CN117159556A

CN117159556A - Pharmaceutical composition and preparation method and application thereof

Info

Publication number: CN117159556A
Application number: CN202210860607.1A
Authority: CN
Inventors: 何红燕; 黄旺; 吴小涛; 王松笛; 鲍标贵
Original assignee: Nanjing Gritpharma Co ltd; Beijing Grand Johamu Pharmaceutical Co Ltd
Current assignee: Nanjing Gritpharma Co ltd; Beijing Grand Johamu Pharmaceutical Co Ltd
Priority date: 2022-05-27
Filing date: 2022-07-21
Publication date: 2023-12-05
Also published as: CN117159555A; CN115252619A; CN115252619B; CN115969858A

Abstract

The present application provides a pharmaceutical composition comprising a crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) with fumaric acid, and a physiologically acceptable/pharmaceutically acceptable excipient; wherein the crystalline form is as defined herein; wherein, the pharmaceutical composition adopts a paddle method, and the dissolution medium contains a surfactant in 500-900ml with a stirring speed of 50-80rpm, and has a dissolution rate of more than or equal to 70% within 60min under the condition of 37+/-0.5 ℃. The application also provides a preparation method of the pharmaceutical composition and application of the pharmaceutical composition in preparing medicines for treating or preventing diseases caused by coronaviruses in subjects. The pharmaceutical composition of the application has faster dissolution rate, higher dissolution rate and better bioavailability.

Description

Pharmaceutical composition and preparation method and application thereof

Technical Field

The present application relates to pharmaceutical compositions comprising a crystalline form of a compound and fumaric acid, to a process for their preparation and to their use in the manufacture of a medicament for the treatment of a disease caused by coronavirus in a subject.

Background

The prior art discloses compounds having therapeutic potential for diseases caused by coronaviruses, in particular novel coronaviruses, such as the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) and its crystalline form of fumaric acid. The crystalline form of fumaric acid, the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione, is poorly soluble and difficult to prepare into a pharmaceutically acceptable pharmaceutical composition, so there is an urgent need for a pharmaceutical composition which has good dissolution and bioavailability and can well meet the requirements of pharmaceutical formulation development.

Disclosure of Invention

The present invention provides a solution to the above problems existing in the prior art.

In a first aspect of the invention, there is provided a pharmaceutical composition comprising a crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) with fumaric acid, wherein the characteristic diffraction peaks of the (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-triazin-2, 4-dione) with fumaric acid using Cu-kα radiation, X-powder diffraction expressed in terms of 2 θ values ± 0.2 ° comprise any three of 10.94, 19.06, 23.50, 24.66;

Wherein, the pharmaceutical composition adopts a paddle method, and has dissolution rate of more than or equal to 70% in 60min under the condition of 37+/-0.5 ℃ in 500-900ml of dissolution medium at a stirring speed of 50-80 rpm; preferably, the dissolution rate is more than or equal to 75% in 60 min; more preferably, the dissolution rate is more than or equal to 80% in 60 min; the dissolution medium contains a surfactant.

In a second aspect of the invention, there is provided a pharmaceutical composition comprising a crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) with fumaric acid, and a physiologically acceptable/pharmaceutically acceptable excipient, wherein the X-ray powder diffraction peak expressed in terms of the 2 theta value ± 0.2 ° comprises a diffraction pattern of any of 10.66, 19.24.50, or any of 10.66, 19.24.6, or any of the following, using Cu-ka radiation for the crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-2, 4-triazol-3-yl) methyl ] -1- [ (2, 5-triazin-2, 4-dione) with fumaric acid;

wherein, the pharmaceutical composition adopts a paddle method, and has dissolution rate of more than or equal to 60% within 30min under the condition of 37+/-0.5 ℃ in 500-900ml of dissolution medium at a stirring speed of 50-80 rpm; preferably, the dissolution rate is more than or equal to 65% within 30 min; more preferably, the dissolution rate is more than or equal to 70% within 30 min; the dissolution medium contains a surfactant.

In a third aspect of the invention, there is provided a pharmaceutical composition comprising a crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) with fumaric acid, and a physiologically acceptable/pharmaceutically acceptable excipient, wherein the characteristic X-ray powder diffraction peak expressed in terms of the 2θ value ± 0.2 ° using Cu-ka radiation of the crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazin-2, 4-dione) with fumaric acid comprises any of diffraction patterns of 10.94, 19.66, 24.50, or any of; the pharmaceutical composition has an absolute bioavailability of 40% -90% after administration to beagle dogs.

In a fourth aspect of the present invention, there is provided a process for the preparation of a pharmaceutical composition of the present invention comprising the steps of:

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

(ii) Granulating the mixture obtained in the step (i), and sieving;

(iii) Optionally mixing the granules obtained in step (ii) with one or more other physiologically acceptable/pharmaceutically acceptable excipients besides the physiologically acceptable/pharmaceutically acceptable excipients described in step (i).

In a fifth aspect of the application, the use of a pharmaceutical composition of the application in the manufacture of a medicament for treating or preventing a disease caused by a coronavirus in a subject.

The application provides a pharmaceutical composition, which has good dissolution and bioavailability, and well meets the requirements of preparation development and clinical treatment.

Drawings

FIG. 1 is an X-ray powder diffraction pattern of 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) with fumaric acid. Wherein the abscissa is 2θ (°), and the ordinate is intensity (count).

FIG. 2 is a dissolution curve of example 8.

FIG. 3 is a dissolution curve of example 10.

Detailed Description

In the present application, relative humidity is represented by RH, and represents the percentage of saturated water vapor (saturated water vapor pressure) in the case where the amount of water vapor (water vapor pressure) contained in a gas (typically, in air) is the same as that of air.

The term "physiologically acceptable/pharmaceutically acceptable excipient" refers to an excipient that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the active ingredient (e.g., (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 crystalline form of fumaric acid that are administered in accordance with the present application.

The physiologically acceptable/pharmaceutically acceptable excipients that are admixed with the crystalline forms of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) of the present application with fumaric acid to form the pharmaceutical compositions of the present application may depend on the intended method of administration of the pharmaceutical composition.

The pharmaceutical composition of the present application is preferably a solid formulation.

The pharmaceutical compositions of the present application may be formulated for oral, inhalation, topical, nasal, rectal, transdermal or injectable administration.

The pharmaceutical composition of the present application may be administered orally.

The pharmaceutical composition of the present application is preferably prepared in the form of an oral formulation. The shape of the oral preparation is not particularly limited, and may be any one of a circle, a capsule, a ring (doughnut), a rectangle, and the like.

For solid preparations, for example, tablets, capsules, powders, granules, lozenges, and the like may be mentioned.

The solid formulation may be coated with a coating agent and may have indicia and letters for identification and further score lines for separation. The coating is carried out with the addition of conventional coating media and film forming agents (commonly referred to collectively as coating materials) familiar to those skilled in the art. The coating may be performed using, for example, a sugar coated substrate, a water-soluble film coated substrate, an enteric film coated substrate, a slow release film coated substrate, or the like. For sugar coated substrates, a combination of sucrose and one or more selected from the group consisting of: talc, precipitated calcium carbonate, gelatin, acacia, pullulan, carnauba wax, and the like. For the water-soluble film-coated substrate, for example, a cellulose polymer such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose, or the like can be used; synthetic polymers such as polyvinyl acetal diethylaminoethyl ester, aminoalkyl methacrylate copolymer E [ Eudragit E (trade name) ], polyvinyl pyrrolidone, and the like; polysaccharides such as pullulan and the like. For the enteric film-coated substrate, for example, a cellulose polymer such as hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethyl ethylcellulose, cellulose acetate phthalate, or the like can be used; acrylic polymers such as methacrylic copolymer L [ Eudragit L (trade name) ], methacrylic copolymer LD [ Eudragit L-30D55 (trade name) ], methacrylic copolymer S [ Eudragit S (trade name) ] and the like; naturally occurring substances, such as shellac and the like; etc. For the sustained-release film-coated substrate, for example, a cellulose polymer such as ethyl cellulose, cellulose acetate, etc. can be used; acrylic polymers such as aminoalkyl methacrylate copolymer RS [ Eudragit RS (trade name) ], ethyl acrylate-methyl methacrylate copolymer suspension [ Eudragit NE (trade name) ] and the like. Two or more of the above coating bases may be mixed in a suitable ratio. Furthermore, coating additives may be used in coating. For the coating additive, for example, a photo masking agent and/or a coloring agent such as titanium oxide, talc, iron oxide, etc. may be used; plasticizers such as polyethylene glycol, triethyl citrate, castor oil, polysorbate, and the like; organic acids such as citric acid, tartaric acid, malic acid, ascorbic acid, and the like.

Solid formulations may be formulated for immediate release (i.e., immediate release) and/or modified release. Modified release formulations include delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release.

When the solid preparation is a tablet, any pharmaceutically acceptable excipient commonly used for preparing solid preparations can be used. Tablets may be prepared by compression or molding, optionally with one or more physiologically acceptable/pharmaceutically acceptable excipients. Compressed tablets may also be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or capsule, optionally mixed with a binder, lubricant, filler, solubilizer or disintegrant. Shaped tablets may be prepared by shaping a mixture of the moistened powdered compound and an inert liquid dispersion medium in a suitable machine. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. The formulation of the tablets is described in "Pharmaceutical Dosage Forms: tablets, vol.1 ", by H.Lieberman and L.Lachman, marcel Dekker, N.Y., 1980.

When the solid formulation is a capsule, any conventional encapsulation is suitable, for example using the carriers mentioned above in a hard gelatin capsule. When the composition is in the form of a soft gelatin capsule, any physiologically acceptable/pharmaceutically acceptable excipient commonly used to prepare dispersing or suspending agents may be considered and incorporated into a soft gelatin capsule.

The pharmaceutical formulation may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy, whereby unit doses may be administered to a subject. Preferably, the pharmaceutical composition is in unit dosage form, e.g., a solid formulation in unit dosage form (e.g., a tablet, powder, dry suspension, granule, or capsule).

The term "subject" 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. In particular, the subject is 0 years old or older, 1 year old or older, 2 years old or older, 4 years old or older, 5 years old or older, 10 years old or older, 12 years old or older, 13 years old or older, 15 years old or older, 16 years old or older, 18 years old or older, 20 years old or older, 25 years old or older, 30 years old or older, 35 years old or older, 40 years old or older, 45 years old or older, 50 years old or older, 55 years old or older, 60 years old or older, 65 years old or older, 70 years old or older, 75 years old or older, 80 years old or older, 85 years old or older, 90 years old or older, 95 years old or older, 100 years old or older, or 105 years old or older.

The term "novel coronavirus" refers to 2019 novel coronavirus (2019-nCoV) or SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) published by the international committee for classification of viruses at month 2 of 2020, which applies that SARS-CoV-2 has the same meaning as 2019-nCoV, and also includes all variants thereof, such as all variants of the 2019 novel coronavirus, as encompassed by NCBI or GISAID (global shared influenza data initiative organization), particularly including important variants of greater importance, such as transmissibility, pathogenicity, or immune evasion, such as the WHO-specified Alpha, beta, gamma, delta, eta, iota, kappa, or Lambda variants, and later-specified important variants.

The term "starch" generally means a starch having the empirical formula (C ₆ H ₁₀ O ₅ ) _n (wherein n is 300-1000) and has a molecular weight of 50,000-160,000 and consists of amylose and amylopectin, both starches being polysaccharides based on alpha-glucose units. Starch is derived from plant material and is usually present in the form of very small particles (5-25 microns in diameter) consisting of a layered layer of starch molecules formed around a core. The starch granules may be round, oval or angular and consist of a radiooriented crystalline aggregate of two anhydrous D-glucose polymers (amylose and amylopectin). Amylose is a linear polymer of hundreds of glucose units linked by alpha-1-4 glycosidic linkages. Amylopectin is thousands of grapes with alpha-1-6 glycosidic linkages at the branched site and alpha-1-4 linkages in the linear region Branched polymers of saccharide units. Individual branches may have 20-30 glucose residues. Specifically, the starch is selected from starches having an amylose content in the range of 10 to 40% by weight. Typical examples are corn starch, potato starch, rice starch, tapioca starch and wheat starch.

The term "pregelatinized starch" is intended to define a starch that is broken down in whole or in part by chemical and/or mechanical processing in the presence of water and subsequently dried. Some types of pregelatinized starch can be modified to provide them with improved compressibility and flowability characteristics. Typical pregelatinized starches contain 5% free amylose, 15% free amylopectin and 80% unmodified starch. The pregelatinized starch can be corn starch processed by the chemical and/or mechanical methods described above. Other types of starches besides corn starch may be pregelatinized, such as rice or potato starch.

The term "surfactant" refers to a substance that significantly reduces the surface tension of a target solution. For example, surfactants can be classified as ionic surfactants (including cationic surfactants and anionic surfactants), nonionic surfactants, amphoteric surfactants, built surfactants, other surfactants, and the like. The surfactant may be selected from one or more of polysorbate 20 (tween-20), polysorbate 40 (tween-40), polysorbate 60 (tween-60), polysorbate 65 (tween-65), polysorbate 80 (tween-80), polysorbate 85 (tween-85), polyoxyethylated castor oil, polyoxyethylated hydrogenated castor oil, lecithin, polyvinylpyrrolidone, polyethylene glycols, polyoxyethylene and polyoxypropylene ethers (poloxamer 188, poloxamer 407, etc.), polyethylene-polypropylene copolymers, polyethylene-polypropylene glycols, polyoxyethylene-stearates, polyoxyethylene alkyl ethers, polyoxyethylene monolauryl ethers, alkylphenyl polyoxyethylene ethers (Triton-X), sodium Lauryl Sulfate (SLS), vitamin E or derivatives thereof (e.g. vitamin E TPGS), sodium docusate, glycerol monooleate, span 65, span 25, capryol 90, pluronic copolymers (e.g. pluronic F108, pluronic P-123), 15-hydroxy polyethylene glycol stearate, sodium Dodecyl Sulfate (SDS), cetyltrimethylammonium bromide (CTAB).

The term "phosphate buffer" refers to a buffer solution consisting of a substance capable of providing phosphate together with a base/acid (depending on the desired pH, either a base or an acid is chosen). Wherein the material capable of providing phosphate groups may be selected from phosphoric acid, hydrogen phosphate, dihydrogen phosphate, or a combination thereof; the base is typically an inorganic base, and may be selected from, for example, alkali metal hydroxides, alkali metal carbonates, alkali metal bicarbonates, or combinations thereof; and/or the acid is typically a mineral acid, which may be selected from hydrochloric acid, phosphoric acid, or a combination thereof, for example.

The term "acetate buffer" refers to a buffer capable of providing acetate ions. The acetate buffer is selected from acetic acid-sodium acetate, acetic acid-histidine salt, acetic acid-potassium acetate, acetic acid-calcium acetate, acetic acid-magnesium acetate, etc.

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

In a specific embodiment, the pharmaceutical composition of the invention has dissolution rate of not less than 70%,. Gtoreq.75%,. Gtoreq.80%,. Gtoreq.85%,. Gtoreq.90% or not less than 95% in a dissolution medium of 500-900ml tested at 37+ -0.5 ℃ using a paddle method at a stirring speed of 50-80rpm, wherein the dissolution medium contains a surfactant, which may be any one of CTAB, SDS, tween 20, tween 40, tween 60, tween 80, poloxamer 188, poloxamer 407, span 25, span 65, alkylphenyl polyoxyethylene ether (Triton-X), sodium Lauryl Sulfate (SLS), preferably any one of CTAB, SDS and tween 80. Preferably, the stirring speed is 55-75rpm. Preferably, the volume of the dissolution medium is 550-900ml.

In a specific embodiment, the dissolution medium further comprises any one selected from water, hydrochloric acid solution with pH value of 1.0-2.2, phosphoric acid (salt) buffer with pH value of 4.5-7.6, and acetic acid (salt) buffer with pH value of 3.4-6.0. In a specific embodiment, the pharmaceutical composition of the invention adopts a paddle method, and has dissolution rate of more than or equal to 70 percent, more than or equal to 75 percent, more than or equal to 80 percent, more than or equal to 85 percent, more than or equal to 90 percent or more than or equal to 95 percent in 500 ml to 900ml dissolution medium at 37+/-0.5 ℃ in 60 min; wherein the dissolution medium is hydrochloric acid solution with pH value of 1.0-2.2 and Tween 80. Specifically, the dissolution medium is pH1.2 hydrochloric acid solution+0.2% Tween 80.

In a specific embodiment, the pharmaceutical composition of the invention adopts a paddle method, and has dissolution rate of more than or equal to 70 percent, more than or equal to 75 percent, more than or equal to 80 percent, more than or equal to 85 percent, more than or equal to 90 percent or more than or equal to 95 percent in 500 ml to 900ml dissolution medium at 37+/-0.5 ℃ in 60 min; wherein the dissolution medium is phosphate buffer solution with pH value of 4.5-7.6 and CTAB. In particular, the dissolution medium is phosphate buffer at ph 6.8+0.1% ctab.

In a specific embodiment, the pharmaceutical composition of the invention adopts a paddle method, and has dissolution rate of more than or equal to 70 percent, more than or equal to 75 percent, more than or equal to 80 percent, more than or equal to 85 percent, more than or equal to 90 percent or more than or equal to 95 percent in 500 ml to 900ml dissolution medium at 37+/-0.5 ℃ in 60 min; wherein the dissolution medium is water+CTAB. Specifically, the dissolution medium is water+0.1% CTAB.

In a specific embodiment, the pharmaceutical composition of the invention adopts a paddle method, and has dissolution rate of more than or equal to 70 percent, more than or equal to 75 percent, more than or equal to 80 percent, more than or equal to 85 percent, more than or equal to 90 percent or more than or equal to 95 percent in 500 ml to 900ml dissolution medium at 37+/-0.5 ℃ in 60 min; wherein the dissolution medium is acetic acid (salt) buffer solution with pH value of 3.4-6.0 and 0.1% CTAB. Specifically, the dissolution medium is acetic acid (salt) buffer solution with pH value of 3.4-6.0 and 0.1% CTAB.

In a specific embodiment, the pharmaceutical composition of the invention adopts a paddle method, and has dissolution rate of more than or equal to 70 percent, more than or equal to 75 percent, more than or equal to 80 percent, more than or equal to 85 percent, more than or equal to 90 percent or more than or equal to 95 percent in 500 ml to 900ml dissolution medium at 37+/-0.5 ℃ in 60 min; wherein the dissolution medium is hydrochloric acid solution with pH value of 1.0-2.2 and CTAB. Specifically, the dissolution medium is hydrochloric acid solution with pH value of 1.0-2.2 and 0.1% CTAB.

In a specific embodiment, the pharmaceutical composition of the invention adopts a paddle method, and has dissolution rate of more than or equal to 70 percent, more than or equal to 75 percent, more than or equal to 80 percent, more than or equal to 85 percent, more than or equal to 90 percent or more than or equal to 95 percent in 500 ml to 900ml dissolution medium at 37+/-0.5 ℃ in 60 min; wherein the dissolution medium is water+SDS. Specifically, the dissolution medium is water+0.2% SDS.

In a specific embodiment, the pharmaceutical composition of the invention has dissolution rate of not less than 60%,. Gtoreq.65%,. Gtoreq.70%,. Gtoreq.75%,. Gtoreq.80%,. Gtoreq.85%,. Gtoreq.90% or more than 95% in 500-900ml of dissolution medium tested at 37+ -0.5 ℃ in 30min using paddle method at 50-80rpm stirring speed; wherein the dissolution medium contains a surfactant, and the surfactant can be any one of CTAB, SDS, tween 20, tween 40, tween 60, tween 80, poloxamer 188, poloxamer 407, span 25, span 65, alkylphenyl polyoxyethylene ether (Triton-X) and Sodium Lauryl Sulfate (SLS). Preferably, the surfactant is any one of CTAB, SDS and Tween 80. Preferably, the stirring speed is 55-75rpm. Preferably, the volume of the dissolution medium is 550-900ml.

In a specific embodiment, the dissolution medium further comprises any one selected from water, hydrochloric acid solution with pH value of 1.0-2.2, phosphoric acid (salt) buffer with pH value of 4.5-7.6, and acetic acid (salt) buffer with pH value of 3.4-6.0. In a specific embodiment, the pharmaceutical composition of the invention has dissolution rate of not less than 60%,. Gtoreq.65%,. Gtoreq.70%,. Gtoreq.75%,. Gtoreq.80%,. Gtoreq.85%,. Gtoreq.90% or more than 95% in 500-900ml of dissolution medium tested at 37+ -0.5 ℃ in 30min using paddle method at 50-80rpm stirring speed; wherein the dissolution medium is hydrochloric acid solution with pH value of 1.0-2.2 and Tween 80. Specifically, the dissolution medium is hydrochloric acid solution with pH value of 1.0-2.2 and Tween 80 with pH value of 0.2%.

In a specific embodiment, the pharmaceutical composition of the invention has dissolution rate of not less than 60%,. Gtoreq.65%,. Gtoreq.70%,. Gtoreq.75%,. Gtoreq.80%,. Gtoreq.85%,. Gtoreq.90% or more than 95% in 500-900ml of dissolution medium tested at 37+ -0.5 ℃ in 30min using paddle method at 50-80rpm stirring speed; the dissolution medium is phosphate buffer solution with pH value of 4.5-7.6 and CTAB. Specifically, the dissolution medium is phosphate buffer solution with pH value of 4.5-7.6 and CTAB with concentration of 0.1%.

In a specific embodiment, the pharmaceutical composition of the invention has dissolution rate of not less than 60%,. Gtoreq.65%,. Gtoreq.70%,. Gtoreq.75%,. Gtoreq.80%,. Gtoreq.85%,. Gtoreq.90% or more than 95% in 500-900ml of dissolution medium tested at 37+ -0.5 ℃ in 30min using paddle method at 50-80rpm stirring speed; wherein the dissolution medium is water+CTAB. Specifically, the dissolution medium is water+0.1% ctab.

In a specific embodiment, the pharmaceutical composition of the invention has dissolution rate of not less than 60%,. Gtoreq.65%,. Gtoreq.70%,. Gtoreq.75%,. Gtoreq.80%,. Gtoreq.85%,. Gtoreq.90% or more than 95% in 500-900ml of dissolution medium tested at 37+ -0.5 ℃ in 30min using paddle method at 50-80rpm stirring speed; wherein the dissolution medium is acetic acid (salt) buffer solution with pH value of 3.4-6.0 and 0.1% CTAB. Specifically, the dissolution medium is acetic acid (salt) buffer solution with pH value of 3.4-6.0 and 0.1% CTAB.

In a specific embodiment, the pharmaceutical composition of the invention has dissolution rate of not less than 60%,. Gtoreq.65%,. Gtoreq.70%,. Gtoreq.75%,. Gtoreq.80%,. Gtoreq.85%,. Gtoreq.90% or more than 95% in 500-900ml of dissolution medium tested at 37+ -0.5 ℃ in 30min using paddle method at 50-80rpm stirring speed; wherein the dissolution medium is hydrochloric acid solution with pH value of 1.0-2.2 and CTAB. Specifically, the dissolution medium is hydrochloric acid solution with pH value of 1.0-2.2 and 0.1% CTAB.

In a specific embodiment, the pharmaceutical composition of the invention has dissolution rate of not less than 60%,. Gtoreq.65%,. Gtoreq.70%,. Gtoreq.75%,. Gtoreq.80%,. Gtoreq.85%,. Gtoreq.90% or more than 95% in 500-900ml of dissolution medium tested at 37+ -0.5 ℃ in 30min using paddle method at 50-80rpm stirring speed; wherein the dissolution medium is water+SDS. Specifically, the dissolution medium is water+0.2% SDS.

In a specific embodiment, the pharmaceutical composition of the invention adopts a paddle method, and has dissolution rate of not less than 70 percent, not less than 75 percent, not less than 80 percent, not less than 85 percent, not less than 90 percent or not less than 95 percent in 60min, and simultaneously has dissolution rate of not less than 60 percent, not less than 65 percent, not less than 70 percent, not less than 75 percent, not less than 80 percent, not less than 85 percent, not less than 90 percent or not less than 95 percent in 30min in 500-900ml dissolution medium at 37+/-0.5 ℃; wherein the dissolution medium comprises a surfactant, and the surfactant can be any one of CTAB, SDS, tween 20, tween 40, tween 60, tween 80, poloxamer 188, poloxamer 407, span 25, span 65, alkylphenyl polyoxyethylene ether (Triton-X) and Sodium Lauryl Sulfate (SLS). Preferably, the surfactant is any one of CTAB, SDS and Tween 80.

In a specific embodiment, the dissolution medium further comprises any one selected from water, hydrochloric acid solution with pH value of 1.0-2.2, phosphoric acid (salt) buffer with pH value of 4.5-7.6, and acetic acid (salt) buffer with pH value of 3.4-6.0.

In a specific embodiment, the pharmaceutical composition of the invention has an absolute bioavailability of 40% -90%, preferably 40% -70% after administration to beagle dogs.

In a specific embodiment, the pharmaceutical composition of the invention has a T of less than 3 hours after administration to beagle dogs _max Values. Preferably, T is less than 2h or 1h _max Values.

In a specific embodiment, the pharmaceutical composition of the invention has a C of 4-11 μg/mL after administration to beagle dogs _max The value is preferably 5-10. Mu.g/mL C _max Values.

In a specific embodiment, the pharmaceutical composition of the invention AUC after administration to beagle dogs _0-inf The range of (2) is 100-200. Mu.g.h/mL.

In a specific embodiment, the pharmaceutical composition of the invention provides a T of less than 2h after administration to rats _max A value of preferably, providing a T of less than 1.5, 1h or 0.5h _max Values.

In a specific embodiment, the pharmaceutical composition of the invention provides C after administration to rats _max The value ranges from 10. Mu.g/mL to 25. Mu.g/mL, preferably, C is provided _max The values ranged from 13 μg/mL to 24 μg/mL.

In a specific embodiment, the pharmaceutical composition of the invention provides an AUC after administration to rats _0-inf In the range of 80. Mu.g.h/mL to 200. Mu.g.h/mL, preferably providing an AUC _0-inf The range of (C) is 100. Mu.g.h/mL-200. Mu.g.h/mL.

In a specific embodiment, the pharmaceutical composition of the invention has a half-life of 2-4 hours, preferably 2.2-3.8 hours, after administration to rats.

In a specific embodiment, the crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) and fumaric acid is present in the pharmaceutical composition in a weight percentage of 15% -60%, preferably 25% -45%, e.g. 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% or 59%.

In a specific embodiment, the physiologically acceptable/pharmaceutically acceptable excipient is selected from one or more of fillers, disintegrants, lubricants, binders, solubilizers, glidants. In particular, the physiologically acceptable/pharmaceutically acceptable excipients consist of fillers, disintegrants, lubricants, optional binders, optional solubilizers, and glidants.

In a specific embodiment, the filler is present in the pharmaceutical composition in a weight percentage of 10% -80%, preferably 30% -65%, for example 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% or 80%. Alternatively, the filler may be present in the pharmaceutical composition (e.g., per unit dose of the pharmaceutical composition) in an amount of 50-300mg, preferably 100-280mg, and more preferably 110-250mg, for example, 50mg, 60mg, 70mg, 80mg, 90mg, 100mg, 110mg, 120mg, 130mg, 140mg, 150mg, 160mg, 170mg, 180mg, 190mg, 200mg, 210mg, 220mg, 230mg, 240mg, 250mg, 260mg, 270mg, 280mg, 290mg, or 300mg.

In a specific embodiment, the weight percentage of disintegrant in the pharmaceutical composition is 1% to 10%, preferably 2% to 5%, for example 2%,3%,4% or 5%. Alternatively, the disintegrant may also be 1mg to 37mg, more preferably 5mg to 30mg, for example 1mg, 2mg, 3mg, 4mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg, 15mg, 16mg, 17mg, 18mg, 19mg, 20mg, 21mg, 22mg, 23mg, 24mg, 25mg, 26mg, 27mg, 28mg, 29mg or 30mg in a pharmaceutical composition (e.g., pharmaceutical composition per unit dose).

In a specific embodiment, the weight percentage of lubricant in the pharmaceutical composition is 0.5% -5%, preferably 1-3%, for example 0.6%,0.7%,0.8%,0.9%,1%,2% or 3%. Alternatively, the lubricant may be 1mg to 15mg, further preferably 5mg to 8mg, for example 1mg, 2mg, 3mg, 4mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg or 14mg.

In a specific embodiment, the weight percentage of binder in the pharmaceutical composition is 0% -10%, preferably 1-3%, for example 1.1%,1.2%,1.3%,1.4%,1.5%,1.6%,1.7%,1.8%,1.9%,2%,2.1%,2.2%, 2.3%,2.4%,2.5%,2.6%,2.7%,2.8%,2.9% or 3%. Alternatively, the binder may also be present in the pharmaceutical composition (e.g. per unit dose of the pharmaceutical composition) in an amount of 1mg-15mg, further preferably 5mg-8mg, e.g. 1mg, 2mg, 3mg, 4mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg or 14mg.

In a specific embodiment, the weight percentage of the solubilizing agent in the pharmaceutical composition is 0% -5%, preferably 0.5-3%, for example 0.6%,0.7%,0.8%,0.9%,1%,1.5%,2%,2.5% or 3%. Alternatively, the solubilizer may be present in the pharmaceutical composition (e.g., pharmaceutical composition per unit dose) in an amount of 1mg to 15mg, more preferably 5mg to 8mg, for example, 1mg, 2mg, 3mg, 4mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg or 14mg.

In a specific embodiment, the glidant is present in the pharmaceutical composition in an amount of 0.5% to 5%, preferably 2-3%, for example 0.6%,0.7%,0.8%,0.9%,1%,1.5%,2%,2.5%,3% or 4% by weight. Alternatively, the glidant may be present in the pharmaceutical composition (e.g. per unit dose of the pharmaceutical composition) in an amount of 1mg to 15mg, more preferably 5mg to 8mg, for example 1mg, 2mg, 3mg, 4mg, 5mg, 5.5mg, 6mg, 6.5mg, 7mg, 7.5mg, 8mg, 9mg, 10mg, 11mg, 12mg, 13mg, 14mg or 15mg.

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

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

In a specific embodiment, the weight ratio of glidant to lubricant is in the range of 1:3 to 3:1, preferably in the range of 1:2 to 2:1.

In a specific embodiment, the weight ratio of solubilizer, if present, to lubricant is in the range of 1:3 to 3:1, preferably in the range of 1:2 to 2:1.

In a specific embodiment, the weight ratio of binder, if present, to lubricant is in the range of 1:3 to 3:1, preferably in the range of 1:2 to 2:1.

In a specific embodiment, the filler comprises one or more of anhydrous calcium bicarbonate, sugar alcohols, celluloses, and starches. For example, the sugar alcohol filler includes one or more of mannitol, maltitol, erythritol, lactitol, sorbitol, and xylitol. For example, the cellulosic filler includes one or more of microcrystalline cellulose, powdered cellulose, and silicified microcrystalline cellulose. For example, the starch-based filler includes one or more of corn starch, potato starch, sweet potato starch, and pregelatinized starch, preferably pregelatinized starch.

Specifically, the filler is selected from one or more of anhydrous calcium bicarbonate, sugar alcohols, celluloses and starches. For example, the sugar alcohol filler is selected from one or more of mannitol, maltitol, erythritol, lactitol, sorbitol and xylitol, preferably mannitol. For example, the cellulose filler is selected from one or more of microcrystalline cellulose, powdered cellulose, and silicified microcrystalline cellulose, preferably microcrystalline cellulose and/or silicified microcrystalline cellulose. For example, the starch-based filler is selected from one or more of corn starch, potato starch, sweet potato starch and pregelatinized starch, preferably pregelatinized starch.

For example, the filler is microcrystalline cellulose, pregelatinized starch, mannitol, or a mixture of two or more thereof (e.g., a mixture of microcrystalline cellulose and pregelatinized starch; or a mixture of microcrystalline cellulose and mannitol).

In a specific embodiment, the disintegrant comprises one or more of crospovidone, croscarmellose sodium, hydroxypropyl cellulose, sodium carboxymethyl starch, corn starch, and potato starch. Specifically, the disintegrating agent is selected from one or more of crospovidone, croscarmellose sodium, hydroxypropyl cellulose, sodium carboxymethyl starch, corn starch and potato starch, preferably crospovidone, croscarmellose sodium and/or hydroxypropyl cellulose.

In a specific embodiment, the lubricant comprises one or more of magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oil, glyceryl behenate, stearic acid and sodium stearyl fumarate. Specifically, the lubricant is selected from one or more of magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oil, glyceryl behenate, stearic acid and sodium stearyl fumarate, preferably magnesium stearate and/or sodium stearyl fumarate.

In a specific embodiment, the binder comprises one or more of hypromellose, hyprolose, methylcellulose, hydroxyethylcellulose, carboxymethylcellulose, copovidone, and polyvinylpyrrolidone. Specifically, the binder is selected from one or more of hypromellose, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, copovidone, and polyvinylpyrrolidone, preferably hypromellose, and/or copovidone, such as hyprolose. Specifically, the binder may be present or absent.

In a specific embodiment, the solubilizing agent comprises one or more of sodium dodecyl sulfate, polysorbate 80, polyoxyethylene hydrogenated castor oil, and poloxamer. Specifically, the solubilizer is selected from one or more of sodium dodecyl sulfate, polysorbate 80, polyoxyethylene hydrogenated castor oil and poloxamer, preferably sodium dodecyl sulfate.

In a specific embodiment, the glidant comprises colloidal silicon dioxide and/or talc. In particular, the glidant is selected from colloidal silicon dioxide and/or talc, for example colloidal silicon dioxide.

In a specific embodiment, the physiologically acceptable/pharmaceutically acceptable excipient is selected from one or more of pregelatinized starch, microcrystalline cellulose, mannitol, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, magnesium stearate, sodium stearyl fumarate, sodium lauryl sulfate, colloidal silicon dioxide, copovidone. In particular, the physiologically acceptable/pharmaceutically acceptable excipients consist of mannitol, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, sodium stearyl fumarate, sodium lauryl sulfate, colloidal silicon dioxide; alternatively, the physiologically acceptable/pharmaceutically acceptable excipient consists of microcrystalline cellulose, pregelatinized starch, crospovidone, magnesium stearate, sodium stearyl fumarate, sodium lauryl sulfate, colloidal silicon dioxide; alternatively, the physiologically acceptable/pharmaceutically acceptable excipient consists of pregelatinized starch, microcrystalline cellulose, croscarmellose sodium, magnesium stearate, sodium stearyl fumarate, sodium lauryl sulfate, colloidal silicon dioxide, copovidone; alternatively, the physiologically acceptable/pharmaceutically acceptable excipient consists of pregelatinized starch, microcrystalline cellulose, hydroxypropyl cellulose, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide; alternatively, the physiologically acceptable/pharmaceutically acceptable excipient consists of microcrystalline cellulose, crospovidone, mannitol, croscarmellose sodium, magnesium stearate, colloidal silicon dioxide; alternatively, the physiologically acceptable/pharmaceutically acceptable excipient consists of microcrystalline cellulose, lactose, croscarmellose sodium, magnesium stearate, sodium stearyl fumarate, sodium lauryl sulfate, colloidal silicon dioxide. Wherein the weight percentage or content of the above specific physiologically acceptable/pharmaceutically acceptable excipients (e.g. pregelatinized starch, microcrystalline cellulose, lactose, mannitol, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, magnesium stearate, sodium stearyl fumarate, sodium lauryl sulfate, colloidal silicon dioxide and/or copovidone) is as defined above.

In a specific embodiment, the crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) with fumaric acid uses Cu-K alpha radiation and the characteristic diffraction peak of the X-ray powder diffraction pattern expressed in terms of 2 theta values.+ -. 0.2 ℃ further comprises any one or more of 9.5, 13.81, 18.61, 22.59, 23.8, preferably further comprises any one or more of 7.81, 10.14, 11.50, 11.93, 12.31, more preferably still further comprises any one or more of 14.73, 20.87, 21.49, 21.97, 25.39.

In a specific embodiment, the crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) with fumaric acid uses Cu-K alpha radiation, and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2 theta values.+ -. 0.2 ℃ are at 10.94, 19.06, 23.50, 24.66, 9.5, 13.81, 18.61, 22.59, 23.8; preferably, it uses Cu-ka radiation, and the X-ray powder diffraction pattern expressed in terms of 2θ values ± 0.2 ° is shown in fig. 1.

In a specific embodiment, the differential scanning calorimeter profile of the crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) with fumaric acid has an endothermic peak in the range of 274 ℃ + -2 ℃.

In a specific embodiment, the thermogravimetric profile of the crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) with fumaric acid is substantially free of weight loss or less than 0.5% weight loss over a range of 150 ℃ and undergoes decomposition at 240 ℃ ± 2 ℃.

In a specific embodiment, the ratio of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) to fumaric acid in the crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione is 1:1.

In a specific embodiment, the pharmaceutical composition is an oral formulation, preferably an oral solid formulation (e.g., tablet, powder, dry suspension, granule or capsule).

In a specific embodiment, the pharmaceutical composition is in unit dosage form, e.g., a solid formulation in unit dosage form (e.g., a tablet, powder, dry suspension, granule, or capsule).

When the oral solid preparation of the present invention is preferably a tablet, the tablet may have a film coating for easy swallowing of the tablet. The film coating may comprise a film coating agent (e.g., hydroxypropyl methylcellulose, polyethylene glycol (macrogol), talc) and a colorant (e.g., titanium dioxide, iron oxide pigment yellow).

In a specific embodiment, when the pharmaceutical composition of the invention is in the form of a solid formulation in unit dosage form (such as a tablet, powder, dry suspension, granule or capsule), 1mg to 500mg, preferably 10mg to 300mg, more preferably 50mg to 200mg of the crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione, and fumaric acid, and optionally one or more other active ingredients, are included per unit dose of the pharmaceutical composition; for example, the pharmaceutical composition comprises 50mg, 55mg, 60mg, 65mg, 70mg, 75mg, 80mg, 85mg, 90mg, 95mg, 100mg, 105mg, 110mg, 115mg, 120mg, 125mg, 130mg, 135mg, 140mg, 145mg, 150mg, 151mg, 152mg, 152.1mg, 152.2mg, 152.3mg, 152.4mg, 152.5mg, 152.6mg, 152.7mg, 152.8mg, 152.9mg, 153mg, 154mg, 155mg, 160mg, 165mg, 170mg, 180mg, 185mg, 190mg, 195mg or 200mg of active ingredient per unit dose. .

When the pharmaceutical composition is an oral preparation (such as tablets, powder, dry suspension, granules and capsules), the administration of the pharmaceutical composition is convenient for a subject, or the administration compliance of the subject (especially children, the elderly or dysphagia patients) is improved, and the risk possibly brought by excessive administration of the injection medicine is avoided.

In a specific embodiment, in the process for the preparation of a pharmaceutical composition according to the application, step (i) is carried out by: the crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione is mixed (homogenized) with fumaric acid in sequence, filler, disintegrant, optional binder, optional solubilizer, glidant. Specifically, step (i) is achieved by: (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione is first mixed (homogenized) with the crystalline form of fumaric acid and with the filler, followed by addition of the disintegrant, optionally the binder, optionally the solubilizer, and the glidant (homogenized). Preferably, step (i) is achieved by: (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione is first mixed (homogenized) with the crystalline form of fumaric acid and the first filler, and then a second filler, a disintegrant, optionally a binder, optionally a solubilizer, a glidant are added to mix (homogenized). The first filler and the second filler may be the same or different, and preferably, the first filler is the cellulose filler according to the present application, and the second filler is the starch filler according to the present application. Preferably, the mixing is achieved by stirring, preferably by manual stirring or stirring in a mixing device such as a hopper mixer.

In a specific embodiment, in the process for the preparation of a pharmaceutical composition according to the invention, step (ii) is carried out by: subjecting the mixture obtained in step (i) to wet granulation or dry granulation and sieving. In particular, wet granulation or dry granulation is a process that one skilled in the art can perform according to formulation requirements. Preferably, wet granulation is carried out by mixing the mixture obtained in step (i) with water and granulating by a wet granulator; alternatively, dry granulation is carried out by granulating the mixture obtained in step (i) by a dry granulator or by compacting the mixture obtained in step (i) into large pieces, crushing, sieving. Preferably, the sieving is accomplished through a 20-80 mesh screen (e.g., a 40-60 mesh screen).

In a specific embodiment, in the process for the preparation of a pharmaceutical composition according to the invention, step (iii) is carried out by: mixing (homogenizing) the particles obtained in step (ii) with a lubricant. Preferably, the mixing is achieved by stirring, preferably by manual stirring or stirring in a mixing device such as a hopper mixer.

In a specific embodiment, the method of preparing a pharmaceutical composition of the present invention further comprises the steps of: (iv) tabletting the mixture obtained in step (iii). In particular, tabletting is performed by a tablet press (e.g., a single punch tablet press).

In a specific embodiment, the subject is a human, preferably a child, adult or elderly human, for example a child aged 0-18 years (e.g. 0-12 years), an adult aged 19-59 years or elderly human aged 60 years or older. In particular, when the pharmaceutical composition of the application is a granule or a dry suspension, the subject is preferably a child (e.g., a child aged 0-12); when the pharmaceutical composition of the present application is in the form of a tablet or capsule, the subject is preferably an adult or an elderly person; when the pharmaceutical composition of the present application is an oral liquid formulation, the subject is preferably a child (e.g., a child aged 0-12 years), an elderly person, or a dysphagia person.

In another aspect, the application also provides the use of the crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) according to the application with fumaric acid for the preparation of a pharmaceutical composition, wherein the pharmaceutical composition comprises (or consists of) the following components: (6E) Crystalline forms of 6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) with fumaric acid and physiologically acceptable/pharmaceutically acceptable excipients. In particular, the physiologically acceptable/pharmaceutically acceptable excipients are as defined above.

In yet another aspect, the present invention provides another method of preparing a pharmaceutical composition of the present invention comprising the steps of: (i) Mixing (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) with a crystalline form of fumaric acid (homogeneity) with a physiologically acceptable/pharmaceutically acceptable excipient; (ii) tabletting the mixture obtained in step (i). In particular, the physiologically acceptable/pharmaceutically acceptable excipients are as defined above.

The various embodiments described herein, or of different preferred classes of embodiments, may be combined arbitrarily unless otherwise indicated.

The present invention is illustrated below by way of examples, but it should not be construed that the scope of the inventive subject matter is limited to the following examples. All techniques implemented based on the above description of the invention are within the scope of the invention. The compounds or reagents used in the following examples are commercially available or are prepared by conventional methods known to those skilled in the art; the laboratory apparatus used is commercially available.

Specifically, in the preparation examples, mannitol was purchased from Qingdao Bicheng seaweed Co., ltd, microcrystalline cellulose was purchased from Sian Gao pharmaceutical Co., ltd, croscarmellose sodium was purchased from Jiangxi alpha Gao pharmaceutical Co., ltd, colloidal silicon dioxide was purchased from Shanghai Feng pharmaceutical Co., ltd, magnesium stearate was purchased from Hebei Pengyo Biotechnology Co., ltd, sodium stearyl fumarate was purchased from Wuhan Kano Biotechnology Co., ltd, sodium dodecyl sulfate was purchased from Sian brocade Source Biotechnology Co., ltd, pregelatinized starch was purchased from Hebei Innova Biotechnology Co., ltd, crospovidone was purchased from Sian Tahua pharmaceutical technology Co., vitamin one was purchased from Hei Ling pharmaceutical technology Co., ltd, hydroxypropyl cellulose was purchased from Miyashilan chemical (Nanj) Co., and lactose was purchased from Shanghai Tao real Co., ltd.

Examples

I. Preparation examples of crystalline forms of the Compound and fumaric acid

45 g 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-trifluoro-phenyl) methyl ] -1,3, 5-triazine-2, 4-dione are added into 450ml of 10V acetone, the mixture is uniformly mixed, 9.8 g of fumaric acid is added after the mixture is uniformly stirred, the mixture is uniformly stirred after the mixture is heated to 55 ℃ for reflux reaction for 4 to 5 hours, the mixture is naturally cooled to room temperature of 25 ℃ after the reaction is completed, the mixture is sufficiently stirred for 4 to 5 hours at room temperature, the mixture is filtered by suction, a filter cake is washed by an appropriate amount of EA, and 52 g of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -1- [ (1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4-trifluoro-phenyl) methyl ] -1, 5-triazine-2, 4-dione is obtained after the mixture is dried in vacuum.

The crystalline form a was subjected to characterization by X-ray powder diffractometer PANalytical Empyrean (PANalytical, NL). The 2 theta scanning angle is from 3 degrees to 45 degrees, the scanning step length is 0.013 degrees, and the testing time is 5 minutes and 8 seconds. The voltage and current of the light pipe are 45kV and 40mA respectively when the sample is tested, and the sample disk is a zero background sample disk.

(6E) XRPD diffraction peak data for crystalline form a of-6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) with fumaric acid

/>

The characteristic diffraction peaks described above, the principal characteristic diffraction peaks selected from any three of 10.94, 19.06, 23.50, 24.66, further comprising any one or more of 9.5, 13.81, 18.61, 22.59, 23.8, further comprising any one or more of 7.81, 10.14, 11.50, 11.93, 12.31, or further comprising any one or more of 14.73, 20.87, 21.49, 21.97, 25.39, or further comprising any one or more of 10.94, 19.06, 23.50, 24.66, 9.5, 13.81, 18.61, 22.59, 23.8, in particular, (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, 5-triazin-2, 4-dioptric acid, as shown in figure xr-1, 4-triazinone, in the spectrum of figure.

Conclusion: by comparing the characteristic peaks of XRPD, the characteristic peaks of the crystal form A and the crystal form B which are obviously different can be determined as two different crystal forms.

The inventors examined the accelerated stability of crystalline form a after determining the different crystalline forms of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) and fumaric acid. Specifically, the crystalline form a of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione prepared and fumaric acid were placed in a stability test box at 40 ℃ under a Relative Humidity (RH) of 75%, placed for 2 months, sampled for 1 month and 2 months, respectively, observed for appearance and checked for purity, and the details are given in the following table.

Results: at 40 ℃ and Relative Humidity (RH) 75%, the (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-triazin-2, 4-dione is stable with the crystalline form A of fumaric acid, and the crystalline form A keeps stable appearance and purity within 2 months, and does not dissociate or transcrystalline.

Due to the characteristic of better crystal form A, preparation investigation and research of the crystal form A are continued.

Pharmacokinetic test of crystalline form A of Compounds with fumaric acid (drug substance)

According to the invention, 6 SD rats are randomly crossed, the 6 SD rats are randomly divided into 4 groups according to weight layering by weighing the rats in the day before the test, and the single gastric lavage administration group is fasted for at least 12 hours before administration, and raw material medicines prepared by solvent (0.5% Methylcellulose (MC)) are respectively administered by gastric lavage. The jugular vein of SD rat is sampled to about 0.2mL to a blood sampling tube containing EDTA-K2, the blood is gently shaken after blood sampling to fully and uniformly mix the blood with an anticoagulant, the blood is temporarily placed in wet ice, the centrifugation is completed within 1.5h after the collection, and the plasma is collected after the centrifugation. The drug concentration in SD rat plasma samples was quantitatively detected by LC-MS/MS method. And (3) fitting the obtained original data through instrument software to obtain a standard curve equation and a correlation coefficient, and calculating the concentration of the drug in the biological sample at each sampling time point. Statistical analysis was performed on the raw data, and the drug concentration and time data in the samples were calculated for pharmacokinetic parameters using WinNonLin software (version 8.3) according to non-compartmental model method (NCA).

The pharmacokinetic results are shown in the following table:

as shown in the table above, under the dosage condition of 10mg/kg of the bulk drug administered to rats, the bulk drug reflects specific bioavailability, the average absolute bioavailability is 74.26%, and the peak time T is reached _max Less than 2 hours. It can be seen that the bioavailability of the drug substance in vivo is higher and the peak time is shorter. When the bulk drug is prepared into a pharmaceutical composition, the dissolution rate of the pharmaceutical composition is an important factor influencing the bioavailability in vivo, and poor dissolution rate of the pharmaceutical composition greatly influences the bioavailability of the drug in vivo, so that the pharmaceutical composition prepared by using the bulk drug has higher dissolution rate and better accumulated dissolution rate on the premise of higher bioavailability of the bulk drug and shorter peak time. Under this guidelines, I have prepared a series of pharmaceutical compositions.

Formulation examples of pharmaceutical compositions

Example 1

The preparation method comprises the following steps:

(1) Uniformly mixing (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) with crystalline form A of fumaric acid and mannitol;

(2) Adding microcrystalline cellulose, croscarmellose sodium, sodium dodecyl sulfate and colloidal silicon dioxide into the mixture obtained in the step (1) and uniformly mixing;

(3) Pressing the mixture obtained in the step (2) into large pieces, crushing and sieving with a 20-mesh sieve;

(4) Uniformly mixing the particles obtained in the step (3) with magnesium stearate and sodium stearyl fumarate;

(5) Tabletting the mixture obtained in the step (4), and adopting 9.5mm round punching to control the average weight difference to +/-3%, wherein the tabletting hardness is 85N, so as to obtain tablets with the tablet weight of 375 mg.

Example 2

The preparation method comprises the following steps:

(1) Uniformly mixing (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) with crystalline form A of fumaric acid and microcrystalline cellulose;

(2) Adding pregelatinized starch, crospovidone, sodium dodecyl sulfate and colloidal silicon dioxide into the mixture obtained in the step (1) and uniformly mixing;

(5) Tabletting the mixture obtained in the step (4), and controlling the average weight difference to +/-3% by adopting 9.5mm round punch, wherein the tabletting hardness is 70N, so as to obtain a tablet with the tablet weight of 375 mg.

Example 3

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The preparation method comprises the following steps:

(2) Adding pregelatinized starch, crosslinked sodium carboxymethyl cellulose, sodium dodecyl sulfate, copovidone and colloidal silicon dioxide into the mixture obtained in the step (1) and uniformly mixing;

(5) Tabletting the mixture obtained in the step (4), and adopting 9.5mm round punching to control the average weight difference to +/-3%, wherein the tabletting hardness is 70N-80N, so as to obtain tablets with the tablet weight of 375 mg.

Example 4

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The preparation method comprises the following steps:

(2) Adding pregelatinized starch, hydroxypropyl cellulose, croscarmellose sodium and colloidal silicon dioxide into the mixture obtained in the step (1), and uniformly mixing;

(3) Performing wet granulation on the mixture obtained in the step (2) by using 34.9874g of purified water, sieving with a 20-mesh sieve, and drying at 60 ℃ for 2 hours;

(4) Uniformly mixing the particles obtained in the step (3) with magnesium stearate;

Example 5

The preparation method comprises the following steps:

1) 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) with fumaric acid was mixed with mannitol, microcrystalline cellulose in a wet granulator, and stirred;

2) Adding water to prepare soft materials, wherein the dosage of the water is 20-30%, stirring in a wet granulator after adding water, and sieving and granulating the soft materials to obtain wet granules;

3) Drying the wet particles obtained in the step 2) in an oven (60 ℃), and sieving and finishing the particles;

4) Adding crosslinked sodium carboxymethyl cellulose, colloidal silicon dioxide and magnesium stearate for total mixing;

5) Tabletting the mixture obtained in the step (4), and controlling the average weight difference to +/-3% by adopting 9.5mm round punch, wherein the tabletting hardness is 70N, so as to obtain a tablet with the tablet weight of 375 mg.

Example 6

The preparation method comprises the following steps:

The dissolution rate of each pharmaceutical composition was further determined on the basis of each pharmaceutical composition prepared.

Dissolution test of pharmaceutical composition

EXAMPLE 7 dissolution experiment at pH1.2 with hydrochloric acid+0.2% Tween 80

The experimental steps are as follows: the dissolution profiles of examples 1-6 were determined using a paddle method at 75 revolutions per minute, a temperature of 37 degrees, 900ml of dissolution medium, ph1.2 hydrochloric acid +0.2% tween 80, wherein 0.2% tween 80 was the surfactant. Taking out proper amount of dissolution liquid at 5min, 10min, 15min, 30min, 45min and 60min respectively, filtering, taking the subsequent filtrate as sample solution, measuring absorbance of the sample solution at 250-320nm wavelength, calculating cumulative dissolution of each point, and drawing dissolution curve. The specific measurement results are shown in the following table:

Conclusion: in a dissolution medium containing a surfactant Tween 80, the pharmaceutical compositions prepared in examples 1-5 have dissolution rate of not less than 65% within 30min, and reach dissolution rate of not less than 70% within 60min, and the dissolution rate is high and the in vitro dissolution rate is high, so that the dissolution requirement can be met. Whereas the dissolution of the pharmaceutical composition prepared in example 6 was still less than 70% within 60 min.

Example 8 dissolution experiment at pH6.8 phosphate buffer+0.1% CTAB

The experimental steps are as follows: the paddle method was used at a speed of 75 revolutions per minute and at a temperature of 37 degrees, 900ml of dissolution medium, ph6.8 phosphate buffer+0.1% ctab, wherein 0.1% ctab was the surfactant. The dissolution curves of examples 1-6 were determined separately. Taking out proper amount of dissolution liquid at 5min, 10min, 15min, 30min, 45min and 60min respectively, filtering, taking the subsequent filtrate as sample solution, measuring absorbance of the sample solution at 250-320nm wavelength, calculating cumulative dissolution of each point, and drawing dissolution curve. The specific measurement results are shown in the following table:

conclusion: in a dissolution medium containing surfactant CTAB, the pharmaceutical compositions prepared in examples 1-5 have dissolution rate of not less than 75% within 30min, and even reach dissolution rate of not less than 80% within 60min, and the dissolution rate is faster and the in vitro dissolution rate is higher, so that the dissolution requirement can be met. The dissolution rate of the pharmaceutical composition prepared in example 6 still does not reach 70% within 60 min.

EXAMPLE 9 dissolution experiment with Water+0.2% SDS

The experimental steps are as follows: the paddle method was used at a speed of 55 revolutions per minute and a temperature of 37 degrees, 550ml of dissolution medium, water +0.2% sds, wherein 0.2% sds was the surfactant. The dissolution curves of examples 1-6 were determined separately. Taking out proper amount of dissolution liquid at 5min, 10min, 15min, 30min, 45min and 60min respectively, filtering, taking the subsequent filtrate as sample solution, measuring absorbance of the sample solution at 250-320nm wavelength, calculating cumulative dissolution of each point, and drawing dissolution curve. The specific measurement results are shown in the following table:

conclusion: in a dissolution medium containing a surfactant SDS, the pharmaceutical compositions prepared in examples 1-5 have dissolution rate of not less than 60% within 30min, reach dissolution rate of not less than 70% within 60min, have higher dissolution rate in vitro and can meet the dissolution requirement. The dissolution rate of the pharmaceutical composition prepared in example 6 was only about 60% within 60 min.

EXAMPLE 10 dissolution experiments of pharmaceutical compositions in different dissolution Medium

Taking the pharmaceutical composition prepared in example 4 as an example, dissolution experiments were performed in different dissolution media and dissolution media without surfactant. The experimental steps are as follows: the method comprises the steps of adopting a paddle method, rotating at 50-80 revolutions per minute and at 37 ℃,500-900ml of dissolution medium, and under the condition of adding 0.1% CTAB (ctab) as a surfactant, determining the cumulative dissolution rate of each time point in different dissolution media, wherein the medium in the dissolution medium is selected from water, pH1.2 hydrochloric acid, pH4.5 acetic acid (salt) buffer solution and pH6.8 phosphoric acid (salt) buffer solution; in addition, the dissolution rate in the dissolution medium containing no surfactant was also measured. Taking out proper amount of dissolution liquid at 5min, 10min, 15min, 30min, 45min and 60min respectively, filtering, taking the subsequent filtrate as sample solution, measuring absorbance of the sample solution at 250-320nm wavelength, calculating cumulative dissolution of each point, and drawing dissolution curve. The specific measurement results are shown in the following table:

Therefore, the dissolution rate of the pharmaceutical composition in the embodiment 4 of the invention can reach more than 80% within 30min and more than 90% within 60min under the condition that the surfactant CTAB is added into water, hydrochloric acid with the pH of 1.2, acetate buffer with the pH of 4.5 and phosphate buffer with the pH of 6.8. In the dissolution medium without adding the surfactant, the dissolution rate is lower than 60% in 30min and lower than 65% in 60 min.

In summary, the pharmaceutical compositions prepared in examples 1-5 all have a faster dissolution rate and a better cumulative dissolution, the dissolution rate is greater than or equal to 60% in 30min, and the dissolution rate is greater than or equal to 70% in 60min, and in order to further verify the bioavailability of the pharmaceutical composition with good dissolution in vivo, we selected the pharmaceutical composition prepared in example 4 for in vivo bioavailability experiments.

Pharmacokinetic testing of pharmaceutical compositions

According to the invention, 4 beagle dogs are randomly studied, and are respectively numbered 1313, 1314, 1315 and 2316, the beagle dogs are weighed 1 day before administration, the pharmaceutical composition prepared in the example 4 is respectively administered by intragastric administration, the beagle dogs are fasted for at least 12 hours but not more than 16 hours before single intragastric administration, and can drink water freely, and ingestion is recovered 4 hours after administration. Blood is collected from the non-dosing limb vein of the beagle in about 1.0mL to a blood collection tube containing EDTA-K2, the blood is mixed with an anticoagulant fully and evenly by gentle shaking after blood collection, the blood is put into wet ice temporarily, centrifugation is completed within 1.5h after collection, and about 300 mu L of plasma is collected after centrifugation. Animals were observed at least 2 times on the day of dosing and at least 1 time each day for the remainder, including observation of the animal's mental state, general condition, and death, with increased observations if necessary. The drug concentration in the beagle plasma sample was quantitatively detected using a validated LC-MS/MS method. And (3) fitting the obtained original data through instrument software to obtain a standard curve equation and a correlation coefficient, and calculating the concentration of the drug in the biological sample at each sampling time point. Statistical analysis was performed on the raw data, and the concentration of drug in the samples and time data were calculated for pharmacokinetic parameters using WinNonLin software (version 8.3) according to non-compartmental model method (NCA).

The pharmacokinetic results are shown in the following table:

as shown in the above table, the administration of the specificThe pharmaceutical composition with good drug dissolution rate also has better absolute bioavailability in vivo under the dosage condition of 125 mg/dog, and can reach peak (T) in a short time _max )。

In summary, the invention utilizes the compound (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) and fumaric acid to develop the pharmaceutical composition, and the invention discovers that the dissolution effect of the added surfactant is better by screening different dissolution conditions, and simultaneously performs in vivo verification on the pharmaceutical composition with better dissolution rate, thus proving that the pharmaceutical composition with better dissolution rate has better absorption effect in vivo, further confirming that the dissolution rate range of the invention can effectively ensure the in vivo absorption of the pharmaceutical composition, and has important reference significance for clinical research.

The pharmaceutical composition provided by the invention has better dissolution rate and cumulative dissolution rate, and has better bioavailability. In particular to a medicine for treating coronavirus, which needs to be released rapidly in vivo and peak in a shorter time, thereby inhibiting the replication and the diffusion of the virus rapidly and meeting the requirements for treating coronavirus better.

The foregoing embodiments have been provided for the purpose of illustrating the general principles, technical solutions and advantages of the present invention in further detail, and it should be understood that the foregoing embodiments are merely illustrative of the present invention and are not intended to limit the scope of the present invention, but any modification, equivalent replacement, improvement, etc. that comes within the spirit and scope of the present invention should be construed as included in the scope of the present invention.

Claims

1. A pharmaceutical composition comprising a crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) with fumaric acid, and a physiologically acceptable/pharmaceutically acceptable excipient, wherein the characteristic diffraction peak of the X-ray powder diffraction expressed in terms of 2 theta values ± 0.2 deg. comprises any of a 10.94, 19.50, 23.24.66 profile of the crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazin-2, 4-dione) with fumaric acid using Cu-ka radiation;

2. A pharmaceutical composition comprising a crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) with fumaric acid, and a physiologically acceptable/pharmaceutically acceptable excipient, wherein the characteristic diffraction peak of the X-ray powder diffraction expressed in terms of 2 theta values ± 0.2 deg. comprises any of a 10.94, 19.50, 23.24.66 profile of the crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazin-2, 4-dione) with fumaric acid using Cu-ka radiation;

3. Pharmaceutical composition according to claim 1 or 2, characterized in that the dissolution medium further comprises any one selected from the group consisting of water, hydrochloric acid solution at pH 1.0-2.2, phosphate buffer at pH 4.5-7.6, acetate buffer at pH 3.4-6.0.

4. A pharmaceutical composition according to any one of claims 1-3, characterized in that the physiologically acceptable/pharmaceutically acceptable excipients comprise one or more of fillers, disintegrants, lubricants, binders, solubilisers, glidants.

5. The pharmaceutical composition according to any one of claims 1-4, wherein the weight percentage of the crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) to fumaric acid in the pharmaceutical composition is 15% to 60%, preferably 25% to 45%.

6. Pharmaceutical composition according to any one of claims 1 to 5, wherein the filler is present in the pharmaceutical composition in a weight percentage of 10% to 80%, preferably 30% to 65%;

wherein the weight percentage of the disintegrating agent in the pharmaceutical composition is 1% -10%, preferably 2% -5%;

wherein the weight percentage of the lubricant in the pharmaceutical composition is 0.5% -5%, preferably 1-3%;

wherein the weight percentage of the binder in the pharmaceutical composition is 0% -10%, preferably 1-3%;

wherein the weight percentage of the solubilizer in the pharmaceutical composition is 0% -5%, preferably 0.5-3%;

And/or

Wherein, the weight percentage of the glidant in the medicine composition is 0.5% -5%, preferably 2% -3%.

7. The pharmaceutical composition according to any one of claims 1-6, wherein the filler comprises one or more of anhydrous calcium bicarbonate, sugar alcohols, celluloses and starches; for example, the sugar alcohol filler includes one or more of mannitol, maltitol, erythritol, lactitol, sorbitol, and xylitol; for example, the cellulosic filler includes one or more of microcrystalline cellulose, powdered cellulose, and silicified microcrystalline cellulose; for example, the starch-based fillers include one or more of corn starch, potato starch, sweet potato starch, and pregelatinized starch;

wherein the disintegrating agent comprises one or more of crospovidone, croscarmellose sodium, hydroxypropyl cellulose, carboxymethyl starch sodium, corn starch and potato starch;

wherein the lubricant comprises one or more of magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oil, glyceryl behenate, stearic acid and sodium stearyl fumarate;

wherein the adhesive comprises one or more of hypromellose, methylcellulose, hydroxyethyl cellulose, carboxymethyl cellulose, copovidone and polyvinylpyrrolidone;

Wherein the solubilizer comprises one or more of sodium dodecyl sulfate, polysorbate 80, polyoxyethylene hydrogenated castor oil and poloxamer;

and/or

Wherein the glidant comprises colloidal silicon dioxide and/or talcum powder.

8. The pharmaceutical composition according to any one of claims 1-7, wherein the crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) with fumaric acid uses Cu-ka radiation and the characteristic diffraction peak of the X-ray powder diffraction pattern expressed in terms of 2Θ values ± 0.2 ° further comprises any one or more of 9.5, 13.81, 18.61, 22.59, 23.8.

9. The pharmaceutical composition according to claim 8, wherein the crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) with fumaric acid uses Cu-ka radiation and the characteristic diffraction peaks of the X-ray powder diffraction pattern expressed in terms of 2Θ values ± 0.2 ° further comprise any one or more of 7.81, 10.14, 11.50, 11.93, 12.31.

10. The pharmaceutical composition according to any one of claims 1-9, wherein the pharmaceutical composition is an oral formulation, preferably an oral solid formulation (e.g. a tablet, powder, dry suspension, granule or capsule);

And/or the number of the groups of groups,

wherein the pharmaceutical composition is in unit dosage form, e.g., a solid formulation in unit dosage form (e.g., a tablet, powder, dry suspension, granule, or capsule).

11. A pharmaceutical composition comprising a crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazine-2, 4-dione) with fumaric acid, and a physiologically acceptable/pharmaceutically acceptable excipient, wherein the characteristic diffraction peak of the X-ray powder diffraction expressed in terms of 2 theta values ± 0.2 deg. comprises any of a 10.94, 19.50, 23.24.66 profile of the crystalline form of (6E) -6- [ (6-chloro-2-methyl-2H-indazol-5-yl) imino ] -3- [ (1-methyl-1H-1, 2, 4-triazol-3-yl) methyl ] -1- [ (2, 4, 5-trifluorophenyl) methyl ] -1,3, 5-triazin-2, 4-dione) with fumaric acid using Cu-ka radiation; the pharmaceutical composition has an absolute bioavailability of 40% -90% after administration to beagle dogs.

12. A process for the preparation of a pharmaceutical composition according to any one of claims 1 to 11, comprising the steps of:

(ii) Granulating the mixture obtained in the step (i), and sieving;

13. Use of the pharmaceutical composition of any one of claims 1-11 in the manufacture of a medicament for treating or preventing a coronavirus-caused disease in a subject; preferably, wherein the subject is a human, such as a child, adult, or elderly person.

14. Use according to claim 13, wherein the coronavirus is a novel coronavirus.