent stability, and a high melting point.SELECTED DRAWING: None

Description

[Technical field]

[0001]

[0001] The present invention relates to the medical field, specifically to certain compounds and crystalline forms of fumaric acid, active pharmaceutical ingredients and pharmaceutical compositions comprising same, and / or methods for treating coronavirus-induced diseases using same.

[0002] [Background technology] Due to the outbreak of Severe Acute Respiratory Syndrome (SARS) in 2003 and Middle East Respiratory Syndrome (MERS) in 2012, coronaviruses have become a research hotspot in the field of virology. Coronavirus disease 2019 (COVID-19) is a novel acute respiratory infectious disease caused by SARS-CoV-2 (also known as 2019-nCoV), which has caused more than 200 million infections and over 4 million deaths since its outbreak in December 2019, and has now become a major public health event worldwide, greatly affecting the society and economy of the world. In light of the severe situation of the epidemic, practical and effective treatment methods are urgently needed.

[0003]

[0003] Some compounds with therapeutic potential for diseases caused by coronaviruses (especially 2019-nCoV) have been invented in the art. However, at the current stage, pharmaceutical compositions for the treatment of diseases caused by coronaviruses (especially 2019-nCoV) are needed to meet the urgent needs of clinical treatment.

[0004] Summary of the Invention

[0004] In order to solve the above problems, the present invention provides a technical solution for solving the above problems. In the first aspect of the present invention, a crystalline form of the compound of formula (I) and fumaric acid is provided. That is, the first aspect of the present invention provides a crystalline form comprising the compound of formula (I) and fumaric acid, characterized in that the X-ray powder diffraction pattern of the crystalline form obtained using Cu-Kα radiation includes at least three peaks selected from the group consisting of 10.94°±0.2°2θ, 19.06°±0.2°2θ, 23.50°±0.2°2θ, and 24.66°±0.2°2θ. JPEG2024045113000001.jpg54170

[0005]

[0006] In a second aspect of the present invention, the present invention provides an active pharmaceutical ingredient comprising a crystalline form of the first aspect, which satisfies at least one of the following conditions: (1) the particle size D of the active pharmaceutical ingredient is 90 (2) the particle size D of the active pharmaceutical ingredient is about 5 μm to about 60 μm; 50 does not exceed about 30 μm.

[0006]

[0007] In a third aspect of the present invention, the present invention provides a pharmaceutical composition comprising an active ingredient, which is the crystalline form of the first aspect, a mixture of crystalline and amorphous forms of the compound of formula (I) and fumaric acid, or an active pharmaceutical ingredient of the second aspect, and a physiologically or pharma- ceutical acceptable excipient comprising one or more selected from the group consisting of fillers, disintegrants, lubricants, binders, and glidants.

[0007]

[0008] In a fourth aspect of the invention, the present invention provides a method for treating a coronavirus-induced disease comprising administering to a subject a pharmaceutical composition of the third aspect.

[0008]

[0009] The crystalline form of the compound of formula (I) and fumaric acid of the present invention has high purity (>98 area% HPLC), good stability (including stability under light irradiation conditions, stability under high temperature and humidity, and stability in accelerated stability tests), and high melting point. Therefore, the active pharmaceutical ingredient containing the crystalline form of the present invention is advantageous for storage and quality control at room temperature, can effectively extend the shelf life of the drug containing it, and can meet the pharmaceutical requirements for production, processing, transportation, and storage.

[0009]

[0010] The inventors have also found through creative research that the pharmaceutical composition described herein has the function of inhibiting coronaviruses, particularly 2019-nCoV, and has potential therapeutic effects in treating diseases caused by 2019-nCoV. Furthermore, the pharmaceutical compounds of the present invention have high solubility, high dissolution rate, and / or high stability. The pharmaceutical composition of the present invention is also suitable for preparing oral formulations, particularly oral solid formulations such as tablets, and is suitable for industrialized large-scale production, and the resulting products have stable and reliable quality and good clinical application value.

[0011] Additional aspects and advantages of the invention will be set forth in part in the description that follows, and in part will be obvious from the description, or may be learned by practice of the invention. [Brief description of the drawings]

[0010] [Figure 1]

[0012] FIG. 1 shows the differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) spectra of the compound of formula (I) and crystalline form A of fumaric acid. [Diagram 2]

[0013] FIG. 2 shows the dynamic vapor sorption (DVS) spectra of the compound of formula (I) and crystalline form A of fumaric acid. [Diagram 3]

[0014] FIG. 3 is a comparison of the X-ray powder diffraction (XRPD) patterns of the compound of formula (I) and the compound with fumaric acid before and after the DVS experiment. [Figure 4]

[0015] FIG. 4 shows a polarized light microscope (PLM) image of active pharmaceutical ingredient (API) 6, which comprises a crystal of the compound of formula (I) and fumaric acid, prepared in accordance with one embodiment of the present invention. [Diagram 5]

[0016] FIG. 5 is a particle size distribution diagram of active pharmaceutical ingredient (API) 5 comprising crystalline form A of the compound of formula (I) and fumaric acid prepared in an example of the present invention, having a D50 of 18.6 μm and a D90 of 34.2 μm. [Figure 6]

[0017] FIG. 6 shows the powder adhesion phenomenon that occurs during tableting of the formulation of Example VI-16. [Figure 7]

[0018] FIG. 7 shows the tablet capping phenomenon occurring during the tableting process of the formulation of Example VI-18.

[0011] DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0019] The technical solutions in the embodiments of the present invention are described clearly and completely with reference to the accompanying drawings in the examples of the present invention. The described embodiments should not be considered as the limitations of the present invention, and all other embodiments obtained by those skilled in the art without creative work fall within the protection scope of the present invention.

[0012]

[0020] Unless otherwise defined, all terms used herein have the same meaning as commonly understood by those skilled in the art to which the present invention belongs. The terms used herein are only for describing the embodiments of the present invention and are not intended to limit the present invention. Before further detailed description of the embodiments of the present invention, the nouns and terms contained in the embodiments of the present invention will be explained. The following explanation applies to the nouns and terms contained in the embodiments of the present invention.

[0013]

[0021] Unless otherwise stated, numerical ranges throughout this specification include any subranges therein and any numerical value incremented by the smallest subunit of the value given therein. Unless otherwise stated, numerical values ​​throughout this specification represent approximate dimensions or limits of the range of embodiments having values ​​approximately recited, including minor deviations from the values ​​given, and having the exact values ​​recited. Except for the examples provided at the end of the detailed description, all numerical values ​​of parameters (e.g., amounts or conditions) in this specification (including the appended claims) should be understood as being modified by the term "about", regardless of whether the term "about" is actually present before the value. "About" means that the value specified allows for some imprecision (some approximation within the value; approximately or reasonably close to the value). If the imprecision provided by the term "about" is not understood as its ordinary meaning in the art, "about" as used herein represents at least the variation that can be made by ordinary methods for measuring and using these parameters. For example, the term "about" generally refers to + / -10% of the stated value, e.g., + / -5%, + / -4%, + / -3%, + / -2%, + / -1%, or + / -0.5% of the stated value.

[0014]

[0022] In the present invention, relative humidity is represented by RH and means the ratio of the amount of water vapor (water vapor partial pressure) in a gas (normal air) to the amount of water vapor saturated with water vapor (saturated water vapor pressure) in the same air at the same temperature.

[0015]

[0023] The term "physiologically or pharma- ceutically acceptable excipient" as used herein refers to an excipient that is not significantly irritating to an organism and does not inhibit the biological activity and properties of the administered active ingredient, such as the compounds of the present invention and crystalline forms of fumaric acid.

[0016]

[0024] The physiologically acceptable or pharma-ceutically acceptable excipients that are mixed with the compounds of the present invention and the crystalline form of fumaric acid to form a pharmaceutical composition may depend on the intended route of administration of the pharmaceutical composition.

[0017]

[0025] The compounds of the present invention and the crystalline forms of fumaric acid may have systemic and / or local activity.To this end, they may be administered in any suitable manner, for example, orally, parenterally, pulmonary, nasal, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, or auricular, or by implants or stents.

[0018]

[0026] In these administration routes, the compounds of the present invention and the crystalline forms of fumaric acid can be administered in appropriate dosage forms.

[0019]

[0027] For example, for oral administration, the compounds of the invention and crystalline forms of fumaric acid can be prepared in dosage forms known in the art for rapid and / or sustained release administration, such as tablets (e.g., uncoated or coated tablets with enteric or controlled release coatings having delayed dissolution or solubility), orally disintegrating tablets, wafers, lyophilisates, capsules (e.g., hard or soft gelatin capsules), sugar-coated tablets, granules, pills, powders, emulsions, suspensions, aerosols, or solutions. According to embodiments of the invention, the compounds of the invention and crystalline forms of fumaric acid may be incorporated into the dosage form in crystalline form and / or mixtures of crystalline and amorphous forms and / or in dissolved form.

[0020]

[0028] According to embodiments of the present invention, parenteral administration can be achieved by an absorption-avoiding step (e.g., intravenous, intraarterial, intracardiac, intrathecal, or intralumbar administration) or an absorption-containing step (e.g., intramuscular, subcutaneous, intradermal, transdermal, or intraperitoneal administration). Suitable dosage forms for parenteral administration are injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates, or sterile powders.

[0021]

[0029] The term "subject" as used herein refers to an animal, including, but not limited to, a primate (e.g., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. Specifically, the subject is 0 years of age or older, 1 year of age or older, 2 years of age or older, 4 years of age or older, 5 years of age or older, 10 years of age or older, 12 years of age or older, 13 years of age or older, 15 years of age or older, 16 years of age or older, 18 years of age or older, 20 years of age or older, 25 years of age or older, 30 years of age or older, 35 years of age or older, 40 years of age or older, 45 years of age or older, 50 years of age or older, 55 years of age or older, 60 years of age or older, 65 years of age or older, 70 years of age or older, 75 years of age or older, 80 years of age or older, 85 years of age or older, 90 years of age or older, 95 years of age or older, 100 years of age or older, or 105 years of age or older.

[0022]

[0030] The term "coronavirus" as used in the present invention belongs to the genus Coronavirus in the Coronaviridae family. A variant of coronavirus is the pathogen that causes SARS. Coronaviruses include, but are not limited to, the 2019 novel coronavirus (2019-nCoV or SARS-CoV-2, which caused the novel coronavirus pneumonia COVID-19), HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, which caused Severe Acute Respiratory Syndrome, and MERS-CoV, which caused Middle East Respiratory Syndrome. Diseases caused by coronaviruses are primarily respiratory infections, including Severe Acute Respiratory Syndrome (SARS).

[0023]

[0031] In the present invention, "2019-nCoV" refers to SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) published by the International Committee on Taxonomy of Viruses in February 2020. In the present disclosure, SARS-CoV-2 is synonymous with 2019-nCoV, and also includes all variants of 2019-nCoV, such as all variants included in NCBI or GISAID (Global Initiative for Sharing Influenza Data), including, in particular, variants of interest with enhanced infectivity, pathogenicity or immune evasion, such as WHO-designated alpha, beta, gamma, delta, eta, iota, kappa, or lambda variants, and subsequently designated variants of interest.

[0024]

[0032] By "free base form of active ingredient" in the present invention is meant the compound of formula (I) described in the present invention. In the present invention, the compound of formula (I) is a compound having the following structure: JPEG2024045113000002.jpg43170, that is, (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.

[0025]

[0034] Depending on their structure, the compounds of the present invention may exist in isomeric forms, such as stereoisomers (enantiomers, diastereomers).The present invention therefore relates to the enantiomers or diastereomers and to their respective mixtures.Stereoisomerically pure components can be separated from such enantiomeric and / or diastereomeric mixtures in known manner.

[0026]

[0035] When the compounds of the present invention exist as optical isomers, the pharmaceutical compositions provided herein will generally contain the optical isomer in substantially pure form.

[0036] The present invention covers all tautomeric forms of the compounds.

[0027]

[0037] The compounds of the present invention may also exist in free form, for example as free bases or free acids or zwitterions, or in the form of salts, which may be any salt commonly used pharmacy, organic or inorganic addition salts, in particular any physiologically acceptable organic or inorganic addition salts.

[0028]

[0038] For the purposes of the present invention, the term "solvate" refers to the form of a complex of a compound formed with a solvent molecule by coordination in solid or liquid state. Hydrates are a special form of solvate in which a compound is coordinated with water. Within the scope of the present invention, hydrates are preferred solvates.

[0029]

[0039] The present invention also includes all suitable isotopic variations of the compounds of the present invention.Isotopic variations 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 found in nature.Isotopes that can be incorporated into the compounds of the present invention include, for example, 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. Specific isotopic variations of the compounds of the present invention (e.g., 3 H or 14 C) are useful for drug and / or matrix tissue distribution studies. Tritium labels and carbon-14 (i.e., 14C) isotopes are particularly preferred due to their ease of preparation and detectability.In addition, substitution with isotopes such as deuterium provides certain therapeutic advantages due to greater metabolic stability, such as increased half-life in vivo or reduced dose requirement, and is therefore preferred in certain circumstances.Isotopic modifications of the compounds described in the present invention can generally be prepared by conventional procedures known to those skilled in the art using appropriate isotopic modifications of suitable reagents.

[0030] Crystal form

[0040] Unless otherwise specified, in the present invention, the crystalline form consisting of the compound of formula (I) and fumaric acid is also referred to as "crystalline form A of the compound of formula (I) and fumaric acid" or "crystalline form of the compound of formula (I) and fumaric acid". Note that the expression "comprising the compound of formula (I) and fumaric acid" used in this specification does not limit the form of existence of the compound of formula (I) and fumaric acid in any way. The compound of formula (I) and fumaric acid can be bonded in the form of a non-covalent bond, such as an ionic bond, van der Waals force, or π-π stacking interaction, or in the form of a covalent bond through a bonding force such as a hydrogen bond.

[0041] In a first aspect, the present invention provides the following embodiments and any combination thereof:

[0031]

[0042] According to one embodiment of the present invention, the crystalline form of the compound of formula (I) and fumaric acid may be anhydrate or hydrate (e.g., may have one or two water molecules of crystallization).

[0032]

[0043] The X-ray powder diffraction patterns (expressed as 2θ values ​​±0.2°) of the compound of formula (I) and the crystalline form of fumaric acid obtained using Cu-Kα radiation contain any three characteristic diffraction peaks selected from the group consisting of 10.94, 19.06, 23.50 and 24.66. According to one embodiment of the present invention, the X-ray powder diffraction pattern (expressed as 2θ values ​​±0.2°) of the compound of formula (I) and the crystalline form of fumaric acid obtained using Cu-Kα radiation further comprises any one or more characteristic diffraction peaks selected from the group consisting of 9.5, 13.81, 18.61, 22.59 and 23.8, preferably any one or more characteristic diffraction peaks selected from the group consisting of 7.81, 10.14, 11.50, 11.93 and 12.31, preferably any one or more characteristic diffraction peaks selected from the group consisting of 14.73, 20.87, 21.49, 21.97 and 25.39, more preferably any one or more characteristic diffraction peaks selected from the group consisting of 10.94, 19.06, 23.50, 24.66, 9.5, 13.81, 18.61, 22.59 and 23.8.

[0033]

[0044] That is, the X-ray powder diffraction pattern of the crystalline form obtained using Cu-Kα radiation contains at least three characteristic diffraction peaks selected from the group consisting of 10.94°±0.2°2θ, 19.06°±0.2°2θ, 23.50°±0.2°2θ, and 24.66°±0.2°2θ. According to one embodiment of the present invention, the X-ray powder diffraction pattern further contains at least one characteristic diffraction peak selected from the group consisting of 9.5°±0.2°2θ, 13.81°±0.2°2θ, 18.61°±0.2°2θ, 22.59°±0.2°2θ, and 23.8°±0.2°2θ. According to one embodiment of the invention, the X-ray powder diffraction pattern further comprises at least one characteristic diffraction peak selected from the group consisting of 7.81°±0.2°2θ, 10.14°±0.2°2θ, 11.50°±0.2°2θ, 11.93°±0.2°2θ, and 12.31°±0.2°2θ. According to one embodiment of the invention, the X-ray powder diffraction pattern of the crystalline form further comprises at least one characteristic diffraction peak selected from the group consisting of 14.73°±0.2°2θ, 20.87°±0.2°2θ, 21.49°±0.2°2θ, 21.97°±0.2°2θ, and 25.39°±0.2°2θ. According to one embodiment of the invention, the X-ray powder diffraction pattern may be 10.94°±0.2°2θ, 19.06°±0.2°2θ, 23.50°±0.2°2θ, 24.66°±0.2°2θ, 9.5°±0.2°2θ, 13.81°±0.2°2θ, 18.61°±0.2°2θ, 22.59°±0.2°2θ, 23.8°±0.2°2θ, 7.81°±0.2°2θ , 10.14°±0.2°2θ, 11.50°±0.2°2θ, 11.93°±0.2°2θ, 12.31°±0.2°2θ, 14.73°±0.2°2θ, 20.87°±0.2°2θ, 21.49°±0.2°2θ, 21.97°±0.2°2θ, and 25.39°±0.2°2θ.According to one embodiment of the invention, the X-ray powder diffraction pattern includes the following characteristic diffraction peaks: 10.94°±0.2°2θ, 19.06°±0.2°2θ, 23.50°±0.2°2θ, 24.66°±0.2°2θ, 9.5°±0.2°2θ, 13.81°±0.2°2θ, 18.61°±0.2°2θ, 22.59°±0.2°2θ, and 23.8°±0.2°2θ. According to one embodiment of the invention, the X-ray powder diffraction pattern includes the following characteristic diffraction peaks: 5.98°±0.2°2θ, 7.81°±0.2°2θ, 9.50°±0.2°2θ, 10.14°±0.2°2θ, 10.94°±0.2°2θ, 11.50°±0.2°2θ, 11.93°±0.2°2θ, 12.31°±0.2°2θ, 13.35°±0.2°2θ, 13.81°±0.2°2θ, 14.73°±0.2°2θ, 15.13°±0.2°2θ, 15.59°±0.2°2θ, 16.35°±0.2°2θ, 17.09°±0.2°2θ, 17.57°±0. 2°2θ, 17.94°±0.2°2θ, 18.07°±0.2°2θ, 18.61°±0.2°2θ, 19.06°±0.2°2θ, 19. 49°±0.2°2θ, 19.82°±0.2°2θ, 20.33°±0.2°2θ, 20.87°±0.2°2θ, 21.49°±0.2°2 θ, 21.71°±0.2°2θ, 21.97°±0.2°2θ, 22.59°±0.2°2θ, 23.01°±0.2°2θ, 23.50°± 0.2°2θ, 23.80°±0.2°2θ, 24.66°±0.2°2θ, 25.39°±0.2°2θ and 25.70°±0.2°2θ.

[0034]

[0045] According to one or more embodiments of the present invention, the crystalline form of the compound of formula (I) and fumaric acid has a 2θ scan angle of 3° to 45°, a scan step of 0.013°, a test time of 5 minutes and 8 seconds, a phototube voltage and current during the test of 45 kV and 40 mA, respectively, and a zero background sample pan. Specifically, the characteristic peaks of the X-ray powder diffraction pattern, expressed as 2θ values ​​of ±0.2°, irradiated with Cu-Kα radiation, are shown in the following table.

[0035]

[0046] XRPD Diffraction Peak Data of Crystalline Form A of the Compound of Formula (I) with Fumaric Acid JPEG2024045113000003.jpg243170JPEG2024045113000004.jpg128170

[0036]

[0047] According to one embodiment of the present invention, the differential scanning calorimetry spectrum of the crystalline form of the compound of formula (I) and fumaric acid has an endothermic peak at 274°C±2°C. More preferably, the differential scanning calorimetry spectrum is as shown in Figure 1. The thermogravimetric analysis spectrum of the crystalline form of the compound of formula (I) and fumaric acid shows that the crystalline form has essentially no weight loss or less than 0.5% weight loss during heating to 150°C±2°C, and the crystalline form decomposes at 240°C±2°C. More preferably, the thermogravimetric analysis spectrum is as shown in Figure 1.

[0037]

[0048] According to one embodiment of the present invention, in the crystalline form, the molar ratio of the compound of formula (I) to fumaric acid is about 1:1.

[0038]

[0049] According to one embodiment of the present invention, the HPLC purity of the compound of formula (I) of the present invention and the crystalline form of fumaric acid is 98% or more, preferably 98.5% or more, more preferably 99% or more, more preferably 99.95% or more, and the maximum content of a single impurity in this crystalline form does not exceed 0.1%. Unless otherwise specified, the term "purity" or "impurity content" used herein refers to the purity rate of the main peak or impurity peak calculated by peak area normalization using the analysis result of the test sample by high performance liquid chromatography.

[0039]

[0050] According to one embodiment of the present invention, in the crystalline form, the compound of formula (I) and fumaric acid may be present in the form of a co-crystal of both, or in the form of two salts, i.e., a co-crystal of the compound of formula (I) and fumaric acid, or a fumarate salt of the compound of formula (I). Active Pharmaceutical Ingredients

[0040]

[0051] In a second aspect, the present invention provides the following embodiments and / or any combination thereof:

[0041]

[0052] In a second aspect of the present invention, there is provided an active pharmaceutical ingredient (API) comprising the crystalline form described in the first aspect, i.e. a crystalline form of the compound of formula (I) and fumaric acid.

[0042]

[0053] An "active pharmaceutical ingredient" is a raw drug substance used in the preparation of various preparations. It is the active ingredient in the preparation and is in the form of powder, crystals, etc., prepared by chemical synthesis or biotechnology techniques for pharmaceutical use, but cannot be directly ingested by the subject.

[0043]

[0054] According to one embodiment of the present invention, the API satisfies at least one of the following conditions: (1) the particle size D of the API 90 (2) the particle size D of the API is about 5 μm to about 60 μm; 50 In certain embodiments of the present invention, the particle size D of the API is 90 is about 5 μm to about 60 μm (e.g., 10 μm to 40 μm), and the particle size D of the API 50 is about 30 μm or less (eg, about 20 μm or less).

[0044]

[0055] According to one embodiment of the present invention, the particle size D of the API 90 is approximately 10 μm or more.

[0045]

[0056] According to one embodiment of the present invention, the particle size D 90 of the API is in the range of about 10 μm to 40 μm.

[0046]

[0057] According to one embodiment of the present invention, the particle size D of the API 50 is approximately 5 μm or more.

[0047]

[0058] According to one embodiment of the present invention, the particle size D of the API 50 is approximately 20 μm or less.

[0048]

[0059] The inventor, through creative research, 50 and / or D. 90 It has been found that an API of the present invention within the range of D ) has a higher dissolution rate and higher solubility in a pharmaceutical composition containing the API. Furthermore, when the pharmaceutical composition of the present invention is in tablet form and the excipients are the same, it is possible to obtain a pharmaceutical composition having a particular particle size (e.g., D 50 and / or D. 90 An API of the present invention within the above range can enable tablets to have acceptable friability and not experience significant sticking or picking phenomena during tablet manufacture (e.g., tableting).

[0049] Pharmaceutical Compositions

[0060] In a third aspect, the present invention provides the following embodiments and / or any combination thereof:

[0050]

[0061] In a third aspect of the present invention, the present invention provides a pharmaceutical composition comprising an active ingredient, which is a crystalline form of the first aspect (i.e. crystalline form A of the compound of formula (I) and fumaric acid) or a mixture of crystalline and amorphous forms of the compound of formula (I) and fumaric acid, or an active pharmaceutical ingredient (API) of the second aspect; and a physiologically or pharma- ceutical acceptable excipient.

[0051]

[0062] According to one embodiment of the invention, the pharmaceutical composition consists of an active ingredient (eg, a crystalline form of the first aspect or an API of the second aspect) and a physiologically or pharma- ceutical acceptable excipient.

[0052]

[0063] According to one embodiment of the present invention, the physiologically or pharma- ceutical acceptable excipient comprises one or more selected from the group consisting of a filler, a disintegrant, a lubricant, a binder, and a glidant.

[0053]

[0064] The pharmaceutical composition of the present invention is preferably a solid formulation.

[0054]

[0065] The pharmaceutical compositions of the present invention may be formulated in a form suitable for oral, inhaled, topical, nasal, rectal, transdermal, or injectable administration.

[0055]

[0066] The pharmaceutical composition of the present invention can be administered orally.

[0056]

[0067] The pharmaceutical composition of the present invention is preferably prepared in the form of an oral preparation. The shape of the oral preparation is not particularly limited and may be any of a circle, a small capsule, a donut, a rectangle, etc.

[0057]

[0068] Examples of solid preparations include tablets, capsules, powders, granules, lozenges, etc.

[0058]

[0069] The solid preparation may be coated with a coating agent, may have a label and letters for identification, and may have a broken line for division. Coating is carried out by adding a conventional coating medium and a film-forming agent (generally collectively referred to as a coating material) well known to those skilled in the art. Coating can be carried out using, for example, a sugar-coated substrate, a water-soluble film-coated substrate, an enteric film-coated substrate, a sustained-release film-coated substrate, etc. As the sugar-coated substrate, a combination of sucrose and one or more substances selected from the group consisting of talc, precipitated calcium carbonate, gelatin, acacia, amylopectin, carnauba wax, etc. can be used. As the water-soluble film-coated substrate, for example, the following can be used: cellulose-based polymers such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, methylhydroxyethyl cellulose, etc. can be used; synthetic polymers such as polyvinyl acetal diethylamino acetate, aminoalkyl methacrylate copolymer E [EudragitE (trade name)], polyvinyl pyrrolidone, etc. can be used; polysaccharides such as amylopectin can be used. Examples of the enteric film coating substrate include cellulose polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; acrylic polymers such as methacrylic acid copolymer L [Eudragit L (trade name)], methacrylic acid copolymer LD [Eudragit L-30D55 ​​(trade name)], and methacrylic acid copolymer S [Eudragit S (trade name)]; and natural products such as shellac. Examples of the sustained release film coating substrate include cellulose polymers such as ethyl cellulose and cellulose acetate; and acrylic polymers such as aminoalkyl methacrylate copolymer RS ​​[Eudragit RS (trade name)] and ethyl acrylate-methyl methacrylate copolymer suspension [Eudragit NE (trade name)].Two or more of the above coating substrates can be mixed in an appropriate ratio for use. In addition, coating additives can be used in the coating. Examples of coating additives include: optical masking agents and / or colorants such as titanium oxide, talc, and iron oxide; plasticizers such as polyethylene glycol, triethyl citrate, castor oil, and polysorbate; and organic acids such as citric acid, tartaric acid, malic acid, and ascorbic acid.

[0059]

[0070] Solid dosage forms can be formulated for immediate and / or modified release. Examples of modified release include delayed, sustained, pulsed, controlled, targeted, and programmed release.

[0060]

[0071] When the solid formulation is a tablet, any pharma- ceutically acceptable excipient generally used in the manufacture of solid formulations can be used. Tablets can be prepared by compression or molding, optionally with one or more physiologically or pharma- ceutically acceptable excipients. Compressed tablets can also be prepared by compressing the active ingredient in a free-flowing form (e.g., powder or capsule), which is optionally mixed with a binder, lubricant, filler, solubilizer, or disintegrant. Molded tablets can be prepared by molding a mixture of moistened powdered compounds with an inert liquid dispersion medium in a suitable machine. Tablets can be optionally coated or scored, and can be formulated to provide sustained or controlled release of the active ingredient therein. Tablet formulations are described in detail in Pharmaceutical Dosage Forms: Tablets, Vol. 1 by H. Lieberman and L. Lachman, Marcel Dekker, NY, 1980.

[0061]

[0072] When the solid formulation is a capsule, any conventional encapsulation is suitable, for example, using the above-mentioned carrier in a hard gelatin capsule.When the composition is in the form of a soft gelatin capsule, any physiologically or pharma- ceutically acceptable excipient that is generally used in the preparation of a dispersion or suspension can be considered and incorporated into the soft gelatin capsule.

[0062]

[0073] The preparation can be conveniently presented in the form of unit dose, and can be prepared by any method well known in the pharmaceutical field, so that the unit dose can be administered to the subject.Preferably, the pharmaceutical composition is in the form of unit dose, for example, the solid preparation (for example, tablet, powder, dry suspension, granule, or capsule) in the form of unit dose.

[0063]

[0074] The term "starch" generally refers to the compound having the empirical formula (CH 10 O5) n It is a substance with molecular weights of 50,000-160,000 (n in the range of 300-1000) and 50,000-160,000, and consists of the polysaccharides amylose and amylopectin based on α-glucose units. Starch is derived from plant materials and typically exists in the form of very small particles (diameter 5 μm-25 μm) consisting of lamellar layers of starch molecules formed around a nucleus. Starch particles can be round, elliptical or angular and consist of radioactive crystalline aggregates of two anhydrous D-glucose polymers (amylose and amylopectin). Amylose is a linear polymer of several hundred glucose units linked by α-1,4 glycosidic bonds. Amylopectin is a branched polymer of several thousand glucose units with α-1,6 glycosidic bonds at the branching sites and α-1,4 bonds in the linear region. One branch can have 20-30 glucose residues. In particular, the starch is chosen from starches with an amylose content of 10-40% by weight. Typical examples are corn starch, potato starch, rice starch, tapioca starch and wheat starch.

[0064]

[0075] The term "pregelatinized starch" is intended to define a chemically and / or mechanically treated starch that breaks down all or part of the particles in the presence of water and then dries. Some types of pregelatinized starch can be modified to have improved compressibility and flow characteristics. A typical pregelatinized starch contains 5% free amylose, 15% free amylopectin, and 80% unmodified starch. The pregelatinized starch can be corn starch that has been chemically and / or mechanically treated as described above. Other types of starches than corn starch, such as rice or potato starch, can be pregelatinized.

[0065]

[0076] According to one embodiment of the present invention, the pharmaceutical composition contains 15% by weight to 60% by weight (e.g., 25% by weight to 45% by weight) or 2% by weight to 45% by weight (e.g., 5% by weight to 29% by weight or 30% by weight to 44% by weight) of an active ingredient based on the total weight of the pharmaceutical composition. Specifically, the weight percentage of the active ingredient in the pharmaceutical composition is 2%, 3%, 4%, 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%, 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%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 1 %, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 40.64%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, or 60%.

[0066]

[0077] According to one embodiment of the present invention, the physiologically or pharma- ceutically acceptable excipient comprises one or more selected from the group consisting of a filler, a disintegrant, a lubricant, a binder, and a lubricant. Specifically, the physiologically or pharma-ceutically acceptable excipient is one or more selected from the group consisting of a filler, a disintegrant, a lubricant, a binder, and a lubricant. More specifically, the physiologically or pharma-ceutically acceptable excipient is one or more selected from the group consisting of a filler, a disintegrant, a lubricant, a binder, and a lubricant.

[0067]

[0078] According to one embodiment of the present invention, the weight ratio of active ingredient to filler is in the range of 1:5 to 1:1 (e.g., in the range of 1:2 to 1:1), or in the range of 1:3 to 3:1 (e.g., in the range of 1:2 to 2:1, specifically in the range of 1:1 to 1:1.5).

[0068]

[0079] According to one embodiment of the present invention, the weight ratio of disintegrant to lubricant is in the range of 1:4 to 4:1, specifically in the range of 1:2 to 2:1, more specifically in the range of 1:1 to 2:1, and even more specifically in the range of 1:0.8 to 1:0.7.

[0069]

[0080] According to one embodiment of the present invention, the weight ratio of the lubricant to the lubricant is in the range of 1:3 to 3:1 (e.g., in the range of 1:2 to 2:1, specifically, in the range of 1:1 to 2:1, more specifically, in the range of 1:1 to 1.5:1, and more specifically, in the range of 1:0.8 to 1:0.7).

[0070]

[0081] According to one embodiment of the present invention, the weight ratio of binder to lubricant is in the range of 1:3 to 3:1, specifically in the range of 1:2 to 2:1, specifically 1:1.

[0071]

[0082] According to one embodiment of the present invention, the weight percentage of the filler in the pharmaceutical composition is in the range of 10% to 80%, further 30% to 70%, preferably 30% to 65%, or 40% to 60%, for example, 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%, 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%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 10 ... %, 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%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, or 80%.

[0072]

[0083] Alternatively, the content of the filler in the pharmaceutical composition (e.g., a pharmaceutical composition in unit dose form) is in the range of 110 mg-265 mg, preferably 130 mg-245 mg, e.g., 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.

[0073]

[0084] According to one embodiment of the present invention, the filler comprises one or more selected from the group consisting of lactose, anhydrous calcium bicarbonate, sugar alcohol, cellulose, or starch. The sugar alcohol as the filler comprises, for example, one or more selected from the group consisting of mannitol, maltitol, erythritol, lactitol, sorbitol, and xylitol. The cellulose as the filler comprises, for example, one or more selected from the group consisting of microcrystalline cellulose, powdered cellulose, and silicified microcrystalline cellulose. For example, the starch as the filler comprises one or more of corn starch, potato starch, sweet potato starch, and pregelatinized starch, preferably pregelatinized starch.

[0074]

[0085] Specifically, the filler is one or more selected from the group consisting of lactose, anhydrous calcium bicarbonate, sugar alcohol, cellulose, and starch. The sugar alcohol as the filler is, for example, one or more selected from the group consisting of mannitol, maltitol, erythritol, lactitol, sorbitol, and xylitol, and is preferably mannitol. The cellulose as the filler is, for example, one or more selected from the group consisting of microcrystalline cellulose, powdered cellulose, and silicified microcrystalline cellulose, and is preferably microcrystalline cellulose and / or microcrystalline cellulose. The starch as the filler is, for example, one or more selected from the group consisting of corn starch, potato starch, sweet potato starch, and pregelatinized starch, and is preferably pregelatinized starch.

[0075]

[0086] According to one embodiment of the present invention, the filler is microcrystalline cellulose, pregelatinized starch, lactose, mannitol (such as D-mannitol), or a mixture of two or more (for example, 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, 3:1, or 3.1:1; 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 1:3.5 to 3.5:1, 3.1:1, or 3.2:1. In the pharmaceutical composition of the present invention, if the weight ratio of the above two fillers (for example, in a mixture of microcrystalline cellulose and pregelatinized starch, or in a mixture of microcrystalline cellulose and mannitol (such as D-mannitol)) is below or above the above range, there will be a capping phenomenon during the preparation (tabletting, etc.) of the pharmaceutical composition, which does not meet pharmaceutical requirements.

[0076]

[0087] According to one embodiment of the present invention, the weight percentage of the disintegrant in the pharmaceutical composition is in the range of 1%-10%, specifically 1%-5%, for example 2%, 3%, or 4%. In the pharmaceutical composition of the present invention, the amount of disintegrant should not be too small or too large. If the amount of disintegrant is too small (e.g., its weight percentage in the pharmaceutical composition is less than 1%), the dissolution rate of the active ingredient is too low, so that the dissolution within 60 minutes (if it has not yet reached 60%) cannot meet the pharmaceutical requirements; if the amount is too large (e.g., its weight percentage in the pharmaceutical composition is more than 5%), the dissolution rate of the active ingredient is too high, so that almost all of the active ingredient is decomposed and dissolved in a short time (e.g., 5 minutes to 10 minutes) (dissolution is greater than 80%, even greater than 90%), which does not meet the pharmaceutical requirements.

[0077]

[0088] Alternatively, the content of the disintegrant in the pharmaceutical composition (e.g., a pharmaceutical composition in a unit dose form) may be in the range of 3.5 mg to 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.

[0078]

[0089] According to one embodiment of the present invention, the disintegrant comprises one or more selected from the group consisting of crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, corn starch, and potato starch. Specifically, the disintegrant is one or more selected from the group consisting of crospovidone, croscarmellose sodium, low-substituted hydroxypropyl cellulose, sodium carboxymethyl starch, corn starch, and potato starch. The disintegrant is preferably one or more selected from the group consisting of crospovidone, croscarmellose sodium, and sodium carboxymethyl starch.

[0090] According to one embodiment of the present invention, the weight percentage of the lubricant in the pharmaceutical composition is in the range of 0.5% to 5%, more preferably 0.5% to 4%, in particular 0.5% to 3%, more particularly 1% to 2%, for example 0.5%, 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%, 3%, 4% or 5%. The amount of lubricant in the pharmaceutical composition of the present invention should not be too little or too much. If the amount of lubricant is too little or too much (e.g., its weight percentage in the pharmaceutical composition is less than 0.5% or more than 4%), the phenomena of powder adhesion, sticking, or picking will occur during the preparation of the pharmaceutical composition (such as tableting), which does not meet pharmaceutical requirements.

[0079]

[0091] Alternatively, the content of the lubricant in a pharmaceutical composition (e.g., a pharmaceutical composition in a unit dose form) may be in the range of 1.5 mg to 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.

[0080]

[0092] According to one embodiment of the present invention, the lubricant includes one or more selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oil, glyceryl behenate, stearic acid, and sodium stearyl fumarate. Specifically, the lubricant is one or more selected from the group consisting of magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oil, glyceryl behenate, stearic acid, and sodium stearyl fumarate, and the lubricant is preferably one or more selected from the group consisting of magnesium stearate, glyceryl behenate, and sodium stearyl fumarate. The lubricant is preferably magnesium stearate, and is preferably a combination of magnesium stearate and sodium stearyl fumarate.

[0081]

[0093] According to one embodiment of the present invention, the weight percentage of the lubricant in the pharmaceutical composition is in the range of 0.5% to 5%, more preferably 0.5% to 4%, particularly preferably 0.5% to 3%, more particularly 2% to 3%, for example 0.5%, 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%, 3% or 4%. In the pharmaceutical composition of the present invention, the amount of lubricant should not be too little or too much. If the amount used is too small or too large (e.g., the weight percentage in the pharmaceutical composition is less than 0.5% or more than 4%), when the pharmaceutical composition is prepared into tablets, the tablet weight of the resulting tablets may be unstable and will not meet pharmaceutical requirements.

[0082]

[0094] Alternatively, the content of the lubricant in the pharmaceutical composition (e.g., a pharmaceutical composition in a unit dose form) may be in the range of 1.5 mg to 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.

[0083]

[0095] According to one embodiment of the present invention, the lubricant comprises colloidal silica and / or talc. In particular, the lubricant is selected from colloidal silica and / or talc, for example, the lubricant is colloidal silica.

[0084]

[0096] As used herein, the term "colloidal silica" is also referred to as "light anhydrous silicic acid."

[0085]

[0097] According to one embodiment of the present invention, the weight percentage of the binder in the pharmaceutical composition is in the range of 0-10%, even more preferably 1%-5%, in particular 1%-3%, such as 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% or 5%. The amount of binder in the pharmaceutical composition of the present invention should not be too little or too much. If the amount of binder is too small or too large (e.g., its weight percentage in the pharmaceutical composition is less than 1% or more than 5%), the phenomenon that the hardness of the resulting tablet is too low (e.g., less than 40N) or too high (e.g., more than 80N) will occur during the preparation of the pharmaceutical composition tablets, which does not meet the pharmaceutical requirements.

[0086]

[0098] Alternatively, the content of the binder in the pharmaceutical composition (e.g., a pharmaceutical composition in a unit dose form) may be in the range of 1 mg to 15 mg, more preferably 5 mg to 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.

[0087]

[0099] Specifically, the binder is one or more selected from the group consisting of hypromellose, hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, copovidone and polyvinylpyrrolidone, and is preferably hypromellose, hydroxypropyl cellulose and / or copovidone.

[0088]

[0100] According to one embodiment of the invention, the physiologically or pharma-ceutically acceptable excipient further comprises a suspending agent and / or a flavoring agent.

[0089]

[0101] Specifically, the suspending agent is selected from the group consisting of low molecular weight suspending agents, high molecular weight suspending agents, silicates, thixotropic agents, and any combination thereof. Specifically, the low molecular weight suspending agent can be selected from the group consisting of glycerin, syrup, and any combination thereof; the high molecular weight suspending agent can be selected from the group consisting of tree gums (such as acacia, tragacanth, peach gum, or any combination thereof), plant mucilages and polysaccharides (such as sodium alginate, agar, starch, pectin, carrageenan, chitosan, or any combination thereof), cellulose derivatives (such as methylcellulose or a salt thereof, carboxymethylcellulose or a salt thereof, hydroxypropylcellulose or a salt thereof, hydroxyethylcellulose or a salt thereof, or any combination thereof), and any combination thereof; the silicate can be selected from the group consisting of bentonite, magnesium aluminum silicate, aluminum silicate, and any combination thereof; and / or the thixotropic agent can be selected from the group consisting of citrates, hydrogen citrates, tartrates, hydrogen tartrates, phosphates, AlCl3, and any combination thereof. Preferably, the suspending agent is one or more selected from the group consisting of hypromellose, hydroxypropylcellulose, methylcellulose, sodium carboxymethylcellulose, sucrose, glycerin, sorbitol, maltitol, xanthan gum, tragacanth, polyacrylic acid cross-polymer, polyvinylpyrrolidone, and microcrystalline cellulose.

[0090]

[0102] Specifically, the weight ratio of the suspending agent in the pharmaceutical composition is in the range of 0 to 30%, preferably 1 to 20%.

[0103] 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.; ascorbic acid is preferred.

[0091]

[0104] Specifically, the weight percentage of the flavor in the pharmaceutical composition is in the range of 0.01% to 10%, preferably 0.05% to 7.5%, and more preferably 1% to 5%.

[0092]

[0105] In certain embodiments, the filler is a mixture of microcrystalline cellulose and D-mannitol (e.g., the weight ratio of the two is as defined in the present invention), the binder is hydroxypropyl cellulose, the disintegrant is croscarmellose sodium, the lubricant is colloidal silica, and / or the lubricant is magnesium stearate. In particular, the weight percentage or content of the above specific physiologically or pharma- ceutically acceptable excipients (such as microcrystalline cellulose, D-mannitol, croscarmellose sodium, hydroxypropyl cellulose, colloidal silica, and / or magnesium stearate) are as defined above.

[0093]

[0106] In certain embodiments, the filler is a mixture of microcrystalline cellulose and pregelatinized starch (e.g., the weight ratio of the two is as defined in the present invention), the binder is hydroxypropyl cellulose, the disintegrant is croscarmellose sodium, the lubricant is colloidal silica, and / or the lubricant is magnesium stearate. In particular, the weight percentage or weight ratio of the above specific physiologically or pharma- ceutically acceptable excipients (such as microcrystalline cellulose, pregelatinized starch, croscarmellose sodium, hydroxypropyl cellulose, colloidal silica, and / or magnesium stearate) in the pharmaceutical composition is as defined above.

[0107] According to one embodiment of the present invention, the pharmaceutical composition is an oral formulation, preferably an oral solid formulation (eg, tablet, powder, dry suspension, granules, or capsule).

[0094]

[0108] In an embodiment of the invention, the pharmaceutical composition is in unit dose form, such as a solid formulation in unit dose form (eg, a tablet, powder, dry suspension, granules, or capsule).

[0095]

[0109] Preferably, when the oral solid preparation of the present invention is a tablet, the tablet may or may not have a film coating for an easy-to-swallow tablet.

[0096]

[0110] The "hardness" of a tablet is measured in N (Newtons) as the force required to break the tablet. According to one embodiment of the present invention, the tablet of the present invention has a hardness in the range of 30N-90N, such as in the range of 40N-80N, such as 70N. It is well known to a person skilled in the art to define the appropriate hardness range depending on the size and shape of the tablet.

[0097]

[0111] According to one embodiment of the present invention, when the pharmaceutical composition of the present invention is in the form of a unit dose (e.g., a solid preparation such as a tablet, powder, dry suspension, granule, or capsule in the form of a unit dose), the pharmaceutical composition is in the form of a unit dose of 1 mg to 500 mg, preferably 10 mg to 300 mg, more preferably 50 mg to 200 mg, and most preferably 120 mg to 155 mg, for example, 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, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 200 mg, 30 ... g, 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, 200 mg, or 250 mg of active ingredient (e.g., the crystalline form of the first aspect or the API of the second aspect) per unit dose. Alternatively, when the pharmaceutical composition of the present invention is in unit dose form (e.g., a solid formulation such as a tablet, powder, dry suspension, granule, capsule, etc., in unit dose form), the pharmaceutical composition comprises 40 mg to 170 mg, preferably 95 mg to 130 mg, of the free base form of the active ingredient per unit dose.For example, the pharmaceutical composition may include 40 mg, 41 mg, 42 mg, 43 mg, 44 mg, 45 mg, 46 mg, 47 mg, 48 mg, 49 mg, 50 mg, 51 mg, 52 mg, 53 mg, 54 mg, 55 mg, 56 mg, 57 mg, 58 mg, 59 mg, 60 mg, 61 mg, 62 mg, 62.1 mg, 62.2 mg, 62.3 mg, 62.4 mg, 62.5 mg, 62.6 mg, 62.7 mg, 62.8 mg, 62.9 mg, 62.10 mg, 62.11 mg, 62.12 mg, 62.13 mg, 62.14 mg, 62.15 mg, 62.16 mg, 62.17 mg, 62.18 mg, 62.19 mg, 62.20 mg, 62.21 mg, 62.22 mg, 62.23 mg, 62.24 mg, 62.25 mg, 62.26 mg, 62.27 mg, 62.28 mg, 62.29 mg, 63.30 mg, 63.31 mg, 63.32 mg, 63.33 mg, 63.34 mg, 63.35 mg, 63.36 mg, 63.37 mg, 63.38 mg, 63.39 mg, 63.40 mg, 63.41 mg, 63.42 mg, 63.43 mg, 63.44 mg, 63.45 mg, 63.46 mg, 63.47 mg, 63.48 mg, 63.49 mg, 64.5 mg, 62.6mg, 62.7mg, 62.8mg, 62.9mg, 63mg, 64mg, 65mg, 66mg, 67mg, 68mg, 69mg, 70mg, 71mg, 72m g, 73mg, 74mg, 75mg, 76mg, 77mg, 78mg, 79mg, 80mg, 81mg, 82mg, 83mg, 84mg, 85mg, 86mg, 87mg, 88m g, 89mg, 90mg, 91mg, 92mg, 93mg, 94mg, 95mg, 96mg, 97mg, 98mg, 99mg, 100mg, 101mg, 102mg, 103m g, 104mg, 105mg, 106mg, 107mg, 108mg, 109mg, 110mg, 111mg, 112mg, 113mg, 114mg, 115mg, 116mg , 117 mg, 118 mg, 119 mg, 120 mg, 121 mg, 122 mg, 123 mg, 124 mg, 125 mg, 126 mg, 127 mg, 128 mg, 129 mg, 130 mg, 135 mg, 140 mg, 145 mg, 150 mg, 155 mg, 160 mg, 165 mg, or 170 mg of the free base form of the active ingredient per unit dose.

[0098]

[0112] When the pharmaceutical composition of the present invention is in the form of an oral preparation (e.g., tablet, powder, dry suspension, granule, capsule), it is convenient for administration to a subject, compliance of a subject (particularly a child, an elderly person, or a patient with swallowing disorder) for use is improved, and the risk of overdosing on an injection can be avoided.

[0099]

[0113] The inventors also investigated preparation parameters such as in vitro dissolution of pharmaceutical compositions (e.g., tablets) containing crystalline form A of the compound of formula (I) and fumaric acid. The results showed that in the same dissolution medium, the pharmaceutical compositions (specifically, tablets) containing crystalline form A had a higher dissolution rate and higher in vitro dissolution, which could meet the dissolution requirements.

[0100]

[0114] According to one embodiment of the present invention, the subject is a human being, preferably a child, an adult, or an elderly person, for example, a child aged 0-18 (e.g., 0-12), an adult aged 19-59, or an elderly person aged 60 or over. Specifically, when the pharmaceutical composition of the present invention is a granule or dry suspension, the subject is preferably a child (e.g., a child aged 0-12); when the pharmaceutical composition of the present invention is a tablet or capsule, the subject is preferably an adult or an elderly person, for example, an adult aged 19-59 or an elderly person aged 60 or over; when the pharmaceutical composition of the present invention is an oral liquid, the subject is preferably a child (a child aged 0-12), an elderly person (an elderly person aged 60 or over), or a patient with dysphagia.

[0101]

[0115] After the pharmaceutical composition of the present invention is placed under accelerated stability testing conditions (e.g., 40°C±2°C and 75%±5% RH) for 1 month or 3 months, the maximum content of a single impurity is 0.2% or less (e.g., 0.1% or less) and / or the total impurity content is 1% or less (e.g., 0.25% or less).

[0102]

[0116] In addition, the pharmaceutical composition of the present invention has high solubility, high dissolution rate and / or high stability. In addition, the pharmaceutical composition of the present invention is suitable for incorporation into oral preparations, particularly oral solid preparations such as tablets (good tablet compressibility), suitable for large-scale industrial production, and the obtained products have stable and reliable quality and good clinical application value.

[0103]

[0117] According to one embodiment of the present invention, the pharmaceutical composition of the present invention comprises an active ingredient (the active pharmaceutical ingredient described in the second aspect) having a specific particle size (D 50 ≦30μm and / or D 90The tablet has a particle size ranging from 5 μm to 60 μm; the filler is a mixture of microcrystalline cellulose and D-mannitol (e.g., the weight ratio of the two is as defined in the present invention), or a mixture of microcrystalline cellulose and pregelatinized starch (e.g., the weight ratio of the two is as defined in the present invention); the binder is hydroxypropyl cellulose; the disintegrant is croscarmellose sodium; the lubricant is colloidal silica; and / or the lubricant is magnesium stearate. In particular, the weight percentage or content of the above specific physiologically or pharma- ceutical acceptable excipients (such as microcrystalline cellulose, mannitol, croscarmellose sodium, hydroxypropyl cellulose, colloidal silica, and / or magnesium stearate) is as defined above. This pharmaceutical composition has a high dissolution rate, high solubility, and acceptable friability, and has no significant sticking or picking phenomenon during the tablet preparation process (such as the tableting process).

[0104] others

[0118] In a fourth aspect of the present invention, the present invention provides the following embodiments and / or any combination thereof:

[0105]

[0119] In a fourth aspect of the present invention, the present invention provides a method for treating a disease caused by a coronavirus, comprising administering to a subject the pharmaceutical composition of the third aspect of the present invention.

[0106]

[0120] According to one embodiment of the present invention, the coronavirus is 2019-nCoV.

[0121] According to one embodiment of the present invention, the subject is a human being, preferably a child, an adult, or an elderly person, for example, a child aged 0-18 years (e.g., 0-12 years), an adult aged 19-59 years, or an elderly person aged 60 years or more. Specifically, when the pharmaceutical composition of the present invention is a granule or dry suspension, the subject is preferably a child (e.g., a child aged 0-12 years); when the pharmaceutical composition of the present invention is a tablet or capsule, the subject is preferably an adult or an elderly person, for example, an adult aged 19-59 years or an elderly person aged 60 years or more; when the pharmaceutical composition of the present invention is an oral liquid, the subject is preferably a child (e.g., a child aged 0-12 years), an elderly person (e.g., an elderly person aged 60 years or more), or a patient with dysphagia.

[0107]

[0122] In a fifth aspect, the present invention provides the following embodiments and any combination thereof:

[0108]

[0123] In a fifth aspect of the present invention, there is also provided a method for preparing a pharmaceutical composition comprising premixing, granulation, and / or mixing; preferably, the method comprises the following steps: (i) premixing: mixing an active ingredient with a physiologically or pharma- ceutically acceptable excipient (one or more physiologically or pharma- ceutically acceptable excipients as described above, such as one of the fillers as described above); (ii) granulation: granulating the mixture obtained in step (i) (such as dry granulation or wet granulation) and then sieving; (iii) mixing: mixing the particles obtained in step (ii) with one or more other physiologically or pharma- ceutically acceptable excipients other than the physiologically or pharma- ceutically acceptable excipients described in step (i).

[0109]

[0124] In the method for preparing the pharmaceutical composition of the present invention, step (i) is achieved by mixing the active ingredient (e.g., the crystalline form of the first aspect or the API of the second aspect) with a filler, a disintegrant, an optional binder, an optional solubilizer, and a lubricant in sequence. Specifically, step (i) is achieved by first mixing the active ingredient with a filler, and then adding and mixing a disintegrant, an optional binder, an optional solubilizer, and a lubricant. Preferably, step (i) is achieved by first mixing the active ingredient with a first filler, and then adding and mixing a second filler, a disintegrant, an optional binder, an optional solubilizer, and a lubricant. In particular, the first filler and the second filler may be the same or different, and preferably, the first filler is cellulose as the filler of the present invention, and the second filler is starch as the filler of the present invention. Preferably, mixing is accomplished by stirring, preferably by hand stirring or in a mixing device such as a hopper mixer.

[0110]

[0125] In the method for producing the pharmaceutical composition of the present invention, step (ii) is achieved by wet granulation or dry granulation of the mixture obtained in step (i), followed by sieving. Specifically, wet granulation or dry granulation can be performed by a person skilled in the art according to the formulation requirements. Preferably, wet granulation is to mix the mixture obtained in step (i) with water and granulate using a wet granulator. Preferably, dry granulation is to granulate the mixture obtained in step (i) using a dry granulator. Preferably, sieving is achieved using a 20-80 mesh sieve (e.g., a 40-60 mesh sieve).

[0111]

[0126] In the method for producing the pharmaceutical composition of the present invention, step (iii) is accomplished by mixing the particles obtained in step (ii) with a lubricant. Preferably, mixing is accomplished by stirring, preferably by hand stirring or in a mixing device such as a hopper mixer.

[0112]

[0127] The method for producing a pharmaceutical composition of the present invention further comprises the step of: (iv) compressing the mixture obtained in step (iii) into tablets.

[0113]

[0128] Specifically, in a pharmaceutical composition, the active ingredient, the physiologically or pharma-ceutically acceptable excipients, and the amounts of each are as defined in the present invention.

[0114]

[0129] Specifically, in the method for producing the pharmaceutical composition of the present invention, the step (i) as the premixing step is realized by an operation of mixing the active ingredient (uniformly) with a filler, a disintegrant, a binder, and a lubricant in order. More specifically, the step (i) as the premixing step is realized by an operation of first mixing the active ingredient (uniformly) with a first filler, and then adding and mixing (uniformly) with a second filler, a disintegrant, a binder, and a lubricant. In particular, the first filler and the second filler may be the same or different. Preferably, when the first filler is cellulose (such as microcrystalline cellulose) as the filler of the present invention, the second filler is starch (such as pregelatinized starch) as the filler of the present invention. Alternatively, when the first filler is a sugar alcohol (such as D-mannitol) as the filler of the present invention, the second filler is cellulose (such as microcrystalline cellulose) as the filler of the present invention. Alternatively, when the first filler is a cellulose (such as microcrystalline cellulose) as a filler of the present invention, the second filler is a sugar alcohol (such as D-mannitol) as a filler of the present invention. Alternatively, when the first filler is a starch (such as pregelatinized starch) as a filler of the present invention, the second filler is a cellulose (such as microcrystalline cellulose) as a filler of the present invention. Preferably, mixing is accomplished by stirring, preferably by hand stirring or stirring in a mixing device such as a hopper mixer.

[0115]

[0130] Specifically, step (ii) as a granulation step is realized by wet granulation or dry granulation of the mixture obtained in step (i), followed by sieving. Specifically, wet granulation or dry granulation can be performed by a person skilled in the art according to the formulation requirements. Preferably, wet granulation can be performed once, twice or more times. Preferably, wet granulation is performed by mixing the mixture obtained in step (i) with a solvent (such as water), followed by granulation through a wet granulator or fluidized bed, sieving, drying (such as at 40°C to 80°C), and optionally secondary sieving. Preferably, dry granulation is performed by granulating the mixture obtained in step (i) through a dry granulator, or compressing the mixture obtained in step (i) into a large sheet, followed by grinding and sieving to granulate. Preferably, sieving or secondary sieving is accomplished through a 20-80 mesh sieve (e.g., a 40-60 mesh sieve). Preferably, drying is accomplished by an oven or a fluidized bed.

[0116]

[0131] Specifically, the binder may be added in the following steps: 1) in step (i) or step (ii), the binder is added in the form of a dry powder; 2) in step (ii), the binder is added as a solution (preferably an aqueous solution, for example, an aqueous solution containing the binder at a concentration of 2 to 10% by weight); 3) in step (ii), a part of the binder is added in the form of a dry powder, and another part of the binder is added in the form of an aqueous solution (preferably an aqueous solution, for example, an aqueous solution containing the binder at a concentration of 2 to 15% by weight).

[0117]

[0132] Specifically, the active ingredient is mixed with a portion of the binder in solution (preferably an aqueous solution, e.g., an aqueous solution containing the binder at a concentration of 2-10% by weight), followed by granulation, sieving (e.g., through a 20-80 mesh sieve), drying (e.g., drying at a temperature in the range of 40°C to 80°C), optional secondary sieving (e.g., through a 20-80 mesh sieve), and then mixing with the first filler, the second filler, the disintegrant, the remaining portion of the binder, and the lubricant (uniformly).

[0118]

[0133] Specifically, step (iii) as a mixing step is realized by (uniformly) mixing the particles obtained in step (ii) with a lubricant, in particular by stirring, preferably by hand stirring or in a mixing device such as a hopper mixer.

[0119]

[0134] Specifically, the manufacturing method further comprises a tableting step, in particular, the tableting step is a step of tableting the mixture obtained in step (iii) and / or the tableting step is carried out by a tablet press (e.g., a single punch tablet press).

[0120]

[0135] The embodiments and technical solutions of different levels described in this specification can be arbitrarily combined unless otherwise specified.

[0121]

[0136] The following examples are illustrative of the present invention, but the scope of the subject matter of the present invention is not limited to the following examples. All technologies realized based on the above content of the present invention belong to the scope of the present invention. The compounds or reagents used in the following examples can be purchased commercially or prepared by conventional methods known to those skilled in the art. The experimental equipment used can be purchased commercially. In the present invention, the content (%) in the examples is the weight percentage of each component in the pharmaceutical composition (i.e., the tablet obtained in each example), and the value obtained by dividing the amount (g) described in each example by the batch amount (i.e., the number of tablets) is the specific content (e.g., mg or g) of each component in the pharmaceutical composition (e.g., the tablet obtained in each example).

[0122] Preparation and pattern determination of crystal forms

[0137] I. Preparation of Crystalline Forms

[0138] Manufacturing Example 1

[0139] The 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-triazine-2,4-dione fumaric acid (15.2 mg) was added to 1.0 mL of acetone to form a suspension, which was stirred at room temperature for 7 days and then separated to obtain a solid. The resulting solid was dried under vacuum to obtain crystalline form A as a white solid.

[0123]

[0140] Manufacturing Example 2

[0141] The 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-triazine-2,4-dione fumaric acid (15.2 mg) was added to 1.0 mL of tetrahydrofuran to form a suspension, which was stirred at room temperature for 7 days and then separated to obtain a solid. The resulting solid was dried under vacuum to obtain crystalline form A as a white solid.

[0124]

[0142] II. Crystalline Form Pattern Determination and Data

[0143] 1. XRPD pattern judgment conditions and diffraction peak data

[0144] The sample of crystalline form A was analyzed by X-ray powder diffractometer PANalytical Empyrean (PANaly, NL). The 2θ scan angle was 3 degrees to 45 degrees, the scan step was 0.013 degrees, and the test time was 5 minutes and 8 seconds. The phototube voltage and current for testing the sample were 45 kV and 40 mA, respectively, and the sample pan was a zero background sample pan.

[0125]

[0145] XRPD Diffraction Peak Data of Crystalline Form A of the Compound of Formula (I) with Fumaric Acid JPEG2024045113000005.jpg243170JPEG2024045113000006.jpg128170

[0126]

[0146] From the XRPD diffraction peak data, the main characteristic peaks of crystalline form A include any three characteristic diffraction peaks selected from the group consisting of 10.94, 19.06, 23.50 and 24.66, and may further include any one or more characteristic diffraction peaks selected from the group consisting of 9.5, 13.81, 18.61, 22.59 and 23.8, or may further include any one or more characteristic diffraction peaks selected from the group consisting of 7.81, 10.14, 11.50, 11.93 and 12.31, or may further include any one or more characteristic diffraction peaks selected from the group consisting of 14.73, 20.87, 21.49, 21.97 and 25.39, and the main characteristic diffraction peaks of crystalline form A may be 10.94, 19.06, 23.50, 24.66, 9.5, 13.81, 18.61, 22.59 and 23.8.

[0127]

[0147] 2. Differential scanning calorimetry (DSC) spectrum determination conditions and data

[0148] The DSC spectrum of the crystalline form A of the compound of formula (I) with fumaric acid was obtained as follows:

[0149] A differential scanning calorimeter (TA Discovery 2500, TA, US) was used. 1-2 mg of sample was accurately weighed, placed in a perforated DSC Tzero sample pan, and heated in a furnace at a rate of 10 °C / min with a nitrogen purge rate of 50 mL / min to the final temperature.

[0150] Results: As shown in FIG. 1, the DSC spectrum of the crystalline form A of the compound of formula (I) and fumaric acid shows that the melting endothermic peak, which is the melting point of the crystalline form A, is around 274° C., which indicates that the crystalline form A has a high melting point and good thermodynamic stability.

[0128]

[0151] 3. Thermogravimetric analysis (TGA) spectrum determination conditions and data

[0152] The TGA spectrum of the crystalline form A of the compound of formula (I) with fumaric acid was obtained as follows.

[0153] A thermogravimetric analyzer, TA Discovery 55 (TA, US), was used. 2 mg to 5 mg of sample was placed in a balanced open aluminum sample pan and automatically weighed in a TGA oven. The sample was heated at a rate of 10 °C / min to the final temperature at 60 mL / min on the sample and 40 mL / min on the balance.

[0154] Results: The TGA spectrum of the crystalline form A of the compound of formula (I) with fumaric acid is shown in FIG. 1. During heating of the crystalline form A to 150°C, there is essentially no weight loss, and the crystalline form A decomposes at temperatures higher than 240°C, indicating that the crystalline form A is anhydrous crystalline form or that the solvent is not absorbed.

[0129]

[0155] 4. Dynamic Vapor Sorption (DVS) Analysis

[0156] Dynamic water vapor sorption analysis was performed using DVS Intrinsic (SMS, UK). When the gradient mode was employed, the humidity change was 50%, 95%, 0% and 50% in sequence, with a humidity change of 10% for each gradient ranging from 0% to 90%, and the gradient end point was determined by the dm / dt method. The gradient end point was determined in response to dm / dt being less than 0.002% and maintained for 10 min.

[0157] Results: The DVS results are shown in Figure 2, with a weight loss of 0.02% at 0% RH and a weight gain of 0.06% at 80% RH, and the sample has little hygroscopicity. Comparison between the XRPD patterns of crystalline form A before and after the DVS experiment shows that crystalline form A is very stable, not easily undergoes crystal transformation, and is not easily hygroscopic, as shown in Figure 3.

[0158] The present inventors also investigated the stability of crystalline form A under the conditions of influencing factor experiments and accelerated stability experiments, and the results are as follows:

[0159] The crystalline form A of the compound of formula (I) and fumaric acid was stable under conditions of high temperature, high humidity and light exposure, and maintained stable appearance and purity within 30 days.

[0130]

[0160] The crystalline form A of the compound of formula (I) and fumaric acid was stable at 40°C and 75% relative humidity, and maintained a stable appearance and purity without dissociation or crystal transformation within 2 months. This indicates that the crystalline form A has very good stability, which is beneficial for the manufacture, transportation, and storage of the drug, and ensures the efficacy and safety of the drug use.

[0131]

[0161] The present inventors have further investigated the particle size parameters of active pharmaceutical ingredients (APIs) and have investigated the effect of the particle size of the APIs on the efficacy of formulations containing them.

[0132] Examples of API production, API content preparation, and effects

[0162] III. Examples of API manufacturing

[0163] The 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-triazinane-2,4-dione fumaric acid (45 g) was added to 450 mL of acetone to form a suspension. According to the conditions shown in the table below, the suspension was heated under reflux to a temperature in the range of 55°C-70°C, and then cooled to a temperature in the range of 20°C-30°C with stirring. Finally, the suspension was separated to obtain a solid. The obtained solid was dried under vacuum to obtain a series of white solids, namely API 1-17 (42.8 g-43.7 g), containing crystalline form A of the compound and fumaric acid, which have the particle size shown in the table below.

[0133]

[0164] The specific reaction temperature, stirring conditions, and particle size of the resulting API (D 50 and / or D. 90 ) JPEG2024045113000007.jpg170170

[0134]

[0165] A small amount of the API (e.g., API6) prepared in the examples of the present invention was taken and placed on a slide glass to observe the morphology of these APIs through a polarizing microscope (Nikon Ci-POL, Nikon, JP). The polarizing microscope (PLM) image of API6 is shown in Figure 4.

[0135]

[0166] The particle size distribution of the API prepared in the examples of the present invention was determined using a laser particle size analyzer Mastersizer 3000 (Malvern Panalytical, UK). Specifically, about 20 mg of the API (e.g., API5) prepared in the examples of the present invention was dispersed in 8 mL of n-heptane, sonicated for 10 seconds, and added to the sample dispersion section until the shading degree was in the range of 10%-20%. The stirring speed of the dispersion chamber was 2000 rpm and the duration was 10 s. The particle size distribution diagram of API5 is shown in Figure 5.

[0136]

[0167] Based on obtaining an API within a particular particle size range, the inventors further investigated a formulation containing that API and its effects.

[0137]

[0168] IV. Preparation example

[0169] In the preparation examples, preparations 1 to 17 were obtained according to the methods and parameters described below.

[0138]

[0170] Preparation of Preparations 1, 2, 3 and 16 JPEG2024045113000008.jpg71170

[0139]

[0171] Manufacturing method:

[0172] (1) An API (active ingredient, i.e., API 1, 2, 3, or 16 containing crystalline form A of the compound of formula (I) and fumaric acid) was homogeneously mixed with microcrystalline cellulose;

[0173] (2) Lactose, hydroxypropyl cellulose, croscarmellose sodium, and colloidal silica were added to the mixture obtained in step (1) and mixed uniformly;

[0174] (3) The mixture obtained in step (2) was wet granulated with 34.9874 g of pure water, circulated, sieved through a 40-60 mesh sieve, and dried at 60°C for 2 hours;

[0175] (4) The particles obtained in step (3) were uniformly mixed with magnesium stearate;

[0176] (5) The mixture obtained in step (4) was tableted using a 9.5 mm round punch, a controlled average weight difference of ±3%, and a tablet hardness in the range of 70N-80N to obtain tablets of 375 mg per tablet.

[0140]

[0177] Preparation of Preparations 4, 5, 6, and 17 JPEG2024045113000009.jpg55170

[0141]

[0178] Manufacturing method:

[0179] (1) An API (active ingredient, i.e., API 4, 5, 6 or 17 containing crystalline form A of the compound of formula (I) and fumaric acid) was homogeneously mixed with microcrystalline cellulose;

[0180] (2) Pregelatinized starch, copovidone, croscarmellose sodium, and colloidal silica were added to the mixture obtained in step (1) and mixed uniformly;

[0181] (3) The mixture obtained in step (2) was granulated in a dry granulator, circulated, and sieved through a 40-60 mesh sieve;

[0182] (4) Magnesium stearate was mixed with the particles obtained in step (3);

[0183] (5) The mixture obtained in step (4) was tableted using a 9.5 mm round punch, a controlled average weight difference of ±3%, and a tablet hardness in the range of 70N-80N to obtain tablets of 375 mg per tablet.

[0142]

[0184] Preparation of Preparations 7, 8, and 9 JPEG2024045113000010.jpg40170

[0143]

[0185] Manufacturing method:

[0186] (1) API (APIs 7, 8, and 9 containing the active ingredient, i.e., crystalline form A of the compound of formula (I) and fumaric acid) was homogeneously mixed with lactose;

[0187] (2) Microcrystalline cellulose and sodium dodecyl sulfate were added to the mixture obtained in step (1) and mixed uniformly;

[0188] (3) pulverizing the mixture obtained in step (2) to obtain a fine powder;

[0189] (4) The fine powder obtained in step (3) was sieved through a 100 to 120 mesh sieve and packed into packaging materials (such as small bags) to obtain a powder or dry suspension weighing 375 mg per bag.

[0144]

[0190] Preparation of Preparations 10, 11, and 12 JPEG2024045113000011.jpg39170

[0145]

[0191] Manufacturing method:

[0192] (1) API (APIs 10, 11, and 12 containing the active ingredient, i.e., crystalline form A of the compound of formula (I) and fumaric acid) was homogeneously mixed with lactose;

[0193] (2) Microcrystalline cellulose and sodium dodecyl sulfate were added to the mixture obtained in step (1) and mixed uniformly;

[0194] (3) pulverizing the mixture obtained in step (2) to obtain a fine powder;

[0195] (4) The fine powder obtained in step (3) was sieved through a 100-120 mesh sieve and packed into packaging materials (such as small bags) to obtain a powder or dry suspension weighing 375 mg per bag.

[0146]

[0196] Preparation of Preparations 13, 14, and 15 JPEG2024045113000012.jpg40170

[0147]

[0197] Manufacturing method:

[0198] (1) API (APIs 13, 14, and 15 containing the active ingredient, i.e., crystalline form A of the compound of formula (I) and fumaric acid) was homogeneously mixed with mannitol;

[0199] (2) Microcrystalline cellulose and sodium dodecyl sulfate were added to the mixture obtained in step (1) and mixed uniformly;

[0200] (3) pulverizing the mixture obtained in step (2) to obtain a fine powder;

[0201] (4) The fine powder obtained in step (3) was sieved through a 100 to 120 mesh sieve and packed into packaging materials (such as small bags) to obtain a powder or dry suspension weighing 375 mg per bag.

[0148]

[0202] Examples of the effects of the preparation

[0203] 1. In vitro dissolution experiments

[0204] The experimental method used a paddle apparatus method, with a rotation speed of 75 rpm and a dissolution medium of 900 ml. The dissolution curves of the present preparations 1-6, 16, and 17 in the dissolution medium, i.e., purified water pH 1.2 + 0.2% Tween 80, were measured respectively. At 5, 10, 15, 30, 45, and 60 minutes, appropriate amounts of the dissolution liquid were collected and filtered, and the filtrate was used as the test liquid to determine the in vitro dissolution.

[0149]

[0205] The test results are shown in the table below. JPEG2024045113000013.jpg75170

[0150]

[0206] Conclusion: In the dissolution medium of purified water pH 1.2 + 0.2% Tween 80, preparations 1 to 6 of the present invention have high dissolution rates and high in vitro solubility, while preparations 16 and 17 have low dissolution rates and relatively low in vitro solubility.

[0151]

[0207] 2. Investigating the main parameters of tablets

[0208] Focusing on investigating the sticking or picking phenomenon that occurred during the tableting process of Preparations 1 to 6, 16, and 17 of the present invention, the friability of the tablets was examined. Specifically, under similar tableting conditions (including temperature, humidity, etc. during tableting), it was determined whether the sticking or picking phenomenon that occurred during the tableting process was observed with the naked eye, and for each preparation example, 18 tablets prepared according to Preparation Examples 1 and 2 were taken and tested with a tablet friability tester (CS-3 friability tester, purchased from Tianjin TuoPu Instrument Co., Ltd.) to measure the friability parameters (i.e., percent weight loss), as specified in the 2020 edition of the Chinese Pharmacopoeia (Part Four, Tablet friability test method).

[0152]

[0209] Specific results are shown in the table below: JPEG2024045113000014.jpg81170

[0153]

[0210] Sticking phenomenon:

[0211] -- indicates essentially no sticking or powder adhesion;

[0212] + indicates traces of attached powder, no significant sticking or astringency;

[0213] ++ indicates significant adhesion to the stamped surface;

[0214] +++ indicates significant sticking or astringency.

[0154]

[0215] Conclusion: In terms of tablet sticking, the present invention's preparations 1-6 were basically non-sticking or significantly non-sticking or non-picking during the tableting process. In terms of tablet friability, the tablet friability parameters of the present invention's preparations 1-6 are complementary to the Chinese Pharmacopoeia's regulations (weight loss rate not exceeding 1%), while the tablets of preparations 16 and 17 did not meet the Chinese Pharmacopoeia's regulations (weight loss rate far exceeds 1%). The inventors have found that the tablet friability parameters of the present invention's preparations 1-6 are complementary to the Chinese Pharmacopoeia's regulations (weight loss rate far exceeds 1%). 50 ≦30μm and / or ≦5μm D 90 It has been found that an active pharmaceutical ingredient comprising crystalline form A of the compound of formula (I) and fumaric acid within a particle size distribution (grain size) of 100 μm or less (≦60 μm) was suitable for compression into tablets.

[0155]

[0216] In addition to small-scale production of the API described in this invention, the inventors have explored large-scale medium-scale trial production of the API described in this disclosure, and the particle size D of the API obtained therein 90 is in the range of about 10 μm to about 60 μm, and / or the particle size D of the resulting API 50 is in the range of about 5 μm to about 30 μm.

[0156]

[0217] The inventors have investigated the effect of various excipients and their content variations (i.e., formulation variations) on the formulation in addition to the particle size parameters of the API and their effect on the preparation.

[0157] Examples of optimized pharmaceutical compositions and their effects

[0218] VI. Preparation example

[0219] As described above, based on the production of crystalline form A, the inventors of the present invention scaled up the production of crystalline form A and further explored the formulation of a pharmaceutical preparation.

[0158]

[0220] Example VI-1 JPEG2024045113000015.jpg90170

[0159]

[0221] Manufacturing method:

[0222] (1) Premix 1: API (active ingredient, i.e., 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-trifluorobenzyl)-1,3,5-triazinane-2,4-dione and fumaric acid) was mixed with microcrystalline cellulose uniformly in weight percentage;

[0223] (2) Premix 2: Pregelatinized starch, hydroxypropyl cellulose, croscarmellose sodium, and colloidal silica were added to the mixture obtained in step (1) in weight percentages and mixed uniformly;

[0224] (3) Granulation: The mixture obtained in step (2) was granulated using a dry granulator until the granulation rate reached 70% or more (60 mesh);

[0225] (4) Mixing: Magnesium stearate was mixed uniformly with the particles obtained in step (3) in a weight percentage;

[0226] (5) Tableting: The mixture obtained in step (4) was tableted using a round punch of 9.5 mm, a controlled average weight difference of ±3%, and a tablet hardness of 70N to 80N to obtain tablets of 375 mg per tablet.

[0160]

[0227] Examples VI-2, VI-3, VI-4, VI-5 JPEG2024045113000016.jpg148170

[0161]

[0228] Manufacturing method:

[0229] (1) Premix 1: API (active ingredient, i.e., 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-trifluorobenzyl)-1,3,5-triazinane-2,4-dione and fumaric acid) was mixed with microcrystalline cellulose uniformly in weight percentage;

[0230] (2) Premix 2: Pregelatinized starch, hydroxypropyl cellulose, croscarmellose sodium, and colloidal silica were added to the mixture obtained in step (1) in weight percentages and mixed uniformly;

[0231] (3) Granulation: The mixture obtained in step (2) was compressed into a large sheet, which was then crushed and sieved through a 20 mesh sieve;

[0232] (4) Mixing: Magnesium stearate was mixed uniformly with the particles obtained in step (3) in a weight percentage;

[0233] (5) Tableting: The mixture obtained in step (4) was tableted using a round punch of 9.5 mm, a controlled average weight difference of ±3%, and a tablet hardness of 70N to 80N to obtain tablets of 375 mg per tablet.

[0162]

[0234] Results: For the formulations of Examples VI-1 to VI-5, picking, sticking, powder adhesion, unstable tablet weight, tablet hardness during tableting, tableting, and other phenomena were neither too high nor too low, and good compressibility was obtained.

[0163]

[0235] The following examples employ the same or similar manufacturing methods as the previous Examples VI-2 to VI-5, but use different formulations to obtain tablets with 375 mg per tablet.

[0164]

[0236] Examples VI-6 and VI-7 JPEG2024045113000017.jpg114170

[0165]

[0237] Results: Compared with Example VI-1, the difference of the formulations of Examples VI-10 and VI-11 was that one of the fillers, pregelatinized starch, was replaced with calcium carbonate or anhydrous calcium hydrogen phosphate. For the formulations of Examples VI-6 and VI-7, there was a picking phenomenon during the tableting process, resulting in relatively poor compressibility.

[0166]

[0238] Examples VI-8 and VI-9 JPEG2024045113000018.jpg114170

[0167]

[0239] Results: Compared with Example VI-1, the difference of the formulations of Examples VI-8 and VI-9 is that hydroxypropyl cellulose is replaced with polyvinylpyrrolidone or hydroxyethyl cellulose as binder. For the preparations of Examples VI-8 and VI-9, sticking phenomenon occurs during the tableting process, and the compression ratio is relatively low.

[0168]

[0240] Examples VI-10 and VI-11 JPEG2024045113000019.jpg114170

[0169]

[0241] Results: Compared with Example VI-1, the main difference between the formulations of Examples VI-10 and VI-11 is that the content of hydroxypropyl cellulose as binder is adjusted to 0.7% and 5.3%, respectively. It was found that the formulation of Example VI-10 had too low tablet hardness (20N), and the formulation of Example VI-11 had too high tablet hardness (95N) during the tableting process, resulting in relatively low compressibility.

[0170]

[0242] Examples VI-12 and VI-13 JPEG2024045113000020.jpg123170

[0171]

[0243] Results: Compared with Example VI-1, the main difference between the formulations of Examples VI-12 and VI-13 is that the content of croscarmellose sodium as disintegrant is adjusted to 0.8% and 5.5%, respectively. As a result, the formulations of Examples VI-12 and VI-13 can obtain good compression ratios without the phenomena of picking, sticking, powder adhesion, unstable tablet weight, too high or too low tablet hardness, tablet capping, etc., during the tableting process. Nevertheless, the formulations of Examples VI-12 and VI-13 result in the dissolution defects described in Section "VII. Examples of the Effect of Preparations".

[0172]

[0244] Examples VI-14 and VI-15 JPEG2024045113000021.jpg114170

[0173]

[0245] Results: Compared with Example VI-1, the main difference between the formulations of Examples VI-14 and VI-15 is that the content of colloidal silica as lubricant is adjusted to 0.3% and 4.5%, respectively. For the formulations of Examples VI-14 and VI-15, there is a phenomenon that the tablet weight becomes unstable during the tableting process, and the compressibility is relatively poor.

[0174]

[0246] Examples VI-16 and VI-17 JPEG2024045113000022.jpg123170

[0175]

[0247] Compared with Example VI-1, the main difference of the formulations of Examples VI-16 and VI-17 is that the content of magnesium stearate as lubricant is adjusted to 0.4% and 4.2%, respectively.For the formulations of Examples VI-16 and VI-17, there are the phenomena of powder adhesion, sticking and picking during the tableting process, which results in relatively low compressibility.In particular, for the formulation of Example VI-16, the phenomenon of powder adhesion during the tableting process is shown in Figure 6.

[0176]

[0248] Examples VI-18 and VI-19 JPEG2024045113000023.jpg123170

[0177]

[0249] Compared with Example VI-1, the main difference of the formulations of Examples VI-18 and VI-19 is that the weight ratio of microcrystalline cellulose as filler and pregelatinized starch is adjusted to 1.3:1 and 4.4:1, respectively. For the formulations of Examples VI-18 and VI-19, there is a phenomenon of tablet capping in the tableting process, which leads to relatively low compressibility. In particular, for the formulation of Example VI-18, the phenomenon of tablet capping in the tableting process is shown in Figure 7.

[0178]

[0250] The above pharmaceutical composition formulations are obtained mainly by a manufacturing method including a dry granulation method, as shown in Examples VI-1 to VI-19, and the effect of changes in the formulation parameters (i.e., the type and / or content of the ingredients) on the tablet compression rate is also determined based on dry granulation. In order to search for tablets manufactured by a manufacturing method including wet granulation, the present inventors also investigated the effect of changes in the formulation parameters of the preparations manufactured by wet granulation on the tablet compression rate and / or dissolution, as shown in the results of Examples VI-20 to VI-29 below.

[0179]

[0251] Example VI-20 JPEG2024045113000024.jpg114170

[0180]

[0252] Manufacturing method:

[0253] Premix 1: API (active ingredient, i.e., 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-trifluorobenzyl)-1,3,5-triazinane-2,4-dione with fumaric acid) was mixed with microcrystalline cellulose uniformly in weight percentage;

[0254] (2) Premix 2: D-mannitol, hydroxypropyl cellulose, croscarmellose sodium, and colloidal silica were added to the mixture obtained in step (1) in weight percentages and mixed uniformly;

[0255] (3) Granulation: The mixture obtained in step (2) was granulated using purified water in a wet granulator, sieved through a 20 mesh sieve, and dried at 60°C for 2 hours;

[0256] (4) Mixing: Magnesium stearate was mixed uniformly with the particles obtained in step (3) in a weight percentage;

[0257] (5) Tabletting: The mixture obtained in step (4) was tableted using a round punch of 9.5 mm, controlled average weight difference of ±3%, and tablet hardness of 70N-80N to obtain tablets of 375 mg per tablet.

[0181]

[0258] Results: For the formulation of Example VI-20, there are no phenomena such as picking, sticking, powder adhesion, unstable tablet weight, too high or too low tablet hardness, and tablet capping during tablet compression, and a good compression ratio is obtained.

[0182]

[0259] Examples VI-21-VI-24 JPEG2024045113000025.jpg140170

[0183]

[0260] Manufacturing method:

[0261] (1) Premix 1: API (active ingredient, i.e., 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-trifluorobenzyl)-1,3,5-triazinane-2,4-dione and fumaric acid) was mixed with microcrystalline cellulose uniformly in weight percentage;

[0262] (2) Premix 2: D-mannitol, hydroxypropyl cellulose, croscarmellose sodium, and colloidal silica were added to the mixture obtained in step (1) in weight percentages and mixed uniformly;

[0263] (3) Granulation: The mixture obtained in step (2) was manually wet-granulated with pure water, sieved through a 20 mesh sieve, and dried at 60°C for 2 hours;

[0264] (4) Mixing: Magnesium stearate was mixed uniformly with the particles obtained in step (3) in a weight percentage;

[0265] (5) Tabletting: The mixture obtained in step (4) was tableted using a 9.5 mm round punch, controlled average weight difference ±3%, and tablet hardness 70N-80N to obtain tablets of 375 mg per tablet.

[0184]

[0266] Results: For the preparations of Examples VI-21 to VI-24, there were no problems such as picking, sticking, powder adhesion, unstable tablet weight, and too high or too low tablet hardness during tablet compression, and good compression ratios were achieved.

[0185]

[0267] The following Examples VI-25 to VI-29 employed substantially the same manufacturing method as Examples VI-21 to VI-24, but with different formulations to obtain tablets of 375 mg per tablet.

[0186]

[0268] Examples VI-25 to VI-27 JPEG2024045113000026.jpg123170

[0187]

[0269] Results: With the formulation of Example VI-25, there are no problems such as picking, sticking, powder adhesion, unstable tablet weight, and too high or too low tablet hardness during tablet compression, and good compressibility can be achieved.

[0188]

[0270] Compared with Examples VI-23 and VI-24, the main difference of the formulations of Examples VI-26 and VI-27 is that the content of colloidal silica as lubricant and magnesium stearate as lubricant is adjusted respectively. For the formulations of Examples VI-26 and VI-27, there is the phenomenon of powder adhesion, picking or sticking during the tableting process, resulting in relatively poor compressibility.

[0189]

[0271] Examples VI-28 and VI-29 JPEG2024045113000027.jpg131170

[0190]

[0272] Results: Compared with Example VI-21, the main difference of the formulations of Examples VI-28 and VI-29 is that the weight ratio of microcrystalline cellulose and D-mannitol as filler is adjusted to 5.3:1 and 1:5.3, respectively. For the formulations of Examples VI-28 and VI-29, there is the phenomenon of tablet capping during the tableting process, resulting in relatively poor compressibility.

[0191]

[0273] For the formulations described in the examples involving wet granulation, in addition to the content of lubricant and / or lubricant in the formulation and the weight ratio of the two fillers (microcrystalline cellulose and D-mannitol), the inventors also investigated other formulation parameters, including the type of filler, the type of binder, and the content of disintegrant. The results are similar to the effect of changes in the formulation parameters of the preparations produced by the manufacturing method involving dry granulation on the tablet compressibility and / or dissolution. That is, 1) the change in the type of filler (e.g., D-mannitol) affects the tablet compressibility (e.g., picking phenomenon occurs during the tableting process); 2) the change in the type of binder (i.e., hydroxypropyl cellulose) and / or the content of the binder exceeding the range defined in the present invention affects the tablet compressibility (e.g., the phenomenon of tablet sticking occurs during the tableting process or the tablet hardness is too low or too high); 3) the content of the disintegrant exceeding the range defined in the present invention does not affect the tablet compressibility and causes defects in tablet dissolution.

[0192]

[0274] In order to facilitate administration to children, the present inventors have explored tablet forms and dosages suitable for children, specifically in Examples VI-30 and VI-31.

[0193]

[0275] Example VI-30 JPEG2024045113000028.jpg72170

[0194]

[0276] Manufacturing method:

[0277] (1) API (active ingredient, i.e., 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) and mannitol were mixed uniformly in weight percentage;

[0278] (2) Sucrose and ascorbic acid were added to the mixture obtained in step (1) in weight percentages and mixed uniformly;

[0279] (3) pulverizing the mixture obtained in step (2) to obtain a fine powder;

[0280] (4) The fine powder obtained in step (3) was sieved through a 120 mesh sieve and packed into a packaging material (such as a small bag) to obtain a powder or a dry suspension.

[0195]

[0281] Example VI-31 JPEG2024045113000029.jpg47170

[0196]

[0282] Manufacturing method:

[0283] (1) API (active ingredient, i.e., 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) is mixed with microcrystalline cellulose in a uniform weight percentage;

[0284] (2) Sucrose and ascorbic acid were added to the mixture obtained in step (1) in weight percentages and mixed uniformly;

[0285] (3) The mixture obtained in step (2) was pulverized and sieved through a 60 mesh sieve.

[0286] (4) The undersized mixture obtained in step (3) was filled into a packaging material (such as a gelatin capsule) to obtain a capsule.

[0197]

[0287] VII. Examples of the Effects of Preparations

[0288] 1. In vitro dissolution experiments

[0289] The experiment was carried out by paddle apparatus method, with a rotation speed of 75 rpm and a dissolution medium of 900 ml. The dissolution curves of the pharmaceutical compositions obtained in Examples VI-1, VI-12, VI-13, and VI-20 in the dissolution medium, namely purified water + 0.1% CTAB, were measured respectively. At 5 minutes, 10 minutes, 15 minutes, 30 minutes, 45 minutes, and 60 minutes, appropriate amounts of the dissolution liquid were taken and filtered, and the filtrate was then used as the test liquid to determine the in vitro dissolution.

[0198]

[0290] The specific measurement results are shown in the table below. JPEG2024045113000030.jpg73170

[0199]

[0291] Conclusion: In the dissolution medium of purified water + 0.1% CTAB, the dissolution degree of the pharmaceutical compositions prepared in Examples VI-1 and VI-20 reached 80% or more within 30 minutes and 90% or more within 60 minutes. That is, the dissolution rate was high, the in vitro dissolution rate was high, and the dissolution requirements could be met. In contrast, the dissolution of the pharmaceutical composition prepared in Example VI-12 did not reach 60% within 60 minutes, while the pharmaceutical composition prepared in Example VI-13 met the dissolution requirements, but reached 80% or more within 5 minutes and 90% or more within 10 minutes, and the dissolution rate was too high. Therefore, the formulations of Examples VI-12 and VI-13 achieve good compressibility during tableting, but result in dissolution defects.

[0200]

[0292] Stability Experiments

[0293] The pharmaceutical compositions prepared according to the representative examples VI-1 and VI-20 were selected and packaged using oral high-density polyvinyl chloride bags as the inner packaging for testing. Routine accelerated experiments were carried out in the stability testing room for 1 month and 3 months under the conditions of 40°C, ±2°C, and 75%±5%RH to investigate the effect on the content of the relevant substances in the tested pharmaceutical compositions. JPEG2024045113000031.jpg82170

[0201]

[0294] Results: The participating substances in the pharmaceutical compositions prepared in Examples VI-1 and VI-20 did not change significantly under accelerated stability test conditions and met the requirements of quality standards, indicating that the pharmaceutical compositions of the present disclosure are stable.

[0202]

[0295] The above-described specific examples further describe the objectives, 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 intended to limit the protection scope of the present invention. Any modifications, equivalent exchanges, replacements, improvements, etc. made within the spirit and essence of the present invention shall be included in the protection scope of the present invention.

Claims

1. A drug substance comprising crystals composed of a compound of formula (I) and fumaric acid, wherein the crystals are crystals whose X-ray powder diffraction pattern obtained using Cu-Kα radiation contains peaks at 10.94°±0.2° 2θ, 19.06°±0.2° 2θ, 23.50°±0.2° 2θ and 24.66°±0.2° 2θ, and satisfy at least one of the following conditions: (1) The particle size D of the active ingredient 90 is in the range of 10 μm to 60 μm, (2) The particle size D of the active ingredient 50 does not exceed 30 μm and is 8.4 μm or more, characterized in that it is a drug substance.

2. The X-ray powder diffraction pattern of the crystals further comprises at least one peak selected from the group consisting of 9.5°±0.2° 2θ, 13.81°±0.2° 2θ, 18.61°±0.2° 2θ, 22.59°±0.2° 2θ, and 23.8°±0.2° 2θ, or further comprises at least one peak selected from the group consisting of 7.81°±0.2° 2θ, 10.14°±0.2° 2θ, 11.50°±0.2° 2θ, 11.93°±0.2° 2θ, and 12.31°±0.2° 2θ, or further comprises at least one peak selected from the group consisting of 14.73°±0.2° 2θ, 20.87°±0.2° 2θ, 21.49°±0.2° 2θ, 21.97°±0.2° 2θ and 25.39°±0.2° 2θ; the drug substance according to claim 1.

3. The X-ray powder diffraction pattern of the crystals contains peaks at 10.94°±0.2° 2θ, 19.06°±0.2° 2θ, 23.50°±0.2° 2θ, 24.66°±0.2° 2θ, 9.5°±0.2° 2θ, 13.81°±0.2° 2θ, 18.61°±0.2° 2θ, 22.59°±0.2° 2θ and 23.8°±0.2° 2θ; the drug substance according to claim 1.

4. In the crystals, the molar ratio of the compound of formula (I) to fumaric acid is 1:1; the drug substance according to claim 1.

5. The crystals have a purity of 98% or more, or the maximum content of a single impurity in the crystals does not exceed 0.1%; the drug substance according to claim 1.

6. The crystals comprise a co-crystal of the compound of formula (I) and fumaric acid, or a fumarate of the compound of formula (I); the drug substance according to claim 1.

7. A pharmaceutical composition comprising an active ingredient and a physiologically or pharmaceutically acceptable excipient, wherein the active ingredient is a crystal or a mixture of the crystal and an amorphous form, The crystal consists of the compound of formula (I) and fumaric acid, The crystal is a crystal whose X-ray powder diffraction pattern obtained using Cu-Kα rays includes peaks at 10.94° ± 0.2° 2θ, 19.06° ± 0.2° 2θ, 23.50° ± 0.2° 2θ, and 24.66° ± 0.2° 2θ, or, the active ingredient is the drug substance according to claim 1, The physiologically or pharmaceutically acceptable excipient includes one or more selected from the group consisting of a filler, a disintegrant, a lubricant, a binder, or a glidant, The filler is a mixture of microcrystalline cellulose and D-mannitol, or a mixture of microcrystalline cellulose and pregelatinized starch, The binder is hydroxypropyl cellulose, The disintegrant is croscarmellose sodium, The lubricant is colloidal silica, and / or, The glidant is magnesium stearate, When the filler is a mixture of microcrystalline cellulose and D-mannitol, the weight ratio of the microcrystalline cellulose to the D-mannitol is within the range of 1:5 to 5:1, The pharmaceutical composition is based on the total weight of the pharmaceutical composition, 30% to 70% by weight of the filler, 0.5% to 4% by weight of the glidant, 1% to 5% by weight of the binder, 0.5% to 4% by weight of the lubricant, and is characterized by a pharmaceutical composition.

8. The X-ray powder diffraction pattern of the crystal is, furthermore, includes at least one peak selected from the group consisting of 9.5° ± 0.2° 2θ, 13.81° ± 0.2° 2θ, 18.61° ± 0.2° 2θ, 22.59° ± 0.2° 2θ, and 23.8° ± 0.2° 2θ, or, furthermore, includes at least one peak selected from the group consisting of 7.81° ± 0.2° 2θ, 10.14° ± 0.2° 2θ, 11.50° ± 0.2° 2θ, 11.93° ± 0.2° 2θ, and 12.31° ± 0.2° 2θ, or, furthermore, includes at least one peak selected from the group consisting of 14.73° ± 0.2° 2θ, 20.87° ± 0.2° 2θ, 21.49° ± 0.2° 2θ, 21.97° ± 0.2° 2θ, and 25.39° ± 0.2° 2θ, and is characterized by the pharmaceutical composition according to claim 7.

9. The X-ray powder diffraction pattern of the crystal is characterized in that it includes peaks at 10.94°±0.2° 2θ, 19.06°±0.2° 2θ, 23.50°±0.2° 2θ, 24.66°±0.2° 2θ, 9.5°±0.2° 2θ, 13.81°±0.2° 2θ, 18.61°±0.2° 2θ, 22.59°±0.2° 2θ and 23.8°±0.2° 2θ. The pharmaceutical composition according to claim 7.

10. In the crystal, the molar ratio of the compound of formula (I) to the fumaric acid is 1:

1. The pharmaceutical composition according to claim 7.

11. The crystal has a purity of 98% or more, or the maximum content of a single impurity in the crystal does not exceed 0.1%. The pharmaceutical composition according to claim 7.

12. The crystal contains a co-crystal of the compound of formula (I) and fumaric acid, or a fumarate of the compound of formula (I). The pharmaceutical composition according to claim 7.

13. The pharmaceutical composition contains 15% to 60% by weight of the active ingredient based on the total weight of the pharmaceutical composition. The pharmaceutical composition according to claim 7.

14. The pharmaceutical composition contains 1% to 5% by weight of the disintegrant based on the total weight of the pharmaceutical composition. The pharmaceutical composition according to claim 7.

15. The pharmaceutical composition is an oral preparation, the pharmaceutical composition is in the form of a unit dose, and the pharmaceutical composition contains 1 mg to 500 mg of the active ingredient per unit dose. The pharmaceutical composition according to claim 7, characterized in that.

16. The pharmaceutical composition is an oral preparation, the pharmaceutical composition is in the form of a unit dose, and the pharmaceutical composition contains 50 mg to 200 mg of the active ingredient per unit dose, or contains the free base form of 40 mg to 170 mg of the active ingredient per unit dose. The pharmaceutical composition according to claim 15, characterized in that.

17. The pharmaceutical composition is in the form of tablets, and each tablet contains 152.4 mg of the active ingredient, or contains the free base form of 125 mg of the active ingredient. The pharmaceutical composition according to claim 16, characterized in that.

18. Containing the active pharmaceutical ingredient according to any one of claims 1 to 6 or the pharmaceutical composition according to any one of claims 7 to 17. A medicament for treating a disease caused by the coronavirus, characterized in that.

19. The pharmaceutical according to claim 18, wherein the coronavirus is 2019-nCoV.

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